Targeted therapies have transformed the treatment of many malignant diseases by inhibiting molecular pathways involved in tumor growth and oncogenesis. Although these therapies can prevent disease progression, toxicities often result. Renal cell carcinoma (RCC) is one of many cancers that responds well to these therapies.

RCC accounts for 2% to 3% of all malignancies in adults worldwide. About 30% of patients with RCC present with metastatic or advanced disease.¹ Cytokine therapy was the standard of care until multitargeted tyrosine kinase inhibitors (TKIs) were developed. Over the past 12 years, the US Food and Drug Administration (FDA) has approved 6 TKIs for the treatment of RCC: axitinib, cabozantinib, lenvatinib, pazopanib, sorafenib, and sunitinib. Vascular endothelial growth factor receptor (VEGFR) is one of many tyrosine kinase receptors targeted by these medications. This mechanism prevents angiogenesis and consequently increases the risk for hypertension, bleeding, and clot formation.

Given these risks, many patients were excluded from the initial clinical trials of these medications if they had a history of uncontrolled hypertension, advanced heart failure (HF), or a significant cardiovascular (CV) event within 6 months prior to study enrollment. Many of these studies did not report the incidence of CV events (other than hypertension) that occurred during the early trials.² The recommended monitoring for TKI therapies is focused mainly on blood pressure. For patients on pazopanib and sunitinib therapy, baseline and periodic electrocardiograms (ECGs) are recommended; echocardiograms are recommended only for patients with a history of cardiac disease.^3,4 In patients on sorafenib therapy, ECG is recommended for those at risk for corrected QT (QTc) intervalprolongation.⁵

According to a meta-analysis of the literature published between 1966 and 2013,many studies reported a CV toxicity risk associated with the TKIs used in RCC treatment.⁶ However, some studies have found modest, not clinically significant changes in cardiac function in patients with advanced disease. In 2013, Hall and colleagues found 73% of patients they studied experienced some type of CV toxicity, whereas only 33% of patients had CV toxicity when hypertension was excluded.⁷ Interestingly, Rini and colleagues found that RCC patients receiving sunitinib had better response rates and progression-free survival when they developed hypertension compared with those who did not develop hypertension.⁸

A review of several studies revealed similar numbers in patients on TKI therapy presenting with symptomatic HF, but Hall and colleagues found that 27% of patients developed asymptomatic left ventricular dysfunction.^7,9,10 These results suggest routine monitoring may allow for appropriate preventive interventions. In patients receiving TKI therapy, CV events, including QTc prolongation, left ventricular HF, myocardial infarction (MI), hypertension, pulmonary hypertension, and stroke, were commonly reported by investigators.^7,9,10 Currently, there are no studies of the incidence of CV events for the 5 TKIs (axitinib, cabozantinib, pazopanib, sorafenib, sunitinib) in this patient population.

TKI therapy may require cardiac monitoring of all patients, as studies have associated TKIs with CV toxicity in varying degrees. Therefore, the authors set out to determine the incidence of CV events as well as time to first CV event in patients with and without a history of CV disease (CVD) who received a TKI for advanced RCC. More frequent monitoring for CV toxicity may present opportunities for clinical interventions for all patients on TKI therapy—especially for those with HF or other diseases in which the goal of therapy is to prevent disease progression. As TKIs have emerged as the standard treatment option for advanced RCC, many patients will continue therapy until disease progression or intolerable toxicity. Identifying and using appropriate monitoring parameters can lead to preventive interventions that allow patients to benefit from TKI therapy longer. At the US Department of Veterans Affairs (VA) San Diego Healthcare System (VASDHS), patients undergo routine cardiac monitoring at the discretion of the provider.

In this retrospective study, the authors wanted to determine the incidence of CV events in patients with and without a history of CVD who were receiving TKIs for advanced RCC. The authors also wanted to evaluate time to CV event from start of therapy in order to determine how often monitoring may be needed. The outcomes of this study may lead to a change in practice and development of monitoring parameters to ensure appropriate and adequate management of TKI therapy in RCC.

Methods

Each year, the VASDHS oncology team diagnose 5 to 10 patients with RCC who begin TKI therapy. When sorafenib was approved by the FDA in 2005, VASDHS estimated that about 100 of its patients had an RCC diagnosis and would be treated with a TKI between December 2005 and July 2017.

The authors identified VASDHS patients with a diagnosis of advanced RCC who received axitinib, cabozantinib, pazopanib, sorafenib, or sunitinib between December 1, 2005 and July 31, 2017. Patients were included if they had been on therapy for at least 30 days. The VASDHS pharmacy informatics team assisted in extracting a list of patients with an ICD-9 or ICD-10 diagnosis of RCC and using prescription fills for any of the 5 TKIs previously noted. Medical records were reviewed for frequency of prescription fills, age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, TKI treatment duration, previous history of CVD, ethnicity, and smoking status. If documented, the incidence of CV events was reviewed for each patient at 0, 1, 3, 6, and 12 months. Patients who received medications (Appendix) for their CVD were assessed for adherence based on history of prescription refills from their medical records. Adherence was evaluated for the duration that patients were concurrently taking an oral TKI. The institutional review board at VASDHS approved the study design.

All patients included in this study started TKI therapy since the December 2005 FDA approval of sorafenib, the first oral TKI for treatment of RCC. Each new start was recorded as a separate event, regardless of previous oral TKI therapy. Albiges and colleagues found that the approximate median time from starting TKI therapy to complete response was 12.6 months, and the median duration of TKI therapy after complete response was 10.3 months.¹¹ Based on these results, the follow-up period for patients in this study was 2 years after the start of each TKI therapy. For data analysis, patients were stratified by CVD history (yes or no). In addition, composite outcomes were evaluated to identify a potential cumulative increased risk for CV events for patients who had been on multiple TKI therapies.

For this study, CV toxicities were characterized using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03; severity of adverse events (AEs) was graded 1 to 5. CTCAE commonly has been used to assess AEs in oncology clinical trials. The CV AEs selected for this study included QTc prolongation, hypertension, left ventricular dysfunction, stroke, myocardial infarction (MI), and pulmonary arterial hypertension. CTCAE was not used to assess left ventricular dysfunction, as the rating is based on symptomology. Instead, worsening left ventricular ejection fraction (LVEF) was based on comparisons of ECG results at baseline with results at 1, 3, 6, and 12 months. A normal ECG result was defined as no structural change in the left ventricle, or LVEF ≥ 55%, and an abnormal result was defined as structural changes in the left ventricle, or LVEF < 55%. Given updates in blood pressure (BP) guidelines and uncertainty regarding the clinical utility of prehypertension, grade 1 hypertension was excluded as an AE.

Primary outcomes included incidence of CV events and time to first CV event after initiation of TKI therapy. Secondary outcomes included changes in ECG or echocardiogram results at 0, 1, 3, 6, and 12 months. Secondary outcomes at scheduled time points were not readily available for every patient, but any available time points were gathered to aid in identifying an optimal period for cardiac monitoring. In addition, patients with a history of CVD were evaluated for adherence to common first-line therapies for each disease.

A Fischer exact test was used to compare the incidence of CV events in patients with and without a history of CVD (significance level, α = 0.05). A subgroup analysis was used to compare the incidence of CV events in patients who experienced a CV event (significance level, α = 0.05). A Kaplan-Meier survival curve was used to determine time to first CV event. A log-rank test with significance level set at α = 0.05 also was used.

Results

An initial database search identified 134 patients who received TKI therapy at VASDHS between December 1, 2005 and July 31, 2017. According to retrospective chart review, 54 patients met the inclusion criteria for the study (Table 1).

Patients without a history of CVD (17%) did not experience any CV events while on TKI therapy. Of the patients with a history of CVD, 9 (20%) experienced ≥ 1 CV event. Fifty-five percent of the events experienced were hypertension. One patient experienced QTc prolongation, and 2 patients experienced MI. As already noted, each new start of TKI was recorded as a separate event, regardless of previous TKI therapy. Among patients with a history of CVD, 2 experienced 2 CV events. Overall, 11 CV events occurred among patients who received ≥ 1 TKI, corresponding to an overall incidence of 24% (Table 2). 

Of the 13 patients who were exposed to ≥ 2 TKI therapies, 2 experienced a CV event. Both patients were started on sunitinib and were switched to sorafenib. One of these used sunitinib for 7 months, experienced a partial response and was switched to sorafenib (with a 3-month break between therapies). The second patient was on sunitinib for 24 months, with multiple doses held because of low blood counts and diarrhea. While on sunitinib, this patient experienced a HF exacerbation, determined to be caused by the underlying disease. This event occurred 17 months after sunitinib was started, and therapy was continued for another 7 months. The patient was switched to sorafenib because of poor tolerability and disease progression. While on sorafenib, this patient experienced grade 1 QTc prolongation.

Discussion

Of the available oral TKI therapies for RCC, sunitinib and sorafenib have the most data associated with nonhypertensive CV toxicity.^2,7-10,12 Instudies, the percentage of patients who experienced CV toxicity while on sunitinib or sorafenib has ranged widely, from 2.7% to 33.8%; the variance may be attributable to differences in how institutions report CV toxicities.^7-9

According to the prescribing information for TKIs, hypertension is frequently reported as an AE for all 5 TKIs, and BP monitoring is recommended.^3,4 However, the development of hypertension with these TKIs has been associated with response to therapy.⁷ With pazopanib, sorafenib, and sunitinib, there is a higher incidence of other AEs: edema, HF, MI, and QTc prolongation. Baseline ECG is recommended for all patients started on pazopanib and sunitinib and for patients with a history of CVD who are started on sorafenib. An ECG is recommended for patients with a history of CVD who are started on pazopanib and sunitinib.

Even with the medication prescribing information recommendations, it is unclear how frequently patients should be monitored. At VASDHS, CV monitoring for any patient started on a TKI remains at the discretion of the oncologist. There are concerns that ordering cardiac monitoring tests, which might be unnecessary, will change or guide therapy. In this study, data evaluation revealed 1 patient who experienced a CV event had a CVD history that was not documented in the patient’s medical history. It is important that providers obtain a detailed clinical assessment of patients CV history during each visit to determine whether CV monitoring should be considered. Patients also may benefit from additional counseling to emphasize the importance of adherence to CV medication therapy to reduce the incidence of these events.

Data from this study indicate that routine CV monitoring should be considered in patients with CVD, in keeping with current medication prescribing information recommendations. Of the patients who had a CV event, 54% experienced hypertension, 18% MI, and 28% stroke, QTc prolongation, or congestive HF. 

Limitations

This retrospective study had several limitations. Many patients did not have a baseline cardiac monitoring test or any monitoring during therapy. Often, a cardiac test was performed only when the patient was symptomatic or experiencing a CV event. In addition, because of intolerance or nonadherence to therapy, many patients discontinued treatment early, before completing 30 days. That axitinib and cabozantinib are newer therapies and not first-line at VASDHS during the data collection period accounts for the small number of patients on these therapies. Therapy was shorter for patients started on pazopanib, axitinib, and cabozantinib than it was for patients on sunitinib and sorafenib. Duration of therapy may affect treatment-related events, but the majority of patients in this study experienced an event within 4 months of therapy. About half of the patients who experienced an event were nonadherent to their CV medication regimen. Another potential limitation is that this study was conducted at VASDHS, where most patients are male (RCC incidence is 2:1 male:female).

Conclusion

In this study, CV events occurred in 24% of patients with a history of CVD; 11% of these events were nonhypertensive. Baseline cardiac monitoring was not performed for most patients started on TKI therapy, but tests were performed once patients became symptomatic. The study results suggest that high-risk patients should undergo routine cardiac monitoring during the first 4 months of TKI therapy, in keeping with medication package insert monitoring recommendations. Cardiac monitoring of high-risk patients will allow for earlier identification of cardiac decline and offer opportunities for interventions, such as pharmacist-driven protocols to start CV medications. Implementation of this study’s recommendations should be evaluated to determine whether outcomes improve with routine cardiac monitoring in these high-risk patients.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, FrontlineMedical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects— before administering pharmacologic therapy to patients.

Targeted therapies have transformed the treatment of many malignant diseases by inhibiting molecular pathways involved in tumor growth and oncogenesis. Although these therapies can prevent disease progression, toxicities often result. Renal cell carcinoma (RCC) is one of many cancers that responds well to these therapies.

RCC accounts for 2% to 3% of all malignancies in adults worldwide. About 30% of patients with RCC present with metastatic or advanced disease.¹ Cytokine therapy was the standard of care until multitargeted tyrosine kinase inhibitors (TKIs) were developed. Over the past 12 years, the US Food and Drug Administration (FDA) has approved 6 TKIs for the treatment of RCC: axitinib, cabozantinib, lenvatinib, pazopanib, sorafenib, and sunitinib. Vascular endothelial growth factor receptor (VEGFR) is one of many tyrosine kinase receptors targeted by these medications. This mechanism prevents angiogenesis and consequently increases the risk for hypertension, bleeding, and clot formation.

Given these risks, many patients were excluded from the initial clinical trials of these medications if they had a history of uncontrolled hypertension, advanced heart failure (HF), or a significant cardiovascular (CV) event within 6 months prior to study enrollment. Many of these studies did not report the incidence of CV events (other than hypertension) that occurred during the early trials.² The recommended monitoring for TKI therapies is focused mainly on blood pressure. For patients on pazopanib and sunitinib therapy, baseline and periodic electrocardiograms (ECGs) are recommended; echocardiograms are recommended only for patients with a history of cardiac disease.^3,4 In patients on sorafenib therapy, ECG is recommended for those at risk for corrected QT (QTc) intervalprolongation.⁵

According to a meta-analysis of the literature published between 1966 and 2013,many studies reported a CV toxicity risk associated with the TKIs used in RCC treatment.⁶ However, some studies have found modest, not clinically significant changes in cardiac function in patients with advanced disease. In 2013, Hall and colleagues found 73% of patients they studied experienced some type of CV toxicity, whereas only 33% of patients had CV toxicity when hypertension was excluded.⁷ Interestingly, Rini and colleagues found that RCC patients receiving sunitinib had better response rates and progression-free survival when they developed hypertension compared with those who did not develop hypertension.⁸

A review of several studies revealed similar numbers in patients on TKI therapy presenting with symptomatic HF, but Hall and colleagues found that 27% of patients developed asymptomatic left ventricular dysfunction.^7,9,10 These results suggest routine monitoring may allow for appropriate preventive interventions. In patients receiving TKI therapy, CV events, including QTc prolongation, left ventricular HF, myocardial infarction (MI), hypertension, pulmonary hypertension, and stroke, were commonly reported by investigators.^7,9,10 Currently, there are no studies of the incidence of CV events for the 5 TKIs (axitinib, cabozantinib, pazopanib, sorafenib, sunitinib) in this patient population.

TKI therapy may require cardiac monitoring of all patients, as studies have associated TKIs with CV toxicity in varying degrees. Therefore, the authors set out to determine the incidence of CV events as well as time to first CV event in patients with and without a history of CV disease (CVD) who received a TKI for advanced RCC. More frequent monitoring for CV toxicity may present opportunities for clinical interventions for all patients on TKI therapy—especially for those with HF or other diseases in which the goal of therapy is to prevent disease progression. As TKIs have emerged as the standard treatment option for advanced RCC, many patients will continue therapy until disease progression or intolerable toxicity. Identifying and using appropriate monitoring parameters can lead to preventive interventions that allow patients to benefit from TKI therapy longer. At the US Department of Veterans Affairs (VA) San Diego Healthcare System (VASDHS), patients undergo routine cardiac monitoring at the discretion of the provider.

In this retrospective study, the authors wanted to determine the incidence of CV events in patients with and without a history of CVD who were receiving TKIs for advanced RCC. The authors also wanted to evaluate time to CV event from start of therapy in order to determine how often monitoring may be needed. The outcomes of this study may lead to a change in practice and development of monitoring parameters to ensure appropriate and adequate management of TKI therapy in RCC.

Methods

Each year, the VASDHS oncology team diagnose 5 to 10 patients with RCC who begin TKI therapy. When sorafenib was approved by the FDA in 2005, VASDHS estimated that about 100 of its patients had an RCC diagnosis and would be treated with a TKI between December 2005 and July 2017.

The authors identified VASDHS patients with a diagnosis of advanced RCC who received axitinib, cabozantinib, pazopanib, sorafenib, or sunitinib between December 1, 2005 and July 31, 2017. Patients were included if they had been on therapy for at least 30 days. The VASDHS pharmacy informatics team assisted in extracting a list of patients with an ICD-9 or ICD-10 diagnosis of RCC and using prescription fills for any of the 5 TKIs previously noted. Medical records were reviewed for frequency of prescription fills, age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, TKI treatment duration, previous history of CVD, ethnicity, and smoking status. If documented, the incidence of CV events was reviewed for each patient at 0, 1, 3, 6, and 12 months. Patients who received medications (Appendix) for their CVD were assessed for adherence based on history of prescription refills from their medical records. Adherence was evaluated for the duration that patients were concurrently taking an oral TKI. The institutional review board at VASDHS approved the study design.

All patients included in this study started TKI therapy since the December 2005 FDA approval of sorafenib, the first oral TKI for treatment of RCC. Each new start was recorded as a separate event, regardless of previous oral TKI therapy. Albiges and colleagues found that the approximate median time from starting TKI therapy to complete response was 12.6 months, and the median duration of TKI therapy after complete response was 10.3 months.¹¹ Based on these results, the follow-up period for patients in this study was 2 years after the start of each TKI therapy. For data analysis, patients were stratified by CVD history (yes or no). In addition, composite outcomes were evaluated to identify a potential cumulative increased risk for CV events for patients who had been on multiple TKI therapies.

For this study, CV toxicities were characterized using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03; severity of adverse events (AEs) was graded 1 to 5. CTCAE commonly has been used to assess AEs in oncology clinical trials. The CV AEs selected for this study included QTc prolongation, hypertension, left ventricular dysfunction, stroke, myocardial infarction (MI), and pulmonary arterial hypertension. CTCAE was not used to assess left ventricular dysfunction, as the rating is based on symptomology. Instead, worsening left ventricular ejection fraction (LVEF) was based on comparisons of ECG results at baseline with results at 1, 3, 6, and 12 months. A normal ECG result was defined as no structural change in the left ventricle, or LVEF ≥ 55%, and an abnormal result was defined as structural changes in the left ventricle, or LVEF < 55%. Given updates in blood pressure (BP) guidelines and uncertainty regarding the clinical utility of prehypertension, grade 1 hypertension was excluded as an AE.

Primary outcomes included incidence of CV events and time to first CV event after initiation of TKI therapy. Secondary outcomes included changes in ECG or echocardiogram results at 0, 1, 3, 6, and 12 months. Secondary outcomes at scheduled time points were not readily available for every patient, but any available time points were gathered to aid in identifying an optimal period for cardiac monitoring. In addition, patients with a history of CVD were evaluated for adherence to common first-line therapies for each disease.

A Fischer exact test was used to compare the incidence of CV events in patients with and without a history of CVD (significance level, α = 0.05). A subgroup analysis was used to compare the incidence of CV events in patients who experienced a CV event (significance level, α = 0.05). A Kaplan-Meier survival curve was used to determine time to first CV event. A log-rank test with significance level set at α = 0.05 also was used.

Results

An initial database search identified 134 patients who received TKI therapy at VASDHS between December 1, 2005 and July 31, 2017. According to retrospective chart review, 54 patients met the inclusion criteria for the study (Table 1).

Patients without a history of CVD (17%) did not experience any CV events while on TKI therapy. Of the patients with a history of CVD, 9 (20%) experienced ≥ 1 CV event. Fifty-five percent of the events experienced were hypertension. One patient experienced QTc prolongation, and 2 patients experienced MI. As already noted, each new start of TKI was recorded as a separate event, regardless of previous TKI therapy. Among patients with a history of CVD, 2 experienced 2 CV events. Overall, 11 CV events occurred among patients who received ≥ 1 TKI, corresponding to an overall incidence of 24% (Table 2). 

Of the 13 patients who were exposed to ≥ 2 TKI therapies, 2 experienced a CV event. Both patients were started on sunitinib and were switched to sorafenib. One of these used sunitinib for 7 months, experienced a partial response and was switched to sorafenib (with a 3-month break between therapies). The second patient was on sunitinib for 24 months, with multiple doses held because of low blood counts and diarrhea. While on sunitinib, this patient experienced a HF exacerbation, determined to be caused by the underlying disease. This event occurred 17 months after sunitinib was started, and therapy was continued for another 7 months. The patient was switched to sorafenib because of poor tolerability and disease progression. While on sorafenib, this patient experienced grade 1 QTc prolongation.

Discussion

Of the available oral TKI therapies for RCC, sunitinib and sorafenib have the most data associated with nonhypertensive CV toxicity.^2,7-10,12 Instudies, the percentage of patients who experienced CV toxicity while on sunitinib or sorafenib has ranged widely, from 2.7% to 33.8%; the variance may be attributable to differences in how institutions report CV toxicities.^7-9

According to the prescribing information for TKIs, hypertension is frequently reported as an AE for all 5 TKIs, and BP monitoring is recommended.^3,4 However, the development of hypertension with these TKIs has been associated with response to therapy.⁷ With pazopanib, sorafenib, and sunitinib, there is a higher incidence of other AEs: edema, HF, MI, and QTc prolongation. Baseline ECG is recommended for all patients started on pazopanib and sunitinib and for patients with a history of CVD who are started on sorafenib. An ECG is recommended for patients with a history of CVD who are started on pazopanib and sunitinib.

Even with the medication prescribing information recommendations, it is unclear how frequently patients should be monitored. At VASDHS, CV monitoring for any patient started on a TKI remains at the discretion of the oncologist. There are concerns that ordering cardiac monitoring tests, which might be unnecessary, will change or guide therapy. In this study, data evaluation revealed 1 patient who experienced a CV event had a CVD history that was not documented in the patient’s medical history. It is important that providers obtain a detailed clinical assessment of patients CV history during each visit to determine whether CV monitoring should be considered. Patients also may benefit from additional counseling to emphasize the importance of adherence to CV medication therapy to reduce the incidence of these events.

Data from this study indicate that routine CV monitoring should be considered in patients with CVD, in keeping with current medication prescribing information recommendations. Of the patients who had a CV event, 54% experienced hypertension, 18% MI, and 28% stroke, QTc prolongation, or congestive HF. 

Limitations

This retrospective study had several limitations. Many patients did not have a baseline cardiac monitoring test or any monitoring during therapy. Often, a cardiac test was performed only when the patient was symptomatic or experiencing a CV event. In addition, because of intolerance or nonadherence to therapy, many patients discontinued treatment early, before completing 30 days. That axitinib and cabozantinib are newer therapies and not first-line at VASDHS during the data collection period accounts for the small number of patients on these therapies. Therapy was shorter for patients started on pazopanib, axitinib, and cabozantinib than it was for patients on sunitinib and sorafenib. Duration of therapy may affect treatment-related events, but the majority of patients in this study experienced an event within 4 months of therapy. About half of the patients who experienced an event were nonadherent to their CV medication regimen. Another potential limitation is that this study was conducted at VASDHS, where most patients are male (RCC incidence is 2:1 male:female).

Conclusion

In this study, CV events occurred in 24% of patients with a history of CVD; 11% of these events were nonhypertensive. Baseline cardiac monitoring was not performed for most patients started on TKI therapy, but tests were performed once patients became symptomatic. The study results suggest that high-risk patients should undergo routine cardiac monitoring during the first 4 months of TKI therapy, in keeping with medication package insert monitoring recommendations. Cardiac monitoring of high-risk patients will allow for earlier identification of cardiac decline and offer opportunities for interventions, such as pharmacist-driven protocols to start CV medications. Implementation of this study’s recommendations should be evaluated to determine whether outcomes improve with routine cardiac monitoring in these high-risk patients.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, FrontlineMedical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects— before administering pharmacologic therapy to patients.

Targeted therapies have transformed the treatment of many malignant diseases by inhibiting molecular pathways involved in tumor growth and oncogenesis. Although these therapies can prevent disease progression, toxicities often result. Renal cell carcinoma (RCC) is one of many cancers that responds well to these therapies.

RCC accounts for 2% to 3% of all malignancies in adults worldwide. About 30% of patients with RCC present with metastatic or advanced disease.¹ Cytokine therapy was the standard of care until multitargeted tyrosine kinase inhibitors (TKIs) were developed. Over the past 12 years, the US Food and Drug Administration (FDA) has approved 6 TKIs for the treatment of RCC: axitinib, cabozantinib, lenvatinib, pazopanib, sorafenib, and sunitinib. Vascular endothelial growth factor receptor (VEGFR) is one of many tyrosine kinase receptors targeted by these medications. This mechanism prevents angiogenesis and consequently increases the risk for hypertension, bleeding, and clot formation.

Given these risks, many patients were excluded from the initial clinical trials of these medications if they had a history of uncontrolled hypertension, advanced heart failure (HF), or a significant cardiovascular (CV) event within 6 months prior to study enrollment. Many of these studies did not report the incidence of CV events (other than hypertension) that occurred during the early trials.² The recommended monitoring for TKI therapies is focused mainly on blood pressure. For patients on pazopanib and sunitinib therapy, baseline and periodic electrocardiograms (ECGs) are recommended; echocardiograms are recommended only for patients with a history of cardiac disease.^3,4 In patients on sorafenib therapy, ECG is recommended for those at risk for corrected QT (QTc) intervalprolongation.⁵

According to a meta-analysis of the literature published between 1966 and 2013,many studies reported a CV toxicity risk associated with the TKIs used in RCC treatment.⁶ However, some studies have found modest, not clinically significant changes in cardiac function in patients with advanced disease. In 2013, Hall and colleagues found 73% of patients they studied experienced some type of CV toxicity, whereas only 33% of patients had CV toxicity when hypertension was excluded.⁷ Interestingly, Rini and colleagues found that RCC patients receiving sunitinib had better response rates and progression-free survival when they developed hypertension compared with those who did not develop hypertension.⁸

A review of several studies revealed similar numbers in patients on TKI therapy presenting with symptomatic HF, but Hall and colleagues found that 27% of patients developed asymptomatic left ventricular dysfunction.^7,9,10 These results suggest routine monitoring may allow for appropriate preventive interventions. In patients receiving TKI therapy, CV events, including QTc prolongation, left ventricular HF, myocardial infarction (MI), hypertension, pulmonary hypertension, and stroke, were commonly reported by investigators.^7,9,10 Currently, there are no studies of the incidence of CV events for the 5 TKIs (axitinib, cabozantinib, pazopanib, sorafenib, sunitinib) in this patient population.

TKI therapy may require cardiac monitoring of all patients, as studies have associated TKIs with CV toxicity in varying degrees. Therefore, the authors set out to determine the incidence of CV events as well as time to first CV event in patients with and without a history of CV disease (CVD) who received a TKI for advanced RCC. More frequent monitoring for CV toxicity may present opportunities for clinical interventions for all patients on TKI therapy—especially for those with HF or other diseases in which the goal of therapy is to prevent disease progression. As TKIs have emerged as the standard treatment option for advanced RCC, many patients will continue therapy until disease progression or intolerable toxicity. Identifying and using appropriate monitoring parameters can lead to preventive interventions that allow patients to benefit from TKI therapy longer. At the US Department of Veterans Affairs (VA) San Diego Healthcare System (VASDHS), patients undergo routine cardiac monitoring at the discretion of the provider.

In this retrospective study, the authors wanted to determine the incidence of CV events in patients with and without a history of CVD who were receiving TKIs for advanced RCC. The authors also wanted to evaluate time to CV event from start of therapy in order to determine how often monitoring may be needed. The outcomes of this study may lead to a change in practice and development of monitoring parameters to ensure appropriate and adequate management of TKI therapy in RCC.

Methods

Each year, the VASDHS oncology team diagnose 5 to 10 patients with RCC who begin TKI therapy. When sorafenib was approved by the FDA in 2005, VASDHS estimated that about 100 of its patients had an RCC diagnosis and would be treated with a TKI between December 2005 and July 2017.

The authors identified VASDHS patients with a diagnosis of advanced RCC who received axitinib, cabozantinib, pazopanib, sorafenib, or sunitinib between December 1, 2005 and July 31, 2017. Patients were included if they had been on therapy for at least 30 days. The VASDHS pharmacy informatics team assisted in extracting a list of patients with an ICD-9 or ICD-10 diagnosis of RCC and using prescription fills for any of the 5 TKIs previously noted. Medical records were reviewed for frequency of prescription fills, age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, TKI treatment duration, previous history of CVD, ethnicity, and smoking status. If documented, the incidence of CV events was reviewed for each patient at 0, 1, 3, 6, and 12 months. Patients who received medications (Appendix) for their CVD were assessed for adherence based on history of prescription refills from their medical records. Adherence was evaluated for the duration that patients were concurrently taking an oral TKI. The institutional review board at VASDHS approved the study design.

All patients included in this study started TKI therapy since the December 2005 FDA approval of sorafenib, the first oral TKI for treatment of RCC. Each new start was recorded as a separate event, regardless of previous oral TKI therapy. Albiges and colleagues found that the approximate median time from starting TKI therapy to complete response was 12.6 months, and the median duration of TKI therapy after complete response was 10.3 months.¹¹ Based on these results, the follow-up period for patients in this study was 2 years after the start of each TKI therapy. For data analysis, patients were stratified by CVD history (yes or no). In addition, composite outcomes were evaluated to identify a potential cumulative increased risk for CV events for patients who had been on multiple TKI therapies.

For this study, CV toxicities were characterized using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03; severity of adverse events (AEs) was graded 1 to 5. CTCAE commonly has been used to assess AEs in oncology clinical trials. The CV AEs selected for this study included QTc prolongation, hypertension, left ventricular dysfunction, stroke, myocardial infarction (MI), and pulmonary arterial hypertension. CTCAE was not used to assess left ventricular dysfunction, as the rating is based on symptomology. Instead, worsening left ventricular ejection fraction (LVEF) was based on comparisons of ECG results at baseline with results at 1, 3, 6, and 12 months. A normal ECG result was defined as no structural change in the left ventricle, or LVEF ≥ 55%, and an abnormal result was defined as structural changes in the left ventricle, or LVEF < 55%. Given updates in blood pressure (BP) guidelines and uncertainty regarding the clinical utility of prehypertension, grade 1 hypertension was excluded as an AE.

Primary outcomes included incidence of CV events and time to first CV event after initiation of TKI therapy. Secondary outcomes included changes in ECG or echocardiogram results at 0, 1, 3, 6, and 12 months. Secondary outcomes at scheduled time points were not readily available for every patient, but any available time points were gathered to aid in identifying an optimal period for cardiac monitoring. In addition, patients with a history of CVD were evaluated for adherence to common first-line therapies for each disease.

