ATLANTA – Mitoxantrone, etoposide, and cytarabine (MEC) in combination with the second-generation proteasome inhibitor ixazomib was well tolerated and effective in a phase 1 expansion study of patients with relapsed or refractory acute myeloid leukemia.

The overall response rate in 30 patients enrolled in the study and treated with the novel combination was 53%; 11 patients had a complete response (CR), and 5 had a complete response with incomplete blood count recovery (CRi). The median overall survival was 4.9 months, Anjali S. Advani, MD, reported at the annual meeting of the American Society of Hematology.

Thirteen patients proceeded to allogeneic hematopoietic cell transplant (AHCT), and one received a donor lymphocyte infusion. Seven of these 14 patients are alive with a median follow-up of 14.5 months, said Dr. Advani of Taussig Cancer Institute, Cleveland Clinic.

The patients, who had a median age of 58 years (range of 18-70 years), were eligible for the study if they had relapsed/refractory acute myeloid leukemia (AML), adequate organ function, and cardiac ejection fraction of at least 45%. The median time from initial diagnosis to enrollment was 7.6 months.

 

Eight patients had a history of an antecedent hematologic disorder; 14 were in their first relapse; and 13 had disease that was refractory to their last treatment. Two had received a prior AHCT; seven had FLT3 internal tandem duplication (ITD) mutations indicative of particularly poor prognosis; and seven had adverse cytogenetics, she said.

They received one cycle of the therapy, which included 8mg/m² of mitoxantrone, 80 mg/m² of etoposide, and 1,000 mg/m² of cytarabine given intravenously on days 1-6, plus ixazomib at doses of 1 mg (27 patients) or 2 mg (3 patients) given orally on days 1, 4, 8, and 11. An additional 18 patients were treated at the maximum tolerated dose (1 mg, as determined in phase 1 of the trial), Dr. Advani said.

The treatment was well tolerated in most patients. Grade 3-5 nonhematologic toxicities occurred in at least 15% of patients and included infection in 74%, febrile neutropenia in 85%, hypotension in 18%, hypoxia in 19%, mucositis in 15%, hypokalemia in 33%, and hypoalbuminemia in 30%, she said. The early mortality rate was 10%.

Of note, prior studies have demonstrated that the number of mutations in DNMT3A, TP53, ASXL1, and NRAS is associated with a worse response to salvage therapy. Of 21 patients in the current study who had available data, 10 patients had at least one of these mutations, and 8 of those 10 patients achieved CR or CRi, Dr. Advani said.

 

“To identify a signature predictive of response to treatment, we performed RNA sequencing on pretreatment samples from 17 patients, and on posttreatment samples from 11 patients,” she said. “We found that genes were differentially expressed between resistant and responding patients in 314 genes in the pretreatment samples, in 217 genes in the posttreatment samples, and in 72 genes at both time points.”

Gene set enrichment analysis identified significantly differentially expressed genes clustering in heme-metabolism and erythroblast differentiation, inflammatory response, cytokine/STAT signaling, nuclear factor-kappa beta (NF-kappaB), and hypoxia. Two genes – gamma-interferon–inducible lysosomal thiol reductase (IFI30) and retinoic acid–related orphan receptor A (ROR-alpha) – were found to be significantly different between responding and resistant patients, and could potentially classify response, she noted.

“IFI30, which may increase the levels of antioxidants and lead to a decreased ER [endoplasmic reticulum] stress response to therapy, was more highly expressed in resistant patients, and ROR-alpha, a tumor-suppressor gene, was down regulated in resistant patients,” she said.

Ixazomib was combined with the AML salvage regimen MEC in this study because proteasome inhibitors like ixazomib induce cell death in AML cells through inhibition of NF-kappaB, and also increase chemosensitivity to anthracyclines and cytarabines, Dr. Advani explained.

 

The findings are encouraging and suggest that results from gene expression profiling may help identify resistant patients and provide further therapeutic targets, she said, noting that in vitro studies are planned to clarify whether the use of ROR-alpha agonists may help sensitize resistant cells to treatment.

Dr. Advani reported receiving research funding from Takeda/Millenium, and serving as a consultant for Pfizer.

[email protected]

 

ATLANTA – Mitoxantrone, etoposide, and cytarabine (MEC) in combination with the second-generation proteasome inhibitor ixazomib was well tolerated and effective in a phase 1 expansion study of patients with relapsed or refractory acute myeloid leukemia.

The overall response rate in 30 patients enrolled in the study and treated with the novel combination was 53%; 11 patients had a complete response (CR), and 5 had a complete response with incomplete blood count recovery (CRi). The median overall survival was 4.9 months, Anjali S. Advani, MD, reported at the annual meeting of the American Society of Hematology.

Thirteen patients proceeded to allogeneic hematopoietic cell transplant (AHCT), and one received a donor lymphocyte infusion. Seven of these 14 patients are alive with a median follow-up of 14.5 months, said Dr. Advani of Taussig Cancer Institute, Cleveland Clinic.

The patients, who had a median age of 58 years (range of 18-70 years), were eligible for the study if they had relapsed/refractory acute myeloid leukemia (AML), adequate organ function, and cardiac ejection fraction of at least 45%. The median time from initial diagnosis to enrollment was 7.6 months.

 

Eight patients had a history of an antecedent hematologic disorder; 14 were in their first relapse; and 13 had disease that was refractory to their last treatment. Two had received a prior AHCT; seven had FLT3 internal tandem duplication (ITD) mutations indicative of particularly poor prognosis; and seven had adverse cytogenetics, she said.

They received one cycle of the therapy, which included 8mg/m² of mitoxantrone, 80 mg/m² of etoposide, and 1,000 mg/m² of cytarabine given intravenously on days 1-6, plus ixazomib at doses of 1 mg (27 patients) or 2 mg (3 patients) given orally on days 1, 4, 8, and 11. An additional 18 patients were treated at the maximum tolerated dose (1 mg, as determined in phase 1 of the trial), Dr. Advani said.

The treatment was well tolerated in most patients. Grade 3-5 nonhematologic toxicities occurred in at least 15% of patients and included infection in 74%, febrile neutropenia in 85%, hypotension in 18%, hypoxia in 19%, mucositis in 15%, hypokalemia in 33%, and hypoalbuminemia in 30%, she said. The early mortality rate was 10%.

Of note, prior studies have demonstrated that the number of mutations in DNMT3A, TP53, ASXL1, and NRAS is associated with a worse response to salvage therapy. Of 21 patients in the current study who had available data, 10 patients had at least one of these mutations, and 8 of those 10 patients achieved CR or CRi, Dr. Advani said.

 

“To identify a signature predictive of response to treatment, we performed RNA sequencing on pretreatment samples from 17 patients, and on posttreatment samples from 11 patients,” she said. “We found that genes were differentially expressed between resistant and responding patients in 314 genes in the pretreatment samples, in 217 genes in the posttreatment samples, and in 72 genes at both time points.”

Gene set enrichment analysis identified significantly differentially expressed genes clustering in heme-metabolism and erythroblast differentiation, inflammatory response, cytokine/STAT signaling, nuclear factor-kappa beta (NF-kappaB), and hypoxia. Two genes – gamma-interferon–inducible lysosomal thiol reductase (IFI30) and retinoic acid–related orphan receptor A (ROR-alpha) – were found to be significantly different between responding and resistant patients, and could potentially classify response, she noted.

“IFI30, which may increase the levels of antioxidants and lead to a decreased ER [endoplasmic reticulum] stress response to therapy, was more highly expressed in resistant patients, and ROR-alpha, a tumor-suppressor gene, was down regulated in resistant patients,” she said.

Ixazomib was combined with the AML salvage regimen MEC in this study because proteasome inhibitors like ixazomib induce cell death in AML cells through inhibition of NF-kappaB, and also increase chemosensitivity to anthracyclines and cytarabines, Dr. Advani explained.

 

The findings are encouraging and suggest that results from gene expression profiling may help identify resistant patients and provide further therapeutic targets, she said, noting that in vitro studies are planned to clarify whether the use of ROR-alpha agonists may help sensitize resistant cells to treatment.

Dr. Advani reported receiving research funding from Takeda/Millenium, and serving as a consultant for Pfizer.

[email protected]

 

ATLANTA – Mitoxantrone, etoposide, and cytarabine (MEC) in combination with the second-generation proteasome inhibitor ixazomib was well tolerated and effective in a phase 1 expansion study of patients with relapsed or refractory acute myeloid leukemia.

The overall response rate in 30 patients enrolled in the study and treated with the novel combination was 53%; 11 patients had a complete response (CR), and 5 had a complete response with incomplete blood count recovery (CRi). The median overall survival was 4.9 months, Anjali S. Advani, MD, reported at the annual meeting of the American Society of Hematology.

Thirteen patients proceeded to allogeneic hematopoietic cell transplant (AHCT), and one received a donor lymphocyte infusion. Seven of these 14 patients are alive with a median follow-up of 14.5 months, said Dr. Advani of Taussig Cancer Institute, Cleveland Clinic.

The patients, who had a median age of 58 years (range of 18-70 years), were eligible for the study if they had relapsed/refractory acute myeloid leukemia (AML), adequate organ function, and cardiac ejection fraction of at least 45%. The median time from initial diagnosis to enrollment was 7.6 months.

 

Eight patients had a history of an antecedent hematologic disorder; 14 were in their first relapse; and 13 had disease that was refractory to their last treatment. Two had received a prior AHCT; seven had FLT3 internal tandem duplication (ITD) mutations indicative of particularly poor prognosis; and seven had adverse cytogenetics, she said.

They received one cycle of the therapy, which included 8mg/m² of mitoxantrone, 80 mg/m² of etoposide, and 1,000 mg/m² of cytarabine given intravenously on days 1-6, plus ixazomib at doses of 1 mg (27 patients) or 2 mg (3 patients) given orally on days 1, 4, 8, and 11. An additional 18 patients were treated at the maximum tolerated dose (1 mg, as determined in phase 1 of the trial), Dr. Advani said.

The treatment was well tolerated in most patients. Grade 3-5 nonhematologic toxicities occurred in at least 15% of patients and included infection in 74%, febrile neutropenia in 85%, hypotension in 18%, hypoxia in 19%, mucositis in 15%, hypokalemia in 33%, and hypoalbuminemia in 30%, she said. The early mortality rate was 10%.

Of note, prior studies have demonstrated that the number of mutations in DNMT3A, TP53, ASXL1, and NRAS is associated with a worse response to salvage therapy. Of 21 patients in the current study who had available data, 10 patients had at least one of these mutations, and 8 of those 10 patients achieved CR or CRi, Dr. Advani said.

 

“To identify a signature predictive of response to treatment, we performed RNA sequencing on pretreatment samples from 17 patients, and on posttreatment samples from 11 patients,” she said. “We found that genes were differentially expressed between resistant and responding patients in 314 genes in the pretreatment samples, in 217 genes in the posttreatment samples, and in 72 genes at both time points.”

Gene set enrichment analysis identified significantly differentially expressed genes clustering in heme-metabolism and erythroblast differentiation, inflammatory response, cytokine/STAT signaling, nuclear factor-kappa beta (NF-kappaB), and hypoxia. Two genes – gamma-interferon–inducible lysosomal thiol reductase (IFI30) and retinoic acid–related orphan receptor A (ROR-alpha) – were found to be significantly different between responding and resistant patients, and could potentially classify response, she noted.

“IFI30, which may increase the levels of antioxidants and lead to a decreased ER [endoplasmic reticulum] stress response to therapy, was more highly expressed in resistant patients, and ROR-alpha, a tumor-suppressor gene, was down regulated in resistant patients,” she said.

Ixazomib was combined with the AML salvage regimen MEC in this study because proteasome inhibitors like ixazomib induce cell death in AML cells through inhibition of NF-kappaB, and also increase chemosensitivity to anthracyclines and cytarabines, Dr. Advani explained.

 

The findings are encouraging and suggest that results from gene expression profiling may help identify resistant patients and provide further therapeutic targets, she said, noting that in vitro studies are planned to clarify whether the use of ROR-alpha agonists may help sensitize resistant cells to treatment.

Dr. Advani reported receiving research funding from Takeda/Millenium, and serving as a consultant for Pfizer.

[email protected]

 

This is the seventh in a series of articles from the National Center for Excellence in Primary Care Research (NCEPCR) in the Agency for Healthcare Research and Quality (AHRQ). This series introduces sets of tools and resources designed to help your practice.

Thus far, this series has discussed topics such as shared decision making, team-based care, and integrating behavioral health and primary care. All of these are important topics, but this raises the question, “How do I make the changes to my practice?” This month’s article discusses AHRQ’s resources for transforming your practice to be able to better introduce these advances.

A good place to start is AHRQ’s Improving Primary Care Practice page, which offers a wide range of resources designed to help practices improve their care. Here are some of the improvement topics for which resources are available:

Building capacity for quality improvement in primary care. Primary care practices often benefit from external support and assistance while they develop the capacity to carry out quality improvement activities as an integral part of their work. These resources describe approaches and supports that are needed to build QI capacity in primary care.

 

Care coordination. The main goal of care coordination is to meet patients’ needs and preferences in the delivery of high-quality, high-value health care. This means that the patient’s needs and preferences are known and communicated at the right time to the right people, which results in safe, appropriate, and effective care. AHRQ’s resources in this area offer examples of care coordination approaches and activities, as well as guidance and models for understanding and measuring patients’ perceptions of care coordination.

Improvement approaches related to patient engagement and support. Several different types of resources related to patient engagement are available. These include the what, why, and how of self-management support, implementing health literacy universal precautions, and engaging patients and families in patient safety efforts.

AHRQ’s Primary Care YouTube channel offers videos from clinical staff, researchers, and others describing their work in many of these areas.

Other resources also are available. One of the most popular approaches to transformation involves taking steps to make your practice a patient-centered medical home (PCMH). AHRQ’s Patient-Centered Medical Home Resource Center website features evidence, examples, and lessons learned from primary care practices that have transformed their approach to the organization and delivery of care. Policymakers, researchers, practices, and practice facilitators can access evidence-based resources about the medical home and its potential to transform primary care and improve the quality, safety, efficiency, and effectiveness of U.S. health care.

 

While the goal of practice transformation is the improvement of patient care and patient outcomes, patient and staff satisfaction (including issues regarding provider burnout) must not be lost in the process. The Clinician & Group Survey of the Consumer Assessment of Healthcare Providers and Systems assesses patient experiences with health care providers and staff in doctors’ offices. Survey results can be used to improve care provided by individual providers, sites of care, medical groups, or provider networks, as well as equip consumers with information they can use to choose physicians and other health care providers, physician practices, or medical groups. The survey includes standardized questionnaires for adults and children. The adult questionnaire can be used in both primary care and specialty care settings; the child questionnaire is designed for primary care settings but could be adapted for specialty care. Users can also add supplemental items to customize their questionnaires.

For many practices, working with a practice facilitator will be a big part of the transformation. Practice facilitation is an evidence-based approach to quality improvement in primary care practices. It will be discussed at length next month. In addition, in July and August, we will discuss optimizing health information technology and workflow in your practice.

Dr. Genevro is a health scientist at AHRQ. Dr. Ganiats is the director of the National Center for Excellence in Primary Care Research at AHRQ.

 

This is the seventh in a series of articles from the National Center for Excellence in Primary Care Research (NCEPCR) in the Agency for Healthcare Research and Quality (AHRQ). This series introduces sets of tools and resources designed to help your practice.

