ATLANTA – For patients with locally advanced head and neck squamous cell carcinomas positive for human papillomavirus type 16, neoadjuvant therapy with the immune checkpoint inhibitor nivolumab combined with stereotactic body radiation therapy (SBRT) was associated with high response rates and a lower toxicity profile compared with the current standard of care, results of a phase 1/1b study suggest.

Neil Osterweil/MDedge News

All of five patients treated with SBRT doses of 8 Gy per day for 5 days (40 Gy total) had pathologic complete responses (pCR), as did four of five patients treated at a deescalated SBRT dose of 8 Gy on alternating days for 3 days (24 Gy total), reported Rom S. Leidner, MD, of Providence Cancer Center in Portland, Ore.

“We’ve met the primary endpoint. This approach certainly was safe as far as not preventing definitive surgery. The potency was much greater than expected, with a pCR rate of 90% and a major response in 100% of patients,” he said at the annual meeting of the American Association for Cancer Research.

Dr. Leidner and colleagues are investigating therapies for locally advanced HPV-associated head and neck squamous cell carcinoma (HNSCC) that are as effective as but less toxic than the current standard of care: definitive chemoradiotherapy or surgery followed by risk-adapted adjuvant radiotherapy with or without chemotherapy.

They enrolled 10 patients, all men, with a mean age of 64.5 years. Seven patients had HPV16-positive oropharyngeal HNSCC, and three had unknown primary HNSCC (HPV-positive lymph nodes in the neck without an identifiable mucosal primary site). All patients had clinical indications for adjuvant radiotherapy or upfront transoral robotic surgery (TORS) but were ineligible because of tumor size.

The patients were assigned to one of two dose-finding cohorts in groups of five each to receive nivolumab (Opdivo) 240 mg intravenously every other week for three cycles prior to surgery, with SBRT to gross tumor volume plus 3 mm delivered between the first and second doses of nivolumab.

One cohort of patients received SBRT 8 Gy daily for 5 consecutive days (Monday-Friday), and the other received deescalated SBRT 8 Gy delivered on alternating days (Monday, Wednesday, Friday).

Patients underwent surgery 5 weeks after SBRT, and 4 weeks after surgery were started on adjuvant nivolumab 480 mg IV every 4 weeks for three cycles.

The trial met its primary endpoint of fewer than one-third of patients having an unplanned surgical delay. None of the 10 patients required a surgical delay, in fact.

Although all patients had radiologic evidence of tumor shrinkage prior to surgery, there were no complete responses according to Response Criteria in Solid Tumors (RECIST, version 1.1). Seven patients had a partial response (PR), and three had stable disease.

Dr. Leidner noted that when a patient with stable disease according to RECIST went to surgery “we found a [pCR] in the primary site, and residual cancer in the neck nodes with less than 10% viable tumor cells and evidence of immune eradication.”

As noted, all five patients in the 40-Gy dose group had complete pathologic responses, as did four of the five patients in the deescalated dose group. The remaining patient in this group had a major pathologic response, with less than 10% residual tumor.

“The secondary tissue endpoint far exceeded our expectations on this trial,” Dr. Leidner said.

There were no reports of acute toxicity in the neoadjuvant phase, but delayed mucositis (grade 1 or 2) and immune-related grade 1 dermatologic and rhinitis events were seen. Mucositis resolved by week 4 in all patients, at least 2 weeks before surgery.

Postoperative delayed toxicities up to grade 3 were seen, with delays in mucosal healing in patients who underwent mucosal resections; there were no cases of delayed healing among patients who underwent neck dissection only.

Grade 3 oropharyngeal pain requiring opiates for more than 4 weeks after surgery was seen in both cohorts, but lasted longer among patients in the 8-Gy-times-5 cohort.

Half of all patients were found to have adrenal insufficiency, a rate higher than that previously reported with the use of anti-PD-1 immune checkpoint inhibitors in HNSCC, Dr. Leidner said.

“Clinically we’re seeing, as one might expect, substantially reduced xerostomia and ageusia, but that was not formally measured,” he said.

Based on the study findings, investigations are proceeding at the deescalated dose.

Neil Osterweil/MDedge News

Invited discussant Christine H. Chung, MD, of H. Lee Moffitt Cancer Center and Research Institute in Tampa, did not appear to share Dr. Leidner’s enthusiasm for the approach, saying that “overall, path CR in already resectable patients with an extremely high cure rate may not be clinically meaningful.”

She said that the role of adjuvant nivolumab following neoadjuvant nivolumab, radiotherapy, and surgery in HPV-positive patients is unclear, and that “the approach may be more suitable for HPV-negative patients with poor prognosis and in need of treatment intensification.”

Providence Cancer Center sponsored the study. Dr. Leidner reported having no relevant disclosures. Dr. Chung reported research funding from Lilly Oncology, and advisory board honoraria from BMS, CUE, and Ignyta.

SOURCE: Leidner RS et al. AACR 2019, Abstract CT182.

ATLANTA – For patients with locally advanced head and neck squamous cell carcinomas positive for human papillomavirus type 16, neoadjuvant therapy with the immune checkpoint inhibitor nivolumab combined with stereotactic body radiation therapy (SBRT) was associated with high response rates and a lower toxicity profile compared with the current standard of care, results of a phase 1/1b study suggest.

Neil Osterweil/MDedge News

All of five patients treated with SBRT doses of 8 Gy per day for 5 days (40 Gy total) had pathologic complete responses (pCR), as did four of five patients treated at a deescalated SBRT dose of 8 Gy on alternating days for 3 days (24 Gy total), reported Rom S. Leidner, MD, of Providence Cancer Center in Portland, Ore.

“We’ve met the primary endpoint. This approach certainly was safe as far as not preventing definitive surgery. The potency was much greater than expected, with a pCR rate of 90% and a major response in 100% of patients,” he said at the annual meeting of the American Association for Cancer Research.

Dr. Leidner and colleagues are investigating therapies for locally advanced HPV-associated head and neck squamous cell carcinoma (HNSCC) that are as effective as but less toxic than the current standard of care: definitive chemoradiotherapy or surgery followed by risk-adapted adjuvant radiotherapy with or without chemotherapy.

They enrolled 10 patients, all men, with a mean age of 64.5 years. Seven patients had HPV16-positive oropharyngeal HNSCC, and three had unknown primary HNSCC (HPV-positive lymph nodes in the neck without an identifiable mucosal primary site). All patients had clinical indications for adjuvant radiotherapy or upfront transoral robotic surgery (TORS) but were ineligible because of tumor size.

The patients were assigned to one of two dose-finding cohorts in groups of five each to receive nivolumab (Opdivo) 240 mg intravenously every other week for three cycles prior to surgery, with SBRT to gross tumor volume plus 3 mm delivered between the first and second doses of nivolumab.

One cohort of patients received SBRT 8 Gy daily for 5 consecutive days (Monday-Friday), and the other received deescalated SBRT 8 Gy delivered on alternating days (Monday, Wednesday, Friday).

Patients underwent surgery 5 weeks after SBRT, and 4 weeks after surgery were started on adjuvant nivolumab 480 mg IV every 4 weeks for three cycles.

The trial met its primary endpoint of fewer than one-third of patients having an unplanned surgical delay. None of the 10 patients required a surgical delay, in fact.

Although all patients had radiologic evidence of tumor shrinkage prior to surgery, there were no complete responses according to Response Criteria in Solid Tumors (RECIST, version 1.1). Seven patients had a partial response (PR), and three had stable disease.

Dr. Leidner noted that when a patient with stable disease according to RECIST went to surgery “we found a [pCR] in the primary site, and residual cancer in the neck nodes with less than 10% viable tumor cells and evidence of immune eradication.”

As noted, all five patients in the 40-Gy dose group had complete pathologic responses, as did four of the five patients in the deescalated dose group. The remaining patient in this group had a major pathologic response, with less than 10% residual tumor.

“The secondary tissue endpoint far exceeded our expectations on this trial,” Dr. Leidner said.

There were no reports of acute toxicity in the neoadjuvant phase, but delayed mucositis (grade 1 or 2) and immune-related grade 1 dermatologic and rhinitis events were seen. Mucositis resolved by week 4 in all patients, at least 2 weeks before surgery.

Postoperative delayed toxicities up to grade 3 were seen, with delays in mucosal healing in patients who underwent mucosal resections; there were no cases of delayed healing among patients who underwent neck dissection only.

Grade 3 oropharyngeal pain requiring opiates for more than 4 weeks after surgery was seen in both cohorts, but lasted longer among patients in the 8-Gy-times-5 cohort.

Half of all patients were found to have adrenal insufficiency, a rate higher than that previously reported with the use of anti-PD-1 immune checkpoint inhibitors in HNSCC, Dr. Leidner said.

“Clinically we’re seeing, as one might expect, substantially reduced xerostomia and ageusia, but that was not formally measured,” he said.

Based on the study findings, investigations are proceeding at the deescalated dose.

Neil Osterweil/MDedge News

Invited discussant Christine H. Chung, MD, of H. Lee Moffitt Cancer Center and Research Institute in Tampa, did not appear to share Dr. Leidner’s enthusiasm for the approach, saying that “overall, path CR in already resectable patients with an extremely high cure rate may not be clinically meaningful.”

She said that the role of adjuvant nivolumab following neoadjuvant nivolumab, radiotherapy, and surgery in HPV-positive patients is unclear, and that “the approach may be more suitable for HPV-negative patients with poor prognosis and in need of treatment intensification.”

Providence Cancer Center sponsored the study. Dr. Leidner reported having no relevant disclosures. Dr. Chung reported research funding from Lilly Oncology, and advisory board honoraria from BMS, CUE, and Ignyta.

SOURCE: Leidner RS et al. AACR 2019, Abstract CT182.

ATLANTA – For patients with locally advanced head and neck squamous cell carcinomas positive for human papillomavirus type 16, neoadjuvant therapy with the immune checkpoint inhibitor nivolumab combined with stereotactic body radiation therapy (SBRT) was associated with high response rates and a lower toxicity profile compared with the current standard of care, results of a phase 1/1b study suggest.

Neil Osterweil/MDedge News

All of five patients treated with SBRT doses of 8 Gy per day for 5 days (40 Gy total) had pathologic complete responses (pCR), as did four of five patients treated at a deescalated SBRT dose of 8 Gy on alternating days for 3 days (24 Gy total), reported Rom S. Leidner, MD, of Providence Cancer Center in Portland, Ore.

“We’ve met the primary endpoint. This approach certainly was safe as far as not preventing definitive surgery. The potency was much greater than expected, with a pCR rate of 90% and a major response in 100% of patients,” he said at the annual meeting of the American Association for Cancer Research.

Dr. Leidner and colleagues are investigating therapies for locally advanced HPV-associated head and neck squamous cell carcinoma (HNSCC) that are as effective as but less toxic than the current standard of care: definitive chemoradiotherapy or surgery followed by risk-adapted adjuvant radiotherapy with or without chemotherapy.

They enrolled 10 patients, all men, with a mean age of 64.5 years. Seven patients had HPV16-positive oropharyngeal HNSCC, and three had unknown primary HNSCC (HPV-positive lymph nodes in the neck without an identifiable mucosal primary site). All patients had clinical indications for adjuvant radiotherapy or upfront transoral robotic surgery (TORS) but were ineligible because of tumor size.

The patients were assigned to one of two dose-finding cohorts in groups of five each to receive nivolumab (Opdivo) 240 mg intravenously every other week for three cycles prior to surgery, with SBRT to gross tumor volume plus 3 mm delivered between the first and second doses of nivolumab.

One cohort of patients received SBRT 8 Gy daily for 5 consecutive days (Monday-Friday), and the other received deescalated SBRT 8 Gy delivered on alternating days (Monday, Wednesday, Friday).

Patients underwent surgery 5 weeks after SBRT, and 4 weeks after surgery were started on adjuvant nivolumab 480 mg IV every 4 weeks for three cycles.

The trial met its primary endpoint of fewer than one-third of patients having an unplanned surgical delay. None of the 10 patients required a surgical delay, in fact.

Although all patients had radiologic evidence of tumor shrinkage prior to surgery, there were no complete responses according to Response Criteria in Solid Tumors (RECIST, version 1.1). Seven patients had a partial response (PR), and three had stable disease.

Dr. Leidner noted that when a patient with stable disease according to RECIST went to surgery “we found a [pCR] in the primary site, and residual cancer in the neck nodes with less than 10% viable tumor cells and evidence of immune eradication.”

As noted, all five patients in the 40-Gy dose group had complete pathologic responses, as did four of the five patients in the deescalated dose group. The remaining patient in this group had a major pathologic response, with less than 10% residual tumor.

“The secondary tissue endpoint far exceeded our expectations on this trial,” Dr. Leidner said.

There were no reports of acute toxicity in the neoadjuvant phase, but delayed mucositis (grade 1 or 2) and immune-related grade 1 dermatologic and rhinitis events were seen. Mucositis resolved by week 4 in all patients, at least 2 weeks before surgery.

Postoperative delayed toxicities up to grade 3 were seen, with delays in mucosal healing in patients who underwent mucosal resections; there were no cases of delayed healing among patients who underwent neck dissection only.

Grade 3 oropharyngeal pain requiring opiates for more than 4 weeks after surgery was seen in both cohorts, but lasted longer among patients in the 8-Gy-times-5 cohort.

Half of all patients were found to have adrenal insufficiency, a rate higher than that previously reported with the use of anti-PD-1 immune checkpoint inhibitors in HNSCC, Dr. Leidner said.

“Clinically we’re seeing, as one might expect, substantially reduced xerostomia and ageusia, but that was not formally measured,” he said.

Based on the study findings, investigations are proceeding at the deescalated dose.

Neil Osterweil/MDedge News

Invited discussant Christine H. Chung, MD, of H. Lee Moffitt Cancer Center and Research Institute in Tampa, did not appear to share Dr. Leidner’s enthusiasm for the approach, saying that “overall, path CR in already resectable patients with an extremely high cure rate may not be clinically meaningful.”