A Fischer exact test was used to compare the incidence of CV events in patients with and without a history of CVD (significance level, α = 0.05). A subgroup analysis was used to compare the incidence of CV events in patients who experienced a CV event (significance level, α = 0.05). A Kaplan-Meier survival curve was used to determine time to first CV event. A log-rank test with significance level set at α = 0.05 also was used.

Results

An initial database search identified 134 patients who received TKI therapy at VASDHS between December 1, 2005 and July 31, 2017. According to retrospective chart review, 54 patients met the inclusion criteria for the study (Table 1).

Patients without a history of CVD (17%) did not experience any CV events while on TKI therapy. Of the patients with a history of CVD, 9 (20%) experienced ≥ 1 CV event. Fifty-five percent of the events experienced were hypertension. One patient experienced QTc prolongation, and 2 patients experienced MI. As already noted, each new start of TKI was recorded as a separate event, regardless of previous TKI therapy. Among patients with a history of CVD, 2 experienced 2 CV events. Overall, 11 CV events occurred among patients who received ≥ 1 TKI, corresponding to an overall incidence of 24% (Table 2). 

Of the 13 patients who were exposed to ≥ 2 TKI therapies, 2 experienced a CV event. Both patients were started on sunitinib and were switched to sorafenib. One of these used sunitinib for 7 months, experienced a partial response and was switched to sorafenib (with a 3-month break between therapies). The second patient was on sunitinib for 24 months, with multiple doses held because of low blood counts and diarrhea. While on sunitinib, this patient experienced a HF exacerbation, determined to be caused by the underlying disease. This event occurred 17 months after sunitinib was started, and therapy was continued for another 7 months. The patient was switched to sorafenib because of poor tolerability and disease progression. While on sorafenib, this patient experienced grade 1 QTc prolongation.

Discussion

Of the available oral TKI therapies for RCC, sunitinib and sorafenib have the most data associated with nonhypertensive CV toxicity.^2,7-10,12 Instudies, the percentage of patients who experienced CV toxicity while on sunitinib or sorafenib has ranged widely, from 2.7% to 33.8%; the variance may be attributable to differences in how institutions report CV toxicities.^7-9

According to the prescribing information for TKIs, hypertension is frequently reported as an AE for all 5 TKIs, and BP monitoring is recommended.^3,4 However, the development of hypertension with these TKIs has been associated with response to therapy.⁷ With pazopanib, sorafenib, and sunitinib, there is a higher incidence of other AEs: edema, HF, MI, and QTc prolongation. Baseline ECG is recommended for all patients started on pazopanib and sunitinib and for patients with a history of CVD who are started on sorafenib. An ECG is recommended for patients with a history of CVD who are started on pazopanib and sunitinib.

Even with the medication prescribing information recommendations, it is unclear how frequently patients should be monitored. At VASDHS, CV monitoring for any patient started on a TKI remains at the discretion of the oncologist. There are concerns that ordering cardiac monitoring tests, which might be unnecessary, will change or guide therapy. In this study, data evaluation revealed 1 patient who experienced a CV event had a CVD history that was not documented in the patient’s medical history. It is important that providers obtain a detailed clinical assessment of patients CV history during each visit to determine whether CV monitoring should be considered. Patients also may benefit from additional counseling to emphasize the importance of adherence to CV medication therapy to reduce the incidence of these events.

Data from this study indicate that routine CV monitoring should be considered in patients with CVD, in keeping with current medication prescribing information recommendations. Of the patients who had a CV event, 54% experienced hypertension, 18% MI, and 28% stroke, QTc prolongation, or congestive HF. 

Limitations

This retrospective study had several limitations. Many patients did not have a baseline cardiac monitoring test or any monitoring during therapy. Often, a cardiac test was performed only when the patient was symptomatic or experiencing a CV event. In addition, because of intolerance or nonadherence to therapy, many patients discontinued treatment early, before completing 30 days. That axitinib and cabozantinib are newer therapies and not first-line at VASDHS during the data collection period accounts for the small number of patients on these therapies. Therapy was shorter for patients started on pazopanib, axitinib, and cabozantinib than it was for patients on sunitinib and sorafenib. Duration of therapy may affect treatment-related events, but the majority of patients in this study experienced an event within 4 months of therapy. About half of the patients who experienced an event were nonadherent to their CV medication regimen. Another potential limitation is that this study was conducted at VASDHS, where most patients are male (RCC incidence is 2:1 male:female).

Conclusion

In this study, CV events occurred in 24% of patients with a history of CVD; 11% of these events were nonhypertensive. Baseline cardiac monitoring was not performed for most patients started on TKI therapy, but tests were performed once patients became symptomatic. The study results suggest that high-risk patients should undergo routine cardiac monitoring during the first 4 months of TKI therapy, in keeping with medication package insert monitoring recommendations. Cardiac monitoring of high-risk patients will allow for earlier identification of cardiac decline and offer opportunities for interventions, such as pharmacist-driven protocols to start CV medications. Implementation of this study’s recommendations should be evaluated to determine whether outcomes improve with routine cardiac monitoring in these high-risk patients.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, FrontlineMedical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects— before administering pharmacologic therapy to patients.

In 2016, the Cancer Care Coordinator at the US Department of Veterans Affairs (VA) Connecticut Healthcare System (VACT) in West Haven partnered with the VA New England Healthcare System to use its telementoring program. The VA Specialty Care Access Network Extension for Community Healthcare Outcomes (VA ECHO) was used to present a series of educational conferences on cancer care. This article describes our experience implementing the program and reviews participant feedback gathered from voluntary surveys.

Background

In 2011, the Veterans Health Administration (VHA) Office of Healthcare Transformation launched VA ECHO, a telementoring program for primary care providers (PCPs) and patient-aligned care team staff. VACT was selected as 1 of 7 hub sites across the US. The VA ECHO system uses video and online technology to provide PCPs with case-based specialist consultation and didactic education. The system enables providers at any VA location to participate in online and telephone conferences in real time. The presentations are recorded and made available online to VA providers through a secure site.

VA ECHO is based on the highly successful Project ECHO model established by Sanjeev Arora and the University of New Mexico in 2007.¹ The rationale for Project ECHO was that patient care could be improved by increasing the competence of PCPs in the management of complex diseases by providing access to disease specialists through a case-based learning approach that used technology, which it termed knowledge networks, to connect the PCPs to specialists.

The original model addressed management of hepatitis C in a medically underserved area where half of the population was widely geographically dispersed, making the provision of specialty care challenging. Developers identified 6 characteristics that make a disease appropriate for treatment using the Project ECHO knowledge network model:

• The disease is common;
• Management of the disease is complex;
• Treatment for the disease is evolving;
• The disease has a high societal impact;
• There are serious outcomes if the disease is not treated; and
• Disease management improves outcomes.¹

VA ECHO conferences are available to all VA personnel. Staff can subscribe to an e-mail group list to be alerted to conference times and topics. Participants can connect directly to the conference using Microsoft Outlook Lync or Skype (Redmond, WA) and see the slides in real time on their computer as they listen to the presentation. The presentations are recorded, and the slides with audio can be accessed easily on the VA ECHO SharePoint site for download, enabling VA staff to listen to conferences at their convenience (Figure).

VA Cancer ECHO

The impetus to create a series of talks related to cancer care using VA ECHO was the frequent and often time-consuming requests we received from colleagues at other VA sites for information about areas of cancer care, such as survivorship and cancer care coordination. It was felt that presenting cancer care information as a VA ECHO series would make this information available to a large group of providers at one time, making the method more time effective than sharing the information via one-on-one conversations.

The cancer care coordinator originally conceived this as a 3-part, 1-time series to present work done at VACT in the areas of survivorship, psychosocial distress monitoring, and coordination of cancer care using the VA Cancer Care Tracking System, an online tracking tool. Information about the series was disseminated via VA group e-mail lists for oncology providers and via the existing VA ECHO subscriber invitation process. The 3-presentation series garnered positive feedback and had attendance that ranged from 49 to 75 participants (mean, 60). Participants expressed enthusiasm for the format via e-mail and phone feedback directly to the West Haven staff.

Expansion

The success of this original 3-part series led to a trial of an ongoing Cancer Care Conference series (Conference) using VA ECHO. This was a novel use of VA ECHO and was outside its traditional format, which is geared to discussion of individual cases and clinical knowledge. Nevertheless, this new style of communication has been embraced by a wide range of VA cancer care professionals.

One reason we considered expanding the program was that oncology fit the framework of the original Project ECHO knowledge network model. Cancer is common at the VA, which cares for 175,000 patients with cancer annually.² The management of cancer is complex involving many disciplines working together, and treatments are constantly changing. In addition, cancer has a high societal impact; there are serious outcomes both in terms of patient survival and patient symptom burden. And lastly, outcomes are improved with proactive disease management that is informed by the most current, evidence-based medicine.

The Conference was conceived as a forum for providers across disciplines to share best practices and discuss common challenges in caring for veterans with cancer. We invited participants to submit proposals for presentations related to cancer care initiatives at their VA sites. Potential speakers across all areas of care for veterans with cancer were invited to submit possible topics for the conference. The submissions were reviewed by the moderators in an effort to create a series of talks on a variety of topics across all aspects of care for oncology patients in the VA. This process of effectively crowd-sourcing educational content inspires providers to think more creatively about their practice and quality improvement projects and has sparked an ongoing dialogue about quality initiatives among VA oncology providers across disciplines and geographic locations. As a result, this approach also has enabled participants to learn from colleagues who work at a wide range of rural and urban VA locations throughout the country and to network with colleagues who are working on similar quality initiatives and challenges related to caring for veterans with cancer.

Program

The first Conference talk was in October 2016. It encompassed ten 1-hour talks during the 2016 to 2017 academic year. Speakers were recruited from the VACT West Haven campus and from several other VA sites nationwide. Topics included survivorship, psychosocial distress, palliative care, cancer navigation, and establishing a clinical trials program.

In its first year, the Conference series had 260 unique attendees representing such disciplines as medicine, nursing, social work, pharmacy, psychology, and clinic administration and representing all 21 Veterans Integrated Services Networks (VISNs). Speakers including oncologists, hepatologists, cancer care coordinators, health psychologists, and a research coordinator gave presentations on psychosocial distress screening and issues, cognitive behavioral therapy for cancer pain, cancer navigation, cancer case tracking, VISN-based liver cancer tumor tracker and liver tumor board, starting a VA-based clinical trial, palliative care, and survivorship.

The Conference accounted for 508 continuing medical education (CME) hours, which accounted for one-third of the total CME hours generated by the VACT West Haven VA ECHO program. Highlights of the talks were presented at the 2017 Association of VA Hematology/Oncology annual meeting in Denver, Colorado.

During the second year of the Conference, speakers were recruited to address new American College of Surgeons Commission on Cancer (CoC) requirements regarding survivorship treatment summaries for a subset of cancer survivors.³ The focus on survivorship was driven by ongoing feedback from participants who were working on initiatives to implement this process at their VA sites and wanted to learn from peers involved in this process throughout the VA system. Several speakers gave talks on implementing survivorship care at their VA and specifically on the use of computerized patient record system templates to create survivorship treatment summaries for veterans in accordance with CoC standards.

Since the first Conference in 2016, the number of unique attendees grew by 20% to 327 in 2018. During its first 2 years, participants have earned a total of 1,095 CME credits through Yale University CME. Conferences are usually broadcast at noon eastern time so that providers can take advantage of sessions during lunch breaks.

Participant Surveys

Attendees were invited to participate in voluntary, anonymous surveys to obtain feedback on and to receive input on topics of interest for future talks. Participants also were asked to comment on resources that they utilized to be updated on practice changes (Table 1). 

The Conference has led to increased awareness of other continuing education opportunities available through VA ECHO-Connecticut. Of survey participants, 20% reported that they had attended other VA ECHO conferences.

The survey samples are self-selecting and may not necessarily be representative of the Conference participants or of the VA oncology interdisciplinary team as a whole; however, the relatively large number of survey participants provides some confidence that these survey results can help inform future planning for this and other continuing education opportunities for VA oncology providers.

An additional online survey was designed to elucidate whether participants were incorporating knowledge gained from the Conference in their cancer care practice. Half of the 32 participants strongly agreed with the following statement: “Participation in the VA Cancer Care Conference has added to my knowledge of information relevant to my practice,” and 13 more agreed with the statement for a total of 90.6% of those surveyed responding affirmatively. Only 3 participants neither agreed nor disagreed, and none disagreed with the statement. More than half of the participants reported that they made changes to their practice or plan to make changes as a result of the Conference.

Conculsion

The VA ECHO program established at the VACT West Haven campus in 2012 now offers regular monthly or bimonthly conferences in 9 specialties: pain, liver/hepatitis C, neurology, nephrology, cardiology, diabetes/endocrinology, mental health and addiction, nursing grand rounds, and cancer care. The VACT ECHO program is led by a medical director, and each specialty has a clinical director who conducts sessions and recruits other specialists from their department.

Teleconferencing can provide opportunities for colleagues living in distant locations to connect; share best practices, common goals, and challenges; and initiate ongoing and lasting relationships. The Conference draws the most diverse audience by discipline of all the VA ECHO conferences hosted at VACT (Table 2). 

Traditionally, the national VA ECHO program has been a forum for specialists to discuss clinical case presentations for the benefit of primary care providers and to deliver didactics about chronic clinical conditions. Our Cancer Care Management VA ECHO has explored new ground by discussing material that has helped sites set up and enhance cancer care clinics and disseminate best practices for cancer survivorship and other aspects of cancer care. As a result, this conference has attracted and provided a forum for the most diverse audience of staff among VA ECHO clinics, with participation from clinic administrators to social workers to primary care providers to tumor registrars.

Through the creation of the Conference, > 300 individuals who care for veterans with cancer have been provided with a regular forum at which to connect with colleagues, receive updates on new treatment options for their patients, and learn about and share best practices specific to VA oncology patients. The VA ECHO technology creates a resource that can be accessed by all VA staff from their desktop computer. The VA ECHO SharePoint saves the slides of the Conference presentations both with and without audio to enable staff who can’t participate in real time to access the information at their convenience.

The Conference has facilitated networking among VA oncology providers who have common interests. Conference participants also have participated in other VA ECHO conferences in disciplines beyond oncology. Participants in the Conference also are encouraged to participate as speakers by presenting quality improvement initiatives at their VA site. This novel approach to generating content for this educational series has led to a dynamic interchange of ideas and increased networking among VA providers related to their practice and quality improvement initiatives at their VA sites. The Conference provides a regular forum for VA staff across a wide range of disciplines to share personal experiences, successes, and frustrations and to get feedback from colleagues.

The Conference combines a structured approach to presenting VA-specific educational content related to cancer care and multiple mechanisms that encourage staff to participate in an ongoing dialogue related to quality initiatives both on the phone during the Conference, online using Outlook LYNC or Skype to ask questions during the Conference, and during conversations on group e-mail. The Conference promotes staff engagement at little or no extra cost to the VA. For more information about the VA ECHO Cancer Care Conference or to submit a presentation for consideration for a future session, please contact julie.beck@va.gov or pradeep.mutalik@va.gov.

In 2016, the Cancer Care Coordinator at the US Department of Veterans Affairs (VA) Connecticut Healthcare System (VACT) in West Haven partnered with the VA New England Healthcare System to use its telementoring program. The VA Specialty Care Access Network Extension for Community Healthcare Outcomes (VA ECHO) was used to present a series of educational conferences on cancer care. This article describes our experience implementing the program and reviews participant feedback gathered from voluntary surveys.

Background

In 2011, the Veterans Health Administration (VHA) Office of Healthcare Transformation launched VA ECHO, a telementoring program for primary care providers (PCPs) and patient-aligned care team staff. VACT was selected as 1 of 7 hub sites across the US. The VA ECHO system uses video and online technology to provide PCPs with case-based specialist consultation and didactic education. The system enables providers at any VA location to participate in online and telephone conferences in real time. The presentations are recorded and made available online to VA providers through a secure site.

VA ECHO is based on the highly successful Project ECHO model established by Sanjeev Arora and the University of New Mexico in 2007.¹ The rationale for Project ECHO was that patient care could be improved by increasing the competence of PCPs in the management of complex diseases by providing access to disease specialists through a case-based learning approach that used technology, which it termed knowledge networks, to connect the PCPs to specialists.

The original model addressed management of hepatitis C in a medically underserved area where half of the population was widely geographically dispersed, making the provision of specialty care challenging. Developers identified 6 characteristics that make a disease appropriate for treatment using the Project ECHO knowledge network model:

• The disease is common;
• Management of the disease is complex;
• Treatment for the disease is evolving;
• The disease has a high societal impact;
• There are serious outcomes if the disease is not treated; and
• Disease management improves outcomes.¹

VA ECHO conferences are available to all VA personnel. Staff can subscribe to an e-mail group list to be alerted to conference times and topics. Participants can connect directly to the conference using Microsoft Outlook Lync or Skype (Redmond, WA) and see the slides in real time on their computer as they listen to the presentation. The presentations are recorded, and the slides with audio can be accessed easily on the VA ECHO SharePoint site for download, enabling VA staff to listen to conferences at their convenience (Figure).

VA Cancer ECHO

The impetus to create a series of talks related to cancer care using VA ECHO was the frequent and often time-consuming requests we received from colleagues at other VA sites for information about areas of cancer care, such as survivorship and cancer care coordination. It was felt that presenting cancer care information as a VA ECHO series would make this information available to a large group of providers at one time, making the method more time effective than sharing the information via one-on-one conversations.

The cancer care coordinator originally conceived this as a 3-part, 1-time series to present work done at VACT in the areas of survivorship, psychosocial distress monitoring, and coordination of cancer care using the VA Cancer Care Tracking System, an online tracking tool. Information about the series was disseminated via VA group e-mail lists for oncology providers and via the existing VA ECHO subscriber invitation process. The 3-presentation series garnered positive feedback and had attendance that ranged from 49 to 75 participants (mean, 60). Participants expressed enthusiasm for the format via e-mail and phone feedback directly to the West Haven staff.

Expansion

The success of this original 3-part series led to a trial of an ongoing Cancer Care Conference series (Conference) using VA ECHO. This was a novel use of VA ECHO and was outside its traditional format, which is geared to discussion of individual cases and clinical knowledge. Nevertheless, this new style of communication has been embraced by a wide range of VA cancer care professionals.

One reason we considered expanding the program was that oncology fit the framework of the original Project ECHO knowledge network model. Cancer is common at the VA, which cares for 175,000 patients with cancer annually.² The management of cancer is complex involving many disciplines working together, and treatments are constantly changing. In addition, cancer has a high societal impact; there are serious outcomes both in terms of patient survival and patient symptom burden. And lastly, outcomes are improved with proactive disease management that is informed by the most current, evidence-based medicine.

The Conference was conceived as a forum for providers across disciplines to share best practices and discuss common challenges in caring for veterans with cancer. We invited participants to submit proposals for presentations related to cancer care initiatives at their VA sites. Potential speakers across all areas of care for veterans with cancer were invited to submit possible topics for the conference. The submissions were reviewed by the moderators in an effort to create a series of talks on a variety of topics across all aspects of care for oncology patients in the VA. This process of effectively crowd-sourcing educational content inspires providers to think more creatively about their practice and quality improvement projects and has sparked an ongoing dialogue about quality initiatives among VA oncology providers across disciplines and geographic locations. As a result, this approach also has enabled participants to learn from colleagues who work at a wide range of rural and urban VA locations throughout the country and to network with colleagues who are working on similar quality initiatives and challenges related to caring for veterans with cancer.

Program

The first Conference talk was in October 2016. It encompassed ten 1-hour talks during the 2016 to 2017 academic year. Speakers were recruited from the VACT West Haven campus and from several other VA sites nationwide. Topics included survivorship, psychosocial distress, palliative care, cancer navigation, and establishing a clinical trials program.

In its first year, the Conference series had 260 unique attendees representing such disciplines as medicine, nursing, social work, pharmacy, psychology, and clinic administration and representing all 21 Veterans Integrated Services Networks (VISNs). Speakers including oncologists, hepatologists, cancer care coordinators, health psychologists, and a research coordinator gave presentations on psychosocial distress screening and issues, cognitive behavioral therapy for cancer pain, cancer navigation, cancer case tracking, VISN-based liver cancer tumor tracker and liver tumor board, starting a VA-based clinical trial, palliative care, and survivorship.

The Conference accounted for 508 continuing medical education (CME) hours, which accounted for one-third of the total CME hours generated by the VACT West Haven VA ECHO program. Highlights of the talks were presented at the 2017 Association of VA Hematology/Oncology annual meeting in Denver, Colorado.

During the second year of the Conference, speakers were recruited to address new American College of Surgeons Commission on Cancer (CoC) requirements regarding survivorship treatment summaries for a subset of cancer survivors.³ The focus on survivorship was driven by ongoing feedback from participants who were working on initiatives to implement this process at their VA sites and wanted to learn from peers involved in this process throughout the VA system. Several speakers gave talks on implementing survivorship care at their VA and specifically on the use of computerized patient record system templates to create survivorship treatment summaries for veterans in accordance with CoC standards.

Since the first Conference in 2016, the number of unique attendees grew by 20% to 327 in 2018. During its first 2 years, participants have earned a total of 1,095 CME credits through Yale University CME. Conferences are usually broadcast at noon eastern time so that providers can take advantage of sessions during lunch breaks.

Participant Surveys

Attendees were invited to participate in voluntary, anonymous surveys to obtain feedback on and to receive input on topics of interest for future talks. Participants also were asked to comment on resources that they utilized to be updated on practice changes (Table 1). 

The Conference has led to increased awareness of other continuing education opportunities available through VA ECHO-Connecticut. Of survey participants, 20% reported that they had attended other VA ECHO conferences.

The survey samples are self-selecting and may not necessarily be representative of the Conference participants or of the VA oncology interdisciplinary team as a whole; however, the relatively large number of survey participants provides some confidence that these survey results can help inform future planning for this and other continuing education opportunities for VA oncology providers.

An additional online survey was designed to elucidate whether participants were incorporating knowledge gained from the Conference in their cancer care practice. Half of the 32 participants strongly agreed with the following statement: “Participation in the VA Cancer Care Conference has added to my knowledge of information relevant to my practice,” and 13 more agreed with the statement for a total of 90.6% of those surveyed responding affirmatively. Only 3 participants neither agreed nor disagreed, and none disagreed with the statement. More than half of the participants reported that they made changes to their practice or plan to make changes as a result of the Conference.

Conculsion

The VA ECHO program established at the VACT West Haven campus in 2012 now offers regular monthly or bimonthly conferences in 9 specialties: pain, liver/hepatitis C, neurology, nephrology, cardiology, diabetes/endocrinology, mental health and addiction, nursing grand rounds, and cancer care. The VACT ECHO program is led by a medical director, and each specialty has a clinical director who conducts sessions and recruits other specialists from their department.

Teleconferencing can provide opportunities for colleagues living in distant locations to connect; share best practices, common goals, and challenges; and initiate ongoing and lasting relationships. The Conference draws the most diverse audience by discipline of all the VA ECHO conferences hosted at VACT (Table 2). 

Traditionally, the national VA ECHO program has been a forum for specialists to discuss clinical case presentations for the benefit of primary care providers and to deliver didactics about chronic clinical conditions. Our Cancer Care Management VA ECHO has explored new ground by discussing material that has helped sites set up and enhance cancer care clinics and disseminate best practices for cancer survivorship and other aspects of cancer care. As a result, this conference has attracted and provided a forum for the most diverse audience of staff among VA ECHO clinics, with participation from clinic administrators to social workers to primary care providers to tumor registrars.

Through the creation of the Conference, > 300 individuals who care for veterans with cancer have been provided with a regular forum at which to connect with colleagues, receive updates on new treatment options for their patients, and learn about and share best practices specific to VA oncology patients. The VA ECHO technology creates a resource that can be accessed by all VA staff from their desktop computer. The VA ECHO SharePoint saves the slides of the Conference presentations both with and without audio to enable staff who can’t participate in real time to access the information at their convenience.

The Conference has facilitated networking among VA oncology providers who have common interests. Conference participants also have participated in other VA ECHO conferences in disciplines beyond oncology. Participants in the Conference also are encouraged to participate as speakers by presenting quality improvement initiatives at their VA site. This novel approach to generating content for this educational series has led to a dynamic interchange of ideas and increased networking among VA providers related to their practice and quality improvement initiatives at their VA sites. The Conference provides a regular forum for VA staff across a wide range of disciplines to share personal experiences, successes, and frustrations and to get feedback from colleagues.

The Conference combines a structured approach to presenting VA-specific educational content related to cancer care and multiple mechanisms that encourage staff to participate in an ongoing dialogue related to quality initiatives both on the phone during the Conference, online using Outlook LYNC or Skype to ask questions during the Conference, and during conversations on group e-mail. The Conference promotes staff engagement at little or no extra cost to the VA. For more information about the VA ECHO Cancer Care Conference or to submit a presentation for consideration for a future session, please contact julie.beck@va.gov or pradeep.mutalik@va.gov.

In 2016, the Cancer Care Coordinator at the US Department of Veterans Affairs (VA) Connecticut Healthcare System (VACT) in West Haven partnered with the VA New England Healthcare System to use its telementoring program. The VA Specialty Care Access Network Extension for Community Healthcare Outcomes (VA ECHO) was used to present a series of educational conferences on cancer care. This article describes our experience implementing the program and reviews participant feedback gathered from voluntary surveys.

Background

In 2011, the Veterans Health Administration (VHA) Office of Healthcare Transformation launched VA ECHO, a telementoring program for primary care providers (PCPs) and patient-aligned care team staff. VACT was selected as 1 of 7 hub sites across the US. The VA ECHO system uses video and online technology to provide PCPs with case-based specialist consultation and didactic education. The system enables providers at any VA location to participate in online and telephone conferences in real time. The presentations are recorded and made available online to VA providers through a secure site.

VA ECHO is based on the highly successful Project ECHO model established by Sanjeev Arora and the University of New Mexico in 2007.¹ The rationale for Project ECHO was that patient care could be improved by increasing the competence of PCPs in the management of complex diseases by providing access to disease specialists through a case-based learning approach that used technology, which it termed knowledge networks, to connect the PCPs to specialists.

The original model addressed management of hepatitis C in a medically underserved area where half of the population was widely geographically dispersed, making the provision of specialty care challenging. Developers identified 6 characteristics that make a disease appropriate for treatment using the Project ECHO knowledge network model:

• The disease is common;
• Management of the disease is complex;
• Treatment for the disease is evolving;
• The disease has a high societal impact;
• There are serious outcomes if the disease is not treated; and
• Disease management improves outcomes.¹

VA ECHO conferences are available to all VA personnel. Staff can subscribe to an e-mail group list to be alerted to conference times and topics. Participants can connect directly to the conference using Microsoft Outlook Lync or Skype (Redmond, WA) and see the slides in real time on their computer as they listen to the presentation. The presentations are recorded, and the slides with audio can be accessed easily on the VA ECHO SharePoint site for download, enabling VA staff to listen to conferences at their convenience (Figure).

VA Cancer ECHO

The impetus to create a series of talks related to cancer care using VA ECHO was the frequent and often time-consuming requests we received from colleagues at other VA sites for information about areas of cancer care, such as survivorship and cancer care coordination. It was felt that presenting cancer care information as a VA ECHO series would make this information available to a large group of providers at one time, making the method more time effective than sharing the information via one-on-one conversations.

The cancer care coordinator originally conceived this as a 3-part, 1-time series to present work done at VACT in the areas of survivorship, psychosocial distress monitoring, and coordination of cancer care using the VA Cancer Care Tracking System, an online tracking tool. Information about the series was disseminated via VA group e-mail lists for oncology providers and via the existing VA ECHO subscriber invitation process. The 3-presentation series garnered positive feedback and had attendance that ranged from 49 to 75 participants (mean, 60). Participants expressed enthusiasm for the format via e-mail and phone feedback directly to the West Haven staff.

Expansion

The success of this original 3-part series led to a trial of an ongoing Cancer Care Conference series (Conference) using VA ECHO. This was a novel use of VA ECHO and was outside its traditional format, which is geared to discussion of individual cases and clinical knowledge. Nevertheless, this new style of communication has been embraced by a wide range of VA cancer care professionals.

One reason we considered expanding the program was that oncology fit the framework of the original Project ECHO knowledge network model. Cancer is common at the VA, which cares for 175,000 patients with cancer annually.² The management of cancer is complex involving many disciplines working together, and treatments are constantly changing. In addition, cancer has a high societal impact; there are serious outcomes both in terms of patient survival and patient symptom burden. And lastly, outcomes are improved with proactive disease management that is informed by the most current, evidence-based medicine.

The Conference was conceived as a forum for providers across disciplines to share best practices and discuss common challenges in caring for veterans with cancer. We invited participants to submit proposals for presentations related to cancer care initiatives at their VA sites. Potential speakers across all areas of care for veterans with cancer were invited to submit possible topics for the conference. The submissions were reviewed by the moderators in an effort to create a series of talks on a variety of topics across all aspects of care for oncology patients in the VA. This process of effectively crowd-sourcing educational content inspires providers to think more creatively about their practice and quality improvement projects and has sparked an ongoing dialogue about quality initiatives among VA oncology providers across disciplines and geographic locations. As a result, this approach also has enabled participants to learn from colleagues who work at a wide range of rural and urban VA locations throughout the country and to network with colleagues who are working on similar quality initiatives and challenges related to caring for veterans with cancer.

Program

The first Conference talk was in October 2016. It encompassed ten 1-hour talks during the 2016 to 2017 academic year. Speakers were recruited from the VACT West Haven campus and from several other VA sites nationwide. Topics included survivorship, psychosocial distress, palliative care, cancer navigation, and establishing a clinical trials program.

In its first year, the Conference series had 260 unique attendees representing such disciplines as medicine, nursing, social work, pharmacy, psychology, and clinic administration and representing all 21 Veterans Integrated Services Networks (VISNs). Speakers including oncologists, hepatologists, cancer care coordinators, health psychologists, and a research coordinator gave presentations on psychosocial distress screening and issues, cognitive behavioral therapy for cancer pain, cancer navigation, cancer case tracking, VISN-based liver cancer tumor tracker and liver tumor board, starting a VA-based clinical trial, palliative care, and survivorship.

The Conference accounted for 508 continuing medical education (CME) hours, which accounted for one-third of the total CME hours generated by the VACT West Haven VA ECHO program. Highlights of the talks were presented at the 2017 Association of VA Hematology/Oncology annual meeting in Denver, Colorado.

