© Todd Buchanan 2017

ATLANTA—Results of a phase 1 study suggest patients with polycythemia vera (PV) can achieve extended treatment-free periods after receiving idasanutlin.

Six of 12 patients who received the drug were able to have a treatment holiday—4 patients for 1 month, 1 for 2 to 3 consecutive months, and 1 for more than 3 consecutive months.

Four patients achieved a complete response (CR) and 3 a partial response (PR), for an overall response rate (ORR) of 58%.

There were no dose-limiting toxicities (DLTs) in the trial.

John Mascarenhas, MD, of Icahn School of Medicine at Mount Sinai in New York, New York, reported these results at the 2017 ASH Annual Meeting as abstract 254.*

The study was supported by Roche and funded by the National Cancer Institute, PDRC, and a grant from the Leukemia and Lymphoma Society.

Study rationale

Patients with PV have higher levels of MDM2 in their CD34+ cells compared to normal CD34+ cells. Nutlins block the interaction between p53 and MDM2, thus activating the p53 pathway.

Investigators previously found that low doses of nutlin and pegylated IFNα 2a promoted apoptosis in PV CD34+ cells.

And treatment with the combination reduced the numbers of JAK2V617-positive cells transplanted into immune-deficient NOD/SCID mice.

So Dr Mascarenhas and his colleagues undertook a study (NCT02407080) to evaluate the toxicity, safety, and tolerability of the MDM2 antagonist idasanutlin in patients with PV and essential thrombocythemia (ET).

The investigators hypothesized that since overexpression of MDM2 negatively regulates wild-type p53 function in primary PV cells, idasanutlin therapy, either alone or in combination with low-dose peg-IFN, could result in selective reduction or elimination of the myeloproliferative neoplasm cells in PV patients.

Study design

The investigators evaluated 2 dose levels of idasanutlin—100 mg daily and 150 mg daily on days 1 to 5, repeated every 28 days. The first cycle was 56 days to allow investigators to evaluate any DLTs.

Dr Mascarenhas pointed out that the dose is 1/6 of that being evaluated in acute myeloid leukemia.

Investigators defined a DLT as a non-hematologic adverse event (AE) of grade 3 or higher or a hematologic AE of grade 2 or higher thrombocytopenia or grade 3 or higher neutropenia or anemia.

If patients did not achieve at least a PR by the end of cycle 3 of single-agent therapy, they could proceed to Part B of the study and receive idasanutlin with pegylated IFN.

After cycle 3, dosing was dependent upon patients hitting a hematocrit greater than 42% and/or platelet counts greater than 400,000.

“So you had to meet parameters, which means that if you did meet parameters, you could get a treatment holiday,” Dr Mascarenhas explained.

Patients were eligible if they had JAK2V617F-positive PV or ET confirmed by WHO diagnostic criteria.

They had to have high-risk disease, be older than 60, and have a history of thrombosis. They also had to be either intolerant or resistant to at least one prior treatment, including hydroxyurea, interferon, or anagrelide.

Patients were excluded if they had post-ET/PV myelofibrosis, blast phase disease, acute thrombosis within 3 months of screening, or uncontrolled inter-current illness.

Baseline patient characteristics

 Eleven of the 12 patients enrolled had PV, and 1 had ET. Their median age was 63.5, and 7 were female. Their median duration of disease was 43.9 months (range, 14.9–154.3), 3 had previous thrombosis, and 10 had prior hydroxyurea therapy.

They had a median leukocyte count of 11.3 x 10⁹/L, median hemoglobin levels of 13.6 g/dL, median hematocrit of 42.3%, and median platelet levels of 443.5 x 10⁹/L.

They all had the JAK2V617F mutation. Some patients had additional mutations, including TET2, DNMT3A, ASXL1, CBL, and EZH2, among others.

“One patient had an inactivating p53 mutation,” Dr Mascarenhas said. “I didn’t know this when we put her on study. . . , but this is an interesting part of the study. So remember, one patient had an inactivating p53 mutation in a trial where I’m using a drug that interrupts wild-type p53-MDM2 interaction.”

Efficacy

Plasma MIC-1 levels were significantly increased (P=0.004) in PV patients following treatment with idasanutlin at day 5 compared to day 1. MIC-1 is a secreted protein strongly induced by activated p53.

“Some patients didn’t need to be treated every month,” Dr Mascarenhas said. “They got treatment holidays. That’s unique. I don’t usually see that in the treatments that we give. In fact, this one person here, after 3 cycles, didn’t need to be re-treated for 9 months.”

In the 100 mg cohort (n=6), patients received a median of 8 cycles of idasanutlin (range, 7-13) and were on study for a median of 34.1 weeks (range, 29.0–127.3). One patient experienced a treatment holiday of 1 month, and another patient had a treatment holiday of more than 3 consecutive months.

In the 150 mg cohort (n=6), patients received a median of 9.5 cycles of therapy (range, 5–17) and were on study for a median of 52.1 weeks (range, 23.1–72.9). Three patients experienced a 1-month treatment holiday, and 1 patient had a 2- to 3-month treatment holiday.

In total, 6 patients continued the single-agent regimen, and 4 proceeded to the combination treatment with pegylated IFN.

Reasons for discontinuation were patient refusal and investigator decision.

The ORR (CR + PR) for both dose cohorts with single-agent idasanutlin was 58%. One patient was not evaluable, 4 had no response, 3 had a PR, and 4 had a CR.

In the combination portion of the study, the ORR was 50%. One patient was not evaluable, 1 had no response, 1 had a PR, and 1 had a CR.

“The 1 non-responder in Part B,” Dr Mascarenhas noted, “was the p53-mutated patient. Makes sense.”

The ORR for both the single-agent and combination parts of the study was 75%.

Eight of 12 patients had a 50% reduction in total symptom score from baseline, which is considered clinically meaningful, according to Dr Mascarenhas.

“What’s also interesting,” he pointed out, “[ is that] patients who didn’t obtain a response also enjoyed symptom benefit.”

Patients had a median 43% reduction in JAK2 mutation from baseline.

“One patient had nearly 92% reduction in JAK2V617F,” Dr Mascarenhas said. “One patient had a 60% increase. But guess what? That was the p53-mutated patient. Makes sense.”

Bone morphology showed reduction in marrow hypercellularity and normalization of megakaryocyte atypia and clustering.

Safety

There were no DLTs with either dose of  idasanutlin.

“This was a well-tolerated drug,” Dr Mascarenhas said.

Three patients experienced grade 3 non-hematologic treatment-emergent AEs, all at 100 mg, of fatigue (1 patient), headache (1 patient), and pain (1 patient).

No grade 4 non-hematologic treatment-emergent AEs occurred at either dose, and investigators observed no hematologic AE of any grade.

Investigators also observed no grade 3–4 gastrointestinal  (GI) treatment-emergent AEs. Constipation (91.7%), nausea (75%), and diarrhea (66.7%) were the most frequent grade 1 or 2 events. Patients received GI prophylaxis upfront with ondansetron, lorazepam, or dexamethasone.

Because of the safety profile and manageable GI toxicity, the higher dose of idasanutlin was chosen as the recommended phase 2 dose.

A global, multicenter, single-arm, phase 2 trial with idasanutlin in patients with hydroxyurea-resistant or -intolerant PV is underway.

*Data in the presentation differ from the abstract.

© Todd Buchanan 2017

ATLANTA—Results of a phase 1 study suggest patients with polycythemia vera (PV) can achieve extended treatment-free periods after receiving idasanutlin.

Six of 12 patients who received the drug were able to have a treatment holiday—4 patients for 1 month, 1 for 2 to 3 consecutive months, and 1 for more than 3 consecutive months.

Four patients achieved a complete response (CR) and 3 a partial response (PR), for an overall response rate (ORR) of 58%.

There were no dose-limiting toxicities (DLTs) in the trial.

John Mascarenhas, MD, of Icahn School of Medicine at Mount Sinai in New York, New York, reported these results at the 2017 ASH Annual Meeting as abstract 254.*

The study was supported by Roche and funded by the National Cancer Institute, PDRC, and a grant from the Leukemia and Lymphoma Society.

Study rationale

Patients with PV have higher levels of MDM2 in their CD34+ cells compared to normal CD34+ cells. Nutlins block the interaction between p53 and MDM2, thus activating the p53 pathway.

Investigators previously found that low doses of nutlin and pegylated IFNα 2a promoted apoptosis in PV CD34+ cells.

And treatment with the combination reduced the numbers of JAK2V617-positive cells transplanted into immune-deficient NOD/SCID mice.

So Dr Mascarenhas and his colleagues undertook a study (NCT02407080) to evaluate the toxicity, safety, and tolerability of the MDM2 antagonist idasanutlin in patients with PV and essential thrombocythemia (ET).

The investigators hypothesized that since overexpression of MDM2 negatively regulates wild-type p53 function in primary PV cells, idasanutlin therapy, either alone or in combination with low-dose peg-IFN, could result in selective reduction or elimination of the myeloproliferative neoplasm cells in PV patients.

Study design

The investigators evaluated 2 dose levels of idasanutlin—100 mg daily and 150 mg daily on days 1 to 5, repeated every 28 days. The first cycle was 56 days to allow investigators to evaluate any DLTs.

Dr Mascarenhas pointed out that the dose is 1/6 of that being evaluated in acute myeloid leukemia.

Investigators defined a DLT as a non-hematologic adverse event (AE) of grade 3 or higher or a hematologic AE of grade 2 or higher thrombocytopenia or grade 3 or higher neutropenia or anemia.

If patients did not achieve at least a PR by the end of cycle 3 of single-agent therapy, they could proceed to Part B of the study and receive idasanutlin with pegylated IFN.

After cycle 3, dosing was dependent upon patients hitting a hematocrit greater than 42% and/or platelet counts greater than 400,000.

“So you had to meet parameters, which means that if you did meet parameters, you could get a treatment holiday,” Dr Mascarenhas explained.

Patients were eligible if they had JAK2V617F-positive PV or ET confirmed by WHO diagnostic criteria.

They had to have high-risk disease, be older than 60, and have a history of thrombosis. They also had to be either intolerant or resistant to at least one prior treatment, including hydroxyurea, interferon, or anagrelide.

Patients were excluded if they had post-ET/PV myelofibrosis, blast phase disease, acute thrombosis within 3 months of screening, or uncontrolled inter-current illness.

Baseline patient characteristics

 Eleven of the 12 patients enrolled had PV, and 1 had ET. Their median age was 63.5, and 7 were female. Their median duration of disease was 43.9 months (range, 14.9–154.3), 3 had previous thrombosis, and 10 had prior hydroxyurea therapy.

They had a median leukocyte count of 11.3 x 10⁹/L, median hemoglobin levels of 13.6 g/dL, median hematocrit of 42.3%, and median platelet levels of 443.5 x 10⁹/L.

They all had the JAK2V617F mutation. Some patients had additional mutations, including TET2, DNMT3A, ASXL1, CBL, and EZH2, among others.

“One patient had an inactivating p53 mutation,” Dr Mascarenhas said. “I didn’t know this when we put her on study. . . , but this is an interesting part of the study. So remember, one patient had an inactivating p53 mutation in a trial where I’m using a drug that interrupts wild-type p53-MDM2 interaction.”

Efficacy

Plasma MIC-1 levels were significantly increased (P=0.004) in PV patients following treatment with idasanutlin at day 5 compared to day 1. MIC-1 is a secreted protein strongly induced by activated p53.

“Some patients didn’t need to be treated every month,” Dr Mascarenhas said. “They got treatment holidays. That’s unique. I don’t usually see that in the treatments that we give. In fact, this one person here, after 3 cycles, didn’t need to be re-treated for 9 months.”

In the 100 mg cohort (n=6), patients received a median of 8 cycles of idasanutlin (range, 7-13) and were on study for a median of 34.1 weeks (range, 29.0–127.3). One patient experienced a treatment holiday of 1 month, and another patient had a treatment holiday of more than 3 consecutive months.

In the 150 mg cohort (n=6), patients received a median of 9.5 cycles of therapy (range, 5–17) and were on study for a median of 52.1 weeks (range, 23.1–72.9). Three patients experienced a 1-month treatment holiday, and 1 patient had a 2- to 3-month treatment holiday.

In total, 6 patients continued the single-agent regimen, and 4 proceeded to the combination treatment with pegylated IFN.

Reasons for discontinuation were patient refusal and investigator decision.

The ORR (CR + PR) for both dose cohorts with single-agent idasanutlin was 58%. One patient was not evaluable, 4 had no response, 3 had a PR, and 4 had a CR.

In the combination portion of the study, the ORR was 50%. One patient was not evaluable, 1 had no response, 1 had a PR, and 1 had a CR.

“The 1 non-responder in Part B,” Dr Mascarenhas noted, “was the p53-mutated patient. Makes sense.”

The ORR for both the single-agent and combination parts of the study was 75%.

Eight of 12 patients had a 50% reduction in total symptom score from baseline, which is considered clinically meaningful, according to Dr Mascarenhas.

“What’s also interesting,” he pointed out, “[ is that] patients who didn’t obtain a response also enjoyed symptom benefit.”

Patients had a median 43% reduction in JAK2 mutation from baseline.

“One patient had nearly 92% reduction in JAK2V617F,” Dr Mascarenhas said. “One patient had a 60% increase. But guess what? That was the p53-mutated patient. Makes sense.”

Bone morphology showed reduction in marrow hypercellularity and normalization of megakaryocyte atypia and clustering.

Safety

There were no DLTs with either dose of  idasanutlin.

“This was a well-tolerated drug,” Dr Mascarenhas said.

Three patients experienced grade 3 non-hematologic treatment-emergent AEs, all at 100 mg, of fatigue (1 patient), headache (1 patient), and pain (1 patient).

No grade 4 non-hematologic treatment-emergent AEs occurred at either dose, and investigators observed no hematologic AE of any grade.

Investigators also observed no grade 3–4 gastrointestinal  (GI) treatment-emergent AEs. Constipation (91.7%), nausea (75%), and diarrhea (66.7%) were the most frequent grade 1 or 2 events. Patients received GI prophylaxis upfront with ondansetron, lorazepam, or dexamethasone.

Because of the safety profile and manageable GI toxicity, the higher dose of idasanutlin was chosen as the recommended phase 2 dose.

A global, multicenter, single-arm, phase 2 trial with idasanutlin in patients with hydroxyurea-resistant or -intolerant PV is underway.

*Data in the presentation differ from the abstract.

© Todd Buchanan 2017

ATLANTA—Results of a phase 1 study suggest patients with polycythemia vera (PV) can achieve extended treatment-free periods after receiving idasanutlin.

Six of 12 patients who received the drug were able to have a treatment holiday—4 patients for 1 month, 1 for 2 to 3 consecutive months, and 1 for more than 3 consecutive months.

Four patients achieved a complete response (CR) and 3 a partial response (PR), for an overall response rate (ORR) of 58%.

There were no dose-limiting toxicities (DLTs) in the trial.

John Mascarenhas, MD, of Icahn School of Medicine at Mount Sinai in New York, New York, reported these results at the 2017 ASH Annual Meeting as abstract 254.*

The study was supported by Roche and funded by the National Cancer Institute, PDRC, and a grant from the Leukemia and Lymphoma Society.

Study rationale

Patients with PV have higher levels of MDM2 in their CD34+ cells compared to normal CD34+ cells. Nutlins block the interaction between p53 and MDM2, thus activating the p53 pathway.

Investigators previously found that low doses of nutlin and pegylated IFNα 2a promoted apoptosis in PV CD34+ cells.

And treatment with the combination reduced the numbers of JAK2V617-positive cells transplanted into immune-deficient NOD/SCID mice.

So Dr Mascarenhas and his colleagues undertook a study (NCT02407080) to evaluate the toxicity, safety, and tolerability of the MDM2 antagonist idasanutlin in patients with PV and essential thrombocythemia (ET).

The investigators hypothesized that since overexpression of MDM2 negatively regulates wild-type p53 function in primary PV cells, idasanutlin therapy, either alone or in combination with low-dose peg-IFN, could result in selective reduction or elimination of the myeloproliferative neoplasm cells in PV patients.

Study design

The investigators evaluated 2 dose levels of idasanutlin—100 mg daily and 150 mg daily on days 1 to 5, repeated every 28 days. The first cycle was 56 days to allow investigators to evaluate any DLTs.

Dr Mascarenhas pointed out that the dose is 1/6 of that being evaluated in acute myeloid leukemia.

Investigators defined a DLT as a non-hematologic adverse event (AE) of grade 3 or higher or a hematologic AE of grade 2 or higher thrombocytopenia or grade 3 or higher neutropenia or anemia.

If patients did not achieve at least a PR by the end of cycle 3 of single-agent therapy, they could proceed to Part B of the study and receive idasanutlin with pegylated IFN.

After cycle 3, dosing was dependent upon patients hitting a hematocrit greater than 42% and/or platelet counts greater than 400,000.

“So you had to meet parameters, which means that if you did meet parameters, you could get a treatment holiday,” Dr Mascarenhas explained.

Patients were eligible if they had JAK2V617F-positive PV or ET confirmed by WHO diagnostic criteria.

They had to have high-risk disease, be older than 60, and have a history of thrombosis. They also had to be either intolerant or resistant to at least one prior treatment, including hydroxyurea, interferon, or anagrelide.

Patients were excluded if they had post-ET/PV myelofibrosis, blast phase disease, acute thrombosis within 3 months of screening, or uncontrolled inter-current illness.

Baseline patient characteristics

 Eleven of the 12 patients enrolled had PV, and 1 had ET. Their median age was 63.5, and 7 were female. Their median duration of disease was 43.9 months (range, 14.9–154.3), 3 had previous thrombosis, and 10 had prior hydroxyurea therapy.

They had a median leukocyte count of 11.3 x 10⁹/L, median hemoglobin levels of 13.6 g/dL, median hematocrit of 42.3%, and median platelet levels of 443.5 x 10⁹/L.

They all had the JAK2V617F mutation. Some patients had additional mutations, including TET2, DNMT3A, ASXL1, CBL, and EZH2, among others.

“One patient had an inactivating p53 mutation,” Dr Mascarenhas said. “I didn’t know this when we put her on study. . . , but this is an interesting part of the study. So remember, one patient had an inactivating p53 mutation in a trial where I’m using a drug that interrupts wild-type p53-MDM2 interaction.”

Efficacy

Plasma MIC-1 levels were significantly increased (P=0.004) in PV patients following treatment with idasanutlin at day 5 compared to day 1. MIC-1 is a secreted protein strongly induced by activated p53.

“Some patients didn’t need to be treated every month,” Dr Mascarenhas said. “They got treatment holidays. That’s unique. I don’t usually see that in the treatments that we give. In fact, this one person here, after 3 cycles, didn’t need to be re-treated for 9 months.”

In the 100 mg cohort (n=6), patients received a median of 8 cycles of idasanutlin (range, 7-13) and were on study for a median of 34.1 weeks (range, 29.0–127.3). One patient experienced a treatment holiday of 1 month, and another patient had a treatment holiday of more than 3 consecutive months.

In the 150 mg cohort (n=6), patients received a median of 9.5 cycles of therapy (range, 5–17) and were on study for a median of 52.1 weeks (range, 23.1–72.9). Three patients experienced a 1-month treatment holiday, and 1 patient had a 2- to 3-month treatment holiday.

In total, 6 patients continued the single-agent regimen, and 4 proceeded to the combination treatment with pegylated IFN.

Reasons for discontinuation were patient refusal and investigator decision.

The ORR (CR + PR) for both dose cohorts with single-agent idasanutlin was 58%. One patient was not evaluable, 4 had no response, 3 had a PR, and 4 had a CR.

In the combination portion of the study, the ORR was 50%. One patient was not evaluable, 1 had no response, 1 had a PR, and 1 had a CR.

“The 1 non-responder in Part B,” Dr Mascarenhas noted, “was the p53-mutated patient. Makes sense.”

The ORR for both the single-agent and combination parts of the study was 75%.

Eight of 12 patients had a 50% reduction in total symptom score from baseline, which is considered clinically meaningful, according to Dr Mascarenhas.

“What’s also interesting,” he pointed out, “[ is that] patients who didn’t obtain a response also enjoyed symptom benefit.”

Patients had a median 43% reduction in JAK2 mutation from baseline.

“One patient had nearly 92% reduction in JAK2V617F,” Dr Mascarenhas said. “One patient had a 60% increase. But guess what? That was the p53-mutated patient. Makes sense.”

Bone morphology showed reduction in marrow hypercellularity and normalization of megakaryocyte atypia and clustering.

Safety

There were no DLTs with either dose of  idasanutlin.

“This was a well-tolerated drug,” Dr Mascarenhas said.

Three patients experienced grade 3 non-hematologic treatment-emergent AEs, all at 100 mg, of fatigue (1 patient), headache (1 patient), and pain (1 patient).

No grade 4 non-hematologic treatment-emergent AEs occurred at either dose, and investigators observed no hematologic AE of any grade.

Investigators also observed no grade 3–4 gastrointestinal  (GI) treatment-emergent AEs. Constipation (91.7%), nausea (75%), and diarrhea (66.7%) were the most frequent grade 1 or 2 events. Patients received GI prophylaxis upfront with ondansetron, lorazepam, or dexamethasone.

