References

1. Crockett SD, Greer KB, Heidelbaugh JJ, et al. American Gastroenterological Association Institute Guideline on the Medical Management of Opioid-Induced Constipation. Gastroenterology. 2019;156:218-226.
2. Rao VL, Micic D, Davis AM. Medical management of opioid-induced constipation. JAMA. 2019;322:2241-2242.
3. Naldemedine (Symproic) for opioid-induced constipation. Med Lett Drugs Ther. 2017;59:196-198.
4. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016. MMWR Recomm Rep. 2016;65:1-49.

References

1. Crockett SD, Greer KB, Heidelbaugh JJ, et al. American Gastroenterological Association Institute Guideline on the Medical Management of Opioid-Induced Constipation. Gastroenterology. 2019;156:218-226.
2. Rao VL, Micic D, Davis AM. Medical management of opioid-induced constipation. JAMA. 2019;322:2241-2242.
3. Naldemedine (Symproic) for opioid-induced constipation. Med Lett Drugs Ther. 2017;59:196-198.
4. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016. MMWR Recomm Rep. 2016;65:1-49.

References

1. Crockett SD, Greer KB, Heidelbaugh JJ, et al. American Gastroenterological Association Institute Guideline on the Medical Management of Opioid-Induced Constipation. Gastroenterology. 2019;156:218-226.
2. Rao VL, Micic D, Davis AM. Medical management of opioid-induced constipation. JAMA. 2019;322:2241-2242.
3. Naldemedine (Symproic) for opioid-induced constipation. Med Lett Drugs Ther. 2017;59:196-198.
4. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016. MMWR Recomm Rep. 2016;65:1-49.

As the debate over how best to address surprise billing continues, new research shows that billing from out-of-network physicians at in-network facilities is adding $40 billion in costs.

utah778/Thinkstock

Researchers focused on four different types of physicians that account for out-of-network billing: anesthesiologists, pathologists, radiologists, and cases involving an assistant surgeon, which had out-of-network bills in about 10% of claims that were examined as part of the research.

“To give a rough estimate of the savings that could be achieved by eliminating the ability of these four types of specialists to readily bill out of network, we simulated what would happen if all of these specialists received the same average payments as orthopedic surgeons did (164% of Medicare rates),” Zack Cooper, PhD, associate professor of health policy at Yale University, New Haven, Conn., and colleagues wrote in a research report published in Health Affairs.

“We estimated that if these physicians were paid the same average rate as orthopedists for all of the services that they delivered in our sample, spending would be lowered on anesthesiologists by 53.5%, on pathologists by 47.4%, on radiologists by 16.3%, and on assistant surgeons by 46.2%,” the authors wrote.

Researchers said that physician spending for these four specialties would be lowered by 13.4% and would lower total spending for people with employer-sponsored insurance by about 3.4%, or $40 billion. If spending on these four specialties were lowered to 150% of Medicare rates, it would lower spending on physicians by 15.3%.

To help combat the issues of surprise billing in a way that lowers total commercial health care spending and helps to preserve a competitive price for physician services, Dr. Cooper and colleagues recommended an approach that would regulate the contracts of physicians who work in hospitals and are not chosen by patients. It would establish a bundled package for services that include the emergency department physicians and the four specialists examined as part of the research and would use the fee associated with the package of services to recruit specialists to work at the hospital.

The authors said this kind of policy would eliminate the possibility of patients seeing out-of-network providers at in-network hospitals and, unlike arbitration (a favored solution among physician groups if it is set up in an agreeable manner), patients are protected without being required to take any action. The policy also sets a competitive rate for these services.

“Under this bundled care approach, physicians would compete to offer their services on the basis of price and quality,” Dr. Cooper and colleagues stated. “Hospitals would compete with one another on the price and quality of their care, including the services provided by the physicians they recruited. Hospitals would also need to compete to retain physicians.”

This approach is not included in any current surprise billing legislation. There was hope that surprise billing would be addressed in a government spending bill that would be signed before year’s end. But a second bipartisan plan was introduced in the House Ways and Means Committee after a bipartisan compromise was reached by the House Energy and Commerce and the Senate Health, Education, Labor, and Pensions committees. This has postponed a decision on surprise billing legislation into the coming year.

[email protected]

SOURCE: Cooper Z et al. Health Aff. 2019 Dec 16. doi: 10.1377/hlthaff.2019.00507.

As the debate over how best to address surprise billing continues, new research shows that billing from out-of-network physicians at in-network facilities is adding $40 billion in costs.

utah778/Thinkstock

Researchers focused on four different types of physicians that account for out-of-network billing: anesthesiologists, pathologists, radiologists, and cases involving an assistant surgeon, which had out-of-network bills in about 10% of claims that were examined as part of the research.