Thus far, this series has discussed topics such as shared decision making, team-based care, and integrating behavioral health and primary care. All of these are important topics, but this raises the question, “How do I make the changes to my practice?” This month’s article discusses AHRQ’s resources for transforming your practice to be able to better introduce these advances.

A good place to start is AHRQ’s Improving Primary Care Practice page, which offers a wide range of resources designed to help practices improve their care. Here are some of the improvement topics for which resources are available:

Building capacity for quality improvement in primary care. Primary care practices often benefit from external support and assistance while they develop the capacity to carry out quality improvement activities as an integral part of their work. These resources describe approaches and supports that are needed to build QI capacity in primary care.

 

Care coordination. The main goal of care coordination is to meet patients’ needs and preferences in the delivery of high-quality, high-value health care. This means that the patient’s needs and preferences are known and communicated at the right time to the right people, which results in safe, appropriate, and effective care. AHRQ’s resources in this area offer examples of care coordination approaches and activities, as well as guidance and models for understanding and measuring patients’ perceptions of care coordination.

Improvement approaches related to patient engagement and support. Several different types of resources related to patient engagement are available. These include the what, why, and how of self-management support, implementing health literacy universal precautions, and engaging patients and families in patient safety efforts.

AHRQ’s Primary Care YouTube channel offers videos from clinical staff, researchers, and others describing their work in many of these areas.

Other resources also are available. One of the most popular approaches to transformation involves taking steps to make your practice a patient-centered medical home (PCMH). AHRQ’s Patient-Centered Medical Home Resource Center website features evidence, examples, and lessons learned from primary care practices that have transformed their approach to the organization and delivery of care. Policymakers, researchers, practices, and practice facilitators can access evidence-based resources about the medical home and its potential to transform primary care and improve the quality, safety, efficiency, and effectiveness of U.S. health care.

 

While the goal of practice transformation is the improvement of patient care and patient outcomes, patient and staff satisfaction (including issues regarding provider burnout) must not be lost in the process. The Clinician & Group Survey of the Consumer Assessment of Healthcare Providers and Systems assesses patient experiences with health care providers and staff in doctors’ offices. Survey results can be used to improve care provided by individual providers, sites of care, medical groups, or provider networks, as well as equip consumers with information they can use to choose physicians and other health care providers, physician practices, or medical groups. The survey includes standardized questionnaires for adults and children. The adult questionnaire can be used in both primary care and specialty care settings; the child questionnaire is designed for primary care settings but could be adapted for specialty care. Users can also add supplemental items to customize their questionnaires.

For many practices, working with a practice facilitator will be a big part of the transformation. Practice facilitation is an evidence-based approach to quality improvement in primary care practices. It will be discussed at length next month. In addition, in July and August, we will discuss optimizing health information technology and workflow in your practice.

Dr. Genevro is a health scientist at AHRQ. Dr. Ganiats is the director of the National Center for Excellence in Primary Care Research at AHRQ.

 

This is the seventh in a series of articles from the National Center for Excellence in Primary Care Research (NCEPCR) in the Agency for Healthcare Research and Quality (AHRQ). This series introduces sets of tools and resources designed to help your practice.

Thus far, this series has discussed topics such as shared decision making, team-based care, and integrating behavioral health and primary care. All of these are important topics, but this raises the question, “How do I make the changes to my practice?” This month’s article discusses AHRQ’s resources for transforming your practice to be able to better introduce these advances.

A good place to start is AHRQ’s Improving Primary Care Practice page, which offers a wide range of resources designed to help practices improve their care. Here are some of the improvement topics for which resources are available:

Building capacity for quality improvement in primary care. Primary care practices often benefit from external support and assistance while they develop the capacity to carry out quality improvement activities as an integral part of their work. These resources describe approaches and supports that are needed to build QI capacity in primary care.

 

Care coordination. The main goal of care coordination is to meet patients’ needs and preferences in the delivery of high-quality, high-value health care. This means that the patient’s needs and preferences are known and communicated at the right time to the right people, which results in safe, appropriate, and effective care. AHRQ’s resources in this area offer examples of care coordination approaches and activities, as well as guidance and models for understanding and measuring patients’ perceptions of care coordination.

Improvement approaches related to patient engagement and support. Several different types of resources related to patient engagement are available. These include the what, why, and how of self-management support, implementing health literacy universal precautions, and engaging patients and families in patient safety efforts.

AHRQ’s Primary Care YouTube channel offers videos from clinical staff, researchers, and others describing their work in many of these areas.

Other resources also are available. One of the most popular approaches to transformation involves taking steps to make your practice a patient-centered medical home (PCMH). AHRQ’s Patient-Centered Medical Home Resource Center website features evidence, examples, and lessons learned from primary care practices that have transformed their approach to the organization and delivery of care. Policymakers, researchers, practices, and practice facilitators can access evidence-based resources about the medical home and its potential to transform primary care and improve the quality, safety, efficiency, and effectiveness of U.S. health care.

 

While the goal of practice transformation is the improvement of patient care and patient outcomes, patient and staff satisfaction (including issues regarding provider burnout) must not be lost in the process. The Clinician & Group Survey of the Consumer Assessment of Healthcare Providers and Systems assesses patient experiences with health care providers and staff in doctors’ offices. Survey results can be used to improve care provided by individual providers, sites of care, medical groups, or provider networks, as well as equip consumers with information they can use to choose physicians and other health care providers, physician practices, or medical groups. The survey includes standardized questionnaires for adults and children. The adult questionnaire can be used in both primary care and specialty care settings; the child questionnaire is designed for primary care settings but could be adapted for specialty care. Users can also add supplemental items to customize their questionnaires.

For many practices, working with a practice facilitator will be a big part of the transformation. Practice facilitation is an evidence-based approach to quality improvement in primary care practices. It will be discussed at length next month. In addition, in July and August, we will discuss optimizing health information technology and workflow in your practice.

Dr. Genevro is a health scientist at AHRQ. Dr. Ganiats is the director of the National Center for Excellence in Primary Care Research at AHRQ.

 

SILVER SPRING, MD. – Federal advisors to the Food and Drug Administration on March 8 voted unanimously to recommend approval of an additional indication for tofacitinib (Xeljanz), this time for ulcerative colitis.

Members of the Gastrointestinal Drugs Advisory Committee unanimously voted to recommend two different dosing regimens: 10 mg twice daily for 16 weeks in patients who have not experienced a therapeutic benefit after 8 weeks of treatment, as well as 10 mg twice daily for patients who have an inadequate or loss of response to TNF-blocker therapy, based on the results of several phase 3 clinical trials.

The committee rejected by a 7-8 vote a recommendation that Pfizer, the drug’s manufacturer, conduct a postmarketing efficacy trial comparing a 10-mg continuous dosing regimen with a 10-mg induction and 5 mg twice daily as maintenance.

The recommended ulcerative colitis (UC) indication was based on the OCTAVE trials (N Engl J Med 2017;376:1723-36), including a phase 2 study, two identical phase 3 induction trials (OCTAVE Induction 1 and OCTAVE Induction 2), a 53-week, phase 3 maintenance trial (OCTAVE Sustain), and an open-label extension study.

 

The induction trials enrolled a total of 1,139 patients with moderate to severe UC. Patients in both studies were administered tofacitinib 10 mg twice daily or placebo and were assessed after 8 weeks to judge clinical response. Patients in both studies displayed notable remission rates (18.5% and 16.6%), compared with placebo, according to Eric Maller, MD, executive director of the UC development program at Pfizer.*

Patients who did not achieve remission, but showed some clinical response (decrease in Mayo score of at least 3 points), were then enrolled in the 53-week OCTAVE Sustain, where they were randomized to receive tofacitinib 10 mg twice daily, 5 mg twice daily, or placebo.

During maintenance treatment, both 5 mg and 10 mg doses demonstrated substantial treatment benefits, with 32.4% and 41.0% of patients achieving remission, an increase of 22.0% and 30.7%, compared with placebo, respectively.

As part of the maintenance study, Pfizer analyzed patients with or without prior TNF-blocker failure. This analysis revealed that patients who had previously failed TNF-blocker therapy experienced a greater treatment benefit than those who had not. While the benefit was noticeable in both dosage groups, patients taking the 10-mg dose experienced the greatest benefit, with 70% increase in remission rates, 39% increase in mucosal healing, and 75% increase in steroid-free remission among baseline remitters, compared with patients in the 5-mg group, Dr. Maller said.

 

Researchers also looked at a subgroup of 295 patients as part of an open-label extension study who had no clinical response to tofacitinib 10 mg twice daily after 8 weeks and subsequently treated them for an additional 8 weeks. After the additional 8 weeks of treatment, over half (51.2%) displayed clinical responses and 8.6% were in remission.

“This is a desperate patient population. These are impressive results,” stated Darrell Pardi, MD, vice chair of the advisory committee and professor of medicine at the Mayo Clinic, Rochester, Minn.

Serious adverse events were seen in 4% of tofacitinib-treated patients in the induction trials, compared with 6% of placebo-treated, according to Lesley Hanes, MD, medical officer with the FDA Center for Drug Evaluation and Research.

Adverse events appeared to be dose dependent, with risk of deaths and malignancies (excluding nonmelanoma skin cancer), opportunistic infections, herpes zoster infection (HZ), “possible” drug-induced liver injury, and cardiovascular and thromboembolic events more common with the 10-mg dose, Dr. Hanes said.*

 

“I think the safety concerns, though, they are dose dependent, the difference between the 5 [mg] and 10 [mg] were not large,” according to Dr. Pardi. “Several of these are mitigatable by dermatologic exam or, hopefully, a vaccine.”

Several of the advisory committee members submitted conflict of interest waivers. Chair and vice chair Jean-Pierre Raufman, MD, and Darrell Pardi, MD, disclosed funding from competing pharmaceutical manufacturers.

*This article was updated on March 12, 2018.

[email protected]

 

SILVER SPRING, MD. – Federal advisors to the Food and Drug Administration on March 8 voted unanimously to recommend approval of an additional indication for tofacitinib (Xeljanz), this time for ulcerative colitis.

Members of the Gastrointestinal Drugs Advisory Committee unanimously voted to recommend two different dosing regimens: 10 mg twice daily for 16 weeks in patients who have not experienced a therapeutic benefit after 8 weeks of treatment, as well as 10 mg twice daily for patients who have an inadequate or loss of response to TNF-blocker therapy, based on the results of several phase 3 clinical trials.

The committee rejected by a 7-8 vote a recommendation that Pfizer, the drug’s manufacturer, conduct a postmarketing efficacy trial comparing a 10-mg continuous dosing regimen with a 10-mg induction and 5 mg twice daily as maintenance.

The recommended ulcerative colitis (UC) indication was based on the OCTAVE trials (N Engl J Med 2017;376:1723-36), including a phase 2 study, two identical phase 3 induction trials (OCTAVE Induction 1 and OCTAVE Induction 2), a 53-week, phase 3 maintenance trial (OCTAVE Sustain), and an open-label extension study.

 

The induction trials enrolled a total of 1,139 patients with moderate to severe UC. Patients in both studies were administered tofacitinib 10 mg twice daily or placebo and were assessed after 8 weeks to judge clinical response. Patients in both studies displayed notable remission rates (18.5% and 16.6%), compared with placebo, according to Eric Maller, MD, executive director of the UC development program at Pfizer.*

Patients who did not achieve remission, but showed some clinical response (decrease in Mayo score of at least 3 points), were then enrolled in the 53-week OCTAVE Sustain, where they were randomized to receive tofacitinib 10 mg twice daily, 5 mg twice daily, or placebo.

During maintenance treatment, both 5 mg and 10 mg doses demonstrated substantial treatment benefits, with 32.4% and 41.0% of patients achieving remission, an increase of 22.0% and 30.7%, compared with placebo, respectively.

As part of the maintenance study, Pfizer analyzed patients with or without prior TNF-blocker failure. This analysis revealed that patients who had previously failed TNF-blocker therapy experienced a greater treatment benefit than those who had not. While the benefit was noticeable in both dosage groups, patients taking the 10-mg dose experienced the greatest benefit, with 70% increase in remission rates, 39% increase in mucosal healing, and 75% increase in steroid-free remission among baseline remitters, compared with patients in the 5-mg group, Dr. Maller said.

 

Researchers also looked at a subgroup of 295 patients as part of an open-label extension study who had no clinical response to tofacitinib 10 mg twice daily after 8 weeks and subsequently treated them for an additional 8 weeks. After the additional 8 weeks of treatment, over half (51.2%) displayed clinical responses and 8.6% were in remission.

“This is a desperate patient population. These are impressive results,” stated Darrell Pardi, MD, vice chair of the advisory committee and professor of medicine at the Mayo Clinic, Rochester, Minn.

Serious adverse events were seen in 4% of tofacitinib-treated patients in the induction trials, compared with 6% of placebo-treated, according to Lesley Hanes, MD, medical officer with the FDA Center for Drug Evaluation and Research.

Adverse events appeared to be dose dependent, with risk of deaths and malignancies (excluding nonmelanoma skin cancer), opportunistic infections, herpes zoster infection (HZ), “possible” drug-induced liver injury, and cardiovascular and thromboembolic events more common with the 10-mg dose, Dr. Hanes said.*

 

“I think the safety concerns, though, they are dose dependent, the difference between the 5 [mg] and 10 [mg] were not large,” according to Dr. Pardi. “Several of these are mitigatable by dermatologic exam or, hopefully, a vaccine.”

Several of the advisory committee members submitted conflict of interest waivers. Chair and vice chair Jean-Pierre Raufman, MD, and Darrell Pardi, MD, disclosed funding from competing pharmaceutical manufacturers.

*This article was updated on March 12, 2018.

[email protected]

 

SILVER SPRING, MD. – Federal advisors to the Food and Drug Administration on March 8 voted unanimously to recommend approval of an additional indication for tofacitinib (Xeljanz), this time for ulcerative colitis.

Members of the Gastrointestinal Drugs Advisory Committee unanimously voted to recommend two different dosing regimens: 10 mg twice daily for 16 weeks in patients who have not experienced a therapeutic benefit after 8 weeks of treatment, as well as 10 mg twice daily for patients who have an inadequate or loss of response to TNF-blocker therapy, based on the results of several phase 3 clinical trials.

The committee rejected by a 7-8 vote a recommendation that Pfizer, the drug’s manufacturer, conduct a postmarketing efficacy trial comparing a 10-mg continuous dosing regimen with a 10-mg induction and 5 mg twice daily as maintenance.

The recommended ulcerative colitis (UC) indication was based on the OCTAVE trials (N Engl J Med 2017;376:1723-36), including a phase 2 study, two identical phase 3 induction trials (OCTAVE Induction 1 and OCTAVE Induction 2), a 53-week, phase 3 maintenance trial (OCTAVE Sustain), and an open-label extension study.

 

The induction trials enrolled a total of 1,139 patients with moderate to severe UC. Patients in both studies were administered tofacitinib 10 mg twice daily or placebo and were assessed after 8 weeks to judge clinical response. Patients in both studies displayed notable remission rates (18.5% and 16.6%), compared with placebo, according to Eric Maller, MD, executive director of the UC development program at Pfizer.*

Patients who did not achieve remission, but showed some clinical response (decrease in Mayo score of at least 3 points), were then enrolled in the 53-week OCTAVE Sustain, where they were randomized to receive tofacitinib 10 mg twice daily, 5 mg twice daily, or placebo.