Because of the safety profile and manageable GI toxicity, the higher dose of idasanutlin was chosen as the recommended phase 2 dose.

A global, multicenter, single-arm, phase 2 trial with idasanutlin in patients with hydroxyurea-resistant or -intolerant PV is underway.

*Data in the presentation differ from the abstract.

© Scott Morgan 2017

ATLANTA—Data suggest a therapeutic window may exist for chimeric antigen receptor (CAR) T-cell expansion with JCAR017, according to a preliminary model.

In a core set of 67 patients with diffuse large B-cell lymphoma (DLBCL) who had received JCAR017 in the TRANSCEND NHL 001 trial, investigators observed that baseline high tumor burden and inflammatory biomarkers were associated with high CAR T-cell expansion and increased rates of cytokine release syndrome (CRS) and neurotoxicity.

If the model holds up, researchers say they could potentially identify patients at risk for low or high T-cell expansion levels and develop a strategy to enhance or limit the expansion.

TRANSCEND NHL 001 (NCT02631044) is a multicenter, phase 1 trial in relapsed or refractory non-Hodgkin lymphoma evaluating 2 dose levels of JCAR017, also known as lisocabtagene maraleucel, or liso-cel for short.

Liso-cel is a CD19-directed 4-1BB CAR T cell administered at precise doses of CD4+ and CD8+ CAR T cells. It had previously demonstrated high complete remission (CR) rates and low incidences of CRS and neurotoxicity.

Tanya Saddiqi, MD, of City of Hope National Medical Center in Duarte, California, presented data from the dose-finding and expansion cohorts at the 2017 ASH Annual Meeting (abstract 193*).

Study design

Patients with DLBCL after 2 lines of prior therapy or mantle cell lymphoma after 1 prior line of therapy were eligible to enroll in TRANSCEND NHL 001.

Patients with de novo DLBCL, those who transformed from follicular lymphoma, or those with high-grade B-cell lymphoma made up the pivotal or core population. All DLBCL patients enrolled on the trial comprised the full population.

Patients were screened, enrolled, and underwent apheresis. Bridging therapy was permitted while their CAR T cells were being manufactured.

Patients then had a PET scan and lab tests prior to lymphodepletion.

“This is the time point of our interest,” Dr Saddiqi said, “to see if there are any patient characteristics or biomarkers that we can identify . . .  that could help us figure out which patients are at higher risk of toxicity, potentially.”

Lymphodepletion consisted of fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m² for 3 days).

Patients received the JCAR017 infusion, and, at specific time points thereafter, cytokine, pharmacokinetic (PK), and clinical lab evaluations were conducted. PK evaluation and scans were performed every 3 months for the first year after JCAR017 infusion, and safety and viral vector follow-up for 15 years.

Dose levels were 5 x 10⁷ cells as a single or double dose (DL1S) and 1 x 10⁸ cells as a single dose (DL2S). Dose level 2 was chosen for further study, and double dosing was discontinued.

“Double dosing was actually not pursued further,” Dr Saddiqi explained, “because it did not seem to add any benefit over single dosing.”

At the time of the presentation, 91 total patients were treated, 67 of whom were the core population.

Results

Dr Saddiqi reported that patients treated with JCAR017 achieved a relatively high best overall response rate (ORR) and high durable CR rates.

“And this seems to be especially true for the core set of patients and particularly for patients at dose level 2,” she added.

At all dose levels, the core patients had a best ORR of 84% (41/49) and a CR rate of 61% (30/49).

At follow-up of 3 months or longer, the core group had an ORR of 65% (26/40) for all dose levels, 52% (11/21) for dose level 1, and 80% (12/15) for dose level 2.

The 3-month CR rate was 53% (21/40) for all dose levels in the core group, 33% (7/21) in dose level 1, and 73% (11/15) in dose level 2.

Dr Saddiqi noted that CRS and neurotoxicity did not differ by dose level or schedule, and there were no grade 5 events of CRS or neurotoxicity.

“Among the core group, dose level change did not add to their toxicity,” she said. “And so the question is: Is it patient factors, is it tumor factors? What is it that is actually causing the toxicities in these patients?”

Dr Saddiqi focused the presentation on patient factors.

Patient factors

The data showed that tumor burden and lactose dehydrogenase (LDH) levels were higher in patients with CRS and neurotoxicity.

Univariate analysis revealed that CRS and neurotoxicity were associated with a shorter time since diagnosis.

However, prior number of therapies, patient weight, and disease stage were not associated with CRS or neurotoxicity.

Investigators were able to identify preliminary risk boundaries. Core patients with high LDH levels (≥ 500 U/L) and sum of the products of diameters (SPD)  ≥ 50 cm² at baseline had an 8-fold increase in risk of CRS and neurotoxicity.

“Inversely, if these patients did not meet the cutoff for LDH or SPD,” Dr Saddiqi pointed out, “if they were lower than that, they have significantly lower CRS and neurotoxicity events.”

Investigators also observed that baseline markers of inflammation and inflammatory cytokines trended higher in patients with CRS and neurotoxicity. For CRS, this includes ferritin, C-reactive protein (CRP), IL-10, IL-15, IL-16, TNFα, and MIP-1β. For neurotoxicity, this includes ferritin, CRP, d-Dimer, IL-6, IL-15, TNFα, and MIP-1α.

The team also observed that tumor burden, baseline markers of inflammation, and inflammatory cytokines trended lower in core patients with durable responses.

“Interestingly, it’s inversely true that patients who did have these higher levels [of inflammation markers], and higher tumor burden, and higher LDH, actually were the ones that were either showing no response at 3 months or had lost their response by the 3-month assessment point,” Dr Saddiqi explained.

And in patients with higher baseline tumor burden and inflammatory cytokine levels, JCAR017 T-cell expansion trended higher.

“Some were deemed to be super expanders because their CAR T-cell levels were very high in their blood,” she added.

The investigators created a preliminary logistic model based on the data that suggests a therapeutic window might be able to limit toxicity and optimize efficacy.

The model indicates that patients with higher tumor burden, higher LDH, and higher inflammatory state at baseline seem to be the ones who are having more CRS and more neurotoxicity after CAR T-cell infusion.

“They are expanding their cells much more, yet their responses at 3 months seem to be affected adversely by this entire situation,” Dr Saddiqi said.

"One explanation, potentially, could be that these CAR T cells are seeing a lot of antigen when they go into the body. They have the perfect cytokine milieu to grow, expand, and go crazy in the body, if you will, and very quickly peter out as well because there’s T-cell exhaustion that happens rather rapidly and clinical responses are then then lost.”

The investigators believe that if they can identify those patients ahead of time who may be at risk of too high expansion or too low expansion of their CAR T cells, they may be able to find strategies to push expansion into the “sweet spot of CAR T-cell expansion and ultimately get the holy grail of having durable responses for all with minimal toxicity,” Dr Saddiqi concluded.

TRANSCEND NHL 001 is sponsored by Juno Therapeutics, Inc. Dr Saddiqi has served on a steering committee for JCAR017.

*Data in the presentation differ from the abstract.

© Scott Morgan 2017

ATLANTA—Data suggest a therapeutic window may exist for chimeric antigen receptor (CAR) T-cell expansion with JCAR017, according to a preliminary model.

In a core set of 67 patients with diffuse large B-cell lymphoma (DLBCL) who had received JCAR017 in the TRANSCEND NHL 001 trial, investigators observed that baseline high tumor burden and inflammatory biomarkers were associated with high CAR T-cell expansion and increased rates of cytokine release syndrome (CRS) and neurotoxicity.

If the model holds up, researchers say they could potentially identify patients at risk for low or high T-cell expansion levels and develop a strategy to enhance or limit the expansion.

TRANSCEND NHL 001 (NCT02631044) is a multicenter, phase 1 trial in relapsed or refractory non-Hodgkin lymphoma evaluating 2 dose levels of JCAR017, also known as lisocabtagene maraleucel, or liso-cel for short.

Liso-cel is a CD19-directed 4-1BB CAR T cell administered at precise doses of CD4+ and CD8+ CAR T cells. It had previously demonstrated high complete remission (CR) rates and low incidences of CRS and neurotoxicity.

Tanya Saddiqi, MD, of City of Hope National Medical Center in Duarte, California, presented data from the dose-finding and expansion cohorts at the 2017 ASH Annual Meeting (abstract 193*).

Study design

Patients with DLBCL after 2 lines of prior therapy or mantle cell lymphoma after 1 prior line of therapy were eligible to enroll in TRANSCEND NHL 001.

Patients with de novo DLBCL, those who transformed from follicular lymphoma, or those with high-grade B-cell lymphoma made up the pivotal or core population. All DLBCL patients enrolled on the trial comprised the full population.

Patients were screened, enrolled, and underwent apheresis. Bridging therapy was permitted while their CAR T cells were being manufactured.

Patients then had a PET scan and lab tests prior to lymphodepletion.

“This is the time point of our interest,” Dr Saddiqi said, “to see if there are any patient characteristics or biomarkers that we can identify . . .  that could help us figure out which patients are at higher risk of toxicity, potentially.”

Lymphodepletion consisted of fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m² for 3 days).

Patients received the JCAR017 infusion, and, at specific time points thereafter, cytokine, pharmacokinetic (PK), and clinical lab evaluations were conducted. PK evaluation and scans were performed every 3 months for the first year after JCAR017 infusion, and safety and viral vector follow-up for 15 years.

Dose levels were 5 x 10⁷ cells as a single or double dose (DL1S) and 1 x 10⁸ cells as a single dose (DL2S). Dose level 2 was chosen for further study, and double dosing was discontinued.

“Double dosing was actually not pursued further,” Dr Saddiqi explained, “because it did not seem to add any benefit over single dosing.”

At the time of the presentation, 91 total patients were treated, 67 of whom were the core population.

Results

Dr Saddiqi reported that patients treated with JCAR017 achieved a relatively high best overall response rate (ORR) and high durable CR rates.

“And this seems to be especially true for the core set of patients and particularly for patients at dose level 2,” she added.

At all dose levels, the core patients had a best ORR of 84% (41/49) and a CR rate of 61% (30/49).

At follow-up of 3 months or longer, the core group had an ORR of 65% (26/40) for all dose levels, 52% (11/21) for dose level 1, and 80% (12/15) for dose level 2.

The 3-month CR rate was 53% (21/40) for all dose levels in the core group, 33% (7/21) in dose level 1, and 73% (11/15) in dose level 2.

Dr Saddiqi noted that CRS and neurotoxicity did not differ by dose level or schedule, and there were no grade 5 events of CRS or neurotoxicity.

“Among the core group, dose level change did not add to their toxicity,” she said. “And so the question is: Is it patient factors, is it tumor factors? What is it that is actually causing the toxicities in these patients?”

Dr Saddiqi focused the presentation on patient factors.

Patient factors

The data showed that tumor burden and lactose dehydrogenase (LDH) levels were higher in patients with CRS and neurotoxicity.

Univariate analysis revealed that CRS and neurotoxicity were associated with a shorter time since diagnosis.

However, prior number of therapies, patient weight, and disease stage were not associated with CRS or neurotoxicity.

Investigators were able to identify preliminary risk boundaries. Core patients with high LDH levels (≥ 500 U/L) and sum of the products of diameters (SPD)  ≥ 50 cm² at baseline had an 8-fold increase in risk of CRS and neurotoxicity.

“Inversely, if these patients did not meet the cutoff for LDH or SPD,” Dr Saddiqi pointed out, “if they were lower than that, they have significantly lower CRS and neurotoxicity events.”

Investigators also observed that baseline markers of inflammation and inflammatory cytokines trended higher in patients with CRS and neurotoxicity. For CRS, this includes ferritin, C-reactive protein (CRP), IL-10, IL-15, IL-16, TNFα, and MIP-1β. For neurotoxicity, this includes ferritin, CRP, d-Dimer, IL-6, IL-15, TNFα, and MIP-1α.

The team also observed that tumor burden, baseline markers of inflammation, and inflammatory cytokines trended lower in core patients with durable responses.

“Interestingly, it’s inversely true that patients who did have these higher levels [of inflammation markers], and higher tumor burden, and higher LDH, actually were the ones that were either showing no response at 3 months or had lost their response by the 3-month assessment point,” Dr Saddiqi explained.

And in patients with higher baseline tumor burden and inflammatory cytokine levels, JCAR017 T-cell expansion trended higher.

“Some were deemed to be super expanders because their CAR T-cell levels were very high in their blood,” she added.

The investigators created a preliminary logistic model based on the data that suggests a therapeutic window might be able to limit toxicity and optimize efficacy.

The model indicates that patients with higher tumor burden, higher LDH, and higher inflammatory state at baseline seem to be the ones who are having more CRS and more neurotoxicity after CAR T-cell infusion.

“They are expanding their cells much more, yet their responses at 3 months seem to be affected adversely by this entire situation,” Dr Saddiqi said.

"One explanation, potentially, could be that these CAR T cells are seeing a lot of antigen when they go into the body. They have the perfect cytokine milieu to grow, expand, and go crazy in the body, if you will, and very quickly peter out as well because there’s T-cell exhaustion that happens rather rapidly and clinical responses are then then lost.”

The investigators believe that if they can identify those patients ahead of time who may be at risk of too high expansion or too low expansion of their CAR T cells, they may be able to find strategies to push expansion into the “sweet spot of CAR T-cell expansion and ultimately get the holy grail of having durable responses for all with minimal toxicity,” Dr Saddiqi concluded.

TRANSCEND NHL 001 is sponsored by Juno Therapeutics, Inc. Dr Saddiqi has served on a steering committee for JCAR017.

*Data in the presentation differ from the abstract.

© Scott Morgan 2017

ATLANTA—Data suggest a therapeutic window may exist for chimeric antigen receptor (CAR) T-cell expansion with JCAR017, according to a preliminary model.

In a core set of 67 patients with diffuse large B-cell lymphoma (DLBCL) who had received JCAR017 in the TRANSCEND NHL 001 trial, investigators observed that baseline high tumor burden and inflammatory biomarkers were associated with high CAR T-cell expansion and increased rates of cytokine release syndrome (CRS) and neurotoxicity.

If the model holds up, researchers say they could potentially identify patients at risk for low or high T-cell expansion levels and develop a strategy to enhance or limit the expansion.

TRANSCEND NHL 001 (NCT02631044) is a multicenter, phase 1 trial in relapsed or refractory non-Hodgkin lymphoma evaluating 2 dose levels of JCAR017, also known as lisocabtagene maraleucel, or liso-cel for short.

Liso-cel is a CD19-directed 4-1BB CAR T cell administered at precise doses of CD4+ and CD8+ CAR T cells. It had previously demonstrated high complete remission (CR) rates and low incidences of CRS and neurotoxicity.

Tanya Saddiqi, MD, of City of Hope National Medical Center in Duarte, California, presented data from the dose-finding and expansion cohorts at the 2017 ASH Annual Meeting (abstract 193*).

Study design

Patients with DLBCL after 2 lines of prior therapy or mantle cell lymphoma after 1 prior line of therapy were eligible to enroll in TRANSCEND NHL 001.

Patients with de novo DLBCL, those who transformed from follicular lymphoma, or those with high-grade B-cell lymphoma made up the pivotal or core population. All DLBCL patients enrolled on the trial comprised the full population.

Patients were screened, enrolled, and underwent apheresis. Bridging therapy was permitted while their CAR T cells were being manufactured.

Patients then had a PET scan and lab tests prior to lymphodepletion.

“This is the time point of our interest,” Dr Saddiqi said, “to see if there are any patient characteristics or biomarkers that we can identify . . .  that could help us figure out which patients are at higher risk of toxicity, potentially.”

Lymphodepletion consisted of fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m² for 3 days).

Patients received the JCAR017 infusion, and, at specific time points thereafter, cytokine, pharmacokinetic (PK), and clinical lab evaluations were conducted. PK evaluation and scans were performed every 3 months for the first year after JCAR017 infusion, and safety and viral vector follow-up for 15 years.

Dose levels were 5 x 10⁷ cells as a single or double dose (DL1S) and 1 x 10⁸ cells as a single dose (DL2S). Dose level 2 was chosen for further study, and double dosing was discontinued.

“Double dosing was actually not pursued further,” Dr Saddiqi explained, “because it did not seem to add any benefit over single dosing.”

At the time of the presentation, 91 total patients were treated, 67 of whom were the core population.

Results

Dr Saddiqi reported that patients treated with JCAR017 achieved a relatively high best overall response rate (ORR) and high durable CR rates.

“And this seems to be especially true for the core set of patients and particularly for patients at dose level 2,” she added.

At all dose levels, the core patients had a best ORR of 84% (41/49) and a CR rate of 61% (30/49).

At follow-up of 3 months or longer, the core group had an ORR of 65% (26/40) for all dose levels, 52% (11/21) for dose level 1, and 80% (12/15) for dose level 2.

The 3-month CR rate was 53% (21/40) for all dose levels in the core group, 33% (7/21) in dose level 1, and 73% (11/15) in dose level 2.

Dr Saddiqi noted that CRS and neurotoxicity did not differ by dose level or schedule, and there were no grade 5 events of CRS or neurotoxicity.

“Among the core group, dose level change did not add to their toxicity,” she said. “And so the question is: Is it patient factors, is it tumor factors? What is it that is actually causing the toxicities in these patients?”

Dr Saddiqi focused the presentation on patient factors.

Patient factors

The data showed that tumor burden and lactose dehydrogenase (LDH) levels were higher in patients with CRS and neurotoxicity.

Univariate analysis revealed that CRS and neurotoxicity were associated with a shorter time since diagnosis.

However, prior number of therapies, patient weight, and disease stage were not associated with CRS or neurotoxicity.

Investigators were able to identify preliminary risk boundaries. Core patients with high LDH levels (≥ 500 U/L) and sum of the products of diameters (SPD)  ≥ 50 cm² at baseline had an 8-fold increase in risk of CRS and neurotoxicity.

“Inversely, if these patients did not meet the cutoff for LDH or SPD,” Dr Saddiqi pointed out, “if they were lower than that, they have significantly lower CRS and neurotoxicity events.”

Investigators also observed that baseline markers of inflammation and inflammatory cytokines trended higher in patients with CRS and neurotoxicity. For CRS, this includes ferritin, C-reactive protein (CRP), IL-10, IL-15, IL-16, TNFα, and MIP-1β. For neurotoxicity, this includes ferritin, CRP, d-Dimer, IL-6, IL-15, TNFα, and MIP-1α.

The team also observed that tumor burden, baseline markers of inflammation, and inflammatory cytokines trended lower in core patients with durable responses.

“Interestingly, it’s inversely true that patients who did have these higher levels [of inflammation markers], and higher tumor burden, and higher LDH, actually were the ones that were either showing no response at 3 months or had lost their response by the 3-month assessment point,” Dr Saddiqi explained.

And in patients with higher baseline tumor burden and inflammatory cytokine levels, JCAR017 T-cell expansion trended higher.

“Some were deemed to be super expanders because their CAR T-cell levels were very high in their blood,” she added.

The investigators created a preliminary logistic model based on the data that suggests a therapeutic window might be able to limit toxicity and optimize efficacy.

The model indicates that patients with higher tumor burden, higher LDH, and higher inflammatory state at baseline seem to be the ones who are having more CRS and more neurotoxicity after CAR T-cell infusion.

“They are expanding their cells much more, yet their responses at 3 months seem to be affected adversely by this entire situation,” Dr Saddiqi said.

"One explanation, potentially, could be that these CAR T cells are seeing a lot of antigen when they go into the body. They have the perfect cytokine milieu to grow, expand, and go crazy in the body, if you will, and very quickly peter out as well because there’s T-cell exhaustion that happens rather rapidly and clinical responses are then then lost.”

The investigators believe that if they can identify those patients ahead of time who may be at risk of too high expansion or too low expansion of their CAR T cells, they may be able to find strategies to push expansion into the “sweet spot of CAR T-cell expansion and ultimately get the holy grail of having durable responses for all with minimal toxicity,” Dr Saddiqi concluded.

TRANSCEND NHL 001 is sponsored by Juno Therapeutics, Inc. Dr Saddiqi has served on a steering committee for JCAR017.

*Data in the presentation differ from the abstract.

Take-Home Points

• Malignant transformation of a benign GCT is extremely rare.
• It is difficult to distinguish between an early malignant transformation and an overlooked malignancy.
• The most common clinical presentation of transformation of GCT into malignancy is pain, often with swelling.
• Interval monitoring of GCTs may be necessary in patients with symptoms concerning for malignant transformation.
• Clinicians should maintain a high clinical suspicion for malignant transformation or late recurrence of GCT in a patient with new pain at the wound site.

Giant cell tumors (GCTs) of bone account for about 5% of all primary bone tumors in adults, with a predominance in the third decade in life.¹ Clinically, GCT of bone often presents with pain, pathologic fracture, and/or soft- tissue expansion in the epiphysis of long bones. However, GCT of bone also has been reported in non-long bones, such as the talus and the calcaneus.^2,3 Histologically, GCT of bone consists of neoplastic stromal cells, mononuclear histiocytic cells, and multinucleated giant cells that resemble osteoclasts.⁴ The radiologic appearance of GCT is often described as a lytic, eccentrically located bony lesion that extends near the articular surface in patients with closed physes. Many GCTs have aggressive radiologic features with possible extensive bony destruction and soft-tissue extension. 

