Chronic lymphocytic leukemia (CLL) is the most common leukemia diagnosed in developed countries, with an estimated 21,040 new diagnoses of CLL expected in the US in 2020. ^1-3 CLL is an indolent cancer characterized by the accumulation of B-lymphocytes in the blood, marrow, and lymphoid tissues. ⁴ It has a heterogeneous clinical course; the majority of patients are observed or receive delayed treatment following diagnosis, while a minority of patients require immediate treatment. After first-line treatment, some patients experience prolonged remissions while others require retreatment within 1 or 2 years. Fortunately, advances in cancer biology and therapeutics in the last decade have increased the number of treatment options available for patients with CLL.

Until recently, most CLL treatments relied on a chemotherapy or a chemoimmunotherapy backbone; however, the last few years have seen novel therapies introduced, such as small molecule inhibitors to target molecular pathways that promote the normal development, expansion, and survival of B-cells.⁵ One such therapy is ibrutinib, a targeted Bruton tyrosine kinase inhibitor that received accelerated approval by the US Food and Drug Administration (FDA) in February 2014 for patients with CLL who received at least 1 prior therapy. The FDA later expanded this approval to include use of ibrutinib in patients with CLL with relapsed or refractory disease, with or without chromosome 17p deletion. In 2016, based on data from the RESONATE-17 study, the FDA approved ibrutinib for first-line therapy in patients with CLL.⁶

Ibrutinib’s efficacy, ease of administration and dosing (all doses are oral and fixed, rather than based on weight or body surface area), and relatively favorable safety profile have resulted in a rapid growth in its adoption.⁷ Since its adverse event (AE) profile is generally more tolerable than that of a typical chemoimmunotherapy, its use in older patients with CLL and patients with significant comorbidities is particularly appealing.⁸

However, the results of some clinical trials suggest an association between treatment with ibrutinib and an increased risk of bleeding-related events of any grade (44%) and major bleeding events (4%).^7,8 The incidence of major bleeding events was reported to be higher (9%) in one clinical trial and at 5-year follow-up, although this trial did not exclude patients receiving concomitant oral anticoagulation with warfarin.^6,9

Heterogeneity in clinical trials’ definitions of major bleeding confounded the ability to calculate bleeding risk in patients treated with ibrutinib in a systematic review and meta-analysis that called for more data.¹⁰ Additionally, patients with factors that might increase the risk of major bleeding with ibrutinib treatment were likely underrepresented in clinical trials, given the carefully selected nature of clinical trial subjects. These factors include renal or hepatic disease, gastrointestinal disease, and use of a number of concomitant medications such as antiplatelets or anticoagulant medications. Accounting for use of the latter is particularly important because patients who develop atrial fibrillation (Afib), one of the recognized AEs of treatment with ibrutinib, often are treated with anticoagulant medications in order to decrease the risk of stroke or other thromboembolic complications.

Methods

The VHA maintains the centralized US Department of Veterans Affairs Cancer Registry System (VACRS), with electronic medical record data and other sources captured in its Corporate Data Warehouse (CDW). The VHA CDW is a national repository comprising data from several VHA clinical and administrative systems. The CDW includes patient identifiers; demographics; vital status; lab information; administrative information (such as diagnostic International Statistical Classification of Diseases and Related Health Problems [ICD-9] codes); medication dispensation tables (such as outpatient fill); IV package information; and notes from radiology, pathology, outpatient and inpatient admission, discharge, and daily progress.

Registrars abstract all cancer cases within the VHA system (or diagnosed outside the VHA, if patients subsequently receive treatment in the VHA). It is estimated that VACRS captures 3% of cancer cases in the US.¹² Like most registries, VACRS captures data such as diagnosis, age, gender, race, and vital status.

Study Definitions

Prevalence of comorbidities that could increase bleeding risk was determined using administrative ICD-9-CM codes. Liver disease was identified by presence of cirrhosis, hepatitis C virus, or alcoholic liver disease using administrative codes validated by Kramer and colleagues, who reported positive and negative predictive values of 90% and 87% for cirrhosis, 93% and 92% for hepatitis C virus, and 71% and 98% for alcoholic liver disease.¹³ Similarly, end-stage liver disease was identified using a validated coding algorithm developed by Goldberg and colleagues, with a positive predictive value of 89.3%.¹⁴ The presence of controlled or uncontrolled diabetes mellitus (DM) was identified using the procedure described by Guzman and colleagues.¹⁵ Quan’s algorithm was used to calculate Charlson Comorbidity Index (CCI) based on ICD-9-CM codes for inpatient and outpatient visits within a 6-month lookback period prior to treatment initiation.¹⁶

A major bleeding event was defined as a hospitalization with an ICD-9-CM code suggestive of major bleeding as the primary reason, as defined by Lane and colleagues in their study of major bleeding related to warfarin in a cohort of patients treated within the VHA.¹⁷ Incidence rates of major bleeding events were identified during the first 6 months of treatment. Incidence of Afib—defined as an inpatient or outpatient encounter with the 427.31 ICD-9-CM code—also was examined within the first 6 months after starting treatment. The period of 6 months was chosen because bendamustine must be discontinued after 6 months.

Study Analysis

Descriptive statistics were used to examine patient demographics, disease characteristics, and treatment history from initial CLL diagnosis through end of study observation period. Categorical variables were summarized using frequencies and accompanying proportions, while a mean and standard deviation were used to summarize continuous variables. For the means of continuous variables and of categorical data, 95% CIs were used. Proportions and accompanying 95% CIs characterized treatment patterns, including line of therapy, comorbidities, and bleeding events. Treatment duration was described using mean and accompanying 95% CI. Statistical tests were not conducted for comparisons among treatment groups. Patients were censored at the end of follow-up, defined as the earliest of the following scenarios: (1) end of study observation period (December 31, 2016); (2) development of a secondary cancer; or (3) last day of contact given absence of care within the VHA for ≥ 18 months (with care defined as oncology and/or oncology/hematology visit with an associated note). Analysis was performed using R 3.4.0.

Results

Between 2010 and 2014, 2,796 patients were diagnosed and received care for CLL within the VHA. Overall, all 172 patients who were treated with ibrutinib during our inclusion period were selected. These patients were treated between January 1, 2014 and December 31, 2016, following ibrutinib’s approval in early 2014. An additional 291 patients were selected who received BR (Table). Reflecting the predominantly male population of the VHA, 282 (97%) BR patients and 167 (97%) ibrutinib patients were male. The median age at diagnosis was 67 years for BR patients and 69 years for ibrutinib patients. About 76% of patients who received ibrutinib and 82% of patients who received BR were non-Hispanic white; 17% and 14% were African American, respectively.

Less than 10% of patients receiving either ibrutinib or BR had liver disease per criteria used by Kramer and colleagues, or end-stage liver disease using criteria developed by Goldberg and colleagues.^12,13 About 5% of patients had a history of previous bleeding in the 6-month period prior to initiating either therapy. Mean CCI (excluding malignancy) score was 1.5 (range, 0-11) for the ibrutinib group, and 2.1 (range, 0-9) for the BR group. About 16% of the ibrutinib group had controlled DM and fewer than 10% had uncontrolled DM, while 4% of patients in the BR group met the criteria for controlled DM and another 4% met the criteria for uncontrolled DM.

There was very low utilization of anticoagulant or antiplatelet medication prior to initiation of ibrutinib (2.9% and 2.3%, respectively) or BR (< 1% each). In the first 6 months after treatment initiation, about 8% of patients in both ibrutinib and BR cohorts received anticoagulant medication while antiplatelet utilization was < 5% in either group.

In the BR group, 8 patients (2.7%) experienced a major bleeding event, while 14 patients (8.1%) in the ibrutinib group experienced a bleeding event (P = .008). While these numbers were too low to perform a formal statistical analysis of the association between clinical covariates and bleeding in either group, there did not seem to be an association between bleeding and liver disease or DM. Of patients who experienced a bleeding event, about 1 in 4 patients had had a prior bleeding event in both the ibrutinib and the BR groups. Interestingly, while none of the patients who experienced a bleeding event while receiving BR were taking concomitant anticoagulant medication, 3 of the 14 patients who experienced a bleeding event in the ibrutinib group showed evidence of anticoagulant utilization. Finally, the incidence of Afib (defined as patients with no evidence of Afib in the 6 months prior to treatment but with evidence of Afib in the 6 months following treatment initiation) was 4% in the BR group, and about 8% in the ibrutinib group (P = .003).

Discussion

To the authors’ knowledge, this study is the first to examine the real-world incidence of bleeding and Afib in veterans who received ibrutinib for CLL in the first year of its availability. The study found minimal use of anticoagulants and/or antiplatelet agents prior to receiving first-line ibrutinib or BR, and very low use of these agents in the first 6 months following the initiation of first-line treatment. This finding suggests a high awareness among VA providers of potential adverse effects (AEs) of ibrutinib and chemotherapy, and a careful selection of patients that lack risk factors for AEs.

In patients treated with first-line ibrutinib when compared with patients treated with first-line BR, moderate increases in bleeding (2.7% vs 8.1%, P = .008) and Afib (10.5% vs 3%, P = .003) also were observed. These results are concordant with previous findings examining the use of ibrutinib in patients with CLL.^18-20

Limitations

The results of this study should be interpreted with caution, as some limitations must be considered. The study was conducted in the early days of ibrutinib adoption. Since then, more patients have been treated with ibrutinib and for longer durations. As clinicians gain more familiarity and with ibrutinib, and as additional novel therapeutics emerge, it is possible that the initial awareness about risks for possible AEs may diminish; patients with high comorbidity burdens and concomitant medications would be especially vulnerable in cases of reduced physician vigilance.

Another limitation of this study stems from the potential for dual system use among patients treated in the VHA. Concurrent or alternating use of multiple health care systems (use of VHA and private-sector facilities) may present gaps in the reconstruction of patient histories, resulting in missing data as patients transition between commercial, the Centers for Medicare and Medicaid Services, and VHA care. As a result, the results presented here do not reflect instances where a patient experienced a bleeding event treated outside the VA.

Problems with missing data also may occur due to incomplete extraction from the electronic health record; these issues were addressed by leveraging an understanding of the multiple data marts within the CDW environment to harmonize missing and/or erroneous information through use of other data marts when possible. Lastly, this research represents a population-level study of the VHA, thus all findings are directly relevant to the VHA. The generalizability of the findings outside the VHA would depend on the characteristics of the external population.

Conclusion

Real-world evidence from a nationwide cohort of veteran patients with CLL treated with ibrutinib suggest that, while there is an association of increased bleeding-related events and Afib, the risk is comparable to those reported in previous studies.^18-20 These findings suggest that patients in real-world clinical care settings with higher levels of comorbidities may be at a slight increased risk for bleeding events and Afib.

Chronic lymphocytic leukemia (CLL) is the most common leukemia diagnosed in developed countries, with an estimated 21,040 new diagnoses of CLL expected in the US in 2020. ^1-3 CLL is an indolent cancer characterized by the accumulation of B-lymphocytes in the blood, marrow, and lymphoid tissues. ⁴ It has a heterogeneous clinical course; the majority of patients are observed or receive delayed treatment following diagnosis, while a minority of patients require immediate treatment. After first-line treatment, some patients experience prolonged remissions while others require retreatment within 1 or 2 years. Fortunately, advances in cancer biology and therapeutics in the last decade have increased the number of treatment options available for patients with CLL.

Until recently, most CLL treatments relied on a chemotherapy or a chemoimmunotherapy backbone; however, the last few years have seen novel therapies introduced, such as small molecule inhibitors to target molecular pathways that promote the normal development, expansion, and survival of B-cells.⁵ One such therapy is ibrutinib, a targeted Bruton tyrosine kinase inhibitor that received accelerated approval by the US Food and Drug Administration (FDA) in February 2014 for patients with CLL who received at least 1 prior therapy. The FDA later expanded this approval to include use of ibrutinib in patients with CLL with relapsed or refractory disease, with or without chromosome 17p deletion. In 2016, based on data from the RESONATE-17 study, the FDA approved ibrutinib for first-line therapy in patients with CLL.⁶

Ibrutinib’s efficacy, ease of administration and dosing (all doses are oral and fixed, rather than based on weight or body surface area), and relatively favorable safety profile have resulted in a rapid growth in its adoption.⁷ Since its adverse event (AE) profile is generally more tolerable than that of a typical chemoimmunotherapy, its use in older patients with CLL and patients with significant comorbidities is particularly appealing.⁸

However, the results of some clinical trials suggest an association between treatment with ibrutinib and an increased risk of bleeding-related events of any grade (44%) and major bleeding events (4%).^7,8 The incidence of major bleeding events was reported to be higher (9%) in one clinical trial and at 5-year follow-up, although this trial did not exclude patients receiving concomitant oral anticoagulation with warfarin.^6,9

Heterogeneity in clinical trials’ definitions of major bleeding confounded the ability to calculate bleeding risk in patients treated with ibrutinib in a systematic review and meta-analysis that called for more data.¹⁰ Additionally, patients with factors that might increase the risk of major bleeding with ibrutinib treatment were likely underrepresented in clinical trials, given the carefully selected nature of clinical trial subjects. These factors include renal or hepatic disease, gastrointestinal disease, and use of a number of concomitant medications such as antiplatelets or anticoagulant medications. Accounting for use of the latter is particularly important because patients who develop atrial fibrillation (Afib), one of the recognized AEs of treatment with ibrutinib, often are treated with anticoagulant medications in order to decrease the risk of stroke or other thromboembolic complications.

Methods

The VHA maintains the centralized US Department of Veterans Affairs Cancer Registry System (VACRS), with electronic medical record data and other sources captured in its Corporate Data Warehouse (CDW). The VHA CDW is a national repository comprising data from several VHA clinical and administrative systems. The CDW includes patient identifiers; demographics; vital status; lab information; administrative information (such as diagnostic International Statistical Classification of Diseases and Related Health Problems [ICD-9] codes); medication dispensation tables (such as outpatient fill); IV package information; and notes from radiology, pathology, outpatient and inpatient admission, discharge, and daily progress.

Registrars abstract all cancer cases within the VHA system (or diagnosed outside the VHA, if patients subsequently receive treatment in the VHA). It is estimated that VACRS captures 3% of cancer cases in the US.¹² Like most registries, VACRS captures data such as diagnosis, age, gender, race, and vital status.

Study Definitions

Prevalence of comorbidities that could increase bleeding risk was determined using administrative ICD-9-CM codes. Liver disease was identified by presence of cirrhosis, hepatitis C virus, or alcoholic liver disease using administrative codes validated by Kramer and colleagues, who reported positive and negative predictive values of 90% and 87% for cirrhosis, 93% and 92% for hepatitis C virus, and 71% and 98% for alcoholic liver disease.¹³ Similarly, end-stage liver disease was identified using a validated coding algorithm developed by Goldberg and colleagues, with a positive predictive value of 89.3%.¹⁴ The presence of controlled or uncontrolled diabetes mellitus (DM) was identified using the procedure described by Guzman and colleagues.¹⁵ Quan’s algorithm was used to calculate Charlson Comorbidity Index (CCI) based on ICD-9-CM codes for inpatient and outpatient visits within a 6-month lookback period prior to treatment initiation.¹⁶

A major bleeding event was defined as a hospitalization with an ICD-9-CM code suggestive of major bleeding as the primary reason, as defined by Lane and colleagues in their study of major bleeding related to warfarin in a cohort of patients treated within the VHA.¹⁷ Incidence rates of major bleeding events were identified during the first 6 months of treatment. Incidence of Afib—defined as an inpatient or outpatient encounter with the 427.31 ICD-9-CM code—also was examined within the first 6 months after starting treatment. The period of 6 months was chosen because bendamustine must be discontinued after 6 months.

Study Analysis

Descriptive statistics were used to examine patient demographics, disease characteristics, and treatment history from initial CLL diagnosis through end of study observation period. Categorical variables were summarized using frequencies and accompanying proportions, while a mean and standard deviation were used to summarize continuous variables. For the means of continuous variables and of categorical data, 95% CIs were used. Proportions and accompanying 95% CIs characterized treatment patterns, including line of therapy, comorbidities, and bleeding events. Treatment duration was described using mean and accompanying 95% CI. Statistical tests were not conducted for comparisons among treatment groups. Patients were censored at the end of follow-up, defined as the earliest of the following scenarios: (1) end of study observation period (December 31, 2016); (2) development of a secondary cancer; or (3) last day of contact given absence of care within the VHA for ≥ 18 months (with care defined as oncology and/or oncology/hematology visit with an associated note). Analysis was performed using R 3.4.0.

Results

Between 2010 and 2014, 2,796 patients were diagnosed and received care for CLL within the VHA. Overall, all 172 patients who were treated with ibrutinib during our inclusion period were selected. These patients were treated between January 1, 2014 and December 31, 2016, following ibrutinib’s approval in early 2014. An additional 291 patients were selected who received BR (Table). Reflecting the predominantly male population of the VHA, 282 (97%) BR patients and 167 (97%) ibrutinib patients were male. The median age at diagnosis was 67 years for BR patients and 69 years for ibrutinib patients. About 76% of patients who received ibrutinib and 82% of patients who received BR were non-Hispanic white; 17% and 14% were African American, respectively.

Less than 10% of patients receiving either ibrutinib or BR had liver disease per criteria used by Kramer and colleagues, or end-stage liver disease using criteria developed by Goldberg and colleagues.^12,13 About 5% of patients had a history of previous bleeding in the 6-month period prior to initiating either therapy. Mean CCI (excluding malignancy) score was 1.5 (range, 0-11) for the ibrutinib group, and 2.1 (range, 0-9) for the BR group. About 16% of the ibrutinib group had controlled DM and fewer than 10% had uncontrolled DM, while 4% of patients in the BR group met the criteria for controlled DM and another 4% met the criteria for uncontrolled DM.

There was very low utilization of anticoagulant or antiplatelet medication prior to initiation of ibrutinib (2.9% and 2.3%, respectively) or BR (< 1% each). In the first 6 months after treatment initiation, about 8% of patients in both ibrutinib and BR cohorts received anticoagulant medication while antiplatelet utilization was < 5% in either group.

In the BR group, 8 patients (2.7%) experienced a major bleeding event, while 14 patients (8.1%) in the ibrutinib group experienced a bleeding event (P = .008). While these numbers were too low to perform a formal statistical analysis of the association between clinical covariates and bleeding in either group, there did not seem to be an association between bleeding and liver disease or DM. Of patients who experienced a bleeding event, about 1 in 4 patients had had a prior bleeding event in both the ibrutinib and the BR groups. Interestingly, while none of the patients who experienced a bleeding event while receiving BR were taking concomitant anticoagulant medication, 3 of the 14 patients who experienced a bleeding event in the ibrutinib group showed evidence of anticoagulant utilization. Finally, the incidence of Afib (defined as patients with no evidence of Afib in the 6 months prior to treatment but with evidence of Afib in the 6 months following treatment initiation) was 4% in the BR group, and about 8% in the ibrutinib group (P = .003).

Discussion

To the authors’ knowledge, this study is the first to examine the real-world incidence of bleeding and Afib in veterans who received ibrutinib for CLL in the first year of its availability. The study found minimal use of anticoagulants and/or antiplatelet agents prior to receiving first-line ibrutinib or BR, and very low use of these agents in the first 6 months following the initiation of first-line treatment. This finding suggests a high awareness among VA providers of potential adverse effects (AEs) of ibrutinib and chemotherapy, and a careful selection of patients that lack risk factors for AEs.