“To give a rough estimate of the savings that could be achieved by eliminating the ability of these four types of specialists to readily bill out of network, we simulated what would happen if all of these specialists received the same average payments as orthopedic surgeons did (164% of Medicare rates),” Zack Cooper, PhD, associate professor of health policy at Yale University, New Haven, Conn., and colleagues wrote in a research report published in Health Affairs.

“We estimated that if these physicians were paid the same average rate as orthopedists for all of the services that they delivered in our sample, spending would be lowered on anesthesiologists by 53.5%, on pathologists by 47.4%, on radiologists by 16.3%, and on assistant surgeons by 46.2%,” the authors wrote.

Researchers said that physician spending for these four specialties would be lowered by 13.4% and would lower total spending for people with employer-sponsored insurance by about 3.4%, or $40 billion. If spending on these four specialties were lowered to 150% of Medicare rates, it would lower spending on physicians by 15.3%.

To help combat the issues of surprise billing in a way that lowers total commercial health care spending and helps to preserve a competitive price for physician services, Dr. Cooper and colleagues recommended an approach that would regulate the contracts of physicians who work in hospitals and are not chosen by patients. It would establish a bundled package for services that include the emergency department physicians and the four specialists examined as part of the research and would use the fee associated with the package of services to recruit specialists to work at the hospital.

The authors said this kind of policy would eliminate the possibility of patients seeing out-of-network providers at in-network hospitals and, unlike arbitration (a favored solution among physician groups if it is set up in an agreeable manner), patients are protected without being required to take any action. The policy also sets a competitive rate for these services.

“Under this bundled care approach, physicians would compete to offer their services on the basis of price and quality,” Dr. Cooper and colleagues stated. “Hospitals would compete with one another on the price and quality of their care, including the services provided by the physicians they recruited. Hospitals would also need to compete to retain physicians.”

This approach is not included in any current surprise billing legislation. There was hope that surprise billing would be addressed in a government spending bill that would be signed before year’s end. But a second bipartisan plan was introduced in the House Ways and Means Committee after a bipartisan compromise was reached by the House Energy and Commerce and the Senate Health, Education, Labor, and Pensions committees. This has postponed a decision on surprise billing legislation into the coming year.

[email protected]

SOURCE: Cooper Z et al. Health Aff. 2019 Dec 16. doi: 10.1377/hlthaff.2019.00507.

As the debate over how best to address surprise billing continues, new research shows that billing from out-of-network physicians at in-network facilities is adding $40 billion in costs.

utah778/Thinkstock

Researchers focused on four different types of physicians that account for out-of-network billing: anesthesiologists, pathologists, radiologists, and cases involving an assistant surgeon, which had out-of-network bills in about 10% of claims that were examined as part of the research.

“To give a rough estimate of the savings that could be achieved by eliminating the ability of these four types of specialists to readily bill out of network, we simulated what would happen if all of these specialists received the same average payments as orthopedic surgeons did (164% of Medicare rates),” Zack Cooper, PhD, associate professor of health policy at Yale University, New Haven, Conn., and colleagues wrote in a research report published in Health Affairs.

“We estimated that if these physicians were paid the same average rate as orthopedists for all of the services that they delivered in our sample, spending would be lowered on anesthesiologists by 53.5%, on pathologists by 47.4%, on radiologists by 16.3%, and on assistant surgeons by 46.2%,” the authors wrote.

Researchers said that physician spending for these four specialties would be lowered by 13.4% and would lower total spending for people with employer-sponsored insurance by about 3.4%, or $40 billion. If spending on these four specialties were lowered to 150% of Medicare rates, it would lower spending on physicians by 15.3%.

To help combat the issues of surprise billing in a way that lowers total commercial health care spending and helps to preserve a competitive price for physician services, Dr. Cooper and colleagues recommended an approach that would regulate the contracts of physicians who work in hospitals and are not chosen by patients. It would establish a bundled package for services that include the emergency department physicians and the four specialists examined as part of the research and would use the fee associated with the package of services to recruit specialists to work at the hospital.

The authors said this kind of policy would eliminate the possibility of patients seeing out-of-network providers at in-network hospitals and, unlike arbitration (a favored solution among physician groups if it is set up in an agreeable manner), patients are protected without being required to take any action. The policy also sets a competitive rate for these services.

“Under this bundled care approach, physicians would compete to offer their services on the basis of price and quality,” Dr. Cooper and colleagues stated. “Hospitals would compete with one another on the price and quality of their care, including the services provided by the physicians they recruited. Hospitals would also need to compete to retain physicians.”