During the second year of the Conference, speakers were recruited to address new American College of Surgeons Commission on Cancer (CoC) requirements regarding survivorship treatment summaries for a subset of cancer survivors.³ The focus on survivorship was driven by ongoing feedback from participants who were working on initiatives to implement this process at their VA sites and wanted to learn from peers involved in this process throughout the VA system. Several speakers gave talks on implementing survivorship care at their VA and specifically on the use of computerized patient record system templates to create survivorship treatment summaries for veterans in accordance with CoC standards.

Since the first Conference in 2016, the number of unique attendees grew by 20% to 327 in 2018. During its first 2 years, participants have earned a total of 1,095 CME credits through Yale University CME. Conferences are usually broadcast at noon eastern time so that providers can take advantage of sessions during lunch breaks.

Participant Surveys

Attendees were invited to participate in voluntary, anonymous surveys to obtain feedback on and to receive input on topics of interest for future talks. Participants also were asked to comment on resources that they utilized to be updated on practice changes (Table 1). 

The Conference has led to increased awareness of other continuing education opportunities available through VA ECHO-Connecticut. Of survey participants, 20% reported that they had attended other VA ECHO conferences.

The survey samples are self-selecting and may not necessarily be representative of the Conference participants or of the VA oncology interdisciplinary team as a whole; however, the relatively large number of survey participants provides some confidence that these survey results can help inform future planning for this and other continuing education opportunities for VA oncology providers.

An additional online survey was designed to elucidate whether participants were incorporating knowledge gained from the Conference in their cancer care practice. Half of the 32 participants strongly agreed with the following statement: “Participation in the VA Cancer Care Conference has added to my knowledge of information relevant to my practice,” and 13 more agreed with the statement for a total of 90.6% of those surveyed responding affirmatively. Only 3 participants neither agreed nor disagreed, and none disagreed with the statement. More than half of the participants reported that they made changes to their practice or plan to make changes as a result of the Conference.

Conculsion

The VA ECHO program established at the VACT West Haven campus in 2012 now offers regular monthly or bimonthly conferences in 9 specialties: pain, liver/hepatitis C, neurology, nephrology, cardiology, diabetes/endocrinology, mental health and addiction, nursing grand rounds, and cancer care. The VACT ECHO program is led by a medical director, and each specialty has a clinical director who conducts sessions and recruits other specialists from their department.

Teleconferencing can provide opportunities for colleagues living in distant locations to connect; share best practices, common goals, and challenges; and initiate ongoing and lasting relationships. The Conference draws the most diverse audience by discipline of all the VA ECHO conferences hosted at VACT (Table 2). 

Traditionally, the national VA ECHO program has been a forum for specialists to discuss clinical case presentations for the benefit of primary care providers and to deliver didactics about chronic clinical conditions. Our Cancer Care Management VA ECHO has explored new ground by discussing material that has helped sites set up and enhance cancer care clinics and disseminate best practices for cancer survivorship and other aspects of cancer care. As a result, this conference has attracted and provided a forum for the most diverse audience of staff among VA ECHO clinics, with participation from clinic administrators to social workers to primary care providers to tumor registrars.

Through the creation of the Conference, > 300 individuals who care for veterans with cancer have been provided with a regular forum at which to connect with colleagues, receive updates on new treatment options for their patients, and learn about and share best practices specific to VA oncology patients. The VA ECHO technology creates a resource that can be accessed by all VA staff from their desktop computer. The VA ECHO SharePoint saves the slides of the Conference presentations both with and without audio to enable staff who can’t participate in real time to access the information at their convenience.

The Conference has facilitated networking among VA oncology providers who have common interests. Conference participants also have participated in other VA ECHO conferences in disciplines beyond oncology. Participants in the Conference also are encouraged to participate as speakers by presenting quality improvement initiatives at their VA site. This novel approach to generating content for this educational series has led to a dynamic interchange of ideas and increased networking among VA providers related to their practice and quality improvement initiatives at their VA sites. The Conference provides a regular forum for VA staff across a wide range of disciplines to share personal experiences, successes, and frustrations and to get feedback from colleagues.

The Conference combines a structured approach to presenting VA-specific educational content related to cancer care and multiple mechanisms that encourage staff to participate in an ongoing dialogue related to quality initiatives both on the phone during the Conference, online using Outlook LYNC or Skype to ask questions during the Conference, and during conversations on group e-mail. The Conference promotes staff engagement at little or no extra cost to the VA. For more information about the VA ECHO Cancer Care Conference or to submit a presentation for consideration for a future session, please contact julie.beck@va.gov or pradeep.mutalik@va.gov.

Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer worldwide.¹ Liver cancer is the fifth most common cancer in men and the seventh in women.² The highest incidence rates are in sub-Saharan Africa and Southeast Asia where hepatitis B virus is endemic. The incidence of HCC in western countries is increasing, particularly due to the rise of hepatitis C virus (HCV) as well as alcoholic liver disease and nonalcoholic fatty liver disease. The incidence of HCC has tripled in the US in the past 2 decades.^1-3

HCC can be diagnosed by radiographic images without the need for biopsy if the typical imaging features are present.³ The European Association for the Study of Liver Disease (EASL) and the American Association for the Study of Liver Diseases (AASLD) recommend screening abdominal ultrasonography at 6-month intervals for high-risk patients.^3,4 High-risk patients include patients with cirrhosis, especially those with hepatitis B or C.³

If screening ultrasonography detects a nodule, size determines whether a follow-up ultrasound is needed vs obtaining a contrast-enhanced dynamic computed tomography (CT) scan or a magnetic resonance image (MRI).³ If ultrasonography detects a nodule > 1 cm in diameter, then a dynamic CT or MRI is performed. Characteristic hyperenhancement during later arterial phase and washout during the venous or delayed phase is associated with a nearly 100% specificity for HCC diagnosis.⁵ Arterial-enhancing contrast is required when using CT and MRI because HCC is a hypervascular lesion.⁶ The portal venous blood dilutes the majority of the liver’s arterial blood; therefore, the liver does not enhance during the arterial phase, while HCC will show maximum enhancement.⁷ Furthermore, HCC should demonstrate a “washout” of contrast during the venous phase on CT and MRI.⁴ Standard imaging protocol dictates that 4 phases are needed to properly diagnose HCC including unenhanced, arterial, venous, and delayed.⁴

Regular surveillance increases the likelihood of detecting HCC before the presentation of clinical symptoms and facilitates receipt of curative therapy.^8-10 Patients with viral hepatitis and cirrhosis with HCC found on screening are more likely to have earlier-stage disease and survive longer from the time of diagnosis.¹¹ Furthermore, it has been observed that HCC detected by surveillance is significantly more likely to undergo curative therapy compared with incidental or symptomatic detection of HCC.⁹

Technical improvements in imaging techniques include advancement in contrast agents, multidetector row helical CT, and the flexibility/range of pulse sequences available in MRI.⁷ Even with technical improvements in all modalities used in HCC imaging, detecting HCC remains difficult, especially when detecting the small (< 2 cm) lesions in a cirrhotic liver.⁷ Interpretation of imaging also remains a challenge as HCC does not always fit strict criteria: lack of “washout” in a hypervascular lesion, determining small HCC lesions from benign nodules, and hypovascular/isovascular HCC.⁵ Radiologic differentials in the diagnosis of HCC include transient hepatic intensity difference (THID)/transient hepatic attenuation difference (THAD), arterio-portal shunt, and regenerative nodules.¹² In the common clinical setting, patients undergo multiple imaging studies that are interpreted by multiple radiologists, which can add to the difficulty in the diagnosis of HCC.¹³

The radiology community recognized the inconsistencies and complexities of HCC imaging. Therefore, the American College of Radiology endorsed the Liver Imaging Reporting and Data System (LI-RADS), which had the goal of reducing variability in lesion interpretation through standardization and improving communication with clinicians.¹⁴ LI-RADS uses a diagnostic algorithm for CT and MRI that categorizes observed liver findings in high-risk individuals based on the probability or relative risk of HCC without assigning a formal diagnosis.¹⁴ LI-RADS takes into account arterial phase enhancement, tumor size, washout appearance, the presence and nature of a capsule, and threshold growth.¹⁵ LI-RADS categorizes an observed liver finding on a scale of 1 to 5, with 1 corresponding to a definitely benign finding and 5 with definitive HCC.¹⁴ Furthermore, LI-RADS sought to limit the technical variabilities among institutions.

LI-RADS was launched in 2011 and has been utilized by many clinical practices while continuing to be expanded and updated.¹⁶ Recent studies examined the specificity of LI-RADS as well as interreader variability.^17,18 For nodules viewed on MRI, both LI-RADS categories 4 and 5 had high specificity for HCC.¹⁷ When looking at interreader repeatability, LI-RADS showed moderate agreement among experts using the diagnostic algorithm.¹⁹ Further studies have compared LI-RADS with the AASLD guidelines and the Organ Procurement and Transplantation Network (OPTN) guidelines.¹⁶ When compared with other guidelines, LI-RADS expands the definition of indeterminate findings into probably benign, intermediate probability of HCC, and probably HCC, which corresponds to LI-RADS categories 2, 3, and 4.¹⁶

We looked retrospectively at a group of patients previously diagnosed with HCC to see whether utilizing the LI-RADS scoring system within our screening system might have allowed an earlier prediction of HCC and a timelier intervention. Prior to this investigation the LI-RADS system was not used for HCC screening at our US Department of Veterans Affairs (VA) facility. We examined screened patients at the Memphis VA Medical Center (MVAMC) in Tennessee who were subsequently diagnosed with HCC to see which LI-RADS category the last surveillance CT prior to diagnosis would fall into, 6 months to a year prior to the diagnosis of HCC. Our control population was a group of patients screened with CT for their liver nodules who were found not to have HCC.

Methods

Patients at MVAMC with cirrhosis and patients with chronic hepatitis B are routinely screened with ultrasound, CT, or MRI in accordance with the AASLD, EASL, and VA guidelines. Of 303 patients with HCV and cirrhosis under care in 2015, 242 (81%) received imaging to screen for HCC according to the VA National Hepatitis C Registry 2015 (Personal Communication, Population Health Service, Office of Patient Care Services).The LI-RADS scoring system was not applied as a standard screening methodology.

Under an institutional review board-approved protocol, we reviewed the charts of all patients diagnosed with HCC at MVAMC from 2009 to 2014, utilizing ICD-9 code of 155.0 for HCC. We identified within these charts patients who had a surveillance CT image performed within a 6- to 13-month period prior to the CTs that diagnosed HCC (prediagnostic HCC CT). Furthermore, we reviewed the charts of all patients diagnosed with benign liver nodules at MVAMC from 2009 to 2014, utilizing the ICD-9 code of 573.8 for other specified disorders of the liver.

Within these charts, we found patients who had a surveillance CT image performed and who were followed after that image with additional imaging for ≥ 2 years or who had a liver biopsy negative for HCC (benign surveillance CT). We compared these 2 sets of CTs utilizing LI-RADS criteria. Once these patients were identified, a list of the CTs to be examined were given to 2 MVAMC radiologists who specialize in CT.

No identifying information of the patients was included, and a 13-digit number unique to each CT exam identified the CTs to be reviewed. Radiologist 1 and 2 examined the CTs on the MVAMC Picture Archiving and Communication System (PACS). Both radiologists were asked to give each nodule a score according to LI-RADS v2014 diagnostic algorithm (Figure).

We hypothesized that the prediagnostic CT images of patients eventually determined to have HCC would have a LI-RADS score of 4 (LR4) or LR5. Furthermore, we hypothesized that the CT images of the benign liver nodule patients would have a score ≤ LR3. If there was a disagreement between the radiologists in terms of a malignant score (LR4 or LR5) vs a benign score (≤ LR3), then a third radiologist (radiologist 3) provided a score for these nodules. The third, tiebreaker radiologist was given the scores of both prior radiologists and asked to choose which score was correct.

Statistical analysis was then applied to the data to determine the sensitivity, specificity, and diagnostic accuracy in diagnosing eventual HCC, as well as the false-negative and false-positive rates of radiologists 1 and 2. Raw data also were used to determine the agreement between raters by calculating the κ statistic with a 95% CI.

Results

A total of 70 nodules were examined by radiologists 1 and 2 with 42 of the nodules in the prediagnostic HCC CTs and 28 of the nodules in the benign surveillance CTs. 

Radiologist 1 identified 11 patients with LR4 and 21 patients with LR5. His scores showed a sensitivity of 64.3% and specificity of 82.1% with accuracy of 71.4% for LI-RADS in identifying eventual HCC. The false-negative rate of the LI-RADS diagnostic algorithm for radiologist 1 was 35.7% and the false-positive rate was 17.9%. Radiologist 2 identified 17 patients LR4 and 19 patients with LR5. Radiologist 2’s scores showed a sensitivity of 69.0% and specificity of 75.0% with accuracy of 71.4% for LI-RADS in identifying eventual HCC.The false-negative rate of the LI-RADS diagnostic algorithm for radiologist 2 was 31.0% and false-positive rate of 25.0%. The κ statistic was calculated to determine the interrater agreement. The radiologists agreed on 58 of 70 samples; 15 without HCC and 43 with HCC. The κ statistic was 0.592, which indicates moderate agreement (Table 2). 

Discussion

If HCC is diagnosed late in the disease process based on symptomatology and not on surveillance imaging, the likelihood of receiving early and potential curative therapy greatly declines as was shown in a systemic literature review.⁹ Surveillance imaging and lesion interpretation by various radiologists has been difficult to standardize as new technologic advances continue to occur in the imaging of HCC.¹⁴ LI-RADS was initiated to help standardize CT and MRI interpretation and reporting of hepatic nodules. As a dynamic algorithm, it continues to adjust with new advances in imaging techniques with the most recent updates being made to the algorithm in 2014.^14,19 LI-RADS applies to patients at high risk for HCC most often who are already enrolled in a surveillance program.¹⁹ The MVAMC has a high incidence of patients with cirrhosis who are at risk for HCC, which is why we chose it as our study population.

LI-RADS can be applied to both MRI and CT imaging. Much of the recent literature have looked at LI-RADS in terms of MRI. A group in China looked at 100 pathologically confirmed patients and assigned a LI-RADS score to the MRI at the time of diagnosis and showed that MRI LI-RADS scoring was highly sensitive and specific in the diagnosis of HCC.²⁰ This study did note a numeric difference in the specificity of LI-RADS algorithm depending on how LR3 scores were viewed. If a LR3 score was considered negative rather than positive for HCC, then the specificity increased by almost 20%.²⁰

Another study looked at patients with liver nodules ≤ 20 mm found on ultrasound and obtained MRIs and biopsies on these patients, assigning the MRI a LI-RADs score.¹⁷ Darnell and colleagues found that MRI LR4 and LR5 have a high specificity for HCC. However, 29 of the 42 LR3 lesions examined were found to be HCC.¹⁷ Furthermore, Choi and colleagues retrospectively looked at patients in a HCC surveillance program who had undergone MRI as part of the program and assigned LI-RADS scores to these MRIs.²¹ Their study showed that LR5 criteria on gadoxetate disodium-enhanced MRI has excellent positive predictive value (PPV) for diagnosing HCC, and LR4 showed good PPV.²¹

In our study, we chose to look at LI-RADS in terms of surveillance CT scans 6 to 13 months prior to the diagnosis of HCC to see whether this method would allow us to intervene earlier with more aggressive diagnostics or therapy in those suspected of having HCC. Although Choi and colleagues looked retrospectively at MRI surveillance imaging, most of the prior studies have looked at LI-RADS scoring in imaging at the time of diagnosis.^17,20,21 By looking at surveillance CT scans, we sought to determine LI-RADS sensitivity, specificity, and diagnostic accuracy as a screening tool compared with CT evaluations without LI-RADS scoring.

We also chose to look at CT scans since most of the prior studies have looked at the more detailed and often more expensive MRIs. For both radiologists 1 and 2, the sensitivity was > 60% and specificity was > 70% with a diagnostic accuracy of 71.4% in predicting a diagnosis of HCC in future scans. Although there was high false negative of > 30% for both radiologists, we did consider LR3 as negative for HCC. As Darnell and colleagues’ study of MRI LI-RADS shows, LR3 may need to be revised in the future as its ambiguity can lead to false-negatives.¹⁷ Our results also showed moderate interreader agreement, which has been seen in previous studies with LI-RADS.¹⁸

Some studies have compared MRI with CT imaging in terms of LI-RADs classification of hepatic nodules to find out whether concordance was seen.^22,23 Both studies found that there was substantial discordance between MRI and CT with CT often underscoring hepatic nodules.^22,23 In Zhang and colleagues, interclass agreement between CT and MRI varied the most in terms of arterial enhancement with CT producing false-negative findings.²² CT also underestimated LI-RADS score by 16.9% for LR3, 37.3% for LR4, and 8.5% for LR5 in this study.²² Furthermore, Corwin and colleagues found a significant upgrade in terms of LI-RADS categorization with MRI for 42.5% of observations.²³ In this study, upgraded LI-RADS scores on MRI included 2 upgraded to LR5V (Figure), 15 upgraded to LR5, and 12 upgraded to LR4.²³ 

Our study shows that the LI-RADS algorithm has a good sensitivity, specificity, and diagnostic accuracy as a screening tool, predicting HCC in scans earlier than standard CT evaluation. In our study, the patients with HCC were shown to have higher LI-RADS scores on prediagnostic imaging, while the benign liver nodule patients were shown to have lower LI-RADS scores. This data would suggest that a LI-RADS score given to surveillance CT of LR4 or higher should recommend either a biopsy or follow-up imaging after a short interval. If LI-RADS is applied to surveillance CTs in patients at risk for HCC, a diagnosis of HCC may be arrived at earlier as compared with not using the LI-RADS algorithm. Earlier detection may lead to earlier intervention and improved treatment outcomes.

Limitations

Limitations to our study occurred because radiologist 3 did not review all of the images nor score them. Radiologist 3 was limited to 12 images where there was disagreement and was limited to 2 scores to choose from for each image. Further limitations include that this study was performed at a single center. Our study focused on one imaging modality and did not include ultrasounds or MRIs. We did not compare the demographics of our patients with those of other VA hospitals. The radiologists interpreted the images individually, and their subjectivity was another limitation.

Conclusion

In the MVAMC population, LI-RADS showed a good sensitivity, specificity, and diagnostic accuracy for CT surveillance scans in patient at high risk for HCC at an earlier time point than did standard evaluation by very experienced CT radiologists. Higher LI-RADS scores on surveillance CTs had good diagnostic accuracy for the probable future diagnosis of HCC, whereas lower LI-RADS scores had a good diagnostic accuracy for probable benign nodules. Utilizing the LI-RADS algorithm on all surveillance CTs in patients at high risk for HCC may lead to obtaining MRIs or follow-up CTs sooner for suspicious nodules, leading to an earlier diagnosis of HCC and possible earlier and more effective intervention.

Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer worldwide.¹ Liver cancer is the fifth most common cancer in men and the seventh in women.² The highest incidence rates are in sub-Saharan Africa and Southeast Asia where hepatitis B virus is endemic. The incidence of HCC in western countries is increasing, particularly due to the rise of hepatitis C virus (HCV) as well as alcoholic liver disease and nonalcoholic fatty liver disease. The incidence of HCC has tripled in the US in the past 2 decades.^1-3

HCC can be diagnosed by radiographic images without the need for biopsy if the typical imaging features are present.³ The European Association for the Study of Liver Disease (EASL) and the American Association for the Study of Liver Diseases (AASLD) recommend screening abdominal ultrasonography at 6-month intervals for high-risk patients.^3,4 High-risk patients include patients with cirrhosis, especially those with hepatitis B or C.³

If screening ultrasonography detects a nodule, size determines whether a follow-up ultrasound is needed vs obtaining a contrast-enhanced dynamic computed tomography (CT) scan or a magnetic resonance image (MRI).³ If ultrasonography detects a nodule > 1 cm in diameter, then a dynamic CT or MRI is performed. Characteristic hyperenhancement during later arterial phase and washout during the venous or delayed phase is associated with a nearly 100% specificity for HCC diagnosis.⁵ Arterial-enhancing contrast is required when using CT and MRI because HCC is a hypervascular lesion.⁶ The portal venous blood dilutes the majority of the liver’s arterial blood; therefore, the liver does not enhance during the arterial phase, while HCC will show maximum enhancement.⁷ Furthermore, HCC should demonstrate a “washout” of contrast during the venous phase on CT and MRI.⁴ Standard imaging protocol dictates that 4 phases are needed to properly diagnose HCC including unenhanced, arterial, venous, and delayed.⁴

Regular surveillance increases the likelihood of detecting HCC before the presentation of clinical symptoms and facilitates receipt of curative therapy.^8-10 Patients with viral hepatitis and cirrhosis with HCC found on screening are more likely to have earlier-stage disease and survive longer from the time of diagnosis.¹¹ Furthermore, it has been observed that HCC detected by surveillance is significantly more likely to undergo curative therapy compared with incidental or symptomatic detection of HCC.⁹

Technical improvements in imaging techniques include advancement in contrast agents, multidetector row helical CT, and the flexibility/range of pulse sequences available in MRI.⁷ Even with technical improvements in all modalities used in HCC imaging, detecting HCC remains difficult, especially when detecting the small (< 2 cm) lesions in a cirrhotic liver.⁷ Interpretation of imaging also remains a challenge as HCC does not always fit strict criteria: lack of “washout” in a hypervascular lesion, determining small HCC lesions from benign nodules, and hypovascular/isovascular HCC.⁵ Radiologic differentials in the diagnosis of HCC include transient hepatic intensity difference (THID)/transient hepatic attenuation difference (THAD), arterio-portal shunt, and regenerative nodules.¹² In the common clinical setting, patients undergo multiple imaging studies that are interpreted by multiple radiologists, which can add to the difficulty in the diagnosis of HCC.¹³

The radiology community recognized the inconsistencies and complexities of HCC imaging. Therefore, the American College of Radiology endorsed the Liver Imaging Reporting and Data System (LI-RADS), which had the goal of reducing variability in lesion interpretation through standardization and improving communication with clinicians.¹⁴ LI-RADS uses a diagnostic algorithm for CT and MRI that categorizes observed liver findings in high-risk individuals based on the probability or relative risk of HCC without assigning a formal diagnosis.¹⁴ LI-RADS takes into account arterial phase enhancement, tumor size, washout appearance, the presence and nature of a capsule, and threshold growth.¹⁵ LI-RADS categorizes an observed liver finding on a scale of 1 to 5, with 1 corresponding to a definitely benign finding and 5 with definitive HCC.¹⁴ Furthermore, LI-RADS sought to limit the technical variabilities among institutions.

LI-RADS was launched in 2011 and has been utilized by many clinical practices while continuing to be expanded and updated.¹⁶ Recent studies examined the specificity of LI-RADS as well as interreader variability.^17,18 For nodules viewed on MRI, both LI-RADS categories 4 and 5 had high specificity for HCC.¹⁷ When looking at interreader repeatability, LI-RADS showed moderate agreement among experts using the diagnostic algorithm.¹⁹ Further studies have compared LI-RADS with the AASLD guidelines and the Organ Procurement and Transplantation Network (OPTN) guidelines.¹⁶ When compared with other guidelines, LI-RADS expands the definition of indeterminate findings into probably benign, intermediate probability of HCC, and probably HCC, which corresponds to LI-RADS categories 2, 3, and 4.¹⁶

We looked retrospectively at a group of patients previously diagnosed with HCC to see whether utilizing the LI-RADS scoring system within our screening system might have allowed an earlier prediction of HCC and a timelier intervention. Prior to this investigation the LI-RADS system was not used for HCC screening at our US Department of Veterans Affairs (VA) facility. We examined screened patients at the Memphis VA Medical Center (MVAMC) in Tennessee who were subsequently diagnosed with HCC to see which LI-RADS category the last surveillance CT prior to diagnosis would fall into, 6 months to a year prior to the diagnosis of HCC. Our control population was a group of patients screened with CT for their liver nodules who were found not to have HCC.

Methods

Patients at MVAMC with cirrhosis and patients with chronic hepatitis B are routinely screened with ultrasound, CT, or MRI in accordance with the AASLD, EASL, and VA guidelines. Of 303 patients with HCV and cirrhosis under care in 2015, 242 (81%) received imaging to screen for HCC according to the VA National Hepatitis C Registry 2015 (Personal Communication, Population Health Service, Office of Patient Care Services).The LI-RADS scoring system was not applied as a standard screening methodology.

Under an institutional review board-approved protocol, we reviewed the charts of all patients diagnosed with HCC at MVAMC from 2009 to 2014, utilizing ICD-9 code of 155.0 for HCC. We identified within these charts patients who had a surveillance CT image performed within a 6- to 13-month period prior to the CTs that diagnosed HCC (prediagnostic HCC CT). Furthermore, we reviewed the charts of all patients diagnosed with benign liver nodules at MVAMC from 2009 to 2014, utilizing the ICD-9 code of 573.8 for other specified disorders of the liver.

Within these charts, we found patients who had a surveillance CT image performed and who were followed after that image with additional imaging for ≥ 2 years or who had a liver biopsy negative for HCC (benign surveillance CT). We compared these 2 sets of CTs utilizing LI-RADS criteria. Once these patients were identified, a list of the CTs to be examined were given to 2 MVAMC radiologists who specialize in CT.

No identifying information of the patients was included, and a 13-digit number unique to each CT exam identified the CTs to be reviewed. Radiologist 1 and 2 examined the CTs on the MVAMC Picture Archiving and Communication System (PACS). Both radiologists were asked to give each nodule a score according to LI-RADS v2014 diagnostic algorithm (Figure).

We hypothesized that the prediagnostic CT images of patients eventually determined to have HCC would have a LI-RADS score of 4 (LR4) or LR5. Furthermore, we hypothesized that the CT images of the benign liver nodule patients would have a score ≤ LR3. If there was a disagreement between the radiologists in terms of a malignant score (LR4 or LR5) vs a benign score (≤ LR3), then a third radiologist (radiologist 3) provided a score for these nodules. The third, tiebreaker radiologist was given the scores of both prior radiologists and asked to choose which score was correct.

Statistical analysis was then applied to the data to determine the sensitivity, specificity, and diagnostic accuracy in diagnosing eventual HCC, as well as the false-negative and false-positive rates of radiologists 1 and 2. Raw data also were used to determine the agreement between raters by calculating the κ statistic with a 95% CI.

Results

A total of 70 nodules were examined by radiologists 1 and 2 with 42 of the nodules in the prediagnostic HCC CTs and 28 of the nodules in the benign surveillance CTs. 

Radiologist 1 identified 11 patients with LR4 and 21 patients with LR5. His scores showed a sensitivity of 64.3% and specificity of 82.1% with accuracy of 71.4% for LI-RADS in identifying eventual HCC. The false-negative rate of the LI-RADS diagnostic algorithm for radiologist 1 was 35.7% and the false-positive rate was 17.9%. Radiologist 2 identified 17 patients LR4 and 19 patients with LR5. Radiologist 2’s scores showed a sensitivity of 69.0% and specificity of 75.0% with accuracy of 71.4% for LI-RADS in identifying eventual HCC.The false-negative rate of the LI-RADS diagnostic algorithm for radiologist 2 was 31.0% and false-positive rate of 25.0%. The κ statistic was calculated to determine the interrater agreement. The radiologists agreed on 58 of 70 samples; 15 without HCC and 43 with HCC. The κ statistic was 0.592, which indicates moderate agreement (Table 2). 

Discussion

If HCC is diagnosed late in the disease process based on symptomatology and not on surveillance imaging, the likelihood of receiving early and potential curative therapy greatly declines as was shown in a systemic literature review.⁹ Surveillance imaging and lesion interpretation by various radiologists has been difficult to standardize as new technologic advances continue to occur in the imaging of HCC.¹⁴ LI-RADS was initiated to help standardize CT and MRI interpretation and reporting of hepatic nodules. As a dynamic algorithm, it continues to adjust with new advances in imaging techniques with the most recent updates being made to the algorithm in 2014.^14,19 LI-RADS applies to patients at high risk for HCC most often who are already enrolled in a surveillance program.¹⁹ The MVAMC has a high incidence of patients with cirrhosis who are at risk for HCC, which is why we chose it as our study population.

LI-RADS can be applied to both MRI and CT imaging. Much of the recent literature have looked at LI-RADS in terms of MRI. A group in China looked at 100 pathologically confirmed patients and assigned a LI-RADS score to the MRI at the time of diagnosis and showed that MRI LI-RADS scoring was highly sensitive and specific in the diagnosis of HCC.²⁰ This study did note a numeric difference in the specificity of LI-RADS algorithm depending on how LR3 scores were viewed. If a LR3 score was considered negative rather than positive for HCC, then the specificity increased by almost 20%.²⁰

Another study looked at patients with liver nodules ≤ 20 mm found on ultrasound and obtained MRIs and biopsies on these patients, assigning the MRI a LI-RADs score.¹⁷ Darnell and colleagues found that MRI LR4 and LR5 have a high specificity for HCC. However, 29 of the 42 LR3 lesions examined were found to be HCC.¹⁷ Furthermore, Choi and colleagues retrospectively looked at patients in a HCC surveillance program who had undergone MRI as part of the program and assigned LI-RADS scores to these MRIs.²¹ Their study showed that LR5 criteria on gadoxetate disodium-enhanced MRI has excellent positive predictive value (PPV) for diagnosing HCC, and LR4 showed good PPV.²¹

In our study, we chose to look at LI-RADS in terms of surveillance CT scans 6 to 13 months prior to the diagnosis of HCC to see whether this method would allow us to intervene earlier with more aggressive diagnostics or therapy in those suspected of having HCC. Although Choi and colleagues looked retrospectively at MRI surveillance imaging, most of the prior studies have looked at LI-RADS scoring in imaging at the time of diagnosis.^17,20,21 By looking at surveillance CT scans, we sought to determine LI-RADS sensitivity, specificity, and diagnostic accuracy as a screening tool compared with CT evaluations without LI-RADS scoring.

