In patients with transfusion-dependent beta-thalassemia, a single gene therapy infusion is capable of yielding durable transfusion independence and substantial improvements in iron overload, an investigator reported at the annual meeting of the American Society of Hematology.

Among patients who received betibeglogene autotemcel (beti-cel) in a phase 3 trial and enrolled in a long-term follow-up study, nearly 90% achieved durable transfusion independence, according to Alexis A. Thompson, MD, MPH, of the hematology section at the Ann & Robert H. Lurie Children’s Hospital of Chicago.

The median duration of ongoing transfusion independence was nearly 3 years as of this report, which Dr. Thompson described in a press conference at the meeting.

In a subanalysis of this international study, Dr. Thompson and co-investigators reported that in patients who achieve transfusion independence, chelation reduced iron, and iron markers stabilized even after chelation was stopped.

Beyond 2 years post-infusion, no adverse events related to the drug product were seen. This suggested that the therapy has a favorable long-term safety profile, according to Dr. Thompson.

“At this point, we believe that beti-cel is potentially curative for patients with TDT [transfusion-dependent beta-thalassemia],” Dr. Thompson said in the press conference.

This study answers one of the major outstanding questions about beti-cel and iron metabolism, according to Arielle L. Langer, MD, MPH, an instructor in medicine at Harvard Medical School and attending physician for adult thalassemia patients at Brigham and Women’s and Dana Farber Cancer Institute, both in Boston.

“Seeing the restoration of iron metabolism, it really takes us a step closer to really thinking the term ‘cure’ might truly apply,” Dr. Langer said in an interview.

Dr. Langer said she looks forward to “very long-term outcomes” of beti-cel-treated patients to see whether endocrinopathies and other long-term sequelae of TDT are also abated.

“This [study] is a great intermediate point, but really, when we think about how thalassemia harms and kills our patients, we really sometimes measure that in decades,” she said.

Beta-thalassemia is caused by mutations in the beta-globin gene, resulting in reduced levels of hemoglobin. Patients with TDT, the most serious form of the disease, have severe anemia and are often dependent on red blood cell transfusions from infancy onward, Dr. Thompson said.

With chronic transfusions needed to maintain hemoglobin levels, TDT patients inevitably experience iron overload, which can lead to organ damage and can be fatal. Consequently, patients will require lifelong iron chelation therapy, she added.

Beti-cel, an investigational ex vivo gene addition therapy currently under review by the U.S. Food and Drug Administration, involves adding functional copies of a modified form of the beta-globin gene into a patient’s own hematopoietic stem cells. Once those cells are reinfused, patients may produce adult hemoglobin at levels that eliminate the need for transfusions, according to Dr. Thompson.

At the meeting, Dr. Thompson reported on patients from two phase 1/2 and two phase 3 beti-cel clinical trials who subsequently enrolled in LTF-303, a 13-year follow-up study of the gene therapy’s safety and efficacy.

A total of 57 patients were included in this report, making it the largest gene therapy program to date in any blood disorder, according to Dr. Thompson. Before receiving beti-cel, the patients, who had a broad range of thalassemia genotypes, were receiving between 10 and almost 40 red blood cell transfusions per year, she reported.

Patients ranged in age from 5 to 35 years. The median age in the phase 1/2 studies was 20 years, while in the phase 3 studies it was 15 years.

“The early experience in the phase 1/2 trials allowed us to be more comfortable with enrolling more children, and that has actually helped us to understand safety and efficacy and children in the phase 3 setting,” Dr. Thompson said.

Fertility preservation measures had been undertaken by about 59% of patients from the phase 1/2 studies and 71% of patients from the phase 3 studies, the data show.

Among patients from the phase 3 beti-cel studies who could be evaluated, 31 out of 35 (or 89%) achieved durable transfusion independence, according to the investigator.

The median duration of ongoing transfusion independence was 32 months, with a range of about 18 to 49 months, she added.

Dr. Thompson also reported a subanalysis intended to assess iron status in 16 patients who restarted and then stopped chelation. That subanalysis demonstrated iron reduction in response to chelation, and then stabilization of iron markers after chelation was stopped. Post-gene therapy chelation led to reductions in liver iron concentration and serum ferritin that remained relatively stable after chelation was stopped, she said.

Serious adverse events occurred in eight patients in the long-term follow-up study. However, adverse events related to beti-cel have been absent beyond 2 years post-infusion, according to Dr. Thompson, who added that there have been no reported cases of replication-competent lentivirus, no clonal expansion, no insertional oncogenesis, and no malignancies observed.

“Very reassuringly, there have been 2 male patients, one of whom underwent fertility preservation, who report having healthy children with their partners,” she added.

Dr. Thompson provided disclosures related to Baxalta, Biomarin, bluebird bio, Inc., Celgene/BMS, CRISPR Therapeutics, Vertex, Editas, Graphite Bio, Novartis, Agios, Beam, and Global Blood Therapeutics.
 

In patients with transfusion-dependent beta-thalassemia, a single gene therapy infusion is capable of yielding durable transfusion independence and substantial improvements in iron overload, an investigator reported at the annual meeting of the American Society of Hematology.

Among patients who received betibeglogene autotemcel (beti-cel) in a phase 3 trial and enrolled in a long-term follow-up study, nearly 90% achieved durable transfusion independence, according to Alexis A. Thompson, MD, MPH, of the hematology section at the Ann & Robert H. Lurie Children’s Hospital of Chicago.

The median duration of ongoing transfusion independence was nearly 3 years as of this report, which Dr. Thompson described in a press conference at the meeting.

In a subanalysis of this international study, Dr. Thompson and co-investigators reported that in patients who achieve transfusion independence, chelation reduced iron, and iron markers stabilized even after chelation was stopped.

Beyond 2 years post-infusion, no adverse events related to the drug product were seen. This suggested that the therapy has a favorable long-term safety profile, according to Dr. Thompson.

“At this point, we believe that beti-cel is potentially curative for patients with TDT [transfusion-dependent beta-thalassemia],” Dr. Thompson said in the press conference.

This study answers one of the major outstanding questions about beti-cel and iron metabolism, according to Arielle L. Langer, MD, MPH, an instructor in medicine at Harvard Medical School and attending physician for adult thalassemia patients at Brigham and Women’s and Dana Farber Cancer Institute, both in Boston.

“Seeing the restoration of iron metabolism, it really takes us a step closer to really thinking the term ‘cure’ might truly apply,” Dr. Langer said in an interview.

Dr. Langer said she looks forward to “very long-term outcomes” of beti-cel-treated patients to see whether endocrinopathies and other long-term sequelae of TDT are also abated.

“This [study] is a great intermediate point, but really, when we think about how thalassemia harms and kills our patients, we really sometimes measure that in decades,” she said.

Beta-thalassemia is caused by mutations in the beta-globin gene, resulting in reduced levels of hemoglobin. Patients with TDT, the most serious form of the disease, have severe anemia and are often dependent on red blood cell transfusions from infancy onward, Dr. Thompson said.

With chronic transfusions needed to maintain hemoglobin levels, TDT patients inevitably experience iron overload, which can lead to organ damage and can be fatal. Consequently, patients will require lifelong iron chelation therapy, she added.

Beti-cel, an investigational ex vivo gene addition therapy currently under review by the U.S. Food and Drug Administration, involves adding functional copies of a modified form of the beta-globin gene into a patient’s own hematopoietic stem cells. Once those cells are reinfused, patients may produce adult hemoglobin at levels that eliminate the need for transfusions, according to Dr. Thompson.

At the meeting, Dr. Thompson reported on patients from two phase 1/2 and two phase 3 beti-cel clinical trials who subsequently enrolled in LTF-303, a 13-year follow-up study of the gene therapy’s safety and efficacy.

A total of 57 patients were included in this report, making it the largest gene therapy program to date in any blood disorder, according to Dr. Thompson. Before receiving beti-cel, the patients, who had a broad range of thalassemia genotypes, were receiving between 10 and almost 40 red blood cell transfusions per year, she reported.

Patients ranged in age from 5 to 35 years. The median age in the phase 1/2 studies was 20 years, while in the phase 3 studies it was 15 years.

“The early experience in the phase 1/2 trials allowed us to be more comfortable with enrolling more children, and that has actually helped us to understand safety and efficacy and children in the phase 3 setting,” Dr. Thompson said.

Fertility preservation measures had been undertaken by about 59% of patients from the phase 1/2 studies and 71% of patients from the phase 3 studies, the data show.

Among patients from the phase 3 beti-cel studies who could be evaluated, 31 out of 35 (or 89%) achieved durable transfusion independence, according to the investigator.

The median duration of ongoing transfusion independence was 32 months, with a range of about 18 to 49 months, she added.

Dr. Thompson also reported a subanalysis intended to assess iron status in 16 patients who restarted and then stopped chelation. That subanalysis demonstrated iron reduction in response to chelation, and then stabilization of iron markers after chelation was stopped. Post-gene therapy chelation led to reductions in liver iron concentration and serum ferritin that remained relatively stable after chelation was stopped, she said.

Serious adverse events occurred in eight patients in the long-term follow-up study. However, adverse events related to beti-cel have been absent beyond 2 years post-infusion, according to Dr. Thompson, who added that there have been no reported cases of replication-competent lentivirus, no clonal expansion, no insertional oncogenesis, and no malignancies observed.

“Very reassuringly, there have been 2 male patients, one of whom underwent fertility preservation, who report having healthy children with their partners,” she added.

Dr. Thompson provided disclosures related to Baxalta, Biomarin, bluebird bio, Inc., Celgene/BMS, CRISPR Therapeutics, Vertex, Editas, Graphite Bio, Novartis, Agios, Beam, and Global Blood Therapeutics.
 

In patients with transfusion-dependent beta-thalassemia, a single gene therapy infusion is capable of yielding durable transfusion independence and substantial improvements in iron overload, an investigator reported at the annual meeting of the American Society of Hematology.

Among patients who received betibeglogene autotemcel (beti-cel) in a phase 3 trial and enrolled in a long-term follow-up study, nearly 90% achieved durable transfusion independence, according to Alexis A. Thompson, MD, MPH, of the hematology section at the Ann & Robert H. Lurie Children’s Hospital of Chicago.

The median duration of ongoing transfusion independence was nearly 3 years as of this report, which Dr. Thompson described in a press conference at the meeting.

In a subanalysis of this international study, Dr. Thompson and co-investigators reported that in patients who achieve transfusion independence, chelation reduced iron, and iron markers stabilized even after chelation was stopped.

Beyond 2 years post-infusion, no adverse events related to the drug product were seen. This suggested that the therapy has a favorable long-term safety profile, according to Dr. Thompson.

“At this point, we believe that beti-cel is potentially curative for patients with TDT [transfusion-dependent beta-thalassemia],” Dr. Thompson said in the press conference.

This study answers one of the major outstanding questions about beti-cel and iron metabolism, according to Arielle L. Langer, MD, MPH, an instructor in medicine at Harvard Medical School and attending physician for adult thalassemia patients at Brigham and Women’s and Dana Farber Cancer Institute, both in Boston.

“Seeing the restoration of iron metabolism, it really takes us a step closer to really thinking the term ‘cure’ might truly apply,” Dr. Langer said in an interview.

Dr. Langer said she looks forward to “very long-term outcomes” of beti-cel-treated patients to see whether endocrinopathies and other long-term sequelae of TDT are also abated.

“This [study] is a great intermediate point, but really, when we think about how thalassemia harms and kills our patients, we really sometimes measure that in decades,” she said.

Beta-thalassemia is caused by mutations in the beta-globin gene, resulting in reduced levels of hemoglobin. Patients with TDT, the most serious form of the disease, have severe anemia and are often dependent on red blood cell transfusions from infancy onward, Dr. Thompson said.

With chronic transfusions needed to maintain hemoglobin levels, TDT patients inevitably experience iron overload, which can lead to organ damage and can be fatal. Consequently, patients will require lifelong iron chelation therapy, she added.

Beti-cel, an investigational ex vivo gene addition therapy currently under review by the U.S. Food and Drug Administration, involves adding functional copies of a modified form of the beta-globin gene into a patient’s own hematopoietic stem cells. Once those cells are reinfused, patients may produce adult hemoglobin at levels that eliminate the need for transfusions, according to Dr. Thompson.

At the meeting, Dr. Thompson reported on patients from two phase 1/2 and two phase 3 beti-cel clinical trials who subsequently enrolled in LTF-303, a 13-year follow-up study of the gene therapy’s safety and efficacy.

A total of 57 patients were included in this report, making it the largest gene therapy program to date in any blood disorder, according to Dr. Thompson. Before receiving beti-cel, the patients, who had a broad range of thalassemia genotypes, were receiving between 10 and almost 40 red blood cell transfusions per year, she reported.

Patients ranged in age from 5 to 35 years. The median age in the phase 1/2 studies was 20 years, while in the phase 3 studies it was 15 years.

“The early experience in the phase 1/2 trials allowed us to be more comfortable with enrolling more children, and that has actually helped us to understand safety and efficacy and children in the phase 3 setting,” Dr. Thompson said.

Fertility preservation measures had been undertaken by about 59% of patients from the phase 1/2 studies and 71% of patients from the phase 3 studies, the data show.

Among patients from the phase 3 beti-cel studies who could be evaluated, 31 out of 35 (or 89%) achieved durable transfusion independence, according to the investigator.

The median duration of ongoing transfusion independence was 32 months, with a range of about 18 to 49 months, she added.

Dr. Thompson also reported a subanalysis intended to assess iron status in 16 patients who restarted and then stopped chelation. That subanalysis demonstrated iron reduction in response to chelation, and then stabilization of iron markers after chelation was stopped. Post-gene therapy chelation led to reductions in liver iron concentration and serum ferritin that remained relatively stable after chelation was stopped, she said.

Serious adverse events occurred in eight patients in the long-term follow-up study. However, adverse events related to beti-cel have been absent beyond 2 years post-infusion, according to Dr. Thompson, who added that there have been no reported cases of replication-competent lentivirus, no clonal expansion, no insertional oncogenesis, and no malignancies observed.

“Very reassuringly, there have been 2 male patients, one of whom underwent fertility preservation, who report having healthy children with their partners,” she added.

Dr. Thompson provided disclosures related to Baxalta, Biomarin, bluebird bio, Inc., Celgene/BMS, CRISPR Therapeutics, Vertex, Editas, Graphite Bio, Novartis, Agios, Beam, and Global Blood Therapeutics.
 

ATLANTA — Chimeric antigen receptor (CAR) T-cell therapy has the potential to replace chemoimmunotherapy for second-line treatment of patients with large B-cell lymphoma (LBCL) that have relapsed or are refractory to first-line therapy, results of the phase 3 ZUMA-7 and TRANSFORM trials suggest.

Meletios Verras/Shutterstock

In the ZUMA-7 trial, at a median follow-up of 24.9 months, patients randomly assigned to receive CAR T-cell therapy with axicabtagene ciloleucel, or axi-cell (Yescarta) had a median event-free survival (EFS) of 8.3 months, compared with 2 months for patients randomly assigned to standard-of-care chemoimmunotherapy, reported Frederick L. Locke, MD, from the Moffitt Cancer Center in Tampa, Fla.

In TRANSFORM, comparing the CAR T construct lisocabtagene maraleucel, or liso-cel (Breyanzi) with standard-of-care second-line chemotherapy, median EFS was 10.1 months with liso-cel, compared with 2.3 months with standard of care, reported Manali Kamdar, MD, from the University of Colorado Cancer Center in Aurora.

The trials differed slightly in eligibility criteria and other details, but their overall results show great promise for improving second-line therapy for patients with relapsed or refractory LBCL, commented Laurie Sehn, MD, MPH, from the BC Cancer Centre for Lymphoid Cancer in Vancouver, Canada.

“It’s really remarkable that the results are so far in favor of the CAR T-cell therapy that I think it’s inevitable that this will become the standard of care,” Dr. Sehn commented. She was not an investigator in either of the two trials.

Dr. Sehn was speaking at a press briefing here during the annual meeting of the American Society of Hematology. The new data from the two studies were presented at oral sessions, and the results from ZUMA-7 were also simultaneously published in the New England Journal of Medicine.

“For somebody who treats patients with large B-cell lymphoma like I do, it’s incredibly frustrating when patients fail frontline therapy,” Dr. Sehn said. “We come into the second line with more chemotherapy and at higher doses to try and slam things down hard. Particularly for the patients who were enrolled in these studies, which were the worst of the worst — the patients who are either refractory to chemotherapy or relapsed relatively early, within 1 year — it’s not surprising that coming in with a novel approach and a cellular therapy that has a proven curative capacity may have outperformed coming in with more chemotherapy.”

In an interview with this news organization, Dr. Locke said that, based on the findings of the ZUMA-7 trial that he presented, it’s likely that chemotherapy in the second-line setting for relapsed/refractory LBCL will largely fall by the wayside.

The first question is to identify the patients who can tolerate CAR T-cell therapy. “We need to refer these patients to a CAR T-cell center to make that decision. That decision really can’t be made in the local oncologist’s office,” he said. “That being said, there are patients who need urgent therapy, and they may need to get second-line chemotherapy right away.”

“What we know with CAR T cells is that older patients and patients with comorbidities can get these therapies safely, so to me there is no obvious patient who can’t get CAR T-cell therapy,” he added.

Also at the briefing, Dr. Kamdar, who presented the TRANSFORM trial results, remarked that “in my opinion, this is a breakthrough therapy, which has shown superiority over standard of care, in terms of not just efficacy but also an extremely favorable safety profile,” she said at a briefing.   

For patients with LBCL for whom first-line therapy has failed, chemoimmunotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT) has been the standard of care, but only about 25% of patients who are candidates for ASCT achieve durable remissions, Dr. Kamdar noted.

Both ZUMA-7 and TRANSFORM were designed to test whether moving CAR T-cell therapy forward into the second line could improve outcomes.

ZUMA-7 results

THE ZUMA-7 trial randomly assigned 180 patients to receive CAR T-cell therapy with axi-cell and 179 patients to standard of care. This consisted of two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy, with patients who had a complete or partial response going onto ASCT.

As noted, the primary endpoint of EFS according to blinded central review favored axi-cel, with 24-month event-free survival rates of 41% vs. 16% for standard of care. The difference translated into a hazard ratio (HR) for progression or death of 0.40 (P < .001).

In all, 65% of patients had a complete response (CR) to axi-cel, compared with 32% with standard of care. The respective overall response rates were 83% and 50% (P < .001).

Dr. Locke pointed out that 94% of the patients assigned to axi-cel received definitive therapy, compared with the 36% of patients in the standard-of-care arm who went on to ASCT.

In an interim analysis, 2-year estimated overall survival was 61% with axi-cel vs. 52% with standard of care, although this difference was not statistically significant.

Median overall survival was not reached with axi-cel, compared with 35.1 months with standard-of-care.

Grade 3 or higher adverse events occurred in 91% of patients with CAR T, and 83% with the standard of care. In the axi-cel arm, 6% of patients had grade 3 or higher cytokine release syndrome (CRS), and 21% had grade 3 or higher neurologic events, although there were no deaths related to CRS or neurologic events.

TRANSFORM results

The TRANSFORM trial had broader eligibility criteria than ZUMA-7, including patients who had diffuse LBCL not otherwise specified (de novo or transformed from indolent NHL), high-grade BCL (double- or triple-hit) with DLBCL histology, follicular lymphoma grade 3B, primary mediastinal LBCL, or T-cell/histocyte-rich LBCL.

A total of 184 patients were randomly assigned, 92 in each group, to receive either liso-cel or standard-of-care. Patients assigned to liso-cel were allowed to have bridging therapy, and crossover to liso-cel was allowed for patients assigned to standard of care who either did not have a response by week 9 after randomization, had disease progression at any time, or started a new antineoplastic therapy after ASCT.

As noted before, the primary endpoint of EFS significantly favored CAR T-cell therapy, with a hazard ratio of 0.349 (P < .0001).

The EFS rates at 6 months were 63.3% with liso-cel vs 33.4% with standard of care, and the EFS rates at 12 months were 44.5% vs. 23.7%, respectively.

“Overall survival data were still immature at the time of this analysis, but show a trend favoring liso-cel, despite crossover,” Dr. Kamdar said.

Grade 3 or higher adverse events (AEs) occurred in 92% of patients on liso-cell and 87% of patients on standard of care. There was one treatment-related death in the liso-cel arm, and two in the standard of care arm, both from grade 3 or higher AEs. Neutropenia, anemia, and thrombocytopenia were the most common treatment-emergent AEs in each group.

ZUMA-7 is supported by Kite. Dr. Locke disclosed serving as a scientific advisor to Kite and relationships with other companies. TRANSFORM is supported by Celgene (BMS). Dr. Kamdar disclosed consultancy fees from BMS and others.


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

ATLANTA — Chimeric antigen receptor (CAR) T-cell therapy has the potential to replace chemoimmunotherapy for second-line treatment of patients with large B-cell lymphoma (LBCL) that have relapsed or are refractory to first-line therapy, results of the phase 3 ZUMA-7 and TRANSFORM trials suggest.

Meletios Verras/Shutterstock

In the ZUMA-7 trial, at a median follow-up of 24.9 months, patients randomly assigned to receive CAR T-cell therapy with axicabtagene ciloleucel, or axi-cell (Yescarta) had a median event-free survival (EFS) of 8.3 months, compared with 2 months for patients randomly assigned to standard-of-care chemoimmunotherapy, reported Frederick L. Locke, MD, from the Moffitt Cancer Center in Tampa, Fla.

In TRANSFORM, comparing the CAR T construct lisocabtagene maraleucel, or liso-cel (Breyanzi) with standard-of-care second-line chemotherapy, median EFS was 10.1 months with liso-cel, compared with 2.3 months with standard of care, reported Manali Kamdar, MD, from the University of Colorado Cancer Center in Aurora.

The trials differed slightly in eligibility criteria and other details, but their overall results show great promise for improving second-line therapy for patients with relapsed or refractory LBCL, commented Laurie Sehn, MD, MPH, from the BC Cancer Centre for Lymphoid Cancer in Vancouver, Canada.

“It’s really remarkable that the results are so far in favor of the CAR T-cell therapy that I think it’s inevitable that this will become the standard of care,” Dr. Sehn commented. She was not an investigator in either of the two trials.

Dr. Sehn was speaking at a press briefing here during the annual meeting of the American Society of Hematology. The new data from the two studies were presented at oral sessions, and the results from ZUMA-7 were also simultaneously published in the New England Journal of Medicine.

“For somebody who treats patients with large B-cell lymphoma like I do, it’s incredibly frustrating when patients fail frontline therapy,” Dr. Sehn said. “We come into the second line with more chemotherapy and at higher doses to try and slam things down hard. Particularly for the patients who were enrolled in these studies, which were the worst of the worst — the patients who are either refractory to chemotherapy or relapsed relatively early, within 1 year — it’s not surprising that coming in with a novel approach and a cellular therapy that has a proven curative capacity may have outperformed coming in with more chemotherapy.”

In an interview with this news organization, Dr. Locke said that, based on the findings of the ZUMA-7 trial that he presented, it’s likely that chemotherapy in the second-line setting for relapsed/refractory LBCL will largely fall by the wayside.

The first question is to identify the patients who can tolerate CAR T-cell therapy. “We need to refer these patients to a CAR T-cell center to make that decision. That decision really can’t be made in the local oncologist’s office,” he said. “That being said, there are patients who need urgent therapy, and they may need to get second-line chemotherapy right away.”

“What we know with CAR T cells is that older patients and patients with comorbidities can get these therapies safely, so to me there is no obvious patient who can’t get CAR T-cell therapy,” he added.

Also at the briefing, Dr. Kamdar, who presented the TRANSFORM trial results, remarked that “in my opinion, this is a breakthrough therapy, which has shown superiority over standard of care, in terms of not just efficacy but also an extremely favorable safety profile,” she said at a briefing.   

For patients with LBCL for whom first-line therapy has failed, chemoimmunotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT) has been the standard of care, but only about 25% of patients who are candidates for ASCT achieve durable remissions, Dr. Kamdar noted.

Both ZUMA-7 and TRANSFORM were designed to test whether moving CAR T-cell therapy forward into the second line could improve outcomes.

ZUMA-7 results

THE ZUMA-7 trial randomly assigned 180 patients to receive CAR T-cell therapy with axi-cell and 179 patients to standard of care. This consisted of two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy, with patients who had a complete or partial response going onto ASCT.

As noted, the primary endpoint of EFS according to blinded central review favored axi-cel, with 24-month event-free survival rates of 41% vs. 16% for standard of care. The difference translated into a hazard ratio (HR) for progression or death of 0.40 (P < .001).

In all, 65% of patients had a complete response (CR) to axi-cel, compared with 32% with standard of care. The respective overall response rates were 83% and 50% (P < .001).

Dr. Locke pointed out that 94% of the patients assigned to axi-cel received definitive therapy, compared with the 36% of patients in the standard-of-care arm who went on to ASCT.

In an interim analysis, 2-year estimated overall survival was 61% with axi-cel vs. 52% with standard of care, although this difference was not statistically significant.

Median overall survival was not reached with axi-cel, compared with 35.1 months with standard-of-care.

Grade 3 or higher adverse events occurred in 91% of patients with CAR T, and 83% with the standard of care. In the axi-cel arm, 6% of patients had grade 3 or higher cytokine release syndrome (CRS), and 21% had grade 3 or higher neurologic events, although there were no deaths related to CRS or neurologic events.

TRANSFORM results

The TRANSFORM trial had broader eligibility criteria than ZUMA-7, including patients who had diffuse LBCL not otherwise specified (de novo or transformed from indolent NHL), high-grade BCL (double- or triple-hit) with DLBCL histology, follicular lymphoma grade 3B, primary mediastinal LBCL, or T-cell/histocyte-rich LBCL.

A total of 184 patients were randomly assigned, 92 in each group, to receive either liso-cel or standard-of-care. Patients assigned to liso-cel were allowed to have bridging therapy, and crossover to liso-cel was allowed for patients assigned to standard of care who either did not have a response by week 9 after randomization, had disease progression at any time, or started a new antineoplastic therapy after ASCT.

As noted before, the primary endpoint of EFS significantly favored CAR T-cell therapy, with a hazard ratio of 0.349 (P < .0001).

The EFS rates at 6 months were 63.3% with liso-cel vs 33.4% with standard of care, and the EFS rates at 12 months were 44.5% vs. 23.7%, respectively.

“Overall survival data were still immature at the time of this analysis, but show a trend favoring liso-cel, despite crossover,” Dr. Kamdar said.

Grade 3 or higher adverse events (AEs) occurred in 92% of patients on liso-cell and 87% of patients on standard of care. There was one treatment-related death in the liso-cel arm, and two in the standard of care arm, both from grade 3 or higher AEs. Neutropenia, anemia, and thrombocytopenia were the most common treatment-emergent AEs in each group.

ZUMA-7 is supported by Kite. Dr. Locke disclosed serving as a scientific advisor to Kite and relationships with other companies. TRANSFORM is supported by Celgene (BMS). Dr. Kamdar disclosed consultancy fees from BMS and others.


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

ATLANTA — Chimeric antigen receptor (CAR) T-cell therapy has the potential to replace chemoimmunotherapy for second-line treatment of patients with large B-cell lymphoma (LBCL) that have relapsed or are refractory to first-line therapy, results of the phase 3 ZUMA-7 and TRANSFORM trials suggest.

Meletios Verras/Shutterstock

In the ZUMA-7 trial, at a median follow-up of 24.9 months, patients randomly assigned to receive CAR T-cell therapy with axicabtagene ciloleucel, or axi-cell (Yescarta) had a median event-free survival (EFS) of 8.3 months, compared with 2 months for patients randomly assigned to standard-of-care chemoimmunotherapy, reported Frederick L. Locke, MD, from the Moffitt Cancer Center in Tampa, Fla.

In TRANSFORM, comparing the CAR T construct lisocabtagene maraleucel, or liso-cel (Breyanzi) with standard-of-care second-line chemotherapy, median EFS was 10.1 months with liso-cel, compared with 2.3 months with standard of care, reported Manali Kamdar, MD, from the University of Colorado Cancer Center in Aurora.

The trials differed slightly in eligibility criteria and other details, but their overall results show great promise for improving second-line therapy for patients with relapsed or refractory LBCL, commented Laurie Sehn, MD, MPH, from the BC Cancer Centre for Lymphoid Cancer in Vancouver, Canada.

“It’s really remarkable that the results are so far in favor of the CAR T-cell therapy that I think it’s inevitable that this will become the standard of care,” Dr. Sehn commented. She was not an investigator in either of the two trials.

Dr. Sehn was speaking at a press briefing here during the annual meeting of the American Society of Hematology. The new data from the two studies were presented at oral sessions, and the results from ZUMA-7 were also simultaneously published in the New England Journal of Medicine.

“For somebody who treats patients with large B-cell lymphoma like I do, it’s incredibly frustrating when patients fail frontline therapy,” Dr. Sehn said. “We come into the second line with more chemotherapy and at higher doses to try and slam things down hard. Particularly for the patients who were enrolled in these studies, which were the worst of the worst — the patients who are either refractory to chemotherapy or relapsed relatively early, within 1 year — it’s not surprising that coming in with a novel approach and a cellular therapy that has a proven curative capacity may have outperformed coming in with more chemotherapy.”

In an interview with this news organization, Dr. Locke said that, based on the findings of the ZUMA-7 trial that he presented, it’s likely that chemotherapy in the second-line setting for relapsed/refractory LBCL will largely fall by the wayside.

The first question is to identify the patients who can tolerate CAR T-cell therapy. “We need to refer these patients to a CAR T-cell center to make that decision. That decision really can’t be made in the local oncologist’s office,” he said. “That being said, there are patients who need urgent therapy, and they may need to get second-line chemotherapy right away.”

“What we know with CAR T cells is that older patients and patients with comorbidities can get these therapies safely, so to me there is no obvious patient who can’t get CAR T-cell therapy,” he added.

Also at the briefing, Dr. Kamdar, who presented the TRANSFORM trial results, remarked that “in my opinion, this is a breakthrough therapy, which has shown superiority over standard of care, in terms of not just efficacy but also an extremely favorable safety profile,” she said at a briefing.   

For patients with LBCL for whom first-line therapy has failed, chemoimmunotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT) has been the standard of care, but only about 25% of patients who are candidates for ASCT achieve durable remissions, Dr. Kamdar noted.

Both ZUMA-7 and TRANSFORM were designed to test whether moving CAR T-cell therapy forward into the second line could improve outcomes.

ZUMA-7 results

THE ZUMA-7 trial randomly assigned 180 patients to receive CAR T-cell therapy with axi-cell and 179 patients to standard of care. This consisted of two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy, with patients who had a complete or partial response going onto ASCT.

As noted, the primary endpoint of EFS according to blinded central review favored axi-cel, with 24-month event-free survival rates of 41% vs. 16% for standard of care. The difference translated into a hazard ratio (HR) for progression or death of 0.40 (P < .001).

In all, 65% of patients had a complete response (CR) to axi-cel, compared with 32% with standard of care. The respective overall response rates were 83% and 50% (P < .001).

Dr. Locke pointed out that 94% of the patients assigned to axi-cel received definitive therapy, compared with the 36% of patients in the standard-of-care arm who went on to ASCT.

In an interim analysis, 2-year estimated overall survival was 61% with axi-cel vs. 52% with standard of care, although this difference was not statistically significant.

Median overall survival was not reached with axi-cel, compared with 35.1 months with standard-of-care.

Grade 3 or higher adverse events occurred in 91% of patients with CAR T, and 83% with the standard of care. In the axi-cel arm, 6% of patients had grade 3 or higher cytokine release syndrome (CRS), and 21% had grade 3 or higher neurologic events, although there were no deaths related to CRS or neurologic events.

TRANSFORM results

The TRANSFORM trial had broader eligibility criteria than ZUMA-7, including patients who had diffuse LBCL not otherwise specified (de novo or transformed from indolent NHL), high-grade BCL (double- or triple-hit) with DLBCL histology, follicular lymphoma grade 3B, primary mediastinal LBCL, or T-cell/histocyte-rich LBCL.

A total of 184 patients were randomly assigned, 92 in each group, to receive either liso-cel or standard-of-care. Patients assigned to liso-cel were allowed to have bridging therapy, and crossover to liso-cel was allowed for patients assigned to standard of care who either did not have a response by week 9 after randomization, had disease progression at any time, or started a new antineoplastic therapy after ASCT.

As noted before, the primary endpoint of EFS significantly favored CAR T-cell therapy, with a hazard ratio of 0.349 (P < .0001).

The EFS rates at 6 months were 63.3% with liso-cel vs 33.4% with standard of care, and the EFS rates at 12 months were 44.5% vs. 23.7%, respectively.

“Overall survival data were still immature at the time of this analysis, but show a trend favoring liso-cel, despite crossover,” Dr. Kamdar said.

Grade 3 or higher adverse events (AEs) occurred in 92% of patients on liso-cell and 87% of patients on standard of care. There was one treatment-related death in the liso-cel arm, and two in the standard of care arm, both from grade 3 or higher AEs. Neutropenia, anemia, and thrombocytopenia were the most common treatment-emergent AEs in each group.

ZUMA-7 is supported by Kite. Dr. Locke disclosed serving as a scientific advisor to Kite and relationships with other companies. TRANSFORM is supported by Celgene (BMS). Dr. Kamdar disclosed consultancy fees from BMS and others.


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

Recent therapeutic advances in HER2-positive metastatic breast cancer (MBC) have begun to reshape the treatment landscape for patients. Since late 2019, the U.S. Food and Drug Administration (FDA) has approved a handful of novel agents for HER2-positive MBC — most notably, the antibody-drug conjugate (ADC) trastuzumab deruxtecan in December 2019 and the tyrosine kinase inhibitors (TKIs) tucatinib and neratinib in 2020. According to the National Cancer Institute›s Surveillance, Epidemiology, and End Results (SEER) program, the 5-year survival rate for patients with advanced disease was already on the rise between 2004 and 2018, and the introduction of these new therapeutic options has continued to improve patients’ survival odds.
 