This approach is not included in any current surprise billing legislation. There was hope that surprise billing would be addressed in a government spending bill that would be signed before year’s end. But a second bipartisan plan was introduced in the House Ways and Means Committee after a bipartisan compromise was reached by the House Energy and Commerce and the Senate Health, Education, Labor, and Pensions committees. This has postponed a decision on surprise billing legislation into the coming year.

[email protected]

SOURCE: Cooper Z et al. Health Aff. 2019 Dec 16. doi: 10.1377/hlthaff.2019.00507.

For third- or fourth-line treatment of metastatic renal cell carcinoma, the vascular epidermal growth factor receptor (VEGFR) tyrosine kinase inhibitor tivozanib may offer better progression-free survival than sorafenib, another VEGFR inhibitor, based on results from the TIVO-3 trial.

Susan London/MDedge News

Tivozanib also had fewer dose reductions and dose interruptions than sorafenib, likely because of less off-target activity, reported lead author Brian I. Rini, MD, of the Cleveland Clinic and Case Western Reserve University, also in Cleveland, and colleagues.

“These results support tivozanib as a treatment option for patients with recurrent and progressive renal cell carcinoma, including those who have progressed after previous immunotherapy,” the investigators wrote in Lancet Oncology.

The open-label, phase 3 trial involved 350 patients with metastatic renal cell carcinoma who had been treated with two or more systemic therapies, at least one of which was a VEGFR inhibitor. Patients were randomized in 1:1 ratio to receive either tivozanib 1.5 mg orally once daily in 4-week cycles or sorafenib 400 mg orally twice daily on a continuous basis. The primary endpoint was progression-free survival. Secondary endpoints included overall survival, objective response rates, and duration of response. Endpoints were evaluated by independent review. Safety was reported for all patients who received one or more doses of therapy.

After a median follow-up of 19 months, tivozanib was associated with a median progression-free survival of 5.6 months, compared with 3.9 months for sorafenib (P = .016). Significantly more patients in the tivozanib group achieved a response, and at 1 year, 71% of patients in the tivozanib group maintained a response, compared with 46% of the patients in the sorafenib group. At data cutoff, median overall survival was not significantly different between groups.

The most common treatment-related grade 3-4 adverse event was hypertension, which occurred in a slightly higher rate among those treated with tivozanib (20% vs. 14%). Serious treatment-related adverse events occurred at comparable rates in each treatment arm, at 11% for tivozanib and 10% for sorafenib. Compared with patients who received sorafenib, those in the tivozanib group had fewer dose reductions (24% vs. 38%) and dose interruptions (48% vs. 63%) because of adverse events, a benefit that the investigators attributed to relatively lower class-related off-target activity.

“To our knowledge, TIVO-3 provides the largest amount of prospective data generated to date regarding the use of VEGFR tyrosine kinase inhibitors after checkpoint inhibitor treatment,” the investigators wrote. “Notably, the benefit of tivozanib extended to patients who had previously received checkpoint inhibitors and those treated with two previous tyrosine kinase inhibitors.”

The study was funded by AVEO Oncology. The investigators reported additional relationships with Pfizer, Eisai, Astellas, and others.

SOURCE: Rini BI et al. Lancet Oncol. 2019 Dec 3. doi: 10.1016/S1470-2045(19)30735-1.

For third- or fourth-line treatment of metastatic renal cell carcinoma, the vascular epidermal growth factor receptor (VEGFR) tyrosine kinase inhibitor tivozanib may offer better progression-free survival than sorafenib, another VEGFR inhibitor, based on results from the TIVO-3 trial.

Susan London/MDedge News

Tivozanib also had fewer dose reductions and dose interruptions than sorafenib, likely because of less off-target activity, reported lead author Brian I. Rini, MD, of the Cleveland Clinic and Case Western Reserve University, also in Cleveland, and colleagues.

“These results support tivozanib as a treatment option for patients with recurrent and progressive renal cell carcinoma, including those who have progressed after previous immunotherapy,” the investigators wrote in Lancet Oncology.

The open-label, phase 3 trial involved 350 patients with metastatic renal cell carcinoma who had been treated with two or more systemic therapies, at least one of which was a VEGFR inhibitor. Patients were randomized in 1:1 ratio to receive either tivozanib 1.5 mg orally once daily in 4-week cycles or sorafenib 400 mg orally twice daily on a continuous basis. The primary endpoint was progression-free survival. Secondary endpoints included overall survival, objective response rates, and duration of response. Endpoints were evaluated by independent review. Safety was reported for all patients who received one or more doses of therapy.