She said that the role of adjuvant nivolumab following neoadjuvant nivolumab, radiotherapy, and surgery in HPV-positive patients is unclear, and that “the approach may be more suitable for HPV-negative patients with poor prognosis and in need of treatment intensification.”

Providence Cancer Center sponsored the study. Dr. Leidner reported having no relevant disclosures. Dr. Chung reported research funding from Lilly Oncology, and advisory board honoraria from BMS, CUE, and Ignyta.

SOURCE: Leidner RS et al. AACR 2019, Abstract CT182.

BALTIMORE – The Eckardt score has been established as a tool to evaluate outcomes of surgery for achalasia, but researchers have developed a report card that uses multiple variables that may provide a more accurate picture of surgical outcomes, according to results of study reported at the annual meeting of the Society of American Gastrointestinal Endoscopic Surgeons.

“The use of an accurate score to assess outcomes after achalasia surgery shows outstanding results,” said Ealaf Shemmeri, MD, of Swedish Medical Center in Seattle. “Using patient-reported symptoms, objective measures, and rates of reinterventions organized into a report card provides a more comprehensive and informative view.”

The Eckardt score evaluates four symptoms to evaluate outcomes of surgery to treat achalasia: weight loss, retrosternal pain, regurgitation, and dysphagia. “However, it does not address the other changes that can occur after myotomy, including the quality of swallowing and the onset of reflux disease,” she said. “Thus, there is a need for a more comprehensive assessment of quality after achalasia treatment.”

So the Swedish investigators set out to devise a report card that provides “a comprehensive and informative assessment” of surgical myotomy outcomes, she said. This involved a retrospective, single-center chart review of 185 patients who had surgical myotomy for primary achalasia from 2005 to 2017.

To determine patient-reported outcomes, the report card defines success as an Eckardt score below 3, Dakkak dysphagia score above 40, and GERD-HRQL (health-related quality of life) score below 10. The objective measures consisted of DeMeester (pH) score below 14.72, no column at 5 minutes on timed barium swallow, normalized integrated relaxation pressure less than 15 on manometry, and absence of esophagitis on endoscopy. For the third pillar of the report card, no reintervention was recorded as a success, Dr. Shemmeri said.

Regarding the etiology of achalasia in the study population, 42 had type 1, 109 had type 2, and 34 had type 3. A total of 71 patients had per oral endoscopic myotomy and 114 had Heller myotomy, 92 with Dor fundoplication and 20 with Toupet. Major perioperative complications included four per oral endoscopic myotomy patients who developed a leak requiring intervention. Six patients required return to the operating room for persistent dysphagia, Dr. Shemmeri said.

After the procedures, 93% of study patients reported an Eckardt score less than 3. However, only 45% have a Dakkak dysphagia score greater than 40 and 71% had a GERD-HRQL score less than 10, Dr. Shemmeri said. The objective measures told a similar story: Integrated relaxation pressure normalized in 80%, barium clearance was achieved in 61%, normal esophageal mucosa was recorded in 71%, “but pH testing was normal only 50% of the time,” Dr. Shemmeri said.

“The final success of not needing intervention is 79%,” she said. At this point in the study, 139 patients were available for follow-up. Among the 29 who needed reintervention, 19 had dilation below 20 mm Hg, 3 underwent pneumatic dilation, and 2 had botulinum toxin. Two patients required a redo myotomy, two had antireflux surgery, and one had an esophagectomy.

“When you only focus on a singular outcome, you can miss the whole story that occurs after myotomy,” Dr. Shemmeri said. “Providing a comprehensive tool gives you the ability to identify areas for improvement in your achalasia practice. Its simplicity allows it to be applied in various settings.” In the academic setting, it can be a tool for evaluating technologies and approaches for postmyotomy management. In hospitals and surgeons’ practices, it can aid in quality improvement, comparative outcomes research, and in evaluating operative approaches to myotomy.

The outcomes highlight the high prevalence of GERD, thus stressing the importance of pH testing after myotomy, Dr. Shemmeri said. Her study team recommends pH testing at 6-month follow-up because patients may not always self-report the extent of esophagitis present. Coauthor Brian Louie, MD, also of Swedish Medical Center, added during the discussion that ongoing follow-up of achalasia patients is necessary to address issues patients encounter with their swallowing over time.

Dr. Shemmeri had no relevant financial relationships to disclose. Dr. Louie reported relationships with Boston Scientific, ERBE, and Olympus.

SOURCE: Shemmeri E et al. SAGES 2019, Presentation S085.

BALTIMORE – The Eckardt score has been established as a tool to evaluate outcomes of surgery for achalasia, but researchers have developed a report card that uses multiple variables that may provide a more accurate picture of surgical outcomes, according to results of study reported at the annual meeting of the Society of American Gastrointestinal Endoscopic Surgeons.

“The use of an accurate score to assess outcomes after achalasia surgery shows outstanding results,” said Ealaf Shemmeri, MD, of Swedish Medical Center in Seattle. “Using patient-reported symptoms, objective measures, and rates of reinterventions organized into a report card provides a more comprehensive and informative view.”

The Eckardt score evaluates four symptoms to evaluate outcomes of surgery to treat achalasia: weight loss, retrosternal pain, regurgitation, and dysphagia. “However, it does not address the other changes that can occur after myotomy, including the quality of swallowing and the onset of reflux disease,” she said. “Thus, there is a need for a more comprehensive assessment of quality after achalasia treatment.”

So the Swedish investigators set out to devise a report card that provides “a comprehensive and informative assessment” of surgical myotomy outcomes, she said. This involved a retrospective, single-center chart review of 185 patients who had surgical myotomy for primary achalasia from 2005 to 2017.

To determine patient-reported outcomes, the report card defines success as an Eckardt score below 3, Dakkak dysphagia score above 40, and GERD-HRQL (health-related quality of life) score below 10. The objective measures consisted of DeMeester (pH) score below 14.72, no column at 5 minutes on timed barium swallow, normalized integrated relaxation pressure less than 15 on manometry, and absence of esophagitis on endoscopy. For the third pillar of the report card, no reintervention was recorded as a success, Dr. Shemmeri said.

Regarding the etiology of achalasia in the study population, 42 had type 1, 109 had type 2, and 34 had type 3. A total of 71 patients had per oral endoscopic myotomy and 114 had Heller myotomy, 92 with Dor fundoplication and 20 with Toupet. Major perioperative complications included four per oral endoscopic myotomy patients who developed a leak requiring intervention. Six patients required return to the operating room for persistent dysphagia, Dr. Shemmeri said.

After the procedures, 93% of study patients reported an Eckardt score less than 3. However, only 45% have a Dakkak dysphagia score greater than 40 and 71% had a GERD-HRQL score less than 10, Dr. Shemmeri said. The objective measures told a similar story: Integrated relaxation pressure normalized in 80%, barium clearance was achieved in 61%, normal esophageal mucosa was recorded in 71%, “but pH testing was normal only 50% of the time,” Dr. Shemmeri said.

“The final success of not needing intervention is 79%,” she said. At this point in the study, 139 patients were available for follow-up. Among the 29 who needed reintervention, 19 had dilation below 20 mm Hg, 3 underwent pneumatic dilation, and 2 had botulinum toxin. Two patients required a redo myotomy, two had antireflux surgery, and one had an esophagectomy.

“When you only focus on a singular outcome, you can miss the whole story that occurs after myotomy,” Dr. Shemmeri said. “Providing a comprehensive tool gives you the ability to identify areas for improvement in your achalasia practice. Its simplicity allows it to be applied in various settings.” In the academic setting, it can be a tool for evaluating technologies and approaches for postmyotomy management. In hospitals and surgeons’ practices, it can aid in quality improvement, comparative outcomes research, and in evaluating operative approaches to myotomy.

The outcomes highlight the high prevalence of GERD, thus stressing the importance of pH testing after myotomy, Dr. Shemmeri said. Her study team recommends pH testing at 6-month follow-up because patients may not always self-report the extent of esophagitis present. Coauthor Brian Louie, MD, also of Swedish Medical Center, added during the discussion that ongoing follow-up of achalasia patients is necessary to address issues patients encounter with their swallowing over time.

Dr. Shemmeri had no relevant financial relationships to disclose. Dr. Louie reported relationships with Boston Scientific, ERBE, and Olympus.

SOURCE: Shemmeri E et al. SAGES 2019, Presentation S085.

BALTIMORE – The Eckardt score has been established as a tool to evaluate outcomes of surgery for achalasia, but researchers have developed a report card that uses multiple variables that may provide a more accurate picture of surgical outcomes, according to results of study reported at the annual meeting of the Society of American Gastrointestinal Endoscopic Surgeons.

“The use of an accurate score to assess outcomes after achalasia surgery shows outstanding results,” said Ealaf Shemmeri, MD, of Swedish Medical Center in Seattle. “Using patient-reported symptoms, objective measures, and rates of reinterventions organized into a report card provides a more comprehensive and informative view.”

The Eckardt score evaluates four symptoms to evaluate outcomes of surgery to treat achalasia: weight loss, retrosternal pain, regurgitation, and dysphagia. “However, it does not address the other changes that can occur after myotomy, including the quality of swallowing and the onset of reflux disease,” she said. “Thus, there is a need for a more comprehensive assessment of quality after achalasia treatment.”

So the Swedish investigators set out to devise a report card that provides “a comprehensive and informative assessment” of surgical myotomy outcomes, she said. This involved a retrospective, single-center chart review of 185 patients who had surgical myotomy for primary achalasia from 2005 to 2017.

To determine patient-reported outcomes, the report card defines success as an Eckardt score below 3, Dakkak dysphagia score above 40, and GERD-HRQL (health-related quality of life) score below 10. The objective measures consisted of DeMeester (pH) score below 14.72, no column at 5 minutes on timed barium swallow, normalized integrated relaxation pressure less than 15 on manometry, and absence of esophagitis on endoscopy. For the third pillar of the report card, no reintervention was recorded as a success, Dr. Shemmeri said.

Regarding the etiology of achalasia in the study population, 42 had type 1, 109 had type 2, and 34 had type 3. A total of 71 patients had per oral endoscopic myotomy and 114 had Heller myotomy, 92 with Dor fundoplication and 20 with Toupet. Major perioperative complications included four per oral endoscopic myotomy patients who developed a leak requiring intervention. Six patients required return to the operating room for persistent dysphagia, Dr. Shemmeri said.

After the procedures, 93% of study patients reported an Eckardt score less than 3. However, only 45% have a Dakkak dysphagia score greater than 40 and 71% had a GERD-HRQL score less than 10, Dr. Shemmeri said. The objective measures told a similar story: Integrated relaxation pressure normalized in 80%, barium clearance was achieved in 61%, normal esophageal mucosa was recorded in 71%, “but pH testing was normal only 50% of the time,” Dr. Shemmeri said.

“The final success of not needing intervention is 79%,” she said. At this point in the study, 139 patients were available for follow-up. Among the 29 who needed reintervention, 19 had dilation below 20 mm Hg, 3 underwent pneumatic dilation, and 2 had botulinum toxin. Two patients required a redo myotomy, two had antireflux surgery, and one had an esophagectomy.

“When you only focus on a singular outcome, you can miss the whole story that occurs after myotomy,” Dr. Shemmeri said. “Providing a comprehensive tool gives you the ability to identify areas for improvement in your achalasia practice. Its simplicity allows it to be applied in various settings.” In the academic setting, it can be a tool for evaluating technologies and approaches for postmyotomy management. In hospitals and surgeons’ practices, it can aid in quality improvement, comparative outcomes research, and in evaluating operative approaches to myotomy.

The outcomes highlight the high prevalence of GERD, thus stressing the importance of pH testing after myotomy, Dr. Shemmeri said. Her study team recommends pH testing at 6-month follow-up because patients may not always self-report the extent of esophagitis present. Coauthor Brian Louie, MD, also of Swedish Medical Center, added during the discussion that ongoing follow-up of achalasia patients is necessary to address issues patients encounter with their swallowing over time.

Dr. Shemmeri had no relevant financial relationships to disclose. Dr. Louie reported relationships with Boston Scientific, ERBE, and Olympus.

SOURCE: Shemmeri E et al. SAGES 2019, Presentation S085.

The CDC estimates that 1.7 million people in the United States acquire sepsis annually; sepsis accounts for nearly 270,000 patient deaths per year. 

Decreasing mortality and improving patient outcomes requires early detection and appropriate timely treatment. The Joint Commission Center for Transforming Healthcare’s recent sepsis project demonstrated this by analyzing root causes and reducing sepsis mortality with five leading hospitals by an aggregate of nearly 25%.

“Most organizations can tell you how they are doing with regard to whether or not they are ordering lactates or fluids, but many can’t tell you where in the process these elements are failing,” said Kelly Barnes, Black Belt III, Joint Commission Center for Transforming Healthcare. “For instance, is the issue in ordering lactates, drawing lactates, or getting the results of lactates in a timely manner? The key is to understand where in the process things are breaking down to identify what solutions an organization needs to put in place.”

During the Joint Commission project, one organization found that patients had inadequate fluid resuscitation due to staff fear of fluid overload, while another organization found they had issues with fluids being disconnected when patients were taken for tests and then not reconnected – different problems that needed different solutions. 

The Joint Commission Center for Transforming Healthcare is currently developing a Targeted Solutions Tool^® (TST^®), scheduled for release in 2019, to help organizations determine their issues with sepsis recognition and barriers to meeting sepsis bundle element requirements and implement targeted solutions to address their specific issues. The tool will be available free of charge to all Joint Commission-accredited customers.
 

Reference

1. “Hospital-Wide Sepsis Project Reduces Mortality by Nearly 25 Percent,” Kelly Barnes, The Joint Commission Center for Transforming Healthcare. 2018, Sep 25.

The CDC estimates that 1.7 million people in the United States acquire sepsis annually; sepsis accounts for nearly 270,000 patient deaths per year. 