During maintenance treatment, both 5 mg and 10 mg doses demonstrated substantial treatment benefits, with 32.4% and 41.0% of patients achieving remission, an increase of 22.0% and 30.7%, compared with placebo, respectively.

As part of the maintenance study, Pfizer analyzed patients with or without prior TNF-blocker failure. This analysis revealed that patients who had previously failed TNF-blocker therapy experienced a greater treatment benefit than those who had not. While the benefit was noticeable in both dosage groups, patients taking the 10-mg dose experienced the greatest benefit, with 70% increase in remission rates, 39% increase in mucosal healing, and 75% increase in steroid-free remission among baseline remitters, compared with patients in the 5-mg group, Dr. Maller said.

 

Researchers also looked at a subgroup of 295 patients as part of an open-label extension study who had no clinical response to tofacitinib 10 mg twice daily after 8 weeks and subsequently treated them for an additional 8 weeks. After the additional 8 weeks of treatment, over half (51.2%) displayed clinical responses and 8.6% were in remission.

“This is a desperate patient population. These are impressive results,” stated Darrell Pardi, MD, vice chair of the advisory committee and professor of medicine at the Mayo Clinic, Rochester, Minn.

Serious adverse events were seen in 4% of tofacitinib-treated patients in the induction trials, compared with 6% of placebo-treated, according to Lesley Hanes, MD, medical officer with the FDA Center for Drug Evaluation and Research.

Adverse events appeared to be dose dependent, with risk of deaths and malignancies (excluding nonmelanoma skin cancer), opportunistic infections, herpes zoster infection (HZ), “possible” drug-induced liver injury, and cardiovascular and thromboembolic events more common with the 10-mg dose, Dr. Hanes said.*

 

“I think the safety concerns, though, they are dose dependent, the difference between the 5 [mg] and 10 [mg] were not large,” according to Dr. Pardi. “Several of these are mitigatable by dermatologic exam or, hopefully, a vaccine.”

Several of the advisory committee members submitted conflict of interest waivers. Chair and vice chair Jean-Pierre Raufman, MD, and Darrell Pardi, MD, disclosed funding from competing pharmaceutical manufacturers.

*This article was updated on March 12, 2018.

[email protected]

 

SAN ANTONIO – While critical care specialists await more data on a so-called sepsis cocktail with varying degrees of hope and skepticism, Paul E. Marik, MD, FCCP, has proclaimed the dawning of a new era.

Dr. Marik became a celebrity in the critical care medicine community after he and his colleagues reported the results of his retrospective study evaluating the combination of hydrocortisone, vitamin C, and thiamine for treatment of severe sepsis and septic shock (Chest. 2017 June. doi: 10.1016/j.chest.2016.11.036).

Since this study, several physicians have already been putting Dr. Marik’s method to practice, the investigator and audience members noted during a session at the Critical Care Congress sponsored by the Society of Critical Care Medicine.

“My point is, steroids work, but they don’t work well alone, and the era of glucocorticoid monotherapy has come to an end,” Dr. Marik said in his presentation at the meeting.

Andrew D. Bowser/Frontline Medical News

These comments echoed Dr. Marik’s May 2017 editorial in Critical Care Medicine, in which he suggested that critically ill and injured patients may benefit from combination therapy with hydrocortisone and vitamin C (Crit Care Med 2017 May;45[5]910-1).

 

That editorial was quickly followed by the report on Dr. Marik and colleagues’ before-after study, in which hospital mortality was 8.5%, versus 0.4% in the treatment and control groups, respectively (P less than .001). This finding led the investigators to suggest that intravenous vitamin C administered along with corticosteroids and thiamine is “effective” in reducing mortality, in their paper published in CHEST®.

During Dr. Marik’s presentation at the meeting, he noted that he had been “misquoted” with regard to the finality of his study’s results. The final line of the CHEST® paper reads, “Additional studies are required to confirm these preliminary findings,” he emphasized.

Nevertheless, Dr. Marik alluded to a “big paradigm shift” in the treatment of sepsis.

“Our experience has been echoed by now hundreds, if not thousands, of clinicians across the world,” said Dr. Marik, chief of the division of pulmonary and critical care medicine, Eastern Virginia Medical School, Norfolk.

He recounted an anecdotal case submitted by “Josh from Ohio” describing an elderly man who was “started on cocktail and within a day his pressor requirements melted away and he was extubated.” Quoting “Josh from Ohio,” Dr. Mark continued, “Tomorrow he will probably leave the ICU with no residual organ dysfunction, no volume overload, (and) no ICU complications.”

Eddy Gutierrez, MD, of Jacksonville, Fla., noted in a question-and-answer period that he has had “positive results” with a similar approach.

“When we first learned about the vitamin C and the ‘Marik protocol,’ so to speak, I was in fellowship and I got laughed at,” Dr. Gutierrez said. “Nobody would let me try it.”

Others are taking a wait-and-see approach.

 

Greg S. Martin, MD, secretary of the Society of Critical Care Medicine, said in an interview that there are “at least two schools of thought” among critical care specialists regarding the use of hydrocortisone, vitamin C, and thiamine for treatment of sepsis and septic shock.

“One school of thought is that this is incredibly important if this is even fractionally as effective as what [Dr. Marik] showed, because we have not found an effective therapy for sepsis,” said Dr. Martin, associate professor of medicine at Grady Memorial Hospital, Atlanta.

“The contrarian approach is to say, ‘yes, but this seems remarkably unlikely to be as effective as what he has shown,’ ” Dr. Martin added. “Particularly in sepsis, people are very skeptical of whether a drug or a drug combination is going to be as effective when you really get down to a high-quality randomized controlled trial that would be the definitive level of evidence.”

The wait may not be long for at least some data. Multiple clinical trials are recruiting or planned, according to Dr. Marik. These included a 140-patient U.S. randomized, double-blind trial of vitamin C, hydrocortisone, and thiamine vs. placebo that started in February 2018 and is expected to be completed by February 2019, according to the study’s ClinicalTrials.gov listing.

“The good news is some people think this is of value,” Dr. Marik said.

As part of his presentation, Dr. Marik reported a disclosure related to Baxter (advisory board).

[email protected]

 

SAN ANTONIO – While critical care specialists await more data on a so-called sepsis cocktail with varying degrees of hope and skepticism, Paul E. Marik, MD, FCCP, has proclaimed the dawning of a new era.

Dr. Marik became a celebrity in the critical care medicine community after he and his colleagues reported the results of his retrospective study evaluating the combination of hydrocortisone, vitamin C, and thiamine for treatment of severe sepsis and septic shock (Chest. 2017 June. doi: 10.1016/j.chest.2016.11.036).

Since this study, several physicians have already been putting Dr. Marik’s method to practice, the investigator and audience members noted during a session at the Critical Care Congress sponsored by the Society of Critical Care Medicine.

“My point is, steroids work, but they don’t work well alone, and the era of glucocorticoid monotherapy has come to an end,” Dr. Marik said in his presentation at the meeting.

Andrew D. Bowser/Frontline Medical News

These comments echoed Dr. Marik’s May 2017 editorial in Critical Care Medicine, in which he suggested that critically ill and injured patients may benefit from combination therapy with hydrocortisone and vitamin C (Crit Care Med 2017 May;45[5]910-1).

 

That editorial was quickly followed by the report on Dr. Marik and colleagues’ before-after study, in which hospital mortality was 8.5%, versus 0.4% in the treatment and control groups, respectively (P less than .001). This finding led the investigators to suggest that intravenous vitamin C administered along with corticosteroids and thiamine is “effective” in reducing mortality, in their paper published in CHEST®.

During Dr. Marik’s presentation at the meeting, he noted that he had been “misquoted” with regard to the finality of his study’s results. The final line of the CHEST® paper reads, “Additional studies are required to confirm these preliminary findings,” he emphasized.

Nevertheless, Dr. Marik alluded to a “big paradigm shift” in the treatment of sepsis.

“Our experience has been echoed by now hundreds, if not thousands, of clinicians across the world,” said Dr. Marik, chief of the division of pulmonary and critical care medicine, Eastern Virginia Medical School, Norfolk.

He recounted an anecdotal case submitted by “Josh from Ohio” describing an elderly man who was “started on cocktail and within a day his pressor requirements melted away and he was extubated.” Quoting “Josh from Ohio,” Dr. Mark continued, “Tomorrow he will probably leave the ICU with no residual organ dysfunction, no volume overload, (and) no ICU complications.”

Eddy Gutierrez, MD, of Jacksonville, Fla., noted in a question-and-answer period that he has had “positive results” with a similar approach.

“When we first learned about the vitamin C and the ‘Marik protocol,’ so to speak, I was in fellowship and I got laughed at,” Dr. Gutierrez said. “Nobody would let me try it.”

Others are taking a wait-and-see approach.

 

Greg S. Martin, MD, secretary of the Society of Critical Care Medicine, said in an interview that there are “at least two schools of thought” among critical care specialists regarding the use of hydrocortisone, vitamin C, and thiamine for treatment of sepsis and septic shock.

“One school of thought is that this is incredibly important if this is even fractionally as effective as what [Dr. Marik] showed, because we have not found an effective therapy for sepsis,” said Dr. Martin, associate professor of medicine at Grady Memorial Hospital, Atlanta.

“The contrarian approach is to say, ‘yes, but this seems remarkably unlikely to be as effective as what he has shown,’ ” Dr. Martin added. “Particularly in sepsis, people are very skeptical of whether a drug or a drug combination is going to be as effective when you really get down to a high-quality randomized controlled trial that would be the definitive level of evidence.”

The wait may not be long for at least some data. Multiple clinical trials are recruiting or planned, according to Dr. Marik. These included a 140-patient U.S. randomized, double-blind trial of vitamin C, hydrocortisone, and thiamine vs. placebo that started in February 2018 and is expected to be completed by February 2019, according to the study’s ClinicalTrials.gov listing.

“The good news is some people think this is of value,” Dr. Marik said.

As part of his presentation, Dr. Marik reported a disclosure related to Baxter (advisory board).

[email protected]

 

SAN ANTONIO – While critical care specialists await more data on a so-called sepsis cocktail with varying degrees of hope and skepticism, Paul E. Marik, MD, FCCP, has proclaimed the dawning of a new era.

Dr. Marik became a celebrity in the critical care medicine community after he and his colleagues reported the results of his retrospective study evaluating the combination of hydrocortisone, vitamin C, and thiamine for treatment of severe sepsis and septic shock (Chest. 2017 June. doi: 10.1016/j.chest.2016.11.036).

Since this study, several physicians have already been putting Dr. Marik’s method to practice, the investigator and audience members noted during a session at the Critical Care Congress sponsored by the Society of Critical Care Medicine.

“My point is, steroids work, but they don’t work well alone, and the era of glucocorticoid monotherapy has come to an end,” Dr. Marik said in his presentation at the meeting.

Andrew D. Bowser/Frontline Medical News

These comments echoed Dr. Marik’s May 2017 editorial in Critical Care Medicine, in which he suggested that critically ill and injured patients may benefit from combination therapy with hydrocortisone and vitamin C (Crit Care Med 2017 May;45[5]910-1).

 

That editorial was quickly followed by the report on Dr. Marik and colleagues’ before-after study, in which hospital mortality was 8.5%, versus 0.4% in the treatment and control groups, respectively (P less than .001). This finding led the investigators to suggest that intravenous vitamin C administered along with corticosteroids and thiamine is “effective” in reducing mortality, in their paper published in CHEST®.

During Dr. Marik’s presentation at the meeting, he noted that he had been “misquoted” with regard to the finality of his study’s results. The final line of the CHEST® paper reads, “Additional studies are required to confirm these preliminary findings,” he emphasized.

Nevertheless, Dr. Marik alluded to a “big paradigm shift” in the treatment of sepsis.

“Our experience has been echoed by now hundreds, if not thousands, of clinicians across the world,” said Dr. Marik, chief of the division of pulmonary and critical care medicine, Eastern Virginia Medical School, Norfolk.

He recounted an anecdotal case submitted by “Josh from Ohio” describing an elderly man who was “started on cocktail and within a day his pressor requirements melted away and he was extubated.” Quoting “Josh from Ohio,” Dr. Mark continued, “Tomorrow he will probably leave the ICU with no residual organ dysfunction, no volume overload, (and) no ICU complications.”

Eddy Gutierrez, MD, of Jacksonville, Fla., noted in a question-and-answer period that he has had “positive results” with a similar approach.

“When we first learned about the vitamin C and the ‘Marik protocol,’ so to speak, I was in fellowship and I got laughed at,” Dr. Gutierrez said. “Nobody would let me try it.”

Others are taking a wait-and-see approach.

 

Greg S. Martin, MD, secretary of the Society of Critical Care Medicine, said in an interview that there are “at least two schools of thought” among critical care specialists regarding the use of hydrocortisone, vitamin C, and thiamine for treatment of sepsis and septic shock.

“One school of thought is that this is incredibly important if this is even fractionally as effective as what [Dr. Marik] showed, because we have not found an effective therapy for sepsis,” said Dr. Martin, associate professor of medicine at Grady Memorial Hospital, Atlanta.

“The contrarian approach is to say, ‘yes, but this seems remarkably unlikely to be as effective as what he has shown,’ ” Dr. Martin added. “Particularly in sepsis, people are very skeptical of whether a drug or a drug combination is going to be as effective when you really get down to a high-quality randomized controlled trial that would be the definitive level of evidence.”

The wait may not be long for at least some data. Multiple clinical trials are recruiting or planned, according to Dr. Marik. These included a 140-patient U.S. randomized, double-blind trial of vitamin C, hydrocortisone, and thiamine vs. placebo that started in February 2018 and is expected to be completed by February 2019, according to the study’s ClinicalTrials.gov listing.

“The good news is some people think this is of value,” Dr. Marik said.

As part of his presentation, Dr. Marik reported a disclosure related to Baxter (advisory board).

[email protected]

 

Brisk walking for at least 40 minutes two or three times a week reduced the risk of heart failure by approximately 25% in postmenopausal women, according to data from more that 89,000 participants in the Women’s Health Initiative.

The benefits of walking are well understood, said Somwail Rasla, MD, of Saint Vincent Hospital in Worcester, Mass., but he and his colleagues focused for the first time on how the speed, frequency, and duration of walking affected health in older women who may be less likely to visit a gym or engage in a formal exercise program.

iStock/thinkstockphotos

“The more they walk, the higher the speed, and the longer the duration, the less likely they are to have heart failure,” Dr. Rasla said in a press briefing in advance of the annual meeting of the American College of Cardiology.

The researchers followed the women, aged 50-79 years, for approximately 10 years.

 

Overall, the risk of heart failure was 20%-25% less for women who walked at least twice a week than it was for women who walked less frequently. In addition, women who walked for at least 40 minutes per walk had a 21%-25% lower heart failure risk than did those who walked less than 40 minutes per walk.

Pace mattered as well, Dr. Rasla pointed out. Women walking at an average pace and a fast pace had, respectively, 26% and 38% lower heart failure risk, compared with women who walked at a casual pace.

The researchers measured the women’s energy expenditure using the Metabolic Equivalent of Task (MET), a value calculated using the women’s self-reports of their walking frequency, duration, and speed. The results were similar across different age groups, ethnicities, and baseline body weight, which suggests the findings can be generalized to apply to most women. “I think we could give the same advice [about walking] to women up to age 79,” said Dr. Rasla.