In patients treated with first-line ibrutinib when compared with patients treated with first-line BR, moderate increases in bleeding (2.7% vs 8.1%, P = .008) and Afib (10.5% vs 3%, P = .003) also were observed. These results are concordant with previous findings examining the use of ibrutinib in patients with CLL.^18-20

Limitations

The results of this study should be interpreted with caution, as some limitations must be considered. The study was conducted in the early days of ibrutinib adoption. Since then, more patients have been treated with ibrutinib and for longer durations. As clinicians gain more familiarity and with ibrutinib, and as additional novel therapeutics emerge, it is possible that the initial awareness about risks for possible AEs may diminish; patients with high comorbidity burdens and concomitant medications would be especially vulnerable in cases of reduced physician vigilance.

Another limitation of this study stems from the potential for dual system use among patients treated in the VHA. Concurrent or alternating use of multiple health care systems (use of VHA and private-sector facilities) may present gaps in the reconstruction of patient histories, resulting in missing data as patients transition between commercial, the Centers for Medicare and Medicaid Services, and VHA care. As a result, the results presented here do not reflect instances where a patient experienced a bleeding event treated outside the VA.

Problems with missing data also may occur due to incomplete extraction from the electronic health record; these issues were addressed by leveraging an understanding of the multiple data marts within the CDW environment to harmonize missing and/or erroneous information through use of other data marts when possible. Lastly, this research represents a population-level study of the VHA, thus all findings are directly relevant to the VHA. The generalizability of the findings outside the VHA would depend on the characteristics of the external population.

Conclusion

Real-world evidence from a nationwide cohort of veteran patients with CLL treated with ibrutinib suggest that, while there is an association of increased bleeding-related events and Afib, the risk is comparable to those reported in previous studies.^18-20 These findings suggest that patients in real-world clinical care settings with higher levels of comorbidities may be at a slight increased risk for bleeding events and Afib.

Chronic lymphocytic leukemia (CLL) is the most common leukemia diagnosed in developed countries, with an estimated 21,040 new diagnoses of CLL expected in the US in 2020. ^1-3 CLL is an indolent cancer characterized by the accumulation of B-lymphocytes in the blood, marrow, and lymphoid tissues. ⁴ It has a heterogeneous clinical course; the majority of patients are observed or receive delayed treatment following diagnosis, while a minority of patients require immediate treatment. After first-line treatment, some patients experience prolonged remissions while others require retreatment within 1 or 2 years. Fortunately, advances in cancer biology and therapeutics in the last decade have increased the number of treatment options available for patients with CLL.

Until recently, most CLL treatments relied on a chemotherapy or a chemoimmunotherapy backbone; however, the last few years have seen novel therapies introduced, such as small molecule inhibitors to target molecular pathways that promote the normal development, expansion, and survival of B-cells.⁵ One such therapy is ibrutinib, a targeted Bruton tyrosine kinase inhibitor that received accelerated approval by the US Food and Drug Administration (FDA) in February 2014 for patients with CLL who received at least 1 prior therapy. The FDA later expanded this approval to include use of ibrutinib in patients with CLL with relapsed or refractory disease, with or without chromosome 17p deletion. In 2016, based on data from the RESONATE-17 study, the FDA approved ibrutinib for first-line therapy in patients with CLL.⁶

Ibrutinib’s efficacy, ease of administration and dosing (all doses are oral and fixed, rather than based on weight or body surface area), and relatively favorable safety profile have resulted in a rapid growth in its adoption.⁷ Since its adverse event (AE) profile is generally more tolerable than that of a typical chemoimmunotherapy, its use in older patients with CLL and patients with significant comorbidities is particularly appealing.⁸

However, the results of some clinical trials suggest an association between treatment with ibrutinib and an increased risk of bleeding-related events of any grade (44%) and major bleeding events (4%).^7,8 The incidence of major bleeding events was reported to be higher (9%) in one clinical trial and at 5-year follow-up, although this trial did not exclude patients receiving concomitant oral anticoagulation with warfarin.^6,9

Heterogeneity in clinical trials’ definitions of major bleeding confounded the ability to calculate bleeding risk in patients treated with ibrutinib in a systematic review and meta-analysis that called for more data.¹⁰ Additionally, patients with factors that might increase the risk of major bleeding with ibrutinib treatment were likely underrepresented in clinical trials, given the carefully selected nature of clinical trial subjects. These factors include renal or hepatic disease, gastrointestinal disease, and use of a number of concomitant medications such as antiplatelets or anticoagulant medications. Accounting for use of the latter is particularly important because patients who develop atrial fibrillation (Afib), one of the recognized AEs of treatment with ibrutinib, often are treated with anticoagulant medications in order to decrease the risk of stroke or other thromboembolic complications.

Methods

The VHA maintains the centralized US Department of Veterans Affairs Cancer Registry System (VACRS), with electronic medical record data and other sources captured in its Corporate Data Warehouse (CDW). The VHA CDW is a national repository comprising data from several VHA clinical and administrative systems. The CDW includes patient identifiers; demographics; vital status; lab information; administrative information (such as diagnostic International Statistical Classification of Diseases and Related Health Problems [ICD-9] codes); medication dispensation tables (such as outpatient fill); IV package information; and notes from radiology, pathology, outpatient and inpatient admission, discharge, and daily progress.

Registrars abstract all cancer cases within the VHA system (or diagnosed outside the VHA, if patients subsequently receive treatment in the VHA). It is estimated that VACRS captures 3% of cancer cases in the US.¹² Like most registries, VACRS captures data such as diagnosis, age, gender, race, and vital status.

Study Definitions

Prevalence of comorbidities that could increase bleeding risk was determined using administrative ICD-9-CM codes. Liver disease was identified by presence of cirrhosis, hepatitis C virus, or alcoholic liver disease using administrative codes validated by Kramer and colleagues, who reported positive and negative predictive values of 90% and 87% for cirrhosis, 93% and 92% for hepatitis C virus, and 71% and 98% for alcoholic liver disease.¹³ Similarly, end-stage liver disease was identified using a validated coding algorithm developed by Goldberg and colleagues, with a positive predictive value of 89.3%.¹⁴ The presence of controlled or uncontrolled diabetes mellitus (DM) was identified using the procedure described by Guzman and colleagues.¹⁵ Quan’s algorithm was used to calculate Charlson Comorbidity Index (CCI) based on ICD-9-CM codes for inpatient and outpatient visits within a 6-month lookback period prior to treatment initiation.¹⁶

A major bleeding event was defined as a hospitalization with an ICD-9-CM code suggestive of major bleeding as the primary reason, as defined by Lane and colleagues in their study of major bleeding related to warfarin in a cohort of patients treated within the VHA.¹⁷ Incidence rates of major bleeding events were identified during the first 6 months of treatment. Incidence of Afib—defined as an inpatient or outpatient encounter with the 427.31 ICD-9-CM code—also was examined within the first 6 months after starting treatment. The period of 6 months was chosen because bendamustine must be discontinued after 6 months.

Study Analysis

Descriptive statistics were used to examine patient demographics, disease characteristics, and treatment history from initial CLL diagnosis through end of study observation period. Categorical variables were summarized using frequencies and accompanying proportions, while a mean and standard deviation were used to summarize continuous variables. For the means of continuous variables and of categorical data, 95% CIs were used. Proportions and accompanying 95% CIs characterized treatment patterns, including line of therapy, comorbidities, and bleeding events. Treatment duration was described using mean and accompanying 95% CI. Statistical tests were not conducted for comparisons among treatment groups. Patients were censored at the end of follow-up, defined as the earliest of the following scenarios: (1) end of study observation period (December 31, 2016); (2) development of a secondary cancer; or (3) last day of contact given absence of care within the VHA for ≥ 18 months (with care defined as oncology and/or oncology/hematology visit with an associated note). Analysis was performed using R 3.4.0.

Results

Between 2010 and 2014, 2,796 patients were diagnosed and received care for CLL within the VHA. Overall, all 172 patients who were treated with ibrutinib during our inclusion period were selected. These patients were treated between January 1, 2014 and December 31, 2016, following ibrutinib’s approval in early 2014. An additional 291 patients were selected who received BR (Table). Reflecting the predominantly male population of the VHA, 282 (97%) BR patients and 167 (97%) ibrutinib patients were male. The median age at diagnosis was 67 years for BR patients and 69 years for ibrutinib patients. About 76% of patients who received ibrutinib and 82% of patients who received BR were non-Hispanic white; 17% and 14% were African American, respectively.

Less than 10% of patients receiving either ibrutinib or BR had liver disease per criteria used by Kramer and colleagues, or end-stage liver disease using criteria developed by Goldberg and colleagues.^12,13 About 5% of patients had a history of previous bleeding in the 6-month period prior to initiating either therapy. Mean CCI (excluding malignancy) score was 1.5 (range, 0-11) for the ibrutinib group, and 2.1 (range, 0-9) for the BR group. About 16% of the ibrutinib group had controlled DM and fewer than 10% had uncontrolled DM, while 4% of patients in the BR group met the criteria for controlled DM and another 4% met the criteria for uncontrolled DM.

There was very low utilization of anticoagulant or antiplatelet medication prior to initiation of ibrutinib (2.9% and 2.3%, respectively) or BR (< 1% each). In the first 6 months after treatment initiation, about 8% of patients in both ibrutinib and BR cohorts received anticoagulant medication while antiplatelet utilization was < 5% in either group.

In the BR group, 8 patients (2.7%) experienced a major bleeding event, while 14 patients (8.1%) in the ibrutinib group experienced a bleeding event (P = .008). While these numbers were too low to perform a formal statistical analysis of the association between clinical covariates and bleeding in either group, there did not seem to be an association between bleeding and liver disease or DM. Of patients who experienced a bleeding event, about 1 in 4 patients had had a prior bleeding event in both the ibrutinib and the BR groups. Interestingly, while none of the patients who experienced a bleeding event while receiving BR were taking concomitant anticoagulant medication, 3 of the 14 patients who experienced a bleeding event in the ibrutinib group showed evidence of anticoagulant utilization. Finally, the incidence of Afib (defined as patients with no evidence of Afib in the 6 months prior to treatment but with evidence of Afib in the 6 months following treatment initiation) was 4% in the BR group, and about 8% in the ibrutinib group (P = .003).

Discussion

To the authors’ knowledge, this study is the first to examine the real-world incidence of bleeding and Afib in veterans who received ibrutinib for CLL in the first year of its availability. The study found minimal use of anticoagulants and/or antiplatelet agents prior to receiving first-line ibrutinib or BR, and very low use of these agents in the first 6 months following the initiation of first-line treatment. This finding suggests a high awareness among VA providers of potential adverse effects (AEs) of ibrutinib and chemotherapy, and a careful selection of patients that lack risk factors for AEs.

In patients treated with first-line ibrutinib when compared with patients treated with first-line BR, moderate increases in bleeding (2.7% vs 8.1%, P = .008) and Afib (10.5% vs 3%, P = .003) also were observed. These results are concordant with previous findings examining the use of ibrutinib in patients with CLL.^18-20

Limitations

The results of this study should be interpreted with caution, as some limitations must be considered. The study was conducted in the early days of ibrutinib adoption. Since then, more patients have been treated with ibrutinib and for longer durations. As clinicians gain more familiarity and with ibrutinib, and as additional novel therapeutics emerge, it is possible that the initial awareness about risks for possible AEs may diminish; patients with high comorbidity burdens and concomitant medications would be especially vulnerable in cases of reduced physician vigilance.

Another limitation of this study stems from the potential for dual system use among patients treated in the VHA. Concurrent or alternating use of multiple health care systems (use of VHA and private-sector facilities) may present gaps in the reconstruction of patient histories, resulting in missing data as patients transition between commercial, the Centers for Medicare and Medicaid Services, and VHA care. As a result, the results presented here do not reflect instances where a patient experienced a bleeding event treated outside the VA.

Problems with missing data also may occur due to incomplete extraction from the electronic health record; these issues were addressed by leveraging an understanding of the multiple data marts within the CDW environment to harmonize missing and/or erroneous information through use of other data marts when possible. Lastly, this research represents a population-level study of the VHA, thus all findings are directly relevant to the VHA. The generalizability of the findings outside the VHA would depend on the characteristics of the external population.

Conclusion

Real-world evidence from a nationwide cohort of veteran patients with CLL treated with ibrutinib suggest that, while there is an association of increased bleeding-related events and Afib, the risk is comparable to those reported in previous studies.^18-20 These findings suggest that patients in real-world clinical care settings with higher levels of comorbidities may be at a slight increased risk for bleeding events and Afib.

Lung cancer is the leading cause of cancer mortality both in the US and worldwide.¹ Many patients diagnosed with lung cancer present with advanced disease with thoracic symptoms such as cough, hemoptysis, dyspnea, and chest pain.^2-4 Palliative radiotherapy is routinely used in patients with locally advanced and metastatic lung cancer with the goal of relieving these symptoms and improving quality of life. Guidelines published by the American Society for Radiation Oncology (ASTRO) in 2011, and updated in 2018, provide recommendations on palliation of lung cancer with external beam radiotherapy (EBRT) and clarify the roles of concurrent chemotherapy and endobronchial brachytherapy (EBB) for palliation.^5,6

After prostate cancer, lung cancer is the second most frequently diagnosed cancer in the Veterans Health Administration (VHA).⁷ The VHA consists of 172 medical centers and is the largest integrated health care system in the US. At the time of this study, 40 of these centers had onsite radiation facilities. The VHA Palliative Radiation Taskforce has conducted a series of surveys to evaluate use of palliative radiotherapy in the VHA, determine VHA practice concordance with ASTRO and American College of Radiology (ACR) guidelines, and direct educational efforts towards addressing gaps in knowledge. These efforts are directed at ensuring best practices throughout this large and heterogeneous healthcare system. In 2016 a survey was conducted to evaluate concordance of VHA radiation oncologist (RO) practice with the 2011 ASTRO guidelines on palliative thoracic radiotherapy for non-small cell lung cancer (NSCLC).

Methods

A survey instrument was generated by VHA National Palliative Radiotherapy Taskforce members. It was reviewed and approved for use by the VHA Patient Care Services office. In May of 2016, the online survey was sent to the 88 VHA ROs practicing at the 40 sites with onsite radiation facilities. The survey aimed to determine patterns of practice for palliation of thoracic symptoms secondary to lung cancer.

Demographic information obtained included years in practice, employment status, academic appointment, board certification, and familiarity with ASTRO lung cancer guidelines. Two clinical scenarios were presented to glean opinions on dose/fractionation schemes preferred, use of concurrent chemotherapy, and use of EBB and/or yttrium aluminum garnet (YAG) laser technology. Survey questions also assessed use of EBRT for palliation of hemoptysis, chest wall pain, and/or stridor as well as use of stereotactic body radiotherapy (SBRT) for palliation.

Survey results were assessed for concordance with published ASTRO guidelines. χ² tests were run to test for associations between demographic factors such as academic appointment, years of practice, full time vs part time employment, and familiarity with ASTRO palliative lung cancer guidelines, with use of EBRT for palliation, dose and fractionation preference, use of concurrent chemotherapy, and strategy for management of endobronchial lesions.

Results

Of the 88 physicians surveyed, 54 responded for a response rate of 61%. Respondents represented 37 of the 40 (93%) VHA radiation oncology departments (Table 1). Among respondents, most were board certified (96%), held academic appointments (91%), and were full-time employees (85%). Forty-four percent of respondents were in practice for > 20 years, 19% for 11 to 20 years, 20% for 6 to 10 years, and 17% for < 6 years. A majority reported familiarity with the ASTRO guidelines (64%), while just 11% reported no familiarity with the guidelines.

When asked about use of SBRT for palliation of hemoptysis, stridor, and/or chest pain, the majority (87%) preferred conventional EBRT. Of the 13% who reported use of SBRT, most (11%) performed it onsite, with 2% of respondents referring offsite to non-VHA centers for the service. When asked about use of EBB for palliation, only 2% reported use of that procedure at their facilities, while 26% reported referral to non-VHA facilities for EBB. The remaining 72% of respondents favor use of conventional EBRT.

Respondents were presented with a case of a male patient aged 70 years who smoked and had widely metastatic NSCLC, a life expectancy of about 3 months, and 10/10 chest wall pain from direct tumor invasion. All respondents recommended palliative radiotherapy. The preferred fractionation was 20 Gray (Gy) in 5 fractions, which was recommended by 69% of respondents. The remainder recommended 30 Gy in 10 fractions (22%) or a single fraction of 10 Gy (9%). No respondent recommended the longer fractionation options of 60 Gy in 30 fractions, 45 Gy in 15 fractions, or 40 Gy in 20 fractions. The majority (98%) did not recommend concurrent chemotherapy.

When the above case was modified for an endobronchial lesion requiring palliation with associated lung collapse, rather than chest wall invasion, 20 respondents (38%) reported they would refer for EBB, and 20 respondents reported they would refer for YAG laser. As > 1 answer could be selected for this question, there were 12 respondents who selected both EBB and YAG laser; 8 selected only EBB, and 8 selected only YAG laser. Many respondents added comments about treating with EBRT, which had not been presented as an answer choice. Nearly half of respondents (49%) were amenable to referral for the use of EBB or YAG laser for lung reexpansion prior to radiotherapy. Three respondents mentioned referral for an endobronchial stent prior to palliative radiotherapy to address this question.

Discussion

This survey was conducted to evaluate concordance of management of metastatic lung cancer in the VHA with ASTRO guidelines. The relationship between respondents’ familiarity with the guidelines and responses also was evaluated to determine the impact such guidelines have on decision-making. The ASTRO guidelines for palliative thoracic radiation make recommendations regarding 3 issues: (1) radiation doses and fractionations for palliation; (2) the role of EBB; and (3) the use of concurrent chemotherapy.^5,6

Radiation Dose and Fractionation for Palliation

A variety of dose/fractionation schemes are considered appropriate in the ASTRO guideline statement, including more prolonged courses such as 30 Gy/10 fractions as well as more hypofractionated regimens (ie, 20 Gy/5 fractions, 17 Gy/2 fractions, and a single fraction of 10 Gy). Higher dose regimens, such as 30 Gy/10 fractions, have been associated with prolonged survival, as well as increased toxicities such as radiation esophagitis.⁸ Therefore, the guidelines support use of 30 Gy/10 fractions for patients with good performance status while encouraging use of more hypofractionated regimens for patients with poor performance status. In considering more hypofractionated regimens, one must consider the possibility of adverse effects that can be associated with higher dose per fraction. For instance, 17 Gy/2 fractions has been associated with myelopathy; therefore it should be used with caution and careful treatment planning.⁹

For the survey case example (a male aged 70 years with a 3-month life expectancy who required palliation for chest wall pain), all respondents selected hypofractionated regimens; with no respondent selected the more prolonged fractionations of 60 Gy/30 fractions, 45 Gy/15 fractions, or 40 Gy/20 fractions. These more prolonged fractionations are not endorsed by the guidelines in general, and particularly not for a patient with poor life expectancy. All responses for this case selected by survey respondents are considered appropriate per the consensus guideline statement.

Role of Concurrent Chemotherapy

The ASTRO guidelines do not support use of concurrent chemotherapy for palliation of stage IV NSCLC.^5,6 The 2018 updated guidelines established a role for concurrent chemotherapy for patients with stage III NSCLC with good performance status and life expectancy of > 3 months. This updated recommendation is based on data from 2 randomized trials demonstrating improvement in overall survival with the addition of chemotherapy for patients with stage III NSCLC undergoing palliative radiotherapy.^10-12

These newer studies are in contrast to an older randomized study by Ball and colleagues that demonstrated greater toxicity from concurrent chemotherapy, with no improvement in outcomes such as palliation of symptoms, overall survival, or progression free survival.¹³ In contrast to the newer studies that included only patients with stage III NSCLC, about half of the patients in the Ball and colleagues study had known metastatic disease.^10-13 Of note, staging for metastatic disease was not carried out routinely, so it is possible that a greater proportion of patients had metastatic disease that would have been seen on imaging. In concordance with the guidelines, 98% of the survey respondents did not recommend concurrent chemotherapy for palliation of intrathoracic symptom; only 1 respondent recommended use of chemotherapy for palliation.