Although categorized as a benign lesion, GCT can be locally aggressive, with a variable local recurrence rate of 0% to 65%, depending on treatment modality and skeletal location. Given the aggressiveness of GCT of bone, recommendations for operative intervention include intralesional curettage with adjuvant therapy (eg, cryotherapy, phenol, argon beam, electrocautery) and placement of bone void fillers (eg, bone graft polymethylmethacrylate). Wide resection is recommended when the articular surface is no longer viable for reconstruction secondary to extensive destruction. Some authors have reported that surgical margin is the only risk factor in local recurrence,^5,6 and thus complete resection may be needed for tumor eradication. In addition, about 3% of GCTs demonstrate benign pulmonary implants, which have been cited as cause of death in 16% to 25% of reported cases of pulmonary spread.^7,8

The literature includes few reports of primary or secondary malignant transformation of GCT. Hutter and colleagues⁹ defined primary malignant GCT as GCT with sarcomatous tissue juxtaposed with zones of typical benign GCT cells. Secondary malignant GCT is a sarcomatous lesion at the site of a previously documented benign GCT. Secondary malignant GCT of bone histologically has been classified as a fibrosarcoma, malignant fibrous histiocytoma, or osteosarcoma transformation.¹⁰ 

Most malignant transformations of GCT of bone have been attributed to previous irradiation of the lesion.^11,12 However, there are some case reports of benign bone GCT malignant transformation in situ without any other medical intervention. It was reported that non-radiation-induced secondary transformations occur relatively early after GCT treatment.¹³ During the early stages of tumor recurrence, however, it is difficult to distinguish between malignant transformation and primary disease overlooked as a result of sampling error.

We report a case of secondary malignant transformation of GCT of bone 11 years after surgical curettage, cryotherapy, and cementation without adjuvant radiation therapy. To our knowledge, this case report is the first to describe transformation of a nonirradiated benign GCT into an aggressive, high-grade epithelioid angiosarcoma, a very rare vascular bone tumor. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

In July 2003, a 46-year-old woman presented with left heel pain of several months’ duration. Plain radiographs showed a nonaggressive-appearing lytic lesion of the superior aspect of the posterior calcaneal tuberosity with a small cortical incongruity along the superior margin of the lesion (Figures 1A-1D).

A postoperative splint was placed, and weight-bearing progressed over 6 weeks. The patient was followed at 2- to 3-month intervals over the first 5 postoperative years. She was able to work and perform activities of daily living, but her postoperative course was complicated by significant chronic pain in multiple extremities and long-term treatment by the chronic pain service. At no time did postoperative imaging—magnetic resonance imaging (MRI) at 6 years, whole-body bone scan at 7 years, plain radiographs at 10 years—show evidence of recurrence.

Radiographs showed stable postoperative changes with a small radiolucent area (with sclerotic rim) surrounding the cement-bone interface. Given its proximity to the Achilles tendon and more motion than usual at the wound site, the radiolucency likely was caused by small movements of the interface. The radiolucent area remained stable over a 15-month period.

Whole-body bone scan showed a small area of osteoblastic activity in the left calcaneus, consistent with inflammation surrounding the bone- cement interface, but the uptake was minor relative to other areas of signal, and there were no significant inflammatory reactive changes on MRI (Figures 3A, 3B).

Over 11 years, regular 6- to 12-month follow-up examinations revealed no significant changes in the left foot or in plain radiographs of the chest. In addition, physical examinations revealed no evidence of a palpable mass of the left foot.

In July 2014 (11 years after curettage and cementation), the patient presented to her pain clinic appointment with severe left foot pain. She said that, over a few weeks, she experienced a significant increase in pain and developed posterolateral foot swelling, which limited her ability to ambulate. Plain radiographs showed a significant soft-tissue prominence around the posterior calcaneus, increased lucency around the bone-cement interface in the calcaneus with elevation, and a cortical break of the superior margin of the posterior calcaneus (Figures 3C, 3D). MRI showed a large lobular mass in the calcaneus and surrounding soft tissue with T1 and T2 signal heterogeneity and enhancement after administration of gadolinium (Figures 4A-4D). There was a large extraosseous extension of the calcaneus-based mass laterally and superiorly with edema in the surrounding hindfoot region (Figure 4).

Physical examination revealed exquisite tenderness along the lateral and posterior aspects of the left hindfoot. The patient was unable to bear weight and had soft-tissue swelling throughout the foot and mid calf as well as a palpable mass in the posterior heel. She was otherwise neurovascularly intact through all distributions of the left lower extremity. It was unclear if the GCT of the calcaneus had recurred or if there was a new, secondary tumor. Given her severe pain and morbidity, the patient decided to proceed with open biopsy and a pathology-pending plan for possible amputation in the near future.

In August 2014, an open biopsy with intraoperative frozen evaluation yielded a diagnosis of malignant neoplasm not otherwise specified. Permanent sections showed a proliferation of malignant epithelioid cells with extensive necrosis, hemorrhage, and hemosiderin deposition but no multinucleated giant cells.

Transformation of the GCT into a high-grade epithelioid angiosarcoma prompted presentation of the patient’s case to a multidisciplinary board of physicians with a focused clinical practice in sarcoma management. The board included board-certified specialists in orthopedic oncology, pathology, musculoskeletal radiology, medical oncology, and radiation oncology. Although discussion included pre-resection use of neoadjuvant chemotherapy to evaluate for disease response, the patient’s severe pain led her to forgo this treatment and proceed directly to below-knee amputation.

Amputation revealed a 7.7-cm hemorrhagic necrotic mass composed of a highly cellular spindle and epithelioid malignancy with abundant hemosiderin deposition (Figure 5). In addition, several atypical mitotic figures and malignant multinucleated tumor giant cells were randomly scattered throughout the neoplasm.

At first follow-up, the patient reported significant pain relief and asked to begin titrating off her chronic pain medicine. Clinical staging, which involved performing whole-body positron emission tomography/computed tomography, revealed nothing concerning for metastases. When this report was being written, the patient was being monitored for recurrent disease in accordance with National Comprehensive Cancer Network guidelines. In the absence of residual sarcoma, our medical oncology team discussed adjuvant chemotherapy options with her. Subsequently, however, she proceeded only with observation and periodic imaging.

Malignant transformation of a benign GCT is extremely rare, especially in cases in which the tumor bed has not previously undergone radiation therapy. Although the literature includes historical case reports, primary and secondary malignant GCTs comprise <9% of all GCTs.^11,13,14 Primary bone epithelioid angiosarcoma is also extremely rare, especially in the calcaneus; only 1 case is described in the literature.¹⁵ In this article, we report on a benign GCT of bone that transformed into an epithelioid angiosarcoma more than a decade after the GCT was treated with curettage and cementation.

The fact that the malignant areas of a previous tumor may have been missed because of sampling error is important for benign GCT of bone in the early postoperative period, as distinguishing between early malignant transformation and an overlooked malignancy may not be possible. However, transformation is more likely the case when a benign GCT becomes a high-grade malignancy after a long disease-free interval. Several authors have indicated that a benign GCT tumor recurring with a secondary malignancy 2 to 5 years after initial GCT treatment suggests malignant transformation.¹⁶ Grote and colleagues¹⁰ compiled reports of malignant transformation of GCT of bone and described the clinicopathologic features of secondary malignant transformation of GCTs. The data they compiled and data from several other studies indicate a poor prognosis after malignant transformation of GCT; 4 years after diagnosis, mean survival is 40% to 50%.^10,16 The most common clinical presentation of transformation of GCT into malignancy is pain, often with coincident swelling of the native wound bed. However, a few cases have been identified with radiologic imaging alone and without a period of clinical symptoms.¹⁶

To our knowledge, this case report is the first to describe a longitudinal assessment of the transformation of a benign GCT of bone into an epithelioid angiosarcoma. Whereas an earlier reported GCT of bone transformed into epithelioid angiosarcoma after irradiation,¹² our patient’s GCT of bone transformed without irradiation. GCTs of bone are locally aggressive benign tumors and are relatively rare. Malignant transformation of a benign bone tumor a decade after initial, definitive treatment is concerning, especially given the poor prognosis after malignant transformation in this clinical scenario. Current adjuvant treatments have not changed the prognosis. The literature includes a wide variety of histologic transformations, including high-grade sarcomas, after a long disease-free interval. Although malignant transformation of benign GCTs is rare, clinicians should be aware of the potential. Interval monitoring of GCTs may be necessary in patients with symptoms concerning for malignant transformation—pain or swelling in the wound bed—and patients should know to immediately inform their physician of any changes in pain level or local wound bed. Clinicians should maintain a high clinical suspicion for malignant transformation or late recurrence of GCT in a patient with new pain at the site of a previously treated GCT of bone with a disease-free interval of several years.

Take-Home Points

• Malignant transformation of a benign GCT is extremely rare.
• It is difficult to distinguish between an early malignant transformation and an overlooked malignancy.
• The most common clinical presentation of transformation of GCT into malignancy is pain, often with swelling.
• Interval monitoring of GCTs may be necessary in patients with symptoms concerning for malignant transformation.
• Clinicians should maintain a high clinical suspicion for malignant transformation or late recurrence of GCT in a patient with new pain at the wound site.

Giant cell tumors (GCTs) of bone account for about 5% of all primary bone tumors in adults, with a predominance in the third decade in life.¹ Clinically, GCT of bone often presents with pain, pathologic fracture, and/or soft- tissue expansion in the epiphysis of long bones. However, GCT of bone also has been reported in non-long bones, such as the talus and the calcaneus.^2,3 Histologically, GCT of bone consists of neoplastic stromal cells, mononuclear histiocytic cells, and multinucleated giant cells that resemble osteoclasts.⁴ The radiologic appearance of GCT is often described as a lytic, eccentrically located bony lesion that extends near the articular surface in patients with closed physes. Many GCTs have aggressive radiologic features with possible extensive bony destruction and soft-tissue extension. 

Although categorized as a benign lesion, GCT can be locally aggressive, with a variable local recurrence rate of 0% to 65%, depending on treatment modality and skeletal location. Given the aggressiveness of GCT of bone, recommendations for operative intervention include intralesional curettage with adjuvant therapy (eg, cryotherapy, phenol, argon beam, electrocautery) and placement of bone void fillers (eg, bone graft polymethylmethacrylate). Wide resection is recommended when the articular surface is no longer viable for reconstruction secondary to extensive destruction. Some authors have reported that surgical margin is the only risk factor in local recurrence,^5,6 and thus complete resection may be needed for tumor eradication. In addition, about 3% of GCTs demonstrate benign pulmonary implants, which have been cited as cause of death in 16% to 25% of reported cases of pulmonary spread.^7,8

The literature includes few reports of primary or secondary malignant transformation of GCT. Hutter and colleagues⁹ defined primary malignant GCT as GCT with sarcomatous tissue juxtaposed with zones of typical benign GCT cells. Secondary malignant GCT is a sarcomatous lesion at the site of a previously documented benign GCT. Secondary malignant GCT of bone histologically has been classified as a fibrosarcoma, malignant fibrous histiocytoma, or osteosarcoma transformation.¹⁰ 

Most malignant transformations of GCT of bone have been attributed to previous irradiation of the lesion.^11,12 However, there are some case reports of benign bone GCT malignant transformation in situ without any other medical intervention. It was reported that non-radiation-induced secondary transformations occur relatively early after GCT treatment.¹³ During the early stages of tumor recurrence, however, it is difficult to distinguish between malignant transformation and primary disease overlooked as a result of sampling error.

We report a case of secondary malignant transformation of GCT of bone 11 years after surgical curettage, cryotherapy, and cementation without adjuvant radiation therapy. To our knowledge, this case report is the first to describe transformation of a nonirradiated benign GCT into an aggressive, high-grade epithelioid angiosarcoma, a very rare vascular bone tumor. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

In July 2003, a 46-year-old woman presented with left heel pain of several months’ duration. Plain radiographs showed a nonaggressive-appearing lytic lesion of the superior aspect of the posterior calcaneal tuberosity with a small cortical incongruity along the superior margin of the lesion (Figures 1A-1D).

A postoperative splint was placed, and weight-bearing progressed over 6 weeks. The patient was followed at 2- to 3-month intervals over the first 5 postoperative years. She was able to work and perform activities of daily living, but her postoperative course was complicated by significant chronic pain in multiple extremities and long-term treatment by the chronic pain service. At no time did postoperative imaging—magnetic resonance imaging (MRI) at 6 years, whole-body bone scan at 7 years, plain radiographs at 10 years—show evidence of recurrence.

Radiographs showed stable postoperative changes with a small radiolucent area (with sclerotic rim) surrounding the cement-bone interface. Given its proximity to the Achilles tendon and more motion than usual at the wound site, the radiolucency likely was caused by small movements of the interface. The radiolucent area remained stable over a 15-month period.

Whole-body bone scan showed a small area of osteoblastic activity in the left calcaneus, consistent with inflammation surrounding the bone- cement interface, but the uptake was minor relative to other areas of signal, and there were no significant inflammatory reactive changes on MRI (Figures 3A, 3B).

Over 11 years, regular 6- to 12-month follow-up examinations revealed no significant changes in the left foot or in plain radiographs of the chest. In addition, physical examinations revealed no evidence of a palpable mass of the left foot.

In July 2014 (11 years after curettage and cementation), the patient presented to her pain clinic appointment with severe left foot pain. She said that, over a few weeks, she experienced a significant increase in pain and developed posterolateral foot swelling, which limited her ability to ambulate. Plain radiographs showed a significant soft-tissue prominence around the posterior calcaneus, increased lucency around the bone-cement interface in the calcaneus with elevation, and a cortical break of the superior margin of the posterior calcaneus (Figures 3C, 3D). MRI showed a large lobular mass in the calcaneus and surrounding soft tissue with T1 and T2 signal heterogeneity and enhancement after administration of gadolinium (Figures 4A-4D). There was a large extraosseous extension of the calcaneus-based mass laterally and superiorly with edema in the surrounding hindfoot region (Figure 4).

Physical examination revealed exquisite tenderness along the lateral and posterior aspects of the left hindfoot. The patient was unable to bear weight and had soft-tissue swelling throughout the foot and mid calf as well as a palpable mass in the posterior heel. She was otherwise neurovascularly intact through all distributions of the left lower extremity. It was unclear if the GCT of the calcaneus had recurred or if there was a new, secondary tumor. Given her severe pain and morbidity, the patient decided to proceed with open biopsy and a pathology-pending plan for possible amputation in the near future.

In August 2014, an open biopsy with intraoperative frozen evaluation yielded a diagnosis of malignant neoplasm not otherwise specified. Permanent sections showed a proliferation of malignant epithelioid cells with extensive necrosis, hemorrhage, and hemosiderin deposition but no multinucleated giant cells.

Transformation of the GCT into a high-grade epithelioid angiosarcoma prompted presentation of the patient’s case to a multidisciplinary board of physicians with a focused clinical practice in sarcoma management. The board included board-certified specialists in orthopedic oncology, pathology, musculoskeletal radiology, medical oncology, and radiation oncology. Although discussion included pre-resection use of neoadjuvant chemotherapy to evaluate for disease response, the patient’s severe pain led her to forgo this treatment and proceed directly to below-knee amputation.

Amputation revealed a 7.7-cm hemorrhagic necrotic mass composed of a highly cellular spindle and epithelioid malignancy with abundant hemosiderin deposition (Figure 5). In addition, several atypical mitotic figures and malignant multinucleated tumor giant cells were randomly scattered throughout the neoplasm.

At first follow-up, the patient reported significant pain relief and asked to begin titrating off her chronic pain medicine. Clinical staging, which involved performing whole-body positron emission tomography/computed tomography, revealed nothing concerning for metastases. When this report was being written, the patient was being monitored for recurrent disease in accordance with National Comprehensive Cancer Network guidelines. In the absence of residual sarcoma, our medical oncology team discussed adjuvant chemotherapy options with her. Subsequently, however, she proceeded only with observation and periodic imaging.

Malignant transformation of a benign GCT is extremely rare, especially in cases in which the tumor bed has not previously undergone radiation therapy. Although the literature includes historical case reports, primary and secondary malignant GCTs comprise <9% of all GCTs.^11,13,14 Primary bone epithelioid angiosarcoma is also extremely rare, especially in the calcaneus; only 1 case is described in the literature.¹⁵ In this article, we report on a benign GCT of bone that transformed into an epithelioid angiosarcoma more than a decade after the GCT was treated with curettage and cementation.

The fact that the malignant areas of a previous tumor may have been missed because of sampling error is important for benign GCT of bone in the early postoperative period, as distinguishing between early malignant transformation and an overlooked malignancy may not be possible. However, transformation is more likely the case when a benign GCT becomes a high-grade malignancy after a long disease-free interval. Several authors have indicated that a benign GCT tumor recurring with a secondary malignancy 2 to 5 years after initial GCT treatment suggests malignant transformation.¹⁶ Grote and colleagues¹⁰ compiled reports of malignant transformation of GCT of bone and described the clinicopathologic features of secondary malignant transformation of GCTs. The data they compiled and data from several other studies indicate a poor prognosis after malignant transformation of GCT; 4 years after diagnosis, mean survival is 40% to 50%.^10,16 The most common clinical presentation of transformation of GCT into malignancy is pain, often with coincident swelling of the native wound bed. However, a few cases have been identified with radiologic imaging alone and without a period of clinical symptoms.¹⁶

To our knowledge, this case report is the first to describe a longitudinal assessment of the transformation of a benign GCT of bone into an epithelioid angiosarcoma. Whereas an earlier reported GCT of bone transformed into epithelioid angiosarcoma after irradiation,¹² our patient’s GCT of bone transformed without irradiation. GCTs of bone are locally aggressive benign tumors and are relatively rare. Malignant transformation of a benign bone tumor a decade after initial, definitive treatment is concerning, especially given the poor prognosis after malignant transformation in this clinical scenario. Current adjuvant treatments have not changed the prognosis. The literature includes a wide variety of histologic transformations, including high-grade sarcomas, after a long disease-free interval. Although malignant transformation of benign GCTs is rare, clinicians should be aware of the potential. Interval monitoring of GCTs may be necessary in patients with symptoms concerning for malignant transformation—pain or swelling in the wound bed—and patients should know to immediately inform their physician of any changes in pain level or local wound bed. Clinicians should maintain a high clinical suspicion for malignant transformation or late recurrence of GCT in a patient with new pain at the site of a previously treated GCT of bone with a disease-free interval of several years.

Take-Home Points

• Malignant transformation of a benign GCT is extremely rare.
• It is difficult to distinguish between an early malignant transformation and an overlooked malignancy.
• The most common clinical presentation of transformation of GCT into malignancy is pain, often with swelling.
• Interval monitoring of GCTs may be necessary in patients with symptoms concerning for malignant transformation.
• Clinicians should maintain a high clinical suspicion for malignant transformation or late recurrence of GCT in a patient with new pain at the wound site.

Giant cell tumors (GCTs) of bone account for about 5% of all primary bone tumors in adults, with a predominance in the third decade in life.¹ Clinically, GCT of bone often presents with pain, pathologic fracture, and/or soft- tissue expansion in the epiphysis of long bones. However, GCT of bone also has been reported in non-long bones, such as the talus and the calcaneus.^2,3 Histologically, GCT of bone consists of neoplastic stromal cells, mononuclear histiocytic cells, and multinucleated giant cells that resemble osteoclasts.⁴ The radiologic appearance of GCT is often described as a lytic, eccentrically located bony lesion that extends near the articular surface in patients with closed physes. Many GCTs have aggressive radiologic features with possible extensive bony destruction and soft-tissue extension. 

Although categorized as a benign lesion, GCT can be locally aggressive, with a variable local recurrence rate of 0% to 65%, depending on treatment modality and skeletal location. Given the aggressiveness of GCT of bone, recommendations for operative intervention include intralesional curettage with adjuvant therapy (eg, cryotherapy, phenol, argon beam, electrocautery) and placement of bone void fillers (eg, bone graft polymethylmethacrylate). Wide resection is recommended when the articular surface is no longer viable for reconstruction secondary to extensive destruction. Some authors have reported that surgical margin is the only risk factor in local recurrence,^5,6 and thus complete resection may be needed for tumor eradication. In addition, about 3% of GCTs demonstrate benign pulmonary implants, which have been cited as cause of death in 16% to 25% of reported cases of pulmonary spread.^7,8

The literature includes few reports of primary or secondary malignant transformation of GCT. Hutter and colleagues⁹ defined primary malignant GCT as GCT with sarcomatous tissue juxtaposed with zones of typical benign GCT cells. Secondary malignant GCT is a sarcomatous lesion at the site of a previously documented benign GCT. Secondary malignant GCT of bone histologically has been classified as a fibrosarcoma, malignant fibrous histiocytoma, or osteosarcoma transformation.¹⁰ 

Most malignant transformations of GCT of bone have been attributed to previous irradiation of the lesion.^11,12 However, there are some case reports of benign bone GCT malignant transformation in situ without any other medical intervention. It was reported that non-radiation-induced secondary transformations occur relatively early after GCT treatment.¹³ During the early stages of tumor recurrence, however, it is difficult to distinguish between malignant transformation and primary disease overlooked as a result of sampling error.