The findings were limited by the use of self-reports, Dr. Rasla noted. However, the results suggest that walking can be a valuable and accessible form of exercise for older women, he said.

The Women’s Health Initiative is sponsored by the National Institutes of Health. The investigators reported no relevant conflicts of interest.

SOURCE: Rasla S et al. ACC 18, Poster 1315M-03.
 

 

Brisk walking for at least 40 minutes two or three times a week reduced the risk of heart failure by approximately 25% in postmenopausal women, according to data from more that 89,000 participants in the Women’s Health Initiative.

The benefits of walking are well understood, said Somwail Rasla, MD, of Saint Vincent Hospital in Worcester, Mass., but he and his colleagues focused for the first time on how the speed, frequency, and duration of walking affected health in older women who may be less likely to visit a gym or engage in a formal exercise program.

iStock/thinkstockphotos

“The more they walk, the higher the speed, and the longer the duration, the less likely they are to have heart failure,” Dr. Rasla said in a press briefing in advance of the annual meeting of the American College of Cardiology.

The researchers followed the women, aged 50-79 years, for approximately 10 years.

 

Overall, the risk of heart failure was 20%-25% less for women who walked at least twice a week than it was for women who walked less frequently. In addition, women who walked for at least 40 minutes per walk had a 21%-25% lower heart failure risk than did those who walked less than 40 minutes per walk.

Pace mattered as well, Dr. Rasla pointed out. Women walking at an average pace and a fast pace had, respectively, 26% and 38% lower heart failure risk, compared with women who walked at a casual pace.

The researchers measured the women’s energy expenditure using the Metabolic Equivalent of Task (MET), a value calculated using the women’s self-reports of their walking frequency, duration, and speed. The results were similar across different age groups, ethnicities, and baseline body weight, which suggests the findings can be generalized to apply to most women. “I think we could give the same advice [about walking] to women up to age 79,” said Dr. Rasla.

The findings were limited by the use of self-reports, Dr. Rasla noted. However, the results suggest that walking can be a valuable and accessible form of exercise for older women, he said.

The Women’s Health Initiative is sponsored by the National Institutes of Health. The investigators reported no relevant conflicts of interest.

SOURCE: Rasla S et al. ACC 18, Poster 1315M-03.
 

 

Brisk walking for at least 40 minutes two or three times a week reduced the risk of heart failure by approximately 25% in postmenopausal women, according to data from more that 89,000 participants in the Women’s Health Initiative.

The benefits of walking are well understood, said Somwail Rasla, MD, of Saint Vincent Hospital in Worcester, Mass., but he and his colleagues focused for the first time on how the speed, frequency, and duration of walking affected health in older women who may be less likely to visit a gym or engage in a formal exercise program.

iStock/thinkstockphotos

“The more they walk, the higher the speed, and the longer the duration, the less likely they are to have heart failure,” Dr. Rasla said in a press briefing in advance of the annual meeting of the American College of Cardiology.

The researchers followed the women, aged 50-79 years, for approximately 10 years.

 

Overall, the risk of heart failure was 20%-25% less for women who walked at least twice a week than it was for women who walked less frequently. In addition, women who walked for at least 40 minutes per walk had a 21%-25% lower heart failure risk than did those who walked less than 40 minutes per walk.

Pace mattered as well, Dr. Rasla pointed out. Women walking at an average pace and a fast pace had, respectively, 26% and 38% lower heart failure risk, compared with women who walked at a casual pace.

The researchers measured the women’s energy expenditure using the Metabolic Equivalent of Task (MET), a value calculated using the women’s self-reports of their walking frequency, duration, and speed. The results were similar across different age groups, ethnicities, and baseline body weight, which suggests the findings can be generalized to apply to most women. “I think we could give the same advice [about walking] to women up to age 79,” said Dr. Rasla.

The findings were limited by the use of self-reports, Dr. Rasla noted. However, the results suggest that walking can be a valuable and accessible form of exercise for older women, he said.

The Women’s Health Initiative is sponsored by the National Institutes of Health. The investigators reported no relevant conflicts of interest.

SOURCE: Rasla S et al. ACC 18, Poster 1315M-03.
 

 

LA JOLLA, CALIF. – When patients with peripheral T-cell lymphoma (PTCL) experience relapse, consider an allogeneic stem cell transplant or clinical trial, investigators advised.

Patients with relapsed PTCL have generally dismal outcomes, with a median progression-free survival (PFS) of 3.7 months and a median overall survival (OS) of just 6.5 months, according to one study (J Clin Oncol. 2013 Jun 1;31[16]:1970-6).

Courtesy Larry Young

But for those patients who had a complete remission (CR) after salvage therapy, median PFS was 12.2 months, and median OS was 18 months, said Claire Dearden, MD, from the Royal Marsden Hospital in London.

“Clearly the problem with most of the relapsed PTCL [cases] is that they don’t achieve a good response to salvage therapy. If they do, then they have much better chance of doing well,” she said at the annual T-cell Lymphoma Forum.

 

She outlined her center’s approach for treating patients with relapsed or refractory PTCL, following a case presentation by Royal Marsden fellow Matthew Cross, MD.

Complex disease, multiple therapies

The patient was a 71-year-old woman who in 2007 had a diagnosis of asymptomatic stage 4A follicular lymphoma managed with observation; in 2010, she was diagnosed with a CD30-positive PTCL not otherwise specified with ongoing low-level bone marrow involvement with follicular lymphoma.

She initially was treated elsewhere with R-CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab) and had a response after four cycles; however, she had progression with new intra-abdominal nodal sites by the sixth cycle and then was started on two cycles of ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin), but she had further progression by May 2011 and opted to forgo additional treatment.

By July 2011, however, she became highly symptomatic with new pruritic rashes on her legs, abdominal pain, and distention. She was referred to the Royal Marsden Hospital, where she was eventually diagnosed with angioimmunoblastic T-cell lymphoma (AITL) with an Epstein-Barr virus–negative clonal large B-cell proliferation in her bone marrow.

 

She was treated with gemcitabine plus methylprednisolone and prophylactic intrathecal methotrexate and had an “excellent clinical and radiological response,” Dr. Cross said.

A subsequent bone marrow biopsy showed marked hypocellularity but no evidence of either T-cell of B-cell lymphomas.

An autologous stem cell transplant was planned, but two attempts at harvesting peripheral blood stem cells – including one with plerixafor (Mozobil) – failed, and a PET scan within 3 months showed signs of early progression.

In April 2012, the patient was started on romidepsin (Istodax) and had a 1-year remission. But in April 2013, a repeat biopsy again showed CD30-positive AITL. Based on the CD30 positivity, the patient was started on brentuximab vedotin (Adcetris) in May 2013. She was observed to have progression in inguinal nodes in January 2014; she was treated with local radiotherapy and continued on brentuximab but had further progression in June 2014. At that time, she had additional gemcitabine-based combination chemotherapy and had stable disease for 10 months.

 

In March 2015, she received lenalidomide for further progression but could not tolerate the drug. She died in September 2015, 5 years after diagnosis and 4.5 years after frontline therapy failed.

Therapeutic rationale

Dr. Dearden walked through the choices that she, along with Dr. Cross and their colleagues, made in treating the patient. They chose gemcitabine-based regimens for salvage therapy because of the drug’s efficacy across various forms on non-Hodgkin and Hodgkin lymphoma, she said.

However, a randomized, phase 3, noninferiority trial in the United Kingdom comparing GEM-P (gemcitabine, cisplatin, and methylprednisolone) with CHOP for first-line therapy of PTCL was halted at the interim analysis because GEM-P had not meet the primary endpoint, she said. Results of that trial have not been published to date.

“Clearly, if it’s the patients who do well, often it’s because they achieve a good enough remission to be able to proceed to some sort of consolidation therapy with autologous or allogeneic stem cell transplants, and I think auto-graft is probably accepted for the younger, fitter patients with relapsed chemo-sensitive disease,” she said.

 

Three-year survival rates for autologous hematopoietic stem cell transplantation range from 36% to 58% and are better than those seen with chemotherapy alone, she said.

“The problem of course is that not many patients receive the planned auto-graft, even if that’s the intention, either because of failure to respond to salvage regimen or early disease progression, which happens before the transplant is able to take place,” she said,

A reasonable alternative for patients with relapsed/refractory PTCL is allogeneic transplantation, as shown in a 2008 study.

Among 77 patients – 57 of whom had received myeloablative conditioning, 31 of whom were in complete remission, and 26 of whom had partial response at the time of transplants – the 5-year treatment-related mortality rate was 33%. However, the 5-year event-free and overall survival rates were 53% and 57%, respectively. Patients with AITL had especially good outcomes (J Clin Oncol. 2008 May 10;26[14]:2264-71).

 

“In an ideal world, if our patient had been a suitable candidate for an allo-transplant, it’s what we would have tried to undertake,” Dr. Dearden said.

Dr. Dearden recommended that all patients with relapsed or refractory PTCL be considered for clinical trials. For fit patients in first relapse, combination platinum-based chemotherapy followed by autologous or allogeneic transplant may be effective.

For patients not eligible for transplant or with chemotherapy-refractory disease, she recommended trying the following monotherapy approaches: pralatrexate for patients with PTCL not otherwise specified, histone deacetylase inhibitors or 5-azacytidine for AITL, brentuximab vedotin for anaplastic large cell lymphoma, and pembrolizumab for natural killer/T-cell lymphomas.

Although two lines of intensive chemotherapy had failed the case patient within 6 months of diagnosis, she still survived for 5 years with sequential monotherapies, Dr. Dearden noted.

 

“I use to say to her, ‘You just need to stay one drug ahead of your disease.’ And she was well, she had a very good quality of life for a period of time, and if you can deliver a treatment that is effective for a patient, it will extend their survival,” Dr. Dearden said.

The T-cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization. Dr. Dearden has consulted for MedImmune, Infinity Pharmaceuticals, Janssen, Gilead Sciences, and Roche, and has received honoraria from Janssen and Gilead. Dr. Cross reported no having no financial disclosures.

 

LA JOLLA, CALIF. – When patients with peripheral T-cell lymphoma (PTCL) experience relapse, consider an allogeneic stem cell transplant or clinical trial, investigators advised.

Patients with relapsed PTCL have generally dismal outcomes, with a median progression-free survival (PFS) of 3.7 months and a median overall survival (OS) of just 6.5 months, according to one study (J Clin Oncol. 2013 Jun 1;31[16]:1970-6).

Courtesy Larry Young

But for those patients who had a complete remission (CR) after salvage therapy, median PFS was 12.2 months, and median OS was 18 months, said Claire Dearden, MD, from the Royal Marsden Hospital in London.

“Clearly the problem with most of the relapsed PTCL [cases] is that they don’t achieve a good response to salvage therapy. If they do, then they have much better chance of doing well,” she said at the annual T-cell Lymphoma Forum.

 

She outlined her center’s approach for treating patients with relapsed or refractory PTCL, following a case presentation by Royal Marsden fellow Matthew Cross, MD.

Complex disease, multiple therapies

The patient was a 71-year-old woman who in 2007 had a diagnosis of asymptomatic stage 4A follicular lymphoma managed with observation; in 2010, she was diagnosed with a CD30-positive PTCL not otherwise specified with ongoing low-level bone marrow involvement with follicular lymphoma.

She initially was treated elsewhere with R-CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab) and had a response after four cycles; however, she had progression with new intra-abdominal nodal sites by the sixth cycle and then was started on two cycles of ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin), but she had further progression by May 2011 and opted to forgo additional treatment.

By July 2011, however, she became highly symptomatic with new pruritic rashes on her legs, abdominal pain, and distention. She was referred to the Royal Marsden Hospital, where she was eventually diagnosed with angioimmunoblastic T-cell lymphoma (AITL) with an Epstein-Barr virus–negative clonal large B-cell proliferation in her bone marrow.

 

She was treated with gemcitabine plus methylprednisolone and prophylactic intrathecal methotrexate and had an “excellent clinical and radiological response,” Dr. Cross said.

A subsequent bone marrow biopsy showed marked hypocellularity but no evidence of either T-cell of B-cell lymphomas.

An autologous stem cell transplant was planned, but two attempts at harvesting peripheral blood stem cells – including one with plerixafor (Mozobil) – failed, and a PET scan within 3 months showed signs of early progression.

In April 2012, the patient was started on romidepsin (Istodax) and had a 1-year remission. But in April 2013, a repeat biopsy again showed CD30-positive AITL. Based on the CD30 positivity, the patient was started on brentuximab vedotin (Adcetris) in May 2013. She was observed to have progression in inguinal nodes in January 2014; she was treated with local radiotherapy and continued on brentuximab but had further progression in June 2014. At that time, she had additional gemcitabine-based combination chemotherapy and had stable disease for 10 months.

 

In March 2015, she received lenalidomide for further progression but could not tolerate the drug. She died in September 2015, 5 years after diagnosis and 4.5 years after frontline therapy failed.

Therapeutic rationale

Dr. Dearden walked through the choices that she, along with Dr. Cross and their colleagues, made in treating the patient. They chose gemcitabine-based regimens for salvage therapy because of the drug’s efficacy across various forms on non-Hodgkin and Hodgkin lymphoma, she said.

However, a randomized, phase 3, noninferiority trial in the United Kingdom comparing GEM-P (gemcitabine, cisplatin, and methylprednisolone) with CHOP for first-line therapy of PTCL was halted at the interim analysis because GEM-P had not meet the primary endpoint, she said. Results of that trial have not been published to date.

“Clearly, if it’s the patients who do well, often it’s because they achieve a good enough remission to be able to proceed to some sort of consolidation therapy with autologous or allogeneic stem cell transplants, and I think auto-graft is probably accepted for the younger, fitter patients with relapsed chemo-sensitive disease,” she said.

 

Three-year survival rates for autologous hematopoietic stem cell transplantation range from 36% to 58% and are better than those seen with chemotherapy alone, she said.

“The problem of course is that not many patients receive the planned auto-graft, even if that’s the intention, either because of failure to respond to salvage regimen or early disease progression, which happens before the transplant is able to take place,” she said,

A reasonable alternative for patients with relapsed/refractory PTCL is allogeneic transplantation, as shown in a 2008 study.

Among 77 patients – 57 of whom had received myeloablative conditioning, 31 of whom were in complete remission, and 26 of whom had partial response at the time of transplants – the 5-year treatment-related mortality rate was 33%. However, the 5-year event-free and overall survival rates were 53% and 57%, respectively. Patients with AITL had especially good outcomes (J Clin Oncol. 2008 May 10;26[14]:2264-71).

 

“In an ideal world, if our patient had been a suitable candidate for an allo-transplant, it’s what we would have tried to undertake,” Dr. Dearden said.

Dr. Dearden recommended that all patients with relapsed or refractory PTCL be considered for clinical trials. For fit patients in first relapse, combination platinum-based chemotherapy followed by autologous or allogeneic transplant may be effective.

For patients not eligible for transplant or with chemotherapy-refractory disease, she recommended trying the following monotherapy approaches: pralatrexate for patients with PTCL not otherwise specified, histone deacetylase inhibitors or 5-azacytidine for AITL, brentuximab vedotin for anaplastic large cell lymphoma, and pembrolizumab for natural killer/T-cell lymphomas.