Role of Endobronchial Brachytherapy

EBB involves implantation of radioactive sources for treatment of endobronchial lesions causing obstructive symptoms.¹⁴ Given the lack of randomized data that demonstrate a benefit of EBB over EBRT, the ASTRO guidelines do not endorse routine use of EBB for initial palliative management.^15,16 The ASTRO guidelines reference a Cochrane Review of 13 trials that concluded that EBRT alone is superior to EBB alone for initial palliation of symptoms from endobronchial NSCLC.¹⁷

Of respondents surveyed, only 1 facility offered onsite EBB. The majority of respondents (72%) preferred the use of conventional EBRT techniques, while 26% refer to non-VHA centers for EBB. Lack of incorporation of EBB into routine VHA practice likely is a reflection of the unclear role of this technology based on the available literature and ASTRO guidelines. In the setting of a right lower lung collapse, more respondents (49%) would consider use of EBB or YAG laser technology for lung reexpansion prior to EBRT.

The ASTRO guidelines recommend that initial EBB in conjunction with EBRT be considered based on randomized data demonstrating significant improvement in lung reexpansion and in patient reported dyspnea with addition of EBB to EBRT over EBRT alone.¹⁸ However, the guidelines do not mandate the use of EBB in this situation. It is possible that targeted education regarding the role of EBB would improve knowledge of the potential benefit in the setting of lung collapse and increase the percentage of VHA ROs who would recommend this procedure.

Limitations

The study is limited by lack of generalizability of these findings to all ROs in the country. It is also possible that physician responses do not represent practice patterns with complete accuracy. The use of EBB varied among practitioners. Further study of this technology is necessary to clarify its role in the management of endobronchial obstructive symptoms and to determine whether efforts should be made to increase access to EBB within the VHA.

Conclusions

Most of the ROs who responded to our survey were cognizant and compliant with current ASTRO guidelines on management of lung cancer. Furthermore, familiarity with ASTRO guidelines and management choices were not associated with the respondents’ years in practice, academic appointment, full-time vs part-time status, or familiarity with ASTRO guidelines. This study is a nationwide survey of ROs in the VHA system that reflects the radiation-related care received by veterans with metastatic lung cancer. Responses were obtained from 93% of the 40 radiation oncology centers, so it is likely that the survey accurately represents the decision-making process at the majority of centers. It is possible that those who did not respond to the survey do not treat thoracic cases.

Lung cancer is the leading cause of cancer mortality both in the US and worldwide.¹ Many patients diagnosed with lung cancer present with advanced disease with thoracic symptoms such as cough, hemoptysis, dyspnea, and chest pain.^2-4 Palliative radiotherapy is routinely used in patients with locally advanced and metastatic lung cancer with the goal of relieving these symptoms and improving quality of life. Guidelines published by the American Society for Radiation Oncology (ASTRO) in 2011, and updated in 2018, provide recommendations on palliation of lung cancer with external beam radiotherapy (EBRT) and clarify the roles of concurrent chemotherapy and endobronchial brachytherapy (EBB) for palliation.^5,6

After prostate cancer, lung cancer is the second most frequently diagnosed cancer in the Veterans Health Administration (VHA).⁷ The VHA consists of 172 medical centers and is the largest integrated health care system in the US. At the time of this study, 40 of these centers had onsite radiation facilities. The VHA Palliative Radiation Taskforce has conducted a series of surveys to evaluate use of palliative radiotherapy in the VHA, determine VHA practice concordance with ASTRO and American College of Radiology (ACR) guidelines, and direct educational efforts towards addressing gaps in knowledge. These efforts are directed at ensuring best practices throughout this large and heterogeneous healthcare system. In 2016 a survey was conducted to evaluate concordance of VHA radiation oncologist (RO) practice with the 2011 ASTRO guidelines on palliative thoracic radiotherapy for non-small cell lung cancer (NSCLC).

Methods

A survey instrument was generated by VHA National Palliative Radiotherapy Taskforce members. It was reviewed and approved for use by the VHA Patient Care Services office. In May of 2016, the online survey was sent to the 88 VHA ROs practicing at the 40 sites with onsite radiation facilities. The survey aimed to determine patterns of practice for palliation of thoracic symptoms secondary to lung cancer.

Demographic information obtained included years in practice, employment status, academic appointment, board certification, and familiarity with ASTRO lung cancer guidelines. Two clinical scenarios were presented to glean opinions on dose/fractionation schemes preferred, use of concurrent chemotherapy, and use of EBB and/or yttrium aluminum garnet (YAG) laser technology. Survey questions also assessed use of EBRT for palliation of hemoptysis, chest wall pain, and/or stridor as well as use of stereotactic body radiotherapy (SBRT) for palliation.

Survey results were assessed for concordance with published ASTRO guidelines. χ² tests were run to test for associations between demographic factors such as academic appointment, years of practice, full time vs part time employment, and familiarity with ASTRO palliative lung cancer guidelines, with use of EBRT for palliation, dose and fractionation preference, use of concurrent chemotherapy, and strategy for management of endobronchial lesions.

Results

Of the 88 physicians surveyed, 54 responded for a response rate of 61%. Respondents represented 37 of the 40 (93%) VHA radiation oncology departments (Table 1). Among respondents, most were board certified (96%), held academic appointments (91%), and were full-time employees (85%). Forty-four percent of respondents were in practice for > 20 years, 19% for 11 to 20 years, 20% for 6 to 10 years, and 17% for < 6 years. A majority reported familiarity with the ASTRO guidelines (64%), while just 11% reported no familiarity with the guidelines.

When asked about use of SBRT for palliation of hemoptysis, stridor, and/or chest pain, the majority (87%) preferred conventional EBRT. Of the 13% who reported use of SBRT, most (11%) performed it onsite, with 2% of respondents referring offsite to non-VHA centers for the service. When asked about use of EBB for palliation, only 2% reported use of that procedure at their facilities, while 26% reported referral to non-VHA facilities for EBB. The remaining 72% of respondents favor use of conventional EBRT.

Respondents were presented with a case of a male patient aged 70 years who smoked and had widely metastatic NSCLC, a life expectancy of about 3 months, and 10/10 chest wall pain from direct tumor invasion. All respondents recommended palliative radiotherapy. The preferred fractionation was 20 Gray (Gy) in 5 fractions, which was recommended by 69% of respondents. The remainder recommended 30 Gy in 10 fractions (22%) or a single fraction of 10 Gy (9%). No respondent recommended the longer fractionation options of 60 Gy in 30 fractions, 45 Gy in 15 fractions, or 40 Gy in 20 fractions. The majority (98%) did not recommend concurrent chemotherapy.

When the above case was modified for an endobronchial lesion requiring palliation with associated lung collapse, rather than chest wall invasion, 20 respondents (38%) reported they would refer for EBB, and 20 respondents reported they would refer for YAG laser. As > 1 answer could be selected for this question, there were 12 respondents who selected both EBB and YAG laser; 8 selected only EBB, and 8 selected only YAG laser. Many respondents added comments about treating with EBRT, which had not been presented as an answer choice. Nearly half of respondents (49%) were amenable to referral for the use of EBB or YAG laser for lung reexpansion prior to radiotherapy. Three respondents mentioned referral for an endobronchial stent prior to palliative radiotherapy to address this question.

Discussion

This survey was conducted to evaluate concordance of management of metastatic lung cancer in the VHA with ASTRO guidelines. The relationship between respondents’ familiarity with the guidelines and responses also was evaluated to determine the impact such guidelines have on decision-making. The ASTRO guidelines for palliative thoracic radiation make recommendations regarding 3 issues: (1) radiation doses and fractionations for palliation; (2) the role of EBB; and (3) the use of concurrent chemotherapy.^5,6

Radiation Dose and Fractionation for Palliation

A variety of dose/fractionation schemes are considered appropriate in the ASTRO guideline statement, including more prolonged courses such as 30 Gy/10 fractions as well as more hypofractionated regimens (ie, 20 Gy/5 fractions, 17 Gy/2 fractions, and a single fraction of 10 Gy). Higher dose regimens, such as 30 Gy/10 fractions, have been associated with prolonged survival, as well as increased toxicities such as radiation esophagitis.⁸ Therefore, the guidelines support use of 30 Gy/10 fractions for patients with good performance status while encouraging use of more hypofractionated regimens for patients with poor performance status. In considering more hypofractionated regimens, one must consider the possibility of adverse effects that can be associated with higher dose per fraction. For instance, 17 Gy/2 fractions has been associated with myelopathy; therefore it should be used with caution and careful treatment planning.⁹

For the survey case example (a male aged 70 years with a 3-month life expectancy who required palliation for chest wall pain), all respondents selected hypofractionated regimens; with no respondent selected the more prolonged fractionations of 60 Gy/30 fractions, 45 Gy/15 fractions, or 40 Gy/20 fractions. These more prolonged fractionations are not endorsed by the guidelines in general, and particularly not for a patient with poor life expectancy. All responses for this case selected by survey respondents are considered appropriate per the consensus guideline statement.

Role of Concurrent Chemotherapy

The ASTRO guidelines do not support use of concurrent chemotherapy for palliation of stage IV NSCLC.^5,6 The 2018 updated guidelines established a role for concurrent chemotherapy for patients with stage III NSCLC with good performance status and life expectancy of > 3 months. This updated recommendation is based on data from 2 randomized trials demonstrating improvement in overall survival with the addition of chemotherapy for patients with stage III NSCLC undergoing palliative radiotherapy.^10-12

These newer studies are in contrast to an older randomized study by Ball and colleagues that demonstrated greater toxicity from concurrent chemotherapy, with no improvement in outcomes such as palliation of symptoms, overall survival, or progression free survival.¹³ In contrast to the newer studies that included only patients with stage III NSCLC, about half of the patients in the Ball and colleagues study had known metastatic disease.^10-13 Of note, staging for metastatic disease was not carried out routinely, so it is possible that a greater proportion of patients had metastatic disease that would have been seen on imaging. In concordance with the guidelines, 98% of the survey respondents did not recommend concurrent chemotherapy for palliation of intrathoracic symptom; only 1 respondent recommended use of chemotherapy for palliation.

Role of Endobronchial Brachytherapy

EBB involves implantation of radioactive sources for treatment of endobronchial lesions causing obstructive symptoms.¹⁴ Given the lack of randomized data that demonstrate a benefit of EBB over EBRT, the ASTRO guidelines do not endorse routine use of EBB for initial palliative management.^15,16 The ASTRO guidelines reference a Cochrane Review of 13 trials that concluded that EBRT alone is superior to EBB alone for initial palliation of symptoms from endobronchial NSCLC.¹⁷

Of respondents surveyed, only 1 facility offered onsite EBB. The majority of respondents (72%) preferred the use of conventional EBRT techniques, while 26% refer to non-VHA centers for EBB. Lack of incorporation of EBB into routine VHA practice likely is a reflection of the unclear role of this technology based on the available literature and ASTRO guidelines. In the setting of a right lower lung collapse, more respondents (49%) would consider use of EBB or YAG laser technology for lung reexpansion prior to EBRT.

The ASTRO guidelines recommend that initial EBB in conjunction with EBRT be considered based on randomized data demonstrating significant improvement in lung reexpansion and in patient reported dyspnea with addition of EBB to EBRT over EBRT alone.¹⁸ However, the guidelines do not mandate the use of EBB in this situation. It is possible that targeted education regarding the role of EBB would improve knowledge of the potential benefit in the setting of lung collapse and increase the percentage of VHA ROs who would recommend this procedure.

Limitations

The study is limited by lack of generalizability of these findings to all ROs in the country. It is also possible that physician responses do not represent practice patterns with complete accuracy. The use of EBB varied among practitioners. Further study of this technology is necessary to clarify its role in the management of endobronchial obstructive symptoms and to determine whether efforts should be made to increase access to EBB within the VHA.

Conclusions

Most of the ROs who responded to our survey were cognizant and compliant with current ASTRO guidelines on management of lung cancer. Furthermore, familiarity with ASTRO guidelines and management choices were not associated with the respondents’ years in practice, academic appointment, full-time vs part-time status, or familiarity with ASTRO guidelines. This study is a nationwide survey of ROs in the VHA system that reflects the radiation-related care received by veterans with metastatic lung cancer. Responses were obtained from 93% of the 40 radiation oncology centers, so it is likely that the survey accurately represents the decision-making process at the majority of centers. It is possible that those who did not respond to the survey do not treat thoracic cases.

Lung cancer is the leading cause of cancer mortality both in the US and worldwide.¹ Many patients diagnosed with lung cancer present with advanced disease with thoracic symptoms such as cough, hemoptysis, dyspnea, and chest pain.^2-4 Palliative radiotherapy is routinely used in patients with locally advanced and metastatic lung cancer with the goal of relieving these symptoms and improving quality of life. Guidelines published by the American Society for Radiation Oncology (ASTRO) in 2011, and updated in 2018, provide recommendations on palliation of lung cancer with external beam radiotherapy (EBRT) and clarify the roles of concurrent chemotherapy and endobronchial brachytherapy (EBB) for palliation.^5,6

After prostate cancer, lung cancer is the second most frequently diagnosed cancer in the Veterans Health Administration (VHA).⁷ The VHA consists of 172 medical centers and is the largest integrated health care system in the US. At the time of this study, 40 of these centers had onsite radiation facilities. The VHA Palliative Radiation Taskforce has conducted a series of surveys to evaluate use of palliative radiotherapy in the VHA, determine VHA practice concordance with ASTRO and American College of Radiology (ACR) guidelines, and direct educational efforts towards addressing gaps in knowledge. These efforts are directed at ensuring best practices throughout this large and heterogeneous healthcare system. In 2016 a survey was conducted to evaluate concordance of VHA radiation oncologist (RO) practice with the 2011 ASTRO guidelines on palliative thoracic radiotherapy for non-small cell lung cancer (NSCLC).

Methods

A survey instrument was generated by VHA National Palliative Radiotherapy Taskforce members. It was reviewed and approved for use by the VHA Patient Care Services office. In May of 2016, the online survey was sent to the 88 VHA ROs practicing at the 40 sites with onsite radiation facilities. The survey aimed to determine patterns of practice for palliation of thoracic symptoms secondary to lung cancer.

Demographic information obtained included years in practice, employment status, academic appointment, board certification, and familiarity with ASTRO lung cancer guidelines. Two clinical scenarios were presented to glean opinions on dose/fractionation schemes preferred, use of concurrent chemotherapy, and use of EBB and/or yttrium aluminum garnet (YAG) laser technology. Survey questions also assessed use of EBRT for palliation of hemoptysis, chest wall pain, and/or stridor as well as use of stereotactic body radiotherapy (SBRT) for palliation.

Survey results were assessed for concordance with published ASTRO guidelines. χ² tests were run to test for associations between demographic factors such as academic appointment, years of practice, full time vs part time employment, and familiarity with ASTRO palliative lung cancer guidelines, with use of EBRT for palliation, dose and fractionation preference, use of concurrent chemotherapy, and strategy for management of endobronchial lesions.

Results

Of the 88 physicians surveyed, 54 responded for a response rate of 61%. Respondents represented 37 of the 40 (93%) VHA radiation oncology departments (Table 1). Among respondents, most were board certified (96%), held academic appointments (91%), and were full-time employees (85%). Forty-four percent of respondents were in practice for > 20 years, 19% for 11 to 20 years, 20% for 6 to 10 years, and 17% for < 6 years. A majority reported familiarity with the ASTRO guidelines (64%), while just 11% reported no familiarity with the guidelines.

When asked about use of SBRT for palliation of hemoptysis, stridor, and/or chest pain, the majority (87%) preferred conventional EBRT. Of the 13% who reported use of SBRT, most (11%) performed it onsite, with 2% of respondents referring offsite to non-VHA centers for the service. When asked about use of EBB for palliation, only 2% reported use of that procedure at their facilities, while 26% reported referral to non-VHA facilities for EBB. The remaining 72% of respondents favor use of conventional EBRT.

Respondents were presented with a case of a male patient aged 70 years who smoked and had widely metastatic NSCLC, a life expectancy of about 3 months, and 10/10 chest wall pain from direct tumor invasion. All respondents recommended palliative radiotherapy. The preferred fractionation was 20 Gray (Gy) in 5 fractions, which was recommended by 69% of respondents. The remainder recommended 30 Gy in 10 fractions (22%) or a single fraction of 10 Gy (9%). No respondent recommended the longer fractionation options of 60 Gy in 30 fractions, 45 Gy in 15 fractions, or 40 Gy in 20 fractions. The majority (98%) did not recommend concurrent chemotherapy.

When the above case was modified for an endobronchial lesion requiring palliation with associated lung collapse, rather than chest wall invasion, 20 respondents (38%) reported they would refer for EBB, and 20 respondents reported they would refer for YAG laser. As > 1 answer could be selected for this question, there were 12 respondents who selected both EBB and YAG laser; 8 selected only EBB, and 8 selected only YAG laser. Many respondents added comments about treating with EBRT, which had not been presented as an answer choice. Nearly half of respondents (49%) were amenable to referral for the use of EBB or YAG laser for lung reexpansion prior to radiotherapy. Three respondents mentioned referral for an endobronchial stent prior to palliative radiotherapy to address this question.

Discussion

This survey was conducted to evaluate concordance of management of metastatic lung cancer in the VHA with ASTRO guidelines. The relationship between respondents’ familiarity with the guidelines and responses also was evaluated to determine the impact such guidelines have on decision-making. The ASTRO guidelines for palliative thoracic radiation make recommendations regarding 3 issues: (1) radiation doses and fractionations for palliation; (2) the role of EBB; and (3) the use of concurrent chemotherapy.^5,6

Radiation Dose and Fractionation for Palliation

A variety of dose/fractionation schemes are considered appropriate in the ASTRO guideline statement, including more prolonged courses such as 30 Gy/10 fractions as well as more hypofractionated regimens (ie, 20 Gy/5 fractions, 17 Gy/2 fractions, and a single fraction of 10 Gy). Higher dose regimens, such as 30 Gy/10 fractions, have been associated with prolonged survival, as well as increased toxicities such as radiation esophagitis.⁸ Therefore, the guidelines support use of 30 Gy/10 fractions for patients with good performance status while encouraging use of more hypofractionated regimens for patients with poor performance status. In considering more hypofractionated regimens, one must consider the possibility of adverse effects that can be associated with higher dose per fraction. For instance, 17 Gy/2 fractions has been associated with myelopathy; therefore it should be used with caution and careful treatment planning.⁹

For the survey case example (a male aged 70 years with a 3-month life expectancy who required palliation for chest wall pain), all respondents selected hypofractionated regimens; with no respondent selected the more prolonged fractionations of 60 Gy/30 fractions, 45 Gy/15 fractions, or 40 Gy/20 fractions. These more prolonged fractionations are not endorsed by the guidelines in general, and particularly not for a patient with poor life expectancy. All responses for this case selected by survey respondents are considered appropriate per the consensus guideline statement.