Decreasing mortality and improving patient outcomes requires early detection and appropriate timely treatment. The Joint Commission Center for Transforming Healthcare’s recent sepsis project demonstrated this by analyzing root causes and reducing sepsis mortality with five leading hospitals by an aggregate of nearly 25%.

“Most organizations can tell you how they are doing with regard to whether or not they are ordering lactates or fluids, but many can’t tell you where in the process these elements are failing,” said Kelly Barnes, Black Belt III, Joint Commission Center for Transforming Healthcare. “For instance, is the issue in ordering lactates, drawing lactates, or getting the results of lactates in a timely manner? The key is to understand where in the process things are breaking down to identify what solutions an organization needs to put in place.”

During the Joint Commission project, one organization found that patients had inadequate fluid resuscitation due to staff fear of fluid overload, while another organization found they had issues with fluids being disconnected when patients were taken for tests and then not reconnected – different problems that needed different solutions. 

The Joint Commission Center for Transforming Healthcare is currently developing a Targeted Solutions Tool^® (TST^®), scheduled for release in 2019, to help organizations determine their issues with sepsis recognition and barriers to meeting sepsis bundle element requirements and implement targeted solutions to address their specific issues. The tool will be available free of charge to all Joint Commission-accredited customers.
 

Reference

1. “Hospital-Wide Sepsis Project Reduces Mortality by Nearly 25 Percent,” Kelly Barnes, The Joint Commission Center for Transforming Healthcare. 2018, Sep 25.

The CDC estimates that 1.7 million people in the United States acquire sepsis annually; sepsis accounts for nearly 270,000 patient deaths per year. 

Decreasing mortality and improving patient outcomes requires early detection and appropriate timely treatment. The Joint Commission Center for Transforming Healthcare’s recent sepsis project demonstrated this by analyzing root causes and reducing sepsis mortality with five leading hospitals by an aggregate of nearly 25%.

“Most organizations can tell you how they are doing with regard to whether or not they are ordering lactates or fluids, but many can’t tell you where in the process these elements are failing,” said Kelly Barnes, Black Belt III, Joint Commission Center for Transforming Healthcare. “For instance, is the issue in ordering lactates, drawing lactates, or getting the results of lactates in a timely manner? The key is to understand where in the process things are breaking down to identify what solutions an organization needs to put in place.”

During the Joint Commission project, one organization found that patients had inadequate fluid resuscitation due to staff fear of fluid overload, while another organization found they had issues with fluids being disconnected when patients were taken for tests and then not reconnected – different problems that needed different solutions. 

The Joint Commission Center for Transforming Healthcare is currently developing a Targeted Solutions Tool^® (TST^®), scheduled for release in 2019, to help organizations determine their issues with sepsis recognition and barriers to meeting sepsis bundle element requirements and implement targeted solutions to address their specific issues. The tool will be available free of charge to all Joint Commission-accredited customers.
 

Reference

1. “Hospital-Wide Sepsis Project Reduces Mortality by Nearly 25 Percent,” Kelly Barnes, The Joint Commission Center for Transforming Healthcare. 2018, Sep 25.

In a large-scale plasma metabolome analysis, metabolic profiling of plasma yielded alterations in high-density lipoprotein (HDL) metabolism in patients with migraine and decreased omega-3 fatty acids only in male migraineurs, a new study found. Researchers sought to identify a plasma metabolomic biomarker signature for migraine. Plasma samples from 8 Dutch cohorts (n=10,153: 2800 migraine patients and 7353 controls) were profiled on a H-NMR-based metabolomics platform to quantify 146 individual metabolites and 79 metabolite ratios. Metabolite measures associated with migraine were obtained after single-metabolite logistic regression combined with random-effects meta-analysis performed in a nonstratified and sex-stratified manner. Among the findings:

• Decreases in the level of apolipoprotein A1 and free cholesterol total lipid ratio present in small HDL subspecies were associated with migraine status.
• A decreased level of omega-3 fatty acids was associated with migraine in male participants only.
• Global test analysis supported that HDL traits were associated with migraine status.

Onderwater GLJ, Ligthart L, Bot M, et al. Large-scale metabolome analysis reveals alterations in HDL metabolism in migraine. [Published online ahead of print April 3, 2019]. Neurology. doi:10.1212/WNL.0000000000007313.

In a large-scale plasma metabolome analysis, metabolic profiling of plasma yielded alterations in high-density lipoprotein (HDL) metabolism in patients with migraine and decreased omega-3 fatty acids only in male migraineurs, a new study found. Researchers sought to identify a plasma metabolomic biomarker signature for migraine. Plasma samples from 8 Dutch cohorts (n=10,153: 2800 migraine patients and 7353 controls) were profiled on a H-NMR-based metabolomics platform to quantify 146 individual metabolites and 79 metabolite ratios. Metabolite measures associated with migraine were obtained after single-metabolite logistic regression combined with random-effects meta-analysis performed in a nonstratified and sex-stratified manner. Among the findings:

• Decreases in the level of apolipoprotein A1 and free cholesterol total lipid ratio present in small HDL subspecies were associated with migraine status.
• A decreased level of omega-3 fatty acids was associated with migraine in male participants only.
• Global test analysis supported that HDL traits were associated with migraine status.

Onderwater GLJ, Ligthart L, Bot M, et al. Large-scale metabolome analysis reveals alterations in HDL metabolism in migraine. [Published online ahead of print April 3, 2019]. Neurology. doi:10.1212/WNL.0000000000007313.

In a large-scale plasma metabolome analysis, metabolic profiling of plasma yielded alterations in high-density lipoprotein (HDL) metabolism in patients with migraine and decreased omega-3 fatty acids only in male migraineurs, a new study found. Researchers sought to identify a plasma metabolomic biomarker signature for migraine. Plasma samples from 8 Dutch cohorts (n=10,153: 2800 migraine patients and 7353 controls) were profiled on a H-NMR-based metabolomics platform to quantify 146 individual metabolites and 79 metabolite ratios. Metabolite measures associated with migraine were obtained after single-metabolite logistic regression combined with random-effects meta-analysis performed in a nonstratified and sex-stratified manner. Among the findings:

• Decreases in the level of apolipoprotein A1 and free cholesterol total lipid ratio present in small HDL subspecies were associated with migraine status.
• A decreased level of omega-3 fatty acids was associated with migraine in male participants only.
• Global test analysis supported that HDL traits were associated with migraine status.

Onderwater GLJ, Ligthart L, Bot M, et al. Large-scale metabolome analysis reveals alterations in HDL metabolism in migraine. [Published online ahead of print April 3, 2019]. Neurology. doi:10.1212/WNL.0000000000007313.

To improve patient care and outcomes, leading dermatologists from the Cutis Editorial Board answered 5 questions on hyperhidrosis. Here’s what we found.

In which areas do patients report hyperhidrosis most frequently?

Nearly 70% of dermatologists see patients with hyperhidrosis of the axillae, followed by the palms and soles (27%). Only 4% of dermatologists indicated that they see hyperhidrosis all over the body. 

Expert Commentary
Provided by Shari R. Lipner, MD, PhD (New York, New York)

Hyperhidrosis affects up to 5% of the US population and may remarkably affect quality of life. Primary hyperhidrosis accounts for 93% of cases. Before puberty, hyperhidrosis affects the palms and soles in up to 90% of patients. In adults, the axillae are most commonly affected (51%), followed by plantar (30%), palmar (24%), and facial (10%) areas (Strutton et al).

Next page: Topical treatment

Approximately what percentage of patients are satisfied with topical treatments for hyperhidrosis?

The majority of dermatologists (88%) reported that less than half of their patients are satisfied with topical treatments for hyperhidrosis. Only 12% indicated that 51% to 70% of their patients were satisfied, and none of the respondents indicated that >70% were satisfied.

Expert Commentary
Provided by Shari R. Lipner, MD, PhD (New York, New York)

There is clearly a need for safe and effective treatments for hyperhidrosis. Treatment of hyperhidrosis should include lifestyle and behavioral modifications. It is helpful to try to avoid hot crowded rooms when feasible, as well as stress, tight clothing, occlusive shoes, alcohol, and spicy foods. Patients should be instructed on proper use of medications, as well as the need to continue therapy for maintenance. Patients should be encouraged to follow up for alternative treatment options in cases of therapy failure.

Next page: Botulinum toxin

On average, how long do the effects of botulinum toxin last in your axillary hyperhidrosis patients?

The effects of botulinum toxin last at least 4 months and up to 6 months in most patients, according to 58% of dermatologists surveyed. Thirty percent reported 2 to 4 months, and 13% reported more than 6 months.

Expert Commentary
Provided by Shari R. Lipner, MD, PhD (New York, New York)

OnabotulinumtoxinA is approved by the US Food and Drug Administration for severe primary axillary hyperhidrosis. Injections are ideally placed at the dermal-subcutaneous junction, with 1 unit placed every 1 to 2 cm. Dosing is 50 to 100 U per axilla with higher dosing required for the palms and soles (off label). Reported efficacy for axillary hyperhidrosis is 82% to 87%; however, 50% of patients with plantar hyperhidrosis are dissatisfied with the treatment. Sweat reduction is most apparent after 2 weeks and typically persists 6 to 8 months in clinical trials (Botox package insert).

Next page: Systemic anticholinergics

When prescribing systemic anticholinergics for hyperhidrosis, what side effect is most common among your patients?

More than three-quarters of dermatologists (81%) reported that dry mouth is the most common side effect of systemic anticholinergics. Dry eyes is the second most common side effect (15%).

Expert Commentary
Provided by Shari R. Lipner, MD, PhD (New York, New York)

Systemic anticholinergics are commonly used off label for the treatment of hyperhidrosis. Adverse effects include dry mouth, blurred vision, dry eyes, orthostatic hypotension, gastrointestinal, urinary retention, tachycardia, and drowsiness. Unfortunately, these side effects cause one-third of patients to discontinue treatment (Bajaj and Langtry). A slow escalation of the dose may increase tolerability and reduce these side effects. These anticholinergics should not be taken with other medications with anticholinergic activity to avoid exacerbating these side effects. 

Next page: Surgical treatment

According to 62% of dermatologists, 10% or less of patients require surgery for treatment of hyperhidrosis after other therapies have failed. Almost one-third indicated that none of their patients require surgical treatment. None of the dermatologists surveyed reported that more than 60% of patients need surgery.

Expert Commentary
Provided by Shari R. Lipner, MD, PhD (New York, New York)

Surgery is an option to treat hyperhidrosis when conservative methods have failed. Surgical therapies include curettage, liposuction, and excision. A last resort is considered sympathectomy. Endoscopic thoracic sympathectomy is employed for palmar, facial, and axillary hyperhidrosis, while endoscopic lumbar sympathectomy is indicated for plantar hyperhidrosis. 

Next page: More tips from derms

More Tips From Dermatologists

The dermatologists we polled had the following advice for their peers:

Patients with focal idiopathic hyperhidrosis of the axillae as well as palms/soles report that this condition interferes with the quality of life in major ways, from social interactions to professional interactions. They often don't even know they have a problem and internalize that they must be overly anxious about things. I have patients that buy 3 of the same shirts and change a few times a day, costing a great deal of money (plus cleaning bills for 3 shirts as well) and costing a great deal of wasted time when they could be doing something more productive. It's great that not only botulinum toxins can be helpful for the underarms but also even less-invasive topical anticholinergics (easy to use, no discomfort, predictable, and helping make treatment for axillary hyperhidrosis much more on the radar).—Joel L. Cohen, MD (Denver, Colorado) 

More and more patients are presenting to request relief from hyperhidrosis, and increasingly in nontraditional areas (ie, areas other than the axilla and forehead). These include the palms and scalp most commonly, and then the breast, chest, and back. Patients with hyperhidrosis of the feet often present requesting help for their malodorous or smelly feet and shoes.—Fran E. Cook-Bolden, MD (New York, New York)

I have found that systemic hyperhidrosis has usually been responsive to oral glycopyrrolate. But localized hyperhidrosis is more difficult to treat. Glycopyrronium has made life so much easier for my axillary hyperhidrosis patients. Now I am waiting for some game changer for palms and soles.—Lawrence J. Green, MD (Washington, DC)

About This Survey

The survey was fielded electronically to Cutis Editorial Board Members within the United States from March 11, 2019, to April 8, 2019. A total of 26 usable responses were received.

To improve patient care and outcomes, leading dermatologists from the Cutis Editorial Board answered 5 questions on hyperhidrosis. Here’s what we found.

In which areas do patients report hyperhidrosis most frequently?

Nearly 70% of dermatologists see patients with hyperhidrosis of the axillae, followed by the palms and soles (27%). Only 4% of dermatologists indicated that they see hyperhidrosis all over the body. 

Expert Commentary
Provided by Shari R. Lipner, MD, PhD (New York, New York)

Hyperhidrosis affects up to 5% of the US population and may remarkably affect quality of life. Primary hyperhidrosis accounts for 93% of cases. Before puberty, hyperhidrosis affects the palms and soles in up to 90% of patients. In adults, the axillae are most commonly affected (51%), followed by plantar (30%), palmar (24%), and facial (10%) areas (Strutton et al).

Next page: Topical treatment

Approximately what percentage of patients are satisfied with topical treatments for hyperhidrosis?

The majority of dermatologists (88%) reported that less than half of their patients are satisfied with topical treatments for hyperhidrosis. Only 12% indicated that 51% to 70% of their patients were satisfied, and none of the respondents indicated that >70% were satisfied.

Expert Commentary
Provided by Shari R. Lipner, MD, PhD (New York, New York)

There is clearly a need for safe and effective treatments for hyperhidrosis. Treatment of hyperhidrosis should include lifestyle and behavioral modifications. It is helpful to try to avoid hot crowded rooms when feasible, as well as stress, tight clothing, occlusive shoes, alcohol, and spicy foods. Patients should be instructed on proper use of medications, as well as the need to continue therapy for maintenance. Patients should be encouraged to follow up for alternative treatment options in cases of therapy failure.