“I’ve been involved in the HER2 space for a long time and have watched the field evolve,” said Adam Brufsky, MD, PhD, associate chief in the division of hematology/oncology and co-director of the Comprehensive Breast Cancer Center at the University of Pittsburgh School of Medicine. “The fact that we’re now talking about fourth- and fifth-line therapies for HER2-positive MBC represents a major advance in the management of these patients.”

Steve Gschmeissner/Getty Images

Oncologists are still building on this progress, focusing on designing more targeted therapies as well as studying different combinations of available agents. The main goal of treatment, experts say, is to prolong patients’ systemic response and prevent recurrences, especially in the brain. This news organization spoke to Dr. Brufksy and others about promising agents and therapeutic strategies on the horizon to treat HER2-positive MBC.

Inside emerging ADCs

Because many patients develop resistance to trastuzumab emtansine (T-DM1) — the first FDA-approved ADC in breast cancer — researchers have focused on developing the next generation of ADCs with more potent payloads, different linkers, and distinct mechanisms of action, according to Sayeh Lavasani, MD, MS, a medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County.

The second-generation ADC trastuzumab deruxtecan showed “really dramatic” results in HER2-positive MBC, demonstrating progression-free survival of 16 months, remarked Kevin Kalinsky, MD, acting associate professor in the department of hematology and medical oncology at Emory University School of Medicine in Atlanta and director of the Glenn Family Breast Center at the Winship Cancer Institute of Emory University. “These outcomes further changed how we treat patients with metastatic disease and prompted considerable excitement over the potential to develop novel ADCs to treat HER2-positive MBC.”

Most recently, two investigational ADCs — trastuzumab duocarmazine (SYD985) and ARX788 — have stood out. The FDA granted fast-track designations to trastuzumab duocarmazine in January 2018 and ARX788 in January 2021. Trastuzumab duocarmazine, the furthest along the pipeline, has shown promising results so far. In June 2021, Netherlands-based biopharmaceutical company Byondis reported preliminary phase 3 data from the TULIP trial. The open-label, randomized phase 3 study enrolled 436 patients with HER2-positive locally advanced or metastatic disease that had progressed on previous anti-HER2 regimens. The company shared early results that trastuzumab duocarmazine achieved its progression-free survival primary endpoint, marking a significant improvement over physician’s choice of chemotherapy, and promised more detailed results to come later this year.

Although only in early-phase trials, ARX788 has also shown robust anti-HER2 activity as well as low toxicity in HER2-positive tumors, according to recent data. The findings from two phase 1 studies, presented at the June 2021 virtual American Society for Clinical Oncology meeting (abstract 1038), revealed an overall response rate of 74% in the breast cancer cohort, but the investigators acknowledged it was too early to report median progression-free survival outcomes. Preclinical data also showed activity in HER2-low and T-DM1–resistant tumors.

Despite the encouraging initial findings, Dr. Kalinsky remains cautiously optimistic about long-term outcomes for both ADCs. “These data are hot off the press, but it’s too soon to know how these two ADCs and others in the pipeline will measure up to approved therapies,” he commented. As experts learn more about the efficacy of these novel ADCs, Dr. Brufsky would also like to better understand resistance mechanisms and how to integrate these agents into current treatment strategies. “The cellular biology of HER2-positive MBC is complicated, and many factors in these tumor cells affect where ADCs are released, how resistance develops, and whether or not resistance to one ADC applies to others,” Dr. Brufsky remarked. “As we gather more data, we’ll understand resistance mechanisms better and begin to figure out where to go with treatment sequencing.”

TKIs and beyond

In addition to ADCs, TKIs continue to make their mark in the targeted HER2 therapeutic space. The approvals of tucatinib and neratinib last year represented an important advance in treating HER2-positive MBC, particularly for patients with brain metastases. The HER2CLIMB trial, for instance, found that tucatinib combined with trastuzumab and capecitabine had a 4.5-month overall survival advantage compared with placebo (21.9 vs 17.4) and a median progression-free survival advantage of 5.4 months in patients with active brain metastases (9.5 vs 4.1) and 8.3 months in patients with stable metastases (13.9 vs 5.6).

Given this progress, experts are looking to add new TKIs to the armamentarium. In particular, pyrotinib — already approved in China for treating HER2-positive MBC — has demonstrated significantly longer progression-free survival compared with a standard TKI, lapatinib. The phase 3 PHOEBE trial results, published in The Lancet in early 2021, found a median progression-free survival of 12.5 months in patients randomly assigned to receive pyrotinib plus capecitabine compared with 6.8 months in those receiving lapatinib plus capecitabine. The investigators also reported “manageable toxicity”; diarrhea was the most common grade 3 adverse event, occurring in 31% of the pyrotinib group vs. 8% of the lapatinib group, and overall serious adverse events occurred in 10% of patients receiving pyrotinib vs. 8% of those receiving lapatinib.

More recent data on pyrotinib come from the phase 2 PERMEATE trial, which focused on the safety and efficacy of the agent in patients with advanced disease and brain metastases. The investigators, who presented their findings at the 2021 virtual ASCO meeting (abstract 1037), reported that radiation therapy–naive patients receiving pyrotinib plus capecitabine had an overall response rate of 74.6% in the central nervous system. Patients experiencing progression after whole-brain or stereotactic radiation therapy, however, had a comparatively lower overall response rate of 42.1%.

Similarly, median progression-free survival was much higher in the radiation therapy–naive patients (12.1 vs 5.6 months in the radiation therapy cohort). Similar to the PHOEBE trial, the most common grade 3 adverse event was diarrhea (23.1%), followed by decreased neutrophil and white blood cell counts (12.8% for both), anemia (9%), and hand-foot syndrome (7.7%). The main question for Dr. Kalinsky is how well pyrotinib will ultimately stack up to tucatinib and neratinib. “Pyrotinib — like neratinib — was shown to be superior to lapatinib plus capecitabine , but its role may be limited by its gastrointestinal toxicity,” he said. In addition to research focused on expanding the selection of novel ADCs and TKIs, researchers are also exploring new combinations of approved treatments and whether these combinations can be used earlier in treatment sequencing.

Take the CompassHER2 trials. The ongoing phase 3 trial in patients with high-risk HER2-positive breast cancer and residual disease will explore whether tucatinib plus T-DM1 compared with T-DM1 alone improves overall survival and recurrence-free survival and prevents brain metastases. Another possibility currently under investigation is pairing tucatinib and trastuzumab deruxtecan, instead of T-DM1. “Overall, it’s exciting that we are increasing the number of therapeutic options and combinations,” commented Debu Tripathy, MD, professor and chairman in the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston. “Having more choices allows us to tailor therapies to manage resistance and prolong patients’ responses.”

Curbing brain metastasis, according to Dr. Brufksy, is particularly important, and experts need to explore the extent to which ADCs can penetrate the blood-brain barrier. Already, a subgroup analysis of the DESTINY-Breast01 trial found that trastuzumab deruxtecan appeared to be active in patients with brain metastases. Investigators reported an overall response rate of 58.3% and a median progression-free survival of 18.1 months — results in line with those in the general study cohort — but the study population did not include patients with untreated or progressive brain metastases. A phase 2 study currently under way will examine whether patients with HER2-positive and HER2-low breast cancer who have untreated or progressive brain metastases respond to trastuzumab deruxtecan as well. Ultimately, Dr. Brufksy hopes the recent successes with preventing brain metastases in pediatric acute lymphoblastic leukemia (ALL) foreshadow what›s to come in HER2-positive MBC.

“When we figured out how to treat brain metastases prophylactically in childhood ALL, we saw a huge improvement in the cure rate, which is ultimately my vision for HER2-positive disease,” Dr. Brufsky remarked. “Are there cures for HER2-positive MBC on the horizon? We don’t know yet, but the field has really exploded in recent years.”

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

Recent therapeutic advances in HER2-positive metastatic breast cancer (MBC) have begun to reshape the treatment landscape for patients. Since late 2019, the U.S. Food and Drug Administration (FDA) has approved a handful of novel agents for HER2-positive MBC — most notably, the antibody-drug conjugate (ADC) trastuzumab deruxtecan in December 2019 and the tyrosine kinase inhibitors (TKIs) tucatinib and neratinib in 2020. According to the National Cancer Institute›s Surveillance, Epidemiology, and End Results (SEER) program, the 5-year survival rate for patients with advanced disease was already on the rise between 2004 and 2018, and the introduction of these new therapeutic options has continued to improve patients’ survival odds.
 

“I’ve been involved in the HER2 space for a long time and have watched the field evolve,” said Adam Brufsky, MD, PhD, associate chief in the division of hematology/oncology and co-director of the Comprehensive Breast Cancer Center at the University of Pittsburgh School of Medicine. “The fact that we’re now talking about fourth- and fifth-line therapies for HER2-positive MBC represents a major advance in the management of these patients.”

Steve Gschmeissner/Getty Images

Oncologists are still building on this progress, focusing on designing more targeted therapies as well as studying different combinations of available agents. The main goal of treatment, experts say, is to prolong patients’ systemic response and prevent recurrences, especially in the brain. This news organization spoke to Dr. Brufksy and others about promising agents and therapeutic strategies on the horizon to treat HER2-positive MBC.

Inside emerging ADCs

Because many patients develop resistance to trastuzumab emtansine (T-DM1) — the first FDA-approved ADC in breast cancer — researchers have focused on developing the next generation of ADCs with more potent payloads, different linkers, and distinct mechanisms of action, according to Sayeh Lavasani, MD, MS, a medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County.

The second-generation ADC trastuzumab deruxtecan showed “really dramatic” results in HER2-positive MBC, demonstrating progression-free survival of 16 months, remarked Kevin Kalinsky, MD, acting associate professor in the department of hematology and medical oncology at Emory University School of Medicine in Atlanta and director of the Glenn Family Breast Center at the Winship Cancer Institute of Emory University. “These outcomes further changed how we treat patients with metastatic disease and prompted considerable excitement over the potential to develop novel ADCs to treat HER2-positive MBC.”

Most recently, two investigational ADCs — trastuzumab duocarmazine (SYD985) and ARX788 — have stood out. The FDA granted fast-track designations to trastuzumab duocarmazine in January 2018 and ARX788 in January 2021. Trastuzumab duocarmazine, the furthest along the pipeline, has shown promising results so far. In June 2021, Netherlands-based biopharmaceutical company Byondis reported preliminary phase 3 data from the TULIP trial. The open-label, randomized phase 3 study enrolled 436 patients with HER2-positive locally advanced or metastatic disease that had progressed on previous anti-HER2 regimens. The company shared early results that trastuzumab duocarmazine achieved its progression-free survival primary endpoint, marking a significant improvement over physician’s choice of chemotherapy, and promised more detailed results to come later this year.

Although only in early-phase trials, ARX788 has also shown robust anti-HER2 activity as well as low toxicity in HER2-positive tumors, according to recent data. The findings from two phase 1 studies, presented at the June 2021 virtual American Society for Clinical Oncology meeting (abstract 1038), revealed an overall response rate of 74% in the breast cancer cohort, but the investigators acknowledged it was too early to report median progression-free survival outcomes. Preclinical data also showed activity in HER2-low and T-DM1–resistant tumors.

Despite the encouraging initial findings, Dr. Kalinsky remains cautiously optimistic about long-term outcomes for both ADCs. “These data are hot off the press, but it’s too soon to know how these two ADCs and others in the pipeline will measure up to approved therapies,” he commented. As experts learn more about the efficacy of these novel ADCs, Dr. Brufsky would also like to better understand resistance mechanisms and how to integrate these agents into current treatment strategies. “The cellular biology of HER2-positive MBC is complicated, and many factors in these tumor cells affect where ADCs are released, how resistance develops, and whether or not resistance to one ADC applies to others,” Dr. Brufsky remarked. “As we gather more data, we’ll understand resistance mechanisms better and begin to figure out where to go with treatment sequencing.”

TKIs and beyond

In addition to ADCs, TKIs continue to make their mark in the targeted HER2 therapeutic space. The approvals of tucatinib and neratinib last year represented an important advance in treating HER2-positive MBC, particularly for patients with brain metastases. The HER2CLIMB trial, for instance, found that tucatinib combined with trastuzumab and capecitabine had a 4.5-month overall survival advantage compared with placebo (21.9 vs 17.4) and a median progression-free survival advantage of 5.4 months in patients with active brain metastases (9.5 vs 4.1) and 8.3 months in patients with stable metastases (13.9 vs 5.6).

Given this progress, experts are looking to add new TKIs to the armamentarium. In particular, pyrotinib — already approved in China for treating HER2-positive MBC — has demonstrated significantly longer progression-free survival compared with a standard TKI, lapatinib. The phase 3 PHOEBE trial results, published in The Lancet in early 2021, found a median progression-free survival of 12.5 months in patients randomly assigned to receive pyrotinib plus capecitabine compared with 6.8 months in those receiving lapatinib plus capecitabine. The investigators also reported “manageable toxicity”; diarrhea was the most common grade 3 adverse event, occurring in 31% of the pyrotinib group vs. 8% of the lapatinib group, and overall serious adverse events occurred in 10% of patients receiving pyrotinib vs. 8% of those receiving lapatinib.

More recent data on pyrotinib come from the phase 2 PERMEATE trial, which focused on the safety and efficacy of the agent in patients with advanced disease and brain metastases. The investigators, who presented their findings at the 2021 virtual ASCO meeting (abstract 1037), reported that radiation therapy–naive patients receiving pyrotinib plus capecitabine had an overall response rate of 74.6% in the central nervous system. Patients experiencing progression after whole-brain or stereotactic radiation therapy, however, had a comparatively lower overall response rate of 42.1%.

Similarly, median progression-free survival was much higher in the radiation therapy–naive patients (12.1 vs 5.6 months in the radiation therapy cohort). Similar to the PHOEBE trial, the most common grade 3 adverse event was diarrhea (23.1%), followed by decreased neutrophil and white blood cell counts (12.8% for both), anemia (9%), and hand-foot syndrome (7.7%). The main question for Dr. Kalinsky is how well pyrotinib will ultimately stack up to tucatinib and neratinib. “Pyrotinib — like neratinib — was shown to be superior to lapatinib plus capecitabine , but its role may be limited by its gastrointestinal toxicity,” he said. In addition to research focused on expanding the selection of novel ADCs and TKIs, researchers are also exploring new combinations of approved treatments and whether these combinations can be used earlier in treatment sequencing.

Take the CompassHER2 trials. The ongoing phase 3 trial in patients with high-risk HER2-positive breast cancer and residual disease will explore whether tucatinib plus T-DM1 compared with T-DM1 alone improves overall survival and recurrence-free survival and prevents brain metastases. Another possibility currently under investigation is pairing tucatinib and trastuzumab deruxtecan, instead of T-DM1. “Overall, it’s exciting that we are increasing the number of therapeutic options and combinations,” commented Debu Tripathy, MD, professor and chairman in the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston. “Having more choices allows us to tailor therapies to manage resistance and prolong patients’ responses.”

Curbing brain metastasis, according to Dr. Brufksy, is particularly important, and experts need to explore the extent to which ADCs can penetrate the blood-brain barrier. Already, a subgroup analysis of the DESTINY-Breast01 trial found that trastuzumab deruxtecan appeared to be active in patients with brain metastases. Investigators reported an overall response rate of 58.3% and a median progression-free survival of 18.1 months — results in line with those in the general study cohort — but the study population did not include patients with untreated or progressive brain metastases. A phase 2 study currently under way will examine whether patients with HER2-positive and HER2-low breast cancer who have untreated or progressive brain metastases respond to trastuzumab deruxtecan as well. Ultimately, Dr. Brufksy hopes the recent successes with preventing brain metastases in pediatric acute lymphoblastic leukemia (ALL) foreshadow what›s to come in HER2-positive MBC.

“When we figured out how to treat brain metastases prophylactically in childhood ALL, we saw a huge improvement in the cure rate, which is ultimately my vision for HER2-positive disease,” Dr. Brufsky remarked. “Are there cures for HER2-positive MBC on the horizon? We don’t know yet, but the field has really exploded in recent years.”

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

Recent therapeutic advances in HER2-positive metastatic breast cancer (MBC) have begun to reshape the treatment landscape for patients. Since late 2019, the U.S. Food and Drug Administration (FDA) has approved a handful of novel agents for HER2-positive MBC — most notably, the antibody-drug conjugate (ADC) trastuzumab deruxtecan in December 2019 and the tyrosine kinase inhibitors (TKIs) tucatinib and neratinib in 2020. According to the National Cancer Institute›s Surveillance, Epidemiology, and End Results (SEER) program, the 5-year survival rate for patients with advanced disease was already on the rise between 2004 and 2018, and the introduction of these new therapeutic options has continued to improve patients’ survival odds.
 

“I’ve been involved in the HER2 space for a long time and have watched the field evolve,” said Adam Brufsky, MD, PhD, associate chief in the division of hematology/oncology and co-director of the Comprehensive Breast Cancer Center at the University of Pittsburgh School of Medicine. “The fact that we’re now talking about fourth- and fifth-line therapies for HER2-positive MBC represents a major advance in the management of these patients.”

Steve Gschmeissner/Getty Images

Oncologists are still building on this progress, focusing on designing more targeted therapies as well as studying different combinations of available agents. The main goal of treatment, experts say, is to prolong patients’ systemic response and prevent recurrences, especially in the brain. This news organization spoke to Dr. Brufksy and others about promising agents and therapeutic strategies on the horizon to treat HER2-positive MBC.

Inside emerging ADCs

Because many patients develop resistance to trastuzumab emtansine (T-DM1) — the first FDA-approved ADC in breast cancer — researchers have focused on developing the next generation of ADCs with more potent payloads, different linkers, and distinct mechanisms of action, according to Sayeh Lavasani, MD, MS, a medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County.

The second-generation ADC trastuzumab deruxtecan showed “really dramatic” results in HER2-positive MBC, demonstrating progression-free survival of 16 months, remarked Kevin Kalinsky, MD, acting associate professor in the department of hematology and medical oncology at Emory University School of Medicine in Atlanta and director of the Glenn Family Breast Center at the Winship Cancer Institute of Emory University. “These outcomes further changed how we treat patients with metastatic disease and prompted considerable excitement over the potential to develop novel ADCs to treat HER2-positive MBC.”

Most recently, two investigational ADCs — trastuzumab duocarmazine (SYD985) and ARX788 — have stood out. The FDA granted fast-track designations to trastuzumab duocarmazine in January 2018 and ARX788 in January 2021. Trastuzumab duocarmazine, the furthest along the pipeline, has shown promising results so far. In June 2021, Netherlands-based biopharmaceutical company Byondis reported preliminary phase 3 data from the TULIP trial. The open-label, randomized phase 3 study enrolled 436 patients with HER2-positive locally advanced or metastatic disease that had progressed on previous anti-HER2 regimens. The company shared early results that trastuzumab duocarmazine achieved its progression-free survival primary endpoint, marking a significant improvement over physician’s choice of chemotherapy, and promised more detailed results to come later this year.

Although only in early-phase trials, ARX788 has also shown robust anti-HER2 activity as well as low toxicity in HER2-positive tumors, according to recent data. The findings from two phase 1 studies, presented at the June 2021 virtual American Society for Clinical Oncology meeting (abstract 1038), revealed an overall response rate of 74% in the breast cancer cohort, but the investigators acknowledged it was too early to report median progression-free survival outcomes. Preclinical data also showed activity in HER2-low and T-DM1–resistant tumors.

Despite the encouraging initial findings, Dr. Kalinsky remains cautiously optimistic about long-term outcomes for both ADCs. “These data are hot off the press, but it’s too soon to know how these two ADCs and others in the pipeline will measure up to approved therapies,” he commented. As experts learn more about the efficacy of these novel ADCs, Dr. Brufsky would also like to better understand resistance mechanisms and how to integrate these agents into current treatment strategies. “The cellular biology of HER2-positive MBC is complicated, and many factors in these tumor cells affect where ADCs are released, how resistance develops, and whether or not resistance to one ADC applies to others,” Dr. Brufsky remarked. “As we gather more data, we’ll understand resistance mechanisms better and begin to figure out where to go with treatment sequencing.”

TKIs and beyond

In addition to ADCs, TKIs continue to make their mark in the targeted HER2 therapeutic space. The approvals of tucatinib and neratinib last year represented an important advance in treating HER2-positive MBC, particularly for patients with brain metastases. The HER2CLIMB trial, for instance, found that tucatinib combined with trastuzumab and capecitabine had a 4.5-month overall survival advantage compared with placebo (21.9 vs 17.4) and a median progression-free survival advantage of 5.4 months in patients with active brain metastases (9.5 vs 4.1) and 8.3 months in patients with stable metastases (13.9 vs 5.6).

Given this progress, experts are looking to add new TKIs to the armamentarium. In particular, pyrotinib — already approved in China for treating HER2-positive MBC — has demonstrated significantly longer progression-free survival compared with a standard TKI, lapatinib. The phase 3 PHOEBE trial results, published in The Lancet in early 2021, found a median progression-free survival of 12.5 months in patients randomly assigned to receive pyrotinib plus capecitabine compared with 6.8 months in those receiving lapatinib plus capecitabine. The investigators also reported “manageable toxicity”; diarrhea was the most common grade 3 adverse event, occurring in 31% of the pyrotinib group vs. 8% of the lapatinib group, and overall serious adverse events occurred in 10% of patients receiving pyrotinib vs. 8% of those receiving lapatinib.

More recent data on pyrotinib come from the phase 2 PERMEATE trial, which focused on the safety and efficacy of the agent in patients with advanced disease and brain metastases. The investigators, who presented their findings at the 2021 virtual ASCO meeting (abstract 1037), reported that radiation therapy–naive patients receiving pyrotinib plus capecitabine had an overall response rate of 74.6% in the central nervous system. Patients experiencing progression after whole-brain or stereotactic radiation therapy, however, had a comparatively lower overall response rate of 42.1%.

Similarly, median progression-free survival was much higher in the radiation therapy–naive patients (12.1 vs 5.6 months in the radiation therapy cohort). Similar to the PHOEBE trial, the most common grade 3 adverse event was diarrhea (23.1%), followed by decreased neutrophil and white blood cell counts (12.8% for both), anemia (9%), and hand-foot syndrome (7.7%). The main question for Dr. Kalinsky is how well pyrotinib will ultimately stack up to tucatinib and neratinib. “Pyrotinib — like neratinib — was shown to be superior to lapatinib plus capecitabine , but its role may be limited by its gastrointestinal toxicity,” he said. In addition to research focused on expanding the selection of novel ADCs and TKIs, researchers are also exploring new combinations of approved treatments and whether these combinations can be used earlier in treatment sequencing.

Take the CompassHER2 trials. The ongoing phase 3 trial in patients with high-risk HER2-positive breast cancer and residual disease will explore whether tucatinib plus T-DM1 compared with T-DM1 alone improves overall survival and recurrence-free survival and prevents brain metastases. Another possibility currently under investigation is pairing tucatinib and trastuzumab deruxtecan, instead of T-DM1. “Overall, it’s exciting that we are increasing the number of therapeutic options and combinations,” commented Debu Tripathy, MD, professor and chairman in the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston. “Having more choices allows us to tailor therapies to manage resistance and prolong patients’ responses.”

Curbing brain metastasis, according to Dr. Brufksy, is particularly important, and experts need to explore the extent to which ADCs can penetrate the blood-brain barrier. Already, a subgroup analysis of the DESTINY-Breast01 trial found that trastuzumab deruxtecan appeared to be active in patients with brain metastases. Investigators reported an overall response rate of 58.3% and a median progression-free survival of 18.1 months — results in line with those in the general study cohort — but the study population did not include patients with untreated or progressive brain metastases. A phase 2 study currently under way will examine whether patients with HER2-positive and HER2-low breast cancer who have untreated or progressive brain metastases respond to trastuzumab deruxtecan as well. Ultimately, Dr. Brufksy hopes the recent successes with preventing brain metastases in pediatric acute lymphoblastic leukemia (ALL) foreshadow what›s to come in HER2-positive MBC.

“When we figured out how to treat brain metastases prophylactically in childhood ALL, we saw a huge improvement in the cure rate, which is ultimately my vision for HER2-positive disease,” Dr. Brufsky remarked. “Are there cures for HER2-positive MBC on the horizon? We don’t know yet, but the field has really exploded in recent years.”

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

This month’s round up of clinical studies is a fitting end to 2021 – they provide a close look at the intersection between pancreatic pathology and SARS CoV-2 infection.  The first study, out of the UK, speculated that SARS CoV-2 virus may be associated with development of idiopathic pancreatitis.¹  They followed 1,476 patients with acute pancreatitis for 12 months (118 of whom were positive for SARS CoV-2, and 1,358 of whom were negative for the virus).  The patients underwent magnetic resonance cholangiopancreatography, endoscopic ultrasound, or biochemical investigations to exclude other causes of pancreatitis.  Remarkably, as the paper states, “Patients who were SARS-CoV-2 positive were more likely to have idiopathic acute pancreatitis (AP, 34.7% vs 13.9%, P < .001) with over five times increased risk after adjusting for age, smoking status, body mass index and ethnicity (odds ration [OR] 5.34, P < .001).”  

Secondarily, the authors aimed to determine if SARS CoV-2 infection would increase risk for diabetes mellitus (DM) and pancreatic exocrine insufficiency (PEI).  Notably, SARS-CoV-2 did not increase the risk of DM (2.3% vs 2.5%, OR 0.61, P = .541) or PEI (OR 1.11, P = .828) (P > .05).  The relationship between pancreatitis and SARS CoV-2 infection is indeed an important one – the authors point out that autopsy studies have demonstrated the presence of virus in pancreatic tissue.  There is clear mechanistic reason for trophism as ACE 2 receptors are found on exocrine and endocrine cells of the pancreas.  

Another study, out of Hubei Province, China, looked at the association of elevated serum amylase (ESA) with mortality and other adverse outcomes  in hospitalized patients with COVID-19.²  Their retrospective study included 1,515 inpatients with COVID-19.  Overall, 196 patients had ESA, of which 9.7% had an ESA of >3 times the upper limit of normal (ULN).  Somewhat not unexpectedly, hyperamylasemia was independently associated with mortality (1-3-times ULN [1-3 ULN]: hazard ratio [HR] 1.63; P = .034; >3-fold ULN [>3 ULN]: HR 8.90; P < .001) and adverse outcomes, such as sepsis (1-3 ULN: odds ratio [OR] 1.15; >3 ULN: OR 1.87), disseminated intravascular coagulation (1-3 ULN: OR 1.13; >3 ULN: OR 1.65), cardiac injury (1-3 ULN: OR 1.24; >3 ULN: OR 1.71), acute respiratory distress syndrome (1-3 ULN: OR 1.21; >3 ULN: OR 1.62), and acute kidney injury (1-3 ULN: OR 1.24; >3 ULN: OR 1.79).  The authors conclude that, “​​Since early intervention might change the outcome, serum amylase should be monitored dynamically during hospitalization.”  It appears to be unclear what would be practice changing, assuming patients would already be receiving appropriate resuscitation.  

More interesting, perhaps, is the question of whether or not the pancreas is merely a bystander casualty or an active protagonist in the role of sepsis and disease severity in highly morbid diseases, such as COVID-19.  

References

1.           Nayar M et al. SARS-CoV-2 infection is associated with an increased risk of idiopathic acute pancreatitis but not pancreatic exocrine insufficiency or diabetes: long-term results of the COVIDPAN study. Gut 2021(Nov 11).

2.           Li G et al. Serum amylase elevation is associated with adverse clinical outcomes in patients with coronavirus disease 2019. Aging (Albany NY) 2021;13(20):23442–58 (Oct 2021).

This month’s round up of clinical studies is a fitting end to 2021 – they provide a close look at the intersection between pancreatic pathology and SARS CoV-2 infection.  The first study, out of the UK, speculated that SARS CoV-2 virus may be associated with development of idiopathic pancreatitis.¹  They followed 1,476 patients with acute pancreatitis for 12 months (118 of whom were positive for SARS CoV-2, and 1,358 of whom were negative for the virus).  The patients underwent magnetic resonance cholangiopancreatography, endoscopic ultrasound, or biochemical investigations to exclude other causes of pancreatitis.  Remarkably, as the paper states, “Patients who were SARS-CoV-2 positive were more likely to have idiopathic acute pancreatitis (AP, 34.7% vs 13.9%, P < .001) with over five times increased risk after adjusting for age, smoking status, body mass index and ethnicity (odds ration [OR] 5.34, P < .001).”  

Secondarily, the authors aimed to determine if SARS CoV-2 infection would increase risk for diabetes mellitus (DM) and pancreatic exocrine insufficiency (PEI).  Notably, SARS-CoV-2 did not increase the risk of DM (2.3% vs 2.5%, OR 0.61, P = .541) or PEI (OR 1.11, P = .828) (P > .05).  The relationship between pancreatitis and SARS CoV-2 infection is indeed an important one – the authors point out that autopsy studies have demonstrated the presence of virus in pancreatic tissue.  There is clear mechanistic reason for trophism as ACE 2 receptors are found on exocrine and endocrine cells of the pancreas.  

Another study, out of Hubei Province, China, looked at the association of elevated serum amylase (ESA) with mortality and other adverse outcomes  in hospitalized patients with COVID-19.²  Their retrospective study included 1,515 inpatients with COVID-19.  Overall, 196 patients had ESA, of which 9.7% had an ESA of >3 times the upper limit of normal (ULN).  Somewhat not unexpectedly, hyperamylasemia was independently associated with mortality (1-3-times ULN [1-3 ULN]: hazard ratio [HR] 1.63; P = .034; >3-fold ULN [>3 ULN]: HR 8.90; P < .001) and adverse outcomes, such as sepsis (1-3 ULN: odds ratio [OR] 1.15; >3 ULN: OR 1.87), disseminated intravascular coagulation (1-3 ULN: OR 1.13; >3 ULN: OR 1.65), cardiac injury (1-3 ULN: OR 1.24; >3 ULN: OR 1.71), acute respiratory distress syndrome (1-3 ULN: OR 1.21; >3 ULN: OR 1.62), and acute kidney injury (1-3 ULN: OR 1.24; >3 ULN: OR 1.79).  The authors conclude that, “​​Since early intervention might change the outcome, serum amylase should be monitored dynamically during hospitalization.”  It appears to be unclear what would be practice changing, assuming patients would already be receiving appropriate resuscitation.  

More interesting, perhaps, is the question of whether or not the pancreas is merely a bystander casualty or an active protagonist in the role of sepsis and disease severity in highly morbid diseases, such as COVID-19.  

References

1.           Nayar M et al. SARS-CoV-2 infection is associated with an increased risk of idiopathic acute pancreatitis but not pancreatic exocrine insufficiency or diabetes: long-term results of the COVIDPAN study. Gut 2021(Nov 11).

2.           Li G et al. Serum amylase elevation is associated with adverse clinical outcomes in patients with coronavirus disease 2019. Aging (Albany NY) 2021;13(20):23442–58 (Oct 2021).

This month’s round up of clinical studies is a fitting end to 2021 – they provide a close look at the intersection between pancreatic pathology and SARS CoV-2 infection.  The first study, out of the UK, speculated that SARS CoV-2 virus may be associated with development of idiopathic pancreatitis.¹  They followed 1,476 patients with acute pancreatitis for 12 months (118 of whom were positive for SARS CoV-2, and 1,358 of whom were negative for the virus).  The patients underwent magnetic resonance cholangiopancreatography, endoscopic ultrasound, or biochemical investigations to exclude other causes of pancreatitis.  Remarkably, as the paper states, “Patients who were SARS-CoV-2 positive were more likely to have idiopathic acute pancreatitis (AP, 34.7% vs 13.9%, P < .001) with over five times increased risk after adjusting for age, smoking status, body mass index and ethnicity (odds ration [OR] 5.34, P < .001).”  

Secondarily, the authors aimed to determine if SARS CoV-2 infection would increase risk for diabetes mellitus (DM) and pancreatic exocrine insufficiency (PEI).  Notably, SARS-CoV-2 did not increase the risk of DM (2.3% vs 2.5%, OR 0.61, P = .541) or PEI (OR 1.11, P = .828) (P > .05).  The relationship between pancreatitis and SARS CoV-2 infection is indeed an important one – the authors point out that autopsy studies have demonstrated the presence of virus in pancreatic tissue.  There is clear mechanistic reason for trophism as ACE 2 receptors are found on exocrine and endocrine cells of the pancreas.  

Another study, out of Hubei Province, China, looked at the association of elevated serum amylase (ESA) with mortality and other adverse outcomes  in hospitalized patients with COVID-19.²  Their retrospective study included 1,515 inpatients with COVID-19.  Overall, 196 patients had ESA, of which 9.7% had an ESA of >3 times the upper limit of normal (ULN).  Somewhat not unexpectedly, hyperamylasemia was independently associated with mortality (1-3-times ULN [1-3 ULN]: hazard ratio [HR] 1.63; P = .034; >3-fold ULN [>3 ULN]: HR 8.90; P < .001) and adverse outcomes, such as sepsis (1-3 ULN: odds ratio [OR] 1.15; >3 ULN: OR 1.87), disseminated intravascular coagulation (1-3 ULN: OR 1.13; >3 ULN: OR 1.65), cardiac injury (1-3 ULN: OR 1.24; >3 ULN: OR 1.71), acute respiratory distress syndrome (1-3 ULN: OR 1.21; >3 ULN: OR 1.62), and acute kidney injury (1-3 ULN: OR 1.24; >3 ULN: OR 1.79).  The authors conclude that, “​​Since early intervention might change the outcome, serum amylase should be monitored dynamically during hospitalization.”  It appears to be unclear what would be practice changing, assuming patients would already be receiving appropriate resuscitation.  

More interesting, perhaps, is the question of whether or not the pancreas is merely a bystander casualty or an active protagonist in the role of sepsis and disease severity in highly morbid diseases, such as COVID-19.  

References

1.           Nayar M et al. SARS-CoV-2 infection is associated with an increased risk of idiopathic acute pancreatitis but not pancreatic exocrine insufficiency or diabetes: long-term results of the COVIDPAN study. Gut 2021(Nov 11).