Role of Concurrent Chemotherapy

The ASTRO guidelines do not support use of concurrent chemotherapy for palliation of stage IV NSCLC.^5,6 The 2018 updated guidelines established a role for concurrent chemotherapy for patients with stage III NSCLC with good performance status and life expectancy of > 3 months. This updated recommendation is based on data from 2 randomized trials demonstrating improvement in overall survival with the addition of chemotherapy for patients with stage III NSCLC undergoing palliative radiotherapy.^10-12

These newer studies are in contrast to an older randomized study by Ball and colleagues that demonstrated greater toxicity from concurrent chemotherapy, with no improvement in outcomes such as palliation of symptoms, overall survival, or progression free survival.¹³ In contrast to the newer studies that included only patients with stage III NSCLC, about half of the patients in the Ball and colleagues study had known metastatic disease.^10-13 Of note, staging for metastatic disease was not carried out routinely, so it is possible that a greater proportion of patients had metastatic disease that would have been seen on imaging. In concordance with the guidelines, 98% of the survey respondents did not recommend concurrent chemotherapy for palliation of intrathoracic symptom; only 1 respondent recommended use of chemotherapy for palliation.

Role of Endobronchial Brachytherapy

EBB involves implantation of radioactive sources for treatment of endobronchial lesions causing obstructive symptoms.¹⁴ Given the lack of randomized data that demonstrate a benefit of EBB over EBRT, the ASTRO guidelines do not endorse routine use of EBB for initial palliative management.^15,16 The ASTRO guidelines reference a Cochrane Review of 13 trials that concluded that EBRT alone is superior to EBB alone for initial palliation of symptoms from endobronchial NSCLC.¹⁷

Of respondents surveyed, only 1 facility offered onsite EBB. The majority of respondents (72%) preferred the use of conventional EBRT techniques, while 26% refer to non-VHA centers for EBB. Lack of incorporation of EBB into routine VHA practice likely is a reflection of the unclear role of this technology based on the available literature and ASTRO guidelines. In the setting of a right lower lung collapse, more respondents (49%) would consider use of EBB or YAG laser technology for lung reexpansion prior to EBRT.

The ASTRO guidelines recommend that initial EBB in conjunction with EBRT be considered based on randomized data demonstrating significant improvement in lung reexpansion and in patient reported dyspnea with addition of EBB to EBRT over EBRT alone.¹⁸ However, the guidelines do not mandate the use of EBB in this situation. It is possible that targeted education regarding the role of EBB would improve knowledge of the potential benefit in the setting of lung collapse and increase the percentage of VHA ROs who would recommend this procedure.

Limitations

The study is limited by lack of generalizability of these findings to all ROs in the country. It is also possible that physician responses do not represent practice patterns with complete accuracy. The use of EBB varied among practitioners. Further study of this technology is necessary to clarify its role in the management of endobronchial obstructive symptoms and to determine whether efforts should be made to increase access to EBB within the VHA.

Conclusions

Most of the ROs who responded to our survey were cognizant and compliant with current ASTRO guidelines on management of lung cancer. Furthermore, familiarity with ASTRO guidelines and management choices were not associated with the respondents’ years in practice, academic appointment, full-time vs part-time status, or familiarity with ASTRO guidelines. This study is a nationwide survey of ROs in the VHA system that reflects the radiation-related care received by veterans with metastatic lung cancer. Responses were obtained from 93% of the 40 radiation oncology centers, so it is likely that the survey accurately represents the decision-making process at the majority of centers. It is possible that those who did not respond to the survey do not treat thoracic cases.

Primary care for LGBTQ+ patients should focus on early identification and management of unique health risks, according to a leading expert.

Patients who are transgender, for instance, are nine times more likely to commit suicide than the general population (2015 U.S. Transgender Survey (USTS). Inter-university Consortium for Political and Social Research. 2019 May 22. doi: 10.3886/ICPSR37229.v1), and those who are also Black have an estimated HIV prevalence of 62%, demonstrating the cumulative, negative health effects of intersectionality (www.cdc.gov/hiv/group/gender/transgender/hiv-prevalence.html).

“Experiences with marginalization and stigma directly relate to some of the poor physical and mental health outcomes that these patients experience,” Megan McNamara, MD, said during a presentation at the American College of Physicians annual Internal Medicine meeting.

Dr. McNamara, who is director of the Gender Identity Veteran’s Experience (GIVE) Clinic, Veterans Affairs Northeast Ohio Healthcare System, Cleveland, offered a brief guide to managing LGBTQ+ patients. She emphasized increased rates of psychological distress and substance abuse, and encouraged familiarity with specific risks associated with three subgroups: men who have sex with men (MSM), women who have sex with women (WSW), and those who are transgender.

Men who have sex with men

According to Dr. McNamara, preexposure prophylaxis (PrEP) should be offered based on Centers for Disease Control and Prevention eligibility criteria, which require that the patient is HIV negative, has had a male sex partner in the past 6 months, is not in a monogamous relationship, and has had anal sex or a bacterial sexually transmitted infection in the past 6 months. The two PrEP options, emtricitabine/tenofovir disoproxil fumarate and emtricitabine/tenofovir alafenamide, are equally effective and have similar safety profiles, Dr. McNamara said, but patients with impaired renal function should receive the alafenamide formulation.

Dr. McNamara also advised screening gay men for extragenital STIs, noting a 13.3% increased risk. When asked about anal Pap testing for HPV, Dr. McNamara called the subject “very controversial,” and ultimately recommended against it, citing a lack of data linking anal HPV infection and dysplasia with later development of rectal carcinoma, as well as the nonactionable impact of a positive result.

“For me, the issue is ... if [a positive anal Pap test] is not going to change my management, if I don’t know that the anal HPV that I diagnose will result in cancer, should I continue to monitor it?” Dr. McNamara said.

Women who have sex with women

Beyond higher rates of psychological distress and substance abuse among lesbian and bisexual women, Dr. McNamara described increased risks of overweight and obesity, higher rates of smoking, and lower rates of Pap testing, all of which should prompt clinicians to advise accordingly, with cervical cancer screening in alignment with guidelines. Clinicians should also discuss HPV vaccination with patients, taking care to weigh benefits and risks, as “catch-up” HPV vaccination is not unilaterally recommended for adults older than 26 years.

Transgender patients

Discussing transgender patients, Dr. McNamara focused on cross-sex hormone therapy (CSHT), first noting the significant psychological benefits, including improvements in depression, somatization, interpersonal sensitivity, hostility, anxiety, phobic anxiety/agoraphobia, and quality of life.

According to Dr. McNamara, CSHT is relatively simple and may be safely administered by primary care providers. For transmasculine patients, testosterone supplementation is all that is needed, whereas transfeminine patients will require spironolactone or GnRH agonists to reduce testosterone and estradiol to increase feminizing hormones to pubertal levels.

CSHT is not without risks, Dr. McNamara said, including “very high” risks of erythrocytosis among transmasculine patients and venous thromboembolic disease among transfeminine patients; but these risks need to be considered in the context of an approximate 40% suicide rate among transgender individuals.

“I can tell you in my own practice that these [suicide] data ring true,” Dr. McNamara said. “Many, many of my patients have attempted suicide, so [CSHT] is something that you really want to think about right away.”

Even when additional risk factors are present, such as preexisting cardiovascular disease, Dr. McNamara suggested that “there are very few absolute contraindications to CSHT,” and described it as a “life-sustaining treatment” that should be viewed analogously with any other long-term management strategy, such as therapy for diabetes or hypertension.

Fostering a transgender-friendly practice

In an interview, Nicole Nisly, MD, codirector of the LGBTQ+ Clinic at the University of Iowa Hospitals and Clinics, Iowa City, reflected upon Dr. McNamara’s presentation, noting that primary care providers – with a little education – are the best candidates to care for transgender patients.

“I think [primary care providers] do a better job [caring for transgender patients] than endocrinologists, honestly, because they can provide care for the whole person,” Dr. Nisly said. “They can do a Pap, they can do STI screening, they can assess mood, they can [evaluate] safety, and the whole person, as opposed to endocrinologists, who do hormone therapy, but somebody else does everything else.”

Dr. Nisly emphasized the importance of personalizing care for transgender individuals, which depends upon a welcoming practice environment, with careful attention to language.

Foremost, Dr. Nisly recommended asking patients for their preferred name, sexual orientation, and gender identity.

“One of the most difficult things [for transgender patients] is to see notes with the wrong name – the name that makes them feel uncomfortable – or the wrong pronoun,” Dr. Nisly said. “That’s very important to the community.”

Dr. Nisly also recommended an alternative term for cross-sex hormone therapy.

“I hate cross-sex hormone therapy terminology, honestly,” Dr. Nisly said. “I just think it’s so unwelcoming, and I think most of our patients don’t like the terminology, so we use ‘gender-affirming hormone therapy.’”

Dr. Nisly explained that the term “cross-sex” assumes a conventional definition of sex, which is inherently flawed.

When discussing certain medical risk factors, such as pregnancy or HIV, it is helpful to know “sex assigned at birth” for both patients and their sexual partners, Dr. Nisly said. It’s best to ask in this way, instead of using terms like “boyfriend” or “girlfriend,” as “sex assigned at birth” is “terminology the community recognizes, affirms, and feels comfortable with.”

Concerning management of medical risk factors, Dr. Nisly offered some additional perspectives.

For one, she recommended giving PrEP to any patient who has a desire to be on PrEP, noting that this desire can indicate a change in future sexual practices, which the CDC criteria do not anticipate. She also advised in-hospital self-swabbing for extragenital STIs, as this can increase patient comfort and adherence. And, in contrast with Dr. McNamara, Dr. Nisly recommended anal Pap screening for any man that has sex with men and anyone with HIV of any gender. She noted that rates of anal dysplasia are “pretty high” among men who have sex with men, and that detection may reduce cancer risk.

For clinicians who would like to learn more about caring for transgender patients, Dr. Nisly recommended that they start by reading the World Professional Association for Transgender Health guidelines.

“It’s about 300 pages,” Dr. Nisly said, “but it is great.”

Dr. McNamara and Dr. Nisly reported no conflicts of interest.

Primary care for LGBTQ+ patients should focus on early identification and management of unique health risks, according to a leading expert.

Patients who are transgender, for instance, are nine times more likely to commit suicide than the general population (2015 U.S. Transgender Survey (USTS). Inter-university Consortium for Political and Social Research. 2019 May 22. doi: 10.3886/ICPSR37229.v1), and those who are also Black have an estimated HIV prevalence of 62%, demonstrating the cumulative, negative health effects of intersectionality (www.cdc.gov/hiv/group/gender/transgender/hiv-prevalence.html).

“Experiences with marginalization and stigma directly relate to some of the poor physical and mental health outcomes that these patients experience,” Megan McNamara, MD, said during a presentation at the American College of Physicians annual Internal Medicine meeting.

Dr. McNamara, who is director of the Gender Identity Veteran’s Experience (GIVE) Clinic, Veterans Affairs Northeast Ohio Healthcare System, Cleveland, offered a brief guide to managing LGBTQ+ patients. She emphasized increased rates of psychological distress and substance abuse, and encouraged familiarity with specific risks associated with three subgroups: men who have sex with men (MSM), women who have sex with women (WSW), and those who are transgender.

Men who have sex with men

According to Dr. McNamara, preexposure prophylaxis (PrEP) should be offered based on Centers for Disease Control and Prevention eligibility criteria, which require that the patient is HIV negative, has had a male sex partner in the past 6 months, is not in a monogamous relationship, and has had anal sex or a bacterial sexually transmitted infection in the past 6 months. The two PrEP options, emtricitabine/tenofovir disoproxil fumarate and emtricitabine/tenofovir alafenamide, are equally effective and have similar safety profiles, Dr. McNamara said, but patients with impaired renal function should receive the alafenamide formulation.

Dr. McNamara also advised screening gay men for extragenital STIs, noting a 13.3% increased risk. When asked about anal Pap testing for HPV, Dr. McNamara called the subject “very controversial,” and ultimately recommended against it, citing a lack of data linking anal HPV infection and dysplasia with later development of rectal carcinoma, as well as the nonactionable impact of a positive result.

“For me, the issue is ... if [a positive anal Pap test] is not going to change my management, if I don’t know that the anal HPV that I diagnose will result in cancer, should I continue to monitor it?” Dr. McNamara said.

Women who have sex with women

Beyond higher rates of psychological distress and substance abuse among lesbian and bisexual women, Dr. McNamara described increased risks of overweight and obesity, higher rates of smoking, and lower rates of Pap testing, all of which should prompt clinicians to advise accordingly, with cervical cancer screening in alignment with guidelines. Clinicians should also discuss HPV vaccination with patients, taking care to weigh benefits and risks, as “catch-up” HPV vaccination is not unilaterally recommended for adults older than 26 years.

Transgender patients

Discussing transgender patients, Dr. McNamara focused on cross-sex hormone therapy (CSHT), first noting the significant psychological benefits, including improvements in depression, somatization, interpersonal sensitivity, hostility, anxiety, phobic anxiety/agoraphobia, and quality of life.

According to Dr. McNamara, CSHT is relatively simple and may be safely administered by primary care providers. For transmasculine patients, testosterone supplementation is all that is needed, whereas transfeminine patients will require spironolactone or GnRH agonists to reduce testosterone and estradiol to increase feminizing hormones to pubertal levels.

CSHT is not without risks, Dr. McNamara said, including “very high” risks of erythrocytosis among transmasculine patients and venous thromboembolic disease among transfeminine patients; but these risks need to be considered in the context of an approximate 40% suicide rate among transgender individuals.

“I can tell you in my own practice that these [suicide] data ring true,” Dr. McNamara said. “Many, many of my patients have attempted suicide, so [CSHT] is something that you really want to think about right away.”

Even when additional risk factors are present, such as preexisting cardiovascular disease, Dr. McNamara suggested that “there are very few absolute contraindications to CSHT,” and described it as a “life-sustaining treatment” that should be viewed analogously with any other long-term management strategy, such as therapy for diabetes or hypertension.

Fostering a transgender-friendly practice

In an interview, Nicole Nisly, MD, codirector of the LGBTQ+ Clinic at the University of Iowa Hospitals and Clinics, Iowa City, reflected upon Dr. McNamara’s presentation, noting that primary care providers – with a little education – are the best candidates to care for transgender patients.

“I think [primary care providers] do a better job [caring for transgender patients] than endocrinologists, honestly, because they can provide care for the whole person,” Dr. Nisly said. “They can do a Pap, they can do STI screening, they can assess mood, they can [evaluate] safety, and the whole person, as opposed to endocrinologists, who do hormone therapy, but somebody else does everything else.”

Dr. Nisly emphasized the importance of personalizing care for transgender individuals, which depends upon a welcoming practice environment, with careful attention to language.

Foremost, Dr. Nisly recommended asking patients for their preferred name, sexual orientation, and gender identity.

“One of the most difficult things [for transgender patients] is to see notes with the wrong name – the name that makes them feel uncomfortable – or the wrong pronoun,” Dr. Nisly said. “That’s very important to the community.”

Dr. Nisly also recommended an alternative term for cross-sex hormone therapy.

“I hate cross-sex hormone therapy terminology, honestly,” Dr. Nisly said. “I just think it’s so unwelcoming, and I think most of our patients don’t like the terminology, so we use ‘gender-affirming hormone therapy.’”

Dr. Nisly explained that the term “cross-sex” assumes a conventional definition of sex, which is inherently flawed.

When discussing certain medical risk factors, such as pregnancy or HIV, it is helpful to know “sex assigned at birth” for both patients and their sexual partners, Dr. Nisly said. It’s best to ask in this way, instead of using terms like “boyfriend” or “girlfriend,” as “sex assigned at birth” is “terminology the community recognizes, affirms, and feels comfortable with.”

Concerning management of medical risk factors, Dr. Nisly offered some additional perspectives.

For one, she recommended giving PrEP to any patient who has a desire to be on PrEP, noting that this desire can indicate a change in future sexual practices, which the CDC criteria do not anticipate. She also advised in-hospital self-swabbing for extragenital STIs, as this can increase patient comfort and adherence. And, in contrast with Dr. McNamara, Dr. Nisly recommended anal Pap screening for any man that has sex with men and anyone with HIV of any gender. She noted that rates of anal dysplasia are “pretty high” among men who have sex with men, and that detection may reduce cancer risk.

For clinicians who would like to learn more about caring for transgender patients, Dr. Nisly recommended that they start by reading the World Professional Association for Transgender Health guidelines.

“It’s about 300 pages,” Dr. Nisly said, “but it is great.”

Dr. McNamara and Dr. Nisly reported no conflicts of interest.

Primary care for LGBTQ+ patients should focus on early identification and management of unique health risks, according to a leading expert.

Patients who are transgender, for instance, are nine times more likely to commit suicide than the general population (2015 U.S. Transgender Survey (USTS). Inter-university Consortium for Political and Social Research. 2019 May 22. doi: 10.3886/ICPSR37229.v1), and those who are also Black have an estimated HIV prevalence of 62%, demonstrating the cumulative, negative health effects of intersectionality (www.cdc.gov/hiv/group/gender/transgender/hiv-prevalence.html).

“Experiences with marginalization and stigma directly relate to some of the poor physical and mental health outcomes that these patients experience,” Megan McNamara, MD, said during a presentation at the American College of Physicians annual Internal Medicine meeting.

Dr. McNamara, who is director of the Gender Identity Veteran’s Experience (GIVE) Clinic, Veterans Affairs Northeast Ohio Healthcare System, Cleveland, offered a brief guide to managing LGBTQ+ patients. She emphasized increased rates of psychological distress and substance abuse, and encouraged familiarity with specific risks associated with three subgroups: men who have sex with men (MSM), women who have sex with women (WSW), and those who are transgender.

Men who have sex with men

According to Dr. McNamara, preexposure prophylaxis (PrEP) should be offered based on Centers for Disease Control and Prevention eligibility criteria, which require that the patient is HIV negative, has had a male sex partner in the past 6 months, is not in a monogamous relationship, and has had anal sex or a bacterial sexually transmitted infection in the past 6 months. The two PrEP options, emtricitabine/tenofovir disoproxil fumarate and emtricitabine/tenofovir alafenamide, are equally effective and have similar safety profiles, Dr. McNamara said, but patients with impaired renal function should receive the alafenamide formulation.

Dr. McNamara also advised screening gay men for extragenital STIs, noting a 13.3% increased risk. When asked about anal Pap testing for HPV, Dr. McNamara called the subject “very controversial,” and ultimately recommended against it, citing a lack of data linking anal HPV infection and dysplasia with later development of rectal carcinoma, as well as the nonactionable impact of a positive result.

“For me, the issue is ... if [a positive anal Pap test] is not going to change my management, if I don’t know that the anal HPV that I diagnose will result in cancer, should I continue to monitor it?” Dr. McNamara said.

Women who have sex with women

Beyond higher rates of psychological distress and substance abuse among lesbian and bisexual women, Dr. McNamara described increased risks of overweight and obesity, higher rates of smoking, and lower rates of Pap testing, all of which should prompt clinicians to advise accordingly, with cervical cancer screening in alignment with guidelines. Clinicians should also discuss HPV vaccination with patients, taking care to weigh benefits and risks, as “catch-up” HPV vaccination is not unilaterally recommended for adults older than 26 years.

Transgender patients

Discussing transgender patients, Dr. McNamara focused on cross-sex hormone therapy (CSHT), first noting the significant psychological benefits, including improvements in depression, somatization, interpersonal sensitivity, hostility, anxiety, phobic anxiety/agoraphobia, and quality of life.

According to Dr. McNamara, CSHT is relatively simple and may be safely administered by primary care providers. For transmasculine patients, testosterone supplementation is all that is needed, whereas transfeminine patients will require spironolactone or GnRH agonists to reduce testosterone and estradiol to increase feminizing hormones to pubertal levels.

CSHT is not without risks, Dr. McNamara said, including “very high” risks of erythrocytosis among transmasculine patients and venous thromboembolic disease among transfeminine patients; but these risks need to be considered in the context of an approximate 40% suicide rate among transgender individuals.

“I can tell you in my own practice that these [suicide] data ring true,” Dr. McNamara said. “Many, many of my patients have attempted suicide, so [CSHT] is something that you really want to think about right away.”