We report a case of secondary malignant transformation of GCT of bone 11 years after surgical curettage, cryotherapy, and cementation without adjuvant radiation therapy. To our knowledge, this case report is the first to describe transformation of a nonirradiated benign GCT into an aggressive, high-grade epithelioid angiosarcoma, a very rare vascular bone tumor. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

In July 2003, a 46-year-old woman presented with left heel pain of several months’ duration. Plain radiographs showed a nonaggressive-appearing lytic lesion of the superior aspect of the posterior calcaneal tuberosity with a small cortical incongruity along the superior margin of the lesion (Figures 1A-1D).

A postoperative splint was placed, and weight-bearing progressed over 6 weeks. The patient was followed at 2- to 3-month intervals over the first 5 postoperative years. She was able to work and perform activities of daily living, but her postoperative course was complicated by significant chronic pain in multiple extremities and long-term treatment by the chronic pain service. At no time did postoperative imaging—magnetic resonance imaging (MRI) at 6 years, whole-body bone scan at 7 years, plain radiographs at 10 years—show evidence of recurrence.

Radiographs showed stable postoperative changes with a small radiolucent area (with sclerotic rim) surrounding the cement-bone interface. Given its proximity to the Achilles tendon and more motion than usual at the wound site, the radiolucency likely was caused by small movements of the interface. The radiolucent area remained stable over a 15-month period.

Whole-body bone scan showed a small area of osteoblastic activity in the left calcaneus, consistent with inflammation surrounding the bone- cement interface, but the uptake was minor relative to other areas of signal, and there were no significant inflammatory reactive changes on MRI (Figures 3A, 3B).

Over 11 years, regular 6- to 12-month follow-up examinations revealed no significant changes in the left foot or in plain radiographs of the chest. In addition, physical examinations revealed no evidence of a palpable mass of the left foot.

In July 2014 (11 years after curettage and cementation), the patient presented to her pain clinic appointment with severe left foot pain. She said that, over a few weeks, she experienced a significant increase in pain and developed posterolateral foot swelling, which limited her ability to ambulate. Plain radiographs showed a significant soft-tissue prominence around the posterior calcaneus, increased lucency around the bone-cement interface in the calcaneus with elevation, and a cortical break of the superior margin of the posterior calcaneus (Figures 3C, 3D). MRI showed a large lobular mass in the calcaneus and surrounding soft tissue with T1 and T2 signal heterogeneity and enhancement after administration of gadolinium (Figures 4A-4D). There was a large extraosseous extension of the calcaneus-based mass laterally and superiorly with edema in the surrounding hindfoot region (Figure 4).

Physical examination revealed exquisite tenderness along the lateral and posterior aspects of the left hindfoot. The patient was unable to bear weight and had soft-tissue swelling throughout the foot and mid calf as well as a palpable mass in the posterior heel. She was otherwise neurovascularly intact through all distributions of the left lower extremity. It was unclear if the GCT of the calcaneus had recurred or if there was a new, secondary tumor. Given her severe pain and morbidity, the patient decided to proceed with open biopsy and a pathology-pending plan for possible amputation in the near future.

In August 2014, an open biopsy with intraoperative frozen evaluation yielded a diagnosis of malignant neoplasm not otherwise specified. Permanent sections showed a proliferation of malignant epithelioid cells with extensive necrosis, hemorrhage, and hemosiderin deposition but no multinucleated giant cells.

Transformation of the GCT into a high-grade epithelioid angiosarcoma prompted presentation of the patient’s case to a multidisciplinary board of physicians with a focused clinical practice in sarcoma management. The board included board-certified specialists in orthopedic oncology, pathology, musculoskeletal radiology, medical oncology, and radiation oncology. Although discussion included pre-resection use of neoadjuvant chemotherapy to evaluate for disease response, the patient’s severe pain led her to forgo this treatment and proceed directly to below-knee amputation.

Amputation revealed a 7.7-cm hemorrhagic necrotic mass composed of a highly cellular spindle and epithelioid malignancy with abundant hemosiderin deposition (Figure 5). In addition, several atypical mitotic figures and malignant multinucleated tumor giant cells were randomly scattered throughout the neoplasm.

At first follow-up, the patient reported significant pain relief and asked to begin titrating off her chronic pain medicine. Clinical staging, which involved performing whole-body positron emission tomography/computed tomography, revealed nothing concerning for metastases. When this report was being written, the patient was being monitored for recurrent disease in accordance with National Comprehensive Cancer Network guidelines. In the absence of residual sarcoma, our medical oncology team discussed adjuvant chemotherapy options with her. Subsequently, however, she proceeded only with observation and periodic imaging.

Malignant transformation of a benign GCT is extremely rare, especially in cases in which the tumor bed has not previously undergone radiation therapy. Although the literature includes historical case reports, primary and secondary malignant GCTs comprise <9% of all GCTs.^11,13,14 Primary bone epithelioid angiosarcoma is also extremely rare, especially in the calcaneus; only 1 case is described in the literature.¹⁵ In this article, we report on a benign GCT of bone that transformed into an epithelioid angiosarcoma more than a decade after the GCT was treated with curettage and cementation.

The fact that the malignant areas of a previous tumor may have been missed because of sampling error is important for benign GCT of bone in the early postoperative period, as distinguishing between early malignant transformation and an overlooked malignancy may not be possible. However, transformation is more likely the case when a benign GCT becomes a high-grade malignancy after a long disease-free interval. Several authors have indicated that a benign GCT tumor recurring with a secondary malignancy 2 to 5 years after initial GCT treatment suggests malignant transformation.¹⁶ Grote and colleagues¹⁰ compiled reports of malignant transformation of GCT of bone and described the clinicopathologic features of secondary malignant transformation of GCTs. The data they compiled and data from several other studies indicate a poor prognosis after malignant transformation of GCT; 4 years after diagnosis, mean survival is 40% to 50%.^10,16 The most common clinical presentation of transformation of GCT into malignancy is pain, often with coincident swelling of the native wound bed. However, a few cases have been identified with radiologic imaging alone and without a period of clinical symptoms.¹⁶

To our knowledge, this case report is the first to describe a longitudinal assessment of the transformation of a benign GCT of bone into an epithelioid angiosarcoma. Whereas an earlier reported GCT of bone transformed into epithelioid angiosarcoma after irradiation,¹² our patient’s GCT of bone transformed without irradiation. GCTs of bone are locally aggressive benign tumors and are relatively rare. Malignant transformation of a benign bone tumor a decade after initial, definitive treatment is concerning, especially given the poor prognosis after malignant transformation in this clinical scenario. Current adjuvant treatments have not changed the prognosis. The literature includes a wide variety of histologic transformations, including high-grade sarcomas, after a long disease-free interval. Although malignant transformation of benign GCTs is rare, clinicians should be aware of the potential. Interval monitoring of GCTs may be necessary in patients with symptoms concerning for malignant transformation—pain or swelling in the wound bed—and patients should know to immediately inform their physician of any changes in pain level or local wound bed. Clinicians should maintain a high clinical suspicion for malignant transformation or late recurrence of GCT in a patient with new pain at the site of a previously treated GCT of bone with a disease-free interval of several years.

Editor’s note: “Everything We Say and Do” provides readers with thoughtful and actionable communication tactics that can positively impact patients’ experience of care. In the current series of columns, physicians share how their experiences as patients have shaped their professional approach.

I have been fortunate to have had very few major health issues throughout my life. I have, however, had three major surgical procedures in the last 10 years – two total hip arthroplasties and a cataract removal with lens implant in between. The most recent THA was October 2017. Going through each procedure helped me see things from a patient’s perspective, and that showed me how important little things are to a patient, things which we may not think are all that big a deal as a provider.

Almost all of the medical personnel who came to care for me during my stays identified themselves and why they were there, and that made me feel comfortable, knowing who they were and their role. However, there were a few who did not do this, and that made me uncomfortable, not knowing who they were and why they were in my room. Not knowing is an uncomfortable feeling for a patient.

Almost every registered nurse who came to me with medication explained what the medicine was and why they were administering it, with the exception of one preop RN I met before to my cataract procedure. She walked up to me, told me to open my eye wide, held the affected eye open, and started dripping cold drops into my eye without explanation. She then said she would be back every 10 minutes to repeat the process. I had to inquire as to what the medication was and why there was a need for this process. It was a jolting experience, and she showed no compassion toward me as a patient or a person, even after I inquired.

This was not a good experience. Although cataract surgery was a totally new experience for me, she had obviously done this many times before and had to do it many times that day. However, she acted as if I should have known what she was going to do and as if she need not explain herself to anyone – which she did not, even after being queried.

Everyone during the admission process for all three procedures was solicitous and warm except for one person. Unfortunately, this individual was the first person to greet my wife and me when we arrived for my last total hip arthroplasty. She was seated at the welcome desk with her head down. After we arrived, she kept her head down and asked “How can I help you?” without ever looking up. I did not realize how unwelcome I would feel when the first person I encountered in the surgical preop admissions area failed to make eye contact with me. Her demeanor was nice enough, but she did not even attempt to make a personal connection with me – and she was at the welcome desk!

Overall, I had tremendously good experiences at three facilities in three different parts of the United States, but as we all know, it is the things that do not go well that stand out. I choose to use those things, along with some of the good things, as “reinforcers” for many of the patient-experience behaviors we identify as best practices.

What I say and do

During each patient encounter, I make eye contact with the patient and each person in the room and identify who I am and why I am there. I sit down during each visit unless there is simply no place for me to do so. I explain the procedures that are to take place, set expectations for those procedures, and then use “teachback” to ensure that my discussion with the patient has been effective. Setting expectations is very important to me: If you do not ensure that patients have appropriate expectations, their expectations will never be met and they will never have a good experience. I explain any new medication I am ordering, what it is for, and any possible significant side effects and again use teachback. The last thing I do is ask “What questions do you have for me today?” giving the patient permission to have questions, and then I respond to those questions with plain talk and teachback.

Why I do it

Not knowing what was going on and feeling marginalized were the most uncomfortable things I experienced as a patient. Using best practices for patient experience shows courtesy and respect. These practices show a willingness to take time with the patient and demonstrate my concern that I am effectively communicating my message for that visit. All of these behaviors decrease uncertainty and/or raise the patient’s feelings of importance, thereby decreasing marginalization.

How I do it

I remind myself each day I am on a clinical shift that my goal is to treat each patient like I would want my family (or myself) to be treated, and then I go out and do it. After “forcing” myself to put these behaviors into my rounding routine, they have become second nature, and I feel better for providing this level of care because it made me feel so good when I was cared for in this manner.

Dr. Sharp is chief hospitalist with Sound Physicians at University of Florida Health in Jacksonville, Fla.

Editor’s note: “Everything We Say and Do” provides readers with thoughtful and actionable communication tactics that can positively impact patients’ experience of care. In the current series of columns, physicians share how their experiences as patients have shaped their professional approach.

I have been fortunate to have had very few major health issues throughout my life. I have, however, had three major surgical procedures in the last 10 years – two total hip arthroplasties and a cataract removal with lens implant in between. The most recent THA was October 2017. Going through each procedure helped me see things from a patient’s perspective, and that showed me how important little things are to a patient, things which we may not think are all that big a deal as a provider.

Almost all of the medical personnel who came to care for me during my stays identified themselves and why they were there, and that made me feel comfortable, knowing who they were and their role. However, there were a few who did not do this, and that made me uncomfortable, not knowing who they were and why they were in my room. Not knowing is an uncomfortable feeling for a patient.

Almost every registered nurse who came to me with medication explained what the medicine was and why they were administering it, with the exception of one preop RN I met before to my cataract procedure. She walked up to me, told me to open my eye wide, held the affected eye open, and started dripping cold drops into my eye without explanation. She then said she would be back every 10 minutes to repeat the process. I had to inquire as to what the medication was and why there was a need for this process. It was a jolting experience, and she showed no compassion toward me as a patient or a person, even after I inquired.

This was not a good experience. Although cataract surgery was a totally new experience for me, she had obviously done this many times before and had to do it many times that day. However, she acted as if I should have known what she was going to do and as if she need not explain herself to anyone – which she did not, even after being queried.

Everyone during the admission process for all three procedures was solicitous and warm except for one person. Unfortunately, this individual was the first person to greet my wife and me when we arrived for my last total hip arthroplasty. She was seated at the welcome desk with her head down. After we arrived, she kept her head down and asked “How can I help you?” without ever looking up. I did not realize how unwelcome I would feel when the first person I encountered in the surgical preop admissions area failed to make eye contact with me. Her demeanor was nice enough, but she did not even attempt to make a personal connection with me – and she was at the welcome desk!

Overall, I had tremendously good experiences at three facilities in three different parts of the United States, but as we all know, it is the things that do not go well that stand out. I choose to use those things, along with some of the good things, as “reinforcers” for many of the patient-experience behaviors we identify as best practices.

What I say and do

During each patient encounter, I make eye contact with the patient and each person in the room and identify who I am and why I am there. I sit down during each visit unless there is simply no place for me to do so. I explain the procedures that are to take place, set expectations for those procedures, and then use “teachback” to ensure that my discussion with the patient has been effective. Setting expectations is very important to me: If you do not ensure that patients have appropriate expectations, their expectations will never be met and they will never have a good experience. I explain any new medication I am ordering, what it is for, and any possible significant side effects and again use teachback. The last thing I do is ask “What questions do you have for me today?” giving the patient permission to have questions, and then I respond to those questions with plain talk and teachback.

Why I do it

Not knowing what was going on and feeling marginalized were the most uncomfortable things I experienced as a patient. Using best practices for patient experience shows courtesy and respect. These practices show a willingness to take time with the patient and demonstrate my concern that I am effectively communicating my message for that visit. All of these behaviors decrease uncertainty and/or raise the patient’s feelings of importance, thereby decreasing marginalization.

How I do it

I remind myself each day I am on a clinical shift that my goal is to treat each patient like I would want my family (or myself) to be treated, and then I go out and do it. After “forcing” myself to put these behaviors into my rounding routine, they have become second nature, and I feel better for providing this level of care because it made me feel so good when I was cared for in this manner.

Dr. Sharp is chief hospitalist with Sound Physicians at University of Florida Health in Jacksonville, Fla.

Editor’s note: “Everything We Say and Do” provides readers with thoughtful and actionable communication tactics that can positively impact patients’ experience of care. In the current series of columns, physicians share how their experiences as patients have shaped their professional approach.

I have been fortunate to have had very few major health issues throughout my life. I have, however, had three major surgical procedures in the last 10 years – two total hip arthroplasties and a cataract removal with lens implant in between. The most recent THA was October 2017. Going through each procedure helped me see things from a patient’s perspective, and that showed me how important little things are to a patient, things which we may not think are all that big a deal as a provider.

Almost all of the medical personnel who came to care for me during my stays identified themselves and why they were there, and that made me feel comfortable, knowing who they were and their role. However, there were a few who did not do this, and that made me uncomfortable, not knowing who they were and why they were in my room. Not knowing is an uncomfortable feeling for a patient.

Almost every registered nurse who came to me with medication explained what the medicine was and why they were administering it, with the exception of one preop RN I met before to my cataract procedure. She walked up to me, told me to open my eye wide, held the affected eye open, and started dripping cold drops into my eye without explanation. She then said she would be back every 10 minutes to repeat the process. I had to inquire as to what the medication was and why there was a need for this process. It was a jolting experience, and she showed no compassion toward me as a patient or a person, even after I inquired.

This was not a good experience. Although cataract surgery was a totally new experience for me, she had obviously done this many times before and had to do it many times that day. However, she acted as if I should have known what she was going to do and as if she need not explain herself to anyone – which she did not, even after being queried.

Everyone during the admission process for all three procedures was solicitous and warm except for one person. Unfortunately, this individual was the first person to greet my wife and me when we arrived for my last total hip arthroplasty. She was seated at the welcome desk with her head down. After we arrived, she kept her head down and asked “How can I help you?” without ever looking up. I did not realize how unwelcome I would feel when the first person I encountered in the surgical preop admissions area failed to make eye contact with me. Her demeanor was nice enough, but she did not even attempt to make a personal connection with me – and she was at the welcome desk!

Overall, I had tremendously good experiences at three facilities in three different parts of the United States, but as we all know, it is the things that do not go well that stand out. I choose to use those things, along with some of the good things, as “reinforcers” for many of the patient-experience behaviors we identify as best practices.

What I say and do

During each patient encounter, I make eye contact with the patient and each person in the room and identify who I am and why I am there. I sit down during each visit unless there is simply no place for me to do so. I explain the procedures that are to take place, set expectations for those procedures, and then use “teachback” to ensure that my discussion with the patient has been effective. Setting expectations is very important to me: If you do not ensure that patients have appropriate expectations, their expectations will never be met and they will never have a good experience. I explain any new medication I am ordering, what it is for, and any possible significant side effects and again use teachback. The last thing I do is ask “What questions do you have for me today?” giving the patient permission to have questions, and then I respond to those questions with plain talk and teachback.

Why I do it

Not knowing what was going on and feeling marginalized were the most uncomfortable things I experienced as a patient. Using best practices for patient experience shows courtesy and respect. These practices show a willingness to take time with the patient and demonstrate my concern that I am effectively communicating my message for that visit. All of these behaviors decrease uncertainty and/or raise the patient’s feelings of importance, thereby decreasing marginalization.

How I do it

I remind myself each day I am on a clinical shift that my goal is to treat each patient like I would want my family (or myself) to be treated, and then I go out and do it. After “forcing” myself to put these behaviors into my rounding routine, they have become second nature, and I feel better for providing this level of care because it made me feel so good when I was cared for in this manner.

Dr. Sharp is chief hospitalist with Sound Physicians at University of Florida Health in Jacksonville, Fla.

Take-Home Points

• At our institution, LALB has shortened our hospital stay.
• There is a trend towards decreased opioid consumption with LALB.
• With the opioid epidemic we face today, LALB can be one of many options in our toolbox towards a solution.
• As stated in prior publications, the effectiveness of LALB is definitely technique dependent.
• Additional clinical studies are warranted to better determine the efficacy and cost-effectiveness of LALB.

Almost 1 million total knee arthroplasties (TKAs) are performed in the United States each year, and the number continues to grow.^1.2 For patients about to undergo TKA, a significant concern is postoperative pain.³ Fear of postoperative pain is often cited as a reason for delaying surgery.³ Recent literature suggests that patients with poor pain management during the first 48 hours after surgery have a 50% chance of gaining satisfactory long-term pain relief.⁴ In addition, inadequate postoperative pain management can interfere with participation in and progression of physical rehabilitation, prolong hospital stay, and increase patient dissatisfaction.⁵ Poorly controlled pain results in decreased range of motion (ROM), strength, stability, and ambulation thereby prolongs hospital stays, and increases costs and overall dissatisfaction with the procedure.

Post-TKA pain management has received much attention in recent years. A multimodal pain management protocol is now a key component of clinical pathways in TKA. Appropriate postoperative pain control lowers postoperative complications and accelerates recovery.⁶ Pain-caused loss of function makes surgical patients more susceptible to edema, deep vein thrombosis, and pulmonary embolism.⁴ Various oral and intravenous medications are used to lessen the pain response during the perioperative period. In addition, regional or neuraxial anesthesia is often added to blunt the immediate surgical pain response.^7,8 At our institution, TKA traditionally has been performed with femoral nerve catheters (FNCs) for postoperative pain control. Although effective, this method often results in decreased quadriceps musculature function, which delays rehabilitation and increases the fall risk. Recently, there has been a shift toward using local anesthetic infusions about the knee to provide adequate pain relief and restore motor function, which is often sacrificed with use of regional nerve blocks and continuous catheter infusions.⁹

Many institutions have started using a new long-acting local anesthetic in their multimodal pain management pathways: Exparel (Pacira Pharmaceuticals), a liposomal membrane-bound bupivacaine with sustained release of approximately 72 hours. Several studies have verified the safety of this medication.¹⁰ A systemic review of prospective studies revealed that, compared with bupivacaine, long-acting liposomal bupivacaine (LALB) in therapeutic doses had a higher safety margin and a favorable safety profile.¹⁰ However, no study has compared the effectiveness of LALB and FNC in a matched TKA cohort with each patient serving as his or her own control.

We recently reviewed our multimodal pain management protocol for any areas in need of improvement and decided to compare the effects of the indwelling FNC protocol that was in use with the effects of injecting the local anesthetic LALB. We conducted a study to compare the 2 methods with respect to pain control, ROM, ability to ambulate, and hospital length of stay (LOS). We hypothesized that the longer acting local anesthetic would provide comparable post-TKA pain control and post-TKA opioid use but would accelerate post-TKA rehabilitation.

Materials and Methods

This retrospective, longitudinal, repeated- measures study was approved by the Greenville Hospital System Institutional Review Board and conducted at the Steadman Hawkins Clinic of the Carolinas, Greenville Health System.

Interventions

Twenty-three patients underwent separately staged bilateral TKAs between 2010 and 2013. For each TKA, a Genesis II implant (Smith & Nephew) was used, and the surgery was performed with the patient under spinal anesthesia. In each case, FNC was used for pain control after the first TKA, and periarticular injection (PAI) of LALB for pain control after the second TKA.

In the first TKAs, FNC-administered ropivacaine 0.2% (2 mg/mL) was maintained at a standard basal rate of 8 mL/h for 48 hours. In the second TKAs, LALB was administered along with bupivacaine/epinephrine. Twenty milliliters of LALB from a single-use vial was diluted in 40 mL of normal (0.9%) saline to obtain a 60-mL solution, and a 25-gauge needle was used to inject this solution into the periarticular soft tissues; another needle was used for PAI of 30 mL of bupivacaine 0.25% with epinephrine.