We also chose to look at CT scans since most of the prior studies have looked at the more detailed and often more expensive MRIs. For both radiologists 1 and 2, the sensitivity was > 60% and specificity was > 70% with a diagnostic accuracy of 71.4% in predicting a diagnosis of HCC in future scans. Although there was high false negative of > 30% for both radiologists, we did consider LR3 as negative for HCC. As Darnell and colleagues’ study of MRI LI-RADS shows, LR3 may need to be revised in the future as its ambiguity can lead to false-negatives.¹⁷ Our results also showed moderate interreader agreement, which has been seen in previous studies with LI-RADS.¹⁸

Some studies have compared MRI with CT imaging in terms of LI-RADs classification of hepatic nodules to find out whether concordance was seen.^22,23 Both studies found that there was substantial discordance between MRI and CT with CT often underscoring hepatic nodules.^22,23 In Zhang and colleagues, interclass agreement between CT and MRI varied the most in terms of arterial enhancement with CT producing false-negative findings.²² CT also underestimated LI-RADS score by 16.9% for LR3, 37.3% for LR4, and 8.5% for LR5 in this study.²² Furthermore, Corwin and colleagues found a significant upgrade in terms of LI-RADS categorization with MRI for 42.5% of observations.²³ In this study, upgraded LI-RADS scores on MRI included 2 upgraded to LR5V (Figure), 15 upgraded to LR5, and 12 upgraded to LR4.²³ 

Our study shows that the LI-RADS algorithm has a good sensitivity, specificity, and diagnostic accuracy as a screening tool, predicting HCC in scans earlier than standard CT evaluation. In our study, the patients with HCC were shown to have higher LI-RADS scores on prediagnostic imaging, while the benign liver nodule patients were shown to have lower LI-RADS scores. This data would suggest that a LI-RADS score given to surveillance CT of LR4 or higher should recommend either a biopsy or follow-up imaging after a short interval. If LI-RADS is applied to surveillance CTs in patients at risk for HCC, a diagnosis of HCC may be arrived at earlier as compared with not using the LI-RADS algorithm. Earlier detection may lead to earlier intervention and improved treatment outcomes.

Limitations

Limitations to our study occurred because radiologist 3 did not review all of the images nor score them. Radiologist 3 was limited to 12 images where there was disagreement and was limited to 2 scores to choose from for each image. Further limitations include that this study was performed at a single center. Our study focused on one imaging modality and did not include ultrasounds or MRIs. We did not compare the demographics of our patients with those of other VA hospitals. The radiologists interpreted the images individually, and their subjectivity was another limitation.

Conclusion

In the MVAMC population, LI-RADS showed a good sensitivity, specificity, and diagnostic accuracy for CT surveillance scans in patient at high risk for HCC at an earlier time point than did standard evaluation by very experienced CT radiologists. Higher LI-RADS scores on surveillance CTs had good diagnostic accuracy for the probable future diagnosis of HCC, whereas lower LI-RADS scores had a good diagnostic accuracy for probable benign nodules. Utilizing the LI-RADS algorithm on all surveillance CTs in patients at high risk for HCC may lead to obtaining MRIs or follow-up CTs sooner for suspicious nodules, leading to an earlier diagnosis of HCC and possible earlier and more effective intervention.

Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer worldwide.¹ Liver cancer is the fifth most common cancer in men and the seventh in women.² The highest incidence rates are in sub-Saharan Africa and Southeast Asia where hepatitis B virus is endemic. The incidence of HCC in western countries is increasing, particularly due to the rise of hepatitis C virus (HCV) as well as alcoholic liver disease and nonalcoholic fatty liver disease. The incidence of HCC has tripled in the US in the past 2 decades.^1-3

HCC can be diagnosed by radiographic images without the need for biopsy if the typical imaging features are present.³ The European Association for the Study of Liver Disease (EASL) and the American Association for the Study of Liver Diseases (AASLD) recommend screening abdominal ultrasonography at 6-month intervals for high-risk patients.^3,4 High-risk patients include patients with cirrhosis, especially those with hepatitis B or C.³

If screening ultrasonography detects a nodule, size determines whether a follow-up ultrasound is needed vs obtaining a contrast-enhanced dynamic computed tomography (CT) scan or a magnetic resonance image (MRI).³ If ultrasonography detects a nodule > 1 cm in diameter, then a dynamic CT or MRI is performed. Characteristic hyperenhancement during later arterial phase and washout during the venous or delayed phase is associated with a nearly 100% specificity for HCC diagnosis.⁵ Arterial-enhancing contrast is required when using CT and MRI because HCC is a hypervascular lesion.⁶ The portal venous blood dilutes the majority of the liver’s arterial blood; therefore, the liver does not enhance during the arterial phase, while HCC will show maximum enhancement.⁷ Furthermore, HCC should demonstrate a “washout” of contrast during the venous phase on CT and MRI.⁴ Standard imaging protocol dictates that 4 phases are needed to properly diagnose HCC including unenhanced, arterial, venous, and delayed.⁴

Regular surveillance increases the likelihood of detecting HCC before the presentation of clinical symptoms and facilitates receipt of curative therapy.^8-10 Patients with viral hepatitis and cirrhosis with HCC found on screening are more likely to have earlier-stage disease and survive longer from the time of diagnosis.¹¹ Furthermore, it has been observed that HCC detected by surveillance is significantly more likely to undergo curative therapy compared with incidental or symptomatic detection of HCC.⁹

Technical improvements in imaging techniques include advancement in contrast agents, multidetector row helical CT, and the flexibility/range of pulse sequences available in MRI.⁷ Even with technical improvements in all modalities used in HCC imaging, detecting HCC remains difficult, especially when detecting the small (< 2 cm) lesions in a cirrhotic liver.⁷ Interpretation of imaging also remains a challenge as HCC does not always fit strict criteria: lack of “washout” in a hypervascular lesion, determining small HCC lesions from benign nodules, and hypovascular/isovascular HCC.⁵ Radiologic differentials in the diagnosis of HCC include transient hepatic intensity difference (THID)/transient hepatic attenuation difference (THAD), arterio-portal shunt, and regenerative nodules.¹² In the common clinical setting, patients undergo multiple imaging studies that are interpreted by multiple radiologists, which can add to the difficulty in the diagnosis of HCC.¹³

The radiology community recognized the inconsistencies and complexities of HCC imaging. Therefore, the American College of Radiology endorsed the Liver Imaging Reporting and Data System (LI-RADS), which had the goal of reducing variability in lesion interpretation through standardization and improving communication with clinicians.¹⁴ LI-RADS uses a diagnostic algorithm for CT and MRI that categorizes observed liver findings in high-risk individuals based on the probability or relative risk of HCC without assigning a formal diagnosis.¹⁴ LI-RADS takes into account arterial phase enhancement, tumor size, washout appearance, the presence and nature of a capsule, and threshold growth.¹⁵ LI-RADS categorizes an observed liver finding on a scale of 1 to 5, with 1 corresponding to a definitely benign finding and 5 with definitive HCC.¹⁴ Furthermore, LI-RADS sought to limit the technical variabilities among institutions.

LI-RADS was launched in 2011 and has been utilized by many clinical practices while continuing to be expanded and updated.¹⁶ Recent studies examined the specificity of LI-RADS as well as interreader variability.^17,18 For nodules viewed on MRI, both LI-RADS categories 4 and 5 had high specificity for HCC.¹⁷ When looking at interreader repeatability, LI-RADS showed moderate agreement among experts using the diagnostic algorithm.¹⁹ Further studies have compared LI-RADS with the AASLD guidelines and the Organ Procurement and Transplantation Network (OPTN) guidelines.¹⁶ When compared with other guidelines, LI-RADS expands the definition of indeterminate findings into probably benign, intermediate probability of HCC, and probably HCC, which corresponds to LI-RADS categories 2, 3, and 4.¹⁶

We looked retrospectively at a group of patients previously diagnosed with HCC to see whether utilizing the LI-RADS scoring system within our screening system might have allowed an earlier prediction of HCC and a timelier intervention. Prior to this investigation the LI-RADS system was not used for HCC screening at our US Department of Veterans Affairs (VA) facility. We examined screened patients at the Memphis VA Medical Center (MVAMC) in Tennessee who were subsequently diagnosed with HCC to see which LI-RADS category the last surveillance CT prior to diagnosis would fall into, 6 months to a year prior to the diagnosis of HCC. Our control population was a group of patients screened with CT for their liver nodules who were found not to have HCC.

Methods

Patients at MVAMC with cirrhosis and patients with chronic hepatitis B are routinely screened with ultrasound, CT, or MRI in accordance with the AASLD, EASL, and VA guidelines. Of 303 patients with HCV and cirrhosis under care in 2015, 242 (81%) received imaging to screen for HCC according to the VA National Hepatitis C Registry 2015 (Personal Communication, Population Health Service, Office of Patient Care Services).The LI-RADS scoring system was not applied as a standard screening methodology.

Under an institutional review board-approved protocol, we reviewed the charts of all patients diagnosed with HCC at MVAMC from 2009 to 2014, utilizing ICD-9 code of 155.0 for HCC. We identified within these charts patients who had a surveillance CT image performed within a 6- to 13-month period prior to the CTs that diagnosed HCC (prediagnostic HCC CT). Furthermore, we reviewed the charts of all patients diagnosed with benign liver nodules at MVAMC from 2009 to 2014, utilizing the ICD-9 code of 573.8 for other specified disorders of the liver.

Within these charts, we found patients who had a surveillance CT image performed and who were followed after that image with additional imaging for ≥ 2 years or who had a liver biopsy negative for HCC (benign surveillance CT). We compared these 2 sets of CTs utilizing LI-RADS criteria. Once these patients were identified, a list of the CTs to be examined were given to 2 MVAMC radiologists who specialize in CT.

No identifying information of the patients was included, and a 13-digit number unique to each CT exam identified the CTs to be reviewed. Radiologist 1 and 2 examined the CTs on the MVAMC Picture Archiving and Communication System (PACS). Both radiologists were asked to give each nodule a score according to LI-RADS v2014 diagnostic algorithm (Figure).

We hypothesized that the prediagnostic CT images of patients eventually determined to have HCC would have a LI-RADS score of 4 (LR4) or LR5. Furthermore, we hypothesized that the CT images of the benign liver nodule patients would have a score ≤ LR3. If there was a disagreement between the radiologists in terms of a malignant score (LR4 or LR5) vs a benign score (≤ LR3), then a third radiologist (radiologist 3) provided a score for these nodules. The third, tiebreaker radiologist was given the scores of both prior radiologists and asked to choose which score was correct.

Statistical analysis was then applied to the data to determine the sensitivity, specificity, and diagnostic accuracy in diagnosing eventual HCC, as well as the false-negative and false-positive rates of radiologists 1 and 2. Raw data also were used to determine the agreement between raters by calculating the κ statistic with a 95% CI.

Results

A total of 70 nodules were examined by radiologists 1 and 2 with 42 of the nodules in the prediagnostic HCC CTs and 28 of the nodules in the benign surveillance CTs. 

Radiologist 1 identified 11 patients with LR4 and 21 patients with LR5. His scores showed a sensitivity of 64.3% and specificity of 82.1% with accuracy of 71.4% for LI-RADS in identifying eventual HCC. The false-negative rate of the LI-RADS diagnostic algorithm for radiologist 1 was 35.7% and the false-positive rate was 17.9%. Radiologist 2 identified 17 patients LR4 and 19 patients with LR5. Radiologist 2’s scores showed a sensitivity of 69.0% and specificity of 75.0% with accuracy of 71.4% for LI-RADS in identifying eventual HCC.The false-negative rate of the LI-RADS diagnostic algorithm for radiologist 2 was 31.0% and false-positive rate of 25.0%. The κ statistic was calculated to determine the interrater agreement. The radiologists agreed on 58 of 70 samples; 15 without HCC and 43 with HCC. The κ statistic was 0.592, which indicates moderate agreement (Table 2). 

Discussion

If HCC is diagnosed late in the disease process based on symptomatology and not on surveillance imaging, the likelihood of receiving early and potential curative therapy greatly declines as was shown in a systemic literature review.⁹ Surveillance imaging and lesion interpretation by various radiologists has been difficult to standardize as new technologic advances continue to occur in the imaging of HCC.¹⁴ LI-RADS was initiated to help standardize CT and MRI interpretation and reporting of hepatic nodules. As a dynamic algorithm, it continues to adjust with new advances in imaging techniques with the most recent updates being made to the algorithm in 2014.^14,19 LI-RADS applies to patients at high risk for HCC most often who are already enrolled in a surveillance program.¹⁹ The MVAMC has a high incidence of patients with cirrhosis who are at risk for HCC, which is why we chose it as our study population.

LI-RADS can be applied to both MRI and CT imaging. Much of the recent literature have looked at LI-RADS in terms of MRI. A group in China looked at 100 pathologically confirmed patients and assigned a LI-RADS score to the MRI at the time of diagnosis and showed that MRI LI-RADS scoring was highly sensitive and specific in the diagnosis of HCC.²⁰ This study did note a numeric difference in the specificity of LI-RADS algorithm depending on how LR3 scores were viewed. If a LR3 score was considered negative rather than positive for HCC, then the specificity increased by almost 20%.²⁰

Another study looked at patients with liver nodules ≤ 20 mm found on ultrasound and obtained MRIs and biopsies on these patients, assigning the MRI a LI-RADs score.¹⁷ Darnell and colleagues found that MRI LR4 and LR5 have a high specificity for HCC. However, 29 of the 42 LR3 lesions examined were found to be HCC.¹⁷ Furthermore, Choi and colleagues retrospectively looked at patients in a HCC surveillance program who had undergone MRI as part of the program and assigned LI-RADS scores to these MRIs.²¹ Their study showed that LR5 criteria on gadoxetate disodium-enhanced MRI has excellent positive predictive value (PPV) for diagnosing HCC, and LR4 showed good PPV.²¹

In our study, we chose to look at LI-RADS in terms of surveillance CT scans 6 to 13 months prior to the diagnosis of HCC to see whether this method would allow us to intervene earlier with more aggressive diagnostics or therapy in those suspected of having HCC. Although Choi and colleagues looked retrospectively at MRI surveillance imaging, most of the prior studies have looked at LI-RADS scoring in imaging at the time of diagnosis.^17,20,21 By looking at surveillance CT scans, we sought to determine LI-RADS sensitivity, specificity, and diagnostic accuracy as a screening tool compared with CT evaluations without LI-RADS scoring.

We also chose to look at CT scans since most of the prior studies have looked at the more detailed and often more expensive MRIs. For both radiologists 1 and 2, the sensitivity was > 60% and specificity was > 70% with a diagnostic accuracy of 71.4% in predicting a diagnosis of HCC in future scans. Although there was high false negative of > 30% for both radiologists, we did consider LR3 as negative for HCC. As Darnell and colleagues’ study of MRI LI-RADS shows, LR3 may need to be revised in the future as its ambiguity can lead to false-negatives.¹⁷ Our results also showed moderate interreader agreement, which has been seen in previous studies with LI-RADS.¹⁸

Some studies have compared MRI with CT imaging in terms of LI-RADs classification of hepatic nodules to find out whether concordance was seen.^22,23 Both studies found that there was substantial discordance between MRI and CT with CT often underscoring hepatic nodules.^22,23 In Zhang and colleagues, interclass agreement between CT and MRI varied the most in terms of arterial enhancement with CT producing false-negative findings.²² CT also underestimated LI-RADS score by 16.9% for LR3, 37.3% for LR4, and 8.5% for LR5 in this study.²² Furthermore, Corwin and colleagues found a significant upgrade in terms of LI-RADS categorization with MRI for 42.5% of observations.²³ In this study, upgraded LI-RADS scores on MRI included 2 upgraded to LR5V (Figure), 15 upgraded to LR5, and 12 upgraded to LR4.²³ 

Our study shows that the LI-RADS algorithm has a good sensitivity, specificity, and diagnostic accuracy as a screening tool, predicting HCC in scans earlier than standard CT evaluation. In our study, the patients with HCC were shown to have higher LI-RADS scores on prediagnostic imaging, while the benign liver nodule patients were shown to have lower LI-RADS scores. This data would suggest that a LI-RADS score given to surveillance CT of LR4 or higher should recommend either a biopsy or follow-up imaging after a short interval. If LI-RADS is applied to surveillance CTs in patients at risk for HCC, a diagnosis of HCC may be arrived at earlier as compared with not using the LI-RADS algorithm. Earlier detection may lead to earlier intervention and improved treatment outcomes.

Limitations

Limitations to our study occurred because radiologist 3 did not review all of the images nor score them. Radiologist 3 was limited to 12 images where there was disagreement and was limited to 2 scores to choose from for each image. Further limitations include that this study was performed at a single center. Our study focused on one imaging modality and did not include ultrasounds or MRIs. We did not compare the demographics of our patients with those of other VA hospitals. The radiologists interpreted the images individually, and their subjectivity was another limitation.

Conclusion

In the MVAMC population, LI-RADS showed a good sensitivity, specificity, and diagnostic accuracy for CT surveillance scans in patient at high risk for HCC at an earlier time point than did standard evaluation by very experienced CT radiologists. Higher LI-RADS scores on surveillance CTs had good diagnostic accuracy for the probable future diagnosis of HCC, whereas lower LI-RADS scores had a good diagnostic accuracy for probable benign nodules. Utilizing the LI-RADS algorithm on all surveillance CTs in patients at high risk for HCC may lead to obtaining MRIs or follow-up CTs sooner for suspicious nodules, leading to an earlier diagnosis of HCC and possible earlier and more effective intervention.

The US Food and Drug Administration (FDA) issued an emergency use authorization on May 1 for remdesivir for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease.

The investigational antiviral drug, manufactured by Gilead Sciences Inc., was shown in a preliminary analysis of a National Institutes of Health (NIH) clinical trial to shorten recovery time in some patients, according to information presented during a White House press conference earlier this week. However, the results of the trial have not been published and little is known about how safe and effective it is in treating people in the hospital with COVID-19.

The emergency use authorization (EUA) designation means remdesivir can be distributed in the United States and administered intravenously by healthcare providers, as appropriate to treat severe disease. Those with severe disease, the FDA said in a press release, are patients with low blood oxygen levels or those who need oxygen therapy or more intensive support such as a mechanical ventilator.

“There’s tremendous interest among all parties to identify and arm ourselves with medicines to combat COVID-19, and through our Coronavirus Treatment Acceleration Program, the FDA is working around-the-clock and using every tool at our disposal to speed these efforts,” FDA Commissioner Stephen M. Hahn, MD, said in a statement.

The FDA writes, “Based on evaluation of the emergency use authorization criteria and the scientific evidence available, it was determined that it is reasonable to believe that remdesivir may be effective in treating COVID-19, and that, given there are no adequate, approved, or available alternative treatments, the known and potential benefits to treat this serious or life-threatening virus currently outweigh the known and potential risks of the drug’s use.”

The drug must be administered intravenously and the optimal dosing and duration are not yet known, the company said in a press release issued May 1.

In addition, Gilead advises that infusion-related reactions and liver transaminase elevations have been seen in patients treated with the drug.

“If signs and symptoms of a clinically significant infusion reaction occur, immediately discontinue administration of remdesivir and initiate appropriate treatment. Patients should have appropriate clinical and laboratory monitoring to aid in early detection of any potential adverse events. Monitor renal and hepatic function prior to initiating and daily during therapy with remdesivir; additionally monitor serum chemistries and hematology daily during therapy,” the company said.

Before granting the emergency use authorization, the FDA had allowed for study of the drug in clinical trials, as well as expanded access use for individual patients and through a multipatient expanded access program coordinated by Gilead.

“The EUA will be effective until the declaration that circumstances exist justifying the authorization of the emergency use of drugs and biologics for prevention and treatment of COVID-19 is terminated and may be revised or revoked if it is determined the EUA no longer meets the statutory criteria for issuance,” the FDA said.


This article first appeared on Medscape.com.

The US Food and Drug Administration (FDA) issued an emergency use authorization on May 1 for remdesivir for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease.

The investigational antiviral drug, manufactured by Gilead Sciences Inc., was shown in a preliminary analysis of a National Institutes of Health (NIH) clinical trial to shorten recovery time in some patients, according to information presented during a White House press conference earlier this week. However, the results of the trial have not been published and little is known about how safe and effective it is in treating people in the hospital with COVID-19.

The emergency use authorization (EUA) designation means remdesivir can be distributed in the United States and administered intravenously by healthcare providers, as appropriate to treat severe disease. Those with severe disease, the FDA said in a press release, are patients with low blood oxygen levels or those who need oxygen therapy or more intensive support such as a mechanical ventilator.

“There’s tremendous interest among all parties to identify and arm ourselves with medicines to combat COVID-19, and through our Coronavirus Treatment Acceleration Program, the FDA is working around-the-clock and using every tool at our disposal to speed these efforts,” FDA Commissioner Stephen M. Hahn, MD, said in a statement.

The FDA writes, “Based on evaluation of the emergency use authorization criteria and the scientific evidence available, it was determined that it is reasonable to believe that remdesivir may be effective in treating COVID-19, and that, given there are no adequate, approved, or available alternative treatments, the known and potential benefits to treat this serious or life-threatening virus currently outweigh the known and potential risks of the drug’s use.”

The drug must be administered intravenously and the optimal dosing and duration are not yet known, the company said in a press release issued May 1.

In addition, Gilead advises that infusion-related reactions and liver transaminase elevations have been seen in patients treated with the drug.

“If signs and symptoms of a clinically significant infusion reaction occur, immediately discontinue administration of remdesivir and initiate appropriate treatment. Patients should have appropriate clinical and laboratory monitoring to aid in early detection of any potential adverse events. Monitor renal and hepatic function prior to initiating and daily during therapy with remdesivir; additionally monitor serum chemistries and hematology daily during therapy,” the company said.

Before granting the emergency use authorization, the FDA had allowed for study of the drug in clinical trials, as well as expanded access use for individual patients and through a multipatient expanded access program coordinated by Gilead.

“The EUA will be effective until the declaration that circumstances exist justifying the authorization of the emergency use of drugs and biologics for prevention and treatment of COVID-19 is terminated and may be revised or revoked if it is determined the EUA no longer meets the statutory criteria for issuance,” the FDA said.


This article first appeared on Medscape.com.

The US Food and Drug Administration (FDA) issued an emergency use authorization on May 1 for remdesivir for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease.

The investigational antiviral drug, manufactured by Gilead Sciences Inc., was shown in a preliminary analysis of a National Institutes of Health (NIH) clinical trial to shorten recovery time in some patients, according to information presented during a White House press conference earlier this week. However, the results of the trial have not been published and little is known about how safe and effective it is in treating people in the hospital with COVID-19.

The emergency use authorization (EUA) designation means remdesivir can be distributed in the United States and administered intravenously by healthcare providers, as appropriate to treat severe disease. Those with severe disease, the FDA said in a press release, are patients with low blood oxygen levels or those who need oxygen therapy or more intensive support such as a mechanical ventilator.

“There’s tremendous interest among all parties to identify and arm ourselves with medicines to combat COVID-19, and through our Coronavirus Treatment Acceleration Program, the FDA is working around-the-clock and using every tool at our disposal to speed these efforts,” FDA Commissioner Stephen M. Hahn, MD, said in a statement.

The FDA writes, “Based on evaluation of the emergency use authorization criteria and the scientific evidence available, it was determined that it is reasonable to believe that remdesivir may be effective in treating COVID-19, and that, given there are no adequate, approved, or available alternative treatments, the known and potential benefits to treat this serious or life-threatening virus currently outweigh the known and potential risks of the drug’s use.”

The drug must be administered intravenously and the optimal dosing and duration are not yet known, the company said in a press release issued May 1.

In addition, Gilead advises that infusion-related reactions and liver transaminase elevations have been seen in patients treated with the drug.

“If signs and symptoms of a clinically significant infusion reaction occur, immediately discontinue administration of remdesivir and initiate appropriate treatment. Patients should have appropriate clinical and laboratory monitoring to aid in early detection of any potential adverse events. Monitor renal and hepatic function prior to initiating and daily during therapy with remdesivir; additionally monitor serum chemistries and hematology daily during therapy,” the company said.

Before granting the emergency use authorization, the FDA had allowed for study of the drug in clinical trials, as well as expanded access use for individual patients and through a multipatient expanded access program coordinated by Gilead.

“The EUA will be effective until the declaration that circumstances exist justifying the authorization of the emergency use of drugs and biologics for prevention and treatment of COVID-19 is terminated and may be revised or revoked if it is determined the EUA no longer meets the statutory criteria for issuance,” the FDA said.


This article first appeared on Medscape.com.

Ustekinumab or a tumor necrosis factor inhibitor (TNFi) are better used alone than with methotrexate in the treatment of psoriatic arthritis suggest the results of PsABio (A Study on Assessment of STELARA and Tumor Necrosis Factor Alpha Inhibitor Therapies in Participants With Psoriatic Arthritis), a large, ongoing, prospective observational study.

The percentages of patients achieving multiple psoriatic arthritis disease activity outcome measures at 6 months were higher if biologic monotherapy was used rather than a biologic in combination with methotrexate.

For example, minimal disease activity (MDA) was achieved by 27.5% of patients taking ustekinumab as monotherapy and by 32.1% of those taking a TNFi alone. When methotrexate was used in combination, the respective percentages of patients achieving MDA were 23.7% and 27.8%.

A similar pattern was seen for very-low disease activity (VLDA), with 9.8% of patients in the ustekinumab monotherapy arm and 12% of those in the TNFi monotherapy arm achieving this target, compared with 5.7% and 5.4% when these drugs were combined with methotrexate.

MDA is defined as meeting five or more cutoffs for seven domains of disease activity, and VLDA for all seven: 0-1 tender joints, 0-1 swollen joints, Psoriasis Area Severity Index 1 or less or body surface area involved 3% or less, 0-1 tender entheseal points, Health Assessment Questionnaire score of 0.5 or less, patient global disease activity visual analog scale score of 20 or lower, and patient pain visual analog scale score of 15 or lower.

Other outcome measures used that showed no advantage of adding methotrexate to these biologics were the Clinical Disease Activity in Psoriatic Arthritis low disease activity and remission scores, the patient acceptable symptoms rate of the 12-item Psoriatic Arthritis Impact of Disease Questionnaire, and improvement in skin involvement.

“Patients were no more likely to achieve lower disease activity or a remission target having received methotrexate than they did just on the biologic drug on its own,” Stefan Siebert, MBBCh, PhD, one of the PsABio investigators, said in an interview.

Dr. Siebert, who is clinical senior lecturer in inflammation and rheumatology at the University of Glasgow (Scotland), was scheduled to present the findings at the British Society for Rheumatology annual conference. The meeting was canceled because of the ongoing COVID-19 crisis. Abstracts and ePosters from the meeting have since been released in a supplement to Rheumatology and via the BSR’s conference app.
 

First data for ustekinumab

“There certainly doesn’t appear to be any added benefit from using methotrexate on a group level in patients getting ustekinumab and TNF inhibitors,” Dr. Siebert said. “We’ve looked at everything,” he emphasized, and “none of the single domains or composite measures were improved by the addition of methotrexate. I think we knew that for TNF inhibitors, but the key thing is we’ve never known that for ustekinumab, and this is the first study to show that.”

Indeed, the findings match up with those from the SEAM-PsA (Etanercept and Methotrexate in Subjects with Psoriatic Arthritis) study in which patients who were treated with the TNFi etanercept as monotherapy did much better than those given the TNFi in combination with methotrexate or methotrexate alone. While not a randomized trial, PsABio now shows that the same is true for ustekinumab.

Obviously, there are some clear differences between a clinical trial and an observational study such as PsABio. For one thing, there was no randomization and patients taking methotrexate were presumably doing so for good reason, Dr. Siebert said. Secondly, there was no methotrexate-only arm.

PsABio recruited patients who were starting treatment with either ustekinumab or a new TNFi as first-, second-, or third-line biologic disease-modifying antirheumatic therapy (DMARD). “These are all people starting on a biologic, so they’ve already got severe disease and have failed methotrexate on some level. So everything we’ve done is biologic without methotrexate or biologic with methotrexate,” Dr. Siebert explained. Patients may not have been taking methotrexate for a variety of reasons, such as inefficacy or side effects, so PsABio “doesn’t tell us anything about methotrexate on its own.”

Time to rethink ingrained methotrexate use

The rationale for using methotrexate in combination with biologics in psoriatic arthritis comes from its long-standing use in rheumatoid arthritis. Much of what is advocated in guidelines comes from experience in RA, Dr. Siebert said.

“In rheumatoid arthritis, we know that the TNF inhibitors work much better if you use methotrexate, that’s a given,” he noted. “We’ve been trained that you have to have methotrexate to have a biologic. However, PsABio, together with other studies, show that you don’t have to, and you should have a good reason to add methotrexate.”

Individual patients may still benefit from methotrexate use, but the decision to treat all patients the same is not supported by the current evidence. “It’s good that it shows that, actually, once you get someone on a decent biologic, it’s working: It’s doing what it ‘says on the tin’ for a lot of patients. I really think that is the key message, here, that you don’t have to; this reassures clinicians and actually makes them think ‘should this patient be on methotrexate?’ ” Dr. Siebert said.

The PsABio study was funded by Janssen. Dr. Siebert has acted as a consultant to and received research funding from Janssen, UCB, Pfizer, Boehringer Ingelheim, Novartis, and Celgene. He has also acted as a consultant for AbbVie and received research support from Bristol-Myers Squibb.

SOURCE: Siebert S et al. Rheumatology. 2020;59(Suppl 2). doi: 10.1093/rheumatology/keaa110.023, Abstract O24.

Ustekinumab or a tumor necrosis factor inhibitor (TNFi) are better used alone than with methotrexate in the treatment of psoriatic arthritis suggest the results of PsABio (A Study on Assessment of STELARA and Tumor Necrosis Factor Alpha Inhibitor Therapies in Participants With Psoriatic Arthritis), a large, ongoing, prospective observational study.

The percentages of patients achieving multiple psoriatic arthritis disease activity outcome measures at 6 months were higher if biologic monotherapy was used rather than a biologic in combination with methotrexate.

For example, minimal disease activity (MDA) was achieved by 27.5% of patients taking ustekinumab as monotherapy and by 32.1% of those taking a TNFi alone. When methotrexate was used in combination, the respective percentages of patients achieving MDA were 23.7% and 27.8%.

A similar pattern was seen for very-low disease activity (VLDA), with 9.8% of patients in the ustekinumab monotherapy arm and 12% of those in the TNFi monotherapy arm achieving this target, compared with 5.7% and 5.4% when these drugs were combined with methotrexate.

MDA is defined as meeting five or more cutoffs for seven domains of disease activity, and VLDA for all seven: 0-1 tender joints, 0-1 swollen joints, Psoriasis Area Severity Index 1 or less or body surface area involved 3% or less, 0-1 tender entheseal points, Health Assessment Questionnaire score of 0.5 or less, patient global disease activity visual analog scale score of 20 or lower, and patient pain visual analog scale score of 15 or lower.