Even when additional risk factors are present, such as preexisting cardiovascular disease, Dr. McNamara suggested that “there are very few absolute contraindications to CSHT,” and described it as a “life-sustaining treatment” that should be viewed analogously with any other long-term management strategy, such as therapy for diabetes or hypertension.

Fostering a transgender-friendly practice

In an interview, Nicole Nisly, MD, codirector of the LGBTQ+ Clinic at the University of Iowa Hospitals and Clinics, Iowa City, reflected upon Dr. McNamara’s presentation, noting that primary care providers – with a little education – are the best candidates to care for transgender patients.

“I think [primary care providers] do a better job [caring for transgender patients] than endocrinologists, honestly, because they can provide care for the whole person,” Dr. Nisly said. “They can do a Pap, they can do STI screening, they can assess mood, they can [evaluate] safety, and the whole person, as opposed to endocrinologists, who do hormone therapy, but somebody else does everything else.”

Dr. Nisly emphasized the importance of personalizing care for transgender individuals, which depends upon a welcoming practice environment, with careful attention to language.

Foremost, Dr. Nisly recommended asking patients for their preferred name, sexual orientation, and gender identity.

“One of the most difficult things [for transgender patients] is to see notes with the wrong name – the name that makes them feel uncomfortable – or the wrong pronoun,” Dr. Nisly said. “That’s very important to the community.”

Dr. Nisly also recommended an alternative term for cross-sex hormone therapy.

“I hate cross-sex hormone therapy terminology, honestly,” Dr. Nisly said. “I just think it’s so unwelcoming, and I think most of our patients don’t like the terminology, so we use ‘gender-affirming hormone therapy.’”

Dr. Nisly explained that the term “cross-sex” assumes a conventional definition of sex, which is inherently flawed.

When discussing certain medical risk factors, such as pregnancy or HIV, it is helpful to know “sex assigned at birth” for both patients and their sexual partners, Dr. Nisly said. It’s best to ask in this way, instead of using terms like “boyfriend” or “girlfriend,” as “sex assigned at birth” is “terminology the community recognizes, affirms, and feels comfortable with.”

Concerning management of medical risk factors, Dr. Nisly offered some additional perspectives.

For one, she recommended giving PrEP to any patient who has a desire to be on PrEP, noting that this desire can indicate a change in future sexual practices, which the CDC criteria do not anticipate. She also advised in-hospital self-swabbing for extragenital STIs, as this can increase patient comfort and adherence. And, in contrast with Dr. McNamara, Dr. Nisly recommended anal Pap screening for any man that has sex with men and anyone with HIV of any gender. She noted that rates of anal dysplasia are “pretty high” among men who have sex with men, and that detection may reduce cancer risk.

For clinicians who would like to learn more about caring for transgender patients, Dr. Nisly recommended that they start by reading the World Professional Association for Transgender Health guidelines.

“It’s about 300 pages,” Dr. Nisly said, “but it is great.”

Dr. McNamara and Dr. Nisly reported no conflicts of interest.

Most people whose medical record says they are allergic to penicillin are not actually intolerant, an allergist said during the first day of sessions at the annual meeting of the American College of Physicians.

The mislabeling has implications for patient outcomes and efforts to fight antibiotic resistance, said Olajumoke Fadugba, MD, program director for the allergy and immunology fellowship at University of Pennsylvania Health System, Philadelphia.

About 10% of the general population reports a history of penicillin allergy (up to 15% of hospitalized patients), but up to 90% of patients with that label are able to tolerate penicillin, Dr. Fadugba said. The mislabeling comes either because reactions were improperly characterized early on or people have outgrown the allergy.

“There are data that tell us penicillin IgE-mediated wanes over time and that after 10 years of avoidance of a drug, greater than 80% of patients have a resolution of their penicillin IgE.”

Data also show patients outgrow their aminopenicillin reactions (including those from amoxicillin and Ampicillin) faster than parenteral penicillin reactions, she noted.

Josune Iglesias, MD, assistant professor of internal medicine at Rush University Medical Center in Chicago, said in an interview that she often sees patients who said their parents told them when they were kids that they were allergic to penicillin and that information just keeps getting entered into their records.

She said physicians are aware the penicillin-allergic label is not always accurate, but there is hesitancy to challenge those labels.

“We are cautious because of the potential side effects and the harm that we could cause if we unlabel the patient,” she said. “I think having this information will help us unlabel those patients well so we don’t cause harm.”

Also, the threat to antibiotic resistance is real, she said, when penicillin is eliminated as an option unnecessarily.

When a person is labeled allergic to penicillin, the treatment choices often go to broad-spectrum antibiotics that are more costly, have potentially worse side effects, and may contribute to resistance.

“It’s really important, especially with older people, patients sicker with chronic conditions to really make sure we unlabel those patients [who are not truly penicillin allergic],” Dr. Iglesias said.

The label can also cause harm in the hospital setting and worsen outcomes, according to Dr. Fadugba.

She noted that the penicillin allergy label has been linked with longer hospital length of stay, higher rate of readmission, acute kidney injury, multidrug-resistant organisms such as MRSA, and nosocomial infections including Clostridioides difficile.

Getting an effective drug history is an important part of determining who really has a penicillin allergy.

A questionnaire should ask whether the patient was likely to have had an immediate hypersensitivity to penicillin, such as hives or anaphylaxis, which would be more worrisome than a delayed rash.

Knowing the time frame of the reaction helps determine how likely or unlikely people are to still have the allergy, Dr. Fadugba said. “We also want to ask, have they received a penicillin antibiotic since that initial reaction and have they tolerated it?”

She continued: “If a patient received amoxicillin 2 weeks ago, and they tolerated it, you can essentially remove the allergy label and essentially change that patient’s potential hospital course – that immediate course or future outcomes.”

After obtaining the history, there are choices to make.

If a patient is not allergic, she said, the next step is removing the label and documenting why so that in the future another clinician doesn’t see the deleted label and put it back. If a person is deemed allergic by history, clinicians should document the nature of the reaction and if the patient needs a beta-lactam during a hospitalization or in clinic, make a decision based on what kind of beta-lactam they need.

“Generally, for a fourth-generation cephalosporin, for a distant history of penicillin allergy, you can probably give the full dose or – if you’re conservative – give it cautiously, perhaps 10% initially and then monitor because cross-reactivity is known to be low, about 2%,” Dr. Fadugba said.

If the patient needs a penicillin antibiotic specifically, options are guided by the resources.

If a clinician has personnel or an allergy specialist available, skin testing may be an option and “if negative, you can rule out the allergy,” Dr. Fadugba said.

“If that’s not available and the patient really needs a penicillin, you can consider desensitization,” she said.

However, she said, “If the patient is very high risk, then you have no choice but to use an alternative, especially if you can’t desensitize.”

Dr. Fadugba is a consultant for the Health Resources & Services Administration. Dr. Iglesias disclosed no relevant financial relationships.

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

Most people whose medical record says they are allergic to penicillin are not actually intolerant, an allergist said during the first day of sessions at the annual meeting of the American College of Physicians.

The mislabeling has implications for patient outcomes and efforts to fight antibiotic resistance, said Olajumoke Fadugba, MD, program director for the allergy and immunology fellowship at University of Pennsylvania Health System, Philadelphia.

About 10% of the general population reports a history of penicillin allergy (up to 15% of hospitalized patients), but up to 90% of patients with that label are able to tolerate penicillin, Dr. Fadugba said. The mislabeling comes either because reactions were improperly characterized early on or people have outgrown the allergy.

“There are data that tell us penicillin IgE-mediated wanes over time and that after 10 years of avoidance of a drug, greater than 80% of patients have a resolution of their penicillin IgE.”

Data also show patients outgrow their aminopenicillin reactions (including those from amoxicillin and Ampicillin) faster than parenteral penicillin reactions, she noted.

Josune Iglesias, MD, assistant professor of internal medicine at Rush University Medical Center in Chicago, said in an interview that she often sees patients who said their parents told them when they were kids that they were allergic to penicillin and that information just keeps getting entered into their records.

She said physicians are aware the penicillin-allergic label is not always accurate, but there is hesitancy to challenge those labels.

“We are cautious because of the potential side effects and the harm that we could cause if we unlabel the patient,” she said. “I think having this information will help us unlabel those patients well so we don’t cause harm.”

Also, the threat to antibiotic resistance is real, she said, when penicillin is eliminated as an option unnecessarily.

When a person is labeled allergic to penicillin, the treatment choices often go to broad-spectrum antibiotics that are more costly, have potentially worse side effects, and may contribute to resistance.

“It’s really important, especially with older people, patients sicker with chronic conditions to really make sure we unlabel those patients [who are not truly penicillin allergic],” Dr. Iglesias said.

The label can also cause harm in the hospital setting and worsen outcomes, according to Dr. Fadugba.

She noted that the penicillin allergy label has been linked with longer hospital length of stay, higher rate of readmission, acute kidney injury, multidrug-resistant organisms such as MRSA, and nosocomial infections including Clostridioides difficile.

Getting an effective drug history is an important part of determining who really has a penicillin allergy.

A questionnaire should ask whether the patient was likely to have had an immediate hypersensitivity to penicillin, such as hives or anaphylaxis, which would be more worrisome than a delayed rash.

Knowing the time frame of the reaction helps determine how likely or unlikely people are to still have the allergy, Dr. Fadugba said. “We also want to ask, have they received a penicillin antibiotic since that initial reaction and have they tolerated it?”

She continued: “If a patient received amoxicillin 2 weeks ago, and they tolerated it, you can essentially remove the allergy label and essentially change that patient’s potential hospital course – that immediate course or future outcomes.”

After obtaining the history, there are choices to make.

If a patient is not allergic, she said, the next step is removing the label and documenting why so that in the future another clinician doesn’t see the deleted label and put it back. If a person is deemed allergic by history, clinicians should document the nature of the reaction and if the patient needs a beta-lactam during a hospitalization or in clinic, make a decision based on what kind of beta-lactam they need.

“Generally, for a fourth-generation cephalosporin, for a distant history of penicillin allergy, you can probably give the full dose or – if you’re conservative – give it cautiously, perhaps 10% initially and then monitor because cross-reactivity is known to be low, about 2%,” Dr. Fadugba said.

If the patient needs a penicillin antibiotic specifically, options are guided by the resources.

If a clinician has personnel or an allergy specialist available, skin testing may be an option and “if negative, you can rule out the allergy,” Dr. Fadugba said.

“If that’s not available and the patient really needs a penicillin, you can consider desensitization,” she said.

However, she said, “If the patient is very high risk, then you have no choice but to use an alternative, especially if you can’t desensitize.”

Dr. Fadugba is a consultant for the Health Resources & Services Administration. Dr. Iglesias disclosed no relevant financial relationships.

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

Most people whose medical record says they are allergic to penicillin are not actually intolerant, an allergist said during the first day of sessions at the annual meeting of the American College of Physicians.

The mislabeling has implications for patient outcomes and efforts to fight antibiotic resistance, said Olajumoke Fadugba, MD, program director for the allergy and immunology fellowship at University of Pennsylvania Health System, Philadelphia.

About 10% of the general population reports a history of penicillin allergy (up to 15% of hospitalized patients), but up to 90% of patients with that label are able to tolerate penicillin, Dr. Fadugba said. The mislabeling comes either because reactions were improperly characterized early on or people have outgrown the allergy.

“There are data that tell us penicillin IgE-mediated wanes over time and that after 10 years of avoidance of a drug, greater than 80% of patients have a resolution of their penicillin IgE.”

Data also show patients outgrow their aminopenicillin reactions (including those from amoxicillin and Ampicillin) faster than parenteral penicillin reactions, she noted.

Josune Iglesias, MD, assistant professor of internal medicine at Rush University Medical Center in Chicago, said in an interview that she often sees patients who said their parents told them when they were kids that they were allergic to penicillin and that information just keeps getting entered into their records.

She said physicians are aware the penicillin-allergic label is not always accurate, but there is hesitancy to challenge those labels.

“We are cautious because of the potential side effects and the harm that we could cause if we unlabel the patient,” she said. “I think having this information will help us unlabel those patients well so we don’t cause harm.”

Also, the threat to antibiotic resistance is real, she said, when penicillin is eliminated as an option unnecessarily.

When a person is labeled allergic to penicillin, the treatment choices often go to broad-spectrum antibiotics that are more costly, have potentially worse side effects, and may contribute to resistance.

“It’s really important, especially with older people, patients sicker with chronic conditions to really make sure we unlabel those patients [who are not truly penicillin allergic],” Dr. Iglesias said.

The label can also cause harm in the hospital setting and worsen outcomes, according to Dr. Fadugba.

She noted that the penicillin allergy label has been linked with longer hospital length of stay, higher rate of readmission, acute kidney injury, multidrug-resistant organisms such as MRSA, and nosocomial infections including Clostridioides difficile.

Getting an effective drug history is an important part of determining who really has a penicillin allergy.

A questionnaire should ask whether the patient was likely to have had an immediate hypersensitivity to penicillin, such as hives or anaphylaxis, which would be more worrisome than a delayed rash.

Knowing the time frame of the reaction helps determine how likely or unlikely people are to still have the allergy, Dr. Fadugba said. “We also want to ask, have they received a penicillin antibiotic since that initial reaction and have they tolerated it?”

She continued: “If a patient received amoxicillin 2 weeks ago, and they tolerated it, you can essentially remove the allergy label and essentially change that patient’s potential hospital course – that immediate course or future outcomes.”

After obtaining the history, there are choices to make.

If a patient is not allergic, she said, the next step is removing the label and documenting why so that in the future another clinician doesn’t see the deleted label and put it back. If a person is deemed allergic by history, clinicians should document the nature of the reaction and if the patient needs a beta-lactam during a hospitalization or in clinic, make a decision based on what kind of beta-lactam they need.

“Generally, for a fourth-generation cephalosporin, for a distant history of penicillin allergy, you can probably give the full dose or – if you’re conservative – give it cautiously, perhaps 10% initially and then monitor because cross-reactivity is known to be low, about 2%,” Dr. Fadugba said.

If the patient needs a penicillin antibiotic specifically, options are guided by the resources.

If a clinician has personnel or an allergy specialist available, skin testing may be an option and “if negative, you can rule out the allergy,” Dr. Fadugba said.

“If that’s not available and the patient really needs a penicillin, you can consider desensitization,” she said.

However, she said, “If the patient is very high risk, then you have no choice but to use an alternative, especially if you can’t desensitize.”

Dr. Fadugba is a consultant for the Health Resources & Services Administration. Dr. Iglesias disclosed no relevant financial relationships.

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

Oral corticosteroid bursts are associated with an increased risk of gastrointestinal bleeding, sepsis, and pneumonia during the month after treatment initiation, according to a nationwide cohort study of children in Taiwan.

The adverse events are rare, and the risk attenuates in subsequent months, the analysis shows. Still, the study “provides evidence that corticosteroid bursts are not innocuous but may pose potentially serious health risks,” study author Tsung-Chieh Yao, MD, PhD, and colleagues said. “Clinicians prescribing corticosteroid bursts to children need to weigh the benefits against the risks of severe adverse events.”

[email protected]

Oral corticosteroid bursts are associated with an increased risk of gastrointestinal bleeding, sepsis, and pneumonia during the month after treatment initiation, according to a nationwide cohort study of children in Taiwan.

The adverse events are rare, and the risk attenuates in subsequent months, the analysis shows. Still, the study “provides evidence that corticosteroid bursts are not innocuous but may pose potentially serious health risks,” study author Tsung-Chieh Yao, MD, PhD, and colleagues said. “Clinicians prescribing corticosteroid bursts to children need to weigh the benefits against the risks of severe adverse events.”

[email protected]

Oral corticosteroid bursts are associated with an increased risk of gastrointestinal bleeding, sepsis, and pneumonia during the month after treatment initiation, according to a nationwide cohort study of children in Taiwan.

The adverse events are rare, and the risk attenuates in subsequent months, the analysis shows. Still, the study “provides evidence that corticosteroid bursts are not innocuous but may pose potentially serious health risks,” study author Tsung-Chieh Yao, MD, PhD, and colleagues said. “Clinicians prescribing corticosteroid bursts to children need to weigh the benefits against the risks of severe adverse events.”

[email protected]

Cognitive remediation (CR), a therapy that encompasses nonpharmacologic approaches to improving cognitive function for patients with severe mental illness, may lead to significant improvement for patients with schizophrenia, new research suggests.
 

verbaska_studio/Getty Images

A systematic review of 130 worldwide studies that included almost 9,000 participants showed that CR significantly improved global cognition and global functioning. In addition, investigators identified key patient characteristics that flagged ideal candidates for the therapy.

“Because pharmacological treatment exerts limited effects on cognitive deficits, and clinical remission does not necessarily result in functional recovery, widespread implementation of CR could be a game-changer for achieving the patient’s personal recovery goals,” the researchers wrote.

“We hope that this systematic review could help clinicians understand how to make CR even more effective and even more personalized,” lead author Antonio Vita, MD, PhD, department of clinical and experimental sciences, University of Brescia, Italy, said in an interview.

Dr. Vita noted that he would also encourage clinicians to consider “proposing it for clinical practice.”

The findings were presented at the virtual congress of the Schizophrenia International Research Society (SIRS 2021) and were published simultaneously in JAMA Psychiatry.
 

Resistance continues

Cognition “should be a focus of treatment because most of the disability and functional consequences of the disease are related to ... neurocognitive impairment and impairment of social cognition,” Dr. Vita said.

He noted that treatments that focus on cognition are crucial for the recovery of patients with schizophrenia.

However, despite a “solid body of evidence” supporting the efficacy of CR and guideline recommendations that CR be included in psychiatric services, reluctance remains, the investigators noted.

The study’s goal was to determine optimal candidates for CR and to assess outcomes of the therapy and its four core elements:

• The presence of an active and trained therapist.
• Repeated practice of cognitive exercises.
• Structured development of cognitive strategies.
• Techniques to improve the transfer of cognitive gains to the real world, such as integrated psychosocial rehabilitation.

The investigators conducted a systematic literature search of the PubMed, Scopus, and PsychInfo databases to find relevant studies of CR published between January 2011 and February 2020. They also “hand-searched” meta-analyses, reviews, and reference lists.

Ultimately, the analysis included 130 randomized clinical trials comparing CR with a control condition in 8,851 patients with schizophrenia spectrum disorders.

Of these studies, 57 were conducted in Europe, 38 in the United States, 22 in Asia, 4 in Canada, 4 in Middle Eastern countries, 3 in Australia, and 2 in Brazil.

The mean age of the participants was 36.7 years, and 68% were men. The average age at the time of schizophrenia onset was 23.3 years, and the mean duration of illness was 13.8 years.

The average duration of CR treatment was 15.2 weeks. The four elements were well represented; each was offered to at least 71% of patients.

The comparator therapy was treatment as usual (TAU), in 34.3% of cases, or active TAU with multidisciplinary rehabilitation, in 15.2% of cases. The remaining interventions were either nonspecific (30.8%) or were devised specifically for the study (19.9%).

Results showed that CR had a significant, albeit moderate, effect on global cognition (Cohen’s d effect size, 0.29; P < .001) and global functioning (effect size, 0.22; P < .01).

Having an active and trained therapist had a significant impact on cognition and functioning (P = .04 for both), as did the structured development of cognitive strategies (P = .002 for cognition; P = .004 for functioning).

The integration of psychosocial rehabilitation also had a significant effect on functioning (P = .003).

Interventions that included all of the core elements had a “highly significant” association with global cognition (P = .02) and global functioning (P < .001), the investigators reported. Longer treatments were significantly associated with greater functional improvement (P = .006).