After a median follow-up of 19 months, tivozanib was associated with a median progression-free survival of 5.6 months, compared with 3.9 months for sorafenib (P = .016). Significantly more patients in the tivozanib group achieved a response, and at 1 year, 71% of patients in the tivozanib group maintained a response, compared with 46% of the patients in the sorafenib group. At data cutoff, median overall survival was not significantly different between groups.

The most common treatment-related grade 3-4 adverse event was hypertension, which occurred in a slightly higher rate among those treated with tivozanib (20% vs. 14%). Serious treatment-related adverse events occurred at comparable rates in each treatment arm, at 11% for tivozanib and 10% for sorafenib. Compared with patients who received sorafenib, those in the tivozanib group had fewer dose reductions (24% vs. 38%) and dose interruptions (48% vs. 63%) because of adverse events, a benefit that the investigators attributed to relatively lower class-related off-target activity.

“To our knowledge, TIVO-3 provides the largest amount of prospective data generated to date regarding the use of VEGFR tyrosine kinase inhibitors after checkpoint inhibitor treatment,” the investigators wrote. “Notably, the benefit of tivozanib extended to patients who had previously received checkpoint inhibitors and those treated with two previous tyrosine kinase inhibitors.”

The study was funded by AVEO Oncology. The investigators reported additional relationships with Pfizer, Eisai, Astellas, and others.

SOURCE: Rini BI et al. Lancet Oncol. 2019 Dec 3. doi: 10.1016/S1470-2045(19)30735-1.

For third- or fourth-line treatment of metastatic renal cell carcinoma, the vascular epidermal growth factor receptor (VEGFR) tyrosine kinase inhibitor tivozanib may offer better progression-free survival than sorafenib, another VEGFR inhibitor, based on results from the TIVO-3 trial.

Susan London/MDedge News

Tivozanib also had fewer dose reductions and dose interruptions than sorafenib, likely because of less off-target activity, reported lead author Brian I. Rini, MD, of the Cleveland Clinic and Case Western Reserve University, also in Cleveland, and colleagues.

“These results support tivozanib as a treatment option for patients with recurrent and progressive renal cell carcinoma, including those who have progressed after previous immunotherapy,” the investigators wrote in Lancet Oncology.

The open-label, phase 3 trial involved 350 patients with metastatic renal cell carcinoma who had been treated with two or more systemic therapies, at least one of which was a VEGFR inhibitor. Patients were randomized in 1:1 ratio to receive either tivozanib 1.5 mg orally once daily in 4-week cycles or sorafenib 400 mg orally twice daily on a continuous basis. The primary endpoint was progression-free survival. Secondary endpoints included overall survival, objective response rates, and duration of response. Endpoints were evaluated by independent review. Safety was reported for all patients who received one or more doses of therapy.

After a median follow-up of 19 months, tivozanib was associated with a median progression-free survival of 5.6 months, compared with 3.9 months for sorafenib (P = .016). Significantly more patients in the tivozanib group achieved a response, and at 1 year, 71% of patients in the tivozanib group maintained a response, compared with 46% of the patients in the sorafenib group. At data cutoff, median overall survival was not significantly different between groups.

The most common treatment-related grade 3-4 adverse event was hypertension, which occurred in a slightly higher rate among those treated with tivozanib (20% vs. 14%). Serious treatment-related adverse events occurred at comparable rates in each treatment arm, at 11% for tivozanib and 10% for sorafenib. Compared with patients who received sorafenib, those in the tivozanib group had fewer dose reductions (24% vs. 38%) and dose interruptions (48% vs. 63%) because of adverse events, a benefit that the investigators attributed to relatively lower class-related off-target activity.

“To our knowledge, TIVO-3 provides the largest amount of prospective data generated to date regarding the use of VEGFR tyrosine kinase inhibitors after checkpoint inhibitor treatment,” the investigators wrote. “Notably, the benefit of tivozanib extended to patients who had previously received checkpoint inhibitors and those treated with two previous tyrosine kinase inhibitors.”

The study was funded by AVEO Oncology. The investigators reported additional relationships with Pfizer, Eisai, Astellas, and others.

SOURCE: Rini BI et al. Lancet Oncol. 2019 Dec 3. doi: 10.1016/S1470-2045(19)30735-1.

SAN ANTONIO – Biofeedback for treatment of dyssynergic constipation is highly effective in the elderly, just as it is in younger patients, Samantha Spilman, MD, reported at the annual meeting of the American College of Gastroenterology.