Next page: Botulinum toxin

On average, how long do the effects of botulinum toxin last in your axillary hyperhidrosis patients?

The effects of botulinum toxin last at least 4 months and up to 6 months in most patients, according to 58% of dermatologists surveyed. Thirty percent reported 2 to 4 months, and 13% reported more than 6 months.

Expert Commentary
Provided by Shari R. Lipner, MD, PhD (New York, New York)

OnabotulinumtoxinA is approved by the US Food and Drug Administration for severe primary axillary hyperhidrosis. Injections are ideally placed at the dermal-subcutaneous junction, with 1 unit placed every 1 to 2 cm. Dosing is 50 to 100 U per axilla with higher dosing required for the palms and soles (off label). Reported efficacy for axillary hyperhidrosis is 82% to 87%; however, 50% of patients with plantar hyperhidrosis are dissatisfied with the treatment. Sweat reduction is most apparent after 2 weeks and typically persists 6 to 8 months in clinical trials (Botox package insert).

Next page: Systemic anticholinergics

When prescribing systemic anticholinergics for hyperhidrosis, what side effect is most common among your patients?

More than three-quarters of dermatologists (81%) reported that dry mouth is the most common side effect of systemic anticholinergics. Dry eyes is the second most common side effect (15%).

Expert Commentary
Provided by Shari R. Lipner, MD, PhD (New York, New York)

Systemic anticholinergics are commonly used off label for the treatment of hyperhidrosis. Adverse effects include dry mouth, blurred vision, dry eyes, orthostatic hypotension, gastrointestinal, urinary retention, tachycardia, and drowsiness. Unfortunately, these side effects cause one-third of patients to discontinue treatment (Bajaj and Langtry). A slow escalation of the dose may increase tolerability and reduce these side effects. These anticholinergics should not be taken with other medications with anticholinergic activity to avoid exacerbating these side effects. 

Next page: Surgical treatment

According to 62% of dermatologists, 10% or less of patients require surgery for treatment of hyperhidrosis after other therapies have failed. Almost one-third indicated that none of their patients require surgical treatment. None of the dermatologists surveyed reported that more than 60% of patients need surgery.

Expert Commentary
Provided by Shari R. Lipner, MD, PhD (New York, New York)

Surgery is an option to treat hyperhidrosis when conservative methods have failed. Surgical therapies include curettage, liposuction, and excision. A last resort is considered sympathectomy. Endoscopic thoracic sympathectomy is employed for palmar, facial, and axillary hyperhidrosis, while endoscopic lumbar sympathectomy is indicated for plantar hyperhidrosis. 

Next page: More tips from derms

More Tips From Dermatologists

The dermatologists we polled had the following advice for their peers:

Patients with focal idiopathic hyperhidrosis of the axillae as well as palms/soles report that this condition interferes with the quality of life in major ways, from social interactions to professional interactions. They often don't even know they have a problem and internalize that they must be overly anxious about things. I have patients that buy 3 of the same shirts and change a few times a day, costing a great deal of money (plus cleaning bills for 3 shirts as well) and costing a great deal of wasted time when they could be doing something more productive. It's great that not only botulinum toxins can be helpful for the underarms but also even less-invasive topical anticholinergics (easy to use, no discomfort, predictable, and helping make treatment for axillary hyperhidrosis much more on the radar).—Joel L. Cohen, MD (Denver, Colorado) 

More and more patients are presenting to request relief from hyperhidrosis, and increasingly in nontraditional areas (ie, areas other than the axilla and forehead). These include the palms and scalp most commonly, and then the breast, chest, and back. Patients with hyperhidrosis of the feet often present requesting help for their malodorous or smelly feet and shoes.—Fran E. Cook-Bolden, MD (New York, New York)

I have found that systemic hyperhidrosis has usually been responsive to oral glycopyrrolate. But localized hyperhidrosis is more difficult to treat. Glycopyrronium has made life so much easier for my axillary hyperhidrosis patients. Now I am waiting for some game changer for palms and soles.—Lawrence J. Green, MD (Washington, DC)

About This Survey

The survey was fielded electronically to Cutis Editorial Board Members within the United States from March 11, 2019, to April 8, 2019. A total of 26 usable responses were received.

To improve patient care and outcomes, leading dermatologists from the Cutis Editorial Board answered 5 questions on hyperhidrosis. Here’s what we found.

In which areas do patients report hyperhidrosis most frequently?

Nearly 70% of dermatologists see patients with hyperhidrosis of the axillae, followed by the palms and soles (27%). Only 4% of dermatologists indicated that they see hyperhidrosis all over the body. 

Expert Commentary
Provided by Shari R. Lipner, MD, PhD (New York, New York)

Hyperhidrosis affects up to 5% of the US population and may remarkably affect quality of life. Primary hyperhidrosis accounts for 93% of cases. Before puberty, hyperhidrosis affects the palms and soles in up to 90% of patients. In adults, the axillae are most commonly affected (51%), followed by plantar (30%), palmar (24%), and facial (10%) areas (Strutton et al).

Next page: Topical treatment

Approximately what percentage of patients are satisfied with topical treatments for hyperhidrosis?

The majority of dermatologists (88%) reported that less than half of their patients are satisfied with topical treatments for hyperhidrosis. Only 12% indicated that 51% to 70% of their patients were satisfied, and none of the respondents indicated that >70% were satisfied.

Expert Commentary
Provided by Shari R. Lipner, MD, PhD (New York, New York)

There is clearly a need for safe and effective treatments for hyperhidrosis. Treatment of hyperhidrosis should include lifestyle and behavioral modifications. It is helpful to try to avoid hot crowded rooms when feasible, as well as stress, tight clothing, occlusive shoes, alcohol, and spicy foods. Patients should be instructed on proper use of medications, as well as the need to continue therapy for maintenance. Patients should be encouraged to follow up for alternative treatment options in cases of therapy failure.

Next page: Botulinum toxin

On average, how long do the effects of botulinum toxin last in your axillary hyperhidrosis patients?

The effects of botulinum toxin last at least 4 months and up to 6 months in most patients, according to 58% of dermatologists surveyed. Thirty percent reported 2 to 4 months, and 13% reported more than 6 months.

Expert Commentary
Provided by Shari R. Lipner, MD, PhD (New York, New York)

OnabotulinumtoxinA is approved by the US Food and Drug Administration for severe primary axillary hyperhidrosis. Injections are ideally placed at the dermal-subcutaneous junction, with 1 unit placed every 1 to 2 cm. Dosing is 50 to 100 U per axilla with higher dosing required for the palms and soles (off label). Reported efficacy for axillary hyperhidrosis is 82% to 87%; however, 50% of patients with plantar hyperhidrosis are dissatisfied with the treatment. Sweat reduction is most apparent after 2 weeks and typically persists 6 to 8 months in clinical trials (Botox package insert).

Next page: Systemic anticholinergics

When prescribing systemic anticholinergics for hyperhidrosis, what side effect is most common among your patients?

More than three-quarters of dermatologists (81%) reported that dry mouth is the most common side effect of systemic anticholinergics. Dry eyes is the second most common side effect (15%).

Expert Commentary
Provided by Shari R. Lipner, MD, PhD (New York, New York)

Systemic anticholinergics are commonly used off label for the treatment of hyperhidrosis. Adverse effects include dry mouth, blurred vision, dry eyes, orthostatic hypotension, gastrointestinal, urinary retention, tachycardia, and drowsiness. Unfortunately, these side effects cause one-third of patients to discontinue treatment (Bajaj and Langtry). A slow escalation of the dose may increase tolerability and reduce these side effects. These anticholinergics should not be taken with other medications with anticholinergic activity to avoid exacerbating these side effects. 

Next page: Surgical treatment

According to 62% of dermatologists, 10% or less of patients require surgery for treatment of hyperhidrosis after other therapies have failed. Almost one-third indicated that none of their patients require surgical treatment. None of the dermatologists surveyed reported that more than 60% of patients need surgery.

Expert Commentary
Provided by Shari R. Lipner, MD, PhD (New York, New York)

Surgery is an option to treat hyperhidrosis when conservative methods have failed. Surgical therapies include curettage, liposuction, and excision. A last resort is considered sympathectomy. Endoscopic thoracic sympathectomy is employed for palmar, facial, and axillary hyperhidrosis, while endoscopic lumbar sympathectomy is indicated for plantar hyperhidrosis. 

Next page: More tips from derms

More Tips From Dermatologists

The dermatologists we polled had the following advice for their peers:

Patients with focal idiopathic hyperhidrosis of the axillae as well as palms/soles report that this condition interferes with the quality of life in major ways, from social interactions to professional interactions. They often don't even know they have a problem and internalize that they must be overly anxious about things. I have patients that buy 3 of the same shirts and change a few times a day, costing a great deal of money (plus cleaning bills for 3 shirts as well) and costing a great deal of wasted time when they could be doing something more productive. It's great that not only botulinum toxins can be helpful for the underarms but also even less-invasive topical anticholinergics (easy to use, no discomfort, predictable, and helping make treatment for axillary hyperhidrosis much more on the radar).—Joel L. Cohen, MD (Denver, Colorado) 

More and more patients are presenting to request relief from hyperhidrosis, and increasingly in nontraditional areas (ie, areas other than the axilla and forehead). These include the palms and scalp most commonly, and then the breast, chest, and back. Patients with hyperhidrosis of the feet often present requesting help for their malodorous or smelly feet and shoes.—Fran E. Cook-Bolden, MD (New York, New York)

I have found that systemic hyperhidrosis has usually been responsive to oral glycopyrrolate. But localized hyperhidrosis is more difficult to treat. Glycopyrronium has made life so much easier for my axillary hyperhidrosis patients. Now I am waiting for some game changer for palms and soles.—Lawrence J. Green, MD (Washington, DC)

About This Survey

The survey was fielded electronically to Cutis Editorial Board Members within the United States from March 11, 2019, to April 8, 2019. A total of 26 usable responses were received.

A recent systematic review and meta-analysis found that spinal manipulation may be an effective therapeutic technique to reduce migraine days and pain intensity. Researchers identified 6 randomized clinical trials (pooled n=677; range of n=42-218) eligible for meta-analysis and evaluated spinal manipulation and migraine-related outcomes through 2017. They found:

• Intervention duration ranged from 2 to 6 months; outcomes included measures of migraine days (primary), migraine pain/intensity, and migraine disability.
• Methodological quality varied across the studies.
• Spinal manipulation reduced migraine days with an overall small effect size, as well as migraine pain/intensity.

Rist PM, Hernandez A, Bernstein C, et al. The impact of spinal manipulation on migraine pain and disability: A systematic review and meta-analysis. Headache. 2019;59(4):532-542. doi:10.1111/head.13501.

A recent systematic review and meta-analysis found that spinal manipulation may be an effective therapeutic technique to reduce migraine days and pain intensity. Researchers identified 6 randomized clinical trials (pooled n=677; range of n=42-218) eligible for meta-analysis and evaluated spinal manipulation and migraine-related outcomes through 2017. They found:

• Intervention duration ranged from 2 to 6 months; outcomes included measures of migraine days (primary), migraine pain/intensity, and migraine disability.
• Methodological quality varied across the studies.
• Spinal manipulation reduced migraine days with an overall small effect size, as well as migraine pain/intensity.

Rist PM, Hernandez A, Bernstein C, et al. The impact of spinal manipulation on migraine pain and disability: A systematic review and meta-analysis. Headache. 2019;59(4):532-542. doi:10.1111/head.13501.

A recent systematic review and meta-analysis found that spinal manipulation may be an effective therapeutic technique to reduce migraine days and pain intensity. Researchers identified 6 randomized clinical trials (pooled n=677; range of n=42-218) eligible for meta-analysis and evaluated spinal manipulation and migraine-related outcomes through 2017. They found:

• Intervention duration ranged from 2 to 6 months; outcomes included measures of migraine days (primary), migraine pain/intensity, and migraine disability.
• Methodological quality varied across the studies.
• Spinal manipulation reduced migraine days with an overall small effect size, as well as migraine pain/intensity.

Rist PM, Hernandez A, Bernstein C, et al. The impact of spinal manipulation on migraine pain and disability: A systematic review and meta-analysis. Headache. 2019;59(4):532-542. doi:10.1111/head.13501.

In individuals with familial hemiplegic migraines (FHM), baseline and serial neuropsychological testing may help identify the potential progression and course of cognitive impairment associated with this condition. This according to a single-case study involving a male aged 24 years who recently endured an atypical, prolonged FHM episode. Researchers found:

• The patient’s overall neuropsychological functioning was intact with low average semantic fluency and processing speed.
• The patient also exhibited mild indication of executive dysfunction.

Trahan EM, Mercado JM. Familial hemiplegic migraines and baseline neuropsychological testing: A case report. [Published online ahead of print March 14, 2019]. Headache. doi:10.1111/head.13505.

In individuals with familial hemiplegic migraines (FHM), baseline and serial neuropsychological testing may help identify the potential progression and course of cognitive impairment associated with this condition. This according to a single-case study involving a male aged 24 years who recently endured an atypical, prolonged FHM episode. Researchers found:

• The patient’s overall neuropsychological functioning was intact with low average semantic fluency and processing speed.
• The patient also exhibited mild indication of executive dysfunction.

Trahan EM, Mercado JM. Familial hemiplegic migraines and baseline neuropsychological testing: A case report. [Published online ahead of print March 14, 2019]. Headache. doi:10.1111/head.13505.

In individuals with familial hemiplegic migraines (FHM), baseline and serial neuropsychological testing may help identify the potential progression and course of cognitive impairment associated with this condition. This according to a single-case study involving a male aged 24 years who recently endured an atypical, prolonged FHM episode. Researchers found:

• The patient’s overall neuropsychological functioning was intact with low average semantic fluency and processing speed.
• The patient also exhibited mild indication of executive dysfunction.