The investigators found that improvements were greater among patients who had fewer years of education (P = .03 for cognition; P = .02 for functioning), lower premorbid IQ scores (P = .04 for functioning), and more severe symptoms at baseline (P = .005 for cognition).

The researchers noted that CR should become more widely available because it has the “potential to be an element of standard care rather than an optional intervention targeting selected individuals.”
 

An overlooked treatment option

Commenting on the findings for this news organization, Alice Medalia, PhD, director of the Lieber Recovery Clinic at Columbia University Irving Medical Center, New York, noted that this study is the second large-scale analysis of the use of CR for patients with schizophrenia to come out this year. The other was published in Schizophrenia Bulletin.

“So this is a banner year for large reviews,” she said. “It’s great to have two studies like this [that] tell a very consistent story.”

Dr. Medalia, who was not involved with the research, said individuals “don’t really talk about cognition very much.”

CR, she added, is “one of an array of services that one should be providing, and the bigger picture is that every single person should have their cognitive health needs addressed.

“If someone is having problems, and it’s getting in the way of them being the kind of person they want to be and doing want they want to do, we need to intervene. How we intervene should always be in the least disruptive and intense way,” she said.

These measures could include examining sleep hygiene, adjusting medications, or introducing exercise.

“But there really does come a time for some people where cognitive remediation is going to be helpful, so it should be more available,” Dr. Medalia said.

Although increased availability is partially dependent on having enough trained therapists, the main reason CR is not more widely available is because “people just don’t think about cognition and they don’t know how to talk about it,” she noted. In addition, she said, even when it is available, clinicians don’t refer patients.

“That tells you something. The solution here is not to put a cognitive remediation program everywhere but ... to get people comfortable talking about cognition and identifying when an intervention is needed,” said Dr. Medalia.

One study author received grants from the National Institute for Health Research during the conduct of the study and is the creator of CIRCuiTs, a cognitive remediation software program. The other investigators and Dr. Medalia have reported no relevant financial relationships.

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

Cognitive remediation (CR), a therapy that encompasses nonpharmacologic approaches to improving cognitive function for patients with severe mental illness, may lead to significant improvement for patients with schizophrenia, new research suggests.
 

verbaska_studio/Getty Images

A systematic review of 130 worldwide studies that included almost 9,000 participants showed that CR significantly improved global cognition and global functioning. In addition, investigators identified key patient characteristics that flagged ideal candidates for the therapy.

“Because pharmacological treatment exerts limited effects on cognitive deficits, and clinical remission does not necessarily result in functional recovery, widespread implementation of CR could be a game-changer for achieving the patient’s personal recovery goals,” the researchers wrote.

“We hope that this systematic review could help clinicians understand how to make CR even more effective and even more personalized,” lead author Antonio Vita, MD, PhD, department of clinical and experimental sciences, University of Brescia, Italy, said in an interview.

Dr. Vita noted that he would also encourage clinicians to consider “proposing it for clinical practice.”

The findings were presented at the virtual congress of the Schizophrenia International Research Society (SIRS 2021) and were published simultaneously in JAMA Psychiatry.
 

Resistance continues

Cognition “should be a focus of treatment because most of the disability and functional consequences of the disease are related to ... neurocognitive impairment and impairment of social cognition,” Dr. Vita said.

He noted that treatments that focus on cognition are crucial for the recovery of patients with schizophrenia.

However, despite a “solid body of evidence” supporting the efficacy of CR and guideline recommendations that CR be included in psychiatric services, reluctance remains, the investigators noted.

The study’s goal was to determine optimal candidates for CR and to assess outcomes of the therapy and its four core elements:

• The presence of an active and trained therapist.
• Repeated practice of cognitive exercises.
• Structured development of cognitive strategies.
• Techniques to improve the transfer of cognitive gains to the real world, such as integrated psychosocial rehabilitation.

The investigators conducted a systematic literature search of the PubMed, Scopus, and PsychInfo databases to find relevant studies of CR published between January 2011 and February 2020. They also “hand-searched” meta-analyses, reviews, and reference lists.

Ultimately, the analysis included 130 randomized clinical trials comparing CR with a control condition in 8,851 patients with schizophrenia spectrum disorders.

Of these studies, 57 were conducted in Europe, 38 in the United States, 22 in Asia, 4 in Canada, 4 in Middle Eastern countries, 3 in Australia, and 2 in Brazil.

The mean age of the participants was 36.7 years, and 68% were men. The average age at the time of schizophrenia onset was 23.3 years, and the mean duration of illness was 13.8 years.

The average duration of CR treatment was 15.2 weeks. The four elements were well represented; each was offered to at least 71% of patients.

The comparator therapy was treatment as usual (TAU), in 34.3% of cases, or active TAU with multidisciplinary rehabilitation, in 15.2% of cases. The remaining interventions were either nonspecific (30.8%) or were devised specifically for the study (19.9%).

Results showed that CR had a significant, albeit moderate, effect on global cognition (Cohen’s d effect size, 0.29; P < .001) and global functioning (effect size, 0.22; P < .01).

Having an active and trained therapist had a significant impact on cognition and functioning (P = .04 for both), as did the structured development of cognitive strategies (P = .002 for cognition; P = .004 for functioning).

The integration of psychosocial rehabilitation also had a significant effect on functioning (P = .003).

Interventions that included all of the core elements had a “highly significant” association with global cognition (P = .02) and global functioning (P < .001), the investigators reported. Longer treatments were significantly associated with greater functional improvement (P = .006).

The investigators found that improvements were greater among patients who had fewer years of education (P = .03 for cognition; P = .02 for functioning), lower premorbid IQ scores (P = .04 for functioning), and more severe symptoms at baseline (P = .005 for cognition).

The researchers noted that CR should become more widely available because it has the “potential to be an element of standard care rather than an optional intervention targeting selected individuals.”
 

An overlooked treatment option

Commenting on the findings for this news organization, Alice Medalia, PhD, director of the Lieber Recovery Clinic at Columbia University Irving Medical Center, New York, noted that this study is the second large-scale analysis of the use of CR for patients with schizophrenia to come out this year. The other was published in Schizophrenia Bulletin.

“So this is a banner year for large reviews,” she said. “It’s great to have two studies like this [that] tell a very consistent story.”

Dr. Medalia, who was not involved with the research, said individuals “don’t really talk about cognition very much.”

CR, she added, is “one of an array of services that one should be providing, and the bigger picture is that every single person should have their cognitive health needs addressed.

“If someone is having problems, and it’s getting in the way of them being the kind of person they want to be and doing want they want to do, we need to intervene. How we intervene should always be in the least disruptive and intense way,” she said.

These measures could include examining sleep hygiene, adjusting medications, or introducing exercise.

“But there really does come a time for some people where cognitive remediation is going to be helpful, so it should be more available,” Dr. Medalia said.

Although increased availability is partially dependent on having enough trained therapists, the main reason CR is not more widely available is because “people just don’t think about cognition and they don’t know how to talk about it,” she noted. In addition, she said, even when it is available, clinicians don’t refer patients.

“That tells you something. The solution here is not to put a cognitive remediation program everywhere but ... to get people comfortable talking about cognition and identifying when an intervention is needed,” said Dr. Medalia.

One study author received grants from the National Institute for Health Research during the conduct of the study and is the creator of CIRCuiTs, a cognitive remediation software program. The other investigators and Dr. Medalia have reported no relevant financial relationships.

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

Cognitive remediation (CR), a therapy that encompasses nonpharmacologic approaches to improving cognitive function for patients with severe mental illness, may lead to significant improvement for patients with schizophrenia, new research suggests.
 

verbaska_studio/Getty Images

A systematic review of 130 worldwide studies that included almost 9,000 participants showed that CR significantly improved global cognition and global functioning. In addition, investigators identified key patient characteristics that flagged ideal candidates for the therapy.

“Because pharmacological treatment exerts limited effects on cognitive deficits, and clinical remission does not necessarily result in functional recovery, widespread implementation of CR could be a game-changer for achieving the patient’s personal recovery goals,” the researchers wrote.

“We hope that this systematic review could help clinicians understand how to make CR even more effective and even more personalized,” lead author Antonio Vita, MD, PhD, department of clinical and experimental sciences, University of Brescia, Italy, said in an interview.

Dr. Vita noted that he would also encourage clinicians to consider “proposing it for clinical practice.”

The findings were presented at the virtual congress of the Schizophrenia International Research Society (SIRS 2021) and were published simultaneously in JAMA Psychiatry.
 

Resistance continues

Cognition “should be a focus of treatment because most of the disability and functional consequences of the disease are related to ... neurocognitive impairment and impairment of social cognition,” Dr. Vita said.

He noted that treatments that focus on cognition are crucial for the recovery of patients with schizophrenia.

However, despite a “solid body of evidence” supporting the efficacy of CR and guideline recommendations that CR be included in psychiatric services, reluctance remains, the investigators noted.

The study’s goal was to determine optimal candidates for CR and to assess outcomes of the therapy and its four core elements:

• The presence of an active and trained therapist.
• Repeated practice of cognitive exercises.
• Structured development of cognitive strategies.
• Techniques to improve the transfer of cognitive gains to the real world, such as integrated psychosocial rehabilitation.

The investigators conducted a systematic literature search of the PubMed, Scopus, and PsychInfo databases to find relevant studies of CR published between January 2011 and February 2020. They also “hand-searched” meta-analyses, reviews, and reference lists.

Ultimately, the analysis included 130 randomized clinical trials comparing CR with a control condition in 8,851 patients with schizophrenia spectrum disorders.

Of these studies, 57 were conducted in Europe, 38 in the United States, 22 in Asia, 4 in Canada, 4 in Middle Eastern countries, 3 in Australia, and 2 in Brazil.

The mean age of the participants was 36.7 years, and 68% were men. The average age at the time of schizophrenia onset was 23.3 years, and the mean duration of illness was 13.8 years.

The average duration of CR treatment was 15.2 weeks. The four elements were well represented; each was offered to at least 71% of patients.

The comparator therapy was treatment as usual (TAU), in 34.3% of cases, or active TAU with multidisciplinary rehabilitation, in 15.2% of cases. The remaining interventions were either nonspecific (30.8%) or were devised specifically for the study (19.9%).

Results showed that CR had a significant, albeit moderate, effect on global cognition (Cohen’s d effect size, 0.29; P < .001) and global functioning (effect size, 0.22; P < .01).

Having an active and trained therapist had a significant impact on cognition and functioning (P = .04 for both), as did the structured development of cognitive strategies (P = .002 for cognition; P = .004 for functioning).

The integration of psychosocial rehabilitation also had a significant effect on functioning (P = .003).

Interventions that included all of the core elements had a “highly significant” association with global cognition (P = .02) and global functioning (P < .001), the investigators reported. Longer treatments were significantly associated with greater functional improvement (P = .006).

The investigators found that improvements were greater among patients who had fewer years of education (P = .03 for cognition; P = .02 for functioning), lower premorbid IQ scores (P = .04 for functioning), and more severe symptoms at baseline (P = .005 for cognition).

The researchers noted that CR should become more widely available because it has the “potential to be an element of standard care rather than an optional intervention targeting selected individuals.”
 

An overlooked treatment option

Commenting on the findings for this news organization, Alice Medalia, PhD, director of the Lieber Recovery Clinic at Columbia University Irving Medical Center, New York, noted that this study is the second large-scale analysis of the use of CR for patients with schizophrenia to come out this year. The other was published in Schizophrenia Bulletin.

“So this is a banner year for large reviews,” she said. “It’s great to have two studies like this [that] tell a very consistent story.”

Dr. Medalia, who was not involved with the research, said individuals “don’t really talk about cognition very much.”

CR, she added, is “one of an array of services that one should be providing, and the bigger picture is that every single person should have their cognitive health needs addressed.

“If someone is having problems, and it’s getting in the way of them being the kind of person they want to be and doing want they want to do, we need to intervene. How we intervene should always be in the least disruptive and intense way,” she said.

These measures could include examining sleep hygiene, adjusting medications, or introducing exercise.

“But there really does come a time for some people where cognitive remediation is going to be helpful, so it should be more available,” Dr. Medalia said.

Although increased availability is partially dependent on having enough trained therapists, the main reason CR is not more widely available is because “people just don’t think about cognition and they don’t know how to talk about it,” she noted. In addition, she said, even when it is available, clinicians don’t refer patients.

“That tells you something. The solution here is not to put a cognitive remediation program everywhere but ... to get people comfortable talking about cognition and identifying when an intervention is needed,” said Dr. Medalia.

One study author received grants from the National Institute for Health Research during the conduct of the study and is the creator of CIRCuiTs, a cognitive remediation software program. The other investigators and Dr. Medalia have reported no relevant financial relationships.

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

Few ever see this side of cancer care. Our cameras go behind the scenes as a surgical oncologist faces a crucial moment in the OR in this first episode of a new video series, The Oncologists.

Medscape Oncology © 2021 WebMD, LLC

Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.

Cite this: A Pivotal Moment in Cancer Surgery, Captured on Film - Medscape - Feb 18, 2021.

Few ever see this side of cancer care. Our cameras go behind the scenes as a surgical oncologist faces a crucial moment in the OR in this first episode of a new video series, The Oncologists.

Medscape Oncology © 2021 WebMD, LLC

Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.

Cite this: A Pivotal Moment in Cancer Surgery, Captured on Film - Medscape - Feb 18, 2021.

Few ever see this side of cancer care. Our cameras go behind the scenes as a surgical oncologist faces a crucial moment in the OR in this first episode of a new video series, The Oncologists.

Medscape Oncology © 2021 WebMD, LLC

Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.

Cite this: A Pivotal Moment in Cancer Surgery, Captured on Film - Medscape - Feb 18, 2021.

Immunotherapy with checkpoint inhibitors has ushered in a new era of cancer therapy, with some patients showing dramatic responses and significantly better outcomes than with other therapies across many cancer types. But some patients do worse, sometimes much worse.

A subset of patients who undergo immunotherapy experience unexpected, rapid disease progression, with a dramatic acceleration of disease trajectory. They also have a shorter progression-free survival and overall survival than would have been expected.

This has been described as hyperprogression and has been termed “hyperprogressive disease” (HPD). It has been seen in a variety of cancers; the incidence ranges from 4% to 29% in the studies reported to date.

There has been some debate over whether this is a real phenomenon or whether it is part of the natural course of disease.

HPD is a “provocative phenomenon,” wrote the authors of a recent commentary entitled “Hyperprogression and Immunotherapy: Fact, Fiction, or Alternative Fact?”

“This phenomenon has polarized oncologists who debate that this could still reflect the natural history of the disease,” said the author of another commentary.

But the tide is now turning toward acceptance of HPD, said Kartik Sehgal, MD, an oncologist at Dana-Farber Cancer Institute and Harvard University, both in Boston.

“With publication of multiple clinical reports of different cancer types worldwide, hyperprogression is now accepted by most oncologists to be a true phenomenon rather than natural progression of disease,” Dr. Sehgal said.

He authored an invited commentary in JAMA Network Openabout one of the latest meta-analyses (JAMA Netw Open. 2021;4[3]:e211136) to investigate HPD during immunotherapy. One of the biggest issues is that the studies that have reported on HPD have been retrospective, with a lack of comparator groups and a lack of a standardized definition of hyperprogression. Dr. Sehgal emphasized the need to study hyperprogression in well-designed prospective studies.
 

Existing data on HPD

HPD was described as “a new pattern of progression” seen in patients undergoing immune checkpoint inhibitor therapy in a 2017 article published in Clinical Cancer Research. Authors Stephane Champiat, MD, PhD, of Institut Gustave Roussy, Universite Paris Saclay, Villejuif, France, and colleagues cited “anecdotal occurrences” of HPD among patients in phase 1 trials of anti–PD-1/PD-L1 agents.

In that study, HPD was defined by tumor growth rate ratio. The incidence was 9% among 213 patients.

The findings raised concerns about treating elderly patients with anti–PD-1/PD-L1 monotherapy, according to the authors, who called for further study.

That same year, Roberto Ferrara, MD, and colleagues from the Insitut Gustave Roussy reported additional data indicating an incidence of HPD of 16% among 333 patients with non–small cell lung cancer who underwent immunotherapy at eight centers from 2012 to 2017. The findings, which were presented at the 2017 World Conference on Lung Cancer and reported at the time by this news organization, also showed that the incidence of HPD was higher with immunotherapy than with single-agent chemotherapy (5%).

Median overall survival (OS) was just 3.4 months among those with HPD, compared with 13 months in the overall study population – worse, even, than the median 5.4-month OS observed among patients with progressive disease who received immunotherapy.

In the wake of these findings, numerous researchers have attempted to better define HPD, its incidence, and patient factors associated with developing HPD while undergoing immunotherapy.

However, there is little so far to show for those efforts, Vivek Subbiah, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in an interview.

“Many questions remain to be answered,” said Dr. Subbiah, clinical medical director of the Clinical Center for Targeted Therapy in the division of cancer medicine at MD Anderson. He was the senior author of the “Fact, Fiction, or Alternative Fact?” commentary.

Work is underway to elucidate biological mechanisms. Some groups have implicated the Fc region of antibodies. Another group has reported EGFR and MDM2/MDM4 amplifications in patients with HPD, Dr. Subbiah and colleagues noted.

Other “proposed contributing pathological mechanisms include modulation of tumor immune microenvironment through macrophages and regulatory T cells as well as activation of oncogenic signaling pathways,” noted Dr. Sehgal.

Both groups of authors emphasize the urgent need for prospective studies.

It is imperative to confirm underlying biology, predict which patients are at risk, and identify therapeutic directions for patients who experience HPD, Dr. Subbiah said.

The main challenge is defining HPD, he added. Definitions that have been proposed include tumor growth at least two times greater than in control persons, a 15% increase in tumor burden in a set period, and disease progression of 50% from the first evaluation before treatment, he said.

The recent meta-analysis by Hyo Jung Park, MD, PhD, and colleagues, which Dr. Sehgal addressed in his invited commentary, highlights the many approaches used for defining HPD.

Depending on the definition used, the incidence of HPD across 24 studies involving more than 3,100 patients ranged from 5.9% to 43.1%.

“Hyperprogressive disease could be overestimated or underestimated based on current assessment,” Dr. Park and colleagues concluded. They highlighted the importance of “establishing uniform and clinically relevant criteria based on currently available evidence.”
 

Steps for solving the HPD mystery

“I think we need to come up with consensus criteria for an HPD definition. We need a unified definition,” Dr. Subbiah said. “We also need to design prospective studies to prove or disprove the immunotherapy-HPD association.”

Prospective registries with independent review of patients with suspected immunotherapy-related HPD would be useful for assessing the true incidence and the biology of HPD among patients undergoing immunotherapy, he suggested.

“We need to know the immunologic signals of HPD. This can give us an idea if patients can be prospectively identified for being at risk,” he said. “We also need to know what to do if they are at risk.”

Dr. Sehgal also called for consensus on an HPD definition, with input from a multidisciplinary group that includes “colleagues from radiology, medical oncology, radiation oncology. Getting expertise from different disciplines would be helpful,” he said.

Dr. Park and colleagues suggested several key requirements for an optimal HP definition, such as the inclusion of multiple variables for measuring tumor growth acceleration, “sufficiently quantitative” criteria for determining time to failure, and establishment of a standardized measure of tumor growth acceleration.

The agreed-upon definition of HPD could be applied to patients in a prospective registry and to existing trial data, Dr. Sehgal said.

“Eventually, the goal of this exercise is to [determine] how we can help our patients the best, having a biomarker that can at least inform us in terms of being aware and being proactive in terms of looking for this ... so that interventions can be brought on earlier,” he said.

“If we know what may be a biological mechanism, we can design trials that are designed to look at how to overcome that HPD,” he said.