Bruce Jancin/MDedge News

“I think the main point of this study is that older adults have a profound burden of constipation with dyssynergic defecation, and we propose that biofeedback be given strong consideration as first-line therapy for this population, in whom overall we’re trying to reduce medication use,” said Dr. Spilman, a gastroenterology fellow at the University of California, San Diego.

The prevalence of constipation in older patients is estimated to be up to 40%. Yet few prior studies have scrutinized how well older patients with constipation actually respond to biofeedback. It’s a legitimate question, since biofeedback training involves operant conditioning and requires learning new techniques. For this reason, she and her coinvestigators conducted a retrospective analysis of 58 patients over age 65 referred from the university’s gastrointestinal motility and physiology program to the biofeedback program for treatment of dyssynergic defection. The patients’ mean age was 74 years, with a 9.5-year history of constipation. The oldest patient was 88. Most of the subjects were high school graduates. Thirteen of the 58 carried a diagnosis of irritable bowel syndrome.

Numerous studies have demonstrated that 70%-80% of younger adults with dyssynergic constipation experience marked improvement in response to biofeedback training, which typically utilizes an inflated rectal balloon to simulate retained stool. The key finding in Dr. Spilman’s study was that the elderly patients did comparably well in terms of both self-reported outcomes and objective high-resolution anorectal manometric parameters upon completing an average of three biofeedback sessions.

Mean global bowel satisfaction on a 1-10 scale nearly doubled from 2.77 at baseline to 5.01 with biofeedback. Moreover, 79% of seniors demonstrated resolution of their dyssynergia on high-resolution anorectal manometry performed with sensors in the rectum and anal canal. The proportion of patients who reported a feeling of incomplete evacuation after stooling – a sensation individuals with constipation find highly bothersome – improved from 95% to 24% with biofeedback.

The strongest response in terms of the defecation index was observed in older patients with type 2 dyssynergia, characterized by defective propulsion coupled with a paradoxical contraction of the sphincter muscles during defecation. Their defecation index score, derived by dividing intrarectal pressure by residual intra-anal pressure during simulated defection, showed a robust improvement from 0.307 at baseline to 0.793. Patients with types 1 and 3 dyssynergia showed lesser improvements on this objective measure.

Dr. Spilman noted as a study limitation that baseline cognitive status wasn’t formally assessed, so the investigators don’t know how many of the older patients had minimal cognitive impairment. However, baseline quality of life assessment via the Short Form-36 indicated that patients scored average or above for physical and social functioning as well as emotional well-being.

Dr. Spilman reported having no financial conflicts regarding her study, conducted free of commercial support.

[email protected]

SOURCE: Spilman S. ACG 2019. Abstract 45.

SAN ANTONIO – Biofeedback for treatment of dyssynergic constipation is highly effective in the elderly, just as it is in younger patients, Samantha Spilman, MD, reported at the annual meeting of the American College of Gastroenterology.

Bruce Jancin/MDedge News

“I think the main point of this study is that older adults have a profound burden of constipation with dyssynergic defecation, and we propose that biofeedback be given strong consideration as first-line therapy for this population, in whom overall we’re trying to reduce medication use,” said Dr. Spilman, a gastroenterology fellow at the University of California, San Diego.

The prevalence of constipation in older patients is estimated to be up to 40%. Yet few prior studies have scrutinized how well older patients with constipation actually respond to biofeedback. It’s a legitimate question, since biofeedback training involves operant conditioning and requires learning new techniques. For this reason, she and her coinvestigators conducted a retrospective analysis of 58 patients over age 65 referred from the university’s gastrointestinal motility and physiology program to the biofeedback program for treatment of dyssynergic defection. The patients’ mean age was 74 years, with a 9.5-year history of constipation. The oldest patient was 88. Most of the subjects were high school graduates. Thirteen of the 58 carried a diagnosis of irritable bowel syndrome.

Numerous studies have demonstrated that 70%-80% of younger adults with dyssynergic constipation experience marked improvement in response to biofeedback training, which typically utilizes an inflated rectal balloon to simulate retained stool. The key finding in Dr. Spilman’s study was that the elderly patients did comparably well in terms of both self-reported outcomes and objective high-resolution anorectal manometric parameters upon completing an average of three biofeedback sessions.

Mean global bowel satisfaction on a 1-10 scale nearly doubled from 2.77 at baseline to 5.01 with biofeedback. Moreover, 79% of seniors demonstrated resolution of their dyssynergia on high-resolution anorectal manometry performed with sensors in the rectum and anal canal. The proportion of patients who reported a feeling of incomplete evacuation after stooling – a sensation individuals with constipation find highly bothersome – improved from 95% to 24% with biofeedback.