Although two lines of intensive chemotherapy had failed the case patient within 6 months of diagnosis, she still survived for 5 years with sequential monotherapies, Dr. Dearden noted.

 

“I use to say to her, ‘You just need to stay one drug ahead of your disease.’ And she was well, she had a very good quality of life for a period of time, and if you can deliver a treatment that is effective for a patient, it will extend their survival,” Dr. Dearden said.

The T-cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization. Dr. Dearden has consulted for MedImmune, Infinity Pharmaceuticals, Janssen, Gilead Sciences, and Roche, and has received honoraria from Janssen and Gilead. Dr. Cross reported no having no financial disclosures.

 

LA JOLLA, CALIF. – When patients with peripheral T-cell lymphoma (PTCL) experience relapse, consider an allogeneic stem cell transplant or clinical trial, investigators advised.

Patients with relapsed PTCL have generally dismal outcomes, with a median progression-free survival (PFS) of 3.7 months and a median overall survival (OS) of just 6.5 months, according to one study (J Clin Oncol. 2013 Jun 1;31[16]:1970-6).

Courtesy Larry Young

But for those patients who had a complete remission (CR) after salvage therapy, median PFS was 12.2 months, and median OS was 18 months, said Claire Dearden, MD, from the Royal Marsden Hospital in London.

“Clearly the problem with most of the relapsed PTCL [cases] is that they don’t achieve a good response to salvage therapy. If they do, then they have much better chance of doing well,” she said at the annual T-cell Lymphoma Forum.

 

She outlined her center’s approach for treating patients with relapsed or refractory PTCL, following a case presentation by Royal Marsden fellow Matthew Cross, MD.

Complex disease, multiple therapies

The patient was a 71-year-old woman who in 2007 had a diagnosis of asymptomatic stage 4A follicular lymphoma managed with observation; in 2010, she was diagnosed with a CD30-positive PTCL not otherwise specified with ongoing low-level bone marrow involvement with follicular lymphoma.

She initially was treated elsewhere with R-CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab) and had a response after four cycles; however, she had progression with new intra-abdominal nodal sites by the sixth cycle and then was started on two cycles of ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin), but she had further progression by May 2011 and opted to forgo additional treatment.

By July 2011, however, she became highly symptomatic with new pruritic rashes on her legs, abdominal pain, and distention. She was referred to the Royal Marsden Hospital, where she was eventually diagnosed with angioimmunoblastic T-cell lymphoma (AITL) with an Epstein-Barr virus–negative clonal large B-cell proliferation in her bone marrow.

 

She was treated with gemcitabine plus methylprednisolone and prophylactic intrathecal methotrexate and had an “excellent clinical and radiological response,” Dr. Cross said.

A subsequent bone marrow biopsy showed marked hypocellularity but no evidence of either T-cell of B-cell lymphomas.

An autologous stem cell transplant was planned, but two attempts at harvesting peripheral blood stem cells – including one with plerixafor (Mozobil) – failed, and a PET scan within 3 months showed signs of early progression.

In April 2012, the patient was started on romidepsin (Istodax) and had a 1-year remission. But in April 2013, a repeat biopsy again showed CD30-positive AITL. Based on the CD30 positivity, the patient was started on brentuximab vedotin (Adcetris) in May 2013. She was observed to have progression in inguinal nodes in January 2014; she was treated with local radiotherapy and continued on brentuximab but had further progression in June 2014. At that time, she had additional gemcitabine-based combination chemotherapy and had stable disease for 10 months.

 

In March 2015, she received lenalidomide for further progression but could not tolerate the drug. She died in September 2015, 5 years after diagnosis and 4.5 years after frontline therapy failed.

Therapeutic rationale

Dr. Dearden walked through the choices that she, along with Dr. Cross and their colleagues, made in treating the patient. They chose gemcitabine-based regimens for salvage therapy because of the drug’s efficacy across various forms on non-Hodgkin and Hodgkin lymphoma, she said.

However, a randomized, phase 3, noninferiority trial in the United Kingdom comparing GEM-P (gemcitabine, cisplatin, and methylprednisolone) with CHOP for first-line therapy of PTCL was halted at the interim analysis because GEM-P had not meet the primary endpoint, she said. Results of that trial have not been published to date.

“Clearly, if it’s the patients who do well, often it’s because they achieve a good enough remission to be able to proceed to some sort of consolidation therapy with autologous or allogeneic stem cell transplants, and I think auto-graft is probably accepted for the younger, fitter patients with relapsed chemo-sensitive disease,” she said.

 

Three-year survival rates for autologous hematopoietic stem cell transplantation range from 36% to 58% and are better than those seen with chemotherapy alone, she said.

“The problem of course is that not many patients receive the planned auto-graft, even if that’s the intention, either because of failure to respond to salvage regimen or early disease progression, which happens before the transplant is able to take place,” she said,

A reasonable alternative for patients with relapsed/refractory PTCL is allogeneic transplantation, as shown in a 2008 study.

Among 77 patients – 57 of whom had received myeloablative conditioning, 31 of whom were in complete remission, and 26 of whom had partial response at the time of transplants – the 5-year treatment-related mortality rate was 33%. However, the 5-year event-free and overall survival rates were 53% and 57%, respectively. Patients with AITL had especially good outcomes (J Clin Oncol. 2008 May 10;26[14]:2264-71).

 

“In an ideal world, if our patient had been a suitable candidate for an allo-transplant, it’s what we would have tried to undertake,” Dr. Dearden said.

Dr. Dearden recommended that all patients with relapsed or refractory PTCL be considered for clinical trials. For fit patients in first relapse, combination platinum-based chemotherapy followed by autologous or allogeneic transplant may be effective.

For patients not eligible for transplant or with chemotherapy-refractory disease, she recommended trying the following monotherapy approaches: pralatrexate for patients with PTCL not otherwise specified, histone deacetylase inhibitors or 5-azacytidine for AITL, brentuximab vedotin for anaplastic large cell lymphoma, and pembrolizumab for natural killer/T-cell lymphomas.

Although two lines of intensive chemotherapy had failed the case patient within 6 months of diagnosis, she still survived for 5 years with sequential monotherapies, Dr. Dearden noted.

 

“I use to say to her, ‘You just need to stay one drug ahead of your disease.’ And she was well, she had a very good quality of life for a period of time, and if you can deliver a treatment that is effective for a patient, it will extend their survival,” Dr. Dearden said.

The T-cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization. Dr. Dearden has consulted for MedImmune, Infinity Pharmaceuticals, Janssen, Gilead Sciences, and Roche, and has received honoraria from Janssen and Gilead. Dr. Cross reported no having no financial disclosures.

 

DALLAS – No clear winner emerged in a first-ever randomized controlled trial comparing Pfannenstiel with vertical incisions for women with obesity having cesarean delivery, though enrollment difficulties limited study numbers, with almost two-thirds of eligible women declining to participate in the surgical trial.

At 6 weeks postdelivery, 21.1% of women who had a vertical incision experienced wound complications, compared with 18.6% of those who had a Pfannenstiel incision, a nonsignificant difference. This was a smaller difference than was seen at 2 weeks postpartum, when 20% of the vertical incision group had wound complications, compared with 10.4% of those who had a Pfannenstiel, also a nonsignificant difference. Maternal and fetal outcomes didn’t differ significantly with the two surgical approaches.

”We were unable to demonstrate a difference in the primary or secondary outcomes in women with class III obesity who received Pfannenstiel versus vertical skin incision,” said Caroline C. Marrs, MD, presenting the study results at the meeting sponsored by the Society for Maternal-Fetal Medicine.

Though there had been several observational studies comparing vertical with Pfannenstiel incisions for cesarean delivery in women with obesity, no randomized, controlled trials had been conducted, and observational study results were mixed, said Dr. Marrs.

 

Each approach comes with theoretical pros and cons: For women who have a large pannus, the incision site may lie in a moist environment with a low transverse incision, and oxygen tension may be low. However, a Pfannenstiel incision usually will have better cosmesis than will a vertical incision, and generally will result in less postoperative pain.

On the other hand, said Dr. Marrs, vertical incisions can provide improved exposure of the uterus during delivery, and the moist environment underlying the pannus is avoided. However, wound tension may be higher, and subcutaneous thickness is likely to be higher than at the Pfannenstiel incision site.

The study, conducted at two academic medical centers, enrolled women with a body mass index (BMI) of at least 40 kg/m² at a gestational age of 24 weeks or greater who required cesarean delivery. Consenting women were then randomized to receive Pfannenstiel or vertical incisions.

Women who had clinical chorioamnionitis, whose amniotic membranes had been ruptured for 18 hours or more, or who had placenta accreta were excluded. Also excluded were women with a private physician and those desiring vaginal delivery, said Dr. Marrs, a maternal-fetal medicine fellow at the University of Texas Medical Branch, Galveston.

 

The study’s primary outcome measure was a composite of wound complications seen within 6 weeks of delivery, including surgical site infection, whether superficial, deep, or involving an organ or tissue space; cellulitis; seroma or hematoma; and wound separation. Other maternal outcomes tracked in the study included postoperative length of stay, transfusion requirement, sepsis, readmission, and death.

Cesarean-specific secondary outcomes included operative time and time from skin incision to delivery, estimated blood loss, and any incidence of hysterectomy through a low transverse incision. Neonatal outcomes included a 5-minute Apgar score of less than 7, umbilical cord pH of less than 7, and neonatal ICU admissions.

Dr. Mars said that the goal enrollment for the study was 300 patients, to ensure adequate statistical power. However, they found enrollment a challenge, with low consent rates during the defined time period from October 2013 to May 2017. They shifted their statistical technique to a Bayesian analysis, taking into account the estimated probability of treatment benefit.

Using this approach, they found a 59% probability that a Pfannenstiel incision would lead to a lower primary outcome rate – a better result – than would a vertical incision. This result just missed the predetermined threshold of 60%, said Dr. Marrs.

 

Of the 789 women who met the BMI threshold for eligibility assessment, 420 (65%) who passed the screening declined to participate. Of those who consented to participation, an additional 137 women either withdrew consent or failed further screening, leaving 50 women who were randomized to the Pfannenstiel arm and 41 who were randomized to the vertical incision arm.

Baseline characteristics were similar between groups, with a mean maternal age of 30 years in the Pfannenstiel group and 28 years in the vertical incision group. Gestational age at delivery was a mean of 37 weeks in both groups, and mean BMI was 48-50 kg/m².

Most patients (80%-90%) had public insurance. Diabetes was more common in the Pfannenstiel group (48%) than in the vertical incision cohort (32%). Just over 40% of patients were African American.

Two women in the Pfannenstiel group and three in the vertical incision group did not receive the intended incision. After accounting for patients lost to follow-up by 6 weeks, 43 women who received Pfannenstiel and 38 women who received vertical incisions were available for full evaluation.

 

Dr. Marrs said that the study, the first randomized trial to address this issue, had several strengths, including its being conducted at two sites with appropriate stratification for the sites. Also, an independent data safety monitoring board and two chart reviewers helped overcome some of the limitations of a surgical study, where complete blinding is impossible.

The Bayesian analysis allowed ascertainment of the probability of treatment benefit despite the lower-than-hoped-for enrollment numbers. The primary weakness of the study, said Dr. Marrs, centered around the low consent rate, which led to a small study that was prematurely terminated.

“It’s difficult to enroll women in a trial that requires random allocation of skin incision, due to their preference to choose their own incision. A larger trial would likewise be challenging, and unlikely to yield different results,” said Dr. Marrs.

Dr. Marrs reported no conflicts of interest.

 

[email protected]

SOURCE: Marrs CC et al. Am J Obstet Gynecol. 2018 Jan;218:S29.
 

 

DALLAS – No clear winner emerged in a first-ever randomized controlled trial comparing Pfannenstiel with vertical incisions for women with obesity having cesarean delivery, though enrollment difficulties limited study numbers, with almost two-thirds of eligible women declining to participate in the surgical trial.

At 6 weeks postdelivery, 21.1% of women who had a vertical incision experienced wound complications, compared with 18.6% of those who had a Pfannenstiel incision, a nonsignificant difference. This was a smaller difference than was seen at 2 weeks postpartum, when 20% of the vertical incision group had wound complications, compared with 10.4% of those who had a Pfannenstiel, also a nonsignificant difference. Maternal and fetal outcomes didn’t differ significantly with the two surgical approaches.

”We were unable to demonstrate a difference in the primary or secondary outcomes in women with class III obesity who received Pfannenstiel versus vertical skin incision,” said Caroline C. Marrs, MD, presenting the study results at the meeting sponsored by the Society for Maternal-Fetal Medicine.

Though there had been several observational studies comparing vertical with Pfannenstiel incisions for cesarean delivery in women with obesity, no randomized, controlled trials had been conducted, and observational study results were mixed, said Dr. Marrs.

 

Each approach comes with theoretical pros and cons: For women who have a large pannus, the incision site may lie in a moist environment with a low transverse incision, and oxygen tension may be low. However, a Pfannenstiel incision usually will have better cosmesis than will a vertical incision, and generally will result in less postoperative pain.

On the other hand, said Dr. Marrs, vertical incisions can provide improved exposure of the uterus during delivery, and the moist environment underlying the pannus is avoided. However, wound tension may be higher, and subcutaneous thickness is likely to be higher than at the Pfannenstiel incision site.

The study, conducted at two academic medical centers, enrolled women with a body mass index (BMI) of at least 40 kg/m² at a gestational age of 24 weeks or greater who required cesarean delivery. Consenting women were then randomized to receive Pfannenstiel or vertical incisions.

Women who had clinical chorioamnionitis, whose amniotic membranes had been ruptured for 18 hours or more, or who had placenta accreta were excluded. Also excluded were women with a private physician and those desiring vaginal delivery, said Dr. Marrs, a maternal-fetal medicine fellow at the University of Texas Medical Branch, Galveston.

 

The study’s primary outcome measure was a composite of wound complications seen within 6 weeks of delivery, including surgical site infection, whether superficial, deep, or involving an organ or tissue space; cellulitis; seroma or hematoma; and wound separation. Other maternal outcomes tracked in the study included postoperative length of stay, transfusion requirement, sepsis, readmission, and death.

Cesarean-specific secondary outcomes included operative time and time from skin incision to delivery, estimated blood loss, and any incidence of hysterectomy through a low transverse incision. Neonatal outcomes included a 5-minute Apgar score of less than 7, umbilical cord pH of less than 7, and neonatal ICU admissions.

Dr. Mars said that the goal enrollment for the study was 300 patients, to ensure adequate statistical power. However, they found enrollment a challenge, with low consent rates during the defined time period from October 2013 to May 2017. They shifted their statistical technique to a Bayesian analysis, taking into account the estimated probability of treatment benefit.

Using this approach, they found a 59% probability that a Pfannenstiel incision would lead to a lower primary outcome rate – a better result – than would a vertical incision. This result just missed the predetermined threshold of 60%, said Dr. Marrs.

 

Of the 789 women who met the BMI threshold for eligibility assessment, 420 (65%) who passed the screening declined to participate. Of those who consented to participation, an additional 137 women either withdrew consent or failed further screening, leaving 50 women who were randomized to the Pfannenstiel arm and 41 who were randomized to the vertical incision arm.

Baseline characteristics were similar between groups, with a mean maternal age of 30 years in the Pfannenstiel group and 28 years in the vertical incision group. Gestational age at delivery was a mean of 37 weeks in both groups, and mean BMI was 48-50 kg/m².