Dr. Sehgal said he believes HPD is triggered in some way by treatment, including immunotherapy, chemotherapy, and targeted therapy, but perhaps in different ways for each.

He estimated the true incidence of immunotherapy-related HPD will be in the 9%-10% range.

“This is a substantial number of patients, so it’s important that we try to understand this phenomenon, using, again, uniform criteria,” he said.
 

Current treatment decision-making

Until more is known, Dr. Sehgal said he considers the potential risk factors when treating patients with immunotherapy.

For example, the presence of MDM2 or MDM4 amplification on a genomic profile may factor into his treatment decision-making when it comes to using immunotherapy or immunotherapy in combination with chemotherapy, he said.

“Is that the only factor that is going to make me choose one thing or another? No,” Dr. Sehgal said. However, he said it would make him more “proactive in making sure the patient is doing clinically okay” and in determining when to obtain on-treatment imaging studies.

Dr. Subbiah emphasized the relative benefit of immunotherapy, noting that survival with chemotherapy for many difficult-to-treat cancers in the relapsed/refractory metastatic setting is less than 2 years.

Immunotherapy with checkpoint inhibitors has allowed some of these patients to live longer (with survival reported to be more than 10 years for patients with metastatic melanoma).

“Immunotherapy has been a game changer; it has been transformative in the lives of these patients,” Dr. Subbiah said. “So unless there is any other contraindication, the benefit of receiving immunotherapy for an approved indication far outweighs the risk of HPD.”

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

Immunotherapy with checkpoint inhibitors has ushered in a new era of cancer therapy, with some patients showing dramatic responses and significantly better outcomes than with other therapies across many cancer types. But some patients do worse, sometimes much worse.

A subset of patients who undergo immunotherapy experience unexpected, rapid disease progression, with a dramatic acceleration of disease trajectory. They also have a shorter progression-free survival and overall survival than would have been expected.

This has been described as hyperprogression and has been termed “hyperprogressive disease” (HPD). It has been seen in a variety of cancers; the incidence ranges from 4% to 29% in the studies reported to date.

There has been some debate over whether this is a real phenomenon or whether it is part of the natural course of disease.

HPD is a “provocative phenomenon,” wrote the authors of a recent commentary entitled “Hyperprogression and Immunotherapy: Fact, Fiction, or Alternative Fact?”

“This phenomenon has polarized oncologists who debate that this could still reflect the natural history of the disease,” said the author of another commentary.

But the tide is now turning toward acceptance of HPD, said Kartik Sehgal, MD, an oncologist at Dana-Farber Cancer Institute and Harvard University, both in Boston.

“With publication of multiple clinical reports of different cancer types worldwide, hyperprogression is now accepted by most oncologists to be a true phenomenon rather than natural progression of disease,” Dr. Sehgal said.

He authored an invited commentary in JAMA Network Openabout one of the latest meta-analyses (JAMA Netw Open. 2021;4[3]:e211136) to investigate HPD during immunotherapy. One of the biggest issues is that the studies that have reported on HPD have been retrospective, with a lack of comparator groups and a lack of a standardized definition of hyperprogression. Dr. Sehgal emphasized the need to study hyperprogression in well-designed prospective studies.
 

Existing data on HPD

HPD was described as “a new pattern of progression” seen in patients undergoing immune checkpoint inhibitor therapy in a 2017 article published in Clinical Cancer Research. Authors Stephane Champiat, MD, PhD, of Institut Gustave Roussy, Universite Paris Saclay, Villejuif, France, and colleagues cited “anecdotal occurrences” of HPD among patients in phase 1 trials of anti–PD-1/PD-L1 agents.

In that study, HPD was defined by tumor growth rate ratio. The incidence was 9% among 213 patients.

The findings raised concerns about treating elderly patients with anti–PD-1/PD-L1 monotherapy, according to the authors, who called for further study.

That same year, Roberto Ferrara, MD, and colleagues from the Insitut Gustave Roussy reported additional data indicating an incidence of HPD of 16% among 333 patients with non–small cell lung cancer who underwent immunotherapy at eight centers from 2012 to 2017. The findings, which were presented at the 2017 World Conference on Lung Cancer and reported at the time by this news organization, also showed that the incidence of HPD was higher with immunotherapy than with single-agent chemotherapy (5%).

Median overall survival (OS) was just 3.4 months among those with HPD, compared with 13 months in the overall study population – worse, even, than the median 5.4-month OS observed among patients with progressive disease who received immunotherapy.

In the wake of these findings, numerous researchers have attempted to better define HPD, its incidence, and patient factors associated with developing HPD while undergoing immunotherapy.

However, there is little so far to show for those efforts, Vivek Subbiah, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in an interview.

“Many questions remain to be answered,” said Dr. Subbiah, clinical medical director of the Clinical Center for Targeted Therapy in the division of cancer medicine at MD Anderson. He was the senior author of the “Fact, Fiction, or Alternative Fact?” commentary.

Work is underway to elucidate biological mechanisms. Some groups have implicated the Fc region of antibodies. Another group has reported EGFR and MDM2/MDM4 amplifications in patients with HPD, Dr. Subbiah and colleagues noted.

Other “proposed contributing pathological mechanisms include modulation of tumor immune microenvironment through macrophages and regulatory T cells as well as activation of oncogenic signaling pathways,” noted Dr. Sehgal.

Both groups of authors emphasize the urgent need for prospective studies.

It is imperative to confirm underlying biology, predict which patients are at risk, and identify therapeutic directions for patients who experience HPD, Dr. Subbiah said.

The main challenge is defining HPD, he added. Definitions that have been proposed include tumor growth at least two times greater than in control persons, a 15% increase in tumor burden in a set period, and disease progression of 50% from the first evaluation before treatment, he said.

The recent meta-analysis by Hyo Jung Park, MD, PhD, and colleagues, which Dr. Sehgal addressed in his invited commentary, highlights the many approaches used for defining HPD.

Depending on the definition used, the incidence of HPD across 24 studies involving more than 3,100 patients ranged from 5.9% to 43.1%.

“Hyperprogressive disease could be overestimated or underestimated based on current assessment,” Dr. Park and colleagues concluded. They highlighted the importance of “establishing uniform and clinically relevant criteria based on currently available evidence.”
 

Steps for solving the HPD mystery

“I think we need to come up with consensus criteria for an HPD definition. We need a unified definition,” Dr. Subbiah said. “We also need to design prospective studies to prove or disprove the immunotherapy-HPD association.”

Prospective registries with independent review of patients with suspected immunotherapy-related HPD would be useful for assessing the true incidence and the biology of HPD among patients undergoing immunotherapy, he suggested.

“We need to know the immunologic signals of HPD. This can give us an idea if patients can be prospectively identified for being at risk,” he said. “We also need to know what to do if they are at risk.”

Dr. Sehgal also called for consensus on an HPD definition, with input from a multidisciplinary group that includes “colleagues from radiology, medical oncology, radiation oncology. Getting expertise from different disciplines would be helpful,” he said.

Dr. Park and colleagues suggested several key requirements for an optimal HP definition, such as the inclusion of multiple variables for measuring tumor growth acceleration, “sufficiently quantitative” criteria for determining time to failure, and establishment of a standardized measure of tumor growth acceleration.

The agreed-upon definition of HPD could be applied to patients in a prospective registry and to existing trial data, Dr. Sehgal said.

“Eventually, the goal of this exercise is to [determine] how we can help our patients the best, having a biomarker that can at least inform us in terms of being aware and being proactive in terms of looking for this ... so that interventions can be brought on earlier,” he said.

“If we know what may be a biological mechanism, we can design trials that are designed to look at how to overcome that HPD,” he said.

Dr. Sehgal said he believes HPD is triggered in some way by treatment, including immunotherapy, chemotherapy, and targeted therapy, but perhaps in different ways for each.

He estimated the true incidence of immunotherapy-related HPD will be in the 9%-10% range.

“This is a substantial number of patients, so it’s important that we try to understand this phenomenon, using, again, uniform criteria,” he said.
 

Current treatment decision-making

Until more is known, Dr. Sehgal said he considers the potential risk factors when treating patients with immunotherapy.

For example, the presence of MDM2 or MDM4 amplification on a genomic profile may factor into his treatment decision-making when it comes to using immunotherapy or immunotherapy in combination with chemotherapy, he said.

“Is that the only factor that is going to make me choose one thing or another? No,” Dr. Sehgal said. However, he said it would make him more “proactive in making sure the patient is doing clinically okay” and in determining when to obtain on-treatment imaging studies.

Dr. Subbiah emphasized the relative benefit of immunotherapy, noting that survival with chemotherapy for many difficult-to-treat cancers in the relapsed/refractory metastatic setting is less than 2 years.

Immunotherapy with checkpoint inhibitors has allowed some of these patients to live longer (with survival reported to be more than 10 years for patients with metastatic melanoma).

“Immunotherapy has been a game changer; it has been transformative in the lives of these patients,” Dr. Subbiah said. “So unless there is any other contraindication, the benefit of receiving immunotherapy for an approved indication far outweighs the risk of HPD.”

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

Immunotherapy with checkpoint inhibitors has ushered in a new era of cancer therapy, with some patients showing dramatic responses and significantly better outcomes than with other therapies across many cancer types. But some patients do worse, sometimes much worse.

A subset of patients who undergo immunotherapy experience unexpected, rapid disease progression, with a dramatic acceleration of disease trajectory. They also have a shorter progression-free survival and overall survival than would have been expected.

This has been described as hyperprogression and has been termed “hyperprogressive disease” (HPD). It has been seen in a variety of cancers; the incidence ranges from 4% to 29% in the studies reported to date.

There has been some debate over whether this is a real phenomenon or whether it is part of the natural course of disease.

HPD is a “provocative phenomenon,” wrote the authors of a recent commentary entitled “Hyperprogression and Immunotherapy: Fact, Fiction, or Alternative Fact?”

“This phenomenon has polarized oncologists who debate that this could still reflect the natural history of the disease,” said the author of another commentary.

But the tide is now turning toward acceptance of HPD, said Kartik Sehgal, MD, an oncologist at Dana-Farber Cancer Institute and Harvard University, both in Boston.

“With publication of multiple clinical reports of different cancer types worldwide, hyperprogression is now accepted by most oncologists to be a true phenomenon rather than natural progression of disease,” Dr. Sehgal said.

He authored an invited commentary in JAMA Network Openabout one of the latest meta-analyses (JAMA Netw Open. 2021;4[3]:e211136) to investigate HPD during immunotherapy. One of the biggest issues is that the studies that have reported on HPD have been retrospective, with a lack of comparator groups and a lack of a standardized definition of hyperprogression. Dr. Sehgal emphasized the need to study hyperprogression in well-designed prospective studies.
 

Existing data on HPD

HPD was described as “a new pattern of progression” seen in patients undergoing immune checkpoint inhibitor therapy in a 2017 article published in Clinical Cancer Research. Authors Stephane Champiat, MD, PhD, of Institut Gustave Roussy, Universite Paris Saclay, Villejuif, France, and colleagues cited “anecdotal occurrences” of HPD among patients in phase 1 trials of anti–PD-1/PD-L1 agents.

In that study, HPD was defined by tumor growth rate ratio. The incidence was 9% among 213 patients.

The findings raised concerns about treating elderly patients with anti–PD-1/PD-L1 monotherapy, according to the authors, who called for further study.

That same year, Roberto Ferrara, MD, and colleagues from the Insitut Gustave Roussy reported additional data indicating an incidence of HPD of 16% among 333 patients with non–small cell lung cancer who underwent immunotherapy at eight centers from 2012 to 2017. The findings, which were presented at the 2017 World Conference on Lung Cancer and reported at the time by this news organization, also showed that the incidence of HPD was higher with immunotherapy than with single-agent chemotherapy (5%).

Median overall survival (OS) was just 3.4 months among those with HPD, compared with 13 months in the overall study population – worse, even, than the median 5.4-month OS observed among patients with progressive disease who received immunotherapy.

In the wake of these findings, numerous researchers have attempted to better define HPD, its incidence, and patient factors associated with developing HPD while undergoing immunotherapy.

However, there is little so far to show for those efforts, Vivek Subbiah, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in an interview.

“Many questions remain to be answered,” said Dr. Subbiah, clinical medical director of the Clinical Center for Targeted Therapy in the division of cancer medicine at MD Anderson. He was the senior author of the “Fact, Fiction, or Alternative Fact?” commentary.

Work is underway to elucidate biological mechanisms. Some groups have implicated the Fc region of antibodies. Another group has reported EGFR and MDM2/MDM4 amplifications in patients with HPD, Dr. Subbiah and colleagues noted.

Other “proposed contributing pathological mechanisms include modulation of tumor immune microenvironment through macrophages and regulatory T cells as well as activation of oncogenic signaling pathways,” noted Dr. Sehgal.

Both groups of authors emphasize the urgent need for prospective studies.

It is imperative to confirm underlying biology, predict which patients are at risk, and identify therapeutic directions for patients who experience HPD, Dr. Subbiah said.

The main challenge is defining HPD, he added. Definitions that have been proposed include tumor growth at least two times greater than in control persons, a 15% increase in tumor burden in a set period, and disease progression of 50% from the first evaluation before treatment, he said.

The recent meta-analysis by Hyo Jung Park, MD, PhD, and colleagues, which Dr. Sehgal addressed in his invited commentary, highlights the many approaches used for defining HPD.

Depending on the definition used, the incidence of HPD across 24 studies involving more than 3,100 patients ranged from 5.9% to 43.1%.

“Hyperprogressive disease could be overestimated or underestimated based on current assessment,” Dr. Park and colleagues concluded. They highlighted the importance of “establishing uniform and clinically relevant criteria based on currently available evidence.”
 

Steps for solving the HPD mystery

“I think we need to come up with consensus criteria for an HPD definition. We need a unified definition,” Dr. Subbiah said. “We also need to design prospective studies to prove or disprove the immunotherapy-HPD association.”

Prospective registries with independent review of patients with suspected immunotherapy-related HPD would be useful for assessing the true incidence and the biology of HPD among patients undergoing immunotherapy, he suggested.

“We need to know the immunologic signals of HPD. This can give us an idea if patients can be prospectively identified for being at risk,” he said. “We also need to know what to do if they are at risk.”

Dr. Sehgal also called for consensus on an HPD definition, with input from a multidisciplinary group that includes “colleagues from radiology, medical oncology, radiation oncology. Getting expertise from different disciplines would be helpful,” he said.

Dr. Park and colleagues suggested several key requirements for an optimal HP definition, such as the inclusion of multiple variables for measuring tumor growth acceleration, “sufficiently quantitative” criteria for determining time to failure, and establishment of a standardized measure of tumor growth acceleration.

The agreed-upon definition of HPD could be applied to patients in a prospective registry and to existing trial data, Dr. Sehgal said.

“Eventually, the goal of this exercise is to [determine] how we can help our patients the best, having a biomarker that can at least inform us in terms of being aware and being proactive in terms of looking for this ... so that interventions can be brought on earlier,” he said.

“If we know what may be a biological mechanism, we can design trials that are designed to look at how to overcome that HPD,” he said.

Dr. Sehgal said he believes HPD is triggered in some way by treatment, including immunotherapy, chemotherapy, and targeted therapy, but perhaps in different ways for each.

He estimated the true incidence of immunotherapy-related HPD will be in the 9%-10% range.

“This is a substantial number of patients, so it’s important that we try to understand this phenomenon, using, again, uniform criteria,” he said.
 

Current treatment decision-making

Until more is known, Dr. Sehgal said he considers the potential risk factors when treating patients with immunotherapy.

For example, the presence of MDM2 or MDM4 amplification on a genomic profile may factor into his treatment decision-making when it comes to using immunotherapy or immunotherapy in combination with chemotherapy, he said.

“Is that the only factor that is going to make me choose one thing or another? No,” Dr. Sehgal said. However, he said it would make him more “proactive in making sure the patient is doing clinically okay” and in determining when to obtain on-treatment imaging studies.

Dr. Subbiah emphasized the relative benefit of immunotherapy, noting that survival with chemotherapy for many difficult-to-treat cancers in the relapsed/refractory metastatic setting is less than 2 years.

Immunotherapy with checkpoint inhibitors has allowed some of these patients to live longer (with survival reported to be more than 10 years for patients with metastatic melanoma).

“Immunotherapy has been a game changer; it has been transformative in the lives of these patients,” Dr. Subbiah said. “So unless there is any other contraindication, the benefit of receiving immunotherapy for an approved indication far outweighs the risk of HPD.”

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

COVID-19 and its resulting lockdowns are linked to posttraumatic stress disorder symptoms and other adverse outcomes among patients with eating disorders (EDs), two new studies show.

Courtesy Bill Branson/National Cancer Institute

Results of the first study show that patients with EDs had more stress, anxiety, depression, and PTSD-related symptoms during the lockdowns than their mentally healthy peers.

In the second study, treatment-related symptom improvement among patients with bulimia nervosa (BN) slowed following lockdown. In addition, patients with BN or anorexia nervosa (AN) experienced significant worsening of disorder-specific behaviors, including binge eating and overexercising.

Because of the strict lockdown measures introduced by the Italian government to contain the COVID-19 pandemic, “everyday life of all citizens was disrupted,” Veronica Nisticò, MS, Università Degli Studi Di Milano, who led the first study, told delegates attending the virtual European Psychiatric Association 2021 Congress.

In addition to difficulties in accessing health care, “it became difficult to go to the supermarket, to the gym, and to have the social support we were all used to,” all of which had a well-documented impact on mental health, added Ms. Nisticò, who is also affiliated with Aldo Ravelli Research Center for Neurotechnology and Experimental Brain Therapeutics.
 

Loss of control

Previous research suggests that individuals with EDs experience high levels of anxiety and an increase in binge eating, exercise, and purging behaviors, said Ms. Nisticò.

To investigate further, the researchers conducted a longitudinal study of the changes in prevalence of adverse outcomes. In the study, two assessments were conducted.

In the first assessment, conducted in April 2020, the researchers assessed 59 outpatients with EDs and 43 unaffected hospital staff and their acquaintances. The second group served as the control group.

Participants completed an online survey that included several standardized depression and anxiety scales, as well as an ad hoc survey adapted from the Eating Disorder Examination Questionnaire. This assessed changes in restrictive dieting, control over food, body image, and psychological well-being in comparison with prepandemic levels.

The results, which were also recently published online in Eating and Weight Disorders – Studies on Anorexia, Bulimia and Obesity, showed that patients with EDs experienced significantly more stress, anxiety, depression, and PTSD-related symptoms in comparison with control persons (P < .05 for all).

In addition, the investigators found that those with EDs were more fearful of losing control over their eating behavior, spent more time thinking about food and their body, and became more uncomfortable seeing their body than before the lockdown in comparison with those without EDs (P < .05).
 

Clinical implications

A second assessment, which occurred in June 2020, after lockdown restrictions were lifted, included 40 patients with EDs who had taken part in the first assessment. This time, participants were asked to compare their current eating behavior with their eating behavior during the lockdown.

Although the lifting of lockdown restrictions was associated with significant improvement in PTSD-related symptoms, the impact on stress, anxiety, and depression persisted.

These findings, said Ms. Nisticó, support the hypothesis that specific conditions that occurred during the lockdown had a direct effect on specific ED symptoms.

These findings, she added, should be considered when developing interventions for EDs in the context of individual psychotherapy and when designing large, preventive interventions.

In the second study, Eleonora Rossi, MD, psychiatric unit, department of health sciences, University of Florence (Italy), and colleagues examined the longitudinal impact of the pandemic on individuals with EDs.

They examined 74 patients with AN or BN who had undergone baseline assessments and had completed a number of questionnaires in the first months of 2019 in conjunction with being enrolled in another study.