The strongest response in terms of the defecation index was observed in older patients with type 2 dyssynergia, characterized by defective propulsion coupled with a paradoxical contraction of the sphincter muscles during defecation. Their defecation index score, derived by dividing intrarectal pressure by residual intra-anal pressure during simulated defection, showed a robust improvement from 0.307 at baseline to 0.793. Patients with types 1 and 3 dyssynergia showed lesser improvements on this objective measure.

Dr. Spilman noted as a study limitation that baseline cognitive status wasn’t formally assessed, so the investigators don’t know how many of the older patients had minimal cognitive impairment. However, baseline quality of life assessment via the Short Form-36 indicated that patients scored average or above for physical and social functioning as well as emotional well-being.

Dr. Spilman reported having no financial conflicts regarding her study, conducted free of commercial support.

[email protected]

SOURCE: Spilman S. ACG 2019. Abstract 45.

SAN ANTONIO – Biofeedback for treatment of dyssynergic constipation is highly effective in the elderly, just as it is in younger patients, Samantha Spilman, MD, reported at the annual meeting of the American College of Gastroenterology.

Bruce Jancin/MDedge News

“I think the main point of this study is that older adults have a profound burden of constipation with dyssynergic defecation, and we propose that biofeedback be given strong consideration as first-line therapy for this population, in whom overall we’re trying to reduce medication use,” said Dr. Spilman, a gastroenterology fellow at the University of California, San Diego.

The prevalence of constipation in older patients is estimated to be up to 40%. Yet few prior studies have scrutinized how well older patients with constipation actually respond to biofeedback. It’s a legitimate question, since biofeedback training involves operant conditioning and requires learning new techniques. For this reason, she and her coinvestigators conducted a retrospective analysis of 58 patients over age 65 referred from the university’s gastrointestinal motility and physiology program to the biofeedback program for treatment of dyssynergic defection. The patients’ mean age was 74 years, with a 9.5-year history of constipation. The oldest patient was 88. Most of the subjects were high school graduates. Thirteen of the 58 carried a diagnosis of irritable bowel syndrome.

Numerous studies have demonstrated that 70%-80% of younger adults with dyssynergic constipation experience marked improvement in response to biofeedback training, which typically utilizes an inflated rectal balloon to simulate retained stool. The key finding in Dr. Spilman’s study was that the elderly patients did comparably well in terms of both self-reported outcomes and objective high-resolution anorectal manometric parameters upon completing an average of three biofeedback sessions.

Mean global bowel satisfaction on a 1-10 scale nearly doubled from 2.77 at baseline to 5.01 with biofeedback. Moreover, 79% of seniors demonstrated resolution of their dyssynergia on high-resolution anorectal manometry performed with sensors in the rectum and anal canal. The proportion of patients who reported a feeling of incomplete evacuation after stooling – a sensation individuals with constipation find highly bothersome – improved from 95% to 24% with biofeedback.

The strongest response in terms of the defecation index was observed in older patients with type 2 dyssynergia, characterized by defective propulsion coupled with a paradoxical contraction of the sphincter muscles during defecation. Their defecation index score, derived by dividing intrarectal pressure by residual intra-anal pressure during simulated defection, showed a robust improvement from 0.307 at baseline to 0.793. Patients with types 1 and 3 dyssynergia showed lesser improvements on this objective measure.

Dr. Spilman noted as a study limitation that baseline cognitive status wasn’t formally assessed, so the investigators don’t know how many of the older patients had minimal cognitive impairment. However, baseline quality of life assessment via the Short Form-36 indicated that patients scored average or above for physical and social functioning as well as emotional well-being.

Dr. Spilman reported having no financial conflicts regarding her study, conducted free of commercial support.

[email protected]

SOURCE: Spilman S. ACG 2019. Abstract 45.

The use of ultrasound in screening for psoriatic arthritis in patients with psoriasis could reduce the number of unnecessary referrals to rheumatologists, according to a research letter published in the British Journal of Dermatology.

Bogdanhoda/Thinkstock

Up to one-third of patients with psoriasis have underlying psoriatic arthritis (PsA), but half of all patients with psoriasis experience nonspecific musculoskeletal complaints.

“Different screening tools have been developed for the dermatology practice to distinguish patients with a higher likelihood of having PsA; however, the low specificities of these tools limit their use in clinical practice,” wrote Dilek Solmaz, MD, and colleagues at the University of Ottawa.

In this prospective study, 51 patients with psoriasis were screened for referral to a rheumatologist using the Early Arthritis for Psoriatic Patients and Psoriasis Epidemiology Screening Tool questionnaires. They also underwent a limited ultrasound scanning of wrists, hands, feet, and the most painful joint, which was reviewed by experienced rheumatologists.