2.           Li G et al. Serum amylase elevation is associated with adverse clinical outcomes in patients with coronavirus disease 2019. Aging (Albany NY) 2021;13(20):23442–58 (Oct 2021).

Lower urinary tract symptoms (LUTS)are common and tend to increase in frequency with age. Managing LUTS can be complicated, requires an informed discussion between the primary care practitioner (PCP) and patient, and is best achieved by a thorough understanding of the many medical and surgical options available. Over the past 3 decades, medications have become the most common therapy; but recently, newer minimally invasive surgeries have challenged this paradigm. This article provides a comprehensive review for PCPs regarding the evaluation and management of LUTS in men and when to consider a urology referral.

Benign prostatic hyperplasia (BPH) and LUTS are common clinical encounters for most PCPs. About 50% of men will develop LUTS associated with BPH, and symptoms associated with these conditions increase as men age.^1,2 Studies have estimated that 90% of men aged 45 to 80 years demonstrate some symptoms of LUTS.³ Strong genetic influence seems to suggest heritability, but BPH also occurs in sporadic forms and is heavily influenced by androgens.⁴

BPH is a histologic diagnosis, whereas LUTS consists of complex symptomatology related to both static or dynamic components.¹ The enlarged prostate gland obstructs the urethra, simultaneously causing an increase in muscle tone and resistance at the bladder neck and prostatic urethra, leading to increased resistance to urine flow. As a result, there is a thickening of the detrusor muscles in the bladder wall and an overall decreased compliance. Urine becomes stored under increased pressure. These changes result in a weak or intermittent urine stream, incomplete emptying of the bladder, postvoid dribble, hesitancy, and irritative symptoms, such as urgency, frequency, and nocturia.

For many patients, BPH associated with LUTS is a quality of life (QOL) issue. The stigma associated with these symptoms often leads to delays in patients seeking care. Many patients do not seek treatment until symptoms have become so severe that changes in bladder health are often irreversible. Early intervention can dramatically improve a patient’s QOL. Also, early intervention has the potential to reduce overall health care expenditures. BPH-related spending exceeds $1 billion each year in the Medicare program alone.⁵

PCPs are in a unique position to help many patients who present with early-stage LUTS. Given the substantial impact this disease has on QOL, early recognition of symptoms and prompt treatment play a major role. Paramount to this effort is awareness and understanding of various treatments, their advantages, and adverse effects (AEs). This article highlights evidence-based evaluation and treatment of BPH/LUTS for PCPs who treat veterans and recommendations as to when to refer a patient to a urologist.

Evaluation of LUTS and BPH

Evaluation begins with a thorough medical history and physical examination. Particular attention should focus on ruling out other causes of LUTS, such as a urinary tract infection (UTI), acute prostatitis, malignancy, bladder dysfunction, neurogenic bladder, and other obstructive pathology, such as urethral stricture disease. The differential diagnosis of LUTS includes BPH, UTI, bladder neck obstruction, urethral stricture, bladder stones, polydipsia, overactive bladder (OAB), nocturnal polyuria, neurologic disease, genitourinary malignancy, renal failure, and acute/chronic urinary retention.⁶

Relevant medical history influencing urinary symptoms includes diabetes mellitus, underlying neurologic diseases, previous trauma, sexually transmitted infections, and certain medications. Symptom severity may be obtained using a validated questionnaire, such as the International Prostate Symptom Score (IPSS), which also aids clinicians in assessing the impact of LUTS on QOL. Additionally, urinary frequency or volume records (voiding diary) may help establish the severity of the patient’s symptoms and provide insight into other potential causes for LUTS. Patients with BPH often have concurrent erectile dysfunction (ED) or other sexual dysfunction symptoms. Patients should be evaluated for baseline sexual dysfunction before the initiation of treatment as many therapies worsen symptoms of ED or ejaculatory dysfunction.

A comprehensive physical examination with a focus on the genitourinary system should, at minimum, assess for abnormalities of the urethral meatus, prepuce, penis, groin nodes, and prior surgical scars. A digital rectal examination also should be performed. Although controversial, a digital rectal examination for prostate cancer screening may provide a rough estimate of prostate size, help rule out prostatitis, and detect incident prostate nodules. Prostate size does not necessarily correlate well with the degree of urinary obstruction or LUTS but is an important consideration when deciding among different therapies.¹

Laboratory and Adjunctive Tests

A urinalysis with microscopy helps identify other potential causes for urinary symptoms, including infection, proteinuria, or glucosuria. In patients who present with gross or microscopic hematuria, additional consideration should be given to bladder calculi and genitourinary cancer.² When a reversible source for the hematuria is not identified, these patients require referral to a urologist for a hematuria evaluation.

There is some controversy regarding prostate specific antigen (PSA) testing. Most professional organizations advocate for a shared decision-making approach before testing. The American Cancer Society recommends this informed discussion occur between the patient and the PCP for men aged > 50 years at average risk, men aged > 45 years at high risk of developing prostate cancer (African Americans or first-degree relative with early prostate cancer diagnosis), and aged 40 years for men with more than one first-degree relative with an early prostate cancer diagnosis.⁷

Adjunctive tests include postvoid residual (PVR), cystoscopy, uroflowmetry, urodynamics, and transrectal ultrasound. However, these are mostly performed by urologists. In some patients with bladder decompensation after prolonged partial bladder outlet obstruction, urodynamics may be used by urologists to determine whether a patient may benefit from an outlet obstruction procedure. Ordering additional imaging or serum studies for the assessment of LUTS is rarely helpful.

Treatment

Treatment includes management with or without lifestyle modification, medication administration, and surgical therapy. New to this paradigm are in-office minimally invasive surgical options. The goal of treatment is not only to reduce patient symptoms and improve QOL, but also to prevent the secondary sequala of urinary retention, bladder failure, and eventual renal impairment.⁷A basic understanding of these treatments can aid PCPs with appropriate patient counseling and urologic referral.⁸

Lifestyle and Behavior Modification

Behavior modification is the starting point for all patients with LUTS. Lifestyle modifications for LUTS include avoiding substances that exacerbate symptoms, such as α-agonists (decongestants), caffeine, alcohol, spicy/acidic foods, chocolate, and soda. These substances are known to be bladder irritants. Common medications contributing to LUTS include antidepressants, decongestants, antihistamines, bronchodilators, anticholinergics, and sympathomimetics. To decrease nocturia, behavioral modifications include limiting evening fluid intake, timed diuretic administration for patients already on a diuretic, and elevating legs 1 hour before bedtime. Counseling obese patients to lose weight and increasing physical activity have been linked to reduced LUTS.⁹ Other behavioral techniques include double voiding: a technique where patients void normally then change positions and return to void to empty the bladder. Another technique is timed voiding: Many patients have impaired sensation when the bladder is full. These patients are encouraged to void at regular intervals.

Complementary and Alternative Medicine

Multiple nutraceutical compounds claim improved urinary health and symptom reduction. These compounds are marketed to patients with little regulation and oversight since supplements are not regulated or held to the same standard as prescription medications. The most popular nutraceutical for prostate health and LUTS is saw palmetto. Despite its common usage for the treatment of LUTS, little data support saw palmetto health claims. In 2012, a systematic review of 32 randomized trials including 5666 patients compared saw palmetto with a placebo. The study found no difference in urinary symptom scores, urinary flow, or prostate size.^10,11 Other phytotherapy compounds often considered for urinary symptoms include stinging nettle extract and β-sitosterol compounds. The mechanism of action of these agents is unknown and efficacy data are lacking.

Historically, acupuncture and pelvic floor physical therapy have been used successfully for OAB symptoms. A meta-analysis found positive beneficial effects of acupuncture compared with a sham control for short- and medium-term follow-up in both IPSS and urine flow rates in some studies; however, when combining the studies for more statistical power, the benefits were less clear.¹² Physical therapists with specialized training and certification in pelvic health can incorporate certain bladder training techniques. These include voiding positional changes (double voiding and postvoid urethral milking) and timed voiding.^13,14 These interventions often address etiologies of LUTS for which medical therapies are not effective as the sole treatment option.

Medication Management

Medical management includes α-blockers, 5-α-reductase inhibitors (5-α-RIs), antimuscarinic or anticholinergic medicines, β-3 agonists, and phosphodiesterase inhibitors (Table). These medications work independently as well as synergistically. The use of medications to improve symptoms must be balanced against potential AEs and the consequences of a lifetime of drug usage, which can be additive.^15,16

First-line pharmacological therapy for BPH is α-blockers, which work by blocking α1A receptors in the prostate and bladder neck, leading to smooth muscle relaxation, increased diameter of the channel, and improved urinary flow. α-receptors in the bladder neck and prostate are expressed with increased frequency with age and are a potential cause for worsening symptoms as men age. Studies demonstrate that these medications reduce symptoms by 30 to 40% and increase flow rates by 16 to 25%.¹⁷ Commonly prescribed α-blockers include tamsulosin, alfuzosin, silodosin, doxazosin, and terazosin. Doxazosin and terazosin require dose titrations because they may cause significant hypotension. Orthostatic hypotension typically improves with time and is avoided if the patient takes the medication at bedtime. Both doxazosin and terazosin are on the American Geriatric Society’s Beers Criteria list and should be avoided in older patients.¹⁸ Tamsulosin, alfuzosin, and silodosin have a standardized dosing regimen and lower rates of hypotension. Significant AEs include ejaculation dysfunction, nasal congestion, and orthostatic hypotension. Duan and colleagues have linked tamsulosin with dementia. However, this association is not causal and further studies are necessary.^19,20 Patients who have taken these agents also are at risk for intraoperative floppy iris syndrome (IFIS). Permanent visual problems can arise if the intraoperative management is not managed to account for IFIS. These medications have a rapid onset of action and work immediately. However, to reach maximum benefit, patients must take the medication for several weeks. Unfortunately, up to one-third of patients will have no improvement with α-blocker therapy, and many patients will discontinue these medications because of significant AEs.^6,21

5-α-RIs (finasteride and dutasteride) inhibit the conversion of testosterone to more potent dihydrotestosterone. They effectively reduce prostate volume by 25 to 30%.²² The results occur slowly and can take 6 to 12 months to reach the desired outcome. These medications are effective in men with larger prostates and not as effective in men with smaller prostates.²³ These medications can improve urinary flow rates by about 10%, reduce IPSS scores by 20 to 30%, reduce the risk of urinary retention by 50%, and reduce the progression of BPH to the point where surgery is required by 50%.²⁴ Furthermore, 5-α-RIs lower PSA by > 50% after 12 months of treatment.²⁵

A baseline PSA should be established before administration and after 6 months of treatment. Any increase in the PSA even if the level is within normal limits should be evaluated for prostate cancer. Sarkar and colleagues recently published a study evaluating prostate cancer diagnosis in patients treated with 5-α-RI and found there was a delay in diagnosing prostate cancer in this population. Controversy also exists as to the potential of these medications increasing the risk for high-grade prostate cancer, which has led to a US Food and Drug Administration (FDA) warning. AEs include decreased libido (1.5%), ejaculatory dysfunction (3.4%), gynecomastia (1.3%), and/or ED (1.6%).^26-28 A recent study evaluating 5-α-RIs demonstrated about a 2-fold increased risk of depression.²⁹

There are well-established studies that note increased effectiveness when using combined α-blocker therapy with 5-α-RI medications. The Medical Therapy of Prostate Symptoms (MTOPS) and Combination Avodart and Tamsulosin (CombAT) trials showed that the combination of both medications was more effective in improving voiding symptoms and flow rates than either agent alone.^15,16 Combination therapy resulted in a 66% reduction in disease progression, 81% reduction in urinary retention, and a 67% reduction in the need for surgery compared with placebo.

Anticholinergic medication use in BPH with LUTS is well established, and their use is often combined with other therapies. Anticholinergics work by inhibiting muscarinic M3 receptors to reduce detrusor muscle contraction. This effectively decreases bladder contractions and delays the desire to void. Kaplan and colleagues showed that tolterodine significantly improved a patient’s QOL when added to α-blocker therapy.³⁰ Patients reported a positive outcome at 12 weeks, which resulted in a reduction in urgency incontinence, urgency, nocturia, and the overall number of voiding episodes within 24 hours.

β-3 agonists are a class of medications for OAB; mirabegron and vibegron have proven effective in reducing similar symptoms. In phase 3 clinical trials, mirabegron improved urinary incontinence episodes by 50% and reduced the number of voids in 24 hours.³¹ Mirabegron is well tolerated and avoids many common anticholinergic effects.³² Vibegron is the newest medication in the class and could soon become the preferred agent given it does not have cytochrome P450 interactions and does not cause hypertension like mirabegron.³³

Anticholinergics should be used with caution in patients with a history of urinary retention, elevated after-void residual, or other medications with known anticholinergic effects. AEs include sedation, confusion, dry mouth, constipation, and potential falls in older patients.¹⁸ Recent studies have noted an association with dementia in the prolonged use of these medications in older patients and should be used cautiously.²⁰

Phosphodiesterase-5 enzyme inhibitors (PDE-5) are adjunctive medications shown to improve LUTS. This class of medication is prescribed mostly for ED. However, tadalafil 5 mg taken daily also is FDA approved for the treatment of LUTS secondary to BPH given its prolonged half-life. The exact mechanism for improved BPH symptoms is unknown. Possibly the effects are due to an increase mediated by PDE-5 in cyclic guanosine monophosphate (cGMP), which increases smooth muscle relaxation and tissue perfusion of the prostate and bladder.³⁴ There have been limited studies on objective improvement in uroflowmetry parameters compared with other treatments. The daily dosing of tadalafil should not be prescribed in men with a creatinine clearance < 30 mL/min.²⁹ Tadalafil is not considered a first-line agent and is usually reserved for patients who experience ED in addition to BPH. When initiating BPH pharmacologic therapy, the PCP should be aware of adherence and high discontinuation rates.³⁵

Surgical Treatments

Surgical treatments are often delayed out of fear of potential AEs or considered a last resort when symptoms are too severe.³⁶ Early intervention is required to prevent irreversible deleterious changes to detrusor muscle structure and function (Figure). Patients fear urinary incontinence, ED or ejaculatory dysfunction, and anesthesia complications associated with surgical interventions.^6,37 Multiple studies show that patients fare better with early surgical intervention, experiencing improved IPSS scores, urinary flow, and QOL. The following is an overview of the most popular procedures.

Prostatic urethral lift (PUL) using the UroLift System is an FDA-approved, minimally-invasive treatment of LUTS secondary to BPH. This procedure treats prostates < 80 g with an absent median lobe.^6,21,38 Permanent implants are placed per the prostatic urethra to displace obstructing prostate tissue laterally. This opens the urethra directly without cutting, heating, or removing any prostate tissue. This procedure is minimally invasive, often done in the office as an outpatient procedure, and offers better symptom relief than medication with a lower risk profile than transurethral resection of the prostate (TURP).^39,40 The LIFT study was a multicenter, randomized, blinded trial; patients were randomized 2:1 to undergo UroLift or a sham operation. At 3 years, average improvements were statistically significant for total IPSS reduction (41%), QOL improvement (49%), and improved maximum flow rates by (51%).⁴¹ Risk for urinary incontinence is low, and the procedure has been shown to preserve erectile and ejaculatory function. Furthermore, patients report significant improvement in their QOL without the need for medications. Surgical retreatment rates at 5 years are 13.6%, with an additional 10.7% of subjects back on medication therapy with α-blockers or 5-α-RIs.⁴²

Water vapor thermal therapy or Rez¯um uses steam as thermal energy to destroy obstructing prostate tissue and relieve the obstruction.⁴³ The procedure differs from older conductive heat thermotherapies because the steam penetrates prostate zonal anatomy without affecting areas outside the targeted treatment zone. The procedure is done in the office with local anesthesia and provides long-lasting relief of LUTS with minimal risks. Following the procedure, patients require an indwelling urethral catheter for 3 to 7 days, and most patients begin to experience symptom improvement 2 to 4 weeks following the procedure.⁴⁴ The procedure received FDA approval in 2015. Four-year data show significant improvement in maximal flow rate (50%), IPSS (47%), and QOL (43%).⁴⁵ Surgical retreatment rates were 4.4%. Criticisms of this treatment include patient discomfort with the office procedure, the requirement for an indwelling catheter for a short period, and lack of long-term outcomes data. Guidelines support use in prostate volumes > 80 g with or without median lobe anatomy.

TURP is the gold standard to which other treatments are compared.⁴⁶ The surgery is performed in the operating room where urologists use a rigid cystoscope and resection element to effectively carve out and cauterize obstructing prostate tissue. Patients typically recover for a short period with an indwelling urethral catheter that is often removed 12 to 24 hours after surgery. New research points out that despite increasing mean age (55% of patients are aged > 70 years with associated comorbidities), the morbidity of TURP was < 1% and mortality rate of 0 to 0.3%.⁴⁷ Postoperative complications include bleeding that requires a transfusion (3%), retrograde ejaculation (65%), and rare urinary incontinence (2%).⁴⁷ Surgical retreatment rates for patients following a TURP are approximately 13 to 15% at 8 years.³⁴

Laser surgery for BPH includes multiple techniques: photovaporization of the prostate using a Greenlight XPS laser, holmium laser ablation, and holmium laser enucleation (HoLEP). Proponents of these treatments cite lower bleeding risks compared with TURP, but the operation is largely surgeon dependent on the technology chosen. Most studies comparing these technologies with TURP show similar outcomes of IPSS reports, quality of life improvements, and complications.

Patients with extremely large prostates, > 100 g or 4 times the normal size, pose a unique challenge to surgical treatment. Historically, patients were treated with an open simple prostatectomy operation or staged TURP procedures. Today, urologists use newer, safer ways to treat these patients. Both HoLEP and robot-assisted simple prostatectomy work well in relieving urinary symptoms with lower complications compared with older open surgery. Other minimally invasive procedures, such as prostatic artery embolism, have been described for the treatment of BPH specifically in men who may be unfit for surgery.⁴⁸Future treatments are constantly evolving. Many unanswered questions remain about BPH and the role of inflammation, metabolic dysfunction, obesity, and other genetic factors driving BPH and prostate growth. Pharmaceutical opportunities exist in mechanisms aimed to reduce prostate growth, induce cellular apoptosis, as well as other drugs to reduce bladder symptoms. Newer, minimally invasive therapies also will become more readily available, such as Aquablation, which is the first FDA-granted surgical robot for the autonomous removal of prostatic tissue due to BPH.⁴⁹ However, the goal of all future therapies should include the balance of alleviating disruptive symptoms while demonstrating a favorable risk profile. Many men discontinue taking medications, yet few present for surgery. Most concerning is the significant population of men who will develop irreversible bladder dysfunction while waiting for the perfect treatment. There are many opportunities for an effective treatment that is less invasive than surgery, provides durable relief, has minimal AEs, and is affordable.

Conclusions

There is no perfect treatment for patients with LUTS. All interventions have potential AEs and associated complications. Medications are often started as first-line therapy but are often discontinued at the onset of significant AEs. This process is often repeated. Many patients will try different medications without any significant improvement in their symptoms or short-term relief, which results in the gradual progression of the disease.

The PCP plays a significant role in the initial evaluation and management of BPH. These frontline clinicians can recognize patients who may already be experiencing sequela of prolonged bladder outlet obstruction and refer these men to urologists promptly. Counseling patients about their treatment options is an important duty for all PCPs.

A clear understanding of the available treatment options will help PCPs counsel patients appropriately about lifestyle modification, medications, and surgical treatment options for their symptoms. The treatment of this disorder is a rapidly evolving topic with the constant introduction of new technologies and medications, which are certain to continue to play an important role for PCPs and urologists.

Lower urinary tract symptoms (LUTS)are common and tend to increase in frequency with age. Managing LUTS can be complicated, requires an informed discussion between the primary care practitioner (PCP) and patient, and is best achieved by a thorough understanding of the many medical and surgical options available. Over the past 3 decades, medications have become the most common therapy; but recently, newer minimally invasive surgeries have challenged this paradigm. This article provides a comprehensive review for PCPs regarding the evaluation and management of LUTS in men and when to consider a urology referral.

Benign prostatic hyperplasia (BPH) and LUTS are common clinical encounters for most PCPs. About 50% of men will develop LUTS associated with BPH, and symptoms associated with these conditions increase as men age.^1,2 Studies have estimated that 90% of men aged 45 to 80 years demonstrate some symptoms of LUTS.³ Strong genetic influence seems to suggest heritability, but BPH also occurs in sporadic forms and is heavily influenced by androgens.⁴

BPH is a histologic diagnosis, whereas LUTS consists of complex symptomatology related to both static or dynamic components.¹ The enlarged prostate gland obstructs the urethra, simultaneously causing an increase in muscle tone and resistance at the bladder neck and prostatic urethra, leading to increased resistance to urine flow. As a result, there is a thickening of the detrusor muscles in the bladder wall and an overall decreased compliance. Urine becomes stored under increased pressure. These changes result in a weak or intermittent urine stream, incomplete emptying of the bladder, postvoid dribble, hesitancy, and irritative symptoms, such as urgency, frequency, and nocturia.

For many patients, BPH associated with LUTS is a quality of life (QOL) issue. The stigma associated with these symptoms often leads to delays in patients seeking care. Many patients do not seek treatment until symptoms have become so severe that changes in bladder health are often irreversible. Early intervention can dramatically improve a patient’s QOL. Also, early intervention has the potential to reduce overall health care expenditures. BPH-related spending exceeds $1 billion each year in the Medicare program alone.⁵

PCPs are in a unique position to help many patients who present with early-stage LUTS. Given the substantial impact this disease has on QOL, early recognition of symptoms and prompt treatment play a major role. Paramount to this effort is awareness and understanding of various treatments, their advantages, and adverse effects (AEs). This article highlights evidence-based evaluation and treatment of BPH/LUTS for PCPs who treat veterans and recommendations as to when to refer a patient to a urologist.

Evaluation of LUTS and BPH

Evaluation begins with a thorough medical history and physical examination. Particular attention should focus on ruling out other causes of LUTS, such as a urinary tract infection (UTI), acute prostatitis, malignancy, bladder dysfunction, neurogenic bladder, and other obstructive pathology, such as urethral stricture disease. The differential diagnosis of LUTS includes BPH, UTI, bladder neck obstruction, urethral stricture, bladder stones, polydipsia, overactive bladder (OAB), nocturnal polyuria, neurologic disease, genitourinary malignancy, renal failure, and acute/chronic urinary retention.⁶

Relevant medical history influencing urinary symptoms includes diabetes mellitus, underlying neurologic diseases, previous trauma, sexually transmitted infections, and certain medications. Symptom severity may be obtained using a validated questionnaire, such as the International Prostate Symptom Score (IPSS), which also aids clinicians in assessing the impact of LUTS on QOL. Additionally, urinary frequency or volume records (voiding diary) may help establish the severity of the patient’s symptoms and provide insight into other potential causes for LUTS. Patients with BPH often have concurrent erectile dysfunction (ED) or other sexual dysfunction symptoms. Patients should be evaluated for baseline sexual dysfunction before the initiation of treatment as many therapies worsen symptoms of ED or ejaculatory dysfunction.

A comprehensive physical examination with a focus on the genitourinary system should, at minimum, assess for abnormalities of the urethral meatus, prepuce, penis, groin nodes, and prior surgical scars. A digital rectal examination also should be performed. Although controversial, a digital rectal examination for prostate cancer screening may provide a rough estimate of prostate size, help rule out prostatitis, and detect incident prostate nodules. Prostate size does not necessarily correlate well with the degree of urinary obstruction or LUTS but is an important consideration when deciding among different therapies.¹

Laboratory and Adjunctive Tests

A urinalysis with microscopy helps identify other potential causes for urinary symptoms, including infection, proteinuria, or glucosuria. In patients who present with gross or microscopic hematuria, additional consideration should be given to bladder calculi and genitourinary cancer.² When a reversible source for the hematuria is not identified, these patients require referral to a urologist for a hematuria evaluation.

There is some controversy regarding prostate specific antigen (PSA) testing. Most professional organizations advocate for a shared decision-making approach before testing. The American Cancer Society recommends this informed discussion occur between the patient and the PCP for men aged > 50 years at average risk, men aged > 45 years at high risk of developing prostate cancer (African Americans or first-degree relative with early prostate cancer diagnosis), and aged 40 years for men with more than one first-degree relative with an early prostate cancer diagnosis.⁷

Adjunctive tests include postvoid residual (PVR), cystoscopy, uroflowmetry, urodynamics, and transrectal ultrasound. However, these are mostly performed by urologists. In some patients with bladder decompensation after prolonged partial bladder outlet obstruction, urodynamics may be used by urologists to determine whether a patient may benefit from an outlet obstruction procedure. Ordering additional imaging or serum studies for the assessment of LUTS is rarely helpful.

Treatment

Treatment includes management with or without lifestyle modification, medication administration, and surgical therapy. New to this paradigm are in-office minimally invasive surgical options. The goal of treatment is not only to reduce patient symptoms and improve QOL, but also to prevent the secondary sequala of urinary retention, bladder failure, and eventual renal impairment.⁷A basic understanding of these treatments can aid PCPs with appropriate patient counseling and urologic referral.⁸

Lifestyle and Behavior Modification

Behavior modification is the starting point for all patients with LUTS. Lifestyle modifications for LUTS include avoiding substances that exacerbate symptoms, such as α-agonists (decongestants), caffeine, alcohol, spicy/acidic foods, chocolate, and soda. These substances are known to be bladder irritants. Common medications contributing to LUTS include antidepressants, decongestants, antihistamines, bronchodilators, anticholinergics, and sympathomimetics. To decrease nocturia, behavioral modifications include limiting evening fluid intake, timed diuretic administration for patients already on a diuretic, and elevating legs 1 hour before bedtime. Counseling obese patients to lose weight and increasing physical activity have been linked to reduced LUTS.⁹ Other behavioral techniques include double voiding: a technique where patients void normally then change positions and return to void to empty the bladder. Another technique is timed voiding: Many patients have impaired sensation when the bladder is full. These patients are encouraged to void at regular intervals.

Complementary and Alternative Medicine

Multiple nutraceutical compounds claim improved urinary health and symptom reduction. These compounds are marketed to patients with little regulation and oversight since supplements are not regulated or held to the same standard as prescription medications. The most popular nutraceutical for prostate health and LUTS is saw palmetto. Despite its common usage for the treatment of LUTS, little data support saw palmetto health claims. In 2012, a systematic review of 32 randomized trials including 5666 patients compared saw palmetto with a placebo. The study found no difference in urinary symptom scores, urinary flow, or prostate size.^10,11 Other phytotherapy compounds often considered for urinary symptoms include stinging nettle extract and β-sitosterol compounds. The mechanism of action of these agents is unknown and efficacy data are lacking.

Historically, acupuncture and pelvic floor physical therapy have been used successfully for OAB symptoms. A meta-analysis found positive beneficial effects of acupuncture compared with a sham control for short- and medium-term follow-up in both IPSS and urine flow rates in some studies; however, when combining the studies for more statistical power, the benefits were less clear.¹² Physical therapists with specialized training and certification in pelvic health can incorporate certain bladder training techniques. These include voiding positional changes (double voiding and postvoid urethral milking) and timed voiding.^13,14 These interventions often address etiologies of LUTS for which medical therapies are not effective as the sole treatment option.

Medication Management

Medical management includes α-blockers, 5-α-reductase inhibitors (5-α-RIs), antimuscarinic or anticholinergic medicines, β-3 agonists, and phosphodiesterase inhibitors (Table). These medications work independently as well as synergistically. The use of medications to improve symptoms must be balanced against potential AEs and the consequences of a lifetime of drug usage, which can be additive.^15,16

First-line pharmacological therapy for BPH is α-blockers, which work by blocking α1A receptors in the prostate and bladder neck, leading to smooth muscle relaxation, increased diameter of the channel, and improved urinary flow. α-receptors in the bladder neck and prostate are expressed with increased frequency with age and are a potential cause for worsening symptoms as men age. Studies demonstrate that these medications reduce symptoms by 30 to 40% and increase flow rates by 16 to 25%.¹⁷ Commonly prescribed α-blockers include tamsulosin, alfuzosin, silodosin, doxazosin, and terazosin. Doxazosin and terazosin require dose titrations because they may cause significant hypotension. Orthostatic hypotension typically improves with time and is avoided if the patient takes the medication at bedtime. Both doxazosin and terazosin are on the American Geriatric Society’s Beers Criteria list and should be avoided in older patients.¹⁸ Tamsulosin, alfuzosin, and silodosin have a standardized dosing regimen and lower rates of hypotension. Significant AEs include ejaculation dysfunction, nasal congestion, and orthostatic hypotension. Duan and colleagues have linked tamsulosin with dementia. However, this association is not causal and further studies are necessary.^19,20 Patients who have taken these agents also are at risk for intraoperative floppy iris syndrome (IFIS). Permanent visual problems can arise if the intraoperative management is not managed to account for IFIS. These medications have a rapid onset of action and work immediately. However, to reach maximum benefit, patients must take the medication for several weeks. Unfortunately, up to one-third of patients will have no improvement with α-blocker therapy, and many patients will discontinue these medications because of significant AEs.^6,21

5-α-RIs (finasteride and dutasteride) inhibit the conversion of testosterone to more potent dihydrotestosterone. They effectively reduce prostate volume by 25 to 30%.²² The results occur slowly and can take 6 to 12 months to reach the desired outcome. These medications are effective in men with larger prostates and not as effective in men with smaller prostates.²³ These medications can improve urinary flow rates by about 10%, reduce IPSS scores by 20 to 30%, reduce the risk of urinary retention by 50%, and reduce the progression of BPH to the point where surgery is required by 50%.²⁴ Furthermore, 5-α-RIs lower PSA by > 50% after 12 months of treatment.²⁵

A baseline PSA should be established before administration and after 6 months of treatment. Any increase in the PSA even if the level is within normal limits should be evaluated for prostate cancer. Sarkar and colleagues recently published a study evaluating prostate cancer diagnosis in patients treated with 5-α-RI and found there was a delay in diagnosing prostate cancer in this population. Controversy also exists as to the potential of these medications increasing the risk for high-grade prostate cancer, which has led to a US Food and Drug Administration (FDA) warning. AEs include decreased libido (1.5%), ejaculatory dysfunction (3.4%), gynecomastia (1.3%), and/or ED (1.6%).^26-28 A recent study evaluating 5-α-RIs demonstrated about a 2-fold increased risk of depression.²⁹

There are well-established studies that note increased effectiveness when using combined α-blocker therapy with 5-α-RI medications. The Medical Therapy of Prostate Symptoms (MTOPS) and Combination Avodart and Tamsulosin (CombAT) trials showed that the combination of both medications was more effective in improving voiding symptoms and flow rates than either agent alone.^15,16 Combination therapy resulted in a 66% reduction in disease progression, 81% reduction in urinary retention, and a 67% reduction in the need for surgery compared with placebo.

Anticholinergic medication use in BPH with LUTS is well established, and their use is often combined with other therapies. Anticholinergics work by inhibiting muscarinic M3 receptors to reduce detrusor muscle contraction. This effectively decreases bladder contractions and delays the desire to void. Kaplan and colleagues showed that tolterodine significantly improved a patient’s QOL when added to α-blocker therapy.³⁰ Patients reported a positive outcome at 12 weeks, which resulted in a reduction in urgency incontinence, urgency, nocturia, and the overall number of voiding episodes within 24 hours.

β-3 agonists are a class of medications for OAB; mirabegron and vibegron have proven effective in reducing similar symptoms. In phase 3 clinical trials, mirabegron improved urinary incontinence episodes by 50% and reduced the number of voids in 24 hours.³¹ Mirabegron is well tolerated and avoids many common anticholinergic effects.³² Vibegron is the newest medication in the class and could soon become the preferred agent given it does not have cytochrome P450 interactions and does not cause hypertension like mirabegron.³³

Anticholinergics should be used with caution in patients with a history of urinary retention, elevated after-void residual, or other medications with known anticholinergic effects. AEs include sedation, confusion, dry mouth, constipation, and potential falls in older patients.¹⁸ Recent studies have noted an association with dementia in the prolonged use of these medications in older patients and should be used cautiously.²⁰

Phosphodiesterase-5 enzyme inhibitors (PDE-5) are adjunctive medications shown to improve LUTS. This class of medication is prescribed mostly for ED. However, tadalafil 5 mg taken daily also is FDA approved for the treatment of LUTS secondary to BPH given its prolonged half-life. The exact mechanism for improved BPH symptoms is unknown. Possibly the effects are due to an increase mediated by PDE-5 in cyclic guanosine monophosphate (cGMP), which increases smooth muscle relaxation and tissue perfusion of the prostate and bladder.³⁴ There have been limited studies on objective improvement in uroflowmetry parameters compared with other treatments. The daily dosing of tadalafil should not be prescribed in men with a creatinine clearance < 30 mL/min.²⁹ Tadalafil is not considered a first-line agent and is usually reserved for patients who experience ED in addition to BPH. When initiating BPH pharmacologic therapy, the PCP should be aware of adherence and high discontinuation rates.³⁵

Surgical Treatments

Surgical treatments are often delayed out of fear of potential AEs or considered a last resort when symptoms are too severe.³⁶ Early intervention is required to prevent irreversible deleterious changes to detrusor muscle structure and function (Figure). Patients fear urinary incontinence, ED or ejaculatory dysfunction, and anesthesia complications associated with surgical interventions.^6,37 Multiple studies show that patients fare better with early surgical intervention, experiencing improved IPSS scores, urinary flow, and QOL. The following is an overview of the most popular procedures.