Trahan EM, Mercado JM. Familial hemiplegic migraines and baseline neuropsychological testing: A case report. [Published online ahead of print March 14, 2019]. Headache. doi:10.1111/head.13505.

The clinical scenario is as follows: A 62-year-old woman comes to see me for a new diagnosis of grade 1 endometrial cancer. She has a normal body mass index of 24 kg/m², a history of four prior full-term pregnancies, no family history of malignancy, and no medical comorbidities. She is otherwise a specimen of good health, and has no clear identifiable risk factors for this malignancy. She then reports that she transitioned through menopause at age 52 years and developed severe hot flashes with sleep and mood disturbance. She did not wish to take conventional hormone replacement therapy (HT) because she had heard it causes cancer. She subsequently researched the Internet and found a provider who has been prescribing compounded bioidentical hormone therapy (CBHT) for her for the past 10 years. She submits saliva for testing of her estrogen levels, and the provider uses this data to compound the appropriate doses of “natural” estrogens and testosterone for her which she applies via vaginal or transdermal creams. She has been prescribed a progesterone suppository, but she doesn’t always take that because she doesn’t notice that it has any effect on how she feels. “Doctor, did my bioidentical hormones give me this uterine cancer?”

Alexander Raths/Fotolia

My answer is, of course, I don’t know. Cancer is a complex disease with a complex array of causative and promoting factors. However, we do know that taking estrogen unopposed with adequate progesterone can cause the development of uterine cancer and its precursor state.¹ If those bioidentical estrogens were effective at controlling her menopausal symptoms, they likely were effective at stimulating her endometrium at the same time.

What are compounded bioidentical hormones?

The term “bioidentical” refers to having the same molecular structure as that which is found in the human body. Examples of bioidentical estrogens include 17-beta-estradiol, estrone, and estriol – which are produced from yams and soy. Micronized progesterone is an example of a bioidentical progesterone. Many of these drugs are approved by the Food and Drug Administration, and prescribed and dispensed by conventional pharmacies.

An alternative, and increasingly popular, version of bioidentical hormones are CBHs. It should be recognized that this is a marketing, and not a scientific, term. These products utilize hormones, in some cases FDA-approved bioidentical hormones, that are broken down and blended by specialized pharmacies and reconstituted (compounded) into different, and sometimes “customized,” dosing and delivery methods (such as capsules, patches, gels, creams, lozenges, suppositories). Frequently used compounded products utilize multiple formulations of estrogens in doublets and triplets as well as progesterone, testosterone, and dehydroepiandrosterone.

How do they differ from synthetic hormones?

Distributors of CBHs state that they differ from conventional HT (synthetic and bioidentical) because of the customization process from which they promise greater efficacy and a sense of personalized medicine. The distributors frequently utilize assays from saliva, blood, vaginal secretions, and urine to measure a woman’s hormone levels, and titrate her compounded formulation based on those results. It should be noted that there is no data to support that titration of hormones to blood, salivary, or urine levels is efficacious or ensures greater safety than titration based on symptom management.

Critics of CBHT, which includes the North American Menopause Society² and the American College of Obstetricians and Gynecologists,³ highlight that the main difference between CBHT and HT is lack of FDA regulation over the CBHT industry. Many of these agents are delivered transdermally and therefore are classified as “dietary supplements.” As such, they do not require FDA regulation or proof of safety or efficacy.

What drives patients’ decision to use compounded bioidentical hormones?

After the Womens’ Health Initiative study was published in 2002⁵, all FDA-regulated estrogen preparations were required to carry specific warnings, particularly in relation to the increased risk for MI, venous thromboembolic events, and breast cancer. There was a clear uptake in use of CBHT after this study was reported. By avoiding FDA regulations, distributors of CBHTs may have avoided providing Womens’ Health Initiative information to patients. The absence of an insert with a written warning, in and of itself, makes these preparations seem safer to the patient.

But is it entirely a lack of information that drives demand for CBHTs? Surveys of current or former users suggest the motivations are more complex than that. A survey of 21 past or present CBHT users inquired about reasons for use of CBHT over conventional HT.⁶ Their responses were categorized as either push motivations away from conventional therapy versus pull motivations toward CBHT. About 95% of current and former users cited distrust of the biomedicine and pharmaceutical industry as reasons for use of CBHT. Fear about the safety of conventional HT, particularly with respect to cancer risk, also was strongly cited at 81%. Motivations pulling toward CBHT included its efficacy (76%) and perception that CBHT is “safer” than conventional HT (76%).

Women in this study also appreciated the tailored, individualized approach that often is associated with CBHT, in which providers spend long consultations discussing individual patient needs and concerns. They enjoy the idea of a customized blend that is created, as opposed to a standard dosing regimen, and intuitively trust the reliability of blood and saliva testing as a prescriptive tool.

Are bioidentical hormones safe with respect to cancer risk?

Hormones themselves are not inert substances, including those derived in vivo and those from plants. They have powerful effects in the human body and can promote malignant transformation or proliferation, alter metabolic pathways, stimulate vascular tone, influence coagulation pathways, along with many other effects. A hormone’s potential for deleterious effect can be present regardless of how that hormone is synthesized, procured, or prepared. While there are no data to suggest that CBHT is associated with increased cancer risk, compared with conventional HT, there are by no means any data to suggest it is safer. Unopposed compounded estrogens place women at increased risk for endometrial cancers, and the prolonged use of hormonal therapy, compounded or otherwise, after menopause increases the risk for breast cancer.

How should we counsel patients?

Patients who desire compounded bioidentical hormone preparations should be counseled that little is known about the safety of these preparations, compared with conventional hormone preparations. The fact that the components are often plant based rather than synthetic does not inherently alter their potential negative impact on biologic pathways. Patients should be educated regarding the difference between FDA-regulated products and nonregulated products so that they can understand that lack of a boxed warning on a non-FDA regulated product does not mean an absence of risk. Women should be informed of the potential inaccuracies in dosing and strength of the CBH preparations they receive.

We should recognize that our patients strongly desire a relationship with their provider in which they are listened to, understood, and treated as individuals. If conversations regarding hormone use are approached with these principles, we will optimize the likelihood our patients are receptive to the highest quality information and not pulled in the direction of unregulated products.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She reported that she had no conflicts of interest. Email Dr. Rossi at [email protected].

References:

1. Maturitas. 2014 Jan;77(1):4-6.

2. Menopause. 2014 Dec;21(12):1298-300.

3. Fertil Steril. 2012 Aug;98(2):308-12.

4. Report: Limited FDA survey of compounded drug products (Silver Spring, Md.: U.S. Food and Drug Administration, 2009).

5. JAMA. 2002;288(3):321-33.

6. BMC Womens Health. 2017 Oct 2;17(1):97.

The clinical scenario is as follows: A 62-year-old woman comes to see me for a new diagnosis of grade 1 endometrial cancer. She has a normal body mass index of 24 kg/m², a history of four prior full-term pregnancies, no family history of malignancy, and no medical comorbidities. She is otherwise a specimen of good health, and has no clear identifiable risk factors for this malignancy. She then reports that she transitioned through menopause at age 52 years and developed severe hot flashes with sleep and mood disturbance. She did not wish to take conventional hormone replacement therapy (HT) because she had heard it causes cancer. She subsequently researched the Internet and found a provider who has been prescribing compounded bioidentical hormone therapy (CBHT) for her for the past 10 years. She submits saliva for testing of her estrogen levels, and the provider uses this data to compound the appropriate doses of “natural” estrogens and testosterone for her which she applies via vaginal or transdermal creams. She has been prescribed a progesterone suppository, but she doesn’t always take that because she doesn’t notice that it has any effect on how she feels. “Doctor, did my bioidentical hormones give me this uterine cancer?”

Alexander Raths/Fotolia

My answer is, of course, I don’t know. Cancer is a complex disease with a complex array of causative and promoting factors. However, we do know that taking estrogen unopposed with adequate progesterone can cause the development of uterine cancer and its precursor state.¹ If those bioidentical estrogens were effective at controlling her menopausal symptoms, they likely were effective at stimulating her endometrium at the same time.

What are compounded bioidentical hormones?

The term “bioidentical” refers to having the same molecular structure as that which is found in the human body. Examples of bioidentical estrogens include 17-beta-estradiol, estrone, and estriol – which are produced from yams and soy. Micronized progesterone is an example of a bioidentical progesterone. Many of these drugs are approved by the Food and Drug Administration, and prescribed and dispensed by conventional pharmacies.

An alternative, and increasingly popular, version of bioidentical hormones are CBHs. It should be recognized that this is a marketing, and not a scientific, term. These products utilize hormones, in some cases FDA-approved bioidentical hormones, that are broken down and blended by specialized pharmacies and reconstituted (compounded) into different, and sometimes “customized,” dosing and delivery methods (such as capsules, patches, gels, creams, lozenges, suppositories). Frequently used compounded products utilize multiple formulations of estrogens in doublets and triplets as well as progesterone, testosterone, and dehydroepiandrosterone.

How do they differ from synthetic hormones?

Distributors of CBHs state that they differ from conventional HT (synthetic and bioidentical) because of the customization process from which they promise greater efficacy and a sense of personalized medicine. The distributors frequently utilize assays from saliva, blood, vaginal secretions, and urine to measure a woman’s hormone levels, and titrate her compounded formulation based on those results. It should be noted that there is no data to support that titration of hormones to blood, salivary, or urine levels is efficacious or ensures greater safety than titration based on symptom management.

Critics of CBHT, which includes the North American Menopause Society² and the American College of Obstetricians and Gynecologists,³ highlight that the main difference between CBHT and HT is lack of FDA regulation over the CBHT industry. Many of these agents are delivered transdermally and therefore are classified as “dietary supplements.” As such, they do not require FDA regulation or proof of safety or efficacy.

What drives patients’ decision to use compounded bioidentical hormones?

After the Womens’ Health Initiative study was published in 2002⁵, all FDA-regulated estrogen preparations were required to carry specific warnings, particularly in relation to the increased risk for MI, venous thromboembolic events, and breast cancer. There was a clear uptake in use of CBHT after this study was reported. By avoiding FDA regulations, distributors of CBHTs may have avoided providing Womens’ Health Initiative information to patients. The absence of an insert with a written warning, in and of itself, makes these preparations seem safer to the patient.

But is it entirely a lack of information that drives demand for CBHTs? Surveys of current or former users suggest the motivations are more complex than that. A survey of 21 past or present CBHT users inquired about reasons for use of CBHT over conventional HT.⁶ Their responses were categorized as either push motivations away from conventional therapy versus pull motivations toward CBHT. About 95% of current and former users cited distrust of the biomedicine and pharmaceutical industry as reasons for use of CBHT. Fear about the safety of conventional HT, particularly with respect to cancer risk, also was strongly cited at 81%. Motivations pulling toward CBHT included its efficacy (76%) and perception that CBHT is “safer” than conventional HT (76%).

Women in this study also appreciated the tailored, individualized approach that often is associated with CBHT, in which providers spend long consultations discussing individual patient needs and concerns. They enjoy the idea of a customized blend that is created, as opposed to a standard dosing regimen, and intuitively trust the reliability of blood and saliva testing as a prescriptive tool.

Are bioidentical hormones safe with respect to cancer risk?

Hormones themselves are not inert substances, including those derived in vivo and those from plants. They have powerful effects in the human body and can promote malignant transformation or proliferation, alter metabolic pathways, stimulate vascular tone, influence coagulation pathways, along with many other effects. A hormone’s potential for deleterious effect can be present regardless of how that hormone is synthesized, procured, or prepared. While there are no data to suggest that CBHT is associated with increased cancer risk, compared with conventional HT, there are by no means any data to suggest it is safer. Unopposed compounded estrogens place women at increased risk for endometrial cancers, and the prolonged use of hormonal therapy, compounded or otherwise, after menopause increases the risk for breast cancer.

How should we counsel patients?

Patients who desire compounded bioidentical hormone preparations should be counseled that little is known about the safety of these preparations, compared with conventional hormone preparations. The fact that the components are often plant based rather than synthetic does not inherently alter their potential negative impact on biologic pathways. Patients should be educated regarding the difference between FDA-regulated products and nonregulated products so that they can understand that lack of a boxed warning on a non-FDA regulated product does not mean an absence of risk. Women should be informed of the potential inaccuracies in dosing and strength of the CBH preparations they receive.

We should recognize that our patients strongly desire a relationship with their provider in which they are listened to, understood, and treated as individuals. If conversations regarding hormone use are approached with these principles, we will optimize the likelihood our patients are receptive to the highest quality information and not pulled in the direction of unregulated products.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She reported that she had no conflicts of interest. Email Dr. Rossi at [email protected].

References:

1. Maturitas. 2014 Jan;77(1):4-6.

2. Menopause. 2014 Dec;21(12):1298-300.

3. Fertil Steril. 2012 Aug;98(2):308-12.

4. Report: Limited FDA survey of compounded drug products (Silver Spring, Md.: U.S. Food and Drug Administration, 2009).

5. JAMA. 2002;288(3):321-33.

6. BMC Womens Health. 2017 Oct 2;17(1):97.

The clinical scenario is as follows: A 62-year-old woman comes to see me for a new diagnosis of grade 1 endometrial cancer. She has a normal body mass index of 24 kg/m², a history of four prior full-term pregnancies, no family history of malignancy, and no medical comorbidities. She is otherwise a specimen of good health, and has no clear identifiable risk factors for this malignancy. She then reports that she transitioned through menopause at age 52 years and developed severe hot flashes with sleep and mood disturbance. She did not wish to take conventional hormone replacement therapy (HT) because she had heard it causes cancer. She subsequently researched the Internet and found a provider who has been prescribing compounded bioidentical hormone therapy (CBHT) for her for the past 10 years. She submits saliva for testing of her estrogen levels, and the provider uses this data to compound the appropriate doses of “natural” estrogens and testosterone for her which she applies via vaginal or transdermal creams. She has been prescribed a progesterone suppository, but she doesn’t always take that because she doesn’t notice that it has any effect on how she feels. “Doctor, did my bioidentical hormones give me this uterine cancer?”