Other outcome measures used that showed no advantage of adding methotrexate to these biologics were the Clinical Disease Activity in Psoriatic Arthritis low disease activity and remission scores, the patient acceptable symptoms rate of the 12-item Psoriatic Arthritis Impact of Disease Questionnaire, and improvement in skin involvement.

“Patients were no more likely to achieve lower disease activity or a remission target having received methotrexate than they did just on the biologic drug on its own,” Stefan Siebert, MBBCh, PhD, one of the PsABio investigators, said in an interview.

Dr. Siebert, who is clinical senior lecturer in inflammation and rheumatology at the University of Glasgow (Scotland), was scheduled to present the findings at the British Society for Rheumatology annual conference. The meeting was canceled because of the ongoing COVID-19 crisis. Abstracts and ePosters from the meeting have since been released in a supplement to Rheumatology and via the BSR’s conference app.
 

First data for ustekinumab

“There certainly doesn’t appear to be any added benefit from using methotrexate on a group level in patients getting ustekinumab and TNF inhibitors,” Dr. Siebert said. “We’ve looked at everything,” he emphasized, and “none of the single domains or composite measures were improved by the addition of methotrexate. I think we knew that for TNF inhibitors, but the key thing is we’ve never known that for ustekinumab, and this is the first study to show that.”

Indeed, the findings match up with those from the SEAM-PsA (Etanercept and Methotrexate in Subjects with Psoriatic Arthritis) study in which patients who were treated with the TNFi etanercept as monotherapy did much better than those given the TNFi in combination with methotrexate or methotrexate alone. While not a randomized trial, PsABio now shows that the same is true for ustekinumab.

Obviously, there are some clear differences between a clinical trial and an observational study such as PsABio. For one thing, there was no randomization and patients taking methotrexate were presumably doing so for good reason, Dr. Siebert said. Secondly, there was no methotrexate-only arm.

PsABio recruited patients who were starting treatment with either ustekinumab or a new TNFi as first-, second-, or third-line biologic disease-modifying antirheumatic therapy (DMARD). “These are all people starting on a biologic, so they’ve already got severe disease and have failed methotrexate on some level. So everything we’ve done is biologic without methotrexate or biologic with methotrexate,” Dr. Siebert explained. Patients may not have been taking methotrexate for a variety of reasons, such as inefficacy or side effects, so PsABio “doesn’t tell us anything about methotrexate on its own.”

Time to rethink ingrained methotrexate use

The rationale for using methotrexate in combination with biologics in psoriatic arthritis comes from its long-standing use in rheumatoid arthritis. Much of what is advocated in guidelines comes from experience in RA, Dr. Siebert said.

“In rheumatoid arthritis, we know that the TNF inhibitors work much better if you use methotrexate, that’s a given,” he noted. “We’ve been trained that you have to have methotrexate to have a biologic. However, PsABio, together with other studies, show that you don’t have to, and you should have a good reason to add methotrexate.”

Individual patients may still benefit from methotrexate use, but the decision to treat all patients the same is not supported by the current evidence. “It’s good that it shows that, actually, once you get someone on a decent biologic, it’s working: It’s doing what it ‘says on the tin’ for a lot of patients. I really think that is the key message, here, that you don’t have to; this reassures clinicians and actually makes them think ‘should this patient be on methotrexate?’ ” Dr. Siebert said.

The PsABio study was funded by Janssen. Dr. Siebert has acted as a consultant to and received research funding from Janssen, UCB, Pfizer, Boehringer Ingelheim, Novartis, and Celgene. He has also acted as a consultant for AbbVie and received research support from Bristol-Myers Squibb.

SOURCE: Siebert S et al. Rheumatology. 2020;59(Suppl 2). doi: 10.1093/rheumatology/keaa110.023, Abstract O24.

Ustekinumab or a tumor necrosis factor inhibitor (TNFi) are better used alone than with methotrexate in the treatment of psoriatic arthritis suggest the results of PsABio (A Study on Assessment of STELARA and Tumor Necrosis Factor Alpha Inhibitor Therapies in Participants With Psoriatic Arthritis), a large, ongoing, prospective observational study.

The percentages of patients achieving multiple psoriatic arthritis disease activity outcome measures at 6 months were higher if biologic monotherapy was used rather than a biologic in combination with methotrexate.

For example, minimal disease activity (MDA) was achieved by 27.5% of patients taking ustekinumab as monotherapy and by 32.1% of those taking a TNFi alone. When methotrexate was used in combination, the respective percentages of patients achieving MDA were 23.7% and 27.8%.

A similar pattern was seen for very-low disease activity (VLDA), with 9.8% of patients in the ustekinumab monotherapy arm and 12% of those in the TNFi monotherapy arm achieving this target, compared with 5.7% and 5.4% when these drugs were combined with methotrexate.

MDA is defined as meeting five or more cutoffs for seven domains of disease activity, and VLDA for all seven: 0-1 tender joints, 0-1 swollen joints, Psoriasis Area Severity Index 1 or less or body surface area involved 3% or less, 0-1 tender entheseal points, Health Assessment Questionnaire score of 0.5 or less, patient global disease activity visual analog scale score of 20 or lower, and patient pain visual analog scale score of 15 or lower.

Other outcome measures used that showed no advantage of adding methotrexate to these biologics were the Clinical Disease Activity in Psoriatic Arthritis low disease activity and remission scores, the patient acceptable symptoms rate of the 12-item Psoriatic Arthritis Impact of Disease Questionnaire, and improvement in skin involvement.

“Patients were no more likely to achieve lower disease activity or a remission target having received methotrexate than they did just on the biologic drug on its own,” Stefan Siebert, MBBCh, PhD, one of the PsABio investigators, said in an interview.

Dr. Siebert, who is clinical senior lecturer in inflammation and rheumatology at the University of Glasgow (Scotland), was scheduled to present the findings at the British Society for Rheumatology annual conference. The meeting was canceled because of the ongoing COVID-19 crisis. Abstracts and ePosters from the meeting have since been released in a supplement to Rheumatology and via the BSR’s conference app.
 

First data for ustekinumab

“There certainly doesn’t appear to be any added benefit from using methotrexate on a group level in patients getting ustekinumab and TNF inhibitors,” Dr. Siebert said. “We’ve looked at everything,” he emphasized, and “none of the single domains or composite measures were improved by the addition of methotrexate. I think we knew that for TNF inhibitors, but the key thing is we’ve never known that for ustekinumab, and this is the first study to show that.”

Indeed, the findings match up with those from the SEAM-PsA (Etanercept and Methotrexate in Subjects with Psoriatic Arthritis) study in which patients who were treated with the TNFi etanercept as monotherapy did much better than those given the TNFi in combination with methotrexate or methotrexate alone. While not a randomized trial, PsABio now shows that the same is true for ustekinumab.

Obviously, there are some clear differences between a clinical trial and an observational study such as PsABio. For one thing, there was no randomization and patients taking methotrexate were presumably doing so for good reason, Dr. Siebert said. Secondly, there was no methotrexate-only arm.

PsABio recruited patients who were starting treatment with either ustekinumab or a new TNFi as first-, second-, or third-line biologic disease-modifying antirheumatic therapy (DMARD). “These are all people starting on a biologic, so they’ve already got severe disease and have failed methotrexate on some level. So everything we’ve done is biologic without methotrexate or biologic with methotrexate,” Dr. Siebert explained. Patients may not have been taking methotrexate for a variety of reasons, such as inefficacy or side effects, so PsABio “doesn’t tell us anything about methotrexate on its own.”

Time to rethink ingrained methotrexate use

The rationale for using methotrexate in combination with biologics in psoriatic arthritis comes from its long-standing use in rheumatoid arthritis. Much of what is advocated in guidelines comes from experience in RA, Dr. Siebert said.

“In rheumatoid arthritis, we know that the TNF inhibitors work much better if you use methotrexate, that’s a given,” he noted. “We’ve been trained that you have to have methotrexate to have a biologic. However, PsABio, together with other studies, show that you don’t have to, and you should have a good reason to add methotrexate.”

Individual patients may still benefit from methotrexate use, but the decision to treat all patients the same is not supported by the current evidence. “It’s good that it shows that, actually, once you get someone on a decent biologic, it’s working: It’s doing what it ‘says on the tin’ for a lot of patients. I really think that is the key message, here, that you don’t have to; this reassures clinicians and actually makes them think ‘should this patient be on methotrexate?’ ” Dr. Siebert said.

The PsABio study was funded by Janssen. Dr. Siebert has acted as a consultant to and received research funding from Janssen, UCB, Pfizer, Boehringer Ingelheim, Novartis, and Celgene. He has also acted as a consultant for AbbVie and received research support from Bristol-Myers Squibb.

SOURCE: Siebert S et al. Rheumatology. 2020;59(Suppl 2). doi: 10.1093/rheumatology/keaa110.023, Abstract O24.

Physicians who are conducting telephone visits during the COVID-19 pandemic will be paid at a higher rate, more closely aligning the rates with payments for face-to-face visits.

On April 30, officials at the Centers for Medicare & Medicaid Services announced the temporary telephone visit rate change and expanded the scope of services that are eligible telephone visits to include many behavioral health and patient education services.

Rates for telephone visits will jump from $14-$41 per visit to about $46-$110. The pay increase is retroactive to March 1, 2020.

The move was welcomed by the American College of Physicians, but the organization said more needs to be done in order help maintain the financial stability of physician practices.

“ACP has repeatedly requested this change from CMS as the country has been dealing with the COVID-19 national emergency, and we are heartened that they have heard our concerns,” ACP President Jacqueline Fincher, MD, said in a statement. “More still needs to be done to ensure that physician practices are able to remain operational and care for their patients, but this change in payment policy addresses one of the biggest issues facing physicians as they struggle to make up for lost revenue and provide appropriate care to patients.”

CMS also is expanding payment availability for audio-only telemedicine services by waiving the video requirement for certain evaluation and management services. The move is aimed at reaching Medicare beneficiaries who may not have access to video technology or choose not to use it.

“This is a major victory for medicine that will enable physicians to care for their patients, especially their elderly patients with chronic conditions who may not have access to audio-visual technology or high-speed Internet,” Patrice Harris, MD, president of the American Medical Association, said in a statement. “This change will help patients address their health challenges that existed before COVID-19.”

Shawn Martin, senior vice president at the American Academy of Family Physicians, said his group is pleased to see CMS roll out this change and noted that it is especially important for patients with underlying health conditions. “This is the only connectivity they may have with a health care system for their ongoing health care needs.”

Samuel Jones, MD, chair of the Health Affairs Committee at the American College of Cardiology, highlighted the expansion and coverage of audio-only telemedicine appointments as a huge plus for patient access.*

“There was a huge hunger to say, ‘Can we just have improvement in the reimbursement for telephone, which is providing a good service, our patients our asking for it,’ and we were able to get that,” Dr. Jones said in an interview. “It really was, I think, a good thing for patient care.”

Dr. Jones also suggested that the temporary policy be extended after the COVID-19 crisis is over.

“Telemedicine is here to stay,” he said. “But if all of these relaxations suddenly go away with a snap of the finger, or if the reimbursement [is lowered], if all that changes as soon as this emergency declaration is over, we are going to have a hard time.”

The pay increase for telephone services was part of a broader package of increased regulatory flexibility CMS rolled out, including expanding the types of providers who can order a COVID-19 test.

gtwachtman@mdedge.com

*Correction, 5/5/2020: An earlier version of this story misstated Dr. Samuel Jones' affiliation.  He is the chair of the Health Affairs Committee at the American College of Cardiology. 

Physicians who are conducting telephone visits during the COVID-19 pandemic will be paid at a higher rate, more closely aligning the rates with payments for face-to-face visits.

On April 30, officials at the Centers for Medicare & Medicaid Services announced the temporary telephone visit rate change and expanded the scope of services that are eligible telephone visits to include many behavioral health and patient education services.

Rates for telephone visits will jump from $14-$41 per visit to about $46-$110. The pay increase is retroactive to March 1, 2020.

The move was welcomed by the American College of Physicians, but the organization said more needs to be done in order help maintain the financial stability of physician practices.

“ACP has repeatedly requested this change from CMS as the country has been dealing with the COVID-19 national emergency, and we are heartened that they have heard our concerns,” ACP President Jacqueline Fincher, MD, said in a statement. “More still needs to be done to ensure that physician practices are able to remain operational and care for their patients, but this change in payment policy addresses one of the biggest issues facing physicians as they struggle to make up for lost revenue and provide appropriate care to patients.”

CMS also is expanding payment availability for audio-only telemedicine services by waiving the video requirement for certain evaluation and management services. The move is aimed at reaching Medicare beneficiaries who may not have access to video technology or choose not to use it.

“This is a major victory for medicine that will enable physicians to care for their patients, especially their elderly patients with chronic conditions who may not have access to audio-visual technology or high-speed Internet,” Patrice Harris, MD, president of the American Medical Association, said in a statement. “This change will help patients address their health challenges that existed before COVID-19.”

Shawn Martin, senior vice president at the American Academy of Family Physicians, said his group is pleased to see CMS roll out this change and noted that it is especially important for patients with underlying health conditions. “This is the only connectivity they may have with a health care system for their ongoing health care needs.”

Samuel Jones, MD, chair of the Health Affairs Committee at the American College of Cardiology, highlighted the expansion and coverage of audio-only telemedicine appointments as a huge plus for patient access.*

“There was a huge hunger to say, ‘Can we just have improvement in the reimbursement for telephone, which is providing a good service, our patients our asking for it,’ and we were able to get that,” Dr. Jones said in an interview. “It really was, I think, a good thing for patient care.”

Dr. Jones also suggested that the temporary policy be extended after the COVID-19 crisis is over.

“Telemedicine is here to stay,” he said. “But if all of these relaxations suddenly go away with a snap of the finger, or if the reimbursement [is lowered], if all that changes as soon as this emergency declaration is over, we are going to have a hard time.”

The pay increase for telephone services was part of a broader package of increased regulatory flexibility CMS rolled out, including expanding the types of providers who can order a COVID-19 test.

gtwachtman@mdedge.com

*Correction, 5/5/2020: An earlier version of this story misstated Dr. Samuel Jones' affiliation.  He is the chair of the Health Affairs Committee at the American College of Cardiology. 

Physicians who are conducting telephone visits during the COVID-19 pandemic will be paid at a higher rate, more closely aligning the rates with payments for face-to-face visits.

On April 30, officials at the Centers for Medicare & Medicaid Services announced the temporary telephone visit rate change and expanded the scope of services that are eligible telephone visits to include many behavioral health and patient education services.

Rates for telephone visits will jump from $14-$41 per visit to about $46-$110. The pay increase is retroactive to March 1, 2020.

The move was welcomed by the American College of Physicians, but the organization said more needs to be done in order help maintain the financial stability of physician practices.

“ACP has repeatedly requested this change from CMS as the country has been dealing with the COVID-19 national emergency, and we are heartened that they have heard our concerns,” ACP President Jacqueline Fincher, MD, said in a statement. “More still needs to be done to ensure that physician practices are able to remain operational and care for their patients, but this change in payment policy addresses one of the biggest issues facing physicians as they struggle to make up for lost revenue and provide appropriate care to patients.”

CMS also is expanding payment availability for audio-only telemedicine services by waiving the video requirement for certain evaluation and management services. The move is aimed at reaching Medicare beneficiaries who may not have access to video technology or choose not to use it.

“This is a major victory for medicine that will enable physicians to care for their patients, especially their elderly patients with chronic conditions who may not have access to audio-visual technology or high-speed Internet,” Patrice Harris, MD, president of the American Medical Association, said in a statement. “This change will help patients address their health challenges that existed before COVID-19.”

Shawn Martin, senior vice president at the American Academy of Family Physicians, said his group is pleased to see CMS roll out this change and noted that it is especially important for patients with underlying health conditions. “This is the only connectivity they may have with a health care system for their ongoing health care needs.”

Samuel Jones, MD, chair of the Health Affairs Committee at the American College of Cardiology, highlighted the expansion and coverage of audio-only telemedicine appointments as a huge plus for patient access.*

“There was a huge hunger to say, ‘Can we just have improvement in the reimbursement for telephone, which is providing a good service, our patients our asking for it,’ and we were able to get that,” Dr. Jones said in an interview. “It really was, I think, a good thing for patient care.”

Dr. Jones also suggested that the temporary policy be extended after the COVID-19 crisis is over.

“Telemedicine is here to stay,” he said. “But if all of these relaxations suddenly go away with a snap of the finger, or if the reimbursement [is lowered], if all that changes as soon as this emergency declaration is over, we are going to have a hard time.”

The pay increase for telephone services was part of a broader package of increased regulatory flexibility CMS rolled out, including expanding the types of providers who can order a COVID-19 test.

gtwachtman@mdedge.com

*Correction, 5/5/2020: An earlier version of this story misstated Dr. Samuel Jones' affiliation.  He is the chair of the Health Affairs Committee at the American College of Cardiology. 

During his shift at a COVID-19 drive-through triage screening area set up outside the University of Arkansas for Medical Sciences in Little Rock, Robert Hopkins Jr., MD, noticed a woman bowled over in the front seat of her car.

Courtesy Dr. Robert Hopkins, Jr.

A nurse practitioner had just informed her that she had met the criteria for undergoing testing for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

“She was very upset and was crying nearly inconsolably,” said Dr. Hopkins, who directs the division of general internal medicine at the University of Arkansas Medical Sciences College of Medicine. “I went over and visited with her for a few minutes. She was scared to death that we [had] told her she was going to die. In her mind, if she had COVID-19 that meant a death sentence, and if we were testing her that meant she was likely to not survive.”

Dr. Hopkins tried his best to put testing in perspective for the woman. “At least she came to a level of comfort and realized that we were doing this for her, that this was not a death sentence, that this was not her fault,” he said. “She was worried about infecting her kids and her grandkids and ending up in the hospital and being a burden. Being able to spend that few minutes with her and help to bring down her level of anxiety – I think that’s where we need to put our efforts as physicians right now, helping people understand, ‘Yes, this is serious. Yes, we need to continue to social distance. Yes, we need to be cautious. But, we will get through this if we all work together to do so.’ ”

Prior to the COVID-19 pandemic, Dr. Hopkins spent part of his time seeing patients in the university’s main hospital, but most of it in an outpatient clinic where he and about 20 other primary care physicians care for patients and precept medical residents. Now, medical residents have been deployed to other services, primarily in the hospital, and he and his physician colleagues are conducting 80%-90% of patient visits by video conferencing or by telephone. It’s a whole new world.

“We’ve gone from a relatively traditional inpatient/outpatient practice where we’re seeing patients face to face to doing some face-to-face visits, but an awful lot of what we do now is in the technology domain,” said Dr. Hopkins, who also assisted with health care relief efforts during hurricanes Rita and Katrina.

“A group of six of us has been redeployed to assist with the surge unit for the inpatient facility, so our outpatient duties are being taken on by some of our partners.”

He also pitches in at the drive-through COVID-19 screening clinic, which was set up on March 27 and operates between 8 a.m. and 8 p.m., 7 days a week. “We’re able to measure people’s temperature, take a quick screening history, decide whether their risk is such that we need to do a COVID-19 PCR [polymerase chain reaction] test,” he said. “Then we make a determination of whether they need to go home on quarantine awaiting those results, or if they don’t have anything that needs to be evaluated, or whether they need to be triaged to an urgent care setting or to the emergency department.”

To minimize his risk of acquiring COVID-19, he follows personal hygiene practices recommended by the Centers for Disease Control and Prevention. He also places his work shoes in a shoebox, which he keeps in his car. “I put them on when I get to the parking deck at work, do my work, and then I put them in the shoebox, slip on another pair of shoes and drive home so I’m not tracking in things I potentially had on me,” said Dr. Hopkins, who is married and a father to two college-aged sons and a daughter in fourth grade. “When I get home I immediately shower, and then I exercise or have dinner with my family.”

Despite the longer-than-usual work hours and upheaval to the traditional medical practice model brought on by the pandemic, Dr. Hopkins, a self-described “glass half full person,” said that he does his best to keep watch over his patients and colleagues. “I’m trying to keep an eye out on my team members – physicians, nurses, medical assistants, and folks at the front desk – trying to make sure that people are getting rest, trying to make sure that people are not overcommitting,” he said. “Because if we’re not all working together and working for the long term, we’re going to be in trouble. This is not going to be a sprint; this is going to be a marathon for us to get through.”

To keep mentally centered, he engages in at least 40 minutes of exercise each day on his bicycle or on the elliptical machine at home. Dr. Hopkins hopes that the current efforts to redeploy resources, expand clinician skill sets, and forge relationships with colleagues in other disciplines will carry over into the delivery of health care when COVID-19 is a distant memory. “I hope that some of those relationships are going to continue and result in better care for all of our patients,” he said.
 

"We are in dire need of hugs"

MaryAnn Dakkak, MD, is another primary care physician whose work week looks drastically different from how it looked before the pandemic. Typically, Dr. Dakkak, a family physician at Boston University, practices a mix of clinic-based family medicine and obstetrics, and works in inpatient medicine 6 weeks a year. Currently, she is leading a COVID-19 team full time at Boston Medical Center, a 300-bed safety-net hospital located on the campus of Boston University Medical Center.

Courtesy Dr. MaryAnn Dakkak

COVID-19 has also shaken up her life at home.

When Dr. Dakkak volunteered to take on her new role, the first thing that came to her mind was how making the switch would affect the well-being of her 8-year-old son and 10-year-old daughter.

“I thought, ‘How do I get my children somewhere where I don’t have to worry about them?’ ” Dr. Dakkak said.

She floated the idea with her husband of flying their children out to stay with her recently retired parents, who live outside of Sacramento, Calif., until the pandemic eases up. “I was thinking to myself, ‘Am I overreacting? Is the pandemic not going to be that bad?’ because the rest of the country seemed to be in some amount of denial,” she said. “So, I called my dad, who’s a retired pediatric anesthesiologist. He’s from Egypt so he’s done crisis medicine in his time. He encouraged me to send the kids.”

On the same day that Dr. Dakkak began her first 12-hour COVID-19 shift at the hospital, her husband and children boarded a plane to California, where the kids remain in the care of her parents. Her husband returned after staying there for 2 weeks. “Every day when I’m working, I validate my decision,” she said. “When I first started, I worked 5 nights in a row, had 2 days off, and then worked 6 nights in a row. I was busy so I didn’t think about [being away from my kids], but at the same time I was grateful that I didn’t have to come home and worry about homeschooling the kids or infecting them.”

She checks in with them as she can via cell phone or FaceTime. “My son has been very honest,” Dr. Dakkak said. “He says, ‘FaceTime makes me miss you more, and I don’t like it,’ which I understand. I’ll call my mom, and if they want to talk to me, they’ll talk to me. If they don’t want to talk to me, I’m okay. This is about them being healthy and safe. I sent them a care package a few days ago with cards and some workbooks. I’m optimistic that in June I can at least see them if not bring them home.”

Dr. Dakkak describes leading a COVID-19 team as a grueling experience that challenges her medical know-how nearly every day, with seemingly ever-changing algorithms. “Our knowledge of this disease is five steps behind, and changing at lightning speed,” said Dr. Dakkak, who completed a fellowship in surgical and high-risk obstetrics. “It’s hard to balance continuing to teach evidence-based medicine for everything else in medicine [with continuing] to practice minimal and ever-changing evidence-based COVID medicine. We just don’t know enough [about the virus] yet. This is nothing like we were taught in medical school. Everyone has elevated d-dimers with COVID-19, and we don’t get CT pulmonary angiograms [CTPAs] on all of them; we wouldn’t physically be able to. Some patients have d-dimers in the thousands, and only some are stable to get CTPAs. We are also finding pulmonary embolisms. Now we’re basing our algorithm on anticoagulation due to d-dimers because sometimes you can’t always do a CTPA even if you want to. On the other hand, we have people who are coming into the hospital too late. We’ve had a few who have come in after having days of stroke symptoms. I worry about our patients at home who hesitate to come in when they really should.”

Sometimes she feels sad for the medical residents on her team because their instinct is to go in and check on each patient, “but I don’t want them to get exposed,” she said. “So, we check in by phone, or if they need a physical check-in, we minimize the check-ins; only one of us goes in. I’m more willing to put myself in the room than to put them in the room. I also feel for them because they came into medicine for the humanity of medicine – not the charting or the ordering of medicine. I also worry about the acuity and sadness they’re seeing. This is a rough introduction to medicine for them.”

When interviewed for this story in late April, Dr. Dakkak had kept track of her intubated COVID-19 patients. “Most of my patients get to go home without having been intubated, but those aren’t the ones I worry about,” she said. “I have two patients I have been watching. One of them has just been extubated and I’m still worried about him, but I’m hoping he’s going to be fine. The other one is the first pregnant woman we intubated. She is now extubated, doing really well, and went home. Her fetus is doing well, never had any issues while she was intubated. Those cases make me happy. They were both under the age of 35. It is nice to follow those intubations and find that the majority are doing okay.”

The first patient she had cared for who died was a young man “who was always in good spirits,” she recalled. “We called his brother right before intubating him. After intubation, his oxygen saturation didn’t jump up, which made me worry a bit.” About a week later, the young man died. “I kept thinking, ‘We intubated him when he was still comfortable talking. Should I have put it off and had him call more people to say goodbye? Should I have known that he wasn’t going to wake up?’ ” said Dr. Dakkak, who is also women’s health director at Manet Community Health Centers. “A lot of us have worked on our end-of-life discussions in the past month, just being able to tell somebody, ‘This might be your last time to call family. Call family and talk to whoever you want.’ Guilt isn’t the right word, but it’s unsettling if I’m the last person a patient talks to. I feel that, if that’s the case, then I didn’t do a good enough job trying to get them to their family or friends. If I am worried about a patient’s clinical status declining, I tell families now, when I call them, ‘I hope I’m wrong; I hope they don’t need to be intubated, but I think this is the time to talk.’ ”

To keep herself grounded during off hours, Dr. Dakkak spends time resting, checking in with her family, journaling “to get a lot of feelings out,” gardening, hiking, and joining Zoom chats with friends. Once recentered, she draws from a sense of obligation to others as she prepares for her next shift caring for COVID-19 patients.

“I have a lot of love for the world that I get to expend by doing this hard work,” she said. “I love humanity and I love humanity in times of crisis. The interactions I have with patients and their families are still central to why I do this work. I love my medical teams, and I would never want to let them down. It is nice to feel the sense of teamwork across the hospital. The nurses that I sit with and experience this with are amazing. I keep saying that the only thing I want to do when this pandemic is over is hug everyone. I think we are in dire need of hugs.”
 

Finding light in the darkness

Internist Katie Jobbins, DO, also has worked in a professional role that was created because of COVID-19.

Shortly before Dr. Jobbins was deployed to Baystate Medical Center in Springfield, Ma., for 2 weeks in April of 2020 to help clinicians with an anticipated surge of COVID-19 cases, she encountered a patient who walked into Baystate’s High Street Health Center.

“I think I have COVID-19,” the patient proclaimed to her, at the outpatient clinic that serves mostly inner-city, Medicaid patients.

Prior to becoming an ambulatory internist, Dr. Jobbins was a surgical resident. “So I went into that mode of ‘I need to do this, this, and this,’ ” she said. “I went through a checklist in my head to make sure I was prepared to take care of the patient.”

She applied that same systems approach during her redeployment assignment in the tertiary care hospital, which typically involved 10-hour shifts overseeing internal medicine residents in a medical telemetry unit. “We would take care of people under investigation for COVID-19, but we were not assigned to the actual COVID unit,” said Dr. Jobbins, who is also associate program director for the internal medicine residency program at the University of Massachusetts Medical School–Baystate Springfield. “They tried to redeploy other people to those units who had special training, and we were trying to back fill into where those people that got moved to the COVID units or the ICU units were actually working. We were taking more of the medical side of the floors.”

Even so, one patient on the unit was suspected of having COVID-19, so Dr. Jobbins suited up with personal protective equipment and conducted a thorough exam with residents waiting outside the patient’s room, a safe distance away. “I explained everything I found on the exam to the residents, trying to give them some educational benefit, even though they couldn’t physically examine the patient because we’re trying to protect them since they’re in training,” she said. “It was anxiety provoking, on some level, knowing that there’s a potential risk of exposure [to the virus], but knowing that Baystate Health has gone to extraordinary measures to make sure we have the correct PPE and support us is reassuring. I knew I had the right equipment and the right tools to take care of the patient, which calmed my nerves and made me feel like I could do the job. That’s the most important thing as a physician during this time: knowing that you have people supporting you who have your back at all times.”

Like Dr. Dakkak, Dr. Jobbins had to make some adjustments to her interaction with her family.

Before she began the deployment, Dr. Jobbins engaged in a frank discussion with her husband and her two young boys about the risks she faced working in a hospital caring for patients with COVID-19. “My husband and I made sure our wills were up to date, and we talked about what we would do if either of us got the virus,” she said. To minimize the potential risk of transmitting the virus to her loved ones during the two-week deployment, she considered living away from her family in a nearby home owned by her father, but decided against that and to “take it day by day.” Following her hospital shifts, Dr. Jobbins changed into a fresh set of clothes before leaving the hospital. Once she arrived home, she showered to reduce the risk of possibly becoming a vector to her family.

She had to tell her kids: “You can’t kiss me right now.”

“As much as it’s hard for them to understand, we had a conversation [in which I explained] ‘This is a virus. It will go away eventually, but it’s a virus we’re fighting.’ It’s interesting to watch a 3-year-old try to process that and take his play samurai sword or Marvel toys and decide he’s going to run around the neighborhood and try to kill the virus.”

At the High Street Health Center, Dr. Jobbins and her colleagues have transitioned to conducting most patient encounters via telephone or video appointments. “We have tried to maintain as much continuity for our patients to address their chronic medical needs through these visits, such as hypertension management and diabetes care,” she said. “We have begun a rigorous screening process to triage and treat patients suspicious for COVID-19 through telehealth in hopes of keeping them safe and in their own homes. We also continue to see patients for nonrespiratory urgent care needs in person once they have screened negative for COVID-19.”

“In terms of the inpatient setting, we’ve noticed that a lot of people are choosing not to go to the hospital now, unless they’re extremely ill,” Dr. Jobbins noted. “We’re going to need to find a balance with when do people truly need to go to the hospital and when do they not? What can we manage as an outpatient versus having someone go to the emergency department? That’s really the role of the primary care physician. We need to help people understand, ‘You don’t need to go to the ED for everything, but here are the things you really need to go for.’ ”

“It will be interesting to see what health care looks like in 6 months or a year. I’m excited to see where we land,” Dr. Jobbins added.