Prostatic urethral lift (PUL) using the UroLift System is an FDA-approved, minimally-invasive treatment of LUTS secondary to BPH. This procedure treats prostates < 80 g with an absent median lobe.^6,21,38 Permanent implants are placed per the prostatic urethra to displace obstructing prostate tissue laterally. This opens the urethra directly without cutting, heating, or removing any prostate tissue. This procedure is minimally invasive, often done in the office as an outpatient procedure, and offers better symptom relief than medication with a lower risk profile than transurethral resection of the prostate (TURP).^39,40 The LIFT study was a multicenter, randomized, blinded trial; patients were randomized 2:1 to undergo UroLift or a sham operation. At 3 years, average improvements were statistically significant for total IPSS reduction (41%), QOL improvement (49%), and improved maximum flow rates by (51%).⁴¹ Risk for urinary incontinence is low, and the procedure has been shown to preserve erectile and ejaculatory function. Furthermore, patients report significant improvement in their QOL without the need for medications. Surgical retreatment rates at 5 years are 13.6%, with an additional 10.7% of subjects back on medication therapy with α-blockers or 5-α-RIs.⁴²

Water vapor thermal therapy or Rez¯um uses steam as thermal energy to destroy obstructing prostate tissue and relieve the obstruction.⁴³ The procedure differs from older conductive heat thermotherapies because the steam penetrates prostate zonal anatomy without affecting areas outside the targeted treatment zone. The procedure is done in the office with local anesthesia and provides long-lasting relief of LUTS with minimal risks. Following the procedure, patients require an indwelling urethral catheter for 3 to 7 days, and most patients begin to experience symptom improvement 2 to 4 weeks following the procedure.⁴⁴ The procedure received FDA approval in 2015. Four-year data show significant improvement in maximal flow rate (50%), IPSS (47%), and QOL (43%).⁴⁵ Surgical retreatment rates were 4.4%. Criticisms of this treatment include patient discomfort with the office procedure, the requirement for an indwelling catheter for a short period, and lack of long-term outcomes data. Guidelines support use in prostate volumes > 80 g with or without median lobe anatomy.

TURP is the gold standard to which other treatments are compared.⁴⁶ The surgery is performed in the operating room where urologists use a rigid cystoscope and resection element to effectively carve out and cauterize obstructing prostate tissue. Patients typically recover for a short period with an indwelling urethral catheter that is often removed 12 to 24 hours after surgery. New research points out that despite increasing mean age (55% of patients are aged > 70 years with associated comorbidities), the morbidity of TURP was < 1% and mortality rate of 0 to 0.3%.⁴⁷ Postoperative complications include bleeding that requires a transfusion (3%), retrograde ejaculation (65%), and rare urinary incontinence (2%).⁴⁷ Surgical retreatment rates for patients following a TURP are approximately 13 to 15% at 8 years.³⁴

Laser surgery for BPH includes multiple techniques: photovaporization of the prostate using a Greenlight XPS laser, holmium laser ablation, and holmium laser enucleation (HoLEP). Proponents of these treatments cite lower bleeding risks compared with TURP, but the operation is largely surgeon dependent on the technology chosen. Most studies comparing these technologies with TURP show similar outcomes of IPSS reports, quality of life improvements, and complications.

Patients with extremely large prostates, > 100 g or 4 times the normal size, pose a unique challenge to surgical treatment. Historically, patients were treated with an open simple prostatectomy operation or staged TURP procedures. Today, urologists use newer, safer ways to treat these patients. Both HoLEP and robot-assisted simple prostatectomy work well in relieving urinary symptoms with lower complications compared with older open surgery. Other minimally invasive procedures, such as prostatic artery embolism, have been described for the treatment of BPH specifically in men who may be unfit for surgery.⁴⁸Future treatments are constantly evolving. Many unanswered questions remain about BPH and the role of inflammation, metabolic dysfunction, obesity, and other genetic factors driving BPH and prostate growth. Pharmaceutical opportunities exist in mechanisms aimed to reduce prostate growth, induce cellular apoptosis, as well as other drugs to reduce bladder symptoms. Newer, minimally invasive therapies also will become more readily available, such as Aquablation, which is the first FDA-granted surgical robot for the autonomous removal of prostatic tissue due to BPH.⁴⁹ However, the goal of all future therapies should include the balance of alleviating disruptive symptoms while demonstrating a favorable risk profile. Many men discontinue taking medications, yet few present for surgery. Most concerning is the significant population of men who will develop irreversible bladder dysfunction while waiting for the perfect treatment. There are many opportunities for an effective treatment that is less invasive than surgery, provides durable relief, has minimal AEs, and is affordable.

Conclusions

There is no perfect treatment for patients with LUTS. All interventions have potential AEs and associated complications. Medications are often started as first-line therapy but are often discontinued at the onset of significant AEs. This process is often repeated. Many patients will try different medications without any significant improvement in their symptoms or short-term relief, which results in the gradual progression of the disease.

The PCP plays a significant role in the initial evaluation and management of BPH. These frontline clinicians can recognize patients who may already be experiencing sequela of prolonged bladder outlet obstruction and refer these men to urologists promptly. Counseling patients about their treatment options is an important duty for all PCPs.

A clear understanding of the available treatment options will help PCPs counsel patients appropriately about lifestyle modification, medications, and surgical treatment options for their symptoms. The treatment of this disorder is a rapidly evolving topic with the constant introduction of new technologies and medications, which are certain to continue to play an important role for PCPs and urologists.

Lower urinary tract symptoms (LUTS)are common and tend to increase in frequency with age. Managing LUTS can be complicated, requires an informed discussion between the primary care practitioner (PCP) and patient, and is best achieved by a thorough understanding of the many medical and surgical options available. Over the past 3 decades, medications have become the most common therapy; but recently, newer minimally invasive surgeries have challenged this paradigm. This article provides a comprehensive review for PCPs regarding the evaluation and management of LUTS in men and when to consider a urology referral.

Benign prostatic hyperplasia (BPH) and LUTS are common clinical encounters for most PCPs. About 50% of men will develop LUTS associated with BPH, and symptoms associated with these conditions increase as men age.^1,2 Studies have estimated that 90% of men aged 45 to 80 years demonstrate some symptoms of LUTS.³ Strong genetic influence seems to suggest heritability, but BPH also occurs in sporadic forms and is heavily influenced by androgens.⁴

BPH is a histologic diagnosis, whereas LUTS consists of complex symptomatology related to both static or dynamic components.¹ The enlarged prostate gland obstructs the urethra, simultaneously causing an increase in muscle tone and resistance at the bladder neck and prostatic urethra, leading to increased resistance to urine flow. As a result, there is a thickening of the detrusor muscles in the bladder wall and an overall decreased compliance. Urine becomes stored under increased pressure. These changes result in a weak or intermittent urine stream, incomplete emptying of the bladder, postvoid dribble, hesitancy, and irritative symptoms, such as urgency, frequency, and nocturia.

For many patients, BPH associated with LUTS is a quality of life (QOL) issue. The stigma associated with these symptoms often leads to delays in patients seeking care. Many patients do not seek treatment until symptoms have become so severe that changes in bladder health are often irreversible. Early intervention can dramatically improve a patient’s QOL. Also, early intervention has the potential to reduce overall health care expenditures. BPH-related spending exceeds $1 billion each year in the Medicare program alone.⁵

PCPs are in a unique position to help many patients who present with early-stage LUTS. Given the substantial impact this disease has on QOL, early recognition of symptoms and prompt treatment play a major role. Paramount to this effort is awareness and understanding of various treatments, their advantages, and adverse effects (AEs). This article highlights evidence-based evaluation and treatment of BPH/LUTS for PCPs who treat veterans and recommendations as to when to refer a patient to a urologist.

Evaluation of LUTS and BPH

Evaluation begins with a thorough medical history and physical examination. Particular attention should focus on ruling out other causes of LUTS, such as a urinary tract infection (UTI), acute prostatitis, malignancy, bladder dysfunction, neurogenic bladder, and other obstructive pathology, such as urethral stricture disease. The differential diagnosis of LUTS includes BPH, UTI, bladder neck obstruction, urethral stricture, bladder stones, polydipsia, overactive bladder (OAB), nocturnal polyuria, neurologic disease, genitourinary malignancy, renal failure, and acute/chronic urinary retention.⁶

Relevant medical history influencing urinary symptoms includes diabetes mellitus, underlying neurologic diseases, previous trauma, sexually transmitted infections, and certain medications. Symptom severity may be obtained using a validated questionnaire, such as the International Prostate Symptom Score (IPSS), which also aids clinicians in assessing the impact of LUTS on QOL. Additionally, urinary frequency or volume records (voiding diary) may help establish the severity of the patient’s symptoms and provide insight into other potential causes for LUTS. Patients with BPH often have concurrent erectile dysfunction (ED) or other sexual dysfunction symptoms. Patients should be evaluated for baseline sexual dysfunction before the initiation of treatment as many therapies worsen symptoms of ED or ejaculatory dysfunction.

A comprehensive physical examination with a focus on the genitourinary system should, at minimum, assess for abnormalities of the urethral meatus, prepuce, penis, groin nodes, and prior surgical scars. A digital rectal examination also should be performed. Although controversial, a digital rectal examination for prostate cancer screening may provide a rough estimate of prostate size, help rule out prostatitis, and detect incident prostate nodules. Prostate size does not necessarily correlate well with the degree of urinary obstruction or LUTS but is an important consideration when deciding among different therapies.¹

Laboratory and Adjunctive Tests

A urinalysis with microscopy helps identify other potential causes for urinary symptoms, including infection, proteinuria, or glucosuria. In patients who present with gross or microscopic hematuria, additional consideration should be given to bladder calculi and genitourinary cancer.² When a reversible source for the hematuria is not identified, these patients require referral to a urologist for a hematuria evaluation.

There is some controversy regarding prostate specific antigen (PSA) testing. Most professional organizations advocate for a shared decision-making approach before testing. The American Cancer Society recommends this informed discussion occur between the patient and the PCP for men aged > 50 years at average risk, men aged > 45 years at high risk of developing prostate cancer (African Americans or first-degree relative with early prostate cancer diagnosis), and aged 40 years for men with more than one first-degree relative with an early prostate cancer diagnosis.⁷

Adjunctive tests include postvoid residual (PVR), cystoscopy, uroflowmetry, urodynamics, and transrectal ultrasound. However, these are mostly performed by urologists. In some patients with bladder decompensation after prolonged partial bladder outlet obstruction, urodynamics may be used by urologists to determine whether a patient may benefit from an outlet obstruction procedure. Ordering additional imaging or serum studies for the assessment of LUTS is rarely helpful.

Treatment

Treatment includes management with or without lifestyle modification, medication administration, and surgical therapy. New to this paradigm are in-office minimally invasive surgical options. The goal of treatment is not only to reduce patient symptoms and improve QOL, but also to prevent the secondary sequala of urinary retention, bladder failure, and eventual renal impairment.⁷A basic understanding of these treatments can aid PCPs with appropriate patient counseling and urologic referral.⁸

Lifestyle and Behavior Modification

Behavior modification is the starting point for all patients with LUTS. Lifestyle modifications for LUTS include avoiding substances that exacerbate symptoms, such as α-agonists (decongestants), caffeine, alcohol, spicy/acidic foods, chocolate, and soda. These substances are known to be bladder irritants. Common medications contributing to LUTS include antidepressants, decongestants, antihistamines, bronchodilators, anticholinergics, and sympathomimetics. To decrease nocturia, behavioral modifications include limiting evening fluid intake, timed diuretic administration for patients already on a diuretic, and elevating legs 1 hour before bedtime. Counseling obese patients to lose weight and increasing physical activity have been linked to reduced LUTS.⁹ Other behavioral techniques include double voiding: a technique where patients void normally then change positions and return to void to empty the bladder. Another technique is timed voiding: Many patients have impaired sensation when the bladder is full. These patients are encouraged to void at regular intervals.

Complementary and Alternative Medicine

Multiple nutraceutical compounds claim improved urinary health and symptom reduction. These compounds are marketed to patients with little regulation and oversight since supplements are not regulated or held to the same standard as prescription medications. The most popular nutraceutical for prostate health and LUTS is saw palmetto. Despite its common usage for the treatment of LUTS, little data support saw palmetto health claims. In 2012, a systematic review of 32 randomized trials including 5666 patients compared saw palmetto with a placebo. The study found no difference in urinary symptom scores, urinary flow, or prostate size.^10,11 Other phytotherapy compounds often considered for urinary symptoms include stinging nettle extract and β-sitosterol compounds. The mechanism of action of these agents is unknown and efficacy data are lacking.

Historically, acupuncture and pelvic floor physical therapy have been used successfully for OAB symptoms. A meta-analysis found positive beneficial effects of acupuncture compared with a sham control for short- and medium-term follow-up in both IPSS and urine flow rates in some studies; however, when combining the studies for more statistical power, the benefits were less clear.¹² Physical therapists with specialized training and certification in pelvic health can incorporate certain bladder training techniques. These include voiding positional changes (double voiding and postvoid urethral milking) and timed voiding.^13,14 These interventions often address etiologies of LUTS for which medical therapies are not effective as the sole treatment option.

Medication Management

Medical management includes α-blockers, 5-α-reductase inhibitors (5-α-RIs), antimuscarinic or anticholinergic medicines, β-3 agonists, and phosphodiesterase inhibitors (Table). These medications work independently as well as synergistically. The use of medications to improve symptoms must be balanced against potential AEs and the consequences of a lifetime of drug usage, which can be additive.^15,16

First-line pharmacological therapy for BPH is α-blockers, which work by blocking α1A receptors in the prostate and bladder neck, leading to smooth muscle relaxation, increased diameter of the channel, and improved urinary flow. α-receptors in the bladder neck and prostate are expressed with increased frequency with age and are a potential cause for worsening symptoms as men age. Studies demonstrate that these medications reduce symptoms by 30 to 40% and increase flow rates by 16 to 25%.¹⁷ Commonly prescribed α-blockers include tamsulosin, alfuzosin, silodosin, doxazosin, and terazosin. Doxazosin and terazosin require dose titrations because they may cause significant hypotension. Orthostatic hypotension typically improves with time and is avoided if the patient takes the medication at bedtime. Both doxazosin and terazosin are on the American Geriatric Society’s Beers Criteria list and should be avoided in older patients.¹⁸ Tamsulosin, alfuzosin, and silodosin have a standardized dosing regimen and lower rates of hypotension. Significant AEs include ejaculation dysfunction, nasal congestion, and orthostatic hypotension. Duan and colleagues have linked tamsulosin with dementia. However, this association is not causal and further studies are necessary.^19,20 Patients who have taken these agents also are at risk for intraoperative floppy iris syndrome (IFIS). Permanent visual problems can arise if the intraoperative management is not managed to account for IFIS. These medications have a rapid onset of action and work immediately. However, to reach maximum benefit, patients must take the medication for several weeks. Unfortunately, up to one-third of patients will have no improvement with α-blocker therapy, and many patients will discontinue these medications because of significant AEs.^6,21

5-α-RIs (finasteride and dutasteride) inhibit the conversion of testosterone to more potent dihydrotestosterone. They effectively reduce prostate volume by 25 to 30%.²² The results occur slowly and can take 6 to 12 months to reach the desired outcome. These medications are effective in men with larger prostates and not as effective in men with smaller prostates.²³ These medications can improve urinary flow rates by about 10%, reduce IPSS scores by 20 to 30%, reduce the risk of urinary retention by 50%, and reduce the progression of BPH to the point where surgery is required by 50%.²⁴ Furthermore, 5-α-RIs lower PSA by > 50% after 12 months of treatment.²⁵

A baseline PSA should be established before administration and after 6 months of treatment. Any increase in the PSA even if the level is within normal limits should be evaluated for prostate cancer. Sarkar and colleagues recently published a study evaluating prostate cancer diagnosis in patients treated with 5-α-RI and found there was a delay in diagnosing prostate cancer in this population. Controversy also exists as to the potential of these medications increasing the risk for high-grade prostate cancer, which has led to a US Food and Drug Administration (FDA) warning. AEs include decreased libido (1.5%), ejaculatory dysfunction (3.4%), gynecomastia (1.3%), and/or ED (1.6%).^26-28 A recent study evaluating 5-α-RIs demonstrated about a 2-fold increased risk of depression.²⁹

There are well-established studies that note increased effectiveness when using combined α-blocker therapy with 5-α-RI medications. The Medical Therapy of Prostate Symptoms (MTOPS) and Combination Avodart and Tamsulosin (CombAT) trials showed that the combination of both medications was more effective in improving voiding symptoms and flow rates than either agent alone.^15,16 Combination therapy resulted in a 66% reduction in disease progression, 81% reduction in urinary retention, and a 67% reduction in the need for surgery compared with placebo.

Anticholinergic medication use in BPH with LUTS is well established, and their use is often combined with other therapies. Anticholinergics work by inhibiting muscarinic M3 receptors to reduce detrusor muscle contraction. This effectively decreases bladder contractions and delays the desire to void. Kaplan and colleagues showed that tolterodine significantly improved a patient’s QOL when added to α-blocker therapy.³⁰ Patients reported a positive outcome at 12 weeks, which resulted in a reduction in urgency incontinence, urgency, nocturia, and the overall number of voiding episodes within 24 hours.

β-3 agonists are a class of medications for OAB; mirabegron and vibegron have proven effective in reducing similar symptoms. In phase 3 clinical trials, mirabegron improved urinary incontinence episodes by 50% and reduced the number of voids in 24 hours.³¹ Mirabegron is well tolerated and avoids many common anticholinergic effects.³² Vibegron is the newest medication in the class and could soon become the preferred agent given it does not have cytochrome P450 interactions and does not cause hypertension like mirabegron.³³

Anticholinergics should be used with caution in patients with a history of urinary retention, elevated after-void residual, or other medications with known anticholinergic effects. AEs include sedation, confusion, dry mouth, constipation, and potential falls in older patients.¹⁸ Recent studies have noted an association with dementia in the prolonged use of these medications in older patients and should be used cautiously.²⁰

Phosphodiesterase-5 enzyme inhibitors (PDE-5) are adjunctive medications shown to improve LUTS. This class of medication is prescribed mostly for ED. However, tadalafil 5 mg taken daily also is FDA approved for the treatment of LUTS secondary to BPH given its prolonged half-life. The exact mechanism for improved BPH symptoms is unknown. Possibly the effects are due to an increase mediated by PDE-5 in cyclic guanosine monophosphate (cGMP), which increases smooth muscle relaxation and tissue perfusion of the prostate and bladder.³⁴ There have been limited studies on objective improvement in uroflowmetry parameters compared with other treatments. The daily dosing of tadalafil should not be prescribed in men with a creatinine clearance < 30 mL/min.²⁹ Tadalafil is not considered a first-line agent and is usually reserved for patients who experience ED in addition to BPH. When initiating BPH pharmacologic therapy, the PCP should be aware of adherence and high discontinuation rates.³⁵

Surgical Treatments

Surgical treatments are often delayed out of fear of potential AEs or considered a last resort when symptoms are too severe.³⁶ Early intervention is required to prevent irreversible deleterious changes to detrusor muscle structure and function (Figure). Patients fear urinary incontinence, ED or ejaculatory dysfunction, and anesthesia complications associated with surgical interventions.^6,37 Multiple studies show that patients fare better with early surgical intervention, experiencing improved IPSS scores, urinary flow, and QOL. The following is an overview of the most popular procedures.

Prostatic urethral lift (PUL) using the UroLift System is an FDA-approved, minimally-invasive treatment of LUTS secondary to BPH. This procedure treats prostates < 80 g with an absent median lobe.^6,21,38 Permanent implants are placed per the prostatic urethra to displace obstructing prostate tissue laterally. This opens the urethra directly without cutting, heating, or removing any prostate tissue. This procedure is minimally invasive, often done in the office as an outpatient procedure, and offers better symptom relief than medication with a lower risk profile than transurethral resection of the prostate (TURP).^39,40 The LIFT study was a multicenter, randomized, blinded trial; patients were randomized 2:1 to undergo UroLift or a sham operation. At 3 years, average improvements were statistically significant for total IPSS reduction (41%), QOL improvement (49%), and improved maximum flow rates by (51%).⁴¹ Risk for urinary incontinence is low, and the procedure has been shown to preserve erectile and ejaculatory function. Furthermore, patients report significant improvement in their QOL without the need for medications. Surgical retreatment rates at 5 years are 13.6%, with an additional 10.7% of subjects back on medication therapy with α-blockers or 5-α-RIs.⁴²

Water vapor thermal therapy or Rez¯um uses steam as thermal energy to destroy obstructing prostate tissue and relieve the obstruction.⁴³ The procedure differs from older conductive heat thermotherapies because the steam penetrates prostate zonal anatomy without affecting areas outside the targeted treatment zone. The procedure is done in the office with local anesthesia and provides long-lasting relief of LUTS with minimal risks. Following the procedure, patients require an indwelling urethral catheter for 3 to 7 days, and most patients begin to experience symptom improvement 2 to 4 weeks following the procedure.⁴⁴ The procedure received FDA approval in 2015. Four-year data show significant improvement in maximal flow rate (50%), IPSS (47%), and QOL (43%).⁴⁵ Surgical retreatment rates were 4.4%. Criticisms of this treatment include patient discomfort with the office procedure, the requirement for an indwelling catheter for a short period, and lack of long-term outcomes data. Guidelines support use in prostate volumes > 80 g with or without median lobe anatomy.

TURP is the gold standard to which other treatments are compared.⁴⁶ The surgery is performed in the operating room where urologists use a rigid cystoscope and resection element to effectively carve out and cauterize obstructing prostate tissue. Patients typically recover for a short period with an indwelling urethral catheter that is often removed 12 to 24 hours after surgery. New research points out that despite increasing mean age (55% of patients are aged > 70 years with associated comorbidities), the morbidity of TURP was < 1% and mortality rate of 0 to 0.3%.⁴⁷ Postoperative complications include bleeding that requires a transfusion (3%), retrograde ejaculation (65%), and rare urinary incontinence (2%).⁴⁷ Surgical retreatment rates for patients following a TURP are approximately 13 to 15% at 8 years.³⁴

Laser surgery for BPH includes multiple techniques: photovaporization of the prostate using a Greenlight XPS laser, holmium laser ablation, and holmium laser enucleation (HoLEP). Proponents of these treatments cite lower bleeding risks compared with TURP, but the operation is largely surgeon dependent on the technology chosen. Most studies comparing these technologies with TURP show similar outcomes of IPSS reports, quality of life improvements, and complications.

Patients with extremely large prostates, > 100 g or 4 times the normal size, pose a unique challenge to surgical treatment. Historically, patients were treated with an open simple prostatectomy operation or staged TURP procedures. Today, urologists use newer, safer ways to treat these patients. Both HoLEP and robot-assisted simple prostatectomy work well in relieving urinary symptoms with lower complications compared with older open surgery. Other minimally invasive procedures, such as prostatic artery embolism, have been described for the treatment of BPH specifically in men who may be unfit for surgery.⁴⁸Future treatments are constantly evolving. Many unanswered questions remain about BPH and the role of inflammation, metabolic dysfunction, obesity, and other genetic factors driving BPH and prostate growth. Pharmaceutical opportunities exist in mechanisms aimed to reduce prostate growth, induce cellular apoptosis, as well as other drugs to reduce bladder symptoms. Newer, minimally invasive therapies also will become more readily available, such as Aquablation, which is the first FDA-granted surgical robot for the autonomous removal of prostatic tissue due to BPH.⁴⁹ However, the goal of all future therapies should include the balance of alleviating disruptive symptoms while demonstrating a favorable risk profile. Many men discontinue taking medications, yet few present for surgery. Most concerning is the significant population of men who will develop irreversible bladder dysfunction while waiting for the perfect treatment. There are many opportunities for an effective treatment that is less invasive than surgery, provides durable relief, has minimal AEs, and is affordable.

Conclusions

There is no perfect treatment for patients with LUTS. All interventions have potential AEs and associated complications. Medications are often started as first-line therapy but are often discontinued at the onset of significant AEs. This process is often repeated. Many patients will try different medications without any significant improvement in their symptoms or short-term relief, which results in the gradual progression of the disease.

The PCP plays a significant role in the initial evaluation and management of BPH. These frontline clinicians can recognize patients who may already be experiencing sequela of prolonged bladder outlet obstruction and refer these men to urologists promptly. Counseling patients about their treatment options is an important duty for all PCPs.

A clear understanding of the available treatment options will help PCPs counsel patients appropriately about lifestyle modification, medications, and surgical treatment options for their symptoms. The treatment of this disorder is a rapidly evolving topic with the constant introduction of new technologies and medications, which are certain to continue to play an important role for PCPs and urologists.

Narrative competence is the ability to acquire, interpret, and act on the stories of others.¹ Developing this skill through guided medical storytelling can improve health care practitioners’ (HCPs) sense of empathy and satisfaction with their work.² Narrative medicine experiences for medical students can foster a deeper understanding of their patients beyond illness-associated identities.³

Within narrative medicine, the “life story” is a specific technique that allows patients to share experiences through open-ended interviews that are entered into the health record.^4,5 By sharing life stories, patients control a narrative encompassing more than their illness and can reinforce a sense of purpose in their lives.⁶ The US Department of Veterans Affairs (VA) My Life My Story (MLMS) program gives veterans the opportunity to share their narrative with staff and volunteer interviewers. MLMS is well received by veterans, has durable positive effects for HCPs who read the stories, and has been used as a tool to teach patient-centered care to medical trainees.^7-9

We created a narrative medicine curriculum at the San Francisco VA Medical Center (SFVAMC) in which medical students interviewed veterans for the MLMS program. Medical students initially collected life stories through in-person conversation. During the COVID-19 pandemic, physical distancing regulations limited direct patient interaction for students and prompted a switch to phone and video interviews. This shift paralleled the widespread adoption of telehealth, which will persist beyond the pandemic and require teachers and learners to develop competency in forming personal connections with patients through videoconferencing.^10,11

There are no published studies describing how to guide medical students (or other historians) in generating life stories without in-person patient contact. This article details the design of a medical student curriculum incorporating MLMS and the transition to remote interaction between instructors, students, and veterans during the early COVID-19 pandemic.

MLMS Program Origins

The MLMS project began at the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin, in 2013 with staff and volunteer interviewers and has expanded to more than 60 VA facilities.⁷ In January 2020, we initiated a narrative medicine curriculum incorporating MLMS at the SFVAMC as a required component of a third-year internal medicine clerkship for medical students at the University of California San Francisco (UCSF). Fifty-four medical students in 10 cohorts participated in the curriculum in 2020. The primary program objectives were for medical students to develop skills for eliciting and recording a life story and to appreciate the impact of this activity on a veteran’s experience of receiving health care. Secondary objectives were for students to understand the mission of the VA health care system and veteran demographics.

The first cohort of 6 UCSF medical students participated in MLMS during their 8-week VA clerkship. Students attended a 1-hour small group session to introduce the program and build narrative medicine skills. Preparation for this session involved listening to 2 podcast episodes introducing the VA health care system and MLMS.^12,13 The session began with a short interactive discussion of veteran demographics with an emphasis on addressing assumptions students might have about the veteran population. Students were taught strategies for engaging in open-ended conversations without emphasizing illness. Each student practiced collecting a life story with a simulated patient portrayed by an instructor and received feedback from classmates and instructors.

Over the following weeks, students selected a hospitalized veteran, typically a patient they were caring for, introduced MLMS, and obtained verbal consent to participate. They conducted a 60- to 90-minute interview, wrote and organized the life story, read it to the veteran, and solicited edits. Once a final version was generated, the student provided the veteran with printed copies and offered to place the story in the Computerized Patient Record System (CPRS).

Near the end of their rotation, students attended a 1-hour small group session in which they shared reflections on the experience of collecting a life story, the impact of veterans’ life experiences on their health and illness, and moments when students confronted their own stereotypes and implicit biases. Students then reviewed narrative medicine skills that are generalizable to all patient interactions.

COVID-19-Related Adaptation

In March 2020, shortly after the second student cohort began, medical students were removed from the clinical setting in response to the COVID-19 pandemic. The 8-week clerkship was converted to a 3-week remote learning rotation. The MLMS experience was preserved by converting small group sessions to videoconferences and expanding the pool of eligible patients to include veterans who students had met on prior rotations, current inpatients, and outpatients from VA primary care clinics. Students contacted veterans after an instructor had introduced MLMS to the veteran and confirmed that the veteran was interested in participating.

Students in the second and third cohorts completed a telephone-based iteration of MLMS in which interviews and life story reviews were conducted over the telephone and printed copies mailed to the veteran. For the fourth, fifth, and sixth cohorts, MLMS was transitioned to a video-based program with inpatients. Instructors collaborated with a volunteer group supplying tablet devices to inpatients to make video calls to their families during the pandemic.¹⁴ Clerkship students coordinated with that volunteer group to interview veterans and review their stories through the tablet devices.

From July to December 2020 medical students returned to 4-week on-site clinical rotations at the SFVAMC. The program returned to the original format for cohorts 7 to 10, with students attending in-person small group sessions and conducting in-person interviews with inpatients.

Curriculum Evaluation

Students completed surveys in the week after the curriculum concluded. Survey completion was voluntary, anonymous, and had no bearing on their evaluation or grade (pass/fail only). Likert scale questions (1, strongly disagree; 5, strongly agree) were used to assess the program (eAppendix 1). One-way analysis of variance testing was used to compare means stratified by method of interview (in person, telephone, or video). Surveys also included free-response questions asking students to highlight aspects of the program they valued or would change; responses were summarized by theme. This program evaluation was deemed exempt from review by the UCSF Human Research Protection Program Institutional Review Board.

Sixty-two veteran stories were collected by 54 participating students (one student was unable to complete an interview, while several students completed multiple interviews). Fifty-four (87%) veterans requested their stories be entered into the medical record.

All 54 students completed the survey. Students reported that the MLMS curriculum helped them develop new skills for eliciting and recording a life story (mean [SD] 4.5 [0.7]). Most students strongly agreed that MLMS helped them understand how sharing a life story can impact a veteran’s experience of receiving health care, with a mean (SD) score of 4.8 (0.4). After completing MLMS, students also reported a better understanding of the mission of the VA and veteran demographics with a mean (SD) score of 4.4 (0.7) and 4.3 (0.7), respectively. Stratification of survey responses by method of interview (in person, telephone, or video) revealed no statistically significant differences in evaluations (Table 1).

Discussion

Previous research has demonstrated that a narrative medicine curriculum can help medicine clerkship students develop narrative competence through patient storytelling with a focus on a patient’s illness narrative.¹⁵ The VA MLMS program extends the patient narrative beyond health care–related experiences and encompasses their broader life story. This article adds to the MLMS and narrative medicine literature by demonstrating that the efficacy of teaching patient-centered care to medical trainees through direct interviews can be maintained in remote formats.⁹ The article also provides guidance for MLMS programs that wish to conduct remote veteran interviews.

The widespread adoption of telemedicine will require trainees to develop communication skills to establish therapeutic relationships with patients both face-to-face and through videoconferencing. In order to promote this important skill across varying levels of physical distancing, narrative medicine programs should be adaptable to a virtual learning environment. As we redesigned MLMS for the remote setting, we learned several key lessons that can guide similar curricular and programmatic innovations at other institutions. For example, videoconferencing created stronger connections between the students and veterans than telephone calls. However, tablet-based video interviews also introduced many technological challenges and required on-site personnel (nurses and volunteers) to connect students, veterans, and technology. Solutions for technology and communication challenges related to the basic personnel and infrastructure needed to start and maintain a remote MLMS program are outlined in Table 2.

Limitations

Limitations of this study include the participation of trainees from a single institution and a lack of assessment of the impact of MLMS on veterans. Future research could assess whether life story skills and practices are maintained after the medicine clerkship. In addition, future studies could examine veterans’ perspectives through interviews with qualitative analysis to learn how MLMS affected their experience of receiving health care.

Conclusions

This is the first report of a remote-capable life story curriculum for medical students. Shifting to a virtual MLMS curriculum requires protocols and people to link interviewers, veterans, and technology. Training for in-person interactions while being prepared for remote interviewing is essential to ensure that the MLMS experience remains available to interviewers and veterans who otherwise may never have the chance to connect. The restrictions and isolation of the COVID-19 pandemic will fade, but using MLMS to virtually connect patients, providers, and students will remain an important capability and opportunity as health care shifts to more virtual interaction.

Acknowledgments

The authors thank Emma Levine, MD, for her assistance coordinating video interviews; Thor Ringler, MS, MFA, for his assistance with manuscript review; and the veterans of the San Francisco VA Health Care System for sharing their stories.

Narrative competence is the ability to acquire, interpret, and act on the stories of others.¹ Developing this skill through guided medical storytelling can improve health care practitioners’ (HCPs) sense of empathy and satisfaction with their work.² Narrative medicine experiences for medical students can foster a deeper understanding of their patients beyond illness-associated identities.³

Within narrative medicine, the “life story” is a specific technique that allows patients to share experiences through open-ended interviews that are entered into the health record.^4,5 By sharing life stories, patients control a narrative encompassing more than their illness and can reinforce a sense of purpose in their lives.⁶ The US Department of Veterans Affairs (VA) My Life My Story (MLMS) program gives veterans the opportunity to share their narrative with staff and volunteer interviewers. MLMS is well received by veterans, has durable positive effects for HCPs who read the stories, and has been used as a tool to teach patient-centered care to medical trainees.^7-9

We created a narrative medicine curriculum at the San Francisco VA Medical Center (SFVAMC) in which medical students interviewed veterans for the MLMS program. Medical students initially collected life stories through in-person conversation. During the COVID-19 pandemic, physical distancing regulations limited direct patient interaction for students and prompted a switch to phone and video interviews. This shift paralleled the widespread adoption of telehealth, which will persist beyond the pandemic and require teachers and learners to develop competency in forming personal connections with patients through videoconferencing.^10,11

There are no published studies describing how to guide medical students (or other historians) in generating life stories without in-person patient contact. This article details the design of a medical student curriculum incorporating MLMS and the transition to remote interaction between instructors, students, and veterans during the early COVID-19 pandemic.