Continuous passive motion devices were not used. Most patients began therapy on day of surgery. Knee immobilizers were not used in the FNC group.

The same standardized multimodal pain management protocol was used for all TKAs. Non- narcotic medications, including acetaminophen, ketorolac, and celecoxib, were given on a scheduled basis. Tramadol and opioid medications were administered as needed for pain. The attending physician based patient discharge timing on pain control, ability to safely ambulate, and absence of complications.

Outcome Measures

Outcome measures were LOS; extension and flexion at discharge and 3-week follow-up; total ROM (extension plus flexion) at discharge and 3-week follow-up; per-day and total hospital stay morphine -equivalent doses (MEDs); and per-attempt walking distance during gait training.

ROM was measured with a standard goniometer. Flexion was tested with the patient supine and the hip and knee in neutral rotation. The goniometer axis was along the lateral epicondyle of the femur with the proximal arm of the goniometer parallel to the long axis of the femur and pointing at the greater trochanter and with the distal arm parallel to the long axis of the fibula and pointing at the lateral malleolus. The patient was instructed to flex the hip and knee by moving the heel toward the buttock. Expected normal ROM is 135°. The same landmarks were used for extension. The patient was instructed to push the back of the knee toward the plinth/bed, for maximal active extension. The same ROM assessment strategy was used during the hospitalization and at the 3-week follow-up.

Several opioid medications (eg, hydrocodone, oxycodone, tramadol, hydromorphone, morphine) with different dosages were used during hospitalization. Opioid doses were converted to MEDs to permit FNC–LALB comparisons. For each patient, total MEDs were divided by LOS to determine MEDs per day.

Mean per-attempt walking distance was calculated by dividing the total distance walked during hospitalization—the sum of the number of feet walked during each and every attempt, as measured by the treating physical therapist—by the total number of walking attempts.

Data Analysis

A paired-samples t test was used to calculate differences between all outcome measures: LOS; extension and flexion at discharge and 3-month follow-up; per-day and total MEDs; and mean per-attempt walking distance. P < .05 was considered significant. We elected not to adjust our α for a potential familywise error.

Results

Of the 23 patients, 14 were female and 9 were male, and 19 were white and 4 were black. Mean (SD) age was 64.4 (6.4) years for the FNC group and 66.0 (6.0) years for the LALB group. The age difference was not statistically significant.

Poor pain control during the post-TKA period may have a significant impact on recovery rate, standard of living, psychological health, and postoperative complications.¹⁰ Inadequate postoperative pain control increases postoperative morbidity, hinders physiotherapy, increases anxiety, disrupts sleep patterns, and decreases patient satisfaction.⁹ There has been increased interest in PAIs. Local anesthetics are additional sources of pain control at surgical sites. However, the half-life of most local anesthetics is short. Soft-tissue infiltration of LALB into a surgical site extends the duration of active analgesia. Our study found that, compared with patients who received FNC, patients who received LALB had comparable pain control, improved knee ROM, and shorter hospital stays. In addition, the LALB group had no reports of quadriceps weakness or falls, both of which are associated with femoral nerve blocks. The FNC group had no reported falls, either. PAIs have the benefit of avoiding the invasiveness of femoral nerve blocks and possible neuritis.

Many complications are associated with or indirectly related to delayed rehabilitation and immobility during the acute post-TKA period. From prolonged hospitalization to need for manipulation, the consequences of inadequate pain control and decreased function can be numerous and costly for patients and the healthcare system. In the present study, LALB use led to a statistically significant overall decrease in mean LOS (LALB group, 2.3 days; FNC, 2.8 days). With LALB, there was a higher likelihood of discharge the day after surgery; 20% of patients in the LALB group and no patients in the FNC group went home that day.

The implication is that inadequate pain control led to decreased motion and decreased progression during postoperative rehabilitation. Local infiltration resulted in increased total ROM (extension plus flexion) at 3-week follow-up (LALB, 116.3°; FNC, 107.2°). In addition, there was an increase in walking distance per day of hospital stay (LALB, 135.9 feet; FNC, 84.2 feet). Furthermore, patients indicated LALB when asked which anesthetic they preferred. To our knowledge, this is the first study to compare LALB and FNC data in a matched TKA cohort with each patient serving as his or her own control.

Our study had several limitations. First was the retrospective design. Second was the small sample size, which made definitive conclusions difficult. However, the statistically significant differences we noted validated our conclusions. A statistically significant difference favoring LALB over FNC was found for total MEDs during hospitalization, but there was no significant difference in per-day MEDs. A possible reason for this difference is that LALB patients had shorter hospital stays, and therefore received fewer doses overall. Another possible reason is the small sample size; whereas a larger study using our protocol may find a statistically significant difference between LALB and FNC, we found only a trend. In the FNC group, anesthetic infiltration occurred with use of a computerized pump, which was removed on postoperative day 2; most of these patients were discharged home that day or the morning of postoperative day 3. As it is possible that some of these patients could have gone home sooner, our LOS data may have been affected. We do not consider this limitation significant, as one of our discharge criteria was 150 feet of ambulation, and most patients who received FNCs could not ambulate that far until after FNC removal. Furthermore, this study compared LALB only with FNC. It is possible that our improved outcomes could have resulted from the PAIs themselves, irrespective of LALB. In a recent TKA study by Bagsby and colleagues,¹¹ pain was controlled better with the less expensive traditional PAI of ropivacaine, epinephrine, and morphine than with the PAI of liposomal bupivacaine. Last, in our study, the experience of undergoing the first TKA may have increased patients’ confidence going into the second TKA and then helped them make faster progress in rehabilitation. Regardless, the promising results of our study and the firsthand use of LALB at our institution led us to modify our intraoperative pain management protocol for surgeons who perform TKA.

As we continue to use LALB, our study numbers will increase, and we may discover other factors that, though now underpowered, will prove to be statistically significant. Additional clinical studies are needed to better determine the efficacy and cost-effectiveness of LALB and other long-acting local anesthetic formulations. 

Take-Home Points

• At our institution, LALB has shortened our hospital stay.
• There is a trend towards decreased opioid consumption with LALB.
• With the opioid epidemic we face today, LALB can be one of many options in our toolbox towards a solution.
• As stated in prior publications, the effectiveness of LALB is definitely technique dependent.
• Additional clinical studies are warranted to better determine the efficacy and cost-effectiveness of LALB.

Almost 1 million total knee arthroplasties (TKAs) are performed in the United States each year, and the number continues to grow.^1.2 For patients about to undergo TKA, a significant concern is postoperative pain.³ Fear of postoperative pain is often cited as a reason for delaying surgery.³ Recent literature suggests that patients with poor pain management during the first 48 hours after surgery have a 50% chance of gaining satisfactory long-term pain relief.⁴ In addition, inadequate postoperative pain management can interfere with participation in and progression of physical rehabilitation, prolong hospital stay, and increase patient dissatisfaction.⁵ Poorly controlled pain results in decreased range of motion (ROM), strength, stability, and ambulation thereby prolongs hospital stays, and increases costs and overall dissatisfaction with the procedure.

Post-TKA pain management has received much attention in recent years. A multimodal pain management protocol is now a key component of clinical pathways in TKA. Appropriate postoperative pain control lowers postoperative complications and accelerates recovery.⁶ Pain-caused loss of function makes surgical patients more susceptible to edema, deep vein thrombosis, and pulmonary embolism.⁴ Various oral and intravenous medications are used to lessen the pain response during the perioperative period. In addition, regional or neuraxial anesthesia is often added to blunt the immediate surgical pain response.^7,8 At our institution, TKA traditionally has been performed with femoral nerve catheters (FNCs) for postoperative pain control. Although effective, this method often results in decreased quadriceps musculature function, which delays rehabilitation and increases the fall risk. Recently, there has been a shift toward using local anesthetic infusions about the knee to provide adequate pain relief and restore motor function, which is often sacrificed with use of regional nerve blocks and continuous catheter infusions.⁹

Many institutions have started using a new long-acting local anesthetic in their multimodal pain management pathways: Exparel (Pacira Pharmaceuticals), a liposomal membrane-bound bupivacaine with sustained release of approximately 72 hours. Several studies have verified the safety of this medication.¹⁰ A systemic review of prospective studies revealed that, compared with bupivacaine, long-acting liposomal bupivacaine (LALB) in therapeutic doses had a higher safety margin and a favorable safety profile.¹⁰ However, no study has compared the effectiveness of LALB and FNC in a matched TKA cohort with each patient serving as his or her own control.

We recently reviewed our multimodal pain management protocol for any areas in need of improvement and decided to compare the effects of the indwelling FNC protocol that was in use with the effects of injecting the local anesthetic LALB. We conducted a study to compare the 2 methods with respect to pain control, ROM, ability to ambulate, and hospital length of stay (LOS). We hypothesized that the longer acting local anesthetic would provide comparable post-TKA pain control and post-TKA opioid use but would accelerate post-TKA rehabilitation.

Materials and Methods

This retrospective, longitudinal, repeated- measures study was approved by the Greenville Hospital System Institutional Review Board and conducted at the Steadman Hawkins Clinic of the Carolinas, Greenville Health System.

Interventions

Twenty-three patients underwent separately staged bilateral TKAs between 2010 and 2013. For each TKA, a Genesis II implant (Smith & Nephew) was used, and the surgery was performed with the patient under spinal anesthesia. In each case, FNC was used for pain control after the first TKA, and periarticular injection (PAI) of LALB for pain control after the second TKA.

In the first TKAs, FNC-administered ropivacaine 0.2% (2 mg/mL) was maintained at a standard basal rate of 8 mL/h for 48 hours. In the second TKAs, LALB was administered along with bupivacaine/epinephrine. Twenty milliliters of LALB from a single-use vial was diluted in 40 mL of normal (0.9%) saline to obtain a 60-mL solution, and a 25-gauge needle was used to inject this solution into the periarticular soft tissues; another needle was used for PAI of 30 mL of bupivacaine 0.25% with epinephrine.

Continuous passive motion devices were not used. Most patients began therapy on day of surgery. Knee immobilizers were not used in the FNC group.

The same standardized multimodal pain management protocol was used for all TKAs. Non- narcotic medications, including acetaminophen, ketorolac, and celecoxib, were given on a scheduled basis. Tramadol and opioid medications were administered as needed for pain. The attending physician based patient discharge timing on pain control, ability to safely ambulate, and absence of complications.

Outcome Measures

Outcome measures were LOS; extension and flexion at discharge and 3-week follow-up; total ROM (extension plus flexion) at discharge and 3-week follow-up; per-day and total hospital stay morphine -equivalent doses (MEDs); and per-attempt walking distance during gait training.

ROM was measured with a standard goniometer. Flexion was tested with the patient supine and the hip and knee in neutral rotation. The goniometer axis was along the lateral epicondyle of the femur with the proximal arm of the goniometer parallel to the long axis of the femur and pointing at the greater trochanter and with the distal arm parallel to the long axis of the fibula and pointing at the lateral malleolus. The patient was instructed to flex the hip and knee by moving the heel toward the buttock. Expected normal ROM is 135°. The same landmarks were used for extension. The patient was instructed to push the back of the knee toward the plinth/bed, for maximal active extension. The same ROM assessment strategy was used during the hospitalization and at the 3-week follow-up.

Several opioid medications (eg, hydrocodone, oxycodone, tramadol, hydromorphone, morphine) with different dosages were used during hospitalization. Opioid doses were converted to MEDs to permit FNC–LALB comparisons. For each patient, total MEDs were divided by LOS to determine MEDs per day.

Mean per-attempt walking distance was calculated by dividing the total distance walked during hospitalization—the sum of the number of feet walked during each and every attempt, as measured by the treating physical therapist—by the total number of walking attempts.

Data Analysis

A paired-samples t test was used to calculate differences between all outcome measures: LOS; extension and flexion at discharge and 3-month follow-up; per-day and total MEDs; and mean per-attempt walking distance. P < .05 was considered significant. We elected not to adjust our α for a potential familywise error.

Results

Of the 23 patients, 14 were female and 9 were male, and 19 were white and 4 were black. Mean (SD) age was 64.4 (6.4) years for the FNC group and 66.0 (6.0) years for the LALB group. The age difference was not statistically significant.

Poor pain control during the post-TKA period may have a significant impact on recovery rate, standard of living, psychological health, and postoperative complications.¹⁰ Inadequate postoperative pain control increases postoperative morbidity, hinders physiotherapy, increases anxiety, disrupts sleep patterns, and decreases patient satisfaction.⁹ There has been increased interest in PAIs. Local anesthetics are additional sources of pain control at surgical sites. However, the half-life of most local anesthetics is short. Soft-tissue infiltration of LALB into a surgical site extends the duration of active analgesia. Our study found that, compared with patients who received FNC, patients who received LALB had comparable pain control, improved knee ROM, and shorter hospital stays. In addition, the LALB group had no reports of quadriceps weakness or falls, both of which are associated with femoral nerve blocks. The FNC group had no reported falls, either. PAIs have the benefit of avoiding the invasiveness of femoral nerve blocks and possible neuritis.

Many complications are associated with or indirectly related to delayed rehabilitation and immobility during the acute post-TKA period. From prolonged hospitalization to need for manipulation, the consequences of inadequate pain control and decreased function can be numerous and costly for patients and the healthcare system. In the present study, LALB use led to a statistically significant overall decrease in mean LOS (LALB group, 2.3 days; FNC, 2.8 days). With LALB, there was a higher likelihood of discharge the day after surgery; 20% of patients in the LALB group and no patients in the FNC group went home that day.

The implication is that inadequate pain control led to decreased motion and decreased progression during postoperative rehabilitation. Local infiltration resulted in increased total ROM (extension plus flexion) at 3-week follow-up (LALB, 116.3°; FNC, 107.2°). In addition, there was an increase in walking distance per day of hospital stay (LALB, 135.9 feet; FNC, 84.2 feet). Furthermore, patients indicated LALB when asked which anesthetic they preferred. To our knowledge, this is the first study to compare LALB and FNC data in a matched TKA cohort with each patient serving as his or her own control.

Our study had several limitations. First was the retrospective design. Second was the small sample size, which made definitive conclusions difficult. However, the statistically significant differences we noted validated our conclusions. A statistically significant difference favoring LALB over FNC was found for total MEDs during hospitalization, but there was no significant difference in per-day MEDs. A possible reason for this difference is that LALB patients had shorter hospital stays, and therefore received fewer doses overall. Another possible reason is the small sample size; whereas a larger study using our protocol may find a statistically significant difference between LALB and FNC, we found only a trend. In the FNC group, anesthetic infiltration occurred with use of a computerized pump, which was removed on postoperative day 2; most of these patients were discharged home that day or the morning of postoperative day 3. As it is possible that some of these patients could have gone home sooner, our LOS data may have been affected. We do not consider this limitation significant, as one of our discharge criteria was 150 feet of ambulation, and most patients who received FNCs could not ambulate that far until after FNC removal. Furthermore, this study compared LALB only with FNC. It is possible that our improved outcomes could have resulted from the PAIs themselves, irrespective of LALB. In a recent TKA study by Bagsby and colleagues,¹¹ pain was controlled better with the less expensive traditional PAI of ropivacaine, epinephrine, and morphine than with the PAI of liposomal bupivacaine. Last, in our study, the experience of undergoing the first TKA may have increased patients’ confidence going into the second TKA and then helped them make faster progress in rehabilitation. Regardless, the promising results of our study and the firsthand use of LALB at our institution led us to modify our intraoperative pain management protocol for surgeons who perform TKA.

As we continue to use LALB, our study numbers will increase, and we may discover other factors that, though now underpowered, will prove to be statistically significant. Additional clinical studies are needed to better determine the efficacy and cost-effectiveness of LALB and other long-acting local anesthetic formulations. 

Take-Home Points

• At our institution, LALB has shortened our hospital stay.
• There is a trend towards decreased opioid consumption with LALB.
• With the opioid epidemic we face today, LALB can be one of many options in our toolbox towards a solution.
• As stated in prior publications, the effectiveness of LALB is definitely technique dependent.
• Additional clinical studies are warranted to better determine the efficacy and cost-effectiveness of LALB.

Almost 1 million total knee arthroplasties (TKAs) are performed in the United States each year, and the number continues to grow.^1.2 For patients about to undergo TKA, a significant concern is postoperative pain.³ Fear of postoperative pain is often cited as a reason for delaying surgery.³ Recent literature suggests that patients with poor pain management during the first 48 hours after surgery have a 50% chance of gaining satisfactory long-term pain relief.⁴ In addition, inadequate postoperative pain management can interfere with participation in and progression of physical rehabilitation, prolong hospital stay, and increase patient dissatisfaction.⁵ Poorly controlled pain results in decreased range of motion (ROM), strength, stability, and ambulation thereby prolongs hospital stays, and increases costs and overall dissatisfaction with the procedure.

Post-TKA pain management has received much attention in recent years. A multimodal pain management protocol is now a key component of clinical pathways in TKA. Appropriate postoperative pain control lowers postoperative complications and accelerates recovery.⁶ Pain-caused loss of function makes surgical patients more susceptible to edema, deep vein thrombosis, and pulmonary embolism.⁴ Various oral and intravenous medications are used to lessen the pain response during the perioperative period. In addition, regional or neuraxial anesthesia is often added to blunt the immediate surgical pain response.^7,8 At our institution, TKA traditionally has been performed with femoral nerve catheters (FNCs) for postoperative pain control. Although effective, this method often results in decreased quadriceps musculature function, which delays rehabilitation and increases the fall risk. Recently, there has been a shift toward using local anesthetic infusions about the knee to provide adequate pain relief and restore motor function, which is often sacrificed with use of regional nerve blocks and continuous catheter infusions.⁹

Many institutions have started using a new long-acting local anesthetic in their multimodal pain management pathways: Exparel (Pacira Pharmaceuticals), a liposomal membrane-bound bupivacaine with sustained release of approximately 72 hours. Several studies have verified the safety of this medication.¹⁰ A systemic review of prospective studies revealed that, compared with bupivacaine, long-acting liposomal bupivacaine (LALB) in therapeutic doses had a higher safety margin and a favorable safety profile.¹⁰ However, no study has compared the effectiveness of LALB and FNC in a matched TKA cohort with each patient serving as his or her own control.

We recently reviewed our multimodal pain management protocol for any areas in need of improvement and decided to compare the effects of the indwelling FNC protocol that was in use with the effects of injecting the local anesthetic LALB. We conducted a study to compare the 2 methods with respect to pain control, ROM, ability to ambulate, and hospital length of stay (LOS). We hypothesized that the longer acting local anesthetic would provide comparable post-TKA pain control and post-TKA opioid use but would accelerate post-TKA rehabilitation.

Materials and Methods

This retrospective, longitudinal, repeated- measures study was approved by the Greenville Hospital System Institutional Review Board and conducted at the Steadman Hawkins Clinic of the Carolinas, Greenville Health System.

Interventions

Twenty-three patients underwent separately staged bilateral TKAs between 2010 and 2013. For each TKA, a Genesis II implant (Smith & Nephew) was used, and the surgery was performed with the patient under spinal anesthesia. In each case, FNC was used for pain control after the first TKA, and periarticular injection (PAI) of LALB for pain control after the second TKA.

In the first TKAs, FNC-administered ropivacaine 0.2% (2 mg/mL) was maintained at a standard basal rate of 8 mL/h for 48 hours. In the second TKAs, LALB was administered along with bupivacaine/epinephrine. Twenty milliliters of LALB from a single-use vial was diluted in 40 mL of normal (0.9%) saline to obtain a 60-mL solution, and a 25-gauge needle was used to inject this solution into the periarticular soft tissues; another needle was used for PAI of 30 mL of bupivacaine 0.25% with epinephrine.

Continuous passive motion devices were not used. Most patients began therapy on day of surgery. Knee immobilizers were not used in the FNC group.

The same standardized multimodal pain management protocol was used for all TKAs. Non- narcotic medications, including acetaminophen, ketorolac, and celecoxib, were given on a scheduled basis. Tramadol and opioid medications were administered as needed for pain. The attending physician based patient discharge timing on pain control, ability to safely ambulate, and absence of complications.

Outcome Measures

Outcome measures were LOS; extension and flexion at discharge and 3-week follow-up; total ROM (extension plus flexion) at discharge and 3-week follow-up; per-day and total hospital stay morphine -equivalent doses (MEDs); and per-attempt walking distance during gait training.

ROM was measured with a standard goniometer. Flexion was tested with the patient supine and the hip and knee in neutral rotation. The goniometer axis was along the lateral epicondyle of the femur with the proximal arm of the goniometer parallel to the long axis of the femur and pointing at the greater trochanter and with the distal arm parallel to the long axis of the fibula and pointing at the lateral malleolus. The patient was instructed to flex the hip and knee by moving the heel toward the buttock. Expected normal ROM is 135°. The same landmarks were used for extension. The patient was instructed to push the back of the knee toward the plinth/bed, for maximal active extension. The same ROM assessment strategy was used during the hospitalization and at the 3-week follow-up.