Alexander Raths/Fotolia

My answer is, of course, I don’t know. Cancer is a complex disease with a complex array of causative and promoting factors. However, we do know that taking estrogen unopposed with adequate progesterone can cause the development of uterine cancer and its precursor state.¹ If those bioidentical estrogens were effective at controlling her menopausal symptoms, they likely were effective at stimulating her endometrium at the same time.

What are compounded bioidentical hormones?

The term “bioidentical” refers to having the same molecular structure as that which is found in the human body. Examples of bioidentical estrogens include 17-beta-estradiol, estrone, and estriol – which are produced from yams and soy. Micronized progesterone is an example of a bioidentical progesterone. Many of these drugs are approved by the Food and Drug Administration, and prescribed and dispensed by conventional pharmacies.

An alternative, and increasingly popular, version of bioidentical hormones are CBHs. It should be recognized that this is a marketing, and not a scientific, term. These products utilize hormones, in some cases FDA-approved bioidentical hormones, that are broken down and blended by specialized pharmacies and reconstituted (compounded) into different, and sometimes “customized,” dosing and delivery methods (such as capsules, patches, gels, creams, lozenges, suppositories). Frequently used compounded products utilize multiple formulations of estrogens in doublets and triplets as well as progesterone, testosterone, and dehydroepiandrosterone.

How do they differ from synthetic hormones?

Distributors of CBHs state that they differ from conventional HT (synthetic and bioidentical) because of the customization process from which they promise greater efficacy and a sense of personalized medicine. The distributors frequently utilize assays from saliva, blood, vaginal secretions, and urine to measure a woman’s hormone levels, and titrate her compounded formulation based on those results. It should be noted that there is no data to support that titration of hormones to blood, salivary, or urine levels is efficacious or ensures greater safety than titration based on symptom management.

Critics of CBHT, which includes the North American Menopause Society² and the American College of Obstetricians and Gynecologists,³ highlight that the main difference between CBHT and HT is lack of FDA regulation over the CBHT industry. Many of these agents are delivered transdermally and therefore are classified as “dietary supplements.” As such, they do not require FDA regulation or proof of safety or efficacy.

What drives patients’ decision to use compounded bioidentical hormones?

After the Womens’ Health Initiative study was published in 2002⁵, all FDA-regulated estrogen preparations were required to carry specific warnings, particularly in relation to the increased risk for MI, venous thromboembolic events, and breast cancer. There was a clear uptake in use of CBHT after this study was reported. By avoiding FDA regulations, distributors of CBHTs may have avoided providing Womens’ Health Initiative information to patients. The absence of an insert with a written warning, in and of itself, makes these preparations seem safer to the patient.

But is it entirely a lack of information that drives demand for CBHTs? Surveys of current or former users suggest the motivations are more complex than that. A survey of 21 past or present CBHT users inquired about reasons for use of CBHT over conventional HT.⁶ Their responses were categorized as either push motivations away from conventional therapy versus pull motivations toward CBHT. About 95% of current and former users cited distrust of the biomedicine and pharmaceutical industry as reasons for use of CBHT. Fear about the safety of conventional HT, particularly with respect to cancer risk, also was strongly cited at 81%. Motivations pulling toward CBHT included its efficacy (76%) and perception that CBHT is “safer” than conventional HT (76%).

Women in this study also appreciated the tailored, individualized approach that often is associated with CBHT, in which providers spend long consultations discussing individual patient needs and concerns. They enjoy the idea of a customized blend that is created, as opposed to a standard dosing regimen, and intuitively trust the reliability of blood and saliva testing as a prescriptive tool.

Are bioidentical hormones safe with respect to cancer risk?

Hormones themselves are not inert substances, including those derived in vivo and those from plants. They have powerful effects in the human body and can promote malignant transformation or proliferation, alter metabolic pathways, stimulate vascular tone, influence coagulation pathways, along with many other effects. A hormone’s potential for deleterious effect can be present regardless of how that hormone is synthesized, procured, or prepared. While there are no data to suggest that CBHT is associated with increased cancer risk, compared with conventional HT, there are by no means any data to suggest it is safer. Unopposed compounded estrogens place women at increased risk for endometrial cancers, and the prolonged use of hormonal therapy, compounded or otherwise, after menopause increases the risk for breast cancer.

How should we counsel patients?

Patients who desire compounded bioidentical hormone preparations should be counseled that little is known about the safety of these preparations, compared with conventional hormone preparations. The fact that the components are often plant based rather than synthetic does not inherently alter their potential negative impact on biologic pathways. Patients should be educated regarding the difference between FDA-regulated products and nonregulated products so that they can understand that lack of a boxed warning on a non-FDA regulated product does not mean an absence of risk. Women should be informed of the potential inaccuracies in dosing and strength of the CBH preparations they receive.

We should recognize that our patients strongly desire a relationship with their provider in which they are listened to, understood, and treated as individuals. If conversations regarding hormone use are approached with these principles, we will optimize the likelihood our patients are receptive to the highest quality information and not pulled in the direction of unregulated products.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She reported that she had no conflicts of interest. Email Dr. Rossi at [email protected].

References:

1. Maturitas. 2014 Jan;77(1):4-6.

2. Menopause. 2014 Dec;21(12):1298-300.

3. Fertil Steril. 2012 Aug;98(2):308-12.

4. Report: Limited FDA survey of compounded drug products (Silver Spring, Md.: U.S. Food and Drug Administration, 2009).

5. JAMA. 2002;288(3):321-33.

6. BMC Womens Health. 2017 Oct 2;17(1):97.

MAUI, HAWAII – The first-ever, double-blind, randomized, controlled clinical trial evidence demonstrating that methotrexate indeed has therapeutic efficacy in psoriatic arthritis has come at an awkward time – on the heels of a basically negative Cochrane Collaboration systematic review as well as the latest American College of Rheumatology/National Psoriasis Foundation guidelines for treatment of psoriatic arthritis, which recommend anti–tumor necrosis factor therapy as first line, ahead of methotrexate.

The timing of the release of the SEAM-PsA randomized trial results was such that neither the Cochrane group nor the ACR/NPF guideline committee was able to consider the new, potentially game-changing study findings.

“I look at SEAM-PsA and have to say, methotrexate does seem to be an effective therapy. I think it calls into question the new guidelines, which were developed before the data were out. Now you look at this and have to ask, can you really say you should use a TNF inhibitor before methotrexate based on these results? I don’t know,” Eric M. Ruderman, MD, said at the 2019 Rheumatology Winter Clinical Symposium.

He also shared other problems he has with the new guidelines, which he considers seriously flawed.
 

The Cochrane Collaboration Systematic Review

The Cochrane group cast a net for all randomized, controlled clinical trials of methotrexate versus placebo or another disease-modifying antirheumatic drug (DMARD). They found eight, which they judged to be of poor quality. Their conclusion: “Low-quality evidence suggests that low-dose (15 mg or less) oral methotrexate might be slightly more effective than placebo when taken for 6 months; however, we are uncertain if it is more harmful” (Cochrane Database Syst Rev. 2019 Jan 18;1:CD012722. doi: 10.1002/14651858.CD012722.pub2).

Bruce Jancin/MDedge News

“The new Cochrane Review concludes methotrexate doesn’t seem to work that well,” observed symposium director Arthur Kavanaugh, MD, professor of medicine at the University of California, San Diego.

“That’s because it’s based on published data, and there’s been very little of that,” said Dr. Ruderman, professor of medicine and associate chief for clinical affairs in the division of rheumatology at Northwestern University in Chicago.

“I think most people assume, based on clinical experience, that it does work well. It’s all we had for years and years and years,” he added.

That is, until SEAM-PsA.
 

SEAM-PsA

SEAM-PsA randomized 851 DMARD- and biologic-naive patients with a median 0.6-year duration of psoriatic arthritis to one of three treatment arms for 48 weeks: once-weekly etanercept at 50 mg plus oral methotrexate at 20 mg, etanercept plus oral placebo, or methotrexate plus injectable placebo.

This is a study that will reshape clinical practice for many rheumatologists, according to Dr. Kavanaugh. The hypothesis was that in psoriatic arthritis, just as has been shown to be the case in rheumatoid arthritis, the combination of a TNF inhibitor plus methotrexate would have greater efficacy than either agent alone. But the study brought a couple of major surprises.

“Methotrexate didn’t do so badly,” Dr. Kavanaugh observed. “And the combination did nothing. I would have bet that the combination would have shown methotrexate had a synergistic effect with the TNF inhibitor, especially for x-ray changes. But the combination didn’t do any better than etanercept alone.”

Make no mistake: Etanercept monotherapy significantly outperformed methotrexate monotherapy for the primary endpoint, the ACR 20 response at week 24, by a margin of 60.9% versus 50.7%. Dr. Ruderman deemed that methotrexate response rate to be quite respectable, although he bemoaned the absence of a double-placebo comparator arm. And the key secondary endpoint, the minimal disease activity response rate at week 24, was also significantly better with etanercept, at 35.9% compared with 22.9%. Moreover, both etanercept arms showed significantly less radiographic progression than with methotrexate alone.

However, that was it. There were no significant differences between etanercept and methotrexate in other secondary endpoints, including the Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC), the Disease Activity in PSoriatic Arthritis (DAPSA) score, the Leeds Dactylitis Instrument (LDI), and quality of life as assessed by the 36-item Short Form Health Survey total score.

“Methotrexate showed generally good efficacy across multiple domains,” the investigators concluded (Arthritis Rheumatol. 2019 Feb 12. doi: 10.1002/art.40851).

“Another intriguing thing to come out of this study for me were the enthesitis and dactylitis results. My clinical experience suggested methotrexate wasn’t so great for that, but this study suggests that’s not true,” Dr. Ruderman said.

“There are a couple of key take-home points from this study,” according to Dr. Kavanaugh. “One is that the combination is not synergistic. When you start a rheumatoid arthritis patient on methotrexate, you try to keep him on methotrexate when you add a TNF inhibitor. This study would say there doesn’t seem like there’s a reason to do that in your psoriatic arthritis patient. And the second message is that methotrexate seems to work.”

New ACR/NPF psoriatic arthritis guidelines under fire

“The new guidelines are fuzzy, aren’t they?” Dr. Kavanaugh said in lobbing the topic over to Dr. Ruderman.

“Where do we start?” he replied, shaking his head. “These are evidence-based guidelines in an area in which there was virtually no evidence.”

Indeed, the guidelines committee proudly employed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, which forces committee members to issue “conditional” recommendations when there’s not enough evidence to make a “strong” recommendation.

“You’re not allowed to say, ‘We don’t know, there’s not enough evidence to make a choice,’ ” Dr. Ruderman said. “The problem with these guidelines is virtually everything in it is a conditional recommendation except ‘stop smoking,’ which was a strong recommendation.

“A conditional recommendation is pretty much a fancy term for expert opinion. It’s basically everybody in the room saying, ‘This is what we think.’ And that makes guidelines challenging because as a rheumatologist, you’re an expert. The people in the room have perhaps looked at the data more carefully than you’ve drilled down into the studies, but ultimately they’ve taken care of these patients and you’ve taken care of these patients, so why is their opinion better than your opinion, if it’s an informed opinion?”

His other critique of the 28-page guidelines is they don’t include the reasoning behind the conditional recommendations.

“If the conditional recommendation is, ‘In this situation, a TNF inhibitor is preferred over an IL-17 inhibitor,’ that would be great if they had also said, ‘This is why we thought that.’ But that’s not in the paper,” Dr. Ruderman said.

He and Dr. Kavanaugh reported serving as consultants to numerous pharmaceutical companies.

[email protected]

MAUI, HAWAII – The first-ever, double-blind, randomized, controlled clinical trial evidence demonstrating that methotrexate indeed has therapeutic efficacy in psoriatic arthritis has come at an awkward time – on the heels of a basically negative Cochrane Collaboration systematic review as well as the latest American College of Rheumatology/National Psoriasis Foundation guidelines for treatment of psoriatic arthritis, which recommend anti–tumor necrosis factor therapy as first line, ahead of methotrexate.

The timing of the release of the SEAM-PsA randomized trial results was such that neither the Cochrane group nor the ACR/NPF guideline committee was able to consider the new, potentially game-changing study findings.

“I look at SEAM-PsA and have to say, methotrexate does seem to be an effective therapy. I think it calls into question the new guidelines, which were developed before the data were out. Now you look at this and have to ask, can you really say you should use a TNF inhibitor before methotrexate based on these results? I don’t know,” Eric M. Ruderman, MD, said at the 2019 Rheumatology Winter Clinical Symposium.

He also shared other problems he has with the new guidelines, which he considers seriously flawed.
 

The Cochrane Collaboration Systematic Review

The Cochrane group cast a net for all randomized, controlled clinical trials of methotrexate versus placebo or another disease-modifying antirheumatic drug (DMARD). They found eight, which they judged to be of poor quality. Their conclusion: “Low-quality evidence suggests that low-dose (15 mg or less) oral methotrexate might be slightly more effective than placebo when taken for 6 months; however, we are uncertain if it is more harmful” (Cochrane Database Syst Rev. 2019 Jan 18;1:CD012722. doi: 10.1002/14651858.CD012722.pub2).

Bruce Jancin/MDedge News

“The new Cochrane Review concludes methotrexate doesn’t seem to work that well,” observed symposium director Arthur Kavanaugh, MD, professor of medicine at the University of California, San Diego.

“That’s because it’s based on published data, and there’s been very little of that,” said Dr. Ruderman, professor of medicine and associate chief for clinical affairs in the division of rheumatology at Northwestern University in Chicago.

“I think most people assume, based on clinical experience, that it does work well. It’s all we had for years and years and years,” he added.