MLMS Program Origins

The MLMS project began at the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin, in 2013 with staff and volunteer interviewers and has expanded to more than 60 VA facilities.⁷ In January 2020, we initiated a narrative medicine curriculum incorporating MLMS at the SFVAMC as a required component of a third-year internal medicine clerkship for medical students at the University of California San Francisco (UCSF). Fifty-four medical students in 10 cohorts participated in the curriculum in 2020. The primary program objectives were for medical students to develop skills for eliciting and recording a life story and to appreciate the impact of this activity on a veteran’s experience of receiving health care. Secondary objectives were for students to understand the mission of the VA health care system and veteran demographics.

The first cohort of 6 UCSF medical students participated in MLMS during their 8-week VA clerkship. Students attended a 1-hour small group session to introduce the program and build narrative medicine skills. Preparation for this session involved listening to 2 podcast episodes introducing the VA health care system and MLMS.^12,13 The session began with a short interactive discussion of veteran demographics with an emphasis on addressing assumptions students might have about the veteran population. Students were taught strategies for engaging in open-ended conversations without emphasizing illness. Each student practiced collecting a life story with a simulated patient portrayed by an instructor and received feedback from classmates and instructors.

Over the following weeks, students selected a hospitalized veteran, typically a patient they were caring for, introduced MLMS, and obtained verbal consent to participate. They conducted a 60- to 90-minute interview, wrote and organized the life story, read it to the veteran, and solicited edits. Once a final version was generated, the student provided the veteran with printed copies and offered to place the story in the Computerized Patient Record System (CPRS).

Near the end of their rotation, students attended a 1-hour small group session in which they shared reflections on the experience of collecting a life story, the impact of veterans’ life experiences on their health and illness, and moments when students confronted their own stereotypes and implicit biases. Students then reviewed narrative medicine skills that are generalizable to all patient interactions.

COVID-19-Related Adaptation

In March 2020, shortly after the second student cohort began, medical students were removed from the clinical setting in response to the COVID-19 pandemic. The 8-week clerkship was converted to a 3-week remote learning rotation. The MLMS experience was preserved by converting small group sessions to videoconferences and expanding the pool of eligible patients to include veterans who students had met on prior rotations, current inpatients, and outpatients from VA primary care clinics. Students contacted veterans after an instructor had introduced MLMS to the veteran and confirmed that the veteran was interested in participating.

Students in the second and third cohorts completed a telephone-based iteration of MLMS in which interviews and life story reviews were conducted over the telephone and printed copies mailed to the veteran. For the fourth, fifth, and sixth cohorts, MLMS was transitioned to a video-based program with inpatients. Instructors collaborated with a volunteer group supplying tablet devices to inpatients to make video calls to their families during the pandemic.¹⁴ Clerkship students coordinated with that volunteer group to interview veterans and review their stories through the tablet devices.

From July to December 2020 medical students returned to 4-week on-site clinical rotations at the SFVAMC. The program returned to the original format for cohorts 7 to 10, with students attending in-person small group sessions and conducting in-person interviews with inpatients.

Curriculum Evaluation

Students completed surveys in the week after the curriculum concluded. Survey completion was voluntary, anonymous, and had no bearing on their evaluation or grade (pass/fail only). Likert scale questions (1, strongly disagree; 5, strongly agree) were used to assess the program (eAppendix 1). One-way analysis of variance testing was used to compare means stratified by method of interview (in person, telephone, or video). Surveys also included free-response questions asking students to highlight aspects of the program they valued or would change; responses were summarized by theme. This program evaluation was deemed exempt from review by the UCSF Human Research Protection Program Institutional Review Board.

Sixty-two veteran stories were collected by 54 participating students (one student was unable to complete an interview, while several students completed multiple interviews). Fifty-four (87%) veterans requested their stories be entered into the medical record.

All 54 students completed the survey. Students reported that the MLMS curriculum helped them develop new skills for eliciting and recording a life story (mean [SD] 4.5 [0.7]). Most students strongly agreed that MLMS helped them understand how sharing a life story can impact a veteran’s experience of receiving health care, with a mean (SD) score of 4.8 (0.4). After completing MLMS, students also reported a better understanding of the mission of the VA and veteran demographics with a mean (SD) score of 4.4 (0.7) and 4.3 (0.7), respectively. Stratification of survey responses by method of interview (in person, telephone, or video) revealed no statistically significant differences in evaluations (Table 1).

Discussion

Previous research has demonstrated that a narrative medicine curriculum can help medicine clerkship students develop narrative competence through patient storytelling with a focus on a patient’s illness narrative.¹⁵ The VA MLMS program extends the patient narrative beyond health care–related experiences and encompasses their broader life story. This article adds to the MLMS and narrative medicine literature by demonstrating that the efficacy of teaching patient-centered care to medical trainees through direct interviews can be maintained in remote formats.⁹ The article also provides guidance for MLMS programs that wish to conduct remote veteran interviews.

The widespread adoption of telemedicine will require trainees to develop communication skills to establish therapeutic relationships with patients both face-to-face and through videoconferencing. In order to promote this important skill across varying levels of physical distancing, narrative medicine programs should be adaptable to a virtual learning environment. As we redesigned MLMS for the remote setting, we learned several key lessons that can guide similar curricular and programmatic innovations at other institutions. For example, videoconferencing created stronger connections between the students and veterans than telephone calls. However, tablet-based video interviews also introduced many technological challenges and required on-site personnel (nurses and volunteers) to connect students, veterans, and technology. Solutions for technology and communication challenges related to the basic personnel and infrastructure needed to start and maintain a remote MLMS program are outlined in Table 2.

Limitations

Limitations of this study include the participation of trainees from a single institution and a lack of assessment of the impact of MLMS on veterans. Future research could assess whether life story skills and practices are maintained after the medicine clerkship. In addition, future studies could examine veterans’ perspectives through interviews with qualitative analysis to learn how MLMS affected their experience of receiving health care.

Conclusions

This is the first report of a remote-capable life story curriculum for medical students. Shifting to a virtual MLMS curriculum requires protocols and people to link interviewers, veterans, and technology. Training for in-person interactions while being prepared for remote interviewing is essential to ensure that the MLMS experience remains available to interviewers and veterans who otherwise may never have the chance to connect. The restrictions and isolation of the COVID-19 pandemic will fade, but using MLMS to virtually connect patients, providers, and students will remain an important capability and opportunity as health care shifts to more virtual interaction.

Acknowledgments

The authors thank Emma Levine, MD, for her assistance coordinating video interviews; Thor Ringler, MS, MFA, for his assistance with manuscript review; and the veterans of the San Francisco VA Health Care System for sharing their stories.

Narrative competence is the ability to acquire, interpret, and act on the stories of others.¹ Developing this skill through guided medical storytelling can improve health care practitioners’ (HCPs) sense of empathy and satisfaction with their work.² Narrative medicine experiences for medical students can foster a deeper understanding of their patients beyond illness-associated identities.³

Within narrative medicine, the “life story” is a specific technique that allows patients to share experiences through open-ended interviews that are entered into the health record.^4,5 By sharing life stories, patients control a narrative encompassing more than their illness and can reinforce a sense of purpose in their lives.⁶ The US Department of Veterans Affairs (VA) My Life My Story (MLMS) program gives veterans the opportunity to share their narrative with staff and volunteer interviewers. MLMS is well received by veterans, has durable positive effects for HCPs who read the stories, and has been used as a tool to teach patient-centered care to medical trainees.^7-9

We created a narrative medicine curriculum at the San Francisco VA Medical Center (SFVAMC) in which medical students interviewed veterans for the MLMS program. Medical students initially collected life stories through in-person conversation. During the COVID-19 pandemic, physical distancing regulations limited direct patient interaction for students and prompted a switch to phone and video interviews. This shift paralleled the widespread adoption of telehealth, which will persist beyond the pandemic and require teachers and learners to develop competency in forming personal connections with patients through videoconferencing.^10,11

There are no published studies describing how to guide medical students (or other historians) in generating life stories without in-person patient contact. This article details the design of a medical student curriculum incorporating MLMS and the transition to remote interaction between instructors, students, and veterans during the early COVID-19 pandemic.

MLMS Program Origins

The MLMS project began at the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin, in 2013 with staff and volunteer interviewers and has expanded to more than 60 VA facilities.⁷ In January 2020, we initiated a narrative medicine curriculum incorporating MLMS at the SFVAMC as a required component of a third-year internal medicine clerkship for medical students at the University of California San Francisco (UCSF). Fifty-four medical students in 10 cohorts participated in the curriculum in 2020. The primary program objectives were for medical students to develop skills for eliciting and recording a life story and to appreciate the impact of this activity on a veteran’s experience of receiving health care. Secondary objectives were for students to understand the mission of the VA health care system and veteran demographics.

The first cohort of 6 UCSF medical students participated in MLMS during their 8-week VA clerkship. Students attended a 1-hour small group session to introduce the program and build narrative medicine skills. Preparation for this session involved listening to 2 podcast episodes introducing the VA health care system and MLMS.^12,13 The session began with a short interactive discussion of veteran demographics with an emphasis on addressing assumptions students might have about the veteran population. Students were taught strategies for engaging in open-ended conversations without emphasizing illness. Each student practiced collecting a life story with a simulated patient portrayed by an instructor and received feedback from classmates and instructors.

Over the following weeks, students selected a hospitalized veteran, typically a patient they were caring for, introduced MLMS, and obtained verbal consent to participate. They conducted a 60- to 90-minute interview, wrote and organized the life story, read it to the veteran, and solicited edits. Once a final version was generated, the student provided the veteran with printed copies and offered to place the story in the Computerized Patient Record System (CPRS).

Near the end of their rotation, students attended a 1-hour small group session in which they shared reflections on the experience of collecting a life story, the impact of veterans’ life experiences on their health and illness, and moments when students confronted their own stereotypes and implicit biases. Students then reviewed narrative medicine skills that are generalizable to all patient interactions.

COVID-19-Related Adaptation

In March 2020, shortly after the second student cohort began, medical students were removed from the clinical setting in response to the COVID-19 pandemic. The 8-week clerkship was converted to a 3-week remote learning rotation. The MLMS experience was preserved by converting small group sessions to videoconferences and expanding the pool of eligible patients to include veterans who students had met on prior rotations, current inpatients, and outpatients from VA primary care clinics. Students contacted veterans after an instructor had introduced MLMS to the veteran and confirmed that the veteran was interested in participating.

Students in the second and third cohorts completed a telephone-based iteration of MLMS in which interviews and life story reviews were conducted over the telephone and printed copies mailed to the veteran. For the fourth, fifth, and sixth cohorts, MLMS was transitioned to a video-based program with inpatients. Instructors collaborated with a volunteer group supplying tablet devices to inpatients to make video calls to their families during the pandemic.¹⁴ Clerkship students coordinated with that volunteer group to interview veterans and review their stories through the tablet devices.

From July to December 2020 medical students returned to 4-week on-site clinical rotations at the SFVAMC. The program returned to the original format for cohorts 7 to 10, with students attending in-person small group sessions and conducting in-person interviews with inpatients.

Curriculum Evaluation

Students completed surveys in the week after the curriculum concluded. Survey completion was voluntary, anonymous, and had no bearing on their evaluation or grade (pass/fail only). Likert scale questions (1, strongly disagree; 5, strongly agree) were used to assess the program (eAppendix 1). One-way analysis of variance testing was used to compare means stratified by method of interview (in person, telephone, or video). Surveys also included free-response questions asking students to highlight aspects of the program they valued or would change; responses were summarized by theme. This program evaluation was deemed exempt from review by the UCSF Human Research Protection Program Institutional Review Board.

Sixty-two veteran stories were collected by 54 participating students (one student was unable to complete an interview, while several students completed multiple interviews). Fifty-four (87%) veterans requested their stories be entered into the medical record.

All 54 students completed the survey. Students reported that the MLMS curriculum helped them develop new skills for eliciting and recording a life story (mean [SD] 4.5 [0.7]). Most students strongly agreed that MLMS helped them understand how sharing a life story can impact a veteran’s experience of receiving health care, with a mean (SD) score of 4.8 (0.4). After completing MLMS, students also reported a better understanding of the mission of the VA and veteran demographics with a mean (SD) score of 4.4 (0.7) and 4.3 (0.7), respectively. Stratification of survey responses by method of interview (in person, telephone, or video) revealed no statistically significant differences in evaluations (Table 1).

Discussion

Previous research has demonstrated that a narrative medicine curriculum can help medicine clerkship students develop narrative competence through patient storytelling with a focus on a patient’s illness narrative.¹⁵ The VA MLMS program extends the patient narrative beyond health care–related experiences and encompasses their broader life story. This article adds to the MLMS and narrative medicine literature by demonstrating that the efficacy of teaching patient-centered care to medical trainees through direct interviews can be maintained in remote formats.⁹ The article also provides guidance for MLMS programs that wish to conduct remote veteran interviews.

The widespread adoption of telemedicine will require trainees to develop communication skills to establish therapeutic relationships with patients both face-to-face and through videoconferencing. In order to promote this important skill across varying levels of physical distancing, narrative medicine programs should be adaptable to a virtual learning environment. As we redesigned MLMS for the remote setting, we learned several key lessons that can guide similar curricular and programmatic innovations at other institutions. For example, videoconferencing created stronger connections between the students and veterans than telephone calls. However, tablet-based video interviews also introduced many technological challenges and required on-site personnel (nurses and volunteers) to connect students, veterans, and technology. Solutions for technology and communication challenges related to the basic personnel and infrastructure needed to start and maintain a remote MLMS program are outlined in Table 2.

Limitations

Limitations of this study include the participation of trainees from a single institution and a lack of assessment of the impact of MLMS on veterans. Future research could assess whether life story skills and practices are maintained after the medicine clerkship. In addition, future studies could examine veterans’ perspectives through interviews with qualitative analysis to learn how MLMS affected their experience of receiving health care.

Conclusions

This is the first report of a remote-capable life story curriculum for medical students. Shifting to a virtual MLMS curriculum requires protocols and people to link interviewers, veterans, and technology. Training for in-person interactions while being prepared for remote interviewing is essential to ensure that the MLMS experience remains available to interviewers and veterans who otherwise may never have the chance to connect. The restrictions and isolation of the COVID-19 pandemic will fade, but using MLMS to virtually connect patients, providers, and students will remain an important capability and opportunity as health care shifts to more virtual interaction.

Acknowledgments

The authors thank Emma Levine, MD, for her assistance coordinating video interviews; Thor Ringler, MS, MFA, for his assistance with manuscript review; and the veterans of the San Francisco VA Health Care System for sharing their stories.

Medication nonadherence is common with oral antipsychotic formulations, resulting in relapse, increased morbidity, and more frequent psychiatric hospitalization.^1-7 Psychiatric hospitalization and illness decompensation is costly to health care systems and leads to reduced quality of life for veterans and families.^6,7 Long-acting injectable antipsychotics (LAIAs) were developed to enhance antipsychotic adherence and improve patient outcomes, including reduced psychiatric hospitalization.^8-12

Little outcomes data exist comparing LAIAs, including biweekly risperidone microspheres and monthly paliperidone palmitate.^10-13 Risperidone microspheres require a 3-week oral crossover and are administered every 2 weeks, whereas paliperidone palmitate does not require an oral crossover and is administered every 4 weeks. The paliperidone palmitate loading regimen replaces an oral crossover.

The primary objective of this study was to compare the number of psychiatric hospitalizations between veterans administered risperidone microspheres and those on paliperidone palmitate pre- and post-LAIA initiation. Secondary objectives were to assess rehospitalization rates between patients taking risperidone microspheres and paliperidone palmitate, reduction in pre- and posthospitalization rates with LAIAs, and medication adherence.

Methods

This observational study with a retrospective cohort design was conducted at the Veterans Affairs Loma Linda Healthcare System (VALLHS) in California. We examined veterans who were initiated on LAIAs risperidone microspheres or paliperidone palmitate from January 01, 2016 through December 31, 2018. Veterans who were aged ≥ 18 years and received ≥ 2 injections of either risperidone microspheres or paliperidone palmitate during the study period were included. Veterans were excluded if they had received < 2 doses of either LAIA, received the LAIA outside of the review period, were nonadherent to risperidone crossover if they received risperidone microspheres, or transferred their care to another facility. At VALLHS, LAIA injections are administered by a nurse, and veterans must travel to the facility to receive the injections.

Extracted patient chart elements included participant demographics; diagnoses; comorbid alcohol, nicotine, opioid, or other substance use; duration on LAIA; psychiatric hospitalizations pre- and postinitiation of the LAIA; medication adherence; and medication discontinuation based on clinician documentation and clinic orders (Table 1).

Data Analysis

Patient demographics were analyzed using descriptive statistics and experimental comparisons between the risperidone microspheres and paliperidone palmitate groups to assess baseline differences between groups. Psychiatric hospitalizations pre- and post-LAIA were analyzed with parallel group (between veterans–independent groups) and pre-post (within veterans–dependent groups) designs. Index hospitalizations were examined for a period equivalent to the length of time veterans were on the LAIA. Psychiatric rehospitalization rates were analyzed for patients who had index hospitalizations and were rehospitalized for any period when they were receiving the LAIA. Incidences of pre- and post-LAIA hospitalizations were calculated in 100 person-years.

Parallel-group analysis was analyzed using the χ² and Mann-Whitney U tests. Pre-post analyses were analyzed using the Wilcoxon rank sum test. P was set at < .05 for statistical significance.

Results

We screened 111 veterans, and 97 were included in this study (risperidone microspheres, 44; paliperidone palmitate, 53). Mean (SD) age was 46 (13.8) years, 92% were male, 38% were White, 94% were diagnosed with schizophrenia or schizoaffective disorder, and 11% were homeless. Substance use was documented as 52% for nicotine products, 40% for alcohol, 31% for cannabis, 27% for methamphetamine, 7% for cocaine, and 3% for opioids. Cannabis, methamphetamine, cocaine, and opioid use were based on clinician documentation and listed as active diagnoses at the time of LAIA initiation. Statistical significance was found in index hospitalizations P = .009) and history of cocaine use disorder (6.8% vs 7.5%, P < .001).

Veterans administered risperidone microspheres had fewer mean (SD) post-LAIA hospitalizations (0.4 [1.0] vs 0.9 [1.5]; P = .02) and were less likely to be rehospitalized (22.7% vs 47.2%, P = .01) compared with paliperidone palmitate. However, veterans taking risperidone microspheres had a shorter mean (SD) treatment duration (41.6 [40.2] vs 58.2 [45.7] weeks, P = .04) compared with paliperidone palmitate, mainly because patients switched to a different LAIA or oral antipsychotic. No differences were detected in nonadherence and discontinuation between risperidone microspheres and paliperidone palmitate. All veterans in the risperidone microspheres group adhered to oral risperidone crossover with an average 87.8% days covered (Table 2).

Discussion

The main finding of this study was that initiation of LAIAs significantly reduced hospitalizations. Veterans taking risperidone microspheres had higher index hospitalizations and lower posttreatment hospitalizations compared with paliperidone palmitate. We found that patients initiated on risperidone microspheres had more hospitalizations before use of a LAIA than those initiated on paliperidone palmitate. Risperidone microspheres reduced the number of hospitalization post-LAIA significantly more than paliperidone palmitate. We also found that veterans taking risperidone microspheres were on the medication for less mean (SD) time than those on paliperidone palmitate (41.6 [40.2] vs 58.2 [45.7] weeks; P = .04).

To our knowledge, this is one of the few studies that compared outcomes of psychiatric hospitalizations, medication adherence, and treatment discontinuation between risperidone microspheres and paliperidone palmitate, specifically in a veteran population.^16-19 Limosin and colleagues aimed to compare length of stay during the initial hospitalization, rehospitalization risk, and treatment duration between risperidone microspheres and paliperidone palmitate in patients with schizophrenia.¹⁶ These researchers detected no differences in initial hospitalization duration and time to rehospitalization between risperidone microspheres and paliperidone palmitate.¹⁶ The study revealed a more favorable trend in time to discontinuation for paliperidone palmitate, but switching between LAIAs might have confounded the data.¹⁶ The authors note that their study lacked power, and patients on paliperidone palmitate had significantly more nonpsychiatric comorbidities.¹⁶ Joshi and colleagues looked at adherence, medication discontinuation, hospitalization rates, emergency department visits, and hospitalization costs between risperidone microspheres and paliperidone palmitate in patients identified in Truven MarketScan Commercial, Medicare Supplemental, and Medicaid Multi-State insurance databases.¹⁷ The authors found paliperidone palmitate to be superior in all objectives with better adherence, lower discontinuation rates, less likelihood of hospitalization, fewer emergency department visits, and lower hospitalization costs compared with risperidone microspheres.¹⁷ Korell and colleagues aimed to establish reference ranges for plasma concentrations of risperidone and paliperidone among adherent patients.¹⁸

The results in our study are somewhat unexpected in part because of the close relationship between risperidone and paliperidone. Risperidone is converted to paliperidone (9-OH-risperidone) via hepatic cytochrome P450 2D6. Although the molecules do not have identical pharmacologic profiles, it is accepted that they are similar enough that risperidone can establish oral tolerability when transitioning therapy to paliperidone palmitate and vice versa.²⁴ Although the active moiety in risperidone microspheres and paliperidone palmitate is similar, the dosing interval for risperidone microspheres is 2 weeks compared with 4 weeks with paliperidone palmitate. One potential explanation as to why veterans started on risperidone microspheres experienced better outcomes is because they had twice as many office visits with the health care team. Facility procedures dictate veterans receive the LAIA at an on-site clinic. During the visits, a licensed vocational nurse administers the injection and monitors the patient for 15 to 30 minutes afterward.

Despite new LAIAs coming to market, high-quality data examining potential differences in treatment outcomes among agents are limited. This is problematic for clinicians who want to optimize care by understanding how administration schedules or other aspects of LAIA use could modify treatment outcomes. Our results suggest that an advantage might exist in selecting an agent with a more frequent administration schedule, at least initially. This could allow for close monitoring and regular therapeutic contact, which could improve short-term outcomes. This conclusion is supported by meta-analyses, randomized controlled trials, and conceptual articles conducted by Wehring and colleagues, Berwaerts and colleagues, and Parellada and colleagues, respectively, who examined patients on different LAIAs and contact with health care professionals as part of their research.^26-28 These researchers concluded that patients who had regular contact with a health care professional had better outcomes when initiated on a LAIA.^26-28

Limitations

There are several limitations in this study. Retrospective and observational methods introduce risks of bias and confounding variables. Sample size might have limited statistical power to detect differences. Veterans might have had undocumented pre- or posthospitalizations at other institutions, which was not accounted for and lack of rehospitalization is not conclusive of a positive outcome. Institutions could improve on our study and help to fill gaps in comparative data by conducting larger analyses over longer periods and including more LAIA agents.

Conclusions

Although veterans that were administered risperidone microspheres had a shorter treatment duration, they were less likely to be rehospitalized, had a fewer mean number of post-LAIA hospitalizations, and had a larger difference in incidence in 100 person-years compared with veterans on paliperidone palmitate. Nonadherence and discontinuation rates were comparable between risperidone microspheres and paliperidone palmitate. Future studies could aim to further clarify differences in outcomes among agents or administration schedules.

Medication nonadherence is common with oral antipsychotic formulations, resulting in relapse, increased morbidity, and more frequent psychiatric hospitalization.^1-7 Psychiatric hospitalization and illness decompensation is costly to health care systems and leads to reduced quality of life for veterans and families.^6,7 Long-acting injectable antipsychotics (LAIAs) were developed to enhance antipsychotic adherence and improve patient outcomes, including reduced psychiatric hospitalization.^8-12

Little outcomes data exist comparing LAIAs, including biweekly risperidone microspheres and monthly paliperidone palmitate.^10-13 Risperidone microspheres require a 3-week oral crossover and are administered every 2 weeks, whereas paliperidone palmitate does not require an oral crossover and is administered every 4 weeks. The paliperidone palmitate loading regimen replaces an oral crossover.

The primary objective of this study was to compare the number of psychiatric hospitalizations between veterans administered risperidone microspheres and those on paliperidone palmitate pre- and post-LAIA initiation. Secondary objectives were to assess rehospitalization rates between patients taking risperidone microspheres and paliperidone palmitate, reduction in pre- and posthospitalization rates with LAIAs, and medication adherence.

Methods

This observational study with a retrospective cohort design was conducted at the Veterans Affairs Loma Linda Healthcare System (VALLHS) in California. We examined veterans who were initiated on LAIAs risperidone microspheres or paliperidone palmitate from January 01, 2016 through December 31, 2018. Veterans who were aged ≥ 18 years and received ≥ 2 injections of either risperidone microspheres or paliperidone palmitate during the study period were included. Veterans were excluded if they had received < 2 doses of either LAIA, received the LAIA outside of the review period, were nonadherent to risperidone crossover if they received risperidone microspheres, or transferred their care to another facility. At VALLHS, LAIA injections are administered by a nurse, and veterans must travel to the facility to receive the injections.

Extracted patient chart elements included participant demographics; diagnoses; comorbid alcohol, nicotine, opioid, or other substance use; duration on LAIA; psychiatric hospitalizations pre- and postinitiation of the LAIA; medication adherence; and medication discontinuation based on clinician documentation and clinic orders (Table 1).

Data Analysis

Patient demographics were analyzed using descriptive statistics and experimental comparisons between the risperidone microspheres and paliperidone palmitate groups to assess baseline differences between groups. Psychiatric hospitalizations pre- and post-LAIA were analyzed with parallel group (between veterans–independent groups) and pre-post (within veterans–dependent groups) designs. Index hospitalizations were examined for a period equivalent to the length of time veterans were on the LAIA. Psychiatric rehospitalization rates were analyzed for patients who had index hospitalizations and were rehospitalized for any period when they were receiving the LAIA. Incidences of pre- and post-LAIA hospitalizations were calculated in 100 person-years.

Parallel-group analysis was analyzed using the χ² and Mann-Whitney U tests. Pre-post analyses were analyzed using the Wilcoxon rank sum test. P was set at < .05 for statistical significance.

Results

We screened 111 veterans, and 97 were included in this study (risperidone microspheres, 44; paliperidone palmitate, 53). Mean (SD) age was 46 (13.8) years, 92% were male, 38% were White, 94% were diagnosed with schizophrenia or schizoaffective disorder, and 11% were homeless. Substance use was documented as 52% for nicotine products, 40% for alcohol, 31% for cannabis, 27% for methamphetamine, 7% for cocaine, and 3% for opioids. Cannabis, methamphetamine, cocaine, and opioid use were based on clinician documentation and listed as active diagnoses at the time of LAIA initiation. Statistical significance was found in index hospitalizations P = .009) and history of cocaine use disorder (6.8% vs 7.5%, P < .001).

Veterans administered risperidone microspheres had fewer mean (SD) post-LAIA hospitalizations (0.4 [1.0] vs 0.9 [1.5]; P = .02) and were less likely to be rehospitalized (22.7% vs 47.2%, P = .01) compared with paliperidone palmitate. However, veterans taking risperidone microspheres had a shorter mean (SD) treatment duration (41.6 [40.2] vs 58.2 [45.7] weeks, P = .04) compared with paliperidone palmitate, mainly because patients switched to a different LAIA or oral antipsychotic. No differences were detected in nonadherence and discontinuation between risperidone microspheres and paliperidone palmitate. All veterans in the risperidone microspheres group adhered to oral risperidone crossover with an average 87.8% days covered (Table 2).

Discussion

The main finding of this study was that initiation of LAIAs significantly reduced hospitalizations. Veterans taking risperidone microspheres had higher index hospitalizations and lower posttreatment hospitalizations compared with paliperidone palmitate. We found that patients initiated on risperidone microspheres had more hospitalizations before use of a LAIA than those initiated on paliperidone palmitate. Risperidone microspheres reduced the number of hospitalization post-LAIA significantly more than paliperidone palmitate. We also found that veterans taking risperidone microspheres were on the medication for less mean (SD) time than those on paliperidone palmitate (41.6 [40.2] vs 58.2 [45.7] weeks; P = .04).

To our knowledge, this is one of the few studies that compared outcomes of psychiatric hospitalizations, medication adherence, and treatment discontinuation between risperidone microspheres and paliperidone palmitate, specifically in a veteran population.^16-19 Limosin and colleagues aimed to compare length of stay during the initial hospitalization, rehospitalization risk, and treatment duration between risperidone microspheres and paliperidone palmitate in patients with schizophrenia.¹⁶ These researchers detected no differences in initial hospitalization duration and time to rehospitalization between risperidone microspheres and paliperidone palmitate.¹⁶ The study revealed a more favorable trend in time to discontinuation for paliperidone palmitate, but switching between LAIAs might have confounded the data.¹⁶ The authors note that their study lacked power, and patients on paliperidone palmitate had significantly more nonpsychiatric comorbidities.¹⁶ Joshi and colleagues looked at adherence, medication discontinuation, hospitalization rates, emergency department visits, and hospitalization costs between risperidone microspheres and paliperidone palmitate in patients identified in Truven MarketScan Commercial, Medicare Supplemental, and Medicaid Multi-State insurance databases.¹⁷ The authors found paliperidone palmitate to be superior in all objectives with better adherence, lower discontinuation rates, less likelihood of hospitalization, fewer emergency department visits, and lower hospitalization costs compared with risperidone microspheres.¹⁷ Korell and colleagues aimed to establish reference ranges for plasma concentrations of risperidone and paliperidone among adherent patients.¹⁸

The results in our study are somewhat unexpected in part because of the close relationship between risperidone and paliperidone. Risperidone is converted to paliperidone (9-OH-risperidone) via hepatic cytochrome P450 2D6. Although the molecules do not have identical pharmacologic profiles, it is accepted that they are similar enough that risperidone can establish oral tolerability when transitioning therapy to paliperidone palmitate and vice versa.²⁴ Although the active moiety in risperidone microspheres and paliperidone palmitate is similar, the dosing interval for risperidone microspheres is 2 weeks compared with 4 weeks with paliperidone palmitate. One potential explanation as to why veterans started on risperidone microspheres experienced better outcomes is because they had twice as many office visits with the health care team. Facility procedures dictate veterans receive the LAIA at an on-site clinic. During the visits, a licensed vocational nurse administers the injection and monitors the patient for 15 to 30 minutes afterward.

Despite new LAIAs coming to market, high-quality data examining potential differences in treatment outcomes among agents are limited. This is problematic for clinicians who want to optimize care by understanding how administration schedules or other aspects of LAIA use could modify treatment outcomes. Our results suggest that an advantage might exist in selecting an agent with a more frequent administration schedule, at least initially. This could allow for close monitoring and regular therapeutic contact, which could improve short-term outcomes. This conclusion is supported by meta-analyses, randomized controlled trials, and conceptual articles conducted by Wehring and colleagues, Berwaerts and colleagues, and Parellada and colleagues, respectively, who examined patients on different LAIAs and contact with health care professionals as part of their research.^26-28 These researchers concluded that patients who had regular contact with a health care professional had better outcomes when initiated on a LAIA.^26-28

Limitations

There are several limitations in this study. Retrospective and observational methods introduce risks of bias and confounding variables. Sample size might have limited statistical power to detect differences. Veterans might have had undocumented pre- or posthospitalizations at other institutions, which was not accounted for and lack of rehospitalization is not conclusive of a positive outcome. Institutions could improve on our study and help to fill gaps in comparative data by conducting larger analyses over longer periods and including more LAIA agents.

Conclusions

Although veterans that were administered risperidone microspheres had a shorter treatment duration, they were less likely to be rehospitalized, had a fewer mean number of post-LAIA hospitalizations, and had a larger difference in incidence in 100 person-years compared with veterans on paliperidone palmitate. Nonadherence and discontinuation rates were comparable between risperidone microspheres and paliperidone palmitate. Future studies could aim to further clarify differences in outcomes among agents or administration schedules.

Medication nonadherence is common with oral antipsychotic formulations, resulting in relapse, increased morbidity, and more frequent psychiatric hospitalization.^1-7 Psychiatric hospitalization and illness decompensation is costly to health care systems and leads to reduced quality of life for veterans and families.^6,7 Long-acting injectable antipsychotics (LAIAs) were developed to enhance antipsychotic adherence and improve patient outcomes, including reduced psychiatric hospitalization.^8-12

Little outcomes data exist comparing LAIAs, including biweekly risperidone microspheres and monthly paliperidone palmitate.^10-13 Risperidone microspheres require a 3-week oral crossover and are administered every 2 weeks, whereas paliperidone palmitate does not require an oral crossover and is administered every 4 weeks. The paliperidone palmitate loading regimen replaces an oral crossover.

The primary objective of this study was to compare the number of psychiatric hospitalizations between veterans administered risperidone microspheres and those on paliperidone palmitate pre- and post-LAIA initiation. Secondary objectives were to assess rehospitalization rates between patients taking risperidone microspheres and paliperidone palmitate, reduction in pre- and posthospitalization rates with LAIAs, and medication adherence.

Methods

This observational study with a retrospective cohort design was conducted at the Veterans Affairs Loma Linda Healthcare System (VALLHS) in California. We examined veterans who were initiated on LAIAs risperidone microspheres or paliperidone palmitate from January 01, 2016 through December 31, 2018. Veterans who were aged ≥ 18 years and received ≥ 2 injections of either risperidone microspheres or paliperidone palmitate during the study period were included. Veterans were excluded if they had received < 2 doses of either LAIA, received the LAIA outside of the review period, were nonadherent to risperidone crossover if they received risperidone microspheres, or transferred their care to another facility. At VALLHS, LAIA injections are administered by a nurse, and veterans must travel to the facility to receive the injections.

Extracted patient chart elements included participant demographics; diagnoses; comorbid alcohol, nicotine, opioid, or other substance use; duration on LAIA; psychiatric hospitalizations pre- and postinitiation of the LAIA; medication adherence; and medication discontinuation based on clinician documentation and clinic orders (Table 1).

Data Analysis

Patient demographics were analyzed using descriptive statistics and experimental comparisons between the risperidone microspheres and paliperidone palmitate groups to assess baseline differences between groups. Psychiatric hospitalizations pre- and post-LAIA were analyzed with parallel group (between veterans–independent groups) and pre-post (within veterans–dependent groups) designs. Index hospitalizations were examined for a period equivalent to the length of time veterans were on the LAIA. Psychiatric rehospitalization rates were analyzed for patients who had index hospitalizations and were rehospitalized for any period when they were receiving the LAIA. Incidences of pre- and post-LAIA hospitalizations were calculated in 100 person-years.