Participants were treated with enhanced cognitive-behavioral therapy and were reevaluated between November 2019 and January 2020. They were then compared with 97 healthy individuals.
 

Bulimia patients more vulnerable

After the outbreak of the pandemic, most treatment was administered online, so patients were able to continue therapy, Dr. Rossi said during her presentation.

All participants were assessed again in April 2020, 6 weeks after the start of Italy’s lockdown.

The results, which were published in the International Journal of Eating Disorders, show that the patients with EDs “underwent a significant improvement in terms of general and eating disorder specific psychopathology” during the first treatment period, Dr. Rossi reported. In addition, among those with AN, body mass index increased significantly (P < .05 for all).

Patients with AN continued to improve during the lockdown when therapy was administered online. However, improvements that had occurred among those with BN slowed, Dr. Rossi noted.

In addition, both groups of patients with EDs experienced a worsening of their pathological eating behaviors during the lockdown, in particular, objective binge eating and compensatory physical exercise (P < .05).

“Indeed, the positive trajectory of improvement observed before lockdown was clearly interrupted during the pandemic period,” Dr. Rossi said. This could “represent a possible hint of an imminent exacerbation of the disease.”

The results also suggest that the occurrence of arguments within the household and fear regarding the safety of loved ones predicted an increase in symptoms during the lockdown, she added.

In addition, patients with BN reported more severe COVID-related PTSD symptoms than did those with AN and the control group. This increase in severity of symptoms was more prevalent among patients who had a history of childhood trauma and among those with insecure attachment, suggesting that such patients may be more vulnerable.
 

Evidence of recovery

Commenting on the studies, David Spiegel, MD, associate chair of psychiatry, Stanford (Calif.) University, noted that EDs commonly occur after physical or sexual trauma earlier in life.

“It’s a standard thing with trauma-related disorders that any other, even relatively minor, traumatic experience can exacerbate PTSD symptoms,” said Dr. Spiegel, who was not involved in the studies. In addition, the trauma of the COVID pandemic “was not minor.

“The relative isolation and the lack of outside contact may focus many people with eating disorders even more on their struggles with how they are taking care of their bodies,” said Dr. Spiegel.

“It struck me that the anorexia nervosa group were more impervious than the bulimia nervosa group, but I think that’s the case with the disorder. In some ways it’s more severe, obviously a more life-threatening disorder,” he added.

The “hopeful thing is that there seemed to be some evidence of recovery and improvement, particularly with the posttraumatic stress exacerbation, as time went on,” Dr. Spiegel said, “and that’s a good thing.”

The study authors and Dr. Spiegel reported no relevant financial relationships.

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

COVID-19 and its resulting lockdowns are linked to posttraumatic stress disorder symptoms and other adverse outcomes among patients with eating disorders (EDs), two new studies show.

Courtesy Bill Branson/National Cancer Institute

Results of the first study show that patients with EDs had more stress, anxiety, depression, and PTSD-related symptoms during the lockdowns than their mentally healthy peers.

In the second study, treatment-related symptom improvement among patients with bulimia nervosa (BN) slowed following lockdown. In addition, patients with BN or anorexia nervosa (AN) experienced significant worsening of disorder-specific behaviors, including binge eating and overexercising.

Because of the strict lockdown measures introduced by the Italian government to contain the COVID-19 pandemic, “everyday life of all citizens was disrupted,” Veronica Nisticò, MS, Università Degli Studi Di Milano, who led the first study, told delegates attending the virtual European Psychiatric Association 2021 Congress.

In addition to difficulties in accessing health care, “it became difficult to go to the supermarket, to the gym, and to have the social support we were all used to,” all of which had a well-documented impact on mental health, added Ms. Nisticò, who is also affiliated with Aldo Ravelli Research Center for Neurotechnology and Experimental Brain Therapeutics.
 

Loss of control

Previous research suggests that individuals with EDs experience high levels of anxiety and an increase in binge eating, exercise, and purging behaviors, said Ms. Nisticò.

To investigate further, the researchers conducted a longitudinal study of the changes in prevalence of adverse outcomes. In the study, two assessments were conducted.

In the first assessment, conducted in April 2020, the researchers assessed 59 outpatients with EDs and 43 unaffected hospital staff and their acquaintances. The second group served as the control group.

Participants completed an online survey that included several standardized depression and anxiety scales, as well as an ad hoc survey adapted from the Eating Disorder Examination Questionnaire. This assessed changes in restrictive dieting, control over food, body image, and psychological well-being in comparison with prepandemic levels.

The results, which were also recently published online in Eating and Weight Disorders – Studies on Anorexia, Bulimia and Obesity, showed that patients with EDs experienced significantly more stress, anxiety, depression, and PTSD-related symptoms in comparison with control persons (P < .05 for all).

In addition, the investigators found that those with EDs were more fearful of losing control over their eating behavior, spent more time thinking about food and their body, and became more uncomfortable seeing their body than before the lockdown in comparison with those without EDs (P < .05).
 

Clinical implications

A second assessment, which occurred in June 2020, after lockdown restrictions were lifted, included 40 patients with EDs who had taken part in the first assessment. This time, participants were asked to compare their current eating behavior with their eating behavior during the lockdown.

Although the lifting of lockdown restrictions was associated with significant improvement in PTSD-related symptoms, the impact on stress, anxiety, and depression persisted.

These findings, said Ms. Nisticó, support the hypothesis that specific conditions that occurred during the lockdown had a direct effect on specific ED symptoms.

These findings, she added, should be considered when developing interventions for EDs in the context of individual psychotherapy and when designing large, preventive interventions.

In the second study, Eleonora Rossi, MD, psychiatric unit, department of health sciences, University of Florence (Italy), and colleagues examined the longitudinal impact of the pandemic on individuals with EDs.

They examined 74 patients with AN or BN who had undergone baseline assessments and had completed a number of questionnaires in the first months of 2019 in conjunction with being enrolled in another study.

Participants were treated with enhanced cognitive-behavioral therapy and were reevaluated between November 2019 and January 2020. They were then compared with 97 healthy individuals.
 

Bulimia patients more vulnerable

After the outbreak of the pandemic, most treatment was administered online, so patients were able to continue therapy, Dr. Rossi said during her presentation.

All participants were assessed again in April 2020, 6 weeks after the start of Italy’s lockdown.

The results, which were published in the International Journal of Eating Disorders, show that the patients with EDs “underwent a significant improvement in terms of general and eating disorder specific psychopathology” during the first treatment period, Dr. Rossi reported. In addition, among those with AN, body mass index increased significantly (P < .05 for all).

Patients with AN continued to improve during the lockdown when therapy was administered online. However, improvements that had occurred among those with BN slowed, Dr. Rossi noted.

In addition, both groups of patients with EDs experienced a worsening of their pathological eating behaviors during the lockdown, in particular, objective binge eating and compensatory physical exercise (P < .05).

“Indeed, the positive trajectory of improvement observed before lockdown was clearly interrupted during the pandemic period,” Dr. Rossi said. This could “represent a possible hint of an imminent exacerbation of the disease.”

The results also suggest that the occurrence of arguments within the household and fear regarding the safety of loved ones predicted an increase in symptoms during the lockdown, she added.

In addition, patients with BN reported more severe COVID-related PTSD symptoms than did those with AN and the control group. This increase in severity of symptoms was more prevalent among patients who had a history of childhood trauma and among those with insecure attachment, suggesting that such patients may be more vulnerable.
 

Evidence of recovery

Commenting on the studies, David Spiegel, MD, associate chair of psychiatry, Stanford (Calif.) University, noted that EDs commonly occur after physical or sexual trauma earlier in life.

“It’s a standard thing with trauma-related disorders that any other, even relatively minor, traumatic experience can exacerbate PTSD symptoms,” said Dr. Spiegel, who was not involved in the studies. In addition, the trauma of the COVID pandemic “was not minor.

“The relative isolation and the lack of outside contact may focus many people with eating disorders even more on their struggles with how they are taking care of their bodies,” said Dr. Spiegel.

“It struck me that the anorexia nervosa group were more impervious than the bulimia nervosa group, but I think that’s the case with the disorder. In some ways it’s more severe, obviously a more life-threatening disorder,” he added.

The “hopeful thing is that there seemed to be some evidence of recovery and improvement, particularly with the posttraumatic stress exacerbation, as time went on,” Dr. Spiegel said, “and that’s a good thing.”

The study authors and Dr. Spiegel reported no relevant financial relationships.

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

COVID-19 and its resulting lockdowns are linked to posttraumatic stress disorder symptoms and other adverse outcomes among patients with eating disorders (EDs), two new studies show.

Courtesy Bill Branson/National Cancer Institute

Results of the first study show that patients with EDs had more stress, anxiety, depression, and PTSD-related symptoms during the lockdowns than their mentally healthy peers.

In the second study, treatment-related symptom improvement among patients with bulimia nervosa (BN) slowed following lockdown. In addition, patients with BN or anorexia nervosa (AN) experienced significant worsening of disorder-specific behaviors, including binge eating and overexercising.

Because of the strict lockdown measures introduced by the Italian government to contain the COVID-19 pandemic, “everyday life of all citizens was disrupted,” Veronica Nisticò, MS, Università Degli Studi Di Milano, who led the first study, told delegates attending the virtual European Psychiatric Association 2021 Congress.

In addition to difficulties in accessing health care, “it became difficult to go to the supermarket, to the gym, and to have the social support we were all used to,” all of which had a well-documented impact on mental health, added Ms. Nisticò, who is also affiliated with Aldo Ravelli Research Center for Neurotechnology and Experimental Brain Therapeutics.
 

Loss of control

Previous research suggests that individuals with EDs experience high levels of anxiety and an increase in binge eating, exercise, and purging behaviors, said Ms. Nisticò.

To investigate further, the researchers conducted a longitudinal study of the changes in prevalence of adverse outcomes. In the study, two assessments were conducted.

In the first assessment, conducted in April 2020, the researchers assessed 59 outpatients with EDs and 43 unaffected hospital staff and their acquaintances. The second group served as the control group.

Participants completed an online survey that included several standardized depression and anxiety scales, as well as an ad hoc survey adapted from the Eating Disorder Examination Questionnaire. This assessed changes in restrictive dieting, control over food, body image, and psychological well-being in comparison with prepandemic levels.

The results, which were also recently published online in Eating and Weight Disorders – Studies on Anorexia, Bulimia and Obesity, showed that patients with EDs experienced significantly more stress, anxiety, depression, and PTSD-related symptoms in comparison with control persons (P < .05 for all).

In addition, the investigators found that those with EDs were more fearful of losing control over their eating behavior, spent more time thinking about food and their body, and became more uncomfortable seeing their body than before the lockdown in comparison with those without EDs (P < .05).
 

Clinical implications

A second assessment, which occurred in June 2020, after lockdown restrictions were lifted, included 40 patients with EDs who had taken part in the first assessment. This time, participants were asked to compare their current eating behavior with their eating behavior during the lockdown.

Although the lifting of lockdown restrictions was associated with significant improvement in PTSD-related symptoms, the impact on stress, anxiety, and depression persisted.

These findings, said Ms. Nisticó, support the hypothesis that specific conditions that occurred during the lockdown had a direct effect on specific ED symptoms.

These findings, she added, should be considered when developing interventions for EDs in the context of individual psychotherapy and when designing large, preventive interventions.

In the second study, Eleonora Rossi, MD, psychiatric unit, department of health sciences, University of Florence (Italy), and colleagues examined the longitudinal impact of the pandemic on individuals with EDs.

They examined 74 patients with AN or BN who had undergone baseline assessments and had completed a number of questionnaires in the first months of 2019 in conjunction with being enrolled in another study.

Participants were treated with enhanced cognitive-behavioral therapy and were reevaluated between November 2019 and January 2020. They were then compared with 97 healthy individuals.
 

Bulimia patients more vulnerable

After the outbreak of the pandemic, most treatment was administered online, so patients were able to continue therapy, Dr. Rossi said during her presentation.

All participants were assessed again in April 2020, 6 weeks after the start of Italy’s lockdown.

The results, which were published in the International Journal of Eating Disorders, show that the patients with EDs “underwent a significant improvement in terms of general and eating disorder specific psychopathology” during the first treatment period, Dr. Rossi reported. In addition, among those with AN, body mass index increased significantly (P < .05 for all).

Patients with AN continued to improve during the lockdown when therapy was administered online. However, improvements that had occurred among those with BN slowed, Dr. Rossi noted.

In addition, both groups of patients with EDs experienced a worsening of their pathological eating behaviors during the lockdown, in particular, objective binge eating and compensatory physical exercise (P < .05).

“Indeed, the positive trajectory of improvement observed before lockdown was clearly interrupted during the pandemic period,” Dr. Rossi said. This could “represent a possible hint of an imminent exacerbation of the disease.”

The results also suggest that the occurrence of arguments within the household and fear regarding the safety of loved ones predicted an increase in symptoms during the lockdown, she added.

In addition, patients with BN reported more severe COVID-related PTSD symptoms than did those with AN and the control group. This increase in severity of symptoms was more prevalent among patients who had a history of childhood trauma and among those with insecure attachment, suggesting that such patients may be more vulnerable.
 

Evidence of recovery

Commenting on the studies, David Spiegel, MD, associate chair of psychiatry, Stanford (Calif.) University, noted that EDs commonly occur after physical or sexual trauma earlier in life.

“It’s a standard thing with trauma-related disorders that any other, even relatively minor, traumatic experience can exacerbate PTSD symptoms,” said Dr. Spiegel, who was not involved in the studies. In addition, the trauma of the COVID pandemic “was not minor.

“The relative isolation and the lack of outside contact may focus many people with eating disorders even more on their struggles with how they are taking care of their bodies,” said Dr. Spiegel.

“It struck me that the anorexia nervosa group were more impervious than the bulimia nervosa group, but I think that’s the case with the disorder. In some ways it’s more severe, obviously a more life-threatening disorder,” he added.

The “hopeful thing is that there seemed to be some evidence of recovery and improvement, particularly with the posttraumatic stress exacerbation, as time went on,” Dr. Spiegel said, “and that’s a good thing.”

The study authors and Dr. Spiegel reported no relevant financial relationships.

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

Background: A pulmonary embolism can be considered ruled out if patients have a low C-PTP for PE and a D-dimer level of less than 500 ng/mL. However, this occurs in approximately 30% of outpatients only. By increasing the D-dimer threshold used to define a negative test to 1,000 ng/mL in patients with a low C-PTP, we might be able to rule out a larger segment of patients and avoid chest imaging.

Study design: Prospective study.

Setting: University-based clinical centers in Canada.

Synopsis: This study enrolled 2,017 patients presenting with symptoms of PE. The Wells’ criteria was used to categorize the patient’s C-PTP as low (0-4.0), moderate (4.5-6.0), or high (6.5 or more). Patients with a low or moderate C-PTP had a D dimer drawn. Those with a low C-PTP and D dimer of less than 1,000 ng/mL or moderate C-PTP and a D dimer of less than 500 ng/mL underwent no further testing. Outcomes were assessed at 90 days. Of the 1,325 patients with a low C-PTP or moderate C-PTP and a negative D-dimer test (less than 1,000 or 500 ng/mL, respectively), none had venous thromboembolism during follow-up (95% confidence interval, 0.00-0.29). This strategy resulted in the use of chest imaging in only 34.3% of patients versus 51.9% using the prior criteria of a D-dimer level of less than 500 ng/mL (difference, –17.6 percentage points; 95% CI, −19.2 to −15.9). One limitation of the study is that almost all patients enrolled were outpatients (only one inpatient).

Bottom line: A combination of a low C-PTP and a D-dimer level of less than 1,000 ng/mL identified a group of patients at low risk for pulmonary embolism during follow-up.

Citation: Kearon C et al. Diagnosis of pulmonary embolism with D-dimer adjusted to clinical probability. N Engl J Med 2019 Nov 28;381:2125-34.

Dr. Santa is assistant professor in the division of hospital medicine, Loyola University Medical Center, Maywood, Ill.

Background: A pulmonary embolism can be considered ruled out if patients have a low C-PTP for PE and a D-dimer level of less than 500 ng/mL. However, this occurs in approximately 30% of outpatients only. By increasing the D-dimer threshold used to define a negative test to 1,000 ng/mL in patients with a low C-PTP, we might be able to rule out a larger segment of patients and avoid chest imaging.

Study design: Prospective study.

Setting: University-based clinical centers in Canada.

Synopsis: This study enrolled 2,017 patients presenting with symptoms of PE. The Wells’ criteria was used to categorize the patient’s C-PTP as low (0-4.0), moderate (4.5-6.0), or high (6.5 or more). Patients with a low or moderate C-PTP had a D dimer drawn. Those with a low C-PTP and D dimer of less than 1,000 ng/mL or moderate C-PTP and a D dimer of less than 500 ng/mL underwent no further testing. Outcomes were assessed at 90 days. Of the 1,325 patients with a low C-PTP or moderate C-PTP and a negative D-dimer test (less than 1,000 or 500 ng/mL, respectively), none had venous thromboembolism during follow-up (95% confidence interval, 0.00-0.29). This strategy resulted in the use of chest imaging in only 34.3% of patients versus 51.9% using the prior criteria of a D-dimer level of less than 500 ng/mL (difference, –17.6 percentage points; 95% CI, −19.2 to −15.9). One limitation of the study is that almost all patients enrolled were outpatients (only one inpatient).

Bottom line: A combination of a low C-PTP and a D-dimer level of less than 1,000 ng/mL identified a group of patients at low risk for pulmonary embolism during follow-up.

Citation: Kearon C et al. Diagnosis of pulmonary embolism with D-dimer adjusted to clinical probability. N Engl J Med 2019 Nov 28;381:2125-34.

Dr. Santa is assistant professor in the division of hospital medicine, Loyola University Medical Center, Maywood, Ill.

Background: A pulmonary embolism can be considered ruled out if patients have a low C-PTP for PE and a D-dimer level of less than 500 ng/mL. However, this occurs in approximately 30% of outpatients only. By increasing the D-dimer threshold used to define a negative test to 1,000 ng/mL in patients with a low C-PTP, we might be able to rule out a larger segment of patients and avoid chest imaging.

Study design: Prospective study.

Setting: University-based clinical centers in Canada.

Synopsis: This study enrolled 2,017 patients presenting with symptoms of PE. The Wells’ criteria was used to categorize the patient’s C-PTP as low (0-4.0), moderate (4.5-6.0), or high (6.5 or more). Patients with a low or moderate C-PTP had a D dimer drawn. Those with a low C-PTP and D dimer of less than 1,000 ng/mL or moderate C-PTP and a D dimer of less than 500 ng/mL underwent no further testing. Outcomes were assessed at 90 days. Of the 1,325 patients with a low C-PTP or moderate C-PTP and a negative D-dimer test (less than 1,000 or 500 ng/mL, respectively), none had venous thromboembolism during follow-up (95% confidence interval, 0.00-0.29). This strategy resulted in the use of chest imaging in only 34.3% of patients versus 51.9% using the prior criteria of a D-dimer level of less than 500 ng/mL (difference, –17.6 percentage points; 95% CI, −19.2 to −15.9). One limitation of the study is that almost all patients enrolled were outpatients (only one inpatient).

Bottom line: A combination of a low C-PTP and a D-dimer level of less than 1,000 ng/mL identified a group of patients at low risk for pulmonary embolism during follow-up.

Citation: Kearon C et al. Diagnosis of pulmonary embolism with D-dimer adjusted to clinical probability. N Engl J Med 2019 Nov 28;381:2125-34.

Dr. Santa is assistant professor in the division of hospital medicine, Loyola University Medical Center, Maywood, Ill.