Several opioid medications (eg, hydrocodone, oxycodone, tramadol, hydromorphone, morphine) with different dosages were used during hospitalization. Opioid doses were converted to MEDs to permit FNC–LALB comparisons. For each patient, total MEDs were divided by LOS to determine MEDs per day.

Mean per-attempt walking distance was calculated by dividing the total distance walked during hospitalization—the sum of the number of feet walked during each and every attempt, as measured by the treating physical therapist—by the total number of walking attempts.

Data Analysis

A paired-samples t test was used to calculate differences between all outcome measures: LOS; extension and flexion at discharge and 3-month follow-up; per-day and total MEDs; and mean per-attempt walking distance. P < .05 was considered significant. We elected not to adjust our α for a potential familywise error.

Results

Of the 23 patients, 14 were female and 9 were male, and 19 were white and 4 were black. Mean (SD) age was 64.4 (6.4) years for the FNC group and 66.0 (6.0) years for the LALB group. The age difference was not statistically significant.

Poor pain control during the post-TKA period may have a significant impact on recovery rate, standard of living, psychological health, and postoperative complications.¹⁰ Inadequate postoperative pain control increases postoperative morbidity, hinders physiotherapy, increases anxiety, disrupts sleep patterns, and decreases patient satisfaction.⁹ There has been increased interest in PAIs. Local anesthetics are additional sources of pain control at surgical sites. However, the half-life of most local anesthetics is short. Soft-tissue infiltration of LALB into a surgical site extends the duration of active analgesia. Our study found that, compared with patients who received FNC, patients who received LALB had comparable pain control, improved knee ROM, and shorter hospital stays. In addition, the LALB group had no reports of quadriceps weakness or falls, both of which are associated with femoral nerve blocks. The FNC group had no reported falls, either. PAIs have the benefit of avoiding the invasiveness of femoral nerve blocks and possible neuritis.

Many complications are associated with or indirectly related to delayed rehabilitation and immobility during the acute post-TKA period. From prolonged hospitalization to need for manipulation, the consequences of inadequate pain control and decreased function can be numerous and costly for patients and the healthcare system. In the present study, LALB use led to a statistically significant overall decrease in mean LOS (LALB group, 2.3 days; FNC, 2.8 days). With LALB, there was a higher likelihood of discharge the day after surgery; 20% of patients in the LALB group and no patients in the FNC group went home that day.

The implication is that inadequate pain control led to decreased motion and decreased progression during postoperative rehabilitation. Local infiltration resulted in increased total ROM (extension plus flexion) at 3-week follow-up (LALB, 116.3°; FNC, 107.2°). In addition, there was an increase in walking distance per day of hospital stay (LALB, 135.9 feet; FNC, 84.2 feet). Furthermore, patients indicated LALB when asked which anesthetic they preferred. To our knowledge, this is the first study to compare LALB and FNC data in a matched TKA cohort with each patient serving as his or her own control.

Our study had several limitations. First was the retrospective design. Second was the small sample size, which made definitive conclusions difficult. However, the statistically significant differences we noted validated our conclusions. A statistically significant difference favoring LALB over FNC was found for total MEDs during hospitalization, but there was no significant difference in per-day MEDs. A possible reason for this difference is that LALB patients had shorter hospital stays, and therefore received fewer doses overall. Another possible reason is the small sample size; whereas a larger study using our protocol may find a statistically significant difference between LALB and FNC, we found only a trend. In the FNC group, anesthetic infiltration occurred with use of a computerized pump, which was removed on postoperative day 2; most of these patients were discharged home that day or the morning of postoperative day 3. As it is possible that some of these patients could have gone home sooner, our LOS data may have been affected. We do not consider this limitation significant, as one of our discharge criteria was 150 feet of ambulation, and most patients who received FNCs could not ambulate that far until after FNC removal. Furthermore, this study compared LALB only with FNC. It is possible that our improved outcomes could have resulted from the PAIs themselves, irrespective of LALB. In a recent TKA study by Bagsby and colleagues,¹¹ pain was controlled better with the less expensive traditional PAI of ropivacaine, epinephrine, and morphine than with the PAI of liposomal bupivacaine. Last, in our study, the experience of undergoing the first TKA may have increased patients’ confidence going into the second TKA and then helped them make faster progress in rehabilitation. Regardless, the promising results of our study and the firsthand use of LALB at our institution led us to modify our intraoperative pain management protocol for surgeons who perform TKA.

As we continue to use LALB, our study numbers will increase, and we may discover other factors that, though now underpowered, will prove to be statistically significant. Additional clinical studies are needed to better determine the efficacy and cost-effectiveness of LALB and other long-acting local anesthetic formulations. 

The smoking cessation aid varenicline tartrate is effective for reducing heavy drinking in men with alcohol use disorder and comorbid cigarette smoking, according to findings published Dec. 20, 2017. The drug also increased smoking abstinence in participants overall, reported Stephanie S. O’Malley, PhD, of the department of psychiatry at Yale University, New Haven, Conn., and her coauthors.

Bunyos/Thinkstock

SOURCE: O’Malley SS et al. JAMA Psychiatry. 2017 Dec 20. doi: 10.1001/jamapsychiatry.2017.3544.
 

The smoking cessation aid varenicline tartrate is effective for reducing heavy drinking in men with alcohol use disorder and comorbid cigarette smoking, according to findings published Dec. 20, 2017. The drug also increased smoking abstinence in participants overall, reported Stephanie S. O’Malley, PhD, of the department of psychiatry at Yale University, New Haven, Conn., and her coauthors.

Bunyos/Thinkstock

SOURCE: O’Malley SS et al. JAMA Psychiatry. 2017 Dec 20. doi: 10.1001/jamapsychiatry.2017.3544.
 

The smoking cessation aid varenicline tartrate is effective for reducing heavy drinking in men with alcohol use disorder and comorbid cigarette smoking, according to findings published Dec. 20, 2017. The drug also increased smoking abstinence in participants overall, reported Stephanie S. O’Malley, PhD, of the department of psychiatry at Yale University, New Haven, Conn., and her coauthors.

Bunyos/Thinkstock

SOURCE: O’Malley SS et al. JAMA Psychiatry. 2017 Dec 20. doi: 10.1001/jamapsychiatry.2017.3544.
 

Based on the appearance and location of the lesions, a diagnosis of recurrent herpes simplex virus-2 (HSV-2) was made. HSV-2 is generally a genital eruption but can also occur on the buttocks, especially in women. (Our patient was not aware that she’d had a genital primary HSV-2 infection.) HSV-2 infects an estimated 5% to 25% of adults in western nations. In 2012, approximately 417 million people ages 15 to 49 were living with HSV-2 worldwide, including 19 million who were newly infected.

Following a genital primary infection, HSV-2 lies dormant in the sacral nerve root ganglia, which innervate both the genitals and sacrum. Reactivation can thus result in recurrences anywhere over the sacral dermatome. The sacral area is the most common nongenital site for recurrent HSV-2. Reactivation of HSV-2 is more common and more severe in patients with human immunodeficiency virus infection.

The mainstay of treatment for HSV is antiviral therapy with acyclovir. Famciclovir and valacyclovir can be used, as well. These antivirals inhibit viral DNA replication, shorten duration of symptoms, increase lesion healing, and decrease viral shedding time. They are generally safe; the main adverse effects of oral therapy are nausea, vomiting, and diarrhea.

In general, nongenital recurrences of HSV are treated the same as genital recurrences. Dosing during prodromal symptoms or at the first sign of a recurrence is recommended for maximum efficacy. Suppressive therapy can be effective in patients who experience frequent recurrences and is generally recommended for 6 months to a year (or longer). Patients should also be warned that because of increased genital viral shedding during sacral recurrences, they should avoid sexual contact during outbreaks.

After a discussion about the benefits and risks of antiviral suppression, the patient decided she was ready to proceed with treatment. The physician prescribed oral valacyclovir 1 g daily for treatment and suppression. She had no recurrences over the next year.

Adapted from: Flowers H, Brodell RT. Recurrent vesicular rash over the sacrum. J Fam Pract. 2015;64:577-579.

Based on the appearance and location of the lesions, a diagnosis of recurrent herpes simplex virus-2 (HSV-2) was made. HSV-2 is generally a genital eruption but can also occur on the buttocks, especially in women. (Our patient was not aware that she’d had a genital primary HSV-2 infection.) HSV-2 infects an estimated 5% to 25% of adults in western nations. In 2012, approximately 417 million people ages 15 to 49 were living with HSV-2 worldwide, including 19 million who were newly infected.

Following a genital primary infection, HSV-2 lies dormant in the sacral nerve root ganglia, which innervate both the genitals and sacrum. Reactivation can thus result in recurrences anywhere over the sacral dermatome. The sacral area is the most common nongenital site for recurrent HSV-2. Reactivation of HSV-2 is more common and more severe in patients with human immunodeficiency virus infection.

The mainstay of treatment for HSV is antiviral therapy with acyclovir. Famciclovir and valacyclovir can be used, as well. These antivirals inhibit viral DNA replication, shorten duration of symptoms, increase lesion healing, and decrease viral shedding time. They are generally safe; the main adverse effects of oral therapy are nausea, vomiting, and diarrhea.

In general, nongenital recurrences of HSV are treated the same as genital recurrences. Dosing during prodromal symptoms or at the first sign of a recurrence is recommended for maximum efficacy. Suppressive therapy can be effective in patients who experience frequent recurrences and is generally recommended for 6 months to a year (or longer). Patients should also be warned that because of increased genital viral shedding during sacral recurrences, they should avoid sexual contact during outbreaks.

After a discussion about the benefits and risks of antiviral suppression, the patient decided she was ready to proceed with treatment. The physician prescribed oral valacyclovir 1 g daily for treatment and suppression. She had no recurrences over the next year.

Adapted from: Flowers H, Brodell RT. Recurrent vesicular rash over the sacrum. J Fam Pract. 2015;64:577-579.

Based on the appearance and location of the lesions, a diagnosis of recurrent herpes simplex virus-2 (HSV-2) was made. HSV-2 is generally a genital eruption but can also occur on the buttocks, especially in women. (Our patient was not aware that she’d had a genital primary HSV-2 infection.) HSV-2 infects an estimated 5% to 25% of adults in western nations. In 2012, approximately 417 million people ages 15 to 49 were living with HSV-2 worldwide, including 19 million who were newly infected.

Following a genital primary infection, HSV-2 lies dormant in the sacral nerve root ganglia, which innervate both the genitals and sacrum. Reactivation can thus result in recurrences anywhere over the sacral dermatome. The sacral area is the most common nongenital site for recurrent HSV-2. Reactivation of HSV-2 is more common and more severe in patients with human immunodeficiency virus infection.

The mainstay of treatment for HSV is antiviral therapy with acyclovir. Famciclovir and valacyclovir can be used, as well. These antivirals inhibit viral DNA replication, shorten duration of symptoms, increase lesion healing, and decrease viral shedding time. They are generally safe; the main adverse effects of oral therapy are nausea, vomiting, and diarrhea.

In general, nongenital recurrences of HSV are treated the same as genital recurrences. Dosing during prodromal symptoms or at the first sign of a recurrence is recommended for maximum efficacy. Suppressive therapy can be effective in patients who experience frequent recurrences and is generally recommended for 6 months to a year (or longer). Patients should also be warned that because of increased genital viral shedding during sacral recurrences, they should avoid sexual contact during outbreaks.

After a discussion about the benefits and risks of antiviral suppression, the patient decided she was ready to proceed with treatment. The physician prescribed oral valacyclovir 1 g daily for treatment and suppression. She had no recurrences over the next year.

Adapted from: Flowers H, Brodell RT. Recurrent vesicular rash over the sacrum. J Fam Pract. 2015;64:577-579.

Gadolinium-based contrast agents (GBCAs) used for MRI will now carry a warning regarding their potential retention in the bodies and brains of treated patients, according to the Food and Drug Administration.

The FDA is requiring the new class warning, along with other safety measures, based on evidence showing that trace amounts of gadolinium can be retained in the body for months to years after treatment.

Wikimedia Commons/FitzColinGerald/Creative Commons License

[email protected]

Gadolinium-based contrast agents (GBCAs) used for MRI will now carry a warning regarding their potential retention in the bodies and brains of treated patients, according to the Food and Drug Administration.

The FDA is requiring the new class warning, along with other safety measures, based on evidence showing that trace amounts of gadolinium can be retained in the body for months to years after treatment.

Wikimedia Commons/FitzColinGerald/Creative Commons License

[email protected]

Gadolinium-based contrast agents (GBCAs) used for MRI will now carry a warning regarding their potential retention in the bodies and brains of treated patients, according to the Food and Drug Administration.

The FDA is requiring the new class warning, along with other safety measures, based on evidence showing that trace amounts of gadolinium can be retained in the body for months to years after treatment.

Wikimedia Commons/FitzColinGerald/Creative Commons License

[email protected]

Clinical question: Can the dual-antiplatelet therapy scoring system be used to determine which patients undergoing percutaneous coronary intervention (PCI) would benefit from prolonged (24 months) DAPT?

Background: Prolonged DAPT therapy has been estimated to prevent 8 myocardial infarctions per 1,000 persons treated for 1 year but at the cost of 6 major bleeding events with no clear mortality benefit. Given these trade-offs, the DAPT score could be used to identify patients who would benefit or would be harmed from prolonged DAPT. The safety and efficacy of DAPT duration as guided by the DAPT score has not been assessed outside the derivation cohort. This study applied the DAPT score to the PRODIGY trial patients to evaluate safety and outcomes of DAPT for 24 months versus a less than 6-month regimen.

Dr. Setji is a hospitalist and medical director, Duke University Hospital.

Clinical question: Can the dual-antiplatelet therapy scoring system be used to determine which patients undergoing percutaneous coronary intervention (PCI) would benefit from prolonged (24 months) DAPT?

Background: Prolonged DAPT therapy has been estimated to prevent 8 myocardial infarctions per 1,000 persons treated for 1 year but at the cost of 6 major bleeding events with no clear mortality benefit. Given these trade-offs, the DAPT score could be used to identify patients who would benefit or would be harmed from prolonged DAPT. The safety and efficacy of DAPT duration as guided by the DAPT score has not been assessed outside the derivation cohort. This study applied the DAPT score to the PRODIGY trial patients to evaluate safety and outcomes of DAPT for 24 months versus a less than 6-month regimen.

Dr. Setji is a hospitalist and medical director, Duke University Hospital.

Clinical question: Can the dual-antiplatelet therapy scoring system be used to determine which patients undergoing percutaneous coronary intervention (PCI) would benefit from prolonged (24 months) DAPT?

Background: Prolonged DAPT therapy has been estimated to prevent 8 myocardial infarctions per 1,000 persons treated for 1 year but at the cost of 6 major bleeding events with no clear mortality benefit. Given these trade-offs, the DAPT score could be used to identify patients who would benefit or would be harmed from prolonged DAPT. The safety and efficacy of DAPT duration as guided by the DAPT score has not been assessed outside the derivation cohort. This study applied the DAPT score to the PRODIGY trial patients to evaluate safety and outcomes of DAPT for 24 months versus a less than 6-month regimen.

Dr. Setji is a hospitalist and medical director, Duke University Hospital.

The aim of palliative care (PC) is to improve quality of life for patients facing serious, life-threatening illness and their families.¹ Due to insufficient numbers of PC specialists to meet the PC needs for every hospitalized patient,² all hospitalists should maintain basic PC skills as recognized by PC being a core competency for hospitalists.^3,4

We summarize and critique PC research articles published between January 1, 2016, and December 31, 2016, that have a high likelihood of impacting the practice of hospital medicine. We hand searched 15 journals and conducted a MEDLINE keyword search of PC terms (see Table). All titles and/or abstracts were reviewed and selected for full review based on the following factors: palliative medicine content, scientific rigor, impact on practice, and relevance to hospital medicine. Fifty-five articles were individually reviewed and scored by all authors according to rigor, impact, and relevance. Articles were ranked according to their mean scores, and 9 articles were chosen for inclusion through consensus discussion.

Antipsychotics Were Inferior to a Placebo in Treating Nonterminal Delirium

Agar MR, Lawlor PG, Quinn S, et al. Efficacy of oral risperidone, haloperidol, or placebo for symptoms of delirium among patients in palliative care: a randomized clinical trial. JAMA Intern Med. 2017;177(1):34-42.

Background

Delirium is highly prevalent in PC and is associated with significant distress.⁵ Antipsychotics are widely used for symptoms of delirium, although current evidence does not support this practice in hospitalized adults.^6,7

Findings

This was a double-blind, parallel-arm, placebo randomized controlled trial (RCT) of 247 patients with delirium with an estimated life expectancy of ≥7 days in 11 PC or hospice units across Australia. Patients were randomized to receive risperidone, haloperidol, or a placebo in addition to nonpharmacological management of delirium. Delirium symptom scores after 3 days of treatment, the use of midazolam as a rescue medication, and the presence of extrapyramidal symptoms (EPS) were measured. The risperidone and haloperidol arms had significantly higher delirium symptom scores (P = .02 and P = .009, respectively), mean EPS symptoms (P < .001), and more use of rescue midazolam than the placebo arm. Mortality was higher for antipsychotics, with a hazard ratio of 1.73 for haloperidol (P = .003), 1.29 for risperidone (P = .14), and 1.47 for any antipsychotic (P = .01).

Cautions

The study population was elderly (mean age >70 years) with mild delirium scores. The use of antipsychotics was associated with more benzodiazepine use, which could itself worsen delirium. As patients with clinician-predicted life expectancy of <7 days were excluded, findings cannot be extrapolated to the treatment of terminal delirium, which can often be more symptomatic and difficult to treat.

Implications

Avoid scheduled antipsychotics in patients with nonterminal delirium, as they can increase risk of harm without advantages, over nonpharmacologic interventions.

Low-Dose Morphine Was Superior to Weak Opioids in the Treatment of Moderate Cancer Pain

Bandieri E, Romero M, Ripamonti CI, et al. Randomized trial of low-dose morphine versus weak opioids in moderate cancer pain. J Clin Oncol. 2016;34(5):436-442.

Background

The World Health Organization guidelines recommend the use of weak opioids (WOs), such as codeine or tramadol, as a sequential step in the management of cancer pain.⁸ This strategy has not been tested against low doses of stronger opioids.

Findings

In this multicenter, open-label RCT, 240 patients in Italy were randomized and stratified by age (<75 years or ≥75 years) to either the WO group or low-dose morphine (M) group. The primary outcome measure was a reduction in pain intensity by 20% or more. Secondary outcomes included an improvement in symptom scores, a ≥30% and ≥50% reduction in pain, increased opioid dosage, and adverse side effects. Compared with the WO group, the M group had more patients with a 20% reduction in pain (88.2% vs 54.7%; P < .001), more evidence of pain control in the first week (80.9% vs 43.6%; P < .001), more patients with a ≥30% and ≥50% reduction in pain, and less need to switch to a stronger opioid (15.5% vs 35.0%; P = .001) or require dose increases. Adverse effects were similar in both groups.

Cautions

Patients with chronic kidney disease (CKD) were excluded due to concerns about the accumulation of morphine metabolites. Additionally, this study was open label, increasing the risk of bias.

Implications

Low-dose morphine should be considered over the use of WOs to achieve better and more rapid pain control in patients without CKD.

The Use of Methadone as a Coanalgesic May Improve Moderate Cancer Pain

Courtemanche F, Dao D, Gagné F, et al. Methadone as a coanalgesic for palliative care cancer patients. J Palliat Med. 2016;19(9):972-978.

Background

Methadone is effective at treating cancer pain and is often utilized when patients have neuropathic pain, fail to respond to traditional opioids, or have renal failure.^9,10 However, its long half-life and many drug interactions make methadone challenging to use.

Findings

This cohort study looked at 153 inpatient or outpatient PC patients in Montreal who received methadone as a coanalgesic for cancer pain. The patients’ median morphine equivalent dose was 120 mg when initiating methadone. The median starting dose of methadone was 3 mg per day. Of patients, 49.3% had a significant response (≥30% pain reduction), with a median response time of 7 days, and 30.1% achieved a substantial response (≥50% pain reduction), with a median response time of 3 days. Patients with higher initial pain scores were more likely to respond to adjuvant methadone. Those who had not responded after a week of methadone were unlikely to respond despite dose escalations. Adverse effects included drowsiness (51.4%), confusion (27.4%), constipation (24.7%), nausea (19.9%), and myoclonia (16.4%).

Cautions

This was an observational study with retrospective data, leading to higher levels of missing data. A high rate of adverse side effects was reported (90.4%). Further study is needed to validate and reproduce the findings.

Implications

The use of adjuvant low-dose methadone may be considered in patients with moderate pain despite high-dose opioids. If a response is not seen within 7 days, then methadone use should be reconsidered.

Many Hospitalized Patients on Comfort Care Still Receive Antimicrobials

Merel SE, Meier CA, McKinney CM, Pottinger PS. Antimicrobial use in patients on a comfort care protocol: a retrospective cohort study. J Palliat Med. 2016;19(11):1210-1214.

Background

It is unknown how often patients who are hospitalized at the end of life continue to receive antimicrobials and what factors are associated with antimicrobial use.