A dermatologist was asked to make a decision on referral based on the questionnaire data alone, then invited to revisit that decision after viewing the ultrasound results. When basing their decision on the questionnaires only, the dermatologist decided to refer 92% of patients to a rheumatologist. Of these patients, 40% were subsequently diagnosed with PsA, which represented a sensitivity of 95% but specificity of just 9%.

After reviewing the ultrasound data, the dermatologist revised their recommendations and only referred 43% of patients. Of these, 68% were later diagnosed with psoriatic arthritis. Among the patients who were not referred after the ultrasound review, five were diagnosed with PsA, but two had isolated axial involvement with no peripheral joint disease. Excluding these two cases, the sensitivity decreased to 88% but specificity increased to 77%.

“Screening tools in psoriasis that have high sensitivities usually have low specificities, which means a higher number of patients to be referred to rheumatology than needed,” the authors wrote. “Our study demonstrated that a musculoskeletal [ultrasound] based on a predefined protocol improves the referrals made to rheumatology.”

The authors did note that the ultrasounds were reviewed by experienced rheumatologists, so the results might not be generalizable to less-experienced sonographers without experience in musculoskeletal disorders.

The study was funded by AbbVie. One author declared receiving funding for a fellowship from UCB. Two authors declared honoraria and advisory consultancies with the pharmaceutical sector, including AbbVie.

SOURCE: Solmaz D et al. Br J Dermatol. 2019 Nov 28. doi: 10.1111/bjd.18515.

The use of ultrasound in screening for psoriatic arthritis in patients with psoriasis could reduce the number of unnecessary referrals to rheumatologists, according to a research letter published in the British Journal of Dermatology.

Bogdanhoda/Thinkstock

Up to one-third of patients with psoriasis have underlying psoriatic arthritis (PsA), but half of all patients with psoriasis experience nonspecific musculoskeletal complaints.

“Different screening tools have been developed for the dermatology practice to distinguish patients with a higher likelihood of having PsA; however, the low specificities of these tools limit their use in clinical practice,” wrote Dilek Solmaz, MD, and colleagues at the University of Ottawa.

In this prospective study, 51 patients with psoriasis were screened for referral to a rheumatologist using the Early Arthritis for Psoriatic Patients and Psoriasis Epidemiology Screening Tool questionnaires. They also underwent a limited ultrasound scanning of wrists, hands, feet, and the most painful joint, which was reviewed by experienced rheumatologists.

A dermatologist was asked to make a decision on referral based on the questionnaire data alone, then invited to revisit that decision after viewing the ultrasound results. When basing their decision on the questionnaires only, the dermatologist decided to refer 92% of patients to a rheumatologist. Of these patients, 40% were subsequently diagnosed with PsA, which represented a sensitivity of 95% but specificity of just 9%.

After reviewing the ultrasound data, the dermatologist revised their recommendations and only referred 43% of patients. Of these, 68% were later diagnosed with psoriatic arthritis. Among the patients who were not referred after the ultrasound review, five were diagnosed with PsA, but two had isolated axial involvement with no peripheral joint disease. Excluding these two cases, the sensitivity decreased to 88% but specificity increased to 77%.

“Screening tools in psoriasis that have high sensitivities usually have low specificities, which means a higher number of patients to be referred to rheumatology than needed,” the authors wrote. “Our study demonstrated that a musculoskeletal [ultrasound] based on a predefined protocol improves the referrals made to rheumatology.”

The authors did note that the ultrasounds were reviewed by experienced rheumatologists, so the results might not be generalizable to less-experienced sonographers without experience in musculoskeletal disorders.

The study was funded by AbbVie. One author declared receiving funding for a fellowship from UCB. Two authors declared honoraria and advisory consultancies with the pharmaceutical sector, including AbbVie.

SOURCE: Solmaz D et al. Br J Dermatol. 2019 Nov 28. doi: 10.1111/bjd.18515.

The use of ultrasound in screening for psoriatic arthritis in patients with psoriasis could reduce the number of unnecessary referrals to rheumatologists, according to a research letter published in the British Journal of Dermatology.

Bogdanhoda/Thinkstock

Up to one-third of patients with psoriasis have underlying psoriatic arthritis (PsA), but half of all patients with psoriasis experience nonspecific musculoskeletal complaints.

“Different screening tools have been developed for the dermatology practice to distinguish patients with a higher likelihood of having PsA; however, the low specificities of these tools limit their use in clinical practice,” wrote Dilek Solmaz, MD, and colleagues at the University of Ottawa.