That is, until SEAM-PsA.
 

SEAM-PsA

SEAM-PsA randomized 851 DMARD- and biologic-naive patients with a median 0.6-year duration of psoriatic arthritis to one of three treatment arms for 48 weeks: once-weekly etanercept at 50 mg plus oral methotrexate at 20 mg, etanercept plus oral placebo, or methotrexate plus injectable placebo.

This is a study that will reshape clinical practice for many rheumatologists, according to Dr. Kavanaugh. The hypothesis was that in psoriatic arthritis, just as has been shown to be the case in rheumatoid arthritis, the combination of a TNF inhibitor plus methotrexate would have greater efficacy than either agent alone. But the study brought a couple of major surprises.

“Methotrexate didn’t do so badly,” Dr. Kavanaugh observed. “And the combination did nothing. I would have bet that the combination would have shown methotrexate had a synergistic effect with the TNF inhibitor, especially for x-ray changes. But the combination didn’t do any better than etanercept alone.”

Make no mistake: Etanercept monotherapy significantly outperformed methotrexate monotherapy for the primary endpoint, the ACR 20 response at week 24, by a margin of 60.9% versus 50.7%. Dr. Ruderman deemed that methotrexate response rate to be quite respectable, although he bemoaned the absence of a double-placebo comparator arm. And the key secondary endpoint, the minimal disease activity response rate at week 24, was also significantly better with etanercept, at 35.9% compared with 22.9%. Moreover, both etanercept arms showed significantly less radiographic progression than with methotrexate alone.

However, that was it. There were no significant differences between etanercept and methotrexate in other secondary endpoints, including the Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC), the Disease Activity in PSoriatic Arthritis (DAPSA) score, the Leeds Dactylitis Instrument (LDI), and quality of life as assessed by the 36-item Short Form Health Survey total score.

“Methotrexate showed generally good efficacy across multiple domains,” the investigators concluded (Arthritis Rheumatol. 2019 Feb 12. doi: 10.1002/art.40851).

“Another intriguing thing to come out of this study for me were the enthesitis and dactylitis results. My clinical experience suggested methotrexate wasn’t so great for that, but this study suggests that’s not true,” Dr. Ruderman said.

“There are a couple of key take-home points from this study,” according to Dr. Kavanaugh. “One is that the combination is not synergistic. When you start a rheumatoid arthritis patient on methotrexate, you try to keep him on methotrexate when you add a TNF inhibitor. This study would say there doesn’t seem like there’s a reason to do that in your psoriatic arthritis patient. And the second message is that methotrexate seems to work.”

New ACR/NPF psoriatic arthritis guidelines under fire

“The new guidelines are fuzzy, aren’t they?” Dr. Kavanaugh said in lobbing the topic over to Dr. Ruderman.

“Where do we start?” he replied, shaking his head. “These are evidence-based guidelines in an area in which there was virtually no evidence.”

Indeed, the guidelines committee proudly employed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, which forces committee members to issue “conditional” recommendations when there’s not enough evidence to make a “strong” recommendation.

“You’re not allowed to say, ‘We don’t know, there’s not enough evidence to make a choice,’ ” Dr. Ruderman said. “The problem with these guidelines is virtually everything in it is a conditional recommendation except ‘stop smoking,’ which was a strong recommendation.

“A conditional recommendation is pretty much a fancy term for expert opinion. It’s basically everybody in the room saying, ‘This is what we think.’ And that makes guidelines challenging because as a rheumatologist, you’re an expert. The people in the room have perhaps looked at the data more carefully than you’ve drilled down into the studies, but ultimately they’ve taken care of these patients and you’ve taken care of these patients, so why is their opinion better than your opinion, if it’s an informed opinion?”

His other critique of the 28-page guidelines is they don’t include the reasoning behind the conditional recommendations.

“If the conditional recommendation is, ‘In this situation, a TNF inhibitor is preferred over an IL-17 inhibitor,’ that would be great if they had also said, ‘This is why we thought that.’ But that’s not in the paper,” Dr. Ruderman said.

He and Dr. Kavanaugh reported serving as consultants to numerous pharmaceutical companies.

[email protected]

MAUI, HAWAII – The first-ever, double-blind, randomized, controlled clinical trial evidence demonstrating that methotrexate indeed has therapeutic efficacy in psoriatic arthritis has come at an awkward time – on the heels of a basically negative Cochrane Collaboration systematic review as well as the latest American College of Rheumatology/National Psoriasis Foundation guidelines for treatment of psoriatic arthritis, which recommend anti–tumor necrosis factor therapy as first line, ahead of methotrexate.

The timing of the release of the SEAM-PsA randomized trial results was such that neither the Cochrane group nor the ACR/NPF guideline committee was able to consider the new, potentially game-changing study findings.

“I look at SEAM-PsA and have to say, methotrexate does seem to be an effective therapy. I think it calls into question the new guidelines, which were developed before the data were out. Now you look at this and have to ask, can you really say you should use a TNF inhibitor before methotrexate based on these results? I don’t know,” Eric M. Ruderman, MD, said at the 2019 Rheumatology Winter Clinical Symposium.

He also shared other problems he has with the new guidelines, which he considers seriously flawed.
 

The Cochrane Collaboration Systematic Review

The Cochrane group cast a net for all randomized, controlled clinical trials of methotrexate versus placebo or another disease-modifying antirheumatic drug (DMARD). They found eight, which they judged to be of poor quality. Their conclusion: “Low-quality evidence suggests that low-dose (15 mg or less) oral methotrexate might be slightly more effective than placebo when taken for 6 months; however, we are uncertain if it is more harmful” (Cochrane Database Syst Rev. 2019 Jan 18;1:CD012722. doi: 10.1002/14651858.CD012722.pub2).

Bruce Jancin/MDedge News

“The new Cochrane Review concludes methotrexate doesn’t seem to work that well,” observed symposium director Arthur Kavanaugh, MD, professor of medicine at the University of California, San Diego.

“That’s because it’s based on published data, and there’s been very little of that,” said Dr. Ruderman, professor of medicine and associate chief for clinical affairs in the division of rheumatology at Northwestern University in Chicago.

“I think most people assume, based on clinical experience, that it does work well. It’s all we had for years and years and years,” he added.

That is, until SEAM-PsA.
 

SEAM-PsA

SEAM-PsA randomized 851 DMARD- and biologic-naive patients with a median 0.6-year duration of psoriatic arthritis to one of three treatment arms for 48 weeks: once-weekly etanercept at 50 mg plus oral methotrexate at 20 mg, etanercept plus oral placebo, or methotrexate plus injectable placebo.

This is a study that will reshape clinical practice for many rheumatologists, according to Dr. Kavanaugh. The hypothesis was that in psoriatic arthritis, just as has been shown to be the case in rheumatoid arthritis, the combination of a TNF inhibitor plus methotrexate would have greater efficacy than either agent alone. But the study brought a couple of major surprises.

“Methotrexate didn’t do so badly,” Dr. Kavanaugh observed. “And the combination did nothing. I would have bet that the combination would have shown methotrexate had a synergistic effect with the TNF inhibitor, especially for x-ray changes. But the combination didn’t do any better than etanercept alone.”

Make no mistake: Etanercept monotherapy significantly outperformed methotrexate monotherapy for the primary endpoint, the ACR 20 response at week 24, by a margin of 60.9% versus 50.7%. Dr. Ruderman deemed that methotrexate response rate to be quite respectable, although he bemoaned the absence of a double-placebo comparator arm. And the key secondary endpoint, the minimal disease activity response rate at week 24, was also significantly better with etanercept, at 35.9% compared with 22.9%. Moreover, both etanercept arms showed significantly less radiographic progression than with methotrexate alone.

However, that was it. There were no significant differences between etanercept and methotrexate in other secondary endpoints, including the Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC), the Disease Activity in PSoriatic Arthritis (DAPSA) score, the Leeds Dactylitis Instrument (LDI), and quality of life as assessed by the 36-item Short Form Health Survey total score.

“Methotrexate showed generally good efficacy across multiple domains,” the investigators concluded (Arthritis Rheumatol. 2019 Feb 12. doi: 10.1002/art.40851).

“Another intriguing thing to come out of this study for me were the enthesitis and dactylitis results. My clinical experience suggested methotrexate wasn’t so great for that, but this study suggests that’s not true,” Dr. Ruderman said.

“There are a couple of key take-home points from this study,” according to Dr. Kavanaugh. “One is that the combination is not synergistic. When you start a rheumatoid arthritis patient on methotrexate, you try to keep him on methotrexate when you add a TNF inhibitor. This study would say there doesn’t seem like there’s a reason to do that in your psoriatic arthritis patient. And the second message is that methotrexate seems to work.”

New ACR/NPF psoriatic arthritis guidelines under fire

“The new guidelines are fuzzy, aren’t they?” Dr. Kavanaugh said in lobbing the topic over to Dr. Ruderman.

“Where do we start?” he replied, shaking his head. “These are evidence-based guidelines in an area in which there was virtually no evidence.”

Indeed, the guidelines committee proudly employed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, which forces committee members to issue “conditional” recommendations when there’s not enough evidence to make a “strong” recommendation.

“You’re not allowed to say, ‘We don’t know, there’s not enough evidence to make a choice,’ ” Dr. Ruderman said. “The problem with these guidelines is virtually everything in it is a conditional recommendation except ‘stop smoking,’ which was a strong recommendation.

“A conditional recommendation is pretty much a fancy term for expert opinion. It’s basically everybody in the room saying, ‘This is what we think.’ And that makes guidelines challenging because as a rheumatologist, you’re an expert. The people in the room have perhaps looked at the data more carefully than you’ve drilled down into the studies, but ultimately they’ve taken care of these patients and you’ve taken care of these patients, so why is their opinion better than your opinion, if it’s an informed opinion?”

His other critique of the 28-page guidelines is they don’t include the reasoning behind the conditional recommendations.

“If the conditional recommendation is, ‘In this situation, a TNF inhibitor is preferred over an IL-17 inhibitor,’ that would be great if they had also said, ‘This is why we thought that.’ But that’s not in the paper,” Dr. Ruderman said.

He and Dr. Kavanaugh reported serving as consultants to numerous pharmaceutical companies.

[email protected]

ATLANTA – Blood tumor mutational burden (bTMB) predicts survival benefit in metastatic non–small cell lung cancer (mNSCLC) patients treated with first-line durvalumab plus tremelimumab versus platinum-based chemotherapy, according to findings from the open-label, phase 3 MYSTIC trial.

Frontline Medical News

Specifically, in patients with bTMB based on circulating tumor DNA at levels of 20 mutations (mut)/megabase (Mb) or greater, overall survival (OS) was significantly improved with durvalumab alone and with durvalumab plus tremelimumab versus chemotherapy (hazard ratios, 0.74 and 0.49, respectively). Progression-free survival (PFS) was also improved (HRs, 0.76 and 0.53, respectively), Solange Peters, MD, PhD, reported at the annual meeting of the American Association for Cancer Research.

Among patients with bTMB less than 20 mut/Mb, the corresponding OS hazard ratios were 1.55 and 1.26, and the corresponding PFS hazard ratios were 1.22 and 1.16, said Dr. Peters, director of teaching and patient care in the area of medical oncology and thoracic malignancies at Centre Hospitalier Universitaire Vaudois, Lausanne (Switzerland) University, and president-elect of the European Society for Medical Oncology.

Study subjects were 1,118 patients with immunotherapy- and chemotherapy-naive EGFR and ALK wild-type mNSCLC who were randomized 1:1 to receive either the programmed death–ligand 1 (PD-L1) agent durvalumab, durvalumab plus the anti-CTLA4 agent tremelimumab, or chemotherapy. At a tissue TMB (tTMB) level of 10 mut/Mb or greater, those who received either durvalumab or durvalumab plus tremelimumab had better OS than did those who received chemotherapy (HRs, 0.70 and 0.72, respectively).

Further, bTMB levels of at least 16 mut/Mb correlated positively with tTMB (Spearman correlation coefficient, 0.6; Pearson correlation coefficient, 0.7), she said, adding that survival probability at 24 months was 41.7% with durvalumab plus tremelimumab versus 35.0% with durvalumab alone and 22.7% with chemotherapy in this patient subgroup.

“When you look at the subgroup of patients with lower number of mutations than 10, this phenomenon is not observed. If anything should be potentially stressed about these hazard ratios – all above 1 – is potentially that chemotherapy represents a better option in this patient population,” she said.

Treatment included intravenous durvalumab at a dose of 20 mg/kg every 4 weeks with or without IV tremelimumab at a dose of 1 mg/kg every 4 weeks for up to four doses (372 and 374 patients, respectively), or platinum-based chemotherapy (372 patients).

“Durvalumab ... is already approved for unresectable stage 3 NSCLC and has shown clinical activity in heavily pretreated patients with mNSCLC in the context of phase 2 and 3 previously presented trials,” Dr. Peters said, noting that the multicenter MYSTIC trial was designed to assess its potential role in the treatment of all-comers with stage IV disease.


Overall survival data from the study were presented at the 2018 ESMO Immuno-Oncology Congress, and showed that the primary endpoint of superiority of durvalumab or durvalumab plus tremelimumab versus chemotherapy for OS in patients with high PD-L1 expression (at least 25% of tumor cells expressing PD-L1) was not met. There did, however, appear to be a clinically meaningful 3-month survival benefit (HR, 0.76) with durvalumab, she said.

The idea of combining durvalumab with tremelimumab was based on the potential for “antitumor activity via nonredundant pathways,” she noted, further explaining that the interest in determining whether bTMB correlates with tTMB relates to the rapid availability and less invasive nature of the latter and the fact that bTMB measured from circulating tumor DNA, “biologically speaking, may be more representative of the heterogeneity of metastatic lesions in the context of an advanced disease.”

The current findings are from exploratory analyses looking at OS based on bTMB and tTMB at varying levels to “better understand optimal outcomes and potential contributions of tremelimumab,” she said, noting that survival benefit was observed in all subgroups defined by a high TMB (equal to or greater than vs. less than 4, 8, 12, 16, and 20 mut/Mb).