Findings

This retrospective cohort study of 1881 hospitalized adults transitioned to a comfort care order (CCO) set at 2 academic medical centers found that 77% of these patients received antimicrobials during their hospital stay (62.4% at 24 hours prior to CCO). Of the 711 still alive at ≥24 hours after CCO, 111 (15.6%) were still on antimicrobials, with that proportion remaining stable for the remainder of hospitalization. In comparing those who did and did not receive antimicrobials after 24 hours of CCO, the presence of a documented infection was not significantly different after adjusting for age. Those with a cancer diagnosis (adjusted risk ratio [ARR] = 1.44: P = .04), a longer length of stay (≥7 days vs <7 days; ARR = 1.49; P = .05), and those discharged home (ARR 2.93; P < .001) or to a facility (ARR 3.63; P < .001) versus dying in the hospital were more likely to be on antimicrobials 24 hours after CCO. Compared with those on a medicine service, patients in the medical and surgical intensive care units (ICUs) were less likely to receive antimicrobials (medical ICU ARR = 0.32; P = .01; surgical ICU and/or neuro-ICU ARR = 0.32; P = .02). The most commonly administered antimicrobials were fluoroquinolones and vancomycin.

Cautions

Only 111 patients were still on antimicrobials at 24 hours, which limited analysis. Investigators relied on retrospective data for medication administration and diagnoses.

Implications

Further work is needed to understand and address the expectations of clinicians, patients, and families regarding the role of antimicrobials at the end of life.

Video Decision Aids Improved Rates of Advance Care Planning and Hospice Use and Decreased Costs

Volandes, AE, Paasche-Orlow MK, Davis AD et al. Use of video decision aids to promote advance care planning in Hilo, Hawai‘i. J Gen Intern Med. 2016;31(9):1035-1040.

Background

Advance care planning (ACP) can be enhanced with the use of video decision aids, which may help address scalability and cost.¹¹ The Hawaii Medical Service Association began an initiative to improve ACP rates, which included a financial incentive. Clinician training and patient access to ACP videos were implemented 1 year into this campaign, which was intended for patients with late-stage disease.

Findings

This study tested the impact of the video intervention on the rates of ACP documentation in Hilo, Hawaii, along with secondary outcomes of hospice use, hospital deaths, and costs. The intervention was sequentially rolled out to Hilo Medical Center (HMC), followed by hospice and primary care practices. Following the video introduction, the proportion of patients discharged from HMC with ACP documentation markedly increased (3.2% to 39.9%; P < .001). The percentage of hospital patients discharged to hospice increased from 5.7% to 13.8% (P < .001). Overall admissions to the Hospice of Hilo increased at a greater rate than in other parts of Hawaii. After the intervention in Hilo, the in-hospital death rate among patients >65 years old declined slightly (P = .14), while in the rest of the state, the rate remained essentially unchanged. ACP planning did not reduce healthcare costs at the end of life, but costs seemed to increase more slowly in Hilo after the intervention than they did in the rest of Hawaii (P < .05).

Cautions

This report relies on before-and-after comparisons, with potential confounding by a background pay-for-quality initiative; however, the timing of the changes in outcomes correlates well with the introduction of the videos. ACP videos have been studied in other settings, so the intervention is likely generalizable to other states.

Implications

A widespread distribution of ACP videos and training for physicians in their use may lead to significant increases in ACP documentation and other beneficial clinical outcomes for patients and health systems.

A Standardized Palliative Care-Led Intervention Did Not Improve Psychological Outcomes in Families of Patients with Chronic Critical Illness

Carson SS, Cox CE, Wallenstein S, et al. Effect of palliative care-led meetings for families of patients with chronic critical illness: a randomized clinical trial. JAMA. 2016;316(1):51-62.

Background

Chronic critical illness (CCI) occurs when a patient neither recovers nor dies for days to weeks after an acute illness requiring aggressive intensive care. CCI is associated with poor patient and family outcomes.¹² Does a protocol-driven support and information meeting led by PC providers improve these outcomes?

Findings

This multicenter RCT compared 130 CCI patients (184 surrogates) who received a structured intervention to 126 patients (181 surrogates) with usual care. The structured intervention was led by PC clinicians in order to provide supportive conversations and information about CCI and prognosis compared with the usual intensivist communication. The support and information team met with the families of patients in the intervention group after day 7 of mechanical ventilation (MV) and again 10 days later. Both the intervention and control groups received validated information about CCI, and all were eligible for specialty PC consultation, as indicated. The primary outcome of the study was the Hospital Anxiety and Depression Scale (HADS) at 90-day follow-up with the surrogates. Secondary endpoints included posttraumatic stress disorder (PTSD) assessment and other communication measures as well as patient outcomes (hospital mortality, 90-day survival, length of stay, and days of MV). At least 1 meeting took place for 89% of patients (82% of surrogates) in the intervention arm. Fewer patients in the intervention arm had nonstudy PC consultations (13% vs 22%). Ninety-day HADS results were similar in the 2 groups. PTSD symptoms, however, were higher in the intervention group (Impact of Event Scale-Revised score: 25.9 for intervention and 21.3 for control; intergroup difference 4.6 [95% confidence interval, 0.01-9.10]). There were no statistically significant differences among the patient-focused measures, including survival.

Cautions

Although the teams contained skilled clinicians led by PC practitioners, this was not an ordinary PC intervention. The intervention included information and emotional support meetings alone rather than support from a PC team driven by clinical considerations. This study included surrogates of patients with CCI but not other conditions.

Implications

Protocol-driven support and information meetings may not improve, and may slightly worsen, outcomes in families of patients with CCI. This study did not evaluate and should not be applied to clinically indicated, specialty PC consultation in the ICU.

Caregivers of Patients Surviving Prolonged Critical Illness Experience High and Persistent Rates of Depression

Cameron JI, Chu LM, Matte A, et al. One-year outcomes in caregivers of critically ill patients. N Engl J Med. 2016;374(19):1831-1841.

Background

More than half of patients with a CCI require caregiver support 1 year after hospitalization.¹³ Caregivers provide tremendous physical and psychosocial support to their loved ones, but that care is often associated with significant burden.¹⁴

Findings

This prospective parallel cohort study followed caregivers of surviving patients ventilated for at least 7 days from 10 academic hospitals in Canada. The prevalence of depression (Center for Epidemiologic Studies–Depression scale ≥16) in this cohort of 280 caregivers (70% were women) was 67%, 49%, 43%, and 43% at the survey intervals of 7 days, 3 months, 6 months, and 12 months after ICU discharge, respectively. Using latent-class linear mixed models, the investigators identified 2 groups of caregivers: those whose depressive symptoms decreased over time (84%) and those whose depressive symptoms persisted at a high level for the year (16%). Patient characteristics (such as age, comorbidity, sex, and functional status) were not associated with caregiver outcomes. Younger caregiver age, greater effect of patient care on other activities, less social support, less mastery (sense of control), and less personal growth were associated with worse caregiver mental health outcomes.

Cautions

Although this is a high-quality prospective study, causality of caregiving on the high rates of depressive symptoms cannot be confirmed without a control group or knowledge of the caregivers’ mental health status prior to the episode of prolonged critical illness.

Implications

Patient critical illness may have serious impacts on caregiver health and well-being. Hospitalists should be attentive to factors associated with caregiver vulnerability and offer support. Improving caregivers’ sense of control and social support may be targets for interventions.

People with Non-normative Sexuality or Gender Face Additional Barriers and Stressors with Partner Loss

Bristowe K, Marshall S, Harding R. The bereavement experiences of lesbian, gay, bisexual and/or trans* people who have lost a partner: A systematic review, thematic synthesis and modelling of the literature. Palliat Med. 2016;30(8):730-744.

Background

Grief and bereavement impact individuals differently as they adjust to a death. Increasingly, it is recognized that lesbian, gay, bisexual, and/or transgender (LGBT) communities may face additional barriers when interacting with the healthcare system. This review sought to identify and appraise the evidence of the bereavement experiences among LGBT communities.

Findings

This systematic review summarized quantitative and qualitative data from 23 articles (13 studies). The synthesis noted that the pain associated with the loss of a partner was a universal experience regardless of sexual identity or gender history. Additional barriers and stressors of bereavement were reported for LGBT people, including homophobia, failure to acknowledge the relationship, additional legal and financial issues, and the shadow of human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS). LGBT people turned to additional resources for bereavement help: professional support, social and familial support, and societal and community support. Caregiver bereavement support experiences were shaped by whether the relationships were disclosed and accepted (acceptance-disclosure model).

Cautions

The quantitative data was mostly from the 1990s and described the context of HIV/AIDS. The qualitative studies, however, were done in the last decade. Very little research was available for transgender or bisexual caregivers.

Implications

People who identify as LGBT face additional barriers and stressors with the loss of a partner. The described acceptance-disclosure model may help providers be mindful of the additional barriers to LGBT bereavement support.

Physician Trainees Experience Significant Moral Distress with Futile Treatments

Dzeng E, Colaianni A, Roland M, et al. Moral distress amongst American physician trainees regarding futile treatments at the end of life: a qualitative study. J Gen Intern Med. 2016;31(1):93-99.

Background

Physician trainees are often faced with ethical challenges in providing end-of-life care. These ethical challenges can create confusion and conflict about the balance between the benefits and burdens experienced by patients.

Findings

The authors used semistructured, in-depth, qualitative interviews of 22 internal medicine trainees from 3 academic medical centers. An analysis of these interviews revealed several themes. Trainees reported moral distress when (1) many of the treatments provided in end-of-life care (ie, feeding tubes in advanced dementia) were perceived to be futile; (2) they felt obligated to provide end-of-life care that was not in the patient’s best interest, leading to “torture” or “suffering” for the patient; (3) they provided care they felt not to be in the patient’s best interest; (4) they perceived themselves to be powerless to affect change in these dilemmas; (5) they attributed some of their powerlessness to the hierarchy of their academic institutions; and (6) they feared that dehumanization and cynicism would be required to endure this distress.

Cautions

Resident recruitment occurred by solicitation, which may invite bias. Generalizability of qualitative studies to other settings can be limited.

Implications

Trainees may experience several dimensions of moral distress in end-of-life care. These findings challenge training programs to find ways to reduce the dehumanization, sense of powerlessness, and cynicism that this distress may cause.

Disclosure

The authors declare that they have no relevant financial conflicts of interest.

The aim of palliative care (PC) is to improve quality of life for patients facing serious, life-threatening illness and their families.¹ Due to insufficient numbers of PC specialists to meet the PC needs for every hospitalized patient,² all hospitalists should maintain basic PC skills as recognized by PC being a core competency for hospitalists.^3,4

We summarize and critique PC research articles published between January 1, 2016, and December 31, 2016, that have a high likelihood of impacting the practice of hospital medicine. We hand searched 15 journals and conducted a MEDLINE keyword search of PC terms (see Table). All titles and/or abstracts were reviewed and selected for full review based on the following factors: palliative medicine content, scientific rigor, impact on practice, and relevance to hospital medicine. Fifty-five articles were individually reviewed and scored by all authors according to rigor, impact, and relevance. Articles were ranked according to their mean scores, and 9 articles were chosen for inclusion through consensus discussion.

Antipsychotics Were Inferior to a Placebo in Treating Nonterminal Delirium

Agar MR, Lawlor PG, Quinn S, et al. Efficacy of oral risperidone, haloperidol, or placebo for symptoms of delirium among patients in palliative care: a randomized clinical trial. JAMA Intern Med. 2017;177(1):34-42.

Background

Delirium is highly prevalent in PC and is associated with significant distress.⁵ Antipsychotics are widely used for symptoms of delirium, although current evidence does not support this practice in hospitalized adults.^6,7

Findings

This was a double-blind, parallel-arm, placebo randomized controlled trial (RCT) of 247 patients with delirium with an estimated life expectancy of ≥7 days in 11 PC or hospice units across Australia. Patients were randomized to receive risperidone, haloperidol, or a placebo in addition to nonpharmacological management of delirium. Delirium symptom scores after 3 days of treatment, the use of midazolam as a rescue medication, and the presence of extrapyramidal symptoms (EPS) were measured. The risperidone and haloperidol arms had significantly higher delirium symptom scores (P = .02 and P = .009, respectively), mean EPS symptoms (P < .001), and more use of rescue midazolam than the placebo arm. Mortality was higher for antipsychotics, with a hazard ratio of 1.73 for haloperidol (P = .003), 1.29 for risperidone (P = .14), and 1.47 for any antipsychotic (P = .01).

Cautions

The study population was elderly (mean age >70 years) with mild delirium scores. The use of antipsychotics was associated with more benzodiazepine use, which could itself worsen delirium. As patients with clinician-predicted life expectancy of <7 days were excluded, findings cannot be extrapolated to the treatment of terminal delirium, which can often be more symptomatic and difficult to treat.

Implications

Avoid scheduled antipsychotics in patients with nonterminal delirium, as they can increase risk of harm without advantages, over nonpharmacologic interventions.

Low-Dose Morphine Was Superior to Weak Opioids in the Treatment of Moderate Cancer Pain

Bandieri E, Romero M, Ripamonti CI, et al. Randomized trial of low-dose morphine versus weak opioids in moderate cancer pain. J Clin Oncol. 2016;34(5):436-442.

Background

The World Health Organization guidelines recommend the use of weak opioids (WOs), such as codeine or tramadol, as a sequential step in the management of cancer pain.⁸ This strategy has not been tested against low doses of stronger opioids.

Findings

In this multicenter, open-label RCT, 240 patients in Italy were randomized and stratified by age (<75 years or ≥75 years) to either the WO group or low-dose morphine (M) group. The primary outcome measure was a reduction in pain intensity by 20% or more. Secondary outcomes included an improvement in symptom scores, a ≥30% and ≥50% reduction in pain, increased opioid dosage, and adverse side effects. Compared with the WO group, the M group had more patients with a 20% reduction in pain (88.2% vs 54.7%; P < .001), more evidence of pain control in the first week (80.9% vs 43.6%; P < .001), more patients with a ≥30% and ≥50% reduction in pain, and less need to switch to a stronger opioid (15.5% vs 35.0%; P = .001) or require dose increases. Adverse effects were similar in both groups.

Cautions

Patients with chronic kidney disease (CKD) were excluded due to concerns about the accumulation of morphine metabolites. Additionally, this study was open label, increasing the risk of bias.

Implications

Low-dose morphine should be considered over the use of WOs to achieve better and more rapid pain control in patients without CKD.

The Use of Methadone as a Coanalgesic May Improve Moderate Cancer Pain

Courtemanche F, Dao D, Gagné F, et al. Methadone as a coanalgesic for palliative care cancer patients. J Palliat Med. 2016;19(9):972-978.

Background

Methadone is effective at treating cancer pain and is often utilized when patients have neuropathic pain, fail to respond to traditional opioids, or have renal failure.^9,10 However, its long half-life and many drug interactions make methadone challenging to use.

Findings

This cohort study looked at 153 inpatient or outpatient PC patients in Montreal who received methadone as a coanalgesic for cancer pain. The patients’ median morphine equivalent dose was 120 mg when initiating methadone. The median starting dose of methadone was 3 mg per day. Of patients, 49.3% had a significant response (≥30% pain reduction), with a median response time of 7 days, and 30.1% achieved a substantial response (≥50% pain reduction), with a median response time of 3 days. Patients with higher initial pain scores were more likely to respond to adjuvant methadone. Those who had not responded after a week of methadone were unlikely to respond despite dose escalations. Adverse effects included drowsiness (51.4%), confusion (27.4%), constipation (24.7%), nausea (19.9%), and myoclonia (16.4%).

Cautions

This was an observational study with retrospective data, leading to higher levels of missing data. A high rate of adverse side effects was reported (90.4%). Further study is needed to validate and reproduce the findings.

Implications

The use of adjuvant low-dose methadone may be considered in patients with moderate pain despite high-dose opioids. If a response is not seen within 7 days, then methadone use should be reconsidered.

Many Hospitalized Patients on Comfort Care Still Receive Antimicrobials

Merel SE, Meier CA, McKinney CM, Pottinger PS. Antimicrobial use in patients on a comfort care protocol: a retrospective cohort study. J Palliat Med. 2016;19(11):1210-1214.

Background

It is unknown how often patients who are hospitalized at the end of life continue to receive antimicrobials and what factors are associated with antimicrobial use.

Findings

This retrospective cohort study of 1881 hospitalized adults transitioned to a comfort care order (CCO) set at 2 academic medical centers found that 77% of these patients received antimicrobials during their hospital stay (62.4% at 24 hours prior to CCO). Of the 711 still alive at ≥24 hours after CCO, 111 (15.6%) were still on antimicrobials, with that proportion remaining stable for the remainder of hospitalization. In comparing those who did and did not receive antimicrobials after 24 hours of CCO, the presence of a documented infection was not significantly different after adjusting for age. Those with a cancer diagnosis (adjusted risk ratio [ARR] = 1.44: P = .04), a longer length of stay (≥7 days vs <7 days; ARR = 1.49; P = .05), and those discharged home (ARR 2.93; P < .001) or to a facility (ARR 3.63; P < .001) versus dying in the hospital were more likely to be on antimicrobials 24 hours after CCO. Compared with those on a medicine service, patients in the medical and surgical intensive care units (ICUs) were less likely to receive antimicrobials (medical ICU ARR = 0.32; P = .01; surgical ICU and/or neuro-ICU ARR = 0.32; P = .02). The most commonly administered antimicrobials were fluoroquinolones and vancomycin.

Cautions

Only 111 patients were still on antimicrobials at 24 hours, which limited analysis. Investigators relied on retrospective data for medication administration and diagnoses.

Implications

Further work is needed to understand and address the expectations of clinicians, patients, and families regarding the role of antimicrobials at the end of life.

Video Decision Aids Improved Rates of Advance Care Planning and Hospice Use and Decreased Costs

Volandes, AE, Paasche-Orlow MK, Davis AD et al. Use of video decision aids to promote advance care planning in Hilo, Hawai‘i. J Gen Intern Med. 2016;31(9):1035-1040.

Background

Advance care planning (ACP) can be enhanced with the use of video decision aids, which may help address scalability and cost.¹¹ The Hawaii Medical Service Association began an initiative to improve ACP rates, which included a financial incentive. Clinician training and patient access to ACP videos were implemented 1 year into this campaign, which was intended for patients with late-stage disease.

Findings

This study tested the impact of the video intervention on the rates of ACP documentation in Hilo, Hawaii, along with secondary outcomes of hospice use, hospital deaths, and costs. The intervention was sequentially rolled out to Hilo Medical Center (HMC), followed by hospice and primary care practices. Following the video introduction, the proportion of patients discharged from HMC with ACP documentation markedly increased (3.2% to 39.9%; P < .001). The percentage of hospital patients discharged to hospice increased from 5.7% to 13.8% (P < .001). Overall admissions to the Hospice of Hilo increased at a greater rate than in other parts of Hawaii. After the intervention in Hilo, the in-hospital death rate among patients >65 years old declined slightly (P = .14), while in the rest of the state, the rate remained essentially unchanged. ACP planning did not reduce healthcare costs at the end of life, but costs seemed to increase more slowly in Hilo after the intervention than they did in the rest of Hawaii (P < .05).

Cautions

This report relies on before-and-after comparisons, with potential confounding by a background pay-for-quality initiative; however, the timing of the changes in outcomes correlates well with the introduction of the videos. ACP videos have been studied in other settings, so the intervention is likely generalizable to other states.

Implications

A widespread distribution of ACP videos and training for physicians in their use may lead to significant increases in ACP documentation and other beneficial clinical outcomes for patients and health systems.

A Standardized Palliative Care-Led Intervention Did Not Improve Psychological Outcomes in Families of Patients with Chronic Critical Illness

Carson SS, Cox CE, Wallenstein S, et al. Effect of palliative care-led meetings for families of patients with chronic critical illness: a randomized clinical trial. JAMA. 2016;316(1):51-62.

Background

Chronic critical illness (CCI) occurs when a patient neither recovers nor dies for days to weeks after an acute illness requiring aggressive intensive care. CCI is associated with poor patient and family outcomes.¹² Does a protocol-driven support and information meeting led by PC providers improve these outcomes?

Findings

This multicenter RCT compared 130 CCI patients (184 surrogates) who received a structured intervention to 126 patients (181 surrogates) with usual care. The structured intervention was led by PC clinicians in order to provide supportive conversations and information about CCI and prognosis compared with the usual intensivist communication. The support and information team met with the families of patients in the intervention group after day 7 of mechanical ventilation (MV) and again 10 days later. Both the intervention and control groups received validated information about CCI, and all were eligible for specialty PC consultation, as indicated. The primary outcome of the study was the Hospital Anxiety and Depression Scale (HADS) at 90-day follow-up with the surrogates. Secondary endpoints included posttraumatic stress disorder (PTSD) assessment and other communication measures as well as patient outcomes (hospital mortality, 90-day survival, length of stay, and days of MV). At least 1 meeting took place for 89% of patients (82% of surrogates) in the intervention arm. Fewer patients in the intervention arm had nonstudy PC consultations (13% vs 22%). Ninety-day HADS results were similar in the 2 groups. PTSD symptoms, however, were higher in the intervention group (Impact of Event Scale-Revised score: 25.9 for intervention and 21.3 for control; intergroup difference 4.6 [95% confidence interval, 0.01-9.10]). There were no statistically significant differences among the patient-focused measures, including survival.