Parallel-group analysis was analyzed using the χ² and Mann-Whitney U tests. Pre-post analyses were analyzed using the Wilcoxon rank sum test. P was set at < .05 for statistical significance.

Results

We screened 111 veterans, and 97 were included in this study (risperidone microspheres, 44; paliperidone palmitate, 53). Mean (SD) age was 46 (13.8) years, 92% were male, 38% were White, 94% were diagnosed with schizophrenia or schizoaffective disorder, and 11% were homeless. Substance use was documented as 52% for nicotine products, 40% for alcohol, 31% for cannabis, 27% for methamphetamine, 7% for cocaine, and 3% for opioids. Cannabis, methamphetamine, cocaine, and opioid use were based on clinician documentation and listed as active diagnoses at the time of LAIA initiation. Statistical significance was found in index hospitalizations P = .009) and history of cocaine use disorder (6.8% vs 7.5%, P < .001).

Veterans administered risperidone microspheres had fewer mean (SD) post-LAIA hospitalizations (0.4 [1.0] vs 0.9 [1.5]; P = .02) and were less likely to be rehospitalized (22.7% vs 47.2%, P = .01) compared with paliperidone palmitate. However, veterans taking risperidone microspheres had a shorter mean (SD) treatment duration (41.6 [40.2] vs 58.2 [45.7] weeks, P = .04) compared with paliperidone palmitate, mainly because patients switched to a different LAIA or oral antipsychotic. No differences were detected in nonadherence and discontinuation between risperidone microspheres and paliperidone palmitate. All veterans in the risperidone microspheres group adhered to oral risperidone crossover with an average 87.8% days covered (Table 2).

Discussion

The main finding of this study was that initiation of LAIAs significantly reduced hospitalizations. Veterans taking risperidone microspheres had higher index hospitalizations and lower posttreatment hospitalizations compared with paliperidone palmitate. We found that patients initiated on risperidone microspheres had more hospitalizations before use of a LAIA than those initiated on paliperidone palmitate. Risperidone microspheres reduced the number of hospitalization post-LAIA significantly more than paliperidone palmitate. We also found that veterans taking risperidone microspheres were on the medication for less mean (SD) time than those on paliperidone palmitate (41.6 [40.2] vs 58.2 [45.7] weeks; P = .04).

To our knowledge, this is one of the few studies that compared outcomes of psychiatric hospitalizations, medication adherence, and treatment discontinuation between risperidone microspheres and paliperidone palmitate, specifically in a veteran population.^16-19 Limosin and colleagues aimed to compare length of stay during the initial hospitalization, rehospitalization risk, and treatment duration between risperidone microspheres and paliperidone palmitate in patients with schizophrenia.¹⁶ These researchers detected no differences in initial hospitalization duration and time to rehospitalization between risperidone microspheres and paliperidone palmitate.¹⁶ The study revealed a more favorable trend in time to discontinuation for paliperidone palmitate, but switching between LAIAs might have confounded the data.¹⁶ The authors note that their study lacked power, and patients on paliperidone palmitate had significantly more nonpsychiatric comorbidities.¹⁶ Joshi and colleagues looked at adherence, medication discontinuation, hospitalization rates, emergency department visits, and hospitalization costs between risperidone microspheres and paliperidone palmitate in patients identified in Truven MarketScan Commercial, Medicare Supplemental, and Medicaid Multi-State insurance databases.¹⁷ The authors found paliperidone palmitate to be superior in all objectives with better adherence, lower discontinuation rates, less likelihood of hospitalization, fewer emergency department visits, and lower hospitalization costs compared with risperidone microspheres.¹⁷ Korell and colleagues aimed to establish reference ranges for plasma concentrations of risperidone and paliperidone among adherent patients.¹⁸

The results in our study are somewhat unexpected in part because of the close relationship between risperidone and paliperidone. Risperidone is converted to paliperidone (9-OH-risperidone) via hepatic cytochrome P450 2D6. Although the molecules do not have identical pharmacologic profiles, it is accepted that they are similar enough that risperidone can establish oral tolerability when transitioning therapy to paliperidone palmitate and vice versa.²⁴ Although the active moiety in risperidone microspheres and paliperidone palmitate is similar, the dosing interval for risperidone microspheres is 2 weeks compared with 4 weeks with paliperidone palmitate. One potential explanation as to why veterans started on risperidone microspheres experienced better outcomes is because they had twice as many office visits with the health care team. Facility procedures dictate veterans receive the LAIA at an on-site clinic. During the visits, a licensed vocational nurse administers the injection and monitors the patient for 15 to 30 minutes afterward.

Despite new LAIAs coming to market, high-quality data examining potential differences in treatment outcomes among agents are limited. This is problematic for clinicians who want to optimize care by understanding how administration schedules or other aspects of LAIA use could modify treatment outcomes. Our results suggest that an advantage might exist in selecting an agent with a more frequent administration schedule, at least initially. This could allow for close monitoring and regular therapeutic contact, which could improve short-term outcomes. This conclusion is supported by meta-analyses, randomized controlled trials, and conceptual articles conducted by Wehring and colleagues, Berwaerts and colleagues, and Parellada and colleagues, respectively, who examined patients on different LAIAs and contact with health care professionals as part of their research.^26-28 These researchers concluded that patients who had regular contact with a health care professional had better outcomes when initiated on a LAIA.^26-28

Limitations

There are several limitations in this study. Retrospective and observational methods introduce risks of bias and confounding variables. Sample size might have limited statistical power to detect differences. Veterans might have had undocumented pre- or posthospitalizations at other institutions, which was not accounted for and lack of rehospitalization is not conclusive of a positive outcome. Institutions could improve on our study and help to fill gaps in comparative data by conducting larger analyses over longer periods and including more LAIA agents.

Conclusions

Although veterans that were administered risperidone microspheres had a shorter treatment duration, they were less likely to be rehospitalized, had a fewer mean number of post-LAIA hospitalizations, and had a larger difference in incidence in 100 person-years compared with veterans on paliperidone palmitate. Nonadherence and discontinuation rates were comparable between risperidone microspheres and paliperidone palmitate. Future studies could aim to further clarify differences in outcomes among agents or administration schedules.

Cisplatin is a potent antineoplastic agent derived from platinum and commonly used in the treatment of head and neck, bladder, ovarian, and testicular malignancies.^1,2 Approximately 20% of all cancer patients are prescribed platinum-based chemotherapeutics.³ Although considered highly effective, cisplatin is also a dose-dependent nephrotoxin, inducing apoptosis in the proximal tubules of the nephron and reducing glomerular filtration rate. This nephron injury leads to inflammation and reduced medullary blood flow, causing further ischemic damage to the tubular cells.⁴ Given that the proximal tubule reabsorbs 67% of all sodium, cisplatin-induced nephron injuries can also lead to hyponatremia.⁵

The primary mechanisms of hyponatremia following cisplatin chemotherapy are syndrome of inappropriate antidiuretic hormone secretion (SIADH) and renal salt wasting syndrome (RSWS). Though these diagnoses have similar presentations, the treatment recommendations are different due to pathophysiologic differences. Fluid restriction is the hallmark of SIADH treatment, while increased sodium intake remains the hallmark of RSWS treatment.⁶ This patient presented with a combination of cisplatin-induced acute kidney injury (AKI) and hyponatremia secondary to RSWS. While RSWS and AKI are known complications of cisplatin chemotherapy, the combination is underreported in the literature. Therefore, this case report highlights the combination of these cisplatin-induced complications, emphasizes the clinical challenges in differentiating SIADH from RSWS, especially in the presence of a concomitant AKI, and suggests a treatment approach during diagnostic uncertainty.

Case Presentation

A 71-year-old man with a medical history of squamous cell carcinoma (SCC) of the left neck on cycle 1, day 8 of cisplatin-based chemotherapy and ongoing radiation therapy (720 cGy of 6300 cGy), lung adenocarcinoma status postresection, and hyperlipidemia presented to the emergency department (ED) at the request of his oncologist for abnormal laboratory values. In the ED, his metabolic panel showed a 131-mmol/L serum sodium, 3.3 mmol/L potassium, 83 mmol/L chloride, 29 mmol/L bicarbonate, 61 mg/dL blood urea nitrogen (BUN), and 8.8 mg/dL creatinine (baseline, 0.9 mg/dL). The patient reported throbbing headaches, persistent nausea, and multiple episodes of nonbloody emesis for several days that he attributed to his chemotherapy. He noted decreased urination without discomfort or changes in color or odor and no fatigue, fevers, chills, hematuria, flank, abdominal pain, thirst, or polydipsia. He reported no toxic ingestions or IV drug use. The patient had no relevant family history or additional social history. His outpatient medications included 10 mg cetirizine, 8 mg ondansetron, and 81 mg aspirin. On initial examination, his 137/66 mm Hg blood pressure was mildly elevated. The physical examination findings were notable for a 5-cm mass in the left neck that was firm and irregularly-shaped. His physical examination was otherwise unremarkable. He was admitted to the inpatient medicine service for an AKI complicated by symptomatic hyponatremia.

Investigations

We evaluated the patient’s AKI based on treatment responsiveness, imaging, and laboratory testing. Renal and bladder ultrasound showed no evidence of hydronephrosis or obstruction. He had a benign urinalysis with microscopy absent for protein, blood, ketones, leukocyte esterase, nitrites, and cellular casts. His urine pH was 5.5 (reference range, 5.0-9.0) and specific gravity was 1.011 (reference range, 1.005-1.030). His urine electrolytes revealed 45-mmol/L urine sodium (reference range, 40-220), 33-mmol/L urine chloride (reference range, 110-250), 10-mmol/L urine potassium (reference range, 25-120), 106.7-mg/dL urine creatinine (reference range, 10-400) and a calculated 2.7% fractional excretion of sodium (FE_Na) and 22.0-mEq/L elevated urine anion gap. As a fluid challenge, he was treated with IV 0.9% sodium chloride at 100-125 mL/h, receiving 3 liters over the first 48 hours of his hospitalization. His creatinine peaked at 9.2 mg/dL and stabilized before improving later in his hospitalization (Figure 1). The patient initially had oliguria (< 0.5 mL/kg/h), which slowly improved over his hospital course. Unfortunately, due to multiple system and clinical factors, accurate inputs and outputs were not adequately maintained during his hospitalization.

We evaluated hyponatremia with a combination of serum and urine laboratory tests. In addition to urine electrolytes, the initial evaluation focused on trending his clinical trajectory. We repeated a basic metabolic panel every 4 to 6 hours. He had 278-mOsm/kg serum osmolality (reference range, 285-295) with an effective 217-mOsm/kg serum tonicity. His urine osmolality was 270.5 mOsm/kg.

Despite administering 462 mEq sodium via crystalloid, his sodium worsened over the first 48 hours, reaching a nadir at 125 mmol/L on hospital day 3 (Figure 2). While he continued to appear euvolemic on physical examination, his blood pressure became difficult to control with 160- to 180-mm Hg systolic blood pressure readings. His thyroid stimulating hormone (TSH) was normal and aldosterone was low (4 ng/dL). Additional urine studies, including a 24-hour urine sample, were collected for further evaluation. His urine uric acid was 140 mg/d (reference range, 120-820); his serum uric acid level was 8.2 mg/dL (reference range, 3.0-9.0). His 24-hour urine creatinine was 0.57 g/d (reference range, 0.50-2.15) and uric acid to creatinine ratio was 246 mg/g (reference range, 60-580). His serum creatinine collected from the same day as his 24-hour urine sample was 7.3 mg/dL. His fractional excretion of uric acid (FE_urate) was 21.9%.

Differential Diagnosis

The patient’s recent administration of cisplatin raised clinical suspicion of cisplatin-induced AKI. To avoid premature diagnostic closure, we used a systematic approach for thinking about our patient’s AKI, considering prerenal, intrarenal, and postrenal etiologies. The unremarkable renal and bladder ultrasound made a postrenal etiology unlikely. The patient’s 2.7% FE_Na in the absence of a diuretic, limited responsiveness to crystalloid fluid resuscitation, 7.5 serum BUN/creatinine ratio, and 270.5 mOsm/kg urine osmolality suggested an intrarenal etiology, which can be further divided into problems with glomeruli, tubules, small vessels, or interstitial space. The patient’s normal urinary microscopy with no evidence of protein, blood, ketones, leukocyte esterase, nitrites, or cellular casts made a glomerular etiology less likely. The acute onset and lack of additional systemic features, other than hypertension, made a vascular etiology less likely. A tubular etiology, such as acute tubular necrosis (ATN), was highest on the differential and was followed by an interstitial etiology, such as acute interstitial nephritis (AIN).

Patients with drug-induced AIN commonly present with signs and symptoms of an allergic-type reaction, including fever, rash, hematuria, pyuria, and costovertebral angle tenderness. The patient lacked these symptoms. However, cisplatin is known to cause ATN in up to 20-30% of patients.⁷ Therefore, despite the lack of the classic muddy-brown, granular casts on urine microscopy, cisplatin-induced ATN remained the most likely etiology of his AKI. Moreover, ATN can cause hyponatremia. ATN is characterized by 3 phases: initiation, maintenance, and recovery phases.⁸ Hyponatremia occurs during the recovery phase, typically starting weeks after renal insult and associated with high urine output and diuresis. This patient presented 1 week after injury and had persistent oliguria, making ATN an unlikely culprit of his hyponatremia.

Our patient presented with hypotonic hyponatremia with a 131 mmol/L initial sodium level and an < 280 mOsm/kg effective serum osmolality, or serum tonicity. The serum tonicity is equivalent to the difference between the measured serum osmolality and the BUN. In the setting of profound AKI, this adjustment is essential for correctly categorizing a patient’s hyponatremia as hyper-, iso-, or hypotonic. The differential diagnosis for this patient’s hypotonic hyponatremia included dilutional effects of hypervolemia, SIADH, hyperthyroidism, adrenal insufficiency, and RSWS. The patient’s volume examination, lack of predisposing comorbidities or suggestive biomarkers, and > 20 mmol/L urinary sodium made hypervolemia unlikely. His urinary osmolality and specific gravity made primary polydipsia unlikely. We worked up his hyponatremia according to a diagnostic algorithm (eAppendix available at doi:10.12788/fp.0198).

The patient had a 217 mOsm/kg serum tonicity and a 270.5 mOsm/kg urine osmolality, consistent with impaired water excretion. His presentation, TSH, and concordant decrease in sodium and potassium made an endocrine etiology of his hyponatremia less likely. In hindsight, a serum cortisol would have been beneficial to more completely exclude adrenal insufficiency. His urine sodium was elevated at 45 mmol/L, raising concern for RSWS or SIADH. The FE_urate helped to distinguish between SIADH and RSWS. While FE_urate is often elevated in both SIADH and RSWS initially, the FE_urate normalizes in SIADH with normalization of the serum sodium. The ideal cutoff for posthyponatremia correction FE_urate is debated; however, a FE_urate value after sodium correction < 11% suggests SIADH while a value > 11% suggests RSWS.⁹ Our patient’s FE_urate following the sodium correction (serum sodium 134 mmol/L) was 21.9%, most suggestive of RSWS.

Treatment

Upon admission, initial treatment focused on resolving the patient’s AKI. The oncology team discontinued the cisplatin-based chemotherapy. His medication dosages were adjusted for his renal function and additional nephrotoxins avoided. In consultation, the nephrology service recommended 100 mL/h fluid resuscitation. After the patient received 3 L of 0.9% sodium chloride, his creatinine showed limited improvement and his sodium worsened, trending from 131 mmol/L to a nadir of 125 mmol/L. We initiated oral free-water restriction while continuing IV infusion of 0.9% sodium chloride at 125 mL/h.

We further augmented his sodium intake with 1-g sodium chloride tablets with each meal. By hospital day 6, the patient’s serum sodium, BUN, and creatinine improved to 130 mEq/L, 50 mg/dL, and 7.7 mg/dL, respectively. We then discontinued the oral sodium chloride tablets, fluid restriction, and IV fluids in a stepwise fashion prior to discharge. At discharge, the patient’s serum sodium was 136 mEq/L and creatinine, 4.8 mg/dL. The patient’s clinical course was complicated by symptomatic hypertension with systolic blood pressures about 180 mm Hg, requiring intermittent IV hydralazine, which was transitioned to daily nifedipine. Concerned that fluid resuscitation contributed to his hypertension, the patient also received several doses of furosemide. At time of discharge, the patient remained hypertensive and was discharged with nifedipine 90 mg daily.

Outcome and Follow-up

The patient has remained stable clinically since discharge. One week after discharge, his serum sodium and creatinine were 138 mmol/L and 3.8 mg/dL, respectively. More than 1 month after discharge, his sodium remains in the reference range and his creatinine was stable at about 3.5 mg/dL. He continues to follow-up with nephrology, oncology, and radiation oncology. He has restarted chemotherapy with a carboplatin-based regimen without recurrence of hyponatremia or AKI. His blood pressure has gradually improved to the point where he no longer requires nifedipine.

Discussion

The US Food and Drug Administration first approved the use of cisplatin, an alkylating agent that inhibits DNA replication, in 1978 for the treatment of testicular cancer.¹⁰ Since its approval, cisplatin has increased in popularity and is now considered one of the most effective antineoplastic agents for the treatment of solid tumors.¹ Unfortunately, cisplatin has a well-documented adverse effect profile that includes neurotoxicity, gastrointestinal toxicity, nephrotoxicity, and ototoxicity.⁴ Despite frequent nephrotoxicity, cisplatin only occasionally causes hyponatremia and rarely causes RSWS, a known but potentially fatal complication. Moreover, the combination of AKI and RSWS is unique. Our patient presented with the unique combination of AKI and hyponatremia, most consistent with RSWS, likely precipitated from cisplatin chemotherapy. Through this case, we review cisplatin-associated electrolyte abnormalities, highlight the challenge of differentiating SIADH and RSWS, and suggest a treatment approach for hyponatremia during the period of diagnostic uncertainty.

Blachley and colleagues first discussed renal and electrolyte disturbances, specifically magnesium wasting, secondary to cisplatin use in 1981. In 1984, Kurtzberg and colleagues noted salt wasting in 2 patients receiving cisplatin therapy. The authors suggested that cisplatin inhibits solute transport in the thick ascending limb, causing clinically significant electrolyte abnormalities, coining the term cisplatin-induced salt wasting.¹¹

The prevalence of cisplatin-induced salt wasting is unclear and likely underreported. In 1988, Hutchinson and colleagues conducted a prospective cohort study and noted 10% of patients (n = 70) developed RSWS at some point over 18 months of cisplatin therapy—a higher rate than previously estimated.¹² In 1992, another prospective cohort study evaluated the adverse effects of 47 patients with non-small cell lung cancer treated with cisplatin and reported hyponatremia in 43% of its 93 courses of chemotherapy. The authors did not report the etiology of these hyponatremia cases.¹³ Given the diagnostic challenge, RSWS may be underrepresented as a confirmed etiology of hyponatremia in cisplatin treatment.

Hyponatremia from cisplatin may present as either SIADH or RSWS, complicating treatment decisions. Both conditions lead to hypotonic hyponatremia with urine osmolality > 100 mOSm/kg and urine sodium levels > 40 mmol/L. However, pathophysiology behind SIADH and RSWS is different. In RSWS, proximal tubule damage causes hyponatremia, decreasing sodium reabsorption, and leading to impaired concentration gradient in every segment of the nephron. As a result, RSWS can lead to profound hyponatremia. Treatment typically consists of increasing sodium intake to correct serum sodium with salt tablets and hypertonic sodium chloride while treating the underlying etiology, in our case removing the offending agent, and waiting for proximal tubule function to recover.⁶ On the other hand, in SIADH, elevated antidiuretic hormone (ADH) increases water reabsorption in the collecting duct, which has no impact on concentration gradients of the other nephron segments.¹⁴ Free-water restriction is the hallmark of SIADH treatment. Severe SIADH may require sodium repletion and/or the initiation of vaptans, ADH antagonists that competitively inhibit V2 receptors in the collecting duct to prevent water reabsorption.¹⁵

Our patient had an uncertain etiology of his hyponatremia throughout most of his treatment course, complicating our treatment decision-making. Initially, his measured serum osmolality was 278 mOsm/kg; however, his effective tonicity was lower. His AKI elevated his BUN, which in turnrequired us to calculate his serum tonicity (217 mOsm/kg) that was consistent with hypotonic hyponatremia. His elevated urine osmolality and urine sodium levels made SIADH and RSWS the most likely etiologies of his hyponatremia. To confirm the etiology, we waited for correction of his serum sodium. Therefore, we treated him with a combination of sodium repletion with 0.9% sodium chloride (154 mEq/L), hypertonic relative to his serum sodium, sodium chloride tablets, and free-water restriction. In this approach, we attempted to harmonize the treatment strategies for both SIADH and RSWS and effectively corrected his serum sodium. We evaluated his response to our treatment with a basic metabolic panel every 6 to 8 hours. Had his serum sodium decreased < 120 mmol/L, we planned to transfer the patient to the intensive care unit for 3% sodium chloride and/or intensification of his fluid restriction. A significant worsening of his hyponatremia would have strongly suggested hyponatremia secondary to SIADH since isotonic saline can worsen hyponatremia due to increased free-water reabsorption in the collecting duct.¹⁶

To differentiate between SIADH and RSWS, we relied on the FE_urate after sodium correction. Multiple case reports from Japan have characterized the distinction between the processes through FE_urate and serum uric acid. While the optimal cut-off values for FE_urate require additional investigation, values < 11% after serum sodium correction suggests SIADH, while a value > 11% suggests RSWS.¹⁷ Prior cases have also emphasized serum hypouricemia as a distinguishing characteristic in RSWS. However, our case illustrates that serum hypouricemia is less reliable in the setting of AKI. Due to his severe AKI, our patient could not efficiently clear uric acid, likely contributing to his hyperuricemia.

Ultimately, our patient had an FE_urate > 20%, which was suggestive of RSWS. Nevertheless, we recognize limitations and confounders in our diagnosis and have reflected on our diagnostic and management choices. First, the sensitivity and specificity of postsodium correction FE_urate is unknown. Tracking the change in FE_urate with our interventions would have increased our diagnostic utility, as suggested by Maesaka and colleagues.¹⁴ Second, our patient’s serum sodium was still at the lower end of the reference range after treatment, which may decrease the specificity of FE_urate. Third, a plasma ADH collected during the initial phase of symptomatic hyponatremia would have helped differentiate between SIADH and RSWS.

Other diagnostic tests that could have excluded alternative diagnoses with even greater certainty include plasma adrenocorticotropic hormone, B-type natriuretic peptide, renin, cortisol, and thyroid function tests. From a practical standpoint, these laboratory results (excluding thyroid function test and brain natriuretic peptide) would have taken several weeks to result at our institution, limiting their clinical utility. Similarly, FE_urate also has limited clinical utility, requiring effective treatment as part of the diagnostic test. Therefore, we recommend focusing on optimal treatment for hyponatremia of uncertain etiology, especially where SIADH and RSWS are the leading diagnoses.

Conclusions

We described a rare case of concomitant cisplatin-induced severe AKI and RSWS. We have emphasized the diagnostic challenge of distinguishing between SIADH and RSWS, especially with concomitant AKI, and have acknowledged that optimal treatment relies on accurate differentiation. However, differentiation may not be clinically feasible. Therefore, we suggest a treatment strategy that incorporates both free-water restriction and sodium supplementation via IV and/or oral administration.

Cisplatin is a potent antineoplastic agent derived from platinum and commonly used in the treatment of head and neck, bladder, ovarian, and testicular malignancies.^1,2 Approximately 20% of all cancer patients are prescribed platinum-based chemotherapeutics.³ Although considered highly effective, cisplatin is also a dose-dependent nephrotoxin, inducing apoptosis in the proximal tubules of the nephron and reducing glomerular filtration rate. This nephron injury leads to inflammation and reduced medullary blood flow, causing further ischemic damage to the tubular cells.⁴ Given that the proximal tubule reabsorbs 67% of all sodium, cisplatin-induced nephron injuries can also lead to hyponatremia.⁵

The primary mechanisms of hyponatremia following cisplatin chemotherapy are syndrome of inappropriate antidiuretic hormone secretion (SIADH) and renal salt wasting syndrome (RSWS). Though these diagnoses have similar presentations, the treatment recommendations are different due to pathophysiologic differences. Fluid restriction is the hallmark of SIADH treatment, while increased sodium intake remains the hallmark of RSWS treatment.⁶ This patient presented with a combination of cisplatin-induced acute kidney injury (AKI) and hyponatremia secondary to RSWS. While RSWS and AKI are known complications of cisplatin chemotherapy, the combination is underreported in the literature. Therefore, this case report highlights the combination of these cisplatin-induced complications, emphasizes the clinical challenges in differentiating SIADH from RSWS, especially in the presence of a concomitant AKI, and suggests a treatment approach during diagnostic uncertainty.

Case Presentation

A 71-year-old man with a medical history of squamous cell carcinoma (SCC) of the left neck on cycle 1, day 8 of cisplatin-based chemotherapy and ongoing radiation therapy (720 cGy of 6300 cGy), lung adenocarcinoma status postresection, and hyperlipidemia presented to the emergency department (ED) at the request of his oncologist for abnormal laboratory values. In the ED, his metabolic panel showed a 131-mmol/L serum sodium, 3.3 mmol/L potassium, 83 mmol/L chloride, 29 mmol/L bicarbonate, 61 mg/dL blood urea nitrogen (BUN), and 8.8 mg/dL creatinine (baseline, 0.9 mg/dL). The patient reported throbbing headaches, persistent nausea, and multiple episodes of nonbloody emesis for several days that he attributed to his chemotherapy. He noted decreased urination without discomfort or changes in color or odor and no fatigue, fevers, chills, hematuria, flank, abdominal pain, thirst, or polydipsia. He reported no toxic ingestions or IV drug use. The patient had no relevant family history or additional social history. His outpatient medications included 10 mg cetirizine, 8 mg ondansetron, and 81 mg aspirin. On initial examination, his 137/66 mm Hg blood pressure was mildly elevated. The physical examination findings were notable for a 5-cm mass in the left neck that was firm and irregularly-shaped. His physical examination was otherwise unremarkable. He was admitted to the inpatient medicine service for an AKI complicated by symptomatic hyponatremia.

Investigations

We evaluated the patient’s AKI based on treatment responsiveness, imaging, and laboratory testing. Renal and bladder ultrasound showed no evidence of hydronephrosis or obstruction. He had a benign urinalysis with microscopy absent for protein, blood, ketones, leukocyte esterase, nitrites, and cellular casts. His urine pH was 5.5 (reference range, 5.0-9.0) and specific gravity was 1.011 (reference range, 1.005-1.030). His urine electrolytes revealed 45-mmol/L urine sodium (reference range, 40-220), 33-mmol/L urine chloride (reference range, 110-250), 10-mmol/L urine potassium (reference range, 25-120), 106.7-mg/dL urine creatinine (reference range, 10-400) and a calculated 2.7% fractional excretion of sodium (FE_Na) and 22.0-mEq/L elevated urine anion gap. As a fluid challenge, he was treated with IV 0.9% sodium chloride at 100-125 mL/h, receiving 3 liters over the first 48 hours of his hospitalization. His creatinine peaked at 9.2 mg/dL and stabilized before improving later in his hospitalization (Figure 1). The patient initially had oliguria (< 0.5 mL/kg/h), which slowly improved over his hospital course. Unfortunately, due to multiple system and clinical factors, accurate inputs and outputs were not adequately maintained during his hospitalization.

We evaluated hyponatremia with a combination of serum and urine laboratory tests. In addition to urine electrolytes, the initial evaluation focused on trending his clinical trajectory. We repeated a basic metabolic panel every 4 to 6 hours. He had 278-mOsm/kg serum osmolality (reference range, 285-295) with an effective 217-mOsm/kg serum tonicity. His urine osmolality was 270.5 mOsm/kg.

Despite administering 462 mEq sodium via crystalloid, his sodium worsened over the first 48 hours, reaching a nadir at 125 mmol/L on hospital day 3 (Figure 2). While he continued to appear euvolemic on physical examination, his blood pressure became difficult to control with 160- to 180-mm Hg systolic blood pressure readings. His thyroid stimulating hormone (TSH) was normal and aldosterone was low (4 ng/dL). Additional urine studies, including a 24-hour urine sample, were collected for further evaluation. His urine uric acid was 140 mg/d (reference range, 120-820); his serum uric acid level was 8.2 mg/dL (reference range, 3.0-9.0). His 24-hour urine creatinine was 0.57 g/d (reference range, 0.50-2.15) and uric acid to creatinine ratio was 246 mg/g (reference range, 60-580). His serum creatinine collected from the same day as his 24-hour urine sample was 7.3 mg/dL. His fractional excretion of uric acid (FE_urate) was 21.9%.

Differential Diagnosis

The patient’s recent administration of cisplatin raised clinical suspicion of cisplatin-induced AKI. To avoid premature diagnostic closure, we used a systematic approach for thinking about our patient’s AKI, considering prerenal, intrarenal, and postrenal etiologies. The unremarkable renal and bladder ultrasound made a postrenal etiology unlikely. The patient’s 2.7% FE_Na in the absence of a diuretic, limited responsiveness to crystalloid fluid resuscitation, 7.5 serum BUN/creatinine ratio, and 270.5 mOsm/kg urine osmolality suggested an intrarenal etiology, which can be further divided into problems with glomeruli, tubules, small vessels, or interstitial space. The patient’s normal urinary microscopy with no evidence of protein, blood, ketones, leukocyte esterase, nitrites, or cellular casts made a glomerular etiology less likely. The acute onset and lack of additional systemic features, other than hypertension, made a vascular etiology less likely. A tubular etiology, such as acute tubular necrosis (ATN), was highest on the differential and was followed by an interstitial etiology, such as acute interstitial nephritis (AIN).

Patients with drug-induced AIN commonly present with signs and symptoms of an allergic-type reaction, including fever, rash, hematuria, pyuria, and costovertebral angle tenderness. The patient lacked these symptoms. However, cisplatin is known to cause ATN in up to 20-30% of patients.⁷ Therefore, despite the lack of the classic muddy-brown, granular casts on urine microscopy, cisplatin-induced ATN remained the most likely etiology of his AKI. Moreover, ATN can cause hyponatremia. ATN is characterized by 3 phases: initiation, maintenance, and recovery phases.⁸ Hyponatremia occurs during the recovery phase, typically starting weeks after renal insult and associated with high urine output and diuresis. This patient presented 1 week after injury and had persistent oliguria, making ATN an unlikely culprit of his hyponatremia.

Our patient presented with hypotonic hyponatremia with a 131 mmol/L initial sodium level and an < 280 mOsm/kg effective serum osmolality, or serum tonicity. The serum tonicity is equivalent to the difference between the measured serum osmolality and the BUN. In the setting of profound AKI, this adjustment is essential for correctly categorizing a patient’s hyponatremia as hyper-, iso-, or hypotonic. The differential diagnosis for this patient’s hypotonic hyponatremia included dilutional effects of hypervolemia, SIADH, hyperthyroidism, adrenal insufficiency, and RSWS. The patient’s volume examination, lack of predisposing comorbidities or suggestive biomarkers, and > 20 mmol/L urinary sodium made hypervolemia unlikely. His urinary osmolality and specific gravity made primary polydipsia unlikely. We worked up his hyponatremia according to a diagnostic algorithm (eAppendix available at doi:10.12788/fp.0198).

The patient had a 217 mOsm/kg serum tonicity and a 270.5 mOsm/kg urine osmolality, consistent with impaired water excretion. His presentation, TSH, and concordant decrease in sodium and potassium made an endocrine etiology of his hyponatremia less likely. In hindsight, a serum cortisol would have been beneficial to more completely exclude adrenal insufficiency. His urine sodium was elevated at 45 mmol/L, raising concern for RSWS or SIADH. The FE_urate helped to distinguish between SIADH and RSWS. While FE_urate is often elevated in both SIADH and RSWS initially, the FE_urate normalizes in SIADH with normalization of the serum sodium. The ideal cutoff for posthyponatremia correction FE_urate is debated; however, a FE_urate value after sodium correction < 11% suggests SIADH while a value > 11% suggests RSWS.⁹ Our patient’s FE_urate following the sodium correction (serum sodium 134 mmol/L) was 21.9%, most suggestive of RSWS.

Treatment

Upon admission, initial treatment focused on resolving the patient’s AKI. The oncology team discontinued the cisplatin-based chemotherapy. His medication dosages were adjusted for his renal function and additional nephrotoxins avoided. In consultation, the nephrology service recommended 100 mL/h fluid resuscitation. After the patient received 3 L of 0.9% sodium chloride, his creatinine showed limited improvement and his sodium worsened, trending from 131 mmol/L to a nadir of 125 mmol/L. We initiated oral free-water restriction while continuing IV infusion of 0.9% sodium chloride at 125 mL/h.

We further augmented his sodium intake with 1-g sodium chloride tablets with each meal. By hospital day 6, the patient’s serum sodium, BUN, and creatinine improved to 130 mEq/L, 50 mg/dL, and 7.7 mg/dL, respectively. We then discontinued the oral sodium chloride tablets, fluid restriction, and IV fluids in a stepwise fashion prior to discharge. At discharge, the patient’s serum sodium was 136 mEq/L and creatinine, 4.8 mg/dL. The patient’s clinical course was complicated by symptomatic hypertension with systolic blood pressures about 180 mm Hg, requiring intermittent IV hydralazine, which was transitioned to daily nifedipine. Concerned that fluid resuscitation contributed to his hypertension, the patient also received several doses of furosemide. At time of discharge, the patient remained hypertensive and was discharged with nifedipine 90 mg daily.

Outcome and Follow-up

The patient has remained stable clinically since discharge. One week after discharge, his serum sodium and creatinine were 138 mmol/L and 3.8 mg/dL, respectively. More than 1 month after discharge, his sodium remains in the reference range and his creatinine was stable at about 3.5 mg/dL. He continues to follow-up with nephrology, oncology, and radiation oncology. He has restarted chemotherapy with a carboplatin-based regimen without recurrence of hyponatremia or AKI. His blood pressure has gradually improved to the point where he no longer requires nifedipine.