Most patients (80%-90%) had public insurance. Diabetes was more common in the Pfannenstiel group (48%) than in the vertical incision cohort (32%). Just over 40% of patients were African American.

Two women in the Pfannenstiel group and three in the vertical incision group did not receive the intended incision. After accounting for patients lost to follow-up by 6 weeks, 43 women who received Pfannenstiel and 38 women who received vertical incisions were available for full evaluation.

 

Dr. Marrs said that the study, the first randomized trial to address this issue, had several strengths, including its being conducted at two sites with appropriate stratification for the sites. Also, an independent data safety monitoring board and two chart reviewers helped overcome some of the limitations of a surgical study, where complete blinding is impossible.

The Bayesian analysis allowed ascertainment of the probability of treatment benefit despite the lower-than-hoped-for enrollment numbers. The primary weakness of the study, said Dr. Marrs, centered around the low consent rate, which led to a small study that was prematurely terminated.

“It’s difficult to enroll women in a trial that requires random allocation of skin incision, due to their preference to choose their own incision. A larger trial would likewise be challenging, and unlikely to yield different results,” said Dr. Marrs.

Dr. Marrs reported no conflicts of interest.

 

[email protected]

SOURCE: Marrs CC et al. Am J Obstet Gynecol. 2018 Jan;218:S29.
 

 

DALLAS – No clear winner emerged in a first-ever randomized controlled trial comparing Pfannenstiel with vertical incisions for women with obesity having cesarean delivery, though enrollment difficulties limited study numbers, with almost two-thirds of eligible women declining to participate in the surgical trial.

At 6 weeks postdelivery, 21.1% of women who had a vertical incision experienced wound complications, compared with 18.6% of those who had a Pfannenstiel incision, a nonsignificant difference. This was a smaller difference than was seen at 2 weeks postpartum, when 20% of the vertical incision group had wound complications, compared with 10.4% of those who had a Pfannenstiel, also a nonsignificant difference. Maternal and fetal outcomes didn’t differ significantly with the two surgical approaches.

”We were unable to demonstrate a difference in the primary or secondary outcomes in women with class III obesity who received Pfannenstiel versus vertical skin incision,” said Caroline C. Marrs, MD, presenting the study results at the meeting sponsored by the Society for Maternal-Fetal Medicine.

Though there had been several observational studies comparing vertical with Pfannenstiel incisions for cesarean delivery in women with obesity, no randomized, controlled trials had been conducted, and observational study results were mixed, said Dr. Marrs.

 

Each approach comes with theoretical pros and cons: For women who have a large pannus, the incision site may lie in a moist environment with a low transverse incision, and oxygen tension may be low. However, a Pfannenstiel incision usually will have better cosmesis than will a vertical incision, and generally will result in less postoperative pain.

On the other hand, said Dr. Marrs, vertical incisions can provide improved exposure of the uterus during delivery, and the moist environment underlying the pannus is avoided. However, wound tension may be higher, and subcutaneous thickness is likely to be higher than at the Pfannenstiel incision site.

The study, conducted at two academic medical centers, enrolled women with a body mass index (BMI) of at least 40 kg/m² at a gestational age of 24 weeks or greater who required cesarean delivery. Consenting women were then randomized to receive Pfannenstiel or vertical incisions.

Women who had clinical chorioamnionitis, whose amniotic membranes had been ruptured for 18 hours or more, or who had placenta accreta were excluded. Also excluded were women with a private physician and those desiring vaginal delivery, said Dr. Marrs, a maternal-fetal medicine fellow at the University of Texas Medical Branch, Galveston.

 

The study’s primary outcome measure was a composite of wound complications seen within 6 weeks of delivery, including surgical site infection, whether superficial, deep, or involving an organ or tissue space; cellulitis; seroma or hematoma; and wound separation. Other maternal outcomes tracked in the study included postoperative length of stay, transfusion requirement, sepsis, readmission, and death.

Cesarean-specific secondary outcomes included operative time and time from skin incision to delivery, estimated blood loss, and any incidence of hysterectomy through a low transverse incision. Neonatal outcomes included a 5-minute Apgar score of less than 7, umbilical cord pH of less than 7, and neonatal ICU admissions.

Dr. Mars said that the goal enrollment for the study was 300 patients, to ensure adequate statistical power. However, they found enrollment a challenge, with low consent rates during the defined time period from October 2013 to May 2017. They shifted their statistical technique to a Bayesian analysis, taking into account the estimated probability of treatment benefit.

Using this approach, they found a 59% probability that a Pfannenstiel incision would lead to a lower primary outcome rate – a better result – than would a vertical incision. This result just missed the predetermined threshold of 60%, said Dr. Marrs.

 

Of the 789 women who met the BMI threshold for eligibility assessment, 420 (65%) who passed the screening declined to participate. Of those who consented to participation, an additional 137 women either withdrew consent or failed further screening, leaving 50 women who were randomized to the Pfannenstiel arm and 41 who were randomized to the vertical incision arm.

Baseline characteristics were similar between groups, with a mean maternal age of 30 years in the Pfannenstiel group and 28 years in the vertical incision group. Gestational age at delivery was a mean of 37 weeks in both groups, and mean BMI was 48-50 kg/m².

Most patients (80%-90%) had public insurance. Diabetes was more common in the Pfannenstiel group (48%) than in the vertical incision cohort (32%). Just over 40% of patients were African American.

Two women in the Pfannenstiel group and three in the vertical incision group did not receive the intended incision. After accounting for patients lost to follow-up by 6 weeks, 43 women who received Pfannenstiel and 38 women who received vertical incisions were available for full evaluation.

 

Dr. Marrs said that the study, the first randomized trial to address this issue, had several strengths, including its being conducted at two sites with appropriate stratification for the sites. Also, an independent data safety monitoring board and two chart reviewers helped overcome some of the limitations of a surgical study, where complete blinding is impossible.

The Bayesian analysis allowed ascertainment of the probability of treatment benefit despite the lower-than-hoped-for enrollment numbers. The primary weakness of the study, said Dr. Marrs, centered around the low consent rate, which led to a small study that was prematurely terminated.

“It’s difficult to enroll women in a trial that requires random allocation of skin incision, due to their preference to choose their own incision. A larger trial would likewise be challenging, and unlikely to yield different results,” said Dr. Marrs.

Dr. Marrs reported no conflicts of interest.

 

[email protected]

SOURCE: Marrs CC et al. Am J Obstet Gynecol. 2018 Jan;218:S29.
 

 

For patients with early-stage non–small-cell lung cancer (NSCLC) who had positive margins following lobectomy, additional radiation therapy was not associated with a long-term survival benefit in a recent retrospective study.

Positive margins were associated with significantly worse 5-year survival in the study of patients with stage I-II NSCLC, which was published in the Journal of Surgical Research (2018 Mar. doi: 10.1016/j.jss.2017.10.025).

The study is one of the latest to suggest radiation may not be of benefit for treatment of positive margins after surgical resection of lung cancer, according to Brian C. Gulack, MD, MHS, department of surgery, Duke University, Durham, N.C., and his coauthors.

“Our analysis adds important findings to the literature as it focuses specifically on patients undergoing a lobectomy for stage I or II disease,” they wrote.

 

Adjuvant radiation therapy and re-resection are considered to be two potential treatment options for patients with NSCLC who undergo lobectomy and have positive margins, wrote Dr. Gulack and his coauthors.

However, guidelines from the National Comprehensive Cancer Network recommend re-resection when possible, they added.

The retrospective analysis by Dr. Gulack and his colleagues was based on information in the National Cancer Data Base, which collects data from more than 1,500 hospitals.

The investigators identified 49,563 patients with stage I-II NSCLC who received lobectomy with no induction therapy between 1998 and 2006. Of those patients, 1,934 (3.9%) had positive margins, the authors reported.

 

Five-year survival was 34.5% for patients with reportedly positive margins, versus 57.2% for patients without positive margins, according to results of an unadjusted analysis.

To evaluate the effects of radiotherapy specifically for treatment of positive margins, the investigators excluded patients who had upstaged disease or who had received palliative radiotherapy. Out of the remaining 1,579 patients, 579 (38.2%) received radiation therapy, according to the report.

In that group, there was no significant difference in likelihood of death associated with radiation treatment (hazard ratio, 1.10, 95% confidence interval, 0.90-1.35).

“Despite the importance of these findings, there is still potential for substantial bias in this retrospective study, and therefore prospective investigation is necessary in order to validate our results,” Dr. Gulack and his colleagues concluded.

Study coauthor Thomas A. D’Amico, MD, reported serving as a consultant for Scanlan, and the rest of the authors had no disclosures.

[email protected]

SOURCE: Gulack et al. J Surg Res 2018 March doi: 10.1016/j.jss.2017.10.025.

 

For patients with early-stage non–small-cell lung cancer (NSCLC) who had positive margins following lobectomy, additional radiation therapy was not associated with a long-term survival benefit in a recent retrospective study.

Positive margins were associated with significantly worse 5-year survival in the study of patients with stage I-II NSCLC, which was published in the Journal of Surgical Research (2018 Mar. doi: 10.1016/j.jss.2017.10.025).

The study is one of the latest to suggest radiation may not be of benefit for treatment of positive margins after surgical resection of lung cancer, according to Brian C. Gulack, MD, MHS, department of surgery, Duke University, Durham, N.C., and his coauthors.

“Our analysis adds important findings to the literature as it focuses specifically on patients undergoing a lobectomy for stage I or II disease,” they wrote.

 

Adjuvant radiation therapy and re-resection are considered to be two potential treatment options for patients with NSCLC who undergo lobectomy and have positive margins, wrote Dr. Gulack and his coauthors.

However, guidelines from the National Comprehensive Cancer Network recommend re-resection when possible, they added.

The retrospective analysis by Dr. Gulack and his colleagues was based on information in the National Cancer Data Base, which collects data from more than 1,500 hospitals.

The investigators identified 49,563 patients with stage I-II NSCLC who received lobectomy with no induction therapy between 1998 and 2006. Of those patients, 1,934 (3.9%) had positive margins, the authors reported.

 

Five-year survival was 34.5% for patients with reportedly positive margins, versus 57.2% for patients without positive margins, according to results of an unadjusted analysis.

To evaluate the effects of radiotherapy specifically for treatment of positive margins, the investigators excluded patients who had upstaged disease or who had received palliative radiotherapy. Out of the remaining 1,579 patients, 579 (38.2%) received radiation therapy, according to the report.

In that group, there was no significant difference in likelihood of death associated with radiation treatment (hazard ratio, 1.10, 95% confidence interval, 0.90-1.35).

“Despite the importance of these findings, there is still potential for substantial bias in this retrospective study, and therefore prospective investigation is necessary in order to validate our results,” Dr. Gulack and his colleagues concluded.

Study coauthor Thomas A. D’Amico, MD, reported serving as a consultant for Scanlan, and the rest of the authors had no disclosures.

[email protected]

SOURCE: Gulack et al. J Surg Res 2018 March doi: 10.1016/j.jss.2017.10.025.

 

For patients with early-stage non–small-cell lung cancer (NSCLC) who had positive margins following lobectomy, additional radiation therapy was not associated with a long-term survival benefit in a recent retrospective study.

Positive margins were associated with significantly worse 5-year survival in the study of patients with stage I-II NSCLC, which was published in the Journal of Surgical Research (2018 Mar. doi: 10.1016/j.jss.2017.10.025).

The study is one of the latest to suggest radiation may not be of benefit for treatment of positive margins after surgical resection of lung cancer, according to Brian C. Gulack, MD, MHS, department of surgery, Duke University, Durham, N.C., and his coauthors.

“Our analysis adds important findings to the literature as it focuses specifically on patients undergoing a lobectomy for stage I or II disease,” they wrote.

 

Adjuvant radiation therapy and re-resection are considered to be two potential treatment options for patients with NSCLC who undergo lobectomy and have positive margins, wrote Dr. Gulack and his coauthors.

However, guidelines from the National Comprehensive Cancer Network recommend re-resection when possible, they added.

The retrospective analysis by Dr. Gulack and his colleagues was based on information in the National Cancer Data Base, which collects data from more than 1,500 hospitals.

The investigators identified 49,563 patients with stage I-II NSCLC who received lobectomy with no induction therapy between 1998 and 2006. Of those patients, 1,934 (3.9%) had positive margins, the authors reported.

 

Five-year survival was 34.5% for patients with reportedly positive margins, versus 57.2% for patients without positive margins, according to results of an unadjusted analysis.

To evaluate the effects of radiotherapy specifically for treatment of positive margins, the investigators excluded patients who had upstaged disease or who had received palliative radiotherapy. Out of the remaining 1,579 patients, 579 (38.2%) received radiation therapy, according to the report.

In that group, there was no significant difference in likelihood of death associated with radiation treatment (hazard ratio, 1.10, 95% confidence interval, 0.90-1.35).

“Despite the importance of these findings, there is still potential for substantial bias in this retrospective study, and therefore prospective investigation is necessary in order to validate our results,” Dr. Gulack and his colleagues concluded.

Study coauthor Thomas A. D’Amico, MD, reported serving as a consultant for Scanlan, and the rest of the authors had no disclosures.

[email protected]

SOURCE: Gulack et al. J Surg Res 2018 March doi: 10.1016/j.jss.2017.10.025.

 

LAS VEGAS – Michael J. Gitlin, MD, was 6 months removed from his psychiatry residency in 1980 when, for the first time, a patient he cared for took his own life.

He was a chronically depressed young man receiving medication and psychotherapy, and had one prior suicide attempt, Dr. Gitlin, now professor of psychiatry and biobehavioral sciences at the University of California, Los Angeles, recalled at an annual psychopharmacology update held by the Nevada Psychiatric Association. “One day he came in and intimated that he was going to kill himself, but not in the near future so as to not upset his parents. I scheduled another visit with him in 2 days and told him, ‘If you’re really having trouble, I’ll put you in the hospital.’ ”

The man never showed for that planned visit. Dr. Gitlin telephoned acquaintances and eventually the police, and through the window of his apartment, they observed his dead body. “That was my first experience, where I began to think, ‘what does this do to us as psychiatrists, and how do we deal with it?’ ”

According to Dr. Gitlin, fewer than 25 papers in the medical literature address the topic of how to cope when a patient takes his or her own life. He considers it ironic, because about 42,000 people in the United States die from suicide each year. “Of that 42,000, a reasonable percentage have seen a health professional, and a little lower percentage a mental health professional, within a number of weeks before the suicide happened,” he said. “Probably 10,000 psychiatrists per year will have this experience.”

 

The best available literature on the topic shows that about one in six psychiatrists reports having more than five patient suicides during an entire career. “There are two issues here,” Dr. Gitlin said. “One is, because it’s such an infrequent event, nobody has a big enough series to write about. The other issue is, because it’s so infrequent, nobody learns particularly well how to cope with it. You can’t become an oncologist if you’re really phobic and overwhelmed every time a patient dies. But it happens infrequently enough in psychiatry that nobody really masters a way of coping.”

Younger age and lesser clinical experience are most powerful predictors of distress. In fact, over a 3-year training period, about one-third of psychiatry residents will have a patient commit suicide. “Is that because our young colleagues just don’t know what to do and they’re not as thoughtful and as wise, and have as good a judgment as we have and do?” Dr. Gitlin asked. “Of course not. It’s because we give the most ill patients to the people with the least experience. Residents treat much more psychiatrically ill patients, who therefore have a higher risk of suicide.”