 

Hopes for the Future of Telemedicine

When the practice of medicine enters a post–COVID-19 era, Dr. Jobbins hopes that telemedicine will be incorporated more into the delivery of patient care. “I’ve found that many of my patients who often are no-shows to the inpatient version of their visits have had a higher success rate of follow-through when we do the telephone visits,” she said. “It’s been very successful. I hope that the insurance companies and [Centers for Medicare & Medicaid] will continue to reimburse this as they see this is a benefit to our patients.

Courtesy Dr. Robert Hopkins, Jr.

Dr. Hopkins is also hopeful that physicians will be able to successfully see patients via telemedicine in the postpandemic world.

“For the ups and downs we’ve had with telemedicine, I’d love for us to be able to enhance the positives and incorporate that into our practice going forward. If we can reach our patients and help treat them where they are, rather than them having to come to us, that may be a plus,” he said.

In the meantime, Dr. Jobbins presses on as the curve of COVID-19 cases flattens in Western Massachusetts and remains grateful that she chose to practice medicine.

“The commitment I have to being an educator in addition to being a physician is part of why I keep doing this,” Dr. Jobbins said. “I find this to be one of the most fulfilling jobs and careers you could ever have: being there for people when they need you the most. That’s really what a physician’s job is: being there for people when a family member has passed away or when they just need to talk because they’re having anxiety. At the end of the day, if we can impart that to those we work with and bring in a positive attitude, it’s infectious and it makes people see this is a reason we keep doing what we’re doing.”

She’s also been heartened by the kindness of strangers during this pandemic, from those who made and donated face shields when they were in short supply, to those who delivered food to the hospital as a gesture of thanks.

“I had a patient who made homemade masks and sent them to my office,” she said. “There’s obviously good and bad during this time, but I get hope from seeing all of the good things that are coming out of this, the whole idea of finding the light in the darkness.”

dbrunk@mdedge.com

During his shift at a COVID-19 drive-through triage screening area set up outside the University of Arkansas for Medical Sciences in Little Rock, Robert Hopkins Jr., MD, noticed a woman bowled over in the front seat of her car.

Courtesy Dr. Robert Hopkins, Jr.

A nurse practitioner had just informed her that she had met the criteria for undergoing testing for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

“She was very upset and was crying nearly inconsolably,” said Dr. Hopkins, who directs the division of general internal medicine at the University of Arkansas Medical Sciences College of Medicine. “I went over and visited with her for a few minutes. She was scared to death that we [had] told her she was going to die. In her mind, if she had COVID-19 that meant a death sentence, and if we were testing her that meant she was likely to not survive.”

Dr. Hopkins tried his best to put testing in perspective for the woman. “At least she came to a level of comfort and realized that we were doing this for her, that this was not a death sentence, that this was not her fault,” he said. “She was worried about infecting her kids and her grandkids and ending up in the hospital and being a burden. Being able to spend that few minutes with her and help to bring down her level of anxiety – I think that’s where we need to put our efforts as physicians right now, helping people understand, ‘Yes, this is serious. Yes, we need to continue to social distance. Yes, we need to be cautious. But, we will get through this if we all work together to do so.’ ”

Prior to the COVID-19 pandemic, Dr. Hopkins spent part of his time seeing patients in the university’s main hospital, but most of it in an outpatient clinic where he and about 20 other primary care physicians care for patients and precept medical residents. Now, medical residents have been deployed to other services, primarily in the hospital, and he and his physician colleagues are conducting 80%-90% of patient visits by video conferencing or by telephone. It’s a whole new world.

“We’ve gone from a relatively traditional inpatient/outpatient practice where we’re seeing patients face to face to doing some face-to-face visits, but an awful lot of what we do now is in the technology domain,” said Dr. Hopkins, who also assisted with health care relief efforts during hurricanes Rita and Katrina.

“A group of six of us has been redeployed to assist with the surge unit for the inpatient facility, so our outpatient duties are being taken on by some of our partners.”

He also pitches in at the drive-through COVID-19 screening clinic, which was set up on March 27 and operates between 8 a.m. and 8 p.m., 7 days a week. “We’re able to measure people’s temperature, take a quick screening history, decide whether their risk is such that we need to do a COVID-19 PCR [polymerase chain reaction] test,” he said. “Then we make a determination of whether they need to go home on quarantine awaiting those results, or if they don’t have anything that needs to be evaluated, or whether they need to be triaged to an urgent care setting or to the emergency department.”

To minimize his risk of acquiring COVID-19, he follows personal hygiene practices recommended by the Centers for Disease Control and Prevention. He also places his work shoes in a shoebox, which he keeps in his car. “I put them on when I get to the parking deck at work, do my work, and then I put them in the shoebox, slip on another pair of shoes and drive home so I’m not tracking in things I potentially had on me,” said Dr. Hopkins, who is married and a father to two college-aged sons and a daughter in fourth grade. “When I get home I immediately shower, and then I exercise or have dinner with my family.”

Despite the longer-than-usual work hours and upheaval to the traditional medical practice model brought on by the pandemic, Dr. Hopkins, a self-described “glass half full person,” said that he does his best to keep watch over his patients and colleagues. “I’m trying to keep an eye out on my team members – physicians, nurses, medical assistants, and folks at the front desk – trying to make sure that people are getting rest, trying to make sure that people are not overcommitting,” he said. “Because if we’re not all working together and working for the long term, we’re going to be in trouble. This is not going to be a sprint; this is going to be a marathon for us to get through.”

To keep mentally centered, he engages in at least 40 minutes of exercise each day on his bicycle or on the elliptical machine at home. Dr. Hopkins hopes that the current efforts to redeploy resources, expand clinician skill sets, and forge relationships with colleagues in other disciplines will carry over into the delivery of health care when COVID-19 is a distant memory. “I hope that some of those relationships are going to continue and result in better care for all of our patients,” he said.
 

"We are in dire need of hugs"

MaryAnn Dakkak, MD, is another primary care physician whose work week looks drastically different from how it looked before the pandemic. Typically, Dr. Dakkak, a family physician at Boston University, practices a mix of clinic-based family medicine and obstetrics, and works in inpatient medicine 6 weeks a year. Currently, she is leading a COVID-19 team full time at Boston Medical Center, a 300-bed safety-net hospital located on the campus of Boston University Medical Center.

Courtesy Dr. MaryAnn Dakkak

COVID-19 has also shaken up her life at home.

When Dr. Dakkak volunteered to take on her new role, the first thing that came to her mind was how making the switch would affect the well-being of her 8-year-old son and 10-year-old daughter.

“I thought, ‘How do I get my children somewhere where I don’t have to worry about them?’ ” Dr. Dakkak said.

She floated the idea with her husband of flying their children out to stay with her recently retired parents, who live outside of Sacramento, Calif., until the pandemic eases up. “I was thinking to myself, ‘Am I overreacting? Is the pandemic not going to be that bad?’ because the rest of the country seemed to be in some amount of denial,” she said. “So, I called my dad, who’s a retired pediatric anesthesiologist. He’s from Egypt so he’s done crisis medicine in his time. He encouraged me to send the kids.”

On the same day that Dr. Dakkak began her first 12-hour COVID-19 shift at the hospital, her husband and children boarded a plane to California, where the kids remain in the care of her parents. Her husband returned after staying there for 2 weeks. “Every day when I’m working, I validate my decision,” she said. “When I first started, I worked 5 nights in a row, had 2 days off, and then worked 6 nights in a row. I was busy so I didn’t think about [being away from my kids], but at the same time I was grateful that I didn’t have to come home and worry about homeschooling the kids or infecting them.”

She checks in with them as she can via cell phone or FaceTime. “My son has been very honest,” Dr. Dakkak said. “He says, ‘FaceTime makes me miss you more, and I don’t like it,’ which I understand. I’ll call my mom, and if they want to talk to me, they’ll talk to me. If they don’t want to talk to me, I’m okay. This is about them being healthy and safe. I sent them a care package a few days ago with cards and some workbooks. I’m optimistic that in June I can at least see them if not bring them home.”

Dr. Dakkak describes leading a COVID-19 team as a grueling experience that challenges her medical know-how nearly every day, with seemingly ever-changing algorithms. “Our knowledge of this disease is five steps behind, and changing at lightning speed,” said Dr. Dakkak, who completed a fellowship in surgical and high-risk obstetrics. “It’s hard to balance continuing to teach evidence-based medicine for everything else in medicine [with continuing] to practice minimal and ever-changing evidence-based COVID medicine. We just don’t know enough [about the virus] yet. This is nothing like we were taught in medical school. Everyone has elevated d-dimers with COVID-19, and we don’t get CT pulmonary angiograms [CTPAs] on all of them; we wouldn’t physically be able to. Some patients have d-dimers in the thousands, and only some are stable to get CTPAs. We are also finding pulmonary embolisms. Now we’re basing our algorithm on anticoagulation due to d-dimers because sometimes you can’t always do a CTPA even if you want to. On the other hand, we have people who are coming into the hospital too late. We’ve had a few who have come in after having days of stroke symptoms. I worry about our patients at home who hesitate to come in when they really should.”

Sometimes she feels sad for the medical residents on her team because their instinct is to go in and check on each patient, “but I don’t want them to get exposed,” she said. “So, we check in by phone, or if they need a physical check-in, we minimize the check-ins; only one of us goes in. I’m more willing to put myself in the room than to put them in the room. I also feel for them because they came into medicine for the humanity of medicine – not the charting or the ordering of medicine. I also worry about the acuity and sadness they’re seeing. This is a rough introduction to medicine for them.”

When interviewed for this story in late April, Dr. Dakkak had kept track of her intubated COVID-19 patients. “Most of my patients get to go home without having been intubated, but those aren’t the ones I worry about,” she said. “I have two patients I have been watching. One of them has just been extubated and I’m still worried about him, but I’m hoping he’s going to be fine. The other one is the first pregnant woman we intubated. She is now extubated, doing really well, and went home. Her fetus is doing well, never had any issues while she was intubated. Those cases make me happy. They were both under the age of 35. It is nice to follow those intubations and find that the majority are doing okay.”

The first patient she had cared for who died was a young man “who was always in good spirits,” she recalled. “We called his brother right before intubating him. After intubation, his oxygen saturation didn’t jump up, which made me worry a bit.” About a week later, the young man died. “I kept thinking, ‘We intubated him when he was still comfortable talking. Should I have put it off and had him call more people to say goodbye? Should I have known that he wasn’t going to wake up?’ ” said Dr. Dakkak, who is also women’s health director at Manet Community Health Centers. “A lot of us have worked on our end-of-life discussions in the past month, just being able to tell somebody, ‘This might be your last time to call family. Call family and talk to whoever you want.’ Guilt isn’t the right word, but it’s unsettling if I’m the last person a patient talks to. I feel that, if that’s the case, then I didn’t do a good enough job trying to get them to their family or friends. If I am worried about a patient’s clinical status declining, I tell families now, when I call them, ‘I hope I’m wrong; I hope they don’t need to be intubated, but I think this is the time to talk.’ ”

To keep herself grounded during off hours, Dr. Dakkak spends time resting, checking in with her family, journaling “to get a lot of feelings out,” gardening, hiking, and joining Zoom chats with friends. Once recentered, she draws from a sense of obligation to others as she prepares for her next shift caring for COVID-19 patients.

“I have a lot of love for the world that I get to expend by doing this hard work,” she said. “I love humanity and I love humanity in times of crisis. The interactions I have with patients and their families are still central to why I do this work. I love my medical teams, and I would never want to let them down. It is nice to feel the sense of teamwork across the hospital. The nurses that I sit with and experience this with are amazing. I keep saying that the only thing I want to do when this pandemic is over is hug everyone. I think we are in dire need of hugs.”
 

Finding light in the darkness

Internist Katie Jobbins, DO, also has worked in a professional role that was created because of COVID-19.

Shortly before Dr. Jobbins was deployed to Baystate Medical Center in Springfield, Ma., for 2 weeks in April of 2020 to help clinicians with an anticipated surge of COVID-19 cases, she encountered a patient who walked into Baystate’s High Street Health Center.

“I think I have COVID-19,” the patient proclaimed to her, at the outpatient clinic that serves mostly inner-city, Medicaid patients.

Prior to becoming an ambulatory internist, Dr. Jobbins was a surgical resident. “So I went into that mode of ‘I need to do this, this, and this,’ ” she said. “I went through a checklist in my head to make sure I was prepared to take care of the patient.”

She applied that same systems approach during her redeployment assignment in the tertiary care hospital, which typically involved 10-hour shifts overseeing internal medicine residents in a medical telemetry unit. “We would take care of people under investigation for COVID-19, but we were not assigned to the actual COVID unit,” said Dr. Jobbins, who is also associate program director for the internal medicine residency program at the University of Massachusetts Medical School–Baystate Springfield. “They tried to redeploy other people to those units who had special training, and we were trying to back fill into where those people that got moved to the COVID units or the ICU units were actually working. We were taking more of the medical side of the floors.”

Even so, one patient on the unit was suspected of having COVID-19, so Dr. Jobbins suited up with personal protective equipment and conducted a thorough exam with residents waiting outside the patient’s room, a safe distance away. “I explained everything I found on the exam to the residents, trying to give them some educational benefit, even though they couldn’t physically examine the patient because we’re trying to protect them since they’re in training,” she said. “It was anxiety provoking, on some level, knowing that there’s a potential risk of exposure [to the virus], but knowing that Baystate Health has gone to extraordinary measures to make sure we have the correct PPE and support us is reassuring. I knew I had the right equipment and the right tools to take care of the patient, which calmed my nerves and made me feel like I could do the job. That’s the most important thing as a physician during this time: knowing that you have people supporting you who have your back at all times.”

Like Dr. Dakkak, Dr. Jobbins had to make some adjustments to her interaction with her family.

Before she began the deployment, Dr. Jobbins engaged in a frank discussion with her husband and her two young boys about the risks she faced working in a hospital caring for patients with COVID-19. “My husband and I made sure our wills were up to date, and we talked about what we would do if either of us got the virus,” she said. To minimize the potential risk of transmitting the virus to her loved ones during the two-week deployment, she considered living away from her family in a nearby home owned by her father, but decided against that and to “take it day by day.” Following her hospital shifts, Dr. Jobbins changed into a fresh set of clothes before leaving the hospital. Once she arrived home, she showered to reduce the risk of possibly becoming a vector to her family.

She had to tell her kids: “You can’t kiss me right now.”

“As much as it’s hard for them to understand, we had a conversation [in which I explained] ‘This is a virus. It will go away eventually, but it’s a virus we’re fighting.’ It’s interesting to watch a 3-year-old try to process that and take his play samurai sword or Marvel toys and decide he’s going to run around the neighborhood and try to kill the virus.”

At the High Street Health Center, Dr. Jobbins and her colleagues have transitioned to conducting most patient encounters via telephone or video appointments. “We have tried to maintain as much continuity for our patients to address their chronic medical needs through these visits, such as hypertension management and diabetes care,” she said. “We have begun a rigorous screening process to triage and treat patients suspicious for COVID-19 through telehealth in hopes of keeping them safe and in their own homes. We also continue to see patients for nonrespiratory urgent care needs in person once they have screened negative for COVID-19.”

“In terms of the inpatient setting, we’ve noticed that a lot of people are choosing not to go to the hospital now, unless they’re extremely ill,” Dr. Jobbins noted. “We’re going to need to find a balance with when do people truly need to go to the hospital and when do they not? What can we manage as an outpatient versus having someone go to the emergency department? That’s really the role of the primary care physician. We need to help people understand, ‘You don’t need to go to the ED for everything, but here are the things you really need to go for.’ ”

“It will be interesting to see what health care looks like in 6 months or a year. I’m excited to see where we land,” Dr. Jobbins added.


 

Hopes for the Future of Telemedicine

When the practice of medicine enters a post–COVID-19 era, Dr. Jobbins hopes that telemedicine will be incorporated more into the delivery of patient care. “I’ve found that many of my patients who often are no-shows to the inpatient version of their visits have had a higher success rate of follow-through when we do the telephone visits,” she said. “It’s been very successful. I hope that the insurance companies and [Centers for Medicare & Medicaid] will continue to reimburse this as they see this is a benefit to our patients.

Courtesy Dr. Robert Hopkins, Jr.

Dr. Hopkins is also hopeful that physicians will be able to successfully see patients via telemedicine in the postpandemic world.

“For the ups and downs we’ve had with telemedicine, I’d love for us to be able to enhance the positives and incorporate that into our practice going forward. If we can reach our patients and help treat them where they are, rather than them having to come to us, that may be a plus,” he said.

In the meantime, Dr. Jobbins presses on as the curve of COVID-19 cases flattens in Western Massachusetts and remains grateful that she chose to practice medicine.

“The commitment I have to being an educator in addition to being a physician is part of why I keep doing this,” Dr. Jobbins said. “I find this to be one of the most fulfilling jobs and careers you could ever have: being there for people when they need you the most. That’s really what a physician’s job is: being there for people when a family member has passed away or when they just need to talk because they’re having anxiety. At the end of the day, if we can impart that to those we work with and bring in a positive attitude, it’s infectious and it makes people see this is a reason we keep doing what we’re doing.”

She’s also been heartened by the kindness of strangers during this pandemic, from those who made and donated face shields when they were in short supply, to those who delivered food to the hospital as a gesture of thanks.

“I had a patient who made homemade masks and sent them to my office,” she said. “There’s obviously good and bad during this time, but I get hope from seeing all of the good things that are coming out of this, the whole idea of finding the light in the darkness.”

dbrunk@mdedge.com

During his shift at a COVID-19 drive-through triage screening area set up outside the University of Arkansas for Medical Sciences in Little Rock, Robert Hopkins Jr., MD, noticed a woman bowled over in the front seat of her car.

Courtesy Dr. Robert Hopkins, Jr.

A nurse practitioner had just informed her that she had met the criteria for undergoing testing for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

“She was very upset and was crying nearly inconsolably,” said Dr. Hopkins, who directs the division of general internal medicine at the University of Arkansas Medical Sciences College of Medicine. “I went over and visited with her for a few minutes. She was scared to death that we [had] told her she was going to die. In her mind, if she had COVID-19 that meant a death sentence, and if we were testing her that meant she was likely to not survive.”

Dr. Hopkins tried his best to put testing in perspective for the woman. “At least she came to a level of comfort and realized that we were doing this for her, that this was not a death sentence, that this was not her fault,” he said. “She was worried about infecting her kids and her grandkids and ending up in the hospital and being a burden. Being able to spend that few minutes with her and help to bring down her level of anxiety – I think that’s where we need to put our efforts as physicians right now, helping people understand, ‘Yes, this is serious. Yes, we need to continue to social distance. Yes, we need to be cautious. But, we will get through this if we all work together to do so.’ ”

Prior to the COVID-19 pandemic, Dr. Hopkins spent part of his time seeing patients in the university’s main hospital, but most of it in an outpatient clinic where he and about 20 other primary care physicians care for patients and precept medical residents. Now, medical residents have been deployed to other services, primarily in the hospital, and he and his physician colleagues are conducting 80%-90% of patient visits by video conferencing or by telephone. It’s a whole new world.

“We’ve gone from a relatively traditional inpatient/outpatient practice where we’re seeing patients face to face to doing some face-to-face visits, but an awful lot of what we do now is in the technology domain,” said Dr. Hopkins, who also assisted with health care relief efforts during hurricanes Rita and Katrina.

“A group of six of us has been redeployed to assist with the surge unit for the inpatient facility, so our outpatient duties are being taken on by some of our partners.”

He also pitches in at the drive-through COVID-19 screening clinic, which was set up on March 27 and operates between 8 a.m. and 8 p.m., 7 days a week. “We’re able to measure people’s temperature, take a quick screening history, decide whether their risk is such that we need to do a COVID-19 PCR [polymerase chain reaction] test,” he said. “Then we make a determination of whether they need to go home on quarantine awaiting those results, or if they don’t have anything that needs to be evaluated, or whether they need to be triaged to an urgent care setting or to the emergency department.”

To minimize his risk of acquiring COVID-19, he follows personal hygiene practices recommended by the Centers for Disease Control and Prevention. He also places his work shoes in a shoebox, which he keeps in his car. “I put them on when I get to the parking deck at work, do my work, and then I put them in the shoebox, slip on another pair of shoes and drive home so I’m not tracking in things I potentially had on me,” said Dr. Hopkins, who is married and a father to two college-aged sons and a daughter in fourth grade. “When I get home I immediately shower, and then I exercise or have dinner with my family.”

Despite the longer-than-usual work hours and upheaval to the traditional medical practice model brought on by the pandemic, Dr. Hopkins, a self-described “glass half full person,” said that he does his best to keep watch over his patients and colleagues. “I’m trying to keep an eye out on my team members – physicians, nurses, medical assistants, and folks at the front desk – trying to make sure that people are getting rest, trying to make sure that people are not overcommitting,” he said. “Because if we’re not all working together and working for the long term, we’re going to be in trouble. This is not going to be a sprint; this is going to be a marathon for us to get through.”

To keep mentally centered, he engages in at least 40 minutes of exercise each day on his bicycle or on the elliptical machine at home. Dr. Hopkins hopes that the current efforts to redeploy resources, expand clinician skill sets, and forge relationships with colleagues in other disciplines will carry over into the delivery of health care when COVID-19 is a distant memory. “I hope that some of those relationships are going to continue and result in better care for all of our patients,” he said.
 

"We are in dire need of hugs"

MaryAnn Dakkak, MD, is another primary care physician whose work week looks drastically different from how it looked before the pandemic. Typically, Dr. Dakkak, a family physician at Boston University, practices a mix of clinic-based family medicine and obstetrics, and works in inpatient medicine 6 weeks a year. Currently, she is leading a COVID-19 team full time at Boston Medical Center, a 300-bed safety-net hospital located on the campus of Boston University Medical Center.

Courtesy Dr. MaryAnn Dakkak

COVID-19 has also shaken up her life at home.

When Dr. Dakkak volunteered to take on her new role, the first thing that came to her mind was how making the switch would affect the well-being of her 8-year-old son and 10-year-old daughter.

“I thought, ‘How do I get my children somewhere where I don’t have to worry about them?’ ” Dr. Dakkak said.

She floated the idea with her husband of flying their children out to stay with her recently retired parents, who live outside of Sacramento, Calif., until the pandemic eases up. “I was thinking to myself, ‘Am I overreacting? Is the pandemic not going to be that bad?’ because the rest of the country seemed to be in some amount of denial,” she said. “So, I called my dad, who’s a retired pediatric anesthesiologist. He’s from Egypt so he’s done crisis medicine in his time. He encouraged me to send the kids.”

On the same day that Dr. Dakkak began her first 12-hour COVID-19 shift at the hospital, her husband and children boarded a plane to California, where the kids remain in the care of her parents. Her husband returned after staying there for 2 weeks. “Every day when I’m working, I validate my decision,” she said. “When I first started, I worked 5 nights in a row, had 2 days off, and then worked 6 nights in a row. I was busy so I didn’t think about [being away from my kids], but at the same time I was grateful that I didn’t have to come home and worry about homeschooling the kids or infecting them.”

She checks in with them as she can via cell phone or FaceTime. “My son has been very honest,” Dr. Dakkak said. “He says, ‘FaceTime makes me miss you more, and I don’t like it,’ which I understand. I’ll call my mom, and if they want to talk to me, they’ll talk to me. If they don’t want to talk to me, I’m okay. This is about them being healthy and safe. I sent them a care package a few days ago with cards and some workbooks. I’m optimistic that in June I can at least see them if not bring them home.”

Dr. Dakkak describes leading a COVID-19 team as a grueling experience that challenges her medical know-how nearly every day, with seemingly ever-changing algorithms. “Our knowledge of this disease is five steps behind, and changing at lightning speed,” said Dr. Dakkak, who completed a fellowship in surgical and high-risk obstetrics. “It’s hard to balance continuing to teach evidence-based medicine for everything else in medicine [with continuing] to practice minimal and ever-changing evidence-based COVID medicine. We just don’t know enough [about the virus] yet. This is nothing like we were taught in medical school. Everyone has elevated d-dimers with COVID-19, and we don’t get CT pulmonary angiograms [CTPAs] on all of them; we wouldn’t physically be able to. Some patients have d-dimers in the thousands, and only some are stable to get CTPAs. We are also finding pulmonary embolisms. Now we’re basing our algorithm on anticoagulation due to d-dimers because sometimes you can’t always do a CTPA even if you want to. On the other hand, we have people who are coming into the hospital too late. We’ve had a few who have come in after having days of stroke symptoms. I worry about our patients at home who hesitate to come in when they really should.”

Sometimes she feels sad for the medical residents on her team because their instinct is to go in and check on each patient, “but I don’t want them to get exposed,” she said. “So, we check in by phone, or if they need a physical check-in, we minimize the check-ins; only one of us goes in. I’m more willing to put myself in the room than to put them in the room. I also feel for them because they came into medicine for the humanity of medicine – not the charting or the ordering of medicine. I also worry about the acuity and sadness they’re seeing. This is a rough introduction to medicine for them.”

When interviewed for this story in late April, Dr. Dakkak had kept track of her intubated COVID-19 patients. “Most of my patients get to go home without having been intubated, but those aren’t the ones I worry about,” she said. “I have two patients I have been watching. One of them has just been extubated and I’m still worried about him, but I’m hoping he’s going to be fine. The other one is the first pregnant woman we intubated. She is now extubated, doing really well, and went home. Her fetus is doing well, never had any issues while she was intubated. Those cases make me happy. They were both under the age of 35. It is nice to follow those intubations and find that the majority are doing okay.”

The first patient she had cared for who died was a young man “who was always in good spirits,” she recalled. “We called his brother right before intubating him. After intubation, his oxygen saturation didn’t jump up, which made me worry a bit.” About a week later, the young man died. “I kept thinking, ‘We intubated him when he was still comfortable talking. Should I have put it off and had him call more people to say goodbye? Should I have known that he wasn’t going to wake up?’ ” said Dr. Dakkak, who is also women’s health director at Manet Community Health Centers. “A lot of us have worked on our end-of-life discussions in the past month, just being able to tell somebody, ‘This might be your last time to call family. Call family and talk to whoever you want.’ Guilt isn’t the right word, but it’s unsettling if I’m the last person a patient talks to. I feel that, if that’s the case, then I didn’t do a good enough job trying to get them to their family or friends. If I am worried about a patient’s clinical status declining, I tell families now, when I call them, ‘I hope I’m wrong; I hope they don’t need to be intubated, but I think this is the time to talk.’ ”

To keep herself grounded during off hours, Dr. Dakkak spends time resting, checking in with her family, journaling “to get a lot of feelings out,” gardening, hiking, and joining Zoom chats with friends. Once recentered, she draws from a sense of obligation to others as she prepares for her next shift caring for COVID-19 patients.

“I have a lot of love for the world that I get to expend by doing this hard work,” she said. “I love humanity and I love humanity in times of crisis. The interactions I have with patients and their families are still central to why I do this work. I love my medical teams, and I would never want to let them down. It is nice to feel the sense of teamwork across the hospital. The nurses that I sit with and experience this with are amazing. I keep saying that the only thing I want to do when this pandemic is over is hug everyone. I think we are in dire need of hugs.”
 

Finding light in the darkness

Internist Katie Jobbins, DO, also has worked in a professional role that was created because of COVID-19.

Shortly before Dr. Jobbins was deployed to Baystate Medical Center in Springfield, Ma., for 2 weeks in April of 2020 to help clinicians with an anticipated surge of COVID-19 cases, she encountered a patient who walked into Baystate’s High Street Health Center.

“I think I have COVID-19,” the patient proclaimed to her, at the outpatient clinic that serves mostly inner-city, Medicaid patients.

Prior to becoming an ambulatory internist, Dr. Jobbins was a surgical resident. “So I went into that mode of ‘I need to do this, this, and this,’ ” she said. “I went through a checklist in my head to make sure I was prepared to take care of the patient.”

She applied that same systems approach during her redeployment assignment in the tertiary care hospital, which typically involved 10-hour shifts overseeing internal medicine residents in a medical telemetry unit. “We would take care of people under investigation for COVID-19, but we were not assigned to the actual COVID unit,” said Dr. Jobbins, who is also associate program director for the internal medicine residency program at the University of Massachusetts Medical School–Baystate Springfield. “They tried to redeploy other people to those units who had special training, and we were trying to back fill into where those people that got moved to the COVID units or the ICU units were actually working. We were taking more of the medical side of the floors.”

Even so, one patient on the unit was suspected of having COVID-19, so Dr. Jobbins suited up with personal protective equipment and conducted a thorough exam with residents waiting outside the patient’s room, a safe distance away. “I explained everything I found on the exam to the residents, trying to give them some educational benefit, even though they couldn’t physically examine the patient because we’re trying to protect them since they’re in training,” she said. “It was anxiety provoking, on some level, knowing that there’s a potential risk of exposure [to the virus], but knowing that Baystate Health has gone to extraordinary measures to make sure we have the correct PPE and support us is reassuring. I knew I had the right equipment and the right tools to take care of the patient, which calmed my nerves and made me feel like I could do the job. That’s the most important thing as a physician during this time: knowing that you have people supporting you who have your back at all times.”

Like Dr. Dakkak, Dr. Jobbins had to make some adjustments to her interaction with her family.

Before she began the deployment, Dr. Jobbins engaged in a frank discussion with her husband and her two young boys about the risks she faced working in a hospital caring for patients with COVID-19. “My husband and I made sure our wills were up to date, and we talked about what we would do if either of us got the virus,” she said. To minimize the potential risk of transmitting the virus to her loved ones during the two-week deployment, she considered living away from her family in a nearby home owned by her father, but decided against that and to “take it day by day.” Following her hospital shifts, Dr. Jobbins changed into a fresh set of clothes before leaving the hospital. Once she arrived home, she showered to reduce the risk of possibly becoming a vector to her family.

She had to tell her kids: “You can’t kiss me right now.”

“As much as it’s hard for them to understand, we had a conversation [in which I explained] ‘This is a virus. It will go away eventually, but it’s a virus we’re fighting.’ It’s interesting to watch a 3-year-old try to process that and take his play samurai sword or Marvel toys and decide he’s going to run around the neighborhood and try to kill the virus.”

At the High Street Health Center, Dr. Jobbins and her colleagues have transitioned to conducting most patient encounters via telephone or video appointments. “We have tried to maintain as much continuity for our patients to address their chronic medical needs through these visits, such as hypertension management and diabetes care,” she said. “We have begun a rigorous screening process to triage and treat patients suspicious for COVID-19 through telehealth in hopes of keeping them safe and in their own homes. We also continue to see patients for nonrespiratory urgent care needs in person once they have screened negative for COVID-19.”