Discussion

The US Food and Drug Administration first approved the use of cisplatin, an alkylating agent that inhibits DNA replication, in 1978 for the treatment of testicular cancer.¹⁰ Since its approval, cisplatin has increased in popularity and is now considered one of the most effective antineoplastic agents for the treatment of solid tumors.¹ Unfortunately, cisplatin has a well-documented adverse effect profile that includes neurotoxicity, gastrointestinal toxicity, nephrotoxicity, and ototoxicity.⁴ Despite frequent nephrotoxicity, cisplatin only occasionally causes hyponatremia and rarely causes RSWS, a known but potentially fatal complication. Moreover, the combination of AKI and RSWS is unique. Our patient presented with the unique combination of AKI and hyponatremia, most consistent with RSWS, likely precipitated from cisplatin chemotherapy. Through this case, we review cisplatin-associated electrolyte abnormalities, highlight the challenge of differentiating SIADH and RSWS, and suggest a treatment approach for hyponatremia during the period of diagnostic uncertainty.

Blachley and colleagues first discussed renal and electrolyte disturbances, specifically magnesium wasting, secondary to cisplatin use in 1981. In 1984, Kurtzberg and colleagues noted salt wasting in 2 patients receiving cisplatin therapy. The authors suggested that cisplatin inhibits solute transport in the thick ascending limb, causing clinically significant electrolyte abnormalities, coining the term cisplatin-induced salt wasting.¹¹

The prevalence of cisplatin-induced salt wasting is unclear and likely underreported. In 1988, Hutchinson and colleagues conducted a prospective cohort study and noted 10% of patients (n = 70) developed RSWS at some point over 18 months of cisplatin therapy—a higher rate than previously estimated.¹² In 1992, another prospective cohort study evaluated the adverse effects of 47 patients with non-small cell lung cancer treated with cisplatin and reported hyponatremia in 43% of its 93 courses of chemotherapy. The authors did not report the etiology of these hyponatremia cases.¹³ Given the diagnostic challenge, RSWS may be underrepresented as a confirmed etiology of hyponatremia in cisplatin treatment.

Hyponatremia from cisplatin may present as either SIADH or RSWS, complicating treatment decisions. Both conditions lead to hypotonic hyponatremia with urine osmolality > 100 mOSm/kg and urine sodium levels > 40 mmol/L. However, pathophysiology behind SIADH and RSWS is different. In RSWS, proximal tubule damage causes hyponatremia, decreasing sodium reabsorption, and leading to impaired concentration gradient in every segment of the nephron. As a result, RSWS can lead to profound hyponatremia. Treatment typically consists of increasing sodium intake to correct serum sodium with salt tablets and hypertonic sodium chloride while treating the underlying etiology, in our case removing the offending agent, and waiting for proximal tubule function to recover.⁶ On the other hand, in SIADH, elevated antidiuretic hormone (ADH) increases water reabsorption in the collecting duct, which has no impact on concentration gradients of the other nephron segments.¹⁴ Free-water restriction is the hallmark of SIADH treatment. Severe SIADH may require sodium repletion and/or the initiation of vaptans, ADH antagonists that competitively inhibit V2 receptors in the collecting duct to prevent water reabsorption.¹⁵

Our patient had an uncertain etiology of his hyponatremia throughout most of his treatment course, complicating our treatment decision-making. Initially, his measured serum osmolality was 278 mOsm/kg; however, his effective tonicity was lower. His AKI elevated his BUN, which in turnrequired us to calculate his serum tonicity (217 mOsm/kg) that was consistent with hypotonic hyponatremia. His elevated urine osmolality and urine sodium levels made SIADH and RSWS the most likely etiologies of his hyponatremia. To confirm the etiology, we waited for correction of his serum sodium. Therefore, we treated him with a combination of sodium repletion with 0.9% sodium chloride (154 mEq/L), hypertonic relative to his serum sodium, sodium chloride tablets, and free-water restriction. In this approach, we attempted to harmonize the treatment strategies for both SIADH and RSWS and effectively corrected his serum sodium. We evaluated his response to our treatment with a basic metabolic panel every 6 to 8 hours. Had his serum sodium decreased < 120 mmol/L, we planned to transfer the patient to the intensive care unit for 3% sodium chloride and/or intensification of his fluid restriction. A significant worsening of his hyponatremia would have strongly suggested hyponatremia secondary to SIADH since isotonic saline can worsen hyponatremia due to increased free-water reabsorption in the collecting duct.¹⁶

To differentiate between SIADH and RSWS, we relied on the FE_urate after sodium correction. Multiple case reports from Japan have characterized the distinction between the processes through FE_urate and serum uric acid. While the optimal cut-off values for FE_urate require additional investigation, values < 11% after serum sodium correction suggests SIADH, while a value > 11% suggests RSWS.¹⁷ Prior cases have also emphasized serum hypouricemia as a distinguishing characteristic in RSWS. However, our case illustrates that serum hypouricemia is less reliable in the setting of AKI. Due to his severe AKI, our patient could not efficiently clear uric acid, likely contributing to his hyperuricemia.

Ultimately, our patient had an FE_urate > 20%, which was suggestive of RSWS. Nevertheless, we recognize limitations and confounders in our diagnosis and have reflected on our diagnostic and management choices. First, the sensitivity and specificity of postsodium correction FE_urate is unknown. Tracking the change in FE_urate with our interventions would have increased our diagnostic utility, as suggested by Maesaka and colleagues.¹⁴ Second, our patient’s serum sodium was still at the lower end of the reference range after treatment, which may decrease the specificity of FE_urate. Third, a plasma ADH collected during the initial phase of symptomatic hyponatremia would have helped differentiate between SIADH and RSWS.

Other diagnostic tests that could have excluded alternative diagnoses with even greater certainty include plasma adrenocorticotropic hormone, B-type natriuretic peptide, renin, cortisol, and thyroid function tests. From a practical standpoint, these laboratory results (excluding thyroid function test and brain natriuretic peptide) would have taken several weeks to result at our institution, limiting their clinical utility. Similarly, FE_urate also has limited clinical utility, requiring effective treatment as part of the diagnostic test. Therefore, we recommend focusing on optimal treatment for hyponatremia of uncertain etiology, especially where SIADH and RSWS are the leading diagnoses.

Conclusions

We described a rare case of concomitant cisplatin-induced severe AKI and RSWS. We have emphasized the diagnostic challenge of distinguishing between SIADH and RSWS, especially with concomitant AKI, and have acknowledged that optimal treatment relies on accurate differentiation. However, differentiation may not be clinically feasible. Therefore, we suggest a treatment strategy that incorporates both free-water restriction and sodium supplementation via IV and/or oral administration.

Cisplatin is a potent antineoplastic agent derived from platinum and commonly used in the treatment of head and neck, bladder, ovarian, and testicular malignancies.^1,2 Approximately 20% of all cancer patients are prescribed platinum-based chemotherapeutics.³ Although considered highly effective, cisplatin is also a dose-dependent nephrotoxin, inducing apoptosis in the proximal tubules of the nephron and reducing glomerular filtration rate. This nephron injury leads to inflammation and reduced medullary blood flow, causing further ischemic damage to the tubular cells.⁴ Given that the proximal tubule reabsorbs 67% of all sodium, cisplatin-induced nephron injuries can also lead to hyponatremia.⁵

The primary mechanisms of hyponatremia following cisplatin chemotherapy are syndrome of inappropriate antidiuretic hormone secretion (SIADH) and renal salt wasting syndrome (RSWS). Though these diagnoses have similar presentations, the treatment recommendations are different due to pathophysiologic differences. Fluid restriction is the hallmark of SIADH treatment, while increased sodium intake remains the hallmark of RSWS treatment.⁶ This patient presented with a combination of cisplatin-induced acute kidney injury (AKI) and hyponatremia secondary to RSWS. While RSWS and AKI are known complications of cisplatin chemotherapy, the combination is underreported in the literature. Therefore, this case report highlights the combination of these cisplatin-induced complications, emphasizes the clinical challenges in differentiating SIADH from RSWS, especially in the presence of a concomitant AKI, and suggests a treatment approach during diagnostic uncertainty.

Case Presentation

A 71-year-old man with a medical history of squamous cell carcinoma (SCC) of the left neck on cycle 1, day 8 of cisplatin-based chemotherapy and ongoing radiation therapy (720 cGy of 6300 cGy), lung adenocarcinoma status postresection, and hyperlipidemia presented to the emergency department (ED) at the request of his oncologist for abnormal laboratory values. In the ED, his metabolic panel showed a 131-mmol/L serum sodium, 3.3 mmol/L potassium, 83 mmol/L chloride, 29 mmol/L bicarbonate, 61 mg/dL blood urea nitrogen (BUN), and 8.8 mg/dL creatinine (baseline, 0.9 mg/dL). The patient reported throbbing headaches, persistent nausea, and multiple episodes of nonbloody emesis for several days that he attributed to his chemotherapy. He noted decreased urination without discomfort or changes in color or odor and no fatigue, fevers, chills, hematuria, flank, abdominal pain, thirst, or polydipsia. He reported no toxic ingestions or IV drug use. The patient had no relevant family history or additional social history. His outpatient medications included 10 mg cetirizine, 8 mg ondansetron, and 81 mg aspirin. On initial examination, his 137/66 mm Hg blood pressure was mildly elevated. The physical examination findings were notable for a 5-cm mass in the left neck that was firm and irregularly-shaped. His physical examination was otherwise unremarkable. He was admitted to the inpatient medicine service for an AKI complicated by symptomatic hyponatremia.

Investigations

We evaluated the patient’s AKI based on treatment responsiveness, imaging, and laboratory testing. Renal and bladder ultrasound showed no evidence of hydronephrosis or obstruction. He had a benign urinalysis with microscopy absent for protein, blood, ketones, leukocyte esterase, nitrites, and cellular casts. His urine pH was 5.5 (reference range, 5.0-9.0) and specific gravity was 1.011 (reference range, 1.005-1.030). His urine electrolytes revealed 45-mmol/L urine sodium (reference range, 40-220), 33-mmol/L urine chloride (reference range, 110-250), 10-mmol/L urine potassium (reference range, 25-120), 106.7-mg/dL urine creatinine (reference range, 10-400) and a calculated 2.7% fractional excretion of sodium (FE_Na) and 22.0-mEq/L elevated urine anion gap. As a fluid challenge, he was treated with IV 0.9% sodium chloride at 100-125 mL/h, receiving 3 liters over the first 48 hours of his hospitalization. His creatinine peaked at 9.2 mg/dL and stabilized before improving later in his hospitalization (Figure 1). The patient initially had oliguria (< 0.5 mL/kg/h), which slowly improved over his hospital course. Unfortunately, due to multiple system and clinical factors, accurate inputs and outputs were not adequately maintained during his hospitalization.

We evaluated hyponatremia with a combination of serum and urine laboratory tests. In addition to urine electrolytes, the initial evaluation focused on trending his clinical trajectory. We repeated a basic metabolic panel every 4 to 6 hours. He had 278-mOsm/kg serum osmolality (reference range, 285-295) with an effective 217-mOsm/kg serum tonicity. His urine osmolality was 270.5 mOsm/kg.

Despite administering 462 mEq sodium via crystalloid, his sodium worsened over the first 48 hours, reaching a nadir at 125 mmol/L on hospital day 3 (Figure 2). While he continued to appear euvolemic on physical examination, his blood pressure became difficult to control with 160- to 180-mm Hg systolic blood pressure readings. His thyroid stimulating hormone (TSH) was normal and aldosterone was low (4 ng/dL). Additional urine studies, including a 24-hour urine sample, were collected for further evaluation. His urine uric acid was 140 mg/d (reference range, 120-820); his serum uric acid level was 8.2 mg/dL (reference range, 3.0-9.0). His 24-hour urine creatinine was 0.57 g/d (reference range, 0.50-2.15) and uric acid to creatinine ratio was 246 mg/g (reference range, 60-580). His serum creatinine collected from the same day as his 24-hour urine sample was 7.3 mg/dL. His fractional excretion of uric acid (FE_urate) was 21.9%.

Differential Diagnosis

The patient’s recent administration of cisplatin raised clinical suspicion of cisplatin-induced AKI. To avoid premature diagnostic closure, we used a systematic approach for thinking about our patient’s AKI, considering prerenal, intrarenal, and postrenal etiologies. The unremarkable renal and bladder ultrasound made a postrenal etiology unlikely. The patient’s 2.7% FE_Na in the absence of a diuretic, limited responsiveness to crystalloid fluid resuscitation, 7.5 serum BUN/creatinine ratio, and 270.5 mOsm/kg urine osmolality suggested an intrarenal etiology, which can be further divided into problems with glomeruli, tubules, small vessels, or interstitial space. The patient’s normal urinary microscopy with no evidence of protein, blood, ketones, leukocyte esterase, nitrites, or cellular casts made a glomerular etiology less likely. The acute onset and lack of additional systemic features, other than hypertension, made a vascular etiology less likely. A tubular etiology, such as acute tubular necrosis (ATN), was highest on the differential and was followed by an interstitial etiology, such as acute interstitial nephritis (AIN).

Patients with drug-induced AIN commonly present with signs and symptoms of an allergic-type reaction, including fever, rash, hematuria, pyuria, and costovertebral angle tenderness. The patient lacked these symptoms. However, cisplatin is known to cause ATN in up to 20-30% of patients.⁷ Therefore, despite the lack of the classic muddy-brown, granular casts on urine microscopy, cisplatin-induced ATN remained the most likely etiology of his AKI. Moreover, ATN can cause hyponatremia. ATN is characterized by 3 phases: initiation, maintenance, and recovery phases.⁸ Hyponatremia occurs during the recovery phase, typically starting weeks after renal insult and associated with high urine output and diuresis. This patient presented 1 week after injury and had persistent oliguria, making ATN an unlikely culprit of his hyponatremia.

Our patient presented with hypotonic hyponatremia with a 131 mmol/L initial sodium level and an < 280 mOsm/kg effective serum osmolality, or serum tonicity. The serum tonicity is equivalent to the difference between the measured serum osmolality and the BUN. In the setting of profound AKI, this adjustment is essential for correctly categorizing a patient’s hyponatremia as hyper-, iso-, or hypotonic. The differential diagnosis for this patient’s hypotonic hyponatremia included dilutional effects of hypervolemia, SIADH, hyperthyroidism, adrenal insufficiency, and RSWS. The patient’s volume examination, lack of predisposing comorbidities or suggestive biomarkers, and > 20 mmol/L urinary sodium made hypervolemia unlikely. His urinary osmolality and specific gravity made primary polydipsia unlikely. We worked up his hyponatremia according to a diagnostic algorithm (eAppendix available at doi:10.12788/fp.0198).

The patient had a 217 mOsm/kg serum tonicity and a 270.5 mOsm/kg urine osmolality, consistent with impaired water excretion. His presentation, TSH, and concordant decrease in sodium and potassium made an endocrine etiology of his hyponatremia less likely. In hindsight, a serum cortisol would have been beneficial to more completely exclude adrenal insufficiency. His urine sodium was elevated at 45 mmol/L, raising concern for RSWS or SIADH. The FE_urate helped to distinguish between SIADH and RSWS. While FE_urate is often elevated in both SIADH and RSWS initially, the FE_urate normalizes in SIADH with normalization of the serum sodium. The ideal cutoff for posthyponatremia correction FE_urate is debated; however, a FE_urate value after sodium correction < 11% suggests SIADH while a value > 11% suggests RSWS.⁹ Our patient’s FE_urate following the sodium correction (serum sodium 134 mmol/L) was 21.9%, most suggestive of RSWS.

Treatment

Upon admission, initial treatment focused on resolving the patient’s AKI. The oncology team discontinued the cisplatin-based chemotherapy. His medication dosages were adjusted for his renal function and additional nephrotoxins avoided. In consultation, the nephrology service recommended 100 mL/h fluid resuscitation. After the patient received 3 L of 0.9% sodium chloride, his creatinine showed limited improvement and his sodium worsened, trending from 131 mmol/L to a nadir of 125 mmol/L. We initiated oral free-water restriction while continuing IV infusion of 0.9% sodium chloride at 125 mL/h.

We further augmented his sodium intake with 1-g sodium chloride tablets with each meal. By hospital day 6, the patient’s serum sodium, BUN, and creatinine improved to 130 mEq/L, 50 mg/dL, and 7.7 mg/dL, respectively. We then discontinued the oral sodium chloride tablets, fluid restriction, and IV fluids in a stepwise fashion prior to discharge. At discharge, the patient’s serum sodium was 136 mEq/L and creatinine, 4.8 mg/dL. The patient’s clinical course was complicated by symptomatic hypertension with systolic blood pressures about 180 mm Hg, requiring intermittent IV hydralazine, which was transitioned to daily nifedipine. Concerned that fluid resuscitation contributed to his hypertension, the patient also received several doses of furosemide. At time of discharge, the patient remained hypertensive and was discharged with nifedipine 90 mg daily.

Outcome and Follow-up

The patient has remained stable clinically since discharge. One week after discharge, his serum sodium and creatinine were 138 mmol/L and 3.8 mg/dL, respectively. More than 1 month after discharge, his sodium remains in the reference range and his creatinine was stable at about 3.5 mg/dL. He continues to follow-up with nephrology, oncology, and radiation oncology. He has restarted chemotherapy with a carboplatin-based regimen without recurrence of hyponatremia or AKI. His blood pressure has gradually improved to the point where he no longer requires nifedipine.

Discussion

The US Food and Drug Administration first approved the use of cisplatin, an alkylating agent that inhibits DNA replication, in 1978 for the treatment of testicular cancer.¹⁰ Since its approval, cisplatin has increased in popularity and is now considered one of the most effective antineoplastic agents for the treatment of solid tumors.¹ Unfortunately, cisplatin has a well-documented adverse effect profile that includes neurotoxicity, gastrointestinal toxicity, nephrotoxicity, and ototoxicity.⁴ Despite frequent nephrotoxicity, cisplatin only occasionally causes hyponatremia and rarely causes RSWS, a known but potentially fatal complication. Moreover, the combination of AKI and RSWS is unique. Our patient presented with the unique combination of AKI and hyponatremia, most consistent with RSWS, likely precipitated from cisplatin chemotherapy. Through this case, we review cisplatin-associated electrolyte abnormalities, highlight the challenge of differentiating SIADH and RSWS, and suggest a treatment approach for hyponatremia during the period of diagnostic uncertainty.

Blachley and colleagues first discussed renal and electrolyte disturbances, specifically magnesium wasting, secondary to cisplatin use in 1981. In 1984, Kurtzberg and colleagues noted salt wasting in 2 patients receiving cisplatin therapy. The authors suggested that cisplatin inhibits solute transport in the thick ascending limb, causing clinically significant electrolyte abnormalities, coining the term cisplatin-induced salt wasting.¹¹

The prevalence of cisplatin-induced salt wasting is unclear and likely underreported. In 1988, Hutchinson and colleagues conducted a prospective cohort study and noted 10% of patients (n = 70) developed RSWS at some point over 18 months of cisplatin therapy—a higher rate than previously estimated.¹² In 1992, another prospective cohort study evaluated the adverse effects of 47 patients with non-small cell lung cancer treated with cisplatin and reported hyponatremia in 43% of its 93 courses of chemotherapy. The authors did not report the etiology of these hyponatremia cases.¹³ Given the diagnostic challenge, RSWS may be underrepresented as a confirmed etiology of hyponatremia in cisplatin treatment.

Hyponatremia from cisplatin may present as either SIADH or RSWS, complicating treatment decisions. Both conditions lead to hypotonic hyponatremia with urine osmolality > 100 mOSm/kg and urine sodium levels > 40 mmol/L. However, pathophysiology behind SIADH and RSWS is different. In RSWS, proximal tubule damage causes hyponatremia, decreasing sodium reabsorption, and leading to impaired concentration gradient in every segment of the nephron. As a result, RSWS can lead to profound hyponatremia. Treatment typically consists of increasing sodium intake to correct serum sodium with salt tablets and hypertonic sodium chloride while treating the underlying etiology, in our case removing the offending agent, and waiting for proximal tubule function to recover.⁶ On the other hand, in SIADH, elevated antidiuretic hormone (ADH) increases water reabsorption in the collecting duct, which has no impact on concentration gradients of the other nephron segments.¹⁴ Free-water restriction is the hallmark of SIADH treatment. Severe SIADH may require sodium repletion and/or the initiation of vaptans, ADH antagonists that competitively inhibit V2 receptors in the collecting duct to prevent water reabsorption.¹⁵

Our patient had an uncertain etiology of his hyponatremia throughout most of his treatment course, complicating our treatment decision-making. Initially, his measured serum osmolality was 278 mOsm/kg; however, his effective tonicity was lower. His AKI elevated his BUN, which in turnrequired us to calculate his serum tonicity (217 mOsm/kg) that was consistent with hypotonic hyponatremia. His elevated urine osmolality and urine sodium levels made SIADH and RSWS the most likely etiologies of his hyponatremia. To confirm the etiology, we waited for correction of his serum sodium. Therefore, we treated him with a combination of sodium repletion with 0.9% sodium chloride (154 mEq/L), hypertonic relative to his serum sodium, sodium chloride tablets, and free-water restriction. In this approach, we attempted to harmonize the treatment strategies for both SIADH and RSWS and effectively corrected his serum sodium. We evaluated his response to our treatment with a basic metabolic panel every 6 to 8 hours. Had his serum sodium decreased < 120 mmol/L, we planned to transfer the patient to the intensive care unit for 3% sodium chloride and/or intensification of his fluid restriction. A significant worsening of his hyponatremia would have strongly suggested hyponatremia secondary to SIADH since isotonic saline can worsen hyponatremia due to increased free-water reabsorption in the collecting duct.¹⁶

To differentiate between SIADH and RSWS, we relied on the FE_urate after sodium correction. Multiple case reports from Japan have characterized the distinction between the processes through FE_urate and serum uric acid. While the optimal cut-off values for FE_urate require additional investigation, values < 11% after serum sodium correction suggests SIADH, while a value > 11% suggests RSWS.¹⁷ Prior cases have also emphasized serum hypouricemia as a distinguishing characteristic in RSWS. However, our case illustrates that serum hypouricemia is less reliable in the setting of AKI. Due to his severe AKI, our patient could not efficiently clear uric acid, likely contributing to his hyperuricemia.

Ultimately, our patient had an FE_urate > 20%, which was suggestive of RSWS. Nevertheless, we recognize limitations and confounders in our diagnosis and have reflected on our diagnostic and management choices. First, the sensitivity and specificity of postsodium correction FE_urate is unknown. Tracking the change in FE_urate with our interventions would have increased our diagnostic utility, as suggested by Maesaka and colleagues.¹⁴ Second, our patient’s serum sodium was still at the lower end of the reference range after treatment, which may decrease the specificity of FE_urate. Third, a plasma ADH collected during the initial phase of symptomatic hyponatremia would have helped differentiate between SIADH and RSWS.

Other diagnostic tests that could have excluded alternative diagnoses with even greater certainty include plasma adrenocorticotropic hormone, B-type natriuretic peptide, renin, cortisol, and thyroid function tests. From a practical standpoint, these laboratory results (excluding thyroid function test and brain natriuretic peptide) would have taken several weeks to result at our institution, limiting their clinical utility. Similarly, FE_urate also has limited clinical utility, requiring effective treatment as part of the diagnostic test. Therefore, we recommend focusing on optimal treatment for hyponatremia of uncertain etiology, especially where SIADH and RSWS are the leading diagnoses.

Conclusions

We described a rare case of concomitant cisplatin-induced severe AKI and RSWS. We have emphasized the diagnostic challenge of distinguishing between SIADH and RSWS, especially with concomitant AKI, and have acknowledged that optimal treatment relies on accurate differentiation. However, differentiation may not be clinically feasible. Therefore, we suggest a treatment strategy that incorporates both free-water restriction and sodium supplementation via IV and/or oral administration.

Ease of access to opioids in the perioperative period is a risk factor for opioid misuse and has been identified as a strong risk factor for heroin use.^1,2 Three-quarters of today’s heroin users were introduced to opioids through prescription medications.² The United States accounts for about 80% of the global opioid supply consumption, and deaths from opioid overdose are increasing: 70,630 deaths in 2019 alone.^3,4

The Centers for Disease Control and Prevention (CDC) has called for changes in opioid prescribing. The American Academy of Orthopaedic Surgeons (AAOS) also has published an information statement with strategies to decrease opioid misuse and abuse.^5,6 Arthroplasty surgeons have recently focused on decreasing use of opioids in total knee arthroplasty (TKA), a procedure traditionally associated with high levels of opioid consumption and historical reliance on opioid monotherapy for postoperative analgesia.^7,8 From a clinical perspective, prolonged postoperative opioid use contributes to poorer surgical outcomes due to increased risk of complications, including stiffness, infection, and revision TKA.⁹

Multimodal pain regimens are increasingly being used to control postoperative pain as data supports their efficacy.^10,11 Previous studies have found that simultaneous modulation of multiple pain pathways decreases narcotics consumption and improves patient outcomes.^12,13 Along with other adjuvant therapies, peripheral nerve blocks, such as adductor canal block (ACB) and femoral nerve block (FNB), have been used to decrease postoperative pain.¹⁴ Studies have shown that ACB has fewer complications and shorter functional recovery times compared with FNB.^15,16 The distribution of the ACB excludes the femoral nerve, thus preserving greater quadriceps strength while providing equivalent levels of analgesia compared with FNB.^15,17,18 The ACB has shown decreased near-fall events and improved balance scores in the immediate postoperative period.¹⁹

Our study analyzed opioid consumption patterns of TKA patients from a US Department of Veterans Affairs (VA) medical center before and after the institution of a multimodal analgesic protocol using ACB. The primary purpose of this study was to determine whether a protocol that included intraoperative spinal anesthesia with a postoperative multimodal analgesic regimen and ACB was associated with a decreased postoperative opioid requirement when compared with patients who received intraoperative general anesthesia and a traditional opioid regimen. Secondary outcomes included the effect of opioid consumption on range of motion on postoperative day (POD) 1 and number of opioid prescriptions written at the first postoperative clinic visit.

Methods

Approval for the study was obtained from the institutional review board at the Dayton Veterans Affairs Medical Center (DVAMC) in Ohio. A retrospective chart review was performed to collect data from all patients undergoing TKA at DVAMC from June 1, 2011, through December 31, 2015. Exclusion criteria included multiple surgeries in the study time frame, documented chronic pain, allergy to local anesthetics, daily preoperative use of opioids, and incomplete data in the health record.

All surgeries were performed by 2 staff arthroplasty surgeons at a single VAMC. All patients attended a preoperative visit where a history, physical, and anesthesia evaluation were performed, and watched an educational video detailing surgical indications and postoperative rehabilitation. All surgeries were performed with tourniquets and a periarticular injection was performed at the conclusion of each case. Surgeon 1 treatment of choice was 10 mL 0.5% bupivacaine, whereas surgeon 2 performed a posterior capsular injection of 30 mL 0.25% bupivacaine and a periarticular injection of 30 mg ketorolac in 10 mL 0.25% bupivacaine with epinephrine.

Prior to August 2014, general endotracheal anesthesia was used intraoperatively. A patient-controlled analgesia (PCA) pump of morphine or hydromorphone and additional oral oxycodone or hydrocodone was used for postoperative pain. PCA pumps were patient dependent. In the control group, 245 patients received the morphine PCA while 61 received the hydromorphone PCA. Morphine PCA dosing consisted of 1-mg doses every 10 minutes with potential baseline infusion rates of 0.5 to 1.0 mg/h and a 4-hour limit of 20 mg. Hydromorphone PCA dosing consisted of 0.2 to 0.4-mg doses with a potential continuous dose of 0.2 to 0.4 mg/h and a 4-hour limit of 4 mg.

Results

During the study period from June 1, 2011, through December 31, 2015, 533 eligible TKAs were performed, 306 in the control group and 227 in the protocol group. The groups had similar sex distribution; body mass index; knee range of motion; diagnoses of diabetes mellitus, coronary artery disease, and chronic kidney disease; and history of deep vein thrombosis (DVT) or pulmonary embolism (P ≥ .05). The protocol group was significantly older (P = .04) and had a significantly higher rate of chronic obstructive pulmonary disease (COPD) (P = .002). There were no significant differences between number of procedures performed by surgeon (P = .48) or total tourniquet time (P = .13) (Table 2). Mean (SD) length of stay was significantly greater in the control group compared with the protocol group (2.5 [1.3] vs 1.4 [0.7] days, P < .001).

Figure 1 shows the distributions of each type of opioid used. Compared with the control group, the protocol group had a significantly lower mean (SD) IV opioid use: 178.2 (98.0) MED vs 12.0 (24.6) MED (P < .001; d = 2.19; Δ = 0.94) and mean (SD) total opioid use: 241.7 (120.1) MED vs 74.8 (42.7) MED (P < .001; d = 1.76; Δ = 0.89). Mean (SD) oral opioid use did not differ between groups (control, 63.6 [45.4] MED; protocol, 62.9 [31.4] MED; P = .85; d = 0.02; Δ = 0.51). A significantly lower percentage of patients in the protocol group received additional opioids at the 3-week follow-up when compared to the control group: 46.7% vs 61.3%, respectively (P < .001; RR, 0.76; 95% CI, 0.65-0.90).

Discussion

Coordinated efforts with major medical organizations are being made to decrease opioid prescriptions and exposure.^5,6 To our knowledge, no study has quantified a decrease in opioid requirement in a VA population after implementation of a protocol that includes intraoperative spinal anesthesia and a postoperative multimodal analgesic regimen including ACB after TKA. The analgesic protocol described in this study aligns with recommendations from both the CDC and the AAOS to decrease opioid use and misuse by maximizing nonopioid medications and limiting the size and number of opioid prescriptions. However, public and medical opinion of opioids as well as prescribing practices have changed over time with a trend toward lower opioid use. The interventions, as part of the described protocol, are a result of these changes and attempt to minimize opioid use while maximizing postoperative analgesia.

Our data showed a significant decrease in total opioid use through POD 1, IV opioid use, and opioid prescriptions provided at the first postoperative visit. The protocol group used only 6.7% of the IV opioids and 30.9% of the total opioids that were used by the control group. The substantial difference in IV opioid requirement, 166.2 MED, is equivalent to 8 mg of IV hydromorphone or 55 mg of IV morphine. The difference in total opioid requirement was similar at 166.9 MED, equivalent to 111 mg of oral oxycodone.

Decreasing opioid use has the additional benefit of improving outcomes, as higher doses of opioids have been associated with increased length of stay, greater rates of DVT, and postoperative infection.²³ These complications occurred in a stepwise manner, suggesting a dose-response gradient that makes the sizable decrease noted in our data of greater relevance.²³ While the adverse effects (AEs) of opioids are well known, there are limited data on opioid dosing and its effect on perioperative outcomes.²³

A significant decrease in the percentage of patients receiving an opioid prescription at the first postoperative visit suggests a decrease in the number of patients on prolonged opioids after TKA with implementation of modern analgesic modalities. The duration of postoperative opioid use has been found to be the strongest predictor of misuse, and each postoperative refill increases the probability of misuse by 44%.²⁴ In addition, opioid use for > 3 months after TKA is associated with increased risk of periprosthetic infection, increased overall revision rate, and stiffness at 1 year postoperatively.⁹ While not entirely under the control of the surgeon, measures to decrease the number of postoperative opioid refills may lead to a decrease in opioid misuse.

Limitations

A number of limitations of this study should be noted. One was a protocol change regarding length of stay, which occurred during the study period and resulted in a significantly shorter length of stay in the protocol group. As a result, opioid use data were analyzed only through midnight at the end of POD 1. Patients who were discharged on POD 1 did not have opioid use data available for the full duration of the first POD, which may exaggerate the decrease in opioid requirements, as opioids used after discharge but prior to midnight on POD 1 were not recorded. However, opioids taken at home are oral with a low MME compared with IV opioids received by hospitalized patients in the control group. In addition, if taken as prescribed, patients at home would only have enough time to take a few doses of opioids prior to the midnight cutoff. We do not believe this difference in time of opioid use meaningfully affected the data. An additional limitation includes the variability between periarticular injections between surgeons. While the percentage of patients that received injections from surgeon 1 vs surgeon 2 were similar, it cannot be ruled out as a potential confounding factor. Other limitations include a lack of pain scores to compare subjective pain ratings, the retrospective nature of the study, and a largely homogenous male VA population.

Conclusions

Ease of access to opioids is a risk factor for opioid abuse, which itself is a risk factor for subsequent heroin use.^1,2 The CDC and AAOS have thus published recommendations regarding opioid prescribing practices to decrease opioid use and abuse.^5,6 Our described protocol, which aligns with these recommendations, resulted in a significant decrease in IV opioid requirement, total opioid requirement, and lower rates of opioid prescriptions provided at the first postoperative visit. These promising findings demonstrate a lower percentage of patients on long-term opioids after TKA and a significantly decreased cumulative opioid exposure.