Responses are wide-ranging and are similar to other meaningful losses in life. One study found that about 38% of psychiatrists experience levels of distress in the first few weeks after a patient suicide, which is comparable to that of a clinical population (Am J Psychiatry. 2004;161:1442-6). “If you take those same people and follow them out, that level drops rather precipitously, from 38% to 5% or 10%,” Dr. Gitlin said. “That means that it feels like an acute stress reaction. By 6 months, the effect has faded significantly. One-third of psychiatrists will say that when a patient commits suicide, it affects their personal life to some significant degree, and 15% say they thought about retirement. But if you push them on it, only about 3% think about it seriously.”

Typically, the first stage of response to a patient suicide is denial, which might include an overwhelming feeling of shock or a sense of depersonalization and de-realization, “where there’s a numbness that kind of shuts you down, because the effect is too overwhelming,” he said. Reflecting on the patient who took his own life as Dr. Gitlin was beginning his career, he said, “I didn’t have denial with this young man; I had depersonalization, where for the next few weeks I was at UCLA hanging out with psychiatrists and I felt like there was some film between me and everybody else.

 

“And nobody else in this department of board-certified psychiatrists noticed a damn thing. It was all internal, and it was a striking thing. It’s the only time in my life I’ve ever felt that.”

Other reactions include “core responses” of grief, guilt, shame/fear of blame, anger, and relief. “This is not in a variant sequence and not everybody has every one of these feelings,” he emphasized. “If you’ve been working with this person for any extended period of time, you can get attached to them, so you grieve the loss of a person,” he said.

A loss of hope also can occur. “We all imagine that we’re going to help people; a suicide shoves that notion aside,” Dr. Gitlin said. “But in many ways the biggest grief is what I call loss of influence to make a change. I suspect this is truer for younger psychiatrists than for older ones. Early on in our career we all have this feeling that if we do right, if we take good care of the patients, if we’re kind to them and respect boundaries, and we return phone calls, that good things are going to happen. Then you work very hard taking care of a patient as best you can, and they kill themselves on your watch. That changes the equation.”

Another common response when a patient takes his or her own life is a sense of shame. “Think about the cardiologist who loses a patient from heart disease,” said Dr. Gitlin, who also directs the UCLA Mood Disorders Clinic. “Do they feel bad? I assume so. Do they feel a sense of shame? I suspect not. Why do we feel the shame and embarrassment, and they don’t? Even the most hard-core psychopharmacologists among us really don’t believe that it’s just the technical aspects of treatment that make our patients better. It’s us; it’s our relationship with them. That makes the failure of a patient who dies not a clinical failure, but a personal failure. To me, that is the core reason why suicide feels different from an oncologist losing a patient to a disorder that has a known fatality rate.”

 

A fear of blame, or of being sued, can materialize. So can anger, which can raise complicated questions. For example, are you angry at the patient for committing suicide? Is the family angry? And who are they angry at? Are they angry at you? Are they angry at the hospital? “If it’s in a broader system, let’s say a hospital system, there’s a hierarchy,” Dr. Gitlin said. “Staff could be angry at the ward chief, who could be angry at the attending physician. It can roll downhill. In a complex environment the possibility of projected blame can become a big deal.”

In his opinion, the most important coping technique is to decrease isolation. “In every major religion in the world, when there’s a loss, you rally around the person,” he said. “The rituals of the rallying around differ across cultures and religions, but the rallying around is universal. As humans, we know that it’s much more painful to sit alone with your pain than with the support of family members, friends, loved ones, and community. Find the right person [to confide in]. Not everybody you know will be the right person.”

After the death of a patient from suicide, Dr. Gitlin makes it a point to offer to meet with loved ones. “If you do meet with them, be prepared,” he cautioned. “You don’t know whether the families are a family of interjectors or projectors. Are they going to come in and say, ‘Doctor, thank you so much for doing your best for helping my relative,’ or are they going to come in and say to you, ‘You jerk; my kid died under your care.’ Be prepared for anything that happens in that room.” He also recommends asking the family’s permission to attend the patient’s funeral.

Another helpful coping strategy is to conduct a “psychological autopsy” with colleagues. “Ask what could have been done differently [in the case], not to blame, but to learn,” Dr. Gitlin said. “I have been to some psychological autopsies where it was just ‘Who can be blamed?’ and it was always the youngest person on the totem pole. If the institution can’t get it right psychologically, they shouldn’t do it. That’s more destructive than not doing it at all.”

 

Maintaining professional boundaries with patients also can help you cope. “We don’t want to put so much into our work with our patients that if it goes bad, we get overwhelmingly devastated,” he said. “Finding that middle ground between blurring boundaries and being too detached is something that every mental health professional should do. Distinguishing between clinical and personal failure is critical. I made a decision some time ago that I want to work with people with prominent psychiatric difficulties. We have some difficult patients, but the philosophical and cognitive relief that I give myself when bad things happen is that I say to myself, ‘I chose to work with sick people. Some of them will die of their illness. I’ll save some, but I can’t save them all.’ There’s a natural mortality rate with mood disorders that is related to suicide, just like 5%-10% of anorexics die from anorexia nervosa. That’s the natural mortality rate of the disease.”

Dr. Gitlin ended his presentation by underscoring the importance of establishing support systems in your workplace or teaching institution. For example, he gives lectures to second-year psychiatry residents at UCLA on the topic of psychiatrist reactions to patient suicide, “because I’m giving them the lecture I wish somebody had given me when I was their age. I and others at UCLA make ourselves available to the residents if and when this happens to them.

“Within our field, most training programs do not deal with this issue as forthrightly as they should. It is our job as the grown-ups in the room to make sure that we do it better. We should be talking with the residents early on about it. Every training institution should have a system set up that when it happens, senior residents help junior residents and faculty is available if a resident is really having trouble dealing with it. Some residencies do this well, and others don’t do it at all.”

Dr. Gitlin reported having no financial disclosures.

 

[email protected]

 

LAS VEGAS – Michael J. Gitlin, MD, was 6 months removed from his psychiatry residency in 1980 when, for the first time, a patient he cared for took his own life.

He was a chronically depressed young man receiving medication and psychotherapy, and had one prior suicide attempt, Dr. Gitlin, now professor of psychiatry and biobehavioral sciences at the University of California, Los Angeles, recalled at an annual psychopharmacology update held by the Nevada Psychiatric Association. “One day he came in and intimated that he was going to kill himself, but not in the near future so as to not upset his parents. I scheduled another visit with him in 2 days and told him, ‘If you’re really having trouble, I’ll put you in the hospital.’ ”

The man never showed for that planned visit. Dr. Gitlin telephoned acquaintances and eventually the police, and through the window of his apartment, they observed his dead body. “That was my first experience, where I began to think, ‘what does this do to us as psychiatrists, and how do we deal with it?’ ”

According to Dr. Gitlin, fewer than 25 papers in the medical literature address the topic of how to cope when a patient takes his or her own life. He considers it ironic, because about 42,000 people in the United States die from suicide each year. “Of that 42,000, a reasonable percentage have seen a health professional, and a little lower percentage a mental health professional, within a number of weeks before the suicide happened,” he said. “Probably 10,000 psychiatrists per year will have this experience.”

 

The best available literature on the topic shows that about one in six psychiatrists reports having more than five patient suicides during an entire career. “There are two issues here,” Dr. Gitlin said. “One is, because it’s such an infrequent event, nobody has a big enough series to write about. The other issue is, because it’s so infrequent, nobody learns particularly well how to cope with it. You can’t become an oncologist if you’re really phobic and overwhelmed every time a patient dies. But it happens infrequently enough in psychiatry that nobody really masters a way of coping.”

Younger age and lesser clinical experience are most powerful predictors of distress. In fact, over a 3-year training period, about one-third of psychiatry residents will have a patient commit suicide. “Is that because our young colleagues just don’t know what to do and they’re not as thoughtful and as wise, and have as good a judgment as we have and do?” Dr. Gitlin asked. “Of course not. It’s because we give the most ill patients to the people with the least experience. Residents treat much more psychiatrically ill patients, who therefore have a higher risk of suicide.”

Responses are wide-ranging and are similar to other meaningful losses in life. One study found that about 38% of psychiatrists experience levels of distress in the first few weeks after a patient suicide, which is comparable to that of a clinical population (Am J Psychiatry. 2004;161:1442-6). “If you take those same people and follow them out, that level drops rather precipitously, from 38% to 5% or 10%,” Dr. Gitlin said. “That means that it feels like an acute stress reaction. By 6 months, the effect has faded significantly. One-third of psychiatrists will say that when a patient commits suicide, it affects their personal life to some significant degree, and 15% say they thought about retirement. But if you push them on it, only about 3% think about it seriously.”

Typically, the first stage of response to a patient suicide is denial, which might include an overwhelming feeling of shock or a sense of depersonalization and de-realization, “where there’s a numbness that kind of shuts you down, because the effect is too overwhelming,” he said. Reflecting on the patient who took his own life as Dr. Gitlin was beginning his career, he said, “I didn’t have denial with this young man; I had depersonalization, where for the next few weeks I was at UCLA hanging out with psychiatrists and I felt like there was some film between me and everybody else.

 

“And nobody else in this department of board-certified psychiatrists noticed a damn thing. It was all internal, and it was a striking thing. It’s the only time in my life I’ve ever felt that.”

Other reactions include “core responses” of grief, guilt, shame/fear of blame, anger, and relief. “This is not in a variant sequence and not everybody has every one of these feelings,” he emphasized. “If you’ve been working with this person for any extended period of time, you can get attached to them, so you grieve the loss of a person,” he said.

A loss of hope also can occur. “We all imagine that we’re going to help people; a suicide shoves that notion aside,” Dr. Gitlin said. “But in many ways the biggest grief is what I call loss of influence to make a change. I suspect this is truer for younger psychiatrists than for older ones. Early on in our career we all have this feeling that if we do right, if we take good care of the patients, if we’re kind to them and respect boundaries, and we return phone calls, that good things are going to happen. Then you work very hard taking care of a patient as best you can, and they kill themselves on your watch. That changes the equation.”

Another common response when a patient takes his or her own life is a sense of shame. “Think about the cardiologist who loses a patient from heart disease,” said Dr. Gitlin, who also directs the UCLA Mood Disorders Clinic. “Do they feel bad? I assume so. Do they feel a sense of shame? I suspect not. Why do we feel the shame and embarrassment, and they don’t? Even the most hard-core psychopharmacologists among us really don’t believe that it’s just the technical aspects of treatment that make our patients better. It’s us; it’s our relationship with them. That makes the failure of a patient who dies not a clinical failure, but a personal failure. To me, that is the core reason why suicide feels different from an oncologist losing a patient to a disorder that has a known fatality rate.”

 

A fear of blame, or of being sued, can materialize. So can anger, which can raise complicated questions. For example, are you angry at the patient for committing suicide? Is the family angry? And who are they angry at? Are they angry at you? Are they angry at the hospital? “If it’s in a broader system, let’s say a hospital system, there’s a hierarchy,” Dr. Gitlin said. “Staff could be angry at the ward chief, who could be angry at the attending physician. It can roll downhill. In a complex environment the possibility of projected blame can become a big deal.”

In his opinion, the most important coping technique is to decrease isolation. “In every major religion in the world, when there’s a loss, you rally around the person,” he said. “The rituals of the rallying around differ across cultures and religions, but the rallying around is universal. As humans, we know that it’s much more painful to sit alone with your pain than with the support of family members, friends, loved ones, and community. Find the right person [to confide in]. Not everybody you know will be the right person.”

After the death of a patient from suicide, Dr. Gitlin makes it a point to offer to meet with loved ones. “If you do meet with them, be prepared,” he cautioned. “You don’t know whether the families are a family of interjectors or projectors. Are they going to come in and say, ‘Doctor, thank you so much for doing your best for helping my relative,’ or are they going to come in and say to you, ‘You jerk; my kid died under your care.’ Be prepared for anything that happens in that room.” He also recommends asking the family’s permission to attend the patient’s funeral.

Another helpful coping strategy is to conduct a “psychological autopsy” with colleagues. “Ask what could have been done differently [in the case], not to blame, but to learn,” Dr. Gitlin said. “I have been to some psychological autopsies where it was just ‘Who can be blamed?’ and it was always the youngest person on the totem pole. If the institution can’t get it right psychologically, they shouldn’t do it. That’s more destructive than not doing it at all.”

 

Maintaining professional boundaries with patients also can help you cope. “We don’t want to put so much into our work with our patients that if it goes bad, we get overwhelmingly devastated,” he said. “Finding that middle ground between blurring boundaries and being too detached is something that every mental health professional should do. Distinguishing between clinical and personal failure is critical. I made a decision some time ago that I want to work with people with prominent psychiatric difficulties. We have some difficult patients, but the philosophical and cognitive relief that I give myself when bad things happen is that I say to myself, ‘I chose to work with sick people. Some of them will die of their illness. I’ll save some, but I can’t save them all.’ There’s a natural mortality rate with mood disorders that is related to suicide, just like 5%-10% of anorexics die from anorexia nervosa. That’s the natural mortality rate of the disease.”

Dr. Gitlin ended his presentation by underscoring the importance of establishing support systems in your workplace or teaching institution. For example, he gives lectures to second-year psychiatry residents at UCLA on the topic of psychiatrist reactions to patient suicide, “because I’m giving them the lecture I wish somebody had given me when I was their age. I and others at UCLA make ourselves available to the residents if and when this happens to them.

“Within our field, most training programs do not deal with this issue as forthrightly as they should. It is our job as the grown-ups in the room to make sure that we do it better. We should be talking with the residents early on about it. Every training institution should have a system set up that when it happens, senior residents help junior residents and faculty is available if a resident is really having trouble dealing with it. Some residencies do this well, and others don’t do it at all.”

Dr. Gitlin reported having no financial disclosures.

 

[email protected]

 

LAS VEGAS – Michael J. Gitlin, MD, was 6 months removed from his psychiatry residency in 1980 when, for the first time, a patient he cared for took his own life.

He was a chronically depressed young man receiving medication and psychotherapy, and had one prior suicide attempt, Dr. Gitlin, now professor of psychiatry and biobehavioral sciences at the University of California, Los Angeles, recalled at an annual psychopharmacology update held by the Nevada Psychiatric Association. “One day he came in and intimated that he was going to kill himself, but not in the near future so as to not upset his parents. I scheduled another visit with him in 2 days and told him, ‘If you’re really having trouble, I’ll put you in the hospital.’ ”

The man never showed for that planned visit. Dr. Gitlin telephoned acquaintances and eventually the police, and through the window of his apartment, they observed his dead body. “That was my first experience, where I began to think, ‘what does this do to us as psychiatrists, and how do we deal with it?’ ”

According to Dr. Gitlin, fewer than 25 papers in the medical literature address the topic of how to cope when a patient takes his or her own life. He considers it ironic, because about 42,000 people in the United States die from suicide each year. “Of that 42,000, a reasonable percentage have seen a health professional, and a little lower percentage a mental health professional, within a number of weeks before the suicide happened,” he said. “Probably 10,000 psychiatrists per year will have this experience.”

 

The best available literature on the topic shows that about one in six psychiatrists reports having more than five patient suicides during an entire career. “There are two issues here,” Dr. Gitlin said. “One is, because it’s such an infrequent event, nobody has a big enough series to write about. The other issue is, because it’s so infrequent, nobody learns particularly well how to cope with it. You can’t become an oncologist if you’re really phobic and overwhelmed every time a patient dies. But it happens infrequently enough in psychiatry that nobody really masters a way of coping.”