“In terms of the inpatient setting, we’ve noticed that a lot of people are choosing not to go to the hospital now, unless they’re extremely ill,” Dr. Jobbins noted. “We’re going to need to find a balance with when do people truly need to go to the hospital and when do they not? What can we manage as an outpatient versus having someone go to the emergency department? That’s really the role of the primary care physician. We need to help people understand, ‘You don’t need to go to the ED for everything, but here are the things you really need to go for.’ ”

“It will be interesting to see what health care looks like in 6 months or a year. I’m excited to see where we land,” Dr. Jobbins added.


 

Hopes for the Future of Telemedicine

When the practice of medicine enters a post–COVID-19 era, Dr. Jobbins hopes that telemedicine will be incorporated more into the delivery of patient care. “I’ve found that many of my patients who often are no-shows to the inpatient version of their visits have had a higher success rate of follow-through when we do the telephone visits,” she said. “It’s been very successful. I hope that the insurance companies and [Centers for Medicare & Medicaid] will continue to reimburse this as they see this is a benefit to our patients.

Courtesy Dr. Robert Hopkins, Jr.

Dr. Hopkins is also hopeful that physicians will be able to successfully see patients via telemedicine in the postpandemic world.

“For the ups and downs we’ve had with telemedicine, I’d love for us to be able to enhance the positives and incorporate that into our practice going forward. If we can reach our patients and help treat them where they are, rather than them having to come to us, that may be a plus,” he said.

In the meantime, Dr. Jobbins presses on as the curve of COVID-19 cases flattens in Western Massachusetts and remains grateful that she chose to practice medicine.

“The commitment I have to being an educator in addition to being a physician is part of why I keep doing this,” Dr. Jobbins said. “I find this to be one of the most fulfilling jobs and careers you could ever have: being there for people when they need you the most. That’s really what a physician’s job is: being there for people when a family member has passed away or when they just need to talk because they’re having anxiety. At the end of the day, if we can impart that to those we work with and bring in a positive attitude, it’s infectious and it makes people see this is a reason we keep doing what we’re doing.”

She’s also been heartened by the kindness of strangers during this pandemic, from those who made and donated face shields when they were in short supply, to those who delivered food to the hospital as a gesture of thanks.

“I had a patient who made homemade masks and sent them to my office,” she said. “There’s obviously good and bad during this time, but I get hope from seeing all of the good things that are coming out of this, the whole idea of finding the light in the darkness.”

dbrunk@mdedge.com

A minimally invasive multicancer blood test used with standard-of-care screening is safe, effective, and feasible for use in routine clinical care, according to interim findings from a large, prospective study.

The DETECT-A blood test, an early version of the CancerSEEK test currently in development, effectively guided patient management in real time, in some cases leading to diagnosis of early cancer and potentially curative surgery in asymptomatic women with no history of cancer.

Nickolas Papadopoulos, PhD, of Johns Hopkins Medicine in Baltimore, reported these findings at the AACR virtual meeting I. The findings were simultaneously published in Science.

The study enrolled 10,006 women, aged 65-75 years, with no prior cancer diagnosis. After exclusion and loss to follow-up, 9,911 women remained.

There were 26 patients who had cancer detected by the DETECT-A blood test, 15 of whom underwent follow-up PET-CT imaging and 9 of whom underwent surgical excision. An additional 24 cancers were detected by standard screening, and 46 were detected by other means.

The positive predictive value of the blood test was 19%. When the blood test was combined with imaging, the positive predictive value was 41%.
 

Improving upon standard screening

“Standard-of-care screening [was used] for three different organs: breast, lung, and colon. It was more sensitive for breast cancer,” Dr. Papadopoulos noted. “Blood testing, though, identified cancer in 10 different organs.”

In fact, the DETECT-A blood test detected 14 of 45 cancers in 7 organs for which no standard screening test is available.

In addition, 12 cancers in 3 organs (breast, lung, and colon) were first detected by DETECT-A rather than by standard screening. This increased the sensitivity of cancer detection from 47% with standard screening alone to 71% with standard screening plus blood testing.

“More important, 65% [of the cancers detected by blood test] were localized or regional, which have higher chance of successful treatment with intent to cure,” Dr. Papadopoulos said.

DETECT-A covers regions of 16 commonly mutated genes and 9 proteins known to be associated with cancer. In this study, 57% of cancers were detected by mutations.
 

Safety and additional screening

DETECT-A also proved safe, “without incurring a large number of futile invasive follow-up tests,” Dr. Papadopoulos said.

In fact, only 1% of patients without cancer underwent PET-CT imaging, and only 0.22% underwent a “futile” invasive follow-up procedure.

Three surgeries occurred in patients who were counted as false-positives, but the surgeries were determined to be indicated, Dr. Papadopoulos said. He explained that one was for large colonic polyps with high-grade dysplasia that could not be removed endoscopically, one was for an in situ carcinoma of the appendix, and one was for a 10-cm ovarian lesion that was found to be a mucinous cystadenoma.

The investigators also analyzed whether the availability of a “liquid biopsy” test like DETECT-A would inadvertently reduce patients’ use of standard screening and found that it did not. Mammography screening habits after receiving the baseline DETECT-A blood test did not differ significantly from those prior to study enrollment.

These findings are important because early detection is a key factor in reducing cancer-specific morbidity and mortality, and although minimally invasive screening tests, including liquid biopsies like DETECT-A, hold great promise, prospective clinical studies of these new methods are needed to ensure that the anticipated benefits outweigh the potential risks, Dr. Papadopoulos explained.

“The problem is that most cancers are detected at advanced stages when they are difficult to treat,” he said. “The earlier cancer is detected, the greater the chance of successful treatment.”
 

Unanswered questions and future studies

This study demonstrates that it is feasible for a minimally invasive blood test to safely detect multiple cancer types in patients without a history of cancer and to enable treatment with curative intent, at least in a subset of individuals, Dr. Papadopoulos said. He added that the findings also inform the design of future randomized trials “to establish clinical utility, cost-effectiveness, and benefit-to-risk ratio of future tests.”

Further studies will also be required to determine the clinical validity and utility of the strategy of using liquid biopsy as a complement to standard-of-care screening, Dr. Papadopoulos said.

Invited discussant David G. Huntsman, MD, of the University of British Columbia in Vancouver, applauded the investigators, saying this study serves to “move the field forward.” However, it still isn’t clear how sensitivity and negative predictive value will be determined and what the optimal testing schedule is.

“This is a prospective study that will provide the data on how this assay will be used [and] whether it should be used going forward,” Dr. Huntsman said, noting that the “much bigger and more important question” is whether it improves survival.

Cost-effectiveness will also be critical, he said.

This research was supported by The Marcus Foundation, Lustgarten Foundation for Pancreatic Cancer Research, The Virginia and D.K. Ludwig Fund for Cancer Research, The Sol Goldman Center for Pancreatic Cancer Research, Susan Wojcicki and Dennis Troper, the Rolfe Foundation, The Conrad R. Hilton Foundation, The John Templeton Foundation, Burroughs Wellcome Career Award For Medical Scientists, and grants/contracts from the National Institutes of Health.

Dr. Papadopoulos disclosed relationships with Thrive Earlier Detection Inc., PGDx Inc., NeoPhore, Cage Pharma, and other companies. Dr. Huntsman is a founder, shareholder, and chief medical officer for Contextual Genomics.

sworcester@mdedge.com

SOURCE: Papadopoulos N et al. AACR 2020, Abstract CT022; Lennon AM et al. Science. 2020 Apr 28. pii: eabb9601. doi: 10.1126/science.abb9601.

A minimally invasive multicancer blood test used with standard-of-care screening is safe, effective, and feasible for use in routine clinical care, according to interim findings from a large, prospective study.

The DETECT-A blood test, an early version of the CancerSEEK test currently in development, effectively guided patient management in real time, in some cases leading to diagnosis of early cancer and potentially curative surgery in asymptomatic women with no history of cancer.

Nickolas Papadopoulos, PhD, of Johns Hopkins Medicine in Baltimore, reported these findings at the AACR virtual meeting I. The findings were simultaneously published in Science.

The study enrolled 10,006 women, aged 65-75 years, with no prior cancer diagnosis. After exclusion and loss to follow-up, 9,911 women remained.

There were 26 patients who had cancer detected by the DETECT-A blood test, 15 of whom underwent follow-up PET-CT imaging and 9 of whom underwent surgical excision. An additional 24 cancers were detected by standard screening, and 46 were detected by other means.

The positive predictive value of the blood test was 19%. When the blood test was combined with imaging, the positive predictive value was 41%.
 

Improving upon standard screening

“Standard-of-care screening [was used] for three different organs: breast, lung, and colon. It was more sensitive for breast cancer,” Dr. Papadopoulos noted. “Blood testing, though, identified cancer in 10 different organs.”

In fact, the DETECT-A blood test detected 14 of 45 cancers in 7 organs for which no standard screening test is available.

In addition, 12 cancers in 3 organs (breast, lung, and colon) were first detected by DETECT-A rather than by standard screening. This increased the sensitivity of cancer detection from 47% with standard screening alone to 71% with standard screening plus blood testing.

“More important, 65% [of the cancers detected by blood test] were localized or regional, which have higher chance of successful treatment with intent to cure,” Dr. Papadopoulos said.

DETECT-A covers regions of 16 commonly mutated genes and 9 proteins known to be associated with cancer. In this study, 57% of cancers were detected by mutations.
 

Safety and additional screening

DETECT-A also proved safe, “without incurring a large number of futile invasive follow-up tests,” Dr. Papadopoulos said.

In fact, only 1% of patients without cancer underwent PET-CT imaging, and only 0.22% underwent a “futile” invasive follow-up procedure.

Three surgeries occurred in patients who were counted as false-positives, but the surgeries were determined to be indicated, Dr. Papadopoulos said. He explained that one was for large colonic polyps with high-grade dysplasia that could not be removed endoscopically, one was for an in situ carcinoma of the appendix, and one was for a 10-cm ovarian lesion that was found to be a mucinous cystadenoma.

The investigators also analyzed whether the availability of a “liquid biopsy” test like DETECT-A would inadvertently reduce patients’ use of standard screening and found that it did not. Mammography screening habits after receiving the baseline DETECT-A blood test did not differ significantly from those prior to study enrollment.

These findings are important because early detection is a key factor in reducing cancer-specific morbidity and mortality, and although minimally invasive screening tests, including liquid biopsies like DETECT-A, hold great promise, prospective clinical studies of these new methods are needed to ensure that the anticipated benefits outweigh the potential risks, Dr. Papadopoulos explained.

“The problem is that most cancers are detected at advanced stages when they are difficult to treat,” he said. “The earlier cancer is detected, the greater the chance of successful treatment.”
 

Unanswered questions and future studies

This study demonstrates that it is feasible for a minimally invasive blood test to safely detect multiple cancer types in patients without a history of cancer and to enable treatment with curative intent, at least in a subset of individuals, Dr. Papadopoulos said. He added that the findings also inform the design of future randomized trials “to establish clinical utility, cost-effectiveness, and benefit-to-risk ratio of future tests.”

Further studies will also be required to determine the clinical validity and utility of the strategy of using liquid biopsy as a complement to standard-of-care screening, Dr. Papadopoulos said.

Invited discussant David G. Huntsman, MD, of the University of British Columbia in Vancouver, applauded the investigators, saying this study serves to “move the field forward.” However, it still isn’t clear how sensitivity and negative predictive value will be determined and what the optimal testing schedule is.

“This is a prospective study that will provide the data on how this assay will be used [and] whether it should be used going forward,” Dr. Huntsman said, noting that the “much bigger and more important question” is whether it improves survival.

Cost-effectiveness will also be critical, he said.

This research was supported by The Marcus Foundation, Lustgarten Foundation for Pancreatic Cancer Research, The Virginia and D.K. Ludwig Fund for Cancer Research, The Sol Goldman Center for Pancreatic Cancer Research, Susan Wojcicki and Dennis Troper, the Rolfe Foundation, The Conrad R. Hilton Foundation, The John Templeton Foundation, Burroughs Wellcome Career Award For Medical Scientists, and grants/contracts from the National Institutes of Health.

Dr. Papadopoulos disclosed relationships with Thrive Earlier Detection Inc., PGDx Inc., NeoPhore, Cage Pharma, and other companies. Dr. Huntsman is a founder, shareholder, and chief medical officer for Contextual Genomics.

sworcester@mdedge.com

SOURCE: Papadopoulos N et al. AACR 2020, Abstract CT022; Lennon AM et al. Science. 2020 Apr 28. pii: eabb9601. doi: 10.1126/science.abb9601.

A minimally invasive multicancer blood test used with standard-of-care screening is safe, effective, and feasible for use in routine clinical care, according to interim findings from a large, prospective study.

The DETECT-A blood test, an early version of the CancerSEEK test currently in development, effectively guided patient management in real time, in some cases leading to diagnosis of early cancer and potentially curative surgery in asymptomatic women with no history of cancer.

Nickolas Papadopoulos, PhD, of Johns Hopkins Medicine in Baltimore, reported these findings at the AACR virtual meeting I. The findings were simultaneously published in Science.

The study enrolled 10,006 women, aged 65-75 years, with no prior cancer diagnosis. After exclusion and loss to follow-up, 9,911 women remained.

There were 26 patients who had cancer detected by the DETECT-A blood test, 15 of whom underwent follow-up PET-CT imaging and 9 of whom underwent surgical excision. An additional 24 cancers were detected by standard screening, and 46 were detected by other means.

The positive predictive value of the blood test was 19%. When the blood test was combined with imaging, the positive predictive value was 41%.
 

Improving upon standard screening

“Standard-of-care screening [was used] for three different organs: breast, lung, and colon. It was more sensitive for breast cancer,” Dr. Papadopoulos noted. “Blood testing, though, identified cancer in 10 different organs.”

In fact, the DETECT-A blood test detected 14 of 45 cancers in 7 organs for which no standard screening test is available.

In addition, 12 cancers in 3 organs (breast, lung, and colon) were first detected by DETECT-A rather than by standard screening. This increased the sensitivity of cancer detection from 47% with standard screening alone to 71% with standard screening plus blood testing.

“More important, 65% [of the cancers detected by blood test] were localized or regional, which have higher chance of successful treatment with intent to cure,” Dr. Papadopoulos said.

DETECT-A covers regions of 16 commonly mutated genes and 9 proteins known to be associated with cancer. In this study, 57% of cancers were detected by mutations.
 

Safety and additional screening

DETECT-A also proved safe, “without incurring a large number of futile invasive follow-up tests,” Dr. Papadopoulos said.

In fact, only 1% of patients without cancer underwent PET-CT imaging, and only 0.22% underwent a “futile” invasive follow-up procedure.

Three surgeries occurred in patients who were counted as false-positives, but the surgeries were determined to be indicated, Dr. Papadopoulos said. He explained that one was for large colonic polyps with high-grade dysplasia that could not be removed endoscopically, one was for an in situ carcinoma of the appendix, and one was for a 10-cm ovarian lesion that was found to be a mucinous cystadenoma.

The investigators also analyzed whether the availability of a “liquid biopsy” test like DETECT-A would inadvertently reduce patients’ use of standard screening and found that it did not. Mammography screening habits after receiving the baseline DETECT-A blood test did not differ significantly from those prior to study enrollment.

These findings are important because early detection is a key factor in reducing cancer-specific morbidity and mortality, and although minimally invasive screening tests, including liquid biopsies like DETECT-A, hold great promise, prospective clinical studies of these new methods are needed to ensure that the anticipated benefits outweigh the potential risks, Dr. Papadopoulos explained.

“The problem is that most cancers are detected at advanced stages when they are difficult to treat,” he said. “The earlier cancer is detected, the greater the chance of successful treatment.”
 

Unanswered questions and future studies

This study demonstrates that it is feasible for a minimally invasive blood test to safely detect multiple cancer types in patients without a history of cancer and to enable treatment with curative intent, at least in a subset of individuals, Dr. Papadopoulos said. He added that the findings also inform the design of future randomized trials “to establish clinical utility, cost-effectiveness, and benefit-to-risk ratio of future tests.”

Further studies will also be required to determine the clinical validity and utility of the strategy of using liquid biopsy as a complement to standard-of-care screening, Dr. Papadopoulos said.

Invited discussant David G. Huntsman, MD, of the University of British Columbia in Vancouver, applauded the investigators, saying this study serves to “move the field forward.” However, it still isn’t clear how sensitivity and negative predictive value will be determined and what the optimal testing schedule is.

“This is a prospective study that will provide the data on how this assay will be used [and] whether it should be used going forward,” Dr. Huntsman said, noting that the “much bigger and more important question” is whether it improves survival.

Cost-effectiveness will also be critical, he said.

This research was supported by The Marcus Foundation, Lustgarten Foundation for Pancreatic Cancer Research, The Virginia and D.K. Ludwig Fund for Cancer Research, The Sol Goldman Center for Pancreatic Cancer Research, Susan Wojcicki and Dennis Troper, the Rolfe Foundation, The Conrad R. Hilton Foundation, The John Templeton Foundation, Burroughs Wellcome Career Award For Medical Scientists, and grants/contracts from the National Institutes of Health.

Dr. Papadopoulos disclosed relationships with Thrive Earlier Detection Inc., PGDx Inc., NeoPhore, Cage Pharma, and other companies. Dr. Huntsman is a founder, shareholder, and chief medical officer for Contextual Genomics.

sworcester@mdedge.com

SOURCE: Papadopoulos N et al. AACR 2020, Abstract CT022; Lennon AM et al. Science. 2020 Apr 28. pii: eabb9601. doi: 10.1126/science.abb9601.

Out-of-hospital cardiac arrests increased 58% during the peak of the COVID-19 outbreak in the hard-hit region of Lombardy, Italy, compared with the same period last year, a new analysis shows.

During the first 40 days of the outbreak beginning Feb. 21, four provinces in northern Italy reported 362 cases of out-of-hospital cardiac arrest compared with 229 during the same period in 2019.

The increases in these provinces varied in magnitude from 18% in Mantua, where there were 1,688 confirmed COVID-19 cases, to 187% in Lodi, which had 2,116 COVID-19 cases. The Cremona province, which had the highest number of COVID-19 cases at 3,869, saw a 143% increase in out-of-hospital cardiac arrests.

The mortality rate in the field was 14.9 percentage points higher in 2020 than in 2019 among patients in whom resuscitation was attempted by emergency medical services (EMS), Enrico Baldi, MD, University of Pavia, Italy, and colleagues reported in a letter April 29 in the New England Journal of Medicine.

“The sex and age of the patients were similar in the 2020 and 2019 periods, but in 2020, the incidence of out-of-hospital cardiac arrest due to a medical cause was 6.5 percentage points higher, the incidence of out-of-hospital cardiac arrest at home was 7.3 percentage points higher, and the incidence of unwitnessed cardiac arrest was 11.3 percentage points higher,” the authors wrote.

Patients were also less likely to receive cardiopulmonary resuscitation from bystanders in 2020 vs 2019 (–15.6 percentage points) and were more likely to die before reaching the hospital when resuscitation was attempted by EMS (+14.9 percentage points).

Among all patients, the death rate in the field increased 11.4 percentage points during the outbreak, from 77.3% in 2019 to 88.7% in 2020.

The cumulative incidence of out-of-hospital cardiac arrest in 2020 was “strongly associated” with the cumulative incidence of COVID-19 (Spearman rank correlation coefficient, 0.87; 95% confidence interval, 0.83-0.91) and the spike in cases “followed the time course of the COVID-19 outbreak,” the researchers noted.

A total of 103 patients, who arrested out of hospital and were diagnosed with or suspected of having COVID-19, “account for 77.4% of the increase in cases of out-of-hospital cardiac arrest observed in these provinces in 2020,” the investigators noted.

As the pandemic has taken hold, hospitals and physicians across the United States are also voicing concerns about the drop in the number of patients presenting with myocardial infarction (MI) or stroke.

Nearly one-third of Americans (29%) report having delayed or avoided medical care because of concerns of catching COVID-19, according to a new poll released April 28 from the American College of Emergency Physicians (ACEP) and Morning Consult, a global data research firm.

Despite many emergency departments reporting a decline in patient volume, 74% of respondents said they were worried about hospital wait times and overcrowding. Another 59% expressed concerns about being turned away from the hospital or doctor’s office.

At the same time, the survey found strong support for emergency physicians and 73% of respondents said they were concerned about overstressing the health care system.

The drop-off in Americans seeking care for MI and strokes nationally prompted eight professional societies – including ACEP, the American Heart Association, and the Association of Black Cardiologists – to issue a joint statement urging those experiencing symptoms to call 911 and seek care for these life-threatening events.

The authors have disclosed no relevant financial relationships.

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

Out-of-hospital cardiac arrests increased 58% during the peak of the COVID-19 outbreak in the hard-hit region of Lombardy, Italy, compared with the same period last year, a new analysis shows.

During the first 40 days of the outbreak beginning Feb. 21, four provinces in northern Italy reported 362 cases of out-of-hospital cardiac arrest compared with 229 during the same period in 2019.

The increases in these provinces varied in magnitude from 18% in Mantua, where there were 1,688 confirmed COVID-19 cases, to 187% in Lodi, which had 2,116 COVID-19 cases. The Cremona province, which had the highest number of COVID-19 cases at 3,869, saw a 143% increase in out-of-hospital cardiac arrests.

The mortality rate in the field was 14.9 percentage points higher in 2020 than in 2019 among patients in whom resuscitation was attempted by emergency medical services (EMS), Enrico Baldi, MD, University of Pavia, Italy, and colleagues reported in a letter April 29 in the New England Journal of Medicine.

“The sex and age of the patients were similar in the 2020 and 2019 periods, but in 2020, the incidence of out-of-hospital cardiac arrest due to a medical cause was 6.5 percentage points higher, the incidence of out-of-hospital cardiac arrest at home was 7.3 percentage points higher, and the incidence of unwitnessed cardiac arrest was 11.3 percentage points higher,” the authors wrote.

Patients were also less likely to receive cardiopulmonary resuscitation from bystanders in 2020 vs 2019 (–15.6 percentage points) and were more likely to die before reaching the hospital when resuscitation was attempted by EMS (+14.9 percentage points).

Among all patients, the death rate in the field increased 11.4 percentage points during the outbreak, from 77.3% in 2019 to 88.7% in 2020.

The cumulative incidence of out-of-hospital cardiac arrest in 2020 was “strongly associated” with the cumulative incidence of COVID-19 (Spearman rank correlation coefficient, 0.87; 95% confidence interval, 0.83-0.91) and the spike in cases “followed the time course of the COVID-19 outbreak,” the researchers noted.

A total of 103 patients, who arrested out of hospital and were diagnosed with or suspected of having COVID-19, “account for 77.4% of the increase in cases of out-of-hospital cardiac arrest observed in these provinces in 2020,” the investigators noted.

As the pandemic has taken hold, hospitals and physicians across the United States are also voicing concerns about the drop in the number of patients presenting with myocardial infarction (MI) or stroke.

Nearly one-third of Americans (29%) report having delayed or avoided medical care because of concerns of catching COVID-19, according to a new poll released April 28 from the American College of Emergency Physicians (ACEP) and Morning Consult, a global data research firm.

Despite many emergency departments reporting a decline in patient volume, 74% of respondents said they were worried about hospital wait times and overcrowding. Another 59% expressed concerns about being turned away from the hospital or doctor’s office.

At the same time, the survey found strong support for emergency physicians and 73% of respondents said they were concerned about overstressing the health care system.

The drop-off in Americans seeking care for MI and strokes nationally prompted eight professional societies – including ACEP, the American Heart Association, and the Association of Black Cardiologists – to issue a joint statement urging those experiencing symptoms to call 911 and seek care for these life-threatening events.

The authors have disclosed no relevant financial relationships.

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

Out-of-hospital cardiac arrests increased 58% during the peak of the COVID-19 outbreak in the hard-hit region of Lombardy, Italy, compared with the same period last year, a new analysis shows.

During the first 40 days of the outbreak beginning Feb. 21, four provinces in northern Italy reported 362 cases of out-of-hospital cardiac arrest compared with 229 during the same period in 2019.

The increases in these provinces varied in magnitude from 18% in Mantua, where there were 1,688 confirmed COVID-19 cases, to 187% in Lodi, which had 2,116 COVID-19 cases. The Cremona province, which had the highest number of COVID-19 cases at 3,869, saw a 143% increase in out-of-hospital cardiac arrests.

The mortality rate in the field was 14.9 percentage points higher in 2020 than in 2019 among patients in whom resuscitation was attempted by emergency medical services (EMS), Enrico Baldi, MD, University of Pavia, Italy, and colleagues reported in a letter April 29 in the New England Journal of Medicine.

“The sex and age of the patients were similar in the 2020 and 2019 periods, but in 2020, the incidence of out-of-hospital cardiac arrest due to a medical cause was 6.5 percentage points higher, the incidence of out-of-hospital cardiac arrest at home was 7.3 percentage points higher, and the incidence of unwitnessed cardiac arrest was 11.3 percentage points higher,” the authors wrote.

Patients were also less likely to receive cardiopulmonary resuscitation from bystanders in 2020 vs 2019 (–15.6 percentage points) and were more likely to die before reaching the hospital when resuscitation was attempted by EMS (+14.9 percentage points).

Among all patients, the death rate in the field increased 11.4 percentage points during the outbreak, from 77.3% in 2019 to 88.7% in 2020.

The cumulative incidence of out-of-hospital cardiac arrest in 2020 was “strongly associated” with the cumulative incidence of COVID-19 (Spearman rank correlation coefficient, 0.87; 95% confidence interval, 0.83-0.91) and the spike in cases “followed the time course of the COVID-19 outbreak,” the researchers noted.

A total of 103 patients, who arrested out of hospital and were diagnosed with or suspected of having COVID-19, “account for 77.4% of the increase in cases of out-of-hospital cardiac arrest observed in these provinces in 2020,” the investigators noted.

As the pandemic has taken hold, hospitals and physicians across the United States are also voicing concerns about the drop in the number of patients presenting with myocardial infarction (MI) or stroke.

Nearly one-third of Americans (29%) report having delayed or avoided medical care because of concerns of catching COVID-19, according to a new poll released April 28 from the American College of Emergency Physicians (ACEP) and Morning Consult, a global data research firm.

Despite many emergency departments reporting a decline in patient volume, 74% of respondents said they were worried about hospital wait times and overcrowding. Another 59% expressed concerns about being turned away from the hospital or doctor’s office.

At the same time, the survey found strong support for emergency physicians and 73% of respondents said they were concerned about overstressing the health care system.

The drop-off in Americans seeking care for MI and strokes nationally prompted eight professional societies – including ACEP, the American Heart Association, and the Association of Black Cardiologists – to issue a joint statement urging those experiencing symptoms to call 911 and seek care for these life-threatening events.

The authors have disclosed no relevant financial relationships.

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

SARS-CoV-2 and the disease it causes, COVID-19, continues to spread around the world with a devastating social and economic impact. Undoubtedly, health care workers are essential to overcoming this crisis. If these issues are left unaddressed, low morale, burnout, or absenteeism could lead to the collapse of health care systems.

Historically, the health care industry has been one of the most hazardous environments in which to work. Employees in this industry are constantly exposed to a complex variety of health and safety hazards.

Particularly, risks from biological exposure to diseases such as tuberculosis, HIV, and currently COVID-19 are taking a considerable toll on health care workers’ health and well-being. Health care workers are leaving their families to work extra shifts, dealing with limited resources, and navigating the chaos. On top of all that, they are sacrificing their lives through these uncertain times.

Despite their resilience, health care workers – like the general population – can have strong psychological reactions of anxiety and fear during a pandemic. Still, they are required to continue their work amid uncertainty and danger.
 

Current research studies on COVID-19

Several studies have identified the impact of working in this type of environment during previous pandemics and disasters. In a study of hospital employees in China during the SARS epidemic (2002-2003), Ping Wu, PhD, and colleagues found that 10% of the participants experienced high levels of posttraumatic stress.¹ In a similar study in Taiwan, researchers found that 17.3% of employees had developed significant mental health symptoms during the SARS outbreak.²

The impact of COVID-19 on health care workers seems to be much worse. A recent study from China indicates that 50.4% of hospital employees showed signs of depression, 44.6% had anxiety, and 34% had insomnia.³

Another recent cross-sectional study conducted by Lijun Kang, PhD, and associates evaluated the impact on mental health among health care workers in Wuhan, China, during the COVID-19 outbreak. This was the first study on the mental health of health care workers. This study recruited health care workers in Wuhan to participate in the survey from Jan. 29 to Feb. 4, 2020. The data were collected online with an anonymous, self-rated questionnaire that was distributed to all workstations. All subjects provided informed consent electronically prior to participating in the survey.

The survey questionnaire was made up of six components: primary demographic data, mental health assessment, risks of direct and indirect exposure to COVID-19, mental health care services accessed, psychological needs, and self-perceived health status, compared with that before the COVID-19 outbreak. A total of 994 health care workers responded to this survey, and the results are fascinating: 36.9% had subthreshold mental health distress (mean Patient Health Questionnaire–9 score, 2.4), 34.4% reported mild disturbances (mean PHQ-9, 5.4), 22.4% had moderate (mean PHQ-9, 9.0), and 6.2% reported severe disturbance (mean PHQ-9, 15.1). In this study, young women experienced more significant psychological distress. Regarding access to mental health services, 36.3% reported access to psychological materials, such as books on mental health; 50.4% used psychological resources available through media, such as online self-help coping methods; and 17.5% participated in counseling or psychotherapy.⁴

These findings emphasize the importance of being equipped to ensure the health and safety of health care workers through mental health interventions, both at work and in the community during this time of anxiety and uncertainty.

We are unaware of any current studies that are addressing the mental health needs of health care workers during the COVID-19 outbreak in United States. Future studies will become more critical in addressing this issue.

Risks to clinicians, families prevail

According to a recent report released by the Centers for Disease Control and Prevention, more than 9,000 health care workers across the United States had contracted COVID-19 as of mid-April, and 27 had died since the start of the pandemic.⁵

Health care workers are at risk around the globe, not only by the nature of their jobs but also by the shortage of personal protective equipment (PPE). In addition, the scarcity of N95 masks, respirators, and COVID-19 testing programs is causing the virus to spread among health care workers all over the world.

A study published recently by Celso Arango, MD, PhD, reported that 18% of staff at a hospital in Madrid had been infected with COVID-19. Dr. Arango speculated that transmission might be attributable to interactions with colleagues rather than with patients.⁶ We know, for example, that large proportions of people in China reportedly carried the virus while being asymptomatic.⁷ Those findings might not be generalizable, but they do suggest that an asymptomatic person could be a cause of contagion among professionals. Therefore, early screening and testing are critical – and should be priorities in health care settings.