Ease of access to opioids in the perioperative period is a risk factor for opioid misuse and has been identified as a strong risk factor for heroin use.^1,2 Three-quarters of today’s heroin users were introduced to opioids through prescription medications.² The United States accounts for about 80% of the global opioid supply consumption, and deaths from opioid overdose are increasing: 70,630 deaths in 2019 alone.^3,4

The Centers for Disease Control and Prevention (CDC) has called for changes in opioid prescribing. The American Academy of Orthopaedic Surgeons (AAOS) also has published an information statement with strategies to decrease opioid misuse and abuse.^5,6 Arthroplasty surgeons have recently focused on decreasing use of opioids in total knee arthroplasty (TKA), a procedure traditionally associated with high levels of opioid consumption and historical reliance on opioid monotherapy for postoperative analgesia.^7,8 From a clinical perspective, prolonged postoperative opioid use contributes to poorer surgical outcomes due to increased risk of complications, including stiffness, infection, and revision TKA.⁹

Multimodal pain regimens are increasingly being used to control postoperative pain as data supports their efficacy.^10,11 Previous studies have found that simultaneous modulation of multiple pain pathways decreases narcotics consumption and improves patient outcomes.^12,13 Along with other adjuvant therapies, peripheral nerve blocks, such as adductor canal block (ACB) and femoral nerve block (FNB), have been used to decrease postoperative pain.¹⁴ Studies have shown that ACB has fewer complications and shorter functional recovery times compared with FNB.^15,16 The distribution of the ACB excludes the femoral nerve, thus preserving greater quadriceps strength while providing equivalent levels of analgesia compared with FNB.^15,17,18 The ACB has shown decreased near-fall events and improved balance scores in the immediate postoperative period.¹⁹

Our study analyzed opioid consumption patterns of TKA patients from a US Department of Veterans Affairs (VA) medical center before and after the institution of a multimodal analgesic protocol using ACB. The primary purpose of this study was to determine whether a protocol that included intraoperative spinal anesthesia with a postoperative multimodal analgesic regimen and ACB was associated with a decreased postoperative opioid requirement when compared with patients who received intraoperative general anesthesia and a traditional opioid regimen. Secondary outcomes included the effect of opioid consumption on range of motion on postoperative day (POD) 1 and number of opioid prescriptions written at the first postoperative clinic visit.

Methods

Approval for the study was obtained from the institutional review board at the Dayton Veterans Affairs Medical Center (DVAMC) in Ohio. A retrospective chart review was performed to collect data from all patients undergoing TKA at DVAMC from June 1, 2011, through December 31, 2015. Exclusion criteria included multiple surgeries in the study time frame, documented chronic pain, allergy to local anesthetics, daily preoperative use of opioids, and incomplete data in the health record.

All surgeries were performed by 2 staff arthroplasty surgeons at a single VAMC. All patients attended a preoperative visit where a history, physical, and anesthesia evaluation were performed, and watched an educational video detailing surgical indications and postoperative rehabilitation. All surgeries were performed with tourniquets and a periarticular injection was performed at the conclusion of each case. Surgeon 1 treatment of choice was 10 mL 0.5% bupivacaine, whereas surgeon 2 performed a posterior capsular injection of 30 mL 0.25% bupivacaine and a periarticular injection of 30 mg ketorolac in 10 mL 0.25% bupivacaine with epinephrine.

Prior to August 2014, general endotracheal anesthesia was used intraoperatively. A patient-controlled analgesia (PCA) pump of morphine or hydromorphone and additional oral oxycodone or hydrocodone was used for postoperative pain. PCA pumps were patient dependent. In the control group, 245 patients received the morphine PCA while 61 received the hydromorphone PCA. Morphine PCA dosing consisted of 1-mg doses every 10 minutes with potential baseline infusion rates of 0.5 to 1.0 mg/h and a 4-hour limit of 20 mg. Hydromorphone PCA dosing consisted of 0.2 to 0.4-mg doses with a potential continuous dose of 0.2 to 0.4 mg/h and a 4-hour limit of 4 mg.

Results

During the study period from June 1, 2011, through December 31, 2015, 533 eligible TKAs were performed, 306 in the control group and 227 in the protocol group. The groups had similar sex distribution; body mass index; knee range of motion; diagnoses of diabetes mellitus, coronary artery disease, and chronic kidney disease; and history of deep vein thrombosis (DVT) or pulmonary embolism (P ≥ .05). The protocol group was significantly older (P = .04) and had a significantly higher rate of chronic obstructive pulmonary disease (COPD) (P = .002). There were no significant differences between number of procedures performed by surgeon (P = .48) or total tourniquet time (P = .13) (Table 2). Mean (SD) length of stay was significantly greater in the control group compared with the protocol group (2.5 [1.3] vs 1.4 [0.7] days, P < .001).

Figure 1 shows the distributions of each type of opioid used. Compared with the control group, the protocol group had a significantly lower mean (SD) IV opioid use: 178.2 (98.0) MED vs 12.0 (24.6) MED (P < .001; d = 2.19; Δ = 0.94) and mean (SD) total opioid use: 241.7 (120.1) MED vs 74.8 (42.7) MED (P < .001; d = 1.76; Δ = 0.89). Mean (SD) oral opioid use did not differ between groups (control, 63.6 [45.4] MED; protocol, 62.9 [31.4] MED; P = .85; d = 0.02; Δ = 0.51). A significantly lower percentage of patients in the protocol group received additional opioids at the 3-week follow-up when compared to the control group: 46.7% vs 61.3%, respectively (P < .001; RR, 0.76; 95% CI, 0.65-0.90).

Discussion

Coordinated efforts with major medical organizations are being made to decrease opioid prescriptions and exposure.^5,6 To our knowledge, no study has quantified a decrease in opioid requirement in a VA population after implementation of a protocol that includes intraoperative spinal anesthesia and a postoperative multimodal analgesic regimen including ACB after TKA. The analgesic protocol described in this study aligns with recommendations from both the CDC and the AAOS to decrease opioid use and misuse by maximizing nonopioid medications and limiting the size and number of opioid prescriptions. However, public and medical opinion of opioids as well as prescribing practices have changed over time with a trend toward lower opioid use. The interventions, as part of the described protocol, are a result of these changes and attempt to minimize opioid use while maximizing postoperative analgesia.

Our data showed a significant decrease in total opioid use through POD 1, IV opioid use, and opioid prescriptions provided at the first postoperative visit. The protocol group used only 6.7% of the IV opioids and 30.9% of the total opioids that were used by the control group. The substantial difference in IV opioid requirement, 166.2 MED, is equivalent to 8 mg of IV hydromorphone or 55 mg of IV morphine. The difference in total opioid requirement was similar at 166.9 MED, equivalent to 111 mg of oral oxycodone.

Decreasing opioid use has the additional benefit of improving outcomes, as higher doses of opioids have been associated with increased length of stay, greater rates of DVT, and postoperative infection.²³ These complications occurred in a stepwise manner, suggesting a dose-response gradient that makes the sizable decrease noted in our data of greater relevance.²³ While the adverse effects (AEs) of opioids are well known, there are limited data on opioid dosing and its effect on perioperative outcomes.²³

A significant decrease in the percentage of patients receiving an opioid prescription at the first postoperative visit suggests a decrease in the number of patients on prolonged opioids after TKA with implementation of modern analgesic modalities. The duration of postoperative opioid use has been found to be the strongest predictor of misuse, and each postoperative refill increases the probability of misuse by 44%.²⁴ In addition, opioid use for > 3 months after TKA is associated with increased risk of periprosthetic infection, increased overall revision rate, and stiffness at 1 year postoperatively.⁹ While not entirely under the control of the surgeon, measures to decrease the number of postoperative opioid refills may lead to a decrease in opioid misuse.

Limitations

A number of limitations of this study should be noted. One was a protocol change regarding length of stay, which occurred during the study period and resulted in a significantly shorter length of stay in the protocol group. As a result, opioid use data were analyzed only through midnight at the end of POD 1. Patients who were discharged on POD 1 did not have opioid use data available for the full duration of the first POD, which may exaggerate the decrease in opioid requirements, as opioids used after discharge but prior to midnight on POD 1 were not recorded. However, opioids taken at home are oral with a low MME compared with IV opioids received by hospitalized patients in the control group. In addition, if taken as prescribed, patients at home would only have enough time to take a few doses of opioids prior to the midnight cutoff. We do not believe this difference in time of opioid use meaningfully affected the data. An additional limitation includes the variability between periarticular injections between surgeons. While the percentage of patients that received injections from surgeon 1 vs surgeon 2 were similar, it cannot be ruled out as a potential confounding factor. Other limitations include a lack of pain scores to compare subjective pain ratings, the retrospective nature of the study, and a largely homogenous male VA population.

Conclusions

Ease of access to opioids is a risk factor for opioid abuse, which itself is a risk factor for subsequent heroin use.^1,2 The CDC and AAOS have thus published recommendations regarding opioid prescribing practices to decrease opioid use and abuse.^5,6 Our described protocol, which aligns with these recommendations, resulted in a significant decrease in IV opioid requirement, total opioid requirement, and lower rates of opioid prescriptions provided at the first postoperative visit. These promising findings demonstrate a lower percentage of patients on long-term opioids after TKA and a significantly decreased cumulative opioid exposure.

Ease of access to opioids in the perioperative period is a risk factor for opioid misuse and has been identified as a strong risk factor for heroin use.^1,2 Three-quarters of today’s heroin users were introduced to opioids through prescription medications.² The United States accounts for about 80% of the global opioid supply consumption, and deaths from opioid overdose are increasing: 70,630 deaths in 2019 alone.^3,4

The Centers for Disease Control and Prevention (CDC) has called for changes in opioid prescribing. The American Academy of Orthopaedic Surgeons (AAOS) also has published an information statement with strategies to decrease opioid misuse and abuse.^5,6 Arthroplasty surgeons have recently focused on decreasing use of opioids in total knee arthroplasty (TKA), a procedure traditionally associated with high levels of opioid consumption and historical reliance on opioid monotherapy for postoperative analgesia.^7,8 From a clinical perspective, prolonged postoperative opioid use contributes to poorer surgical outcomes due to increased risk of complications, including stiffness, infection, and revision TKA.⁹

Multimodal pain regimens are increasingly being used to control postoperative pain as data supports their efficacy.^10,11 Previous studies have found that simultaneous modulation of multiple pain pathways decreases narcotics consumption and improves patient outcomes.^12,13 Along with other adjuvant therapies, peripheral nerve blocks, such as adductor canal block (ACB) and femoral nerve block (FNB), have been used to decrease postoperative pain.¹⁴ Studies have shown that ACB has fewer complications and shorter functional recovery times compared with FNB.^15,16 The distribution of the ACB excludes the femoral nerve, thus preserving greater quadriceps strength while providing equivalent levels of analgesia compared with FNB.^15,17,18 The ACB has shown decreased near-fall events and improved balance scores in the immediate postoperative period.¹⁹

Our study analyzed opioid consumption patterns of TKA patients from a US Department of Veterans Affairs (VA) medical center before and after the institution of a multimodal analgesic protocol using ACB. The primary purpose of this study was to determine whether a protocol that included intraoperative spinal anesthesia with a postoperative multimodal analgesic regimen and ACB was associated with a decreased postoperative opioid requirement when compared with patients who received intraoperative general anesthesia and a traditional opioid regimen. Secondary outcomes included the effect of opioid consumption on range of motion on postoperative day (POD) 1 and number of opioid prescriptions written at the first postoperative clinic visit.

Methods

Approval for the study was obtained from the institutional review board at the Dayton Veterans Affairs Medical Center (DVAMC) in Ohio. A retrospective chart review was performed to collect data from all patients undergoing TKA at DVAMC from June 1, 2011, through December 31, 2015. Exclusion criteria included multiple surgeries in the study time frame, documented chronic pain, allergy to local anesthetics, daily preoperative use of opioids, and incomplete data in the health record.

All surgeries were performed by 2 staff arthroplasty surgeons at a single VAMC. All patients attended a preoperative visit where a history, physical, and anesthesia evaluation were performed, and watched an educational video detailing surgical indications and postoperative rehabilitation. All surgeries were performed with tourniquets and a periarticular injection was performed at the conclusion of each case. Surgeon 1 treatment of choice was 10 mL 0.5% bupivacaine, whereas surgeon 2 performed a posterior capsular injection of 30 mL 0.25% bupivacaine and a periarticular injection of 30 mg ketorolac in 10 mL 0.25% bupivacaine with epinephrine.

Prior to August 2014, general endotracheal anesthesia was used intraoperatively. A patient-controlled analgesia (PCA) pump of morphine or hydromorphone and additional oral oxycodone or hydrocodone was used for postoperative pain. PCA pumps were patient dependent. In the control group, 245 patients received the morphine PCA while 61 received the hydromorphone PCA. Morphine PCA dosing consisted of 1-mg doses every 10 minutes with potential baseline infusion rates of 0.5 to 1.0 mg/h and a 4-hour limit of 20 mg. Hydromorphone PCA dosing consisted of 0.2 to 0.4-mg doses with a potential continuous dose of 0.2 to 0.4 mg/h and a 4-hour limit of 4 mg.

Results

During the study period from June 1, 2011, through December 31, 2015, 533 eligible TKAs were performed, 306 in the control group and 227 in the protocol group. The groups had similar sex distribution; body mass index; knee range of motion; diagnoses of diabetes mellitus, coronary artery disease, and chronic kidney disease; and history of deep vein thrombosis (DVT) or pulmonary embolism (P ≥ .05). The protocol group was significantly older (P = .04) and had a significantly higher rate of chronic obstructive pulmonary disease (COPD) (P = .002). There were no significant differences between number of procedures performed by surgeon (P = .48) or total tourniquet time (P = .13) (Table 2). Mean (SD) length of stay was significantly greater in the control group compared with the protocol group (2.5 [1.3] vs 1.4 [0.7] days, P < .001).

Figure 1 shows the distributions of each type of opioid used. Compared with the control group, the protocol group had a significantly lower mean (SD) IV opioid use: 178.2 (98.0) MED vs 12.0 (24.6) MED (P < .001; d = 2.19; Δ = 0.94) and mean (SD) total opioid use: 241.7 (120.1) MED vs 74.8 (42.7) MED (P < .001; d = 1.76; Δ = 0.89). Mean (SD) oral opioid use did not differ between groups (control, 63.6 [45.4] MED; protocol, 62.9 [31.4] MED; P = .85; d = 0.02; Δ = 0.51). A significantly lower percentage of patients in the protocol group received additional opioids at the 3-week follow-up when compared to the control group: 46.7% vs 61.3%, respectively (P < .001; RR, 0.76; 95% CI, 0.65-0.90).

Discussion

Coordinated efforts with major medical organizations are being made to decrease opioid prescriptions and exposure.^5,6 To our knowledge, no study has quantified a decrease in opioid requirement in a VA population after implementation of a protocol that includes intraoperative spinal anesthesia and a postoperative multimodal analgesic regimen including ACB after TKA. The analgesic protocol described in this study aligns with recommendations from both the CDC and the AAOS to decrease opioid use and misuse by maximizing nonopioid medications and limiting the size and number of opioid prescriptions. However, public and medical opinion of opioids as well as prescribing practices have changed over time with a trend toward lower opioid use. The interventions, as part of the described protocol, are a result of these changes and attempt to minimize opioid use while maximizing postoperative analgesia.

Our data showed a significant decrease in total opioid use through POD 1, IV opioid use, and opioid prescriptions provided at the first postoperative visit. The protocol group used only 6.7% of the IV opioids and 30.9% of the total opioids that were used by the control group. The substantial difference in IV opioid requirement, 166.2 MED, is equivalent to 8 mg of IV hydromorphone or 55 mg of IV morphine. The difference in total opioid requirement was similar at 166.9 MED, equivalent to 111 mg of oral oxycodone.

Decreasing opioid use has the additional benefit of improving outcomes, as higher doses of opioids have been associated with increased length of stay, greater rates of DVT, and postoperative infection.²³ These complications occurred in a stepwise manner, suggesting a dose-response gradient that makes the sizable decrease noted in our data of greater relevance.²³ While the adverse effects (AEs) of opioids are well known, there are limited data on opioid dosing and its effect on perioperative outcomes.²³

A significant decrease in the percentage of patients receiving an opioid prescription at the first postoperative visit suggests a decrease in the number of patients on prolonged opioids after TKA with implementation of modern analgesic modalities. The duration of postoperative opioid use has been found to be the strongest predictor of misuse, and each postoperative refill increases the probability of misuse by 44%.²⁴ In addition, opioid use for > 3 months after TKA is associated with increased risk of periprosthetic infection, increased overall revision rate, and stiffness at 1 year postoperatively.⁹ While not entirely under the control of the surgeon, measures to decrease the number of postoperative opioid refills may lead to a decrease in opioid misuse.

Limitations

A number of limitations of this study should be noted. One was a protocol change regarding length of stay, which occurred during the study period and resulted in a significantly shorter length of stay in the protocol group. As a result, opioid use data were analyzed only through midnight at the end of POD 1. Patients who were discharged on POD 1 did not have opioid use data available for the full duration of the first POD, which may exaggerate the decrease in opioid requirements, as opioids used after discharge but prior to midnight on POD 1 were not recorded. However, opioids taken at home are oral with a low MME compared with IV opioids received by hospitalized patients in the control group. In addition, if taken as prescribed, patients at home would only have enough time to take a few doses of opioids prior to the midnight cutoff. We do not believe this difference in time of opioid use meaningfully affected the data. An additional limitation includes the variability between periarticular injections between surgeons. While the percentage of patients that received injections from surgeon 1 vs surgeon 2 were similar, it cannot be ruled out as a potential confounding factor. Other limitations include a lack of pain scores to compare subjective pain ratings, the retrospective nature of the study, and a largely homogenous male VA population.

Conclusions

Ease of access to opioids is a risk factor for opioid abuse, which itself is a risk factor for subsequent heroin use.^1,2 The CDC and AAOS have thus published recommendations regarding opioid prescribing practices to decrease opioid use and abuse.^5,6 Our described protocol, which aligns with these recommendations, resulted in a significant decrease in IV opioid requirement, total opioid requirement, and lower rates of opioid prescriptions provided at the first postoperative visit. These promising findings demonstrate a lower percentage of patients on long-term opioids after TKA and a significantly decreased cumulative opioid exposure.

Readers of this column may recall that since I have been the Editor-in-Chief of Federal Practitioner, my December editorial focuses on the best and worst of the year in federal medicine. In 2021, these evaluative terms fail to capture the sadness and global devastation that mark this grim epoch of the continuing pandemic, increasing climate disasters, rising political tensions, and racial violence. Thus, this year my editorial is framed in terms of the philosophical or theological categories of good and evil as the only concepts that can even begin to express the horrendous events that occurred in West Virginia.

On June 28, 2018, then US Department of Veterans Affairs (VA) Veterans Health Administration (VHA) Executive-in-Charge, Carolyn Clancy, MD, contacted Inspector General Michael Missal to alert him that “there may be an ‘Angel of Death’ in Clarksburg [West Virginia].”¹ Two years later Reta Mays, a 46-year-old VA nursing assistant, entered a guilty plea in federal court to the deaths of 7 vulnerable veterans. The legal charges were second-degree murder and 1 count of assault with intent to commit murder by injecting insulin. The victims were all patients on Ward 3 at the Louis A. Johnson VA, Medical Center in Clarksburg, where Mays worked the night shift from 2015 to 2018.² Mays was sentenced in May of this year to 7 consecutive life terms for each of the veterans whose lives she cruelly ended and an additional 240 months for the eighth patient who survived her murder attempt.3

The term angel of death has religious roots in Judaism, although not strictly in the Hebrew scriptures. Neither the Jewish nor Christian Bible identifies a specific figure who is the angel of death. The idea first appears in Rabbinic literature and Jewish tradition.⁴ The angel God sends as a messenger of death is known as malakh ha-mavet in Hebrew. The revered Jewish physician and philosopher Moses Maimonides taught in his Guide for the Perplexed the angel of death is synonymous with the devil, and the evil inclination that dwells in the mind of all human beings.⁵In modern times, the concept of an angel of death has come to designate a serial killer who is a health care professional (HCP). A group of forensic scientists, HCPs, and attorneys, including former VA Under Secretary for Health Dr. Kenneth Kizer, published a study of HCPs who had been prosecuted or convicted of serial murder. Nurses constituted the largest group of offenders (60%) with nursing aides like Mays responsible for 18% of murders, and physicians 12%. The review found that though health care serial killers are rare, they operate in nations across the Western world, in many different states in this country, and in almost all health care settings, including previous VA angels of death.⁶Nursing aides who are not supposed to have access to medications—a major problem in Mays’ case—nor permitted to administer them more often resort to noncontrolled substances to kill their victims.¹ Mays chose insulin as her murder weapon as did 13% of serial killers. Just as insulin may be difficult to detect in toxicology, so Mays and others like her committed their crimes on the night shift when they were less likely to be discovered.⁶

Many of us feel compelled to seek a rational motivation for why healers would mutate into killers: If we can find a reason for this heinous behavior it somehow helps us feel the world is more intelligible and controllable. Unfortunately, despite intensive forensic investigations of multiple angels of death, there is little definitive understanding of the motives of these murders.⁶ Mays disclosed more than most. As part of a plea bargain, she provided investigators with 2 rationales for her killing: She wanted to ease the patients’ suffering. Such claims of being an angel of mercy are common among HCP serial murders, which the patterns of the killings generally disprove. The patients Mays lethally injected, while mostly old and ill, were all expected to recover and leave the hospital. The Inspector General report uncovered a cautionary detail that has at least indirect bearing on the nursing assistant’s contention that she “wanted to let the patient’s die gently”: Contrary to VHA requirements, the facility had no functioning palliative care team. This finding in no way excuses or even explains Mays’ actions; it does, however, reinforce the essential value of palliative care expertise in an aging veteran population with many life-limiting conditions.⁷

Mays’ second motivation seems more plausible, based on her life narrative and the literature on HCP serial killers. Mays disclosed to investigators that she “had a lot of stress and chaos in [her] personal and professional life and these actions gave [her] a sense of control.”¹ Her prior use of excessive force when employed at a prison as well as forensic science indicating that feelings of wielding power over life and death often drive health care murders, suggest this may have been a factor in Mays’ horrific conduct.⁸

It seems blasphemous to associate the word good in the same pages with this terrible evil. Nothing can compensate or justify the betrayal of the sacred oath of an HCP and the public trust of a VHA employee. Yet that very impossibility carries with it an obligation to ask, as did the author of an article about a recent Canadian nurse serial killer, “What can we learn from the [Mays] story?”⁹

Mays could never have taken the lives of 8 patients without clinical and administrative lapses and shortcuts at all levels of the health care system. Indeed, the 100-plus page Inspector General report makes 15 recommendations for the VHA, the Veterans Integrated Service Network, and the facility, encompassing areas of personnel hiring and performance evaluation, medication management and security, reporting and responding to unexplained events, quality and safety programs oversight, leaders’ responses, corrective actions, and even computer systems data analysis.

I want to suggest 2 ethical additions to this list addressed to all of us as VHA staff and especially to those of us who are HCPs. From the perspective of virtue ethics, Reta Mays is a tragedy about complacency and compromise in everyday work that the pandemic has made even more frequent and challenging to avoid and resist. This is what the Roman Virgil means in the epigraph that the road down to hell is easy and the road back very difficult.

I propose the need for discernment in trying to listen to our moral intuitions that tell us something is amiss and diligence in adhering to best practices even when we are fearful, exhausted, demoralized, or apathetic. These 2 habits of commitment to veterans, one of compassion and the other of competence, can help us follow the good inclinations of our hearts and together with system changes can bar the doors of our hospitals to the visits of future angels of death. This dedication is the least we owe to the families of the patients at Clarksburg whose loved ones never came home and whose questions likely can never be fully answered.

Readers of this column may recall that since I have been the Editor-in-Chief of Federal Practitioner, my December editorial focuses on the best and worst of the year in federal medicine. In 2021, these evaluative terms fail to capture the sadness and global devastation that mark this grim epoch of the continuing pandemic, increasing climate disasters, rising political tensions, and racial violence. Thus, this year my editorial is framed in terms of the philosophical or theological categories of good and evil as the only concepts that can even begin to express the horrendous events that occurred in West Virginia.

On June 28, 2018, then US Department of Veterans Affairs (VA) Veterans Health Administration (VHA) Executive-in-Charge, Carolyn Clancy, MD, contacted Inspector General Michael Missal to alert him that “there may be an ‘Angel of Death’ in Clarksburg [West Virginia].”¹ Two years later Reta Mays, a 46-year-old VA nursing assistant, entered a guilty plea in federal court to the deaths of 7 vulnerable veterans. The legal charges were second-degree murder and 1 count of assault with intent to commit murder by injecting insulin. The victims were all patients on Ward 3 at the Louis A. Johnson VA, Medical Center in Clarksburg, where Mays worked the night shift from 2015 to 2018.² Mays was sentenced in May of this year to 7 consecutive life terms for each of the veterans whose lives she cruelly ended and an additional 240 months for the eighth patient who survived her murder attempt.3

The term angel of death has religious roots in Judaism, although not strictly in the Hebrew scriptures. Neither the Jewish nor Christian Bible identifies a specific figure who is the angel of death. The idea first appears in Rabbinic literature and Jewish tradition.⁴ The angel God sends as a messenger of death is known as malakh ha-mavet in Hebrew. The revered Jewish physician and philosopher Moses Maimonides taught in his Guide for the Perplexed the angel of death is synonymous with the devil, and the evil inclination that dwells in the mind of all human beings.⁵In modern times, the concept of an angel of death has come to designate a serial killer who is a health care professional (HCP). A group of forensic scientists, HCPs, and attorneys, including former VA Under Secretary for Health Dr. Kenneth Kizer, published a study of HCPs who had been prosecuted or convicted of serial murder. Nurses constituted the largest group of offenders (60%) with nursing aides like Mays responsible for 18% of murders, and physicians 12%. The review found that though health care serial killers are rare, they operate in nations across the Western world, in many different states in this country, and in almost all health care settings, including previous VA angels of death.⁶Nursing aides who are not supposed to have access to medications—a major problem in Mays’ case—nor permitted to administer them more often resort to noncontrolled substances to kill their victims.¹ Mays chose insulin as her murder weapon as did 13% of serial killers. Just as insulin may be difficult to detect in toxicology, so Mays and others like her committed their crimes on the night shift when they were less likely to be discovered.⁶

Many of us feel compelled to seek a rational motivation for why healers would mutate into killers: If we can find a reason for this heinous behavior it somehow helps us feel the world is more intelligible and controllable. Unfortunately, despite intensive forensic investigations of multiple angels of death, there is little definitive understanding of the motives of these murders.⁶ Mays disclosed more than most. As part of a plea bargain, she provided investigators with 2 rationales for her killing: She wanted to ease the patients’ suffering. Such claims of being an angel of mercy are common among HCP serial murders, which the patterns of the killings generally disprove. The patients Mays lethally injected, while mostly old and ill, were all expected to recover and leave the hospital. The Inspector General report uncovered a cautionary detail that has at least indirect bearing on the nursing assistant’s contention that she “wanted to let the patient’s die gently”: Contrary to VHA requirements, the facility had no functioning palliative care team. This finding in no way excuses or even explains Mays’ actions; it does, however, reinforce the essential value of palliative care expertise in an aging veteran population with many life-limiting conditions.⁷

Mays’ second motivation seems more plausible, based on her life narrative and the literature on HCP serial killers. Mays disclosed to investigators that she “had a lot of stress and chaos in [her] personal and professional life and these actions gave [her] a sense of control.”¹ Her prior use of excessive force when employed at a prison as well as forensic science indicating that feelings of wielding power over life and death often drive health care murders, suggest this may have been a factor in Mays’ horrific conduct.⁸

It seems blasphemous to associate the word good in the same pages with this terrible evil. Nothing can compensate or justify the betrayal of the sacred oath of an HCP and the public trust of a VHA employee. Yet that very impossibility carries with it an obligation to ask, as did the author of an article about a recent Canadian nurse serial killer, “What can we learn from the [Mays] story?”⁹

Mays could never have taken the lives of 8 patients without clinical and administrative lapses and shortcuts at all levels of the health care system. Indeed, the 100-plus page Inspector General report makes 15 recommendations for the VHA, the Veterans Integrated Service Network, and the facility, encompassing areas of personnel hiring and performance evaluation, medication management and security, reporting and responding to unexplained events, quality and safety programs oversight, leaders’ responses, corrective actions, and even computer systems data analysis.

I want to suggest 2 ethical additions to this list addressed to all of us as VHA staff and especially to those of us who are HCPs. From the perspective of virtue ethics, Reta Mays is a tragedy about complacency and compromise in everyday work that the pandemic has made even more frequent and challenging to avoid and resist. This is what the Roman Virgil means in the epigraph that the road down to hell is easy and the road back very difficult.

I propose the need for discernment in trying to listen to our moral intuitions that tell us something is amiss and diligence in adhering to best practices even when we are fearful, exhausted, demoralized, or apathetic. These 2 habits of commitment to veterans, one of compassion and the other of competence, can help us follow the good inclinations of our hearts and together with system changes can bar the doors of our hospitals to the visits of future angels of death. This dedication is the least we owe to the families of the patients at Clarksburg whose loved ones never came home and whose questions likely can never be fully answered.

Readers of this column may recall that since I have been the Editor-in-Chief of Federal Practitioner, my December editorial focuses on the best and worst of the year in federal medicine. In 2021, these evaluative terms fail to capture the sadness and global devastation that mark this grim epoch of the continuing pandemic, increasing climate disasters, rising political tensions, and racial violence. Thus, this year my editorial is framed in terms of the philosophical or theological categories of good and evil as the only concepts that can even begin to express the horrendous events that occurred in West Virginia.

On June 28, 2018, then US Department of Veterans Affairs (VA) Veterans Health Administration (VHA) Executive-in-Charge, Carolyn Clancy, MD, contacted Inspector General Michael Missal to alert him that “there may be an ‘Angel of Death’ in Clarksburg [West Virginia].”¹ Two years later Reta Mays, a 46-year-old VA nursing assistant, entered a guilty plea in federal court to the deaths of 7 vulnerable veterans. The legal charges were second-degree murder and 1 count of assault with intent to commit murder by injecting insulin. The victims were all patients on Ward 3 at the Louis A. Johnson VA, Medical Center in Clarksburg, where Mays worked the night shift from 2015 to 2018.² Mays was sentenced in May of this year to 7 consecutive life terms for each of the veterans whose lives she cruelly ended and an additional 240 months for the eighth patient who survived her murder attempt.3

The term angel of death has religious roots in Judaism, although not strictly in the Hebrew scriptures. Neither the Jewish nor Christian Bible identifies a specific figure who is the angel of death. The idea first appears in Rabbinic literature and Jewish tradition.⁴ The angel God sends as a messenger of death is known as malakh ha-mavet in Hebrew. The revered Jewish physician and philosopher Moses Maimonides taught in his Guide for the Perplexed the angel of death is synonymous with the devil, and the evil inclination that dwells in the mind of all human beings.⁵In modern times, the concept of an angel of death has come to designate a serial killer who is a health care professional (HCP). A group of forensic scientists, HCPs, and attorneys, including former VA Under Secretary for Health Dr. Kenneth Kizer, published a study of HCPs who had been prosecuted or convicted of serial murder. Nurses constituted the largest group of offenders (60%) with nursing aides like Mays responsible for 18% of murders, and physicians 12%. The review found that though health care serial killers are rare, they operate in nations across the Western world, in many different states in this country, and in almost all health care settings, including previous VA angels of death.⁶Nursing aides who are not supposed to have access to medications—a major problem in Mays’ case—nor permitted to administer them more often resort to noncontrolled substances to kill their victims.¹ Mays chose insulin as her murder weapon as did 13% of serial killers. Just as insulin may be difficult to detect in toxicology, so Mays and others like her committed their crimes on the night shift when they were less likely to be discovered.⁶

Many of us feel compelled to seek a rational motivation for why healers would mutate into killers: If we can find a reason for this heinous behavior it somehow helps us feel the world is more intelligible and controllable. Unfortunately, despite intensive forensic investigations of multiple angels of death, there is little definitive understanding of the motives of these murders.⁶ Mays disclosed more than most. As part of a plea bargain, she provided investigators with 2 rationales for her killing: She wanted to ease the patients’ suffering. Such claims of being an angel of mercy are common among HCP serial murders, which the patterns of the killings generally disprove. The patients Mays lethally injected, while mostly old and ill, were all expected to recover and leave the hospital. The Inspector General report uncovered a cautionary detail that has at least indirect bearing on the nursing assistant’s contention that she “wanted to let the patient’s die gently”: Contrary to VHA requirements, the facility had no functioning palliative care team. This finding in no way excuses or even explains Mays’ actions; it does, however, reinforce the essential value of palliative care expertise in an aging veteran population with many life-limiting conditions.⁷

Mays’ second motivation seems more plausible, based on her life narrative and the literature on HCP serial killers. Mays disclosed to investigators that she “had a lot of stress and chaos in [her] personal and professional life and these actions gave [her] a sense of control.”¹ Her prior use of excessive force when employed at a prison as well as forensic science indicating that feelings of wielding power over life and death often drive health care murders, suggest this may have been a factor in Mays’ horrific conduct.⁸

It seems blasphemous to associate the word good in the same pages with this terrible evil. Nothing can compensate or justify the betrayal of the sacred oath of an HCP and the public trust of a VHA employee. Yet that very impossibility carries with it an obligation to ask, as did the author of an article about a recent Canadian nurse serial killer, “What can we learn from the [Mays] story?”⁹

Mays could never have taken the lives of 8 patients without clinical and administrative lapses and shortcuts at all levels of the health care system. Indeed, the 100-plus page Inspector General report makes 15 recommendations for the VHA, the Veterans Integrated Service Network, and the facility, encompassing areas of personnel hiring and performance evaluation, medication management and security, reporting and responding to unexplained events, quality and safety programs oversight, leaders’ responses, corrective actions, and even computer systems data analysis.

I want to suggest 2 ethical additions to this list addressed to all of us as VHA staff and especially to those of us who are HCPs. From the perspective of virtue ethics, Reta Mays is a tragedy about complacency and compromise in everyday work that the pandemic has made even more frequent and challenging to avoid and resist. This is what the Roman Virgil means in the epigraph that the road down to hell is easy and the road back very difficult.

I propose the need for discernment in trying to listen to our moral intuitions that tell us something is amiss and diligence in adhering to best practices even when we are fearful, exhausted, demoralized, or apathetic. These 2 habits of commitment to veterans, one of compassion and the other of competence, can help us follow the good inclinations of our hearts and together with system changes can bar the doors of our hospitals to the visits of future angels of death. This dedication is the least we owe to the families of the patients at Clarksburg whose loved ones never came home and whose questions likely can never be fully answered.