Younger age and lesser clinical experience are most powerful predictors of distress. In fact, over a 3-year training period, about one-third of psychiatry residents will have a patient commit suicide. “Is that because our young colleagues just don’t know what to do and they’re not as thoughtful and as wise, and have as good a judgment as we have and do?” Dr. Gitlin asked. “Of course not. It’s because we give the most ill patients to the people with the least experience. Residents treat much more psychiatrically ill patients, who therefore have a higher risk of suicide.”

Responses are wide-ranging and are similar to other meaningful losses in life. One study found that about 38% of psychiatrists experience levels of distress in the first few weeks after a patient suicide, which is comparable to that of a clinical population (Am J Psychiatry. 2004;161:1442-6). “If you take those same people and follow them out, that level drops rather precipitously, from 38% to 5% or 10%,” Dr. Gitlin said. “That means that it feels like an acute stress reaction. By 6 months, the effect has faded significantly. One-third of psychiatrists will say that when a patient commits suicide, it affects their personal life to some significant degree, and 15% say they thought about retirement. But if you push them on it, only about 3% think about it seriously.”

Typically, the first stage of response to a patient suicide is denial, which might include an overwhelming feeling of shock or a sense of depersonalization and de-realization, “where there’s a numbness that kind of shuts you down, because the effect is too overwhelming,” he said. Reflecting on the patient who took his own life as Dr. Gitlin was beginning his career, he said, “I didn’t have denial with this young man; I had depersonalization, where for the next few weeks I was at UCLA hanging out with psychiatrists and I felt like there was some film between me and everybody else.

 

“And nobody else in this department of board-certified psychiatrists noticed a damn thing. It was all internal, and it was a striking thing. It’s the only time in my life I’ve ever felt that.”

Other reactions include “core responses” of grief, guilt, shame/fear of blame, anger, and relief. “This is not in a variant sequence and not everybody has every one of these feelings,” he emphasized. “If you’ve been working with this person for any extended period of time, you can get attached to them, so you grieve the loss of a person,” he said.

A loss of hope also can occur. “We all imagine that we’re going to help people; a suicide shoves that notion aside,” Dr. Gitlin said. “But in many ways the biggest grief is what I call loss of influence to make a change. I suspect this is truer for younger psychiatrists than for older ones. Early on in our career we all have this feeling that if we do right, if we take good care of the patients, if we’re kind to them and respect boundaries, and we return phone calls, that good things are going to happen. Then you work very hard taking care of a patient as best you can, and they kill themselves on your watch. That changes the equation.”

Another common response when a patient takes his or her own life is a sense of shame. “Think about the cardiologist who loses a patient from heart disease,” said Dr. Gitlin, who also directs the UCLA Mood Disorders Clinic. “Do they feel bad? I assume so. Do they feel a sense of shame? I suspect not. Why do we feel the shame and embarrassment, and they don’t? Even the most hard-core psychopharmacologists among us really don’t believe that it’s just the technical aspects of treatment that make our patients better. It’s us; it’s our relationship with them. That makes the failure of a patient who dies not a clinical failure, but a personal failure. To me, that is the core reason why suicide feels different from an oncologist losing a patient to a disorder that has a known fatality rate.”

 

A fear of blame, or of being sued, can materialize. So can anger, which can raise complicated questions. For example, are you angry at the patient for committing suicide? Is the family angry? And who are they angry at? Are they angry at you? Are they angry at the hospital? “If it’s in a broader system, let’s say a hospital system, there’s a hierarchy,” Dr. Gitlin said. “Staff could be angry at the ward chief, who could be angry at the attending physician. It can roll downhill. In a complex environment the possibility of projected blame can become a big deal.”

In his opinion, the most important coping technique is to decrease isolation. “In every major religion in the world, when there’s a loss, you rally around the person,” he said. “The rituals of the rallying around differ across cultures and religions, but the rallying around is universal. As humans, we know that it’s much more painful to sit alone with your pain than with the support of family members, friends, loved ones, and community. Find the right person [to confide in]. Not everybody you know will be the right person.”

After the death of a patient from suicide, Dr. Gitlin makes it a point to offer to meet with loved ones. “If you do meet with them, be prepared,” he cautioned. “You don’t know whether the families are a family of interjectors or projectors. Are they going to come in and say, ‘Doctor, thank you so much for doing your best for helping my relative,’ or are they going to come in and say to you, ‘You jerk; my kid died under your care.’ Be prepared for anything that happens in that room.” He also recommends asking the family’s permission to attend the patient’s funeral.

Another helpful coping strategy is to conduct a “psychological autopsy” with colleagues. “Ask what could have been done differently [in the case], not to blame, but to learn,” Dr. Gitlin said. “I have been to some psychological autopsies where it was just ‘Who can be blamed?’ and it was always the youngest person on the totem pole. If the institution can’t get it right psychologically, they shouldn’t do it. That’s more destructive than not doing it at all.”

 

Maintaining professional boundaries with patients also can help you cope. “We don’t want to put so much into our work with our patients that if it goes bad, we get overwhelmingly devastated,” he said. “Finding that middle ground between blurring boundaries and being too detached is something that every mental health professional should do. Distinguishing between clinical and personal failure is critical. I made a decision some time ago that I want to work with people with prominent psychiatric difficulties. We have some difficult patients, but the philosophical and cognitive relief that I give myself when bad things happen is that I say to myself, ‘I chose to work with sick people. Some of them will die of their illness. I’ll save some, but I can’t save them all.’ There’s a natural mortality rate with mood disorders that is related to suicide, just like 5%-10% of anorexics die from anorexia nervosa. That’s the natural mortality rate of the disease.”

Dr. Gitlin ended his presentation by underscoring the importance of establishing support systems in your workplace or teaching institution. For example, he gives lectures to second-year psychiatry residents at UCLA on the topic of psychiatrist reactions to patient suicide, “because I’m giving them the lecture I wish somebody had given me when I was their age. I and others at UCLA make ourselves available to the residents if and when this happens to them.

“Within our field, most training programs do not deal with this issue as forthrightly as they should. It is our job as the grown-ups in the room to make sure that we do it better. We should be talking with the residents early on about it. Every training institution should have a system set up that when it happens, senior residents help junior residents and faculty is available if a resident is really having trouble dealing with it. Some residencies do this well, and others don’t do it at all.”

Dr. Gitlin reported having no financial disclosures.

 

[email protected]

 

SAN ANTONIO – When corticosteroids are used for septic shock, the dose should be low to moderate, the timing should be early, and the duration should be at least 3 days, said a speaker at the Critical Care Congress sponsored by the Society for Critical Care.

Dosing, timing, and duration are “three critical questions” critical care specialists face that are answered by the new critical illness–related corticosteroid insufficiency (CIRCI) guidelines, continued Stephen M. Pastores, MD, a cochair of the task force that developed guidelines for the diagnosis and management of CIRCI in critically ill patients.

Andrew D. Bowser/Frontline Medical News

The recently published guidelines come in two parts. The first takes into account the most current evidence on the use of corticosteroids in disorders that most clinicians associate with CIRCI, including sepsis/septic shock, acute respiratory distress syndrome, and major trauma (Crit Care Med. 2017 Dec;45[12]:2078-88). Part two of the guidelines, published separately, covers other syndromes, such as influenza, meningitis, burns, and other conditions that at least 80% of the task force members agreed were associated with CIRCI (Crit Care Med. 2018 Jan;46[1]:146-148).

During his presentation, Dr. Pastores limited his remarks to discussion of sepsis and septic shock with corticosteroids. He cautioned that, despite careful deliberations by the panel, the level of evidence behind some of the recommendations was “low to moderate and never high” and that not all task force members agreed with all recommendations.

 

“There were a lot of back and forth disagreements behind these recommendations,” said Dr. Pastores, who is the director of the critical care medicine fellowship training and research programs at Memorial Sloan Kettering Cancer Center, New York. “We only required 80% of the panelists to agree that these were the recommendations and statements that we were going to go by.”

The guidelines recommend against the use of corticosteroids in adult patients who have sepsis without shock, Dr. Pastores noted.

In contrast, the guidelines do suggest using corticosteroids for hospitalized adults patients with septic shock that is not responsive to fluid and moderate- to high-dose vasopressor therapy.

In an analysis of available data from randomized clinical trials including patients with septic shock, corticosteroids significantly reduced 28-day mortality when compared with placebo, Dr. Pastores said.

 

That survival benefit seems to be dependent on several factors: dose of the corticosteroids (hydrocortisone less than 400 mg/day), longer duration (at least 3 or more days), and severity of sepsis. “The more severe the sepsis, the more septic shock the patient was in, the more likely the corticosteroids were likely to help those patients,” Dr. Pastores explained.

Accordingly, the guidelines further suggest using long-course, low-dose corticosteroid treatment, namely intravenous hydrocortisone at no more than 400 mg/day for at least 3 days.

The expert panel specifically recommended hydrocortisone as the corticosteroid of choice in this setting, according to Dr. Pastores. That recommendation was based in part on a recent systematic review and meta-analysis showing that hydrocortisone, given as a bolus or an infusion, was more likely than placebo or methylprednisolone to result in shock reversal.

Dr. Pastores reported disclosures related to Theravance Biopharma, Bayer HealthCare Pharmaceuticals, Spectral Diagnostics, and Asahi-Kasei.

[email protected]

 

SAN ANTONIO – When corticosteroids are used for septic shock, the dose should be low to moderate, the timing should be early, and the duration should be at least 3 days, said a speaker at the Critical Care Congress sponsored by the Society for Critical Care.

Dosing, timing, and duration are “three critical questions” critical care specialists face that are answered by the new critical illness–related corticosteroid insufficiency (CIRCI) guidelines, continued Stephen M. Pastores, MD, a cochair of the task force that developed guidelines for the diagnosis and management of CIRCI in critically ill patients.

Andrew D. Bowser/Frontline Medical News

The recently published guidelines come in two parts. The first takes into account the most current evidence on the use of corticosteroids in disorders that most clinicians associate with CIRCI, including sepsis/septic shock, acute respiratory distress syndrome, and major trauma (Crit Care Med. 2017 Dec;45[12]:2078-88). Part two of the guidelines, published separately, covers other syndromes, such as influenza, meningitis, burns, and other conditions that at least 80% of the task force members agreed were associated with CIRCI (Crit Care Med. 2018 Jan;46[1]:146-148).

During his presentation, Dr. Pastores limited his remarks to discussion of sepsis and septic shock with corticosteroids. He cautioned that, despite careful deliberations by the panel, the level of evidence behind some of the recommendations was “low to moderate and never high” and that not all task force members agreed with all recommendations.

 

“There were a lot of back and forth disagreements behind these recommendations,” said Dr. Pastores, who is the director of the critical care medicine fellowship training and research programs at Memorial Sloan Kettering Cancer Center, New York. “We only required 80% of the panelists to agree that these were the recommendations and statements that we were going to go by.”

The guidelines recommend against the use of corticosteroids in adult patients who have sepsis without shock, Dr. Pastores noted.

In contrast, the guidelines do suggest using corticosteroids for hospitalized adults patients with septic shock that is not responsive to fluid and moderate- to high-dose vasopressor therapy.

In an analysis of available data from randomized clinical trials including patients with septic shock, corticosteroids significantly reduced 28-day mortality when compared with placebo, Dr. Pastores said.

 

That survival benefit seems to be dependent on several factors: dose of the corticosteroids (hydrocortisone less than 400 mg/day), longer duration (at least 3 or more days), and severity of sepsis. “The more severe the sepsis, the more septic shock the patient was in, the more likely the corticosteroids were likely to help those patients,” Dr. Pastores explained.

Accordingly, the guidelines further suggest using long-course, low-dose corticosteroid treatment, namely intravenous hydrocortisone at no more than 400 mg/day for at least 3 days.

The expert panel specifically recommended hydrocortisone as the corticosteroid of choice in this setting, according to Dr. Pastores. That recommendation was based in part on a recent systematic review and meta-analysis showing that hydrocortisone, given as a bolus or an infusion, was more likely than placebo or methylprednisolone to result in shock reversal.

Dr. Pastores reported disclosures related to Theravance Biopharma, Bayer HealthCare Pharmaceuticals, Spectral Diagnostics, and Asahi-Kasei.

[email protected]

 

SAN ANTONIO – When corticosteroids are used for septic shock, the dose should be low to moderate, the timing should be early, and the duration should be at least 3 days, said a speaker at the Critical Care Congress sponsored by the Society for Critical Care.

Dosing, timing, and duration are “three critical questions” critical care specialists face that are answered by the new critical illness–related corticosteroid insufficiency (CIRCI) guidelines, continued Stephen M. Pastores, MD, a cochair of the task force that developed guidelines for the diagnosis and management of CIRCI in critically ill patients.

Andrew D. Bowser/Frontline Medical News

The recently published guidelines come in two parts. The first takes into account the most current evidence on the use of corticosteroids in disorders that most clinicians associate with CIRCI, including sepsis/septic shock, acute respiratory distress syndrome, and major trauma (Crit Care Med. 2017 Dec;45[12]:2078-88). Part two of the guidelines, published separately, covers other syndromes, such as influenza, meningitis, burns, and other conditions that at least 80% of the task force members agreed were associated with CIRCI (Crit Care Med. 2018 Jan;46[1]:146-148).

During his presentation, Dr. Pastores limited his remarks to discussion of sepsis and septic shock with corticosteroids. He cautioned that, despite careful deliberations by the panel, the level of evidence behind some of the recommendations was “low to moderate and never high” and that not all task force members agreed with all recommendations.

 

“There were a lot of back and forth disagreements behind these recommendations,” said Dr. Pastores, who is the director of the critical care medicine fellowship training and research programs at Memorial Sloan Kettering Cancer Center, New York. “We only required 80% of the panelists to agree that these were the recommendations and statements that we were going to go by.”

The guidelines recommend against the use of corticosteroids in adult patients who have sepsis without shock, Dr. Pastores noted.

In contrast, the guidelines do suggest using corticosteroids for hospitalized adults patients with septic shock that is not responsive to fluid and moderate- to high-dose vasopressor therapy.

In an analysis of available data from randomized clinical trials including patients with septic shock, corticosteroids significantly reduced 28-day mortality when compared with placebo, Dr. Pastores said.

 

That survival benefit seems to be dependent on several factors: dose of the corticosteroids (hydrocortisone less than 400 mg/day), longer duration (at least 3 or more days), and severity of sepsis. “The more severe the sepsis, the more septic shock the patient was in, the more likely the corticosteroids were likely to help those patients,” Dr. Pastores explained.

Accordingly, the guidelines further suggest using long-course, low-dose corticosteroid treatment, namely intravenous hydrocortisone at no more than 400 mg/day for at least 3 days.

The expert panel specifically recommended hydrocortisone as the corticosteroid of choice in this setting, according to Dr. Pastores. That recommendation was based in part on a recent systematic review and meta-analysis showing that hydrocortisone, given as a bolus or an infusion, was more likely than placebo or methylprednisolone to result in shock reversal.

Dr. Pastores reported disclosures related to Theravance Biopharma, Bayer HealthCare Pharmaceuticals, Spectral Diagnostics, and Asahi-Kasei.

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