Outcomes using the bTMB cutoff of 16 or greater mut/Mb were also presented at the ESMO meeting, and showed an OS benefit with durvalumab and durvalumab plus tremelimumab versus chemotherapy in those patients; the finding was more pronounced with durvalumab plus tremelimumab (HR, 0.82 and 0.62, respectively), and the effect increased with increasing bTMB levels.

“Based on that, we decided to [use the 20 mut/Mb or greater] cutoff to conduct a subsequent analysis,” Dr. Peters said, noting again the “very significantly improved” OS and PFS for combined treatment versus chemotherapy with 20 or greater versus less than 20 mut/Mb, and the value of chemotherapy in those with lower bTMB.

Tumor response was also better with durvalumab plus tremelimumab versus chemotherapy at this cutoff; objective response rates were 29.9% and 48.4% with durvalumab and durvalumab plus tremelimumab, respectively, versus 21.4% with chemotherapy.

“Again, under this threshold [less than 20 mut/Mb], it looked like chemotherapy was offering a better response rate with 31.4% as compared to 20% and less for the immunotherapy strategy,” she said.

Also of note, the percentage of patients remaining in response at 6 and 12 months was much better in those who received immunotherapy with durvalumab plus tremelimumab versus chemotherapy; this was more pronounced in those with high TMB (85.6% vs. 14.4% at 6 months; 81.7% vs. 7.2% at 12 months).

No differences were seen in toxicity patterns in the subgroup of patients with bTMB greater than 20 mut/Mb when compared with the overall safety population from MYSTIC, she added.

“Based on this exploratory analysis, further investigation and prospective validation of bTMB as a predictive biomarker for immunotherapy is warranted and should potentially be evaluated in as many as possible future clinical trials looking at immunotherapy across various solid tumors,” Dr. Peters said.

MYSTIC is sponsored by AstraZeneca. Dr. Peters reported relationships – including receipt of honoraria or consulting fees, receipt of grant/research support, and/or speaking engagements – with numerous pharmaceutical companies.

[email protected]

ATLANTA – Blood tumor mutational burden (bTMB) predicts survival benefit in metastatic non–small cell lung cancer (mNSCLC) patients treated with first-line durvalumab plus tremelimumab versus platinum-based chemotherapy, according to findings from the open-label, phase 3 MYSTIC trial.

Frontline Medical News

Specifically, in patients with bTMB based on circulating tumor DNA at levels of 20 mutations (mut)/megabase (Mb) or greater, overall survival (OS) was significantly improved with durvalumab alone and with durvalumab plus tremelimumab versus chemotherapy (hazard ratios, 0.74 and 0.49, respectively). Progression-free survival (PFS) was also improved (HRs, 0.76 and 0.53, respectively), Solange Peters, MD, PhD, reported at the annual meeting of the American Association for Cancer Research.

Among patients with bTMB less than 20 mut/Mb, the corresponding OS hazard ratios were 1.55 and 1.26, and the corresponding PFS hazard ratios were 1.22 and 1.16, said Dr. Peters, director of teaching and patient care in the area of medical oncology and thoracic malignancies at Centre Hospitalier Universitaire Vaudois, Lausanne (Switzerland) University, and president-elect of the European Society for Medical Oncology.

Study subjects were 1,118 patients with immunotherapy- and chemotherapy-naive EGFR and ALK wild-type mNSCLC who were randomized 1:1 to receive either the programmed death–ligand 1 (PD-L1) agent durvalumab, durvalumab plus the anti-CTLA4 agent tremelimumab, or chemotherapy. At a tissue TMB (tTMB) level of 10 mut/Mb or greater, those who received either durvalumab or durvalumab plus tremelimumab had better OS than did those who received chemotherapy (HRs, 0.70 and 0.72, respectively).

Further, bTMB levels of at least 16 mut/Mb correlated positively with tTMB (Spearman correlation coefficient, 0.6; Pearson correlation coefficient, 0.7), she said, adding that survival probability at 24 months was 41.7% with durvalumab plus tremelimumab versus 35.0% with durvalumab alone and 22.7% with chemotherapy in this patient subgroup.

“When you look at the subgroup of patients with lower number of mutations than 10, this phenomenon is not observed. If anything should be potentially stressed about these hazard ratios – all above 1 – is potentially that chemotherapy represents a better option in this patient population,” she said.

Treatment included intravenous durvalumab at a dose of 20 mg/kg every 4 weeks with or without IV tremelimumab at a dose of 1 mg/kg every 4 weeks for up to four doses (372 and 374 patients, respectively), or platinum-based chemotherapy (372 patients).

“Durvalumab ... is already approved for unresectable stage 3 NSCLC and has shown clinical activity in heavily pretreated patients with mNSCLC in the context of phase 2 and 3 previously presented trials,” Dr. Peters said, noting that the multicenter MYSTIC trial was designed to assess its potential role in the treatment of all-comers with stage IV disease.


Overall survival data from the study were presented at the 2018 ESMO Immuno-Oncology Congress, and showed that the primary endpoint of superiority of durvalumab or durvalumab plus tremelimumab versus chemotherapy for OS in patients with high PD-L1 expression (at least 25% of tumor cells expressing PD-L1) was not met. There did, however, appear to be a clinically meaningful 3-month survival benefit (HR, 0.76) with durvalumab, she said.

The idea of combining durvalumab with tremelimumab was based on the potential for “antitumor activity via nonredundant pathways,” she noted, further explaining that the interest in determining whether bTMB correlates with tTMB relates to the rapid availability and less invasive nature of the latter and the fact that bTMB measured from circulating tumor DNA, “biologically speaking, may be more representative of the heterogeneity of metastatic lesions in the context of an advanced disease.”

The current findings are from exploratory analyses looking at OS based on bTMB and tTMB at varying levels to “better understand optimal outcomes and potential contributions of tremelimumab,” she said, noting that survival benefit was observed in all subgroups defined by a high TMB (equal to or greater than vs. less than 4, 8, 12, 16, and 20 mut/Mb).

Outcomes using the bTMB cutoff of 16 or greater mut/Mb were also presented at the ESMO meeting, and showed an OS benefit with durvalumab and durvalumab plus tremelimumab versus chemotherapy in those patients; the finding was more pronounced with durvalumab plus tremelimumab (HR, 0.82 and 0.62, respectively), and the effect increased with increasing bTMB levels.

“Based on that, we decided to [use the 20 mut/Mb or greater] cutoff to conduct a subsequent analysis,” Dr. Peters said, noting again the “very significantly improved” OS and PFS for combined treatment versus chemotherapy with 20 or greater versus less than 20 mut/Mb, and the value of chemotherapy in those with lower bTMB.

Tumor response was also better with durvalumab plus tremelimumab versus chemotherapy at this cutoff; objective response rates were 29.9% and 48.4% with durvalumab and durvalumab plus tremelimumab, respectively, versus 21.4% with chemotherapy.

“Again, under this threshold [less than 20 mut/Mb], it looked like chemotherapy was offering a better response rate with 31.4% as compared to 20% and less for the immunotherapy strategy,” she said.

Also of note, the percentage of patients remaining in response at 6 and 12 months was much better in those who received immunotherapy with durvalumab plus tremelimumab versus chemotherapy; this was more pronounced in those with high TMB (85.6% vs. 14.4% at 6 months; 81.7% vs. 7.2% at 12 months).

No differences were seen in toxicity patterns in the subgroup of patients with bTMB greater than 20 mut/Mb when compared with the overall safety population from MYSTIC, she added.

“Based on this exploratory analysis, further investigation and prospective validation of bTMB as a predictive biomarker for immunotherapy is warranted and should potentially be evaluated in as many as possible future clinical trials looking at immunotherapy across various solid tumors,” Dr. Peters said.

MYSTIC is sponsored by AstraZeneca. Dr. Peters reported relationships – including receipt of honoraria or consulting fees, receipt of grant/research support, and/or speaking engagements – with numerous pharmaceutical companies.

[email protected]

ATLANTA – Blood tumor mutational burden (bTMB) predicts survival benefit in metastatic non–small cell lung cancer (mNSCLC) patients treated with first-line durvalumab plus tremelimumab versus platinum-based chemotherapy, according to findings from the open-label, phase 3 MYSTIC trial.

Frontline Medical News

Specifically, in patients with bTMB based on circulating tumor DNA at levels of 20 mutations (mut)/megabase (Mb) or greater, overall survival (OS) was significantly improved with durvalumab alone and with durvalumab plus tremelimumab versus chemotherapy (hazard ratios, 0.74 and 0.49, respectively). Progression-free survival (PFS) was also improved (HRs, 0.76 and 0.53, respectively), Solange Peters, MD, PhD, reported at the annual meeting of the American Association for Cancer Research.

Among patients with bTMB less than 20 mut/Mb, the corresponding OS hazard ratios were 1.55 and 1.26, and the corresponding PFS hazard ratios were 1.22 and 1.16, said Dr. Peters, director of teaching and patient care in the area of medical oncology and thoracic malignancies at Centre Hospitalier Universitaire Vaudois, Lausanne (Switzerland) University, and president-elect of the European Society for Medical Oncology.

Study subjects were 1,118 patients with immunotherapy- and chemotherapy-naive EGFR and ALK wild-type mNSCLC who were randomized 1:1 to receive either the programmed death–ligand 1 (PD-L1) agent durvalumab, durvalumab plus the anti-CTLA4 agent tremelimumab, or chemotherapy. At a tissue TMB (tTMB) level of 10 mut/Mb or greater, those who received either durvalumab or durvalumab plus tremelimumab had better OS than did those who received chemotherapy (HRs, 0.70 and 0.72, respectively).

Further, bTMB levels of at least 16 mut/Mb correlated positively with tTMB (Spearman correlation coefficient, 0.6; Pearson correlation coefficient, 0.7), she said, adding that survival probability at 24 months was 41.7% with durvalumab plus tremelimumab versus 35.0% with durvalumab alone and 22.7% with chemotherapy in this patient subgroup.

“When you look at the subgroup of patients with lower number of mutations than 10, this phenomenon is not observed. If anything should be potentially stressed about these hazard ratios – all above 1 – is potentially that chemotherapy represents a better option in this patient population,” she said.

Treatment included intravenous durvalumab at a dose of 20 mg/kg every 4 weeks with or without IV tremelimumab at a dose of 1 mg/kg every 4 weeks for up to four doses (372 and 374 patients, respectively), or platinum-based chemotherapy (372 patients).

“Durvalumab ... is already approved for unresectable stage 3 NSCLC and has shown clinical activity in heavily pretreated patients with mNSCLC in the context of phase 2 and 3 previously presented trials,” Dr. Peters said, noting that the multicenter MYSTIC trial was designed to assess its potential role in the treatment of all-comers with stage IV disease.


Overall survival data from the study were presented at the 2018 ESMO Immuno-Oncology Congress, and showed that the primary endpoint of superiority of durvalumab or durvalumab plus tremelimumab versus chemotherapy for OS in patients with high PD-L1 expression (at least 25% of tumor cells expressing PD-L1) was not met. There did, however, appear to be a clinically meaningful 3-month survival benefit (HR, 0.76) with durvalumab, she said.

The idea of combining durvalumab with tremelimumab was based on the potential for “antitumor activity via nonredundant pathways,” she noted, further explaining that the interest in determining whether bTMB correlates with tTMB relates to the rapid availability and less invasive nature of the latter and the fact that bTMB measured from circulating tumor DNA, “biologically speaking, may be more representative of the heterogeneity of metastatic lesions in the context of an advanced disease.”

The current findings are from exploratory analyses looking at OS based on bTMB and tTMB at varying levels to “better understand optimal outcomes and potential contributions of tremelimumab,” she said, noting that survival benefit was observed in all subgroups defined by a high TMB (equal to or greater than vs. less than 4, 8, 12, 16, and 20 mut/Mb).

Outcomes using the bTMB cutoff of 16 or greater mut/Mb were also presented at the ESMO meeting, and showed an OS benefit with durvalumab and durvalumab plus tremelimumab versus chemotherapy in those patients; the finding was more pronounced with durvalumab plus tremelimumab (HR, 0.82 and 0.62, respectively), and the effect increased with increasing bTMB levels.

“Based on that, we decided to [use the 20 mut/Mb or greater] cutoff to conduct a subsequent analysis,” Dr. Peters said, noting again the “very significantly improved” OS and PFS for combined treatment versus chemotherapy with 20 or greater versus less than 20 mut/Mb, and the value of chemotherapy in those with lower bTMB.

Tumor response was also better with durvalumab plus tremelimumab versus chemotherapy at this cutoff; objective response rates were 29.9% and 48.4% with durvalumab and durvalumab plus tremelimumab, respectively, versus 21.4% with chemotherapy.

“Again, under this threshold [less than 20 mut/Mb], it looked like chemotherapy was offering a better response rate with 31.4% as compared to 20% and less for the immunotherapy strategy,” she said.

Also of note, the percentage of patients remaining in response at 6 and 12 months was much better in those who received immunotherapy with durvalumab plus tremelimumab versus chemotherapy; this was more pronounced in those with high TMB (85.6% vs. 14.4% at 6 months; 81.7% vs. 7.2% at 12 months).

No differences were seen in toxicity patterns in the subgroup of patients with bTMB greater than 20 mut/Mb when compared with the overall safety population from MYSTIC, she added.

“Based on this exploratory analysis, further investigation and prospective validation of bTMB as a predictive biomarker for immunotherapy is warranted and should potentially be evaluated in as many as possible future clinical trials looking at immunotherapy across various solid tumors,” Dr. Peters said.

MYSTIC is sponsored by AstraZeneca. Dr. Peters reported relationships – including receipt of honoraria or consulting fees, receipt of grant/research support, and/or speaking engagements – with numerous pharmaceutical companies.

[email protected]