Cautions

Although the teams contained skilled clinicians led by PC practitioners, this was not an ordinary PC intervention. The intervention included information and emotional support meetings alone rather than support from a PC team driven by clinical considerations. This study included surrogates of patients with CCI but not other conditions.

Implications

Protocol-driven support and information meetings may not improve, and may slightly worsen, outcomes in families of patients with CCI. This study did not evaluate and should not be applied to clinically indicated, specialty PC consultation in the ICU.

Caregivers of Patients Surviving Prolonged Critical Illness Experience High and Persistent Rates of Depression

Cameron JI, Chu LM, Matte A, et al. One-year outcomes in caregivers of critically ill patients. N Engl J Med. 2016;374(19):1831-1841.

Background

More than half of patients with a CCI require caregiver support 1 year after hospitalization.¹³ Caregivers provide tremendous physical and psychosocial support to their loved ones, but that care is often associated with significant burden.¹⁴

Findings

This prospective parallel cohort study followed caregivers of surviving patients ventilated for at least 7 days from 10 academic hospitals in Canada. The prevalence of depression (Center for Epidemiologic Studies–Depression scale ≥16) in this cohort of 280 caregivers (70% were women) was 67%, 49%, 43%, and 43% at the survey intervals of 7 days, 3 months, 6 months, and 12 months after ICU discharge, respectively. Using latent-class linear mixed models, the investigators identified 2 groups of caregivers: those whose depressive symptoms decreased over time (84%) and those whose depressive symptoms persisted at a high level for the year (16%). Patient characteristics (such as age, comorbidity, sex, and functional status) were not associated with caregiver outcomes. Younger caregiver age, greater effect of patient care on other activities, less social support, less mastery (sense of control), and less personal growth were associated with worse caregiver mental health outcomes.

Cautions

Although this is a high-quality prospective study, causality of caregiving on the high rates of depressive symptoms cannot be confirmed without a control group or knowledge of the caregivers’ mental health status prior to the episode of prolonged critical illness.

Implications

Patient critical illness may have serious impacts on caregiver health and well-being. Hospitalists should be attentive to factors associated with caregiver vulnerability and offer support. Improving caregivers’ sense of control and social support may be targets for interventions.

People with Non-normative Sexuality or Gender Face Additional Barriers and Stressors with Partner Loss

Bristowe K, Marshall S, Harding R. The bereavement experiences of lesbian, gay, bisexual and/or trans* people who have lost a partner: A systematic review, thematic synthesis and modelling of the literature. Palliat Med. 2016;30(8):730-744.

Background

Grief and bereavement impact individuals differently as they adjust to a death. Increasingly, it is recognized that lesbian, gay, bisexual, and/or transgender (LGBT) communities may face additional barriers when interacting with the healthcare system. This review sought to identify and appraise the evidence of the bereavement experiences among LGBT communities.

Findings

This systematic review summarized quantitative and qualitative data from 23 articles (13 studies). The synthesis noted that the pain associated with the loss of a partner was a universal experience regardless of sexual identity or gender history. Additional barriers and stressors of bereavement were reported for LGBT people, including homophobia, failure to acknowledge the relationship, additional legal and financial issues, and the shadow of human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS). LGBT people turned to additional resources for bereavement help: professional support, social and familial support, and societal and community support. Caregiver bereavement support experiences were shaped by whether the relationships were disclosed and accepted (acceptance-disclosure model).

Cautions

The quantitative data was mostly from the 1990s and described the context of HIV/AIDS. The qualitative studies, however, were done in the last decade. Very little research was available for transgender or bisexual caregivers.

Implications

People who identify as LGBT face additional barriers and stressors with the loss of a partner. The described acceptance-disclosure model may help providers be mindful of the additional barriers to LGBT bereavement support.

Physician Trainees Experience Significant Moral Distress with Futile Treatments

Dzeng E, Colaianni A, Roland M, et al. Moral distress amongst American physician trainees regarding futile treatments at the end of life: a qualitative study. J Gen Intern Med. 2016;31(1):93-99.

Background

Physician trainees are often faced with ethical challenges in providing end-of-life care. These ethical challenges can create confusion and conflict about the balance between the benefits and burdens experienced by patients.

Findings

The authors used semistructured, in-depth, qualitative interviews of 22 internal medicine trainees from 3 academic medical centers. An analysis of these interviews revealed several themes. Trainees reported moral distress when (1) many of the treatments provided in end-of-life care (ie, feeding tubes in advanced dementia) were perceived to be futile; (2) they felt obligated to provide end-of-life care that was not in the patient’s best interest, leading to “torture” or “suffering” for the patient; (3) they provided care they felt not to be in the patient’s best interest; (4) they perceived themselves to be powerless to affect change in these dilemmas; (5) they attributed some of their powerlessness to the hierarchy of their academic institutions; and (6) they feared that dehumanization and cynicism would be required to endure this distress.

Cautions

Resident recruitment occurred by solicitation, which may invite bias. Generalizability of qualitative studies to other settings can be limited.

Implications

Trainees may experience several dimensions of moral distress in end-of-life care. These findings challenge training programs to find ways to reduce the dehumanization, sense of powerlessness, and cynicism that this distress may cause.

Disclosure

The authors declare that they have no relevant financial conflicts of interest.

The aim of palliative care (PC) is to improve quality of life for patients facing serious, life-threatening illness and their families.¹ Due to insufficient numbers of PC specialists to meet the PC needs for every hospitalized patient,² all hospitalists should maintain basic PC skills as recognized by PC being a core competency for hospitalists.^3,4

We summarize and critique PC research articles published between January 1, 2016, and December 31, 2016, that have a high likelihood of impacting the practice of hospital medicine. We hand searched 15 journals and conducted a MEDLINE keyword search of PC terms (see Table). All titles and/or abstracts were reviewed and selected for full review based on the following factors: palliative medicine content, scientific rigor, impact on practice, and relevance to hospital medicine. Fifty-five articles were individually reviewed and scored by all authors according to rigor, impact, and relevance. Articles were ranked according to their mean scores, and 9 articles were chosen for inclusion through consensus discussion.

Antipsychotics Were Inferior to a Placebo in Treating Nonterminal Delirium

Agar MR, Lawlor PG, Quinn S, et al. Efficacy of oral risperidone, haloperidol, or placebo for symptoms of delirium among patients in palliative care: a randomized clinical trial. JAMA Intern Med. 2017;177(1):34-42.

Background

Delirium is highly prevalent in PC and is associated with significant distress.⁵ Antipsychotics are widely used for symptoms of delirium, although current evidence does not support this practice in hospitalized adults.^6,7

Findings

This was a double-blind, parallel-arm, placebo randomized controlled trial (RCT) of 247 patients with delirium with an estimated life expectancy of ≥7 days in 11 PC or hospice units across Australia. Patients were randomized to receive risperidone, haloperidol, or a placebo in addition to nonpharmacological management of delirium. Delirium symptom scores after 3 days of treatment, the use of midazolam as a rescue medication, and the presence of extrapyramidal symptoms (EPS) were measured. The risperidone and haloperidol arms had significantly higher delirium symptom scores (P = .02 and P = .009, respectively), mean EPS symptoms (P < .001), and more use of rescue midazolam than the placebo arm. Mortality was higher for antipsychotics, with a hazard ratio of 1.73 for haloperidol (P = .003), 1.29 for risperidone (P = .14), and 1.47 for any antipsychotic (P = .01).

Cautions

The study population was elderly (mean age >70 years) with mild delirium scores. The use of antipsychotics was associated with more benzodiazepine use, which could itself worsen delirium. As patients with clinician-predicted life expectancy of <7 days were excluded, findings cannot be extrapolated to the treatment of terminal delirium, which can often be more symptomatic and difficult to treat.

Implications

Avoid scheduled antipsychotics in patients with nonterminal delirium, as they can increase risk of harm without advantages, over nonpharmacologic interventions.

Low-Dose Morphine Was Superior to Weak Opioids in the Treatment of Moderate Cancer Pain

Bandieri E, Romero M, Ripamonti CI, et al. Randomized trial of low-dose morphine versus weak opioids in moderate cancer pain. J Clin Oncol. 2016;34(5):436-442.

Background

The World Health Organization guidelines recommend the use of weak opioids (WOs), such as codeine or tramadol, as a sequential step in the management of cancer pain.⁸ This strategy has not been tested against low doses of stronger opioids.

Findings

In this multicenter, open-label RCT, 240 patients in Italy were randomized and stratified by age (<75 years or ≥75 years) to either the WO group or low-dose morphine (M) group. The primary outcome measure was a reduction in pain intensity by 20% or more. Secondary outcomes included an improvement in symptom scores, a ≥30% and ≥50% reduction in pain, increased opioid dosage, and adverse side effects. Compared with the WO group, the M group had more patients with a 20% reduction in pain (88.2% vs 54.7%; P < .001), more evidence of pain control in the first week (80.9% vs 43.6%; P < .001), more patients with a ≥30% and ≥50% reduction in pain, and less need to switch to a stronger opioid (15.5% vs 35.0%; P = .001) or require dose increases. Adverse effects were similar in both groups.

Cautions

Patients with chronic kidney disease (CKD) were excluded due to concerns about the accumulation of morphine metabolites. Additionally, this study was open label, increasing the risk of bias.

Implications

Low-dose morphine should be considered over the use of WOs to achieve better and more rapid pain control in patients without CKD.

The Use of Methadone as a Coanalgesic May Improve Moderate Cancer Pain

Courtemanche F, Dao D, Gagné F, et al. Methadone as a coanalgesic for palliative care cancer patients. J Palliat Med. 2016;19(9):972-978.

Background

Methadone is effective at treating cancer pain and is often utilized when patients have neuropathic pain, fail to respond to traditional opioids, or have renal failure.^9,10 However, its long half-life and many drug interactions make methadone challenging to use.

Findings

This cohort study looked at 153 inpatient or outpatient PC patients in Montreal who received methadone as a coanalgesic for cancer pain. The patients’ median morphine equivalent dose was 120 mg when initiating methadone. The median starting dose of methadone was 3 mg per day. Of patients, 49.3% had a significant response (≥30% pain reduction), with a median response time of 7 days, and 30.1% achieved a substantial response (≥50% pain reduction), with a median response time of 3 days. Patients with higher initial pain scores were more likely to respond to adjuvant methadone. Those who had not responded after a week of methadone were unlikely to respond despite dose escalations. Adverse effects included drowsiness (51.4%), confusion (27.4%), constipation (24.7%), nausea (19.9%), and myoclonia (16.4%).

Cautions

This was an observational study with retrospective data, leading to higher levels of missing data. A high rate of adverse side effects was reported (90.4%). Further study is needed to validate and reproduce the findings.

Implications

The use of adjuvant low-dose methadone may be considered in patients with moderate pain despite high-dose opioids. If a response is not seen within 7 days, then methadone use should be reconsidered.

Many Hospitalized Patients on Comfort Care Still Receive Antimicrobials

Merel SE, Meier CA, McKinney CM, Pottinger PS. Antimicrobial use in patients on a comfort care protocol: a retrospective cohort study. J Palliat Med. 2016;19(11):1210-1214.

Background

It is unknown how often patients who are hospitalized at the end of life continue to receive antimicrobials and what factors are associated with antimicrobial use.

Findings

This retrospective cohort study of 1881 hospitalized adults transitioned to a comfort care order (CCO) set at 2 academic medical centers found that 77% of these patients received antimicrobials during their hospital stay (62.4% at 24 hours prior to CCO). Of the 711 still alive at ≥24 hours after CCO, 111 (15.6%) were still on antimicrobials, with that proportion remaining stable for the remainder of hospitalization. In comparing those who did and did not receive antimicrobials after 24 hours of CCO, the presence of a documented infection was not significantly different after adjusting for age. Those with a cancer diagnosis (adjusted risk ratio [ARR] = 1.44: P = .04), a longer length of stay (≥7 days vs <7 days; ARR = 1.49; P = .05), and those discharged home (ARR 2.93; P < .001) or to a facility (ARR 3.63; P < .001) versus dying in the hospital were more likely to be on antimicrobials 24 hours after CCO. Compared with those on a medicine service, patients in the medical and surgical intensive care units (ICUs) were less likely to receive antimicrobials (medical ICU ARR = 0.32; P = .01; surgical ICU and/or neuro-ICU ARR = 0.32; P = .02). The most commonly administered antimicrobials were fluoroquinolones and vancomycin.

Cautions

Only 111 patients were still on antimicrobials at 24 hours, which limited analysis. Investigators relied on retrospective data for medication administration and diagnoses.

Implications

Further work is needed to understand and address the expectations of clinicians, patients, and families regarding the role of antimicrobials at the end of life.

Video Decision Aids Improved Rates of Advance Care Planning and Hospice Use and Decreased Costs

Volandes, AE, Paasche-Orlow MK, Davis AD et al. Use of video decision aids to promote advance care planning in Hilo, Hawai‘i. J Gen Intern Med. 2016;31(9):1035-1040.

Background

Advance care planning (ACP) can be enhanced with the use of video decision aids, which may help address scalability and cost.¹¹ The Hawaii Medical Service Association began an initiative to improve ACP rates, which included a financial incentive. Clinician training and patient access to ACP videos were implemented 1 year into this campaign, which was intended for patients with late-stage disease.

Findings

This study tested the impact of the video intervention on the rates of ACP documentation in Hilo, Hawaii, along with secondary outcomes of hospice use, hospital deaths, and costs. The intervention was sequentially rolled out to Hilo Medical Center (HMC), followed by hospice and primary care practices. Following the video introduction, the proportion of patients discharged from HMC with ACP documentation markedly increased (3.2% to 39.9%; P < .001). The percentage of hospital patients discharged to hospice increased from 5.7% to 13.8% (P < .001). Overall admissions to the Hospice of Hilo increased at a greater rate than in other parts of Hawaii. After the intervention in Hilo, the in-hospital death rate among patients >65 years old declined slightly (P = .14), while in the rest of the state, the rate remained essentially unchanged. ACP planning did not reduce healthcare costs at the end of life, but costs seemed to increase more slowly in Hilo after the intervention than they did in the rest of Hawaii (P < .05).

Cautions

This report relies on before-and-after comparisons, with potential confounding by a background pay-for-quality initiative; however, the timing of the changes in outcomes correlates well with the introduction of the videos. ACP videos have been studied in other settings, so the intervention is likely generalizable to other states.

Implications

A widespread distribution of ACP videos and training for physicians in their use may lead to significant increases in ACP documentation and other beneficial clinical outcomes for patients and health systems.

A Standardized Palliative Care-Led Intervention Did Not Improve Psychological Outcomes in Families of Patients with Chronic Critical Illness

Carson SS, Cox CE, Wallenstein S, et al. Effect of palliative care-led meetings for families of patients with chronic critical illness: a randomized clinical trial. JAMA. 2016;316(1):51-62.

Background

Chronic critical illness (CCI) occurs when a patient neither recovers nor dies for days to weeks after an acute illness requiring aggressive intensive care. CCI is associated with poor patient and family outcomes.¹² Does a protocol-driven support and information meeting led by PC providers improve these outcomes?

Findings

This multicenter RCT compared 130 CCI patients (184 surrogates) who received a structured intervention to 126 patients (181 surrogates) with usual care. The structured intervention was led by PC clinicians in order to provide supportive conversations and information about CCI and prognosis compared with the usual intensivist communication. The support and information team met with the families of patients in the intervention group after day 7 of mechanical ventilation (MV) and again 10 days later. Both the intervention and control groups received validated information about CCI, and all were eligible for specialty PC consultation, as indicated. The primary outcome of the study was the Hospital Anxiety and Depression Scale (HADS) at 90-day follow-up with the surrogates. Secondary endpoints included posttraumatic stress disorder (PTSD) assessment and other communication measures as well as patient outcomes (hospital mortality, 90-day survival, length of stay, and days of MV). At least 1 meeting took place for 89% of patients (82% of surrogates) in the intervention arm. Fewer patients in the intervention arm had nonstudy PC consultations (13% vs 22%). Ninety-day HADS results were similar in the 2 groups. PTSD symptoms, however, were higher in the intervention group (Impact of Event Scale-Revised score: 25.9 for intervention and 21.3 for control; intergroup difference 4.6 [95% confidence interval, 0.01-9.10]). There were no statistically significant differences among the patient-focused measures, including survival.

Cautions

Although the teams contained skilled clinicians led by PC practitioners, this was not an ordinary PC intervention. The intervention included information and emotional support meetings alone rather than support from a PC team driven by clinical considerations. This study included surrogates of patients with CCI but not other conditions.

Implications

Protocol-driven support and information meetings may not improve, and may slightly worsen, outcomes in families of patients with CCI. This study did not evaluate and should not be applied to clinically indicated, specialty PC consultation in the ICU.

Caregivers of Patients Surviving Prolonged Critical Illness Experience High and Persistent Rates of Depression

Cameron JI, Chu LM, Matte A, et al. One-year outcomes in caregivers of critically ill patients. N Engl J Med. 2016;374(19):1831-1841.

Background

More than half of patients with a CCI require caregiver support 1 year after hospitalization.¹³ Caregivers provide tremendous physical and psychosocial support to their loved ones, but that care is often associated with significant burden.¹⁴

Findings

This prospective parallel cohort study followed caregivers of surviving patients ventilated for at least 7 days from 10 academic hospitals in Canada. The prevalence of depression (Center for Epidemiologic Studies–Depression scale ≥16) in this cohort of 280 caregivers (70% were women) was 67%, 49%, 43%, and 43% at the survey intervals of 7 days, 3 months, 6 months, and 12 months after ICU discharge, respectively. Using latent-class linear mixed models, the investigators identified 2 groups of caregivers: those whose depressive symptoms decreased over time (84%) and those whose depressive symptoms persisted at a high level for the year (16%). Patient characteristics (such as age, comorbidity, sex, and functional status) were not associated with caregiver outcomes. Younger caregiver age, greater effect of patient care on other activities, less social support, less mastery (sense of control), and less personal growth were associated with worse caregiver mental health outcomes.

Cautions

Although this is a high-quality prospective study, causality of caregiving on the high rates of depressive symptoms cannot be confirmed without a control group or knowledge of the caregivers’ mental health status prior to the episode of prolonged critical illness.

Implications

Patient critical illness may have serious impacts on caregiver health and well-being. Hospitalists should be attentive to factors associated with caregiver vulnerability and offer support. Improving caregivers’ sense of control and social support may be targets for interventions.

People with Non-normative Sexuality or Gender Face Additional Barriers and Stressors with Partner Loss

Bristowe K, Marshall S, Harding R. The bereavement experiences of lesbian, gay, bisexual and/or trans* people who have lost a partner: A systematic review, thematic synthesis and modelling of the literature. Palliat Med. 2016;30(8):730-744.

Background

Grief and bereavement impact individuals differently as they adjust to a death. Increasingly, it is recognized that lesbian, gay, bisexual, and/or transgender (LGBT) communities may face additional barriers when interacting with the healthcare system. This review sought to identify and appraise the evidence of the bereavement experiences among LGBT communities.

Findings

This systematic review summarized quantitative and qualitative data from 23 articles (13 studies). The synthesis noted that the pain associated with the loss of a partner was a universal experience regardless of sexual identity or gender history. Additional barriers and stressors of bereavement were reported for LGBT people, including homophobia, failure to acknowledge the relationship, additional legal and financial issues, and the shadow of human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS). LGBT people turned to additional resources for bereavement help: professional support, social and familial support, and societal and community support. Caregiver bereavement support experiences were shaped by whether the relationships were disclosed and accepted (acceptance-disclosure model).

Cautions

The quantitative data was mostly from the 1990s and described the context of HIV/AIDS. The qualitative studies, however, were done in the last decade. Very little research was available for transgender or bisexual caregivers.

Implications

People who identify as LGBT face additional barriers and stressors with the loss of a partner. The described acceptance-disclosure model may help providers be mindful of the additional barriers to LGBT bereavement support.

Physician Trainees Experience Significant Moral Distress with Futile Treatments

Dzeng E, Colaianni A, Roland M, et al. Moral distress amongst American physician trainees regarding futile treatments at the end of life: a qualitative study. J Gen Intern Med. 2016;31(1):93-99.

Background

Physician trainees are often faced with ethical challenges in providing end-of-life care. These ethical challenges can create confusion and conflict about the balance between the benefits and burdens experienced by patients.

Findings

The authors used semistructured, in-depth, qualitative interviews of 22 internal medicine trainees from 3 academic medical centers. An analysis of these interviews revealed several themes. Trainees reported moral distress when (1) many of the treatments provided in end-of-life care (ie, feeding tubes in advanced dementia) were perceived to be futile; (2) they felt obligated to provide end-of-life care that was not in the patient’s best interest, leading to “torture” or “suffering” for the patient; (3) they provided care they felt not to be in the patient’s best interest; (4) they perceived themselves to be powerless to affect change in these dilemmas; (5) they attributed some of their powerlessness to the hierarchy of their academic institutions; and (6) they feared that dehumanization and cynicism would be required to endure this distress.

Cautions

Resident recruitment occurred by solicitation, which may invite bias. Generalizability of qualitative studies to other settings can be limited.

Implications

Trainees may experience several dimensions of moral distress in end-of-life care. These findings challenge training programs to find ways to reduce the dehumanization, sense of powerlessness, and cynicism that this distress may cause.

Disclosure

The authors declare that they have no relevant financial conflicts of interest.