Another problem clinicians can encounter is that, when they are called on to deal with very agitated patients, they might not get enough time to put on PPE. In addition, PPE can easily break and tear during the physical restraint process.

Working long hours is also putting a significant strain on health care workers and exposes them to the risk of infection. Also, health care workers not only worry about their safety but also fear bringing the virus to their families. They can also feel guilty about their conflicting feelings about exposing themselves and their families to risk. It is quite possible that, during this COVID-19 pandemic, health care workers will face a “care paradox,” in which they must choose between patients’ safety and their own. This care paradox can significantly contribute to a feeling of burnout, stress, and anxiety. Ultimately, this pandemic could lead to attrition ^{from the field at a time when we most need all hands on deck.8}

Further, according to a World Health Organization report on mental health and psychosocial consideration during the COVID-19 outbreak, some health care workers, unfortunately, experience avoidance by their family members or communities because of stigma, fear, and anxiety. This avoidance threatens to make an already challenging situation far worse for health care workers by increasing isolation.

Even after acute outbreak are over, the effects on health care workers can persist for years. In a follow-up study 13-26 months after the SARS outbreak, Robert G. Maunder, MD, and associates found that Toronto-area health care workers reported significantly higher levels of burnout, psychological distress, and posttraumatic stress. They were more likely to have reduced patient contact and work hours, and to have avoided behavioral consequences of stress.⁹ Exposure to stressful work conditions during a pandemic also might put hospital employees at a much higher risk of alcohol and substance use disorders.¹⁰
 

Potential solutions for improving care

COVID-19 has had a massive impact on the mental health of health care workers around the globe. Fortunately, there are evidence-based strategies aimed at mitigating the effects of this pandemic on health care workers. Fostering self-efficacy and optimism has been shown to improve coping and efficiency during disasters.⁹ Higher perceived workplace safety is associated with a lower risk of anxiety, depression, and posttraumatic stress among health care workers, while a lack of social support has been linked to adverse behavioral outcomes.¹⁰

A recent study found that, among Chinese physicians who cared for COVID-19 victims, more significant social support was associated with better sleep quality, greater self-effectiveness, and less psychological distress.¹¹ Positive leadership and a professional culture of trust, and openness with unambiguous communication have been shown to improve the engagement of the medical workforce.^12,13 Psychiatrists must advocate for the adoption of these practices in the workplace. Assessing and addressing mental health needs, in addition to the physical health of the health care workforce, is of utmost importance.

We can accomplish this in many ways, but we have to access our health care workers. Similar to our patient population, health care workers also experience stigma and anxiety tied to the disclosure of mental health challenges. This was reported in a study conducted in China, in which a specific psychological intervention using a hotline program was used for the medical team.¹⁴ This program provided psychological interventions/group activities aimed at releasing stress and anxiety. However, initially, the implementation of psychological interventions encountered obstacles.

For example, some members of the medical staff declined to participate in group or individual psychological interventions. Moreover, nurses showed irritability, unwillingness to join, and some staff refused, stating that “they did not have any problems.” Finally, psychological counselors regularly visited the facility to listen to difficulties or stories encountered by staff at work and provide support accordingly. More than 100 frontline medical staff participated and reported feeling better.¹⁵

Currently, several U.S. universities/institutes have implemented programs aimed at protecting the health and well-being of their staff during the COVID-19 pandemic. For instance, the department of psychiatry and behavioral health at Hackensack Meridian Health has put comprehensive system programs in place for at 16 affiliated medical centers and other patient care facilities to provide support during the COVID-19 crisis. A 24/7 team member support hotline connecting team members with a behavioral health specialist has become available when needed. This hotline is backed up by social workers, who provide mental health resources. In addition, another service called “Coping with COVID Talks” is available. This service is a virtual psychoeducational group facilitated by psychologists focusing on building coping skills and resilience.

Also, the consultation-liaison psychiatrists in the medical centers provide daily support to clinicians working in ICUs. These efforts have led to paradoxical benefits for employers, further leading to less commuting, more safety, and enhanced productivity for the clinician, according to Ramon Solhkhah, MD, MBA, chairman of the psychiatry department.¹⁶

Some universities, such as the University of North Carolina at Chapel Hill, have created mental health/telehealth support for health care workers, where they are conducting webinars on coping with uncertainty tied to COVID-19.¹⁷ The University of California, San Francisco, also has been a leader in this effort. That institution has employed its psychiatric workforce as volunteers – encouraging health care workers to use digital health apps and referral resources. Also, these volunteers provide peer counseling, phone support, and spiritual counseling to their health care workers.¹⁸

These approaches are crucial in this uncertain, challenging time. Our mental health system is deeply flawed, understaffed, and not well prepared to manage the mental health issues among health care workers. Psychiatric institutes/facilities should follow comprehensive and multifaceted approaches to combat the COVID-19 crisis. Several preventive measures can be considered in coping with this pandemic, such as stress reduction, mindfulness, and disseminating educational materials. Also, increased use of technology, such as in-the-moment measures, development of hotlines, crisis support, and treatment telepsychiatry for therapy and medication, should play a pivotal role in addressing the mental health needs of health care workers.

In addition, it is expected that, as a nation, we will see a surge of mental health needs for illnesses such as depression and PTSD, just as we do after “natural disasters” caused by a variety of reasons, including economic downturns. After the SARS outbreak in 2003, for example, health care workers showed symptoms of PTSD. The COVID-19 pandemic could have a similar impact.

The severity of mental health challenges among clinicians cannot be predicted at this time, but we can speculate that the traumatic impact of COVID-19 will prove long lasting, particularly among clinicians who served vulnerable populations and witnessed suffering, misery, and deaths. The long-term consequences might range from stress and anxiety to fear, depression, and PTSD. Implementation of mental health programs/psychological interventions/support will reduce the impact of mental health issues among these clinicians.

We must think about the best ways to optimize mental health among health care workers while also come up with innovative ways to target this at-risk group. The mental health of people who are saving lives – our frontline heroes – should be taken into consideration seriously around the globe. We also must prioritize the mental health of these workers during this unprecedented, challenging, and anxiety-provoking time.

Dr. Malik and Mr. Van Wert are affiliated with Johns Hopkins University, Baltimore. Dr. Kumari, Dr. Afzal, Dr. Doumas, and Dr. Solhkhah are affiliated with Hackensack Meridian Health at Ocean Medical Center, Brick, N.J. All six authors disclosed having no conflicts of interest. The authors would like to thank Vinay Kumar for his assistance with the literature review and for proofreading and editing this article.

References

1. Wu P et al. Can J Psychiatry. 2009;54(5):302-11.

2. Lu YC et al. Psychother Psychosom. 2006;75(6):370-5.

3. Lai J et al. JAMA Netw Open. 2020;3(3):e203976.

4. Kang L et al. Brain Behav Immun. 2020 Mar 30. doi: 10.1016/j.bbi.2020.03.028.

5. Centers for Disease Control and Prevention COVID-19 Response Team. MMWR. 2020 Apr 17;69(15):477-81.

6. Arango C. Biol Psychiatry. 2020 Apr 8. doi: 10.1016/j.biopsych.2020.04.003.

7. Day M. BMJ. 2020 Apr 2. doi: 10.1136/bmj.m1375.

8. Kirsch T. “Coronavirus, COVID-19: What happens if health care workers stop showing up?” The Atlantic. 2020 Mar 24.

9. Maunder RG et al. Emerg Infect Dis. 2006;12(12):1924-32.

10. Wu P et al. Alcohol Alcohol. 2008;43(6):706-12.

11. Brooks SK et al. BMC Psychol. 2016 Apr 26;4:18.

12. Smith BW et al. Am J Infect Control. 2009; 37:371-80.

13. Chen Q et al. Lancet Psychiatry. 2020 Apr 1;7(14):PE15-6.

14. Xiao H et al. Med Sci Monit. 2020;26:e923549.

15. Bergus GR et al. Acad Med. 2001;76:1148-52.

16. Bergeron T. “Working from home will be stressful. Here’s how employees (and employers) can handle it.” roi-nj.com. 2020 Mar 23.

17. UNChealthcare.org. “Mental Health/Emotional Support Resources for Coworkers and Providers Coping with COVID-19.”

18. Psych.ucsf.edu/coronoavirus. “Resources to Support Your Mental Health During the COVID-19 Outbreak.”

SARS-CoV-2 and the disease it causes, COVID-19, continues to spread around the world with a devastating social and economic impact. Undoubtedly, health care workers are essential to overcoming this crisis. If these issues are left unaddressed, low morale, burnout, or absenteeism could lead to the collapse of health care systems.

Historically, the health care industry has been one of the most hazardous environments in which to work. Employees in this industry are constantly exposed to a complex variety of health and safety hazards.

Particularly, risks from biological exposure to diseases such as tuberculosis, HIV, and currently COVID-19 are taking a considerable toll on health care workers’ health and well-being. Health care workers are leaving their families to work extra shifts, dealing with limited resources, and navigating the chaos. On top of all that, they are sacrificing their lives through these uncertain times.

Despite their resilience, health care workers – like the general population – can have strong psychological reactions of anxiety and fear during a pandemic. Still, they are required to continue their work amid uncertainty and danger.
 

Current research studies on COVID-19

Several studies have identified the impact of working in this type of environment during previous pandemics and disasters. In a study of hospital employees in China during the SARS epidemic (2002-2003), Ping Wu, PhD, and colleagues found that 10% of the participants experienced high levels of posttraumatic stress.¹ In a similar study in Taiwan, researchers found that 17.3% of employees had developed significant mental health symptoms during the SARS outbreak.²

The impact of COVID-19 on health care workers seems to be much worse. A recent study from China indicates that 50.4% of hospital employees showed signs of depression, 44.6% had anxiety, and 34% had insomnia.³

Another recent cross-sectional study conducted by Lijun Kang, PhD, and associates evaluated the impact on mental health among health care workers in Wuhan, China, during the COVID-19 outbreak. This was the first study on the mental health of health care workers. This study recruited health care workers in Wuhan to participate in the survey from Jan. 29 to Feb. 4, 2020. The data were collected online with an anonymous, self-rated questionnaire that was distributed to all workstations. All subjects provided informed consent electronically prior to participating in the survey.

The survey questionnaire was made up of six components: primary demographic data, mental health assessment, risks of direct and indirect exposure to COVID-19, mental health care services accessed, psychological needs, and self-perceived health status, compared with that before the COVID-19 outbreak. A total of 994 health care workers responded to this survey, and the results are fascinating: 36.9% had subthreshold mental health distress (mean Patient Health Questionnaire–9 score, 2.4), 34.4% reported mild disturbances (mean PHQ-9, 5.4), 22.4% had moderate (mean PHQ-9, 9.0), and 6.2% reported severe disturbance (mean PHQ-9, 15.1). In this study, young women experienced more significant psychological distress. Regarding access to mental health services, 36.3% reported access to psychological materials, such as books on mental health; 50.4% used psychological resources available through media, such as online self-help coping methods; and 17.5% participated in counseling or psychotherapy.⁴

These findings emphasize the importance of being equipped to ensure the health and safety of health care workers through mental health interventions, both at work and in the community during this time of anxiety and uncertainty.

We are unaware of any current studies that are addressing the mental health needs of health care workers during the COVID-19 outbreak in United States. Future studies will become more critical in addressing this issue.

Risks to clinicians, families prevail

According to a recent report released by the Centers for Disease Control and Prevention, more than 9,000 health care workers across the United States had contracted COVID-19 as of mid-April, and 27 had died since the start of the pandemic.⁵

Health care workers are at risk around the globe, not only by the nature of their jobs but also by the shortage of personal protective equipment (PPE). In addition, the scarcity of N95 masks, respirators, and COVID-19 testing programs is causing the virus to spread among health care workers all over the world.

A study published recently by Celso Arango, MD, PhD, reported that 18% of staff at a hospital in Madrid had been infected with COVID-19. Dr. Arango speculated that transmission might be attributable to interactions with colleagues rather than with patients.⁶ We know, for example, that large proportions of people in China reportedly carried the virus while being asymptomatic.⁷ Those findings might not be generalizable, but they do suggest that an asymptomatic person could be a cause of contagion among professionals. Therefore, early screening and testing are critical – and should be priorities in health care settings.

Another problem clinicians can encounter is that, when they are called on to deal with very agitated patients, they might not get enough time to put on PPE. In addition, PPE can easily break and tear during the physical restraint process.

Working long hours is also putting a significant strain on health care workers and exposes them to the risk of infection. Also, health care workers not only worry about their safety but also fear bringing the virus to their families. They can also feel guilty about their conflicting feelings about exposing themselves and their families to risk. It is quite possible that, during this COVID-19 pandemic, health care workers will face a “care paradox,” in which they must choose between patients’ safety and their own. This care paradox can significantly contribute to a feeling of burnout, stress, and anxiety. Ultimately, this pandemic could lead to attrition ^{from the field at a time when we most need all hands on deck.8}

Further, according to a World Health Organization report on mental health and psychosocial consideration during the COVID-19 outbreak, some health care workers, unfortunately, experience avoidance by their family members or communities because of stigma, fear, and anxiety. This avoidance threatens to make an already challenging situation far worse for health care workers by increasing isolation.

Even after acute outbreak are over, the effects on health care workers can persist for years. In a follow-up study 13-26 months after the SARS outbreak, Robert G. Maunder, MD, and associates found that Toronto-area health care workers reported significantly higher levels of burnout, psychological distress, and posttraumatic stress. They were more likely to have reduced patient contact and work hours, and to have avoided behavioral consequences of stress.⁹ Exposure to stressful work conditions during a pandemic also might put hospital employees at a much higher risk of alcohol and substance use disorders.¹⁰
 

Potential solutions for improving care

COVID-19 has had a massive impact on the mental health of health care workers around the globe. Fortunately, there are evidence-based strategies aimed at mitigating the effects of this pandemic on health care workers. Fostering self-efficacy and optimism has been shown to improve coping and efficiency during disasters.⁹ Higher perceived workplace safety is associated with a lower risk of anxiety, depression, and posttraumatic stress among health care workers, while a lack of social support has been linked to adverse behavioral outcomes.¹⁰

A recent study found that, among Chinese physicians who cared for COVID-19 victims, more significant social support was associated with better sleep quality, greater self-effectiveness, and less psychological distress.¹¹ Positive leadership and a professional culture of trust, and openness with unambiguous communication have been shown to improve the engagement of the medical workforce.^12,13 Psychiatrists must advocate for the adoption of these practices in the workplace. Assessing and addressing mental health needs, in addition to the physical health of the health care workforce, is of utmost importance.

We can accomplish this in many ways, but we have to access our health care workers. Similar to our patient population, health care workers also experience stigma and anxiety tied to the disclosure of mental health challenges. This was reported in a study conducted in China, in which a specific psychological intervention using a hotline program was used for the medical team.¹⁴ This program provided psychological interventions/group activities aimed at releasing stress and anxiety. However, initially, the implementation of psychological interventions encountered obstacles.

For example, some members of the medical staff declined to participate in group or individual psychological interventions. Moreover, nurses showed irritability, unwillingness to join, and some staff refused, stating that “they did not have any problems.” Finally, psychological counselors regularly visited the facility to listen to difficulties or stories encountered by staff at work and provide support accordingly. More than 100 frontline medical staff participated and reported feeling better.¹⁵

Currently, several U.S. universities/institutes have implemented programs aimed at protecting the health and well-being of their staff during the COVID-19 pandemic. For instance, the department of psychiatry and behavioral health at Hackensack Meridian Health has put comprehensive system programs in place for at 16 affiliated medical centers and other patient care facilities to provide support during the COVID-19 crisis. A 24/7 team member support hotline connecting team members with a behavioral health specialist has become available when needed. This hotline is backed up by social workers, who provide mental health resources. In addition, another service called “Coping with COVID Talks” is available. This service is a virtual psychoeducational group facilitated by psychologists focusing on building coping skills and resilience.

Also, the consultation-liaison psychiatrists in the medical centers provide daily support to clinicians working in ICUs. These efforts have led to paradoxical benefits for employers, further leading to less commuting, more safety, and enhanced productivity for the clinician, according to Ramon Solhkhah, MD, MBA, chairman of the psychiatry department.¹⁶

Some universities, such as the University of North Carolina at Chapel Hill, have created mental health/telehealth support for health care workers, where they are conducting webinars on coping with uncertainty tied to COVID-19.¹⁷ The University of California, San Francisco, also has been a leader in this effort. That institution has employed its psychiatric workforce as volunteers – encouraging health care workers to use digital health apps and referral resources. Also, these volunteers provide peer counseling, phone support, and spiritual counseling to their health care workers.¹⁸

These approaches are crucial in this uncertain, challenging time. Our mental health system is deeply flawed, understaffed, and not well prepared to manage the mental health issues among health care workers. Psychiatric institutes/facilities should follow comprehensive and multifaceted approaches to combat the COVID-19 crisis. Several preventive measures can be considered in coping with this pandemic, such as stress reduction, mindfulness, and disseminating educational materials. Also, increased use of technology, such as in-the-moment measures, development of hotlines, crisis support, and treatment telepsychiatry for therapy and medication, should play a pivotal role in addressing the mental health needs of health care workers.

In addition, it is expected that, as a nation, we will see a surge of mental health needs for illnesses such as depression and PTSD, just as we do after “natural disasters” caused by a variety of reasons, including economic downturns. After the SARS outbreak in 2003, for example, health care workers showed symptoms of PTSD. The COVID-19 pandemic could have a similar impact.

The severity of mental health challenges among clinicians cannot be predicted at this time, but we can speculate that the traumatic impact of COVID-19 will prove long lasting, particularly among clinicians who served vulnerable populations and witnessed suffering, misery, and deaths. The long-term consequences might range from stress and anxiety to fear, depression, and PTSD. Implementation of mental health programs/psychological interventions/support will reduce the impact of mental health issues among these clinicians.

We must think about the best ways to optimize mental health among health care workers while also come up with innovative ways to target this at-risk group. The mental health of people who are saving lives – our frontline heroes – should be taken into consideration seriously around the globe. We also must prioritize the mental health of these workers during this unprecedented, challenging, and anxiety-provoking time.

Dr. Malik and Mr. Van Wert are affiliated with Johns Hopkins University, Baltimore. Dr. Kumari, Dr. Afzal, Dr. Doumas, and Dr. Solhkhah are affiliated with Hackensack Meridian Health at Ocean Medical Center, Brick, N.J. All six authors disclosed having no conflicts of interest. The authors would like to thank Vinay Kumar for his assistance with the literature review and for proofreading and editing this article.

References

1. Wu P et al. Can J Psychiatry. 2009;54(5):302-11.

2. Lu YC et al. Psychother Psychosom. 2006;75(6):370-5.

3. Lai J et al. JAMA Netw Open. 2020;3(3):e203976.

4. Kang L et al. Brain Behav Immun. 2020 Mar 30. doi: 10.1016/j.bbi.2020.03.028.

5. Centers for Disease Control and Prevention COVID-19 Response Team. MMWR. 2020 Apr 17;69(15):477-81.

6. Arango C. Biol Psychiatry. 2020 Apr 8. doi: 10.1016/j.biopsych.2020.04.003.

7. Day M. BMJ. 2020 Apr 2. doi: 10.1136/bmj.m1375.

8. Kirsch T. “Coronavirus, COVID-19: What happens if health care workers stop showing up?” The Atlantic. 2020 Mar 24.

9. Maunder RG et al. Emerg Infect Dis. 2006;12(12):1924-32.

10. Wu P et al. Alcohol Alcohol. 2008;43(6):706-12.

11. Brooks SK et al. BMC Psychol. 2016 Apr 26;4:18.

12. Smith BW et al. Am J Infect Control. 2009; 37:371-80.

13. Chen Q et al. Lancet Psychiatry. 2020 Apr 1;7(14):PE15-6.

14. Xiao H et al. Med Sci Monit. 2020;26:e923549.

15. Bergus GR et al. Acad Med. 2001;76:1148-52.

16. Bergeron T. “Working from home will be stressful. Here’s how employees (and employers) can handle it.” roi-nj.com. 2020 Mar 23.

17. UNChealthcare.org. “Mental Health/Emotional Support Resources for Coworkers and Providers Coping with COVID-19.”

18. Psych.ucsf.edu/coronoavirus. “Resources to Support Your Mental Health During the COVID-19 Outbreak.”

SARS-CoV-2 and the disease it causes, COVID-19, continues to spread around the world with a devastating social and economic impact. Undoubtedly, health care workers are essential to overcoming this crisis. If these issues are left unaddressed, low morale, burnout, or absenteeism could lead to the collapse of health care systems.

Historically, the health care industry has been one of the most hazardous environments in which to work. Employees in this industry are constantly exposed to a complex variety of health and safety hazards.

Particularly, risks from biological exposure to diseases such as tuberculosis, HIV, and currently COVID-19 are taking a considerable toll on health care workers’ health and well-being. Health care workers are leaving their families to work extra shifts, dealing with limited resources, and navigating the chaos. On top of all that, they are sacrificing their lives through these uncertain times.

Despite their resilience, health care workers – like the general population – can have strong psychological reactions of anxiety and fear during a pandemic. Still, they are required to continue their work amid uncertainty and danger.
 

Current research studies on COVID-19

Several studies have identified the impact of working in this type of environment during previous pandemics and disasters. In a study of hospital employees in China during the SARS epidemic (2002-2003), Ping Wu, PhD, and colleagues found that 10% of the participants experienced high levels of posttraumatic stress.¹ In a similar study in Taiwan, researchers found that 17.3% of employees had developed significant mental health symptoms during the SARS outbreak.²

The impact of COVID-19 on health care workers seems to be much worse. A recent study from China indicates that 50.4% of hospital employees showed signs of depression, 44.6% had anxiety, and 34% had insomnia.³

Another recent cross-sectional study conducted by Lijun Kang, PhD, and associates evaluated the impact on mental health among health care workers in Wuhan, China, during the COVID-19 outbreak. This was the first study on the mental health of health care workers. This study recruited health care workers in Wuhan to participate in the survey from Jan. 29 to Feb. 4, 2020. The data were collected online with an anonymous, self-rated questionnaire that was distributed to all workstations. All subjects provided informed consent electronically prior to participating in the survey.

The survey questionnaire was made up of six components: primary demographic data, mental health assessment, risks of direct and indirect exposure to COVID-19, mental health care services accessed, psychological needs, and self-perceived health status, compared with that before the COVID-19 outbreak. A total of 994 health care workers responded to this survey, and the results are fascinating: 36.9% had subthreshold mental health distress (mean Patient Health Questionnaire–9 score, 2.4), 34.4% reported mild disturbances (mean PHQ-9, 5.4), 22.4% had moderate (mean PHQ-9, 9.0), and 6.2% reported severe disturbance (mean PHQ-9, 15.1). In this study, young women experienced more significant psychological distress. Regarding access to mental health services, 36.3% reported access to psychological materials, such as books on mental health; 50.4% used psychological resources available through media, such as online self-help coping methods; and 17.5% participated in counseling or psychotherapy.⁴

These findings emphasize the importance of being equipped to ensure the health and safety of health care workers through mental health interventions, both at work and in the community during this time of anxiety and uncertainty.

We are unaware of any current studies that are addressing the mental health needs of health care workers during the COVID-19 outbreak in United States. Future studies will become more critical in addressing this issue.

Risks to clinicians, families prevail

According to a recent report released by the Centers for Disease Control and Prevention, more than 9,000 health care workers across the United States had contracted COVID-19 as of mid-April, and 27 had died since the start of the pandemic.⁵

Health care workers are at risk around the globe, not only by the nature of their jobs but also by the shortage of personal protective equipment (PPE). In addition, the scarcity of N95 masks, respirators, and COVID-19 testing programs is causing the virus to spread among health care workers all over the world.

A study published recently by Celso Arango, MD, PhD, reported that 18% of staff at a hospital in Madrid had been infected with COVID-19. Dr. Arango speculated that transmission might be attributable to interactions with colleagues rather than with patients.⁶ We know, for example, that large proportions of people in China reportedly carried the virus while being asymptomatic.⁷ Those findings might not be generalizable, but they do suggest that an asymptomatic person could be a cause of contagion among professionals. Therefore, early screening and testing are critical – and should be priorities in health care settings.

Another problem clinicians can encounter is that, when they are called on to deal with very agitated patients, they might not get enough time to put on PPE. In addition, PPE can easily break and tear during the physical restraint process.

Working long hours is also putting a significant strain on health care workers and exposes them to the risk of infection. Also, health care workers not only worry about their safety but also fear bringing the virus to their families. They can also feel guilty about their conflicting feelings about exposing themselves and their families to risk. It is quite possible that, during this COVID-19 pandemic, health care workers will face a “care paradox,” in which they must choose between patients’ safety and their own. This care paradox can significantly contribute to a feeling of burnout, stress, and anxiety. Ultimately, this pandemic could lead to attrition ^{from the field at a time when we most need all hands on deck.8}

Further, according to a World Health Organization report on mental health and psychosocial consideration during the COVID-19 outbreak, some health care workers, unfortunately, experience avoidance by their family members or communities because of stigma, fear, and anxiety. This avoidance threatens to make an already challenging situation far worse for health care workers by increasing isolation.

Even after acute outbreak are over, the effects on health care workers can persist for years. In a follow-up study 13-26 months after the SARS outbreak, Robert G. Maunder, MD, and associates found that Toronto-area health care workers reported significantly higher levels of burnout, psychological distress, and posttraumatic stress. They were more likely to have reduced patient contact and work hours, and to have avoided behavioral consequences of stress.⁹ Exposure to stressful work conditions during a pandemic also might put hospital employees at a much higher risk of alcohol and substance use disorders.¹⁰
 

Potential solutions for improving care

COVID-19 has had a massive impact on the mental health of health care workers around the globe. Fortunately, there are evidence-based strategies aimed at mitigating the effects of this pandemic on health care workers. Fostering self-efficacy and optimism has been shown to improve coping and efficiency during disasters.⁹ Higher perceived workplace safety is associated with a lower risk of anxiety, depression, and posttraumatic stress among health care workers, while a lack of social support has been linked to adverse behavioral outcomes.¹⁰

A recent study found that, among Chinese physicians who cared for COVID-19 victims, more significant social support was associated with better sleep quality, greater self-effectiveness, and less psychological distress.¹¹ Positive leadership and a professional culture of trust, and openness with unambiguous communication have been shown to improve the engagement of the medical workforce.^12,13 Psychiatrists must advocate for the adoption of these practices in the workplace. Assessing and addressing mental health needs, in addition to the physical health of the health care workforce, is of utmost importance.

We can accomplish this in many ways, but we have to access our health care workers. Similar to our patient population, health care workers also experience stigma and anxiety tied to the disclosure of mental health challenges. This was reported in a study conducted in China, in which a specific psychological intervention using a hotline program was used for the medical team.¹⁴ This program provided psychological interventions/group activities aimed at releasing stress and anxiety. However, initially, the implementation of psychological interventions encountered obstacles.

For example, some members of the medical staff declined to participate in group or individual psychological interventions. Moreover, nurses showed irritability, unwillingness to join, and some staff refused, stating that “they did not have any problems.” Finally, psychological counselors regularly visited the facility to listen to difficulties or stories encountered by staff at work and provide support accordingly. More than 100 frontline medical staff participated and reported feeling better.¹⁵

Currently, several U.S. universities/institutes have implemented programs aimed at protecting the health and well-being of their staff during the COVID-19 pandemic. For instance, the department of psychiatry and behavioral health at Hackensack Meridian Health has put comprehensive system programs in place for at 16 affiliated medical centers and other patient care facilities to provide support during the COVID-19 crisis. A 24/7 team member support hotline connecting team members with a behavioral health specialist has become available when needed. This hotline is backed up by social workers, who provide mental health resources. In addition, another service called “Coping with COVID Talks” is available. This service is a virtual psychoeducational group facilitated by psychologists focusing on building coping skills and resilience.

Also, the consultation-liaison psychiatrists in the medical centers provide daily support to clinicians working in ICUs. These efforts have led to paradoxical benefits for employers, further leading to less commuting, more safety, and enhanced productivity for the clinician, according to Ramon Solhkhah, MD, MBA, chairman of the psychiatry department.¹⁶

Some universities, such as the University of North Carolina at Chapel Hill, have created mental health/telehealth support for health care workers, where they are conducting webinars on coping with uncertainty tied to COVID-19.¹⁷ The University of California, San Francisco, also has been a leader in this effort. That institution has employed its psychiatric workforce as volunteers – encouraging health care workers to use digital health apps and referral resources. Also, these volunteers provide peer counseling, phone support, and spiritual counseling to their health care workers.¹⁸

These approaches are crucial in this uncertain, challenging time. Our mental health system is deeply flawed, understaffed, and not well prepared to manage the mental health issues among health care workers. Psychiatric institutes/facilities should follow comprehensive and multifaceted approaches to combat the COVID-19 crisis. Several preventive measures can be considered in coping with this pandemic, such as stress reduction, mindfulness, and disseminating educational materials. Also, increased use of technology, such as in-the-moment measures, development of hotlines, crisis support, and treatment telepsychiatry for therapy and medication, should play a pivotal role in addressing the mental health needs of health care workers.

In addition, it is expected that, as a nation, we will see a surge of mental health needs for illnesses such as depression and PTSD, just as we do after “natural disasters” caused by a variety of reasons, including economic downturns. After the SARS outbreak in 2003, for example, health care workers showed symptoms of PTSD. The COVID-19 pandemic could have a similar impact.

The severity of mental health challenges among clinicians cannot be predicted at this time, but we can speculate that the traumatic impact of COVID-19 will prove long lasting, particularly among clinicians who served vulnerable populations and witnessed suffering, misery, and deaths. The long-term consequences might range from stress and anxiety to fear, depression, and PTSD. Implementation of mental health programs/psychological interventions/support will reduce the impact of mental health issues among these clinicians.

We must think about the best ways to optimize mental health among health care workers while also come up with innovative ways to target this at-risk group. The mental health of people who are saving lives – our frontline heroes – should be taken into consideration seriously around the globe. We also must prioritize the mental health of these workers during this unprecedented, challenging, and anxiety-provoking time.

Dr. Malik and Mr. Van Wert are affiliated with Johns Hopkins University, Baltimore. Dr. Kumari, Dr. Afzal, Dr. Doumas, and Dr. Solhkhah are affiliated with Hackensack Meridian Health at Ocean Medical Center, Brick, N.J. All six authors disclosed having no conflicts of interest. The authors would like to thank Vinay Kumar for his assistance with the literature review and for proofreading and editing this article.

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