In this prospective study, 51 patients with psoriasis were screened for referral to a rheumatologist using the Early Arthritis for Psoriatic Patients and Psoriasis Epidemiology Screening Tool questionnaires. They also underwent a limited ultrasound scanning of wrists, hands, feet, and the most painful joint, which was reviewed by experienced rheumatologists.

A dermatologist was asked to make a decision on referral based on the questionnaire data alone, then invited to revisit that decision after viewing the ultrasound results. When basing their decision on the questionnaires only, the dermatologist decided to refer 92% of patients to a rheumatologist. Of these patients, 40% were subsequently diagnosed with PsA, which represented a sensitivity of 95% but specificity of just 9%.

After reviewing the ultrasound data, the dermatologist revised their recommendations and only referred 43% of patients. Of these, 68% were later diagnosed with psoriatic arthritis. Among the patients who were not referred after the ultrasound review, five were diagnosed with PsA, but two had isolated axial involvement with no peripheral joint disease. Excluding these two cases, the sensitivity decreased to 88% but specificity increased to 77%.

“Screening tools in psoriasis that have high sensitivities usually have low specificities, which means a higher number of patients to be referred to rheumatology than needed,” the authors wrote. “Our study demonstrated that a musculoskeletal [ultrasound] based on a predefined protocol improves the referrals made to rheumatology.”

The authors did note that the ultrasounds were reviewed by experienced rheumatologists, so the results might not be generalizable to less-experienced sonographers without experience in musculoskeletal disorders.

The study was funded by AbbVie. One author declared receiving funding for a fellowship from UCB. Two authors declared honoraria and advisory consultancies with the pharmaceutical sector, including AbbVie.

SOURCE: Solmaz D et al. Br J Dermatol. 2019 Nov 28. doi: 10.1111/bjd.18515.

BALTIMORE – Investigators from the University of California, San Francisco, are working with medical directors across the state to update county emergency medical services protocols to ensure patients in status epilepticus get 10 mg IM midazolam in the field, per national treatment guidelines from the American Epilepsy Society.

The work comes in the wake of a recent research letter in JAMA where the UCSF team reported that, across 33 emergency medical services (EMS) in California, only 2 included 10 mg midazolam IM per the guidelines, advice based on randomized, controlled clinical trials that found it to be safe and effective for stopping prehospital seizures in adults.

“Making people aware of the problem [is having] an impact,” said investigator Elan Guterman, MD, a neurology hospitalist and assistant professor of neurology at the university.

In a follow-up review at the annual meeting of the American Epilepsy Society, the team took a deep dive into the situation in Alameda County, just east of San Francisco and including the city of Oakland, as an indicator of what’s been going on across the state.

Patients had to have an EMS record of active seizures, meaning more than two within 5 minutes or a single seizure lasting more than 5 minutes. Alameda ambulance crews, like most, carry intramuscular midazolam because it’s more shelf stable than the two other first-line options, lorazepam and diazepam, and doesn’t require an intravenous line.

Among the 2,494 adults treated for status epilepticus from 2013 to 2018, just 62% received intramuscular midazolam, and only 39% got a dose of 5 mg or more. Not a single patient received the recommended 10-mg IM injection.

In short, “at the time when it’s the most important to act quickly, patients were not receiving the care they needed,” and the problem isn’t likely limited to California, Dr. Guterman said.

When patients did get 5 mg or more, they were less likely to reseize and require additional doses (adjusted odds ratio, 0.59; 95% CI, 0.4-0.86). Also – and counterintuitively given the concern about benzodiazepines and respiratory depression – the team found that higher initial doses of 5 mg or more were actually associated with a lower need for respiratory support, including intubation (OR, 0.81; 95% CI, 0.67-0.99).

It’s possible ambulance crews were erring on the side of caution. People who got midazolam were more likely to have an established diagnosis of epilepsy (68% vs. 62%; P less than .01) and less likely to have been abusing drugs or alcohol (12.5% vs. 16.3%; P less than .01).

But an abundance of caution doesn’t fully explain it; even among people known to have epilepsy, many weren’t treated with midazolam and none at the appropriate dose.

Dr. Guterman thinks the bigger issue is what was reported in the research letter: Local EMS protocols simply haven’t been updated to include current best practices. EMS services might not even be aware of them, which is why she and her colleagues have been meeting with county medical directors.

“The first step is making sure the EMS world is aware of this gap in care, and motivating them to address it,” she said.

Patients in the study were a mean of 53 years old, and just over half were men.

There was no industry funding for the study, and Dr. Guterman didn’t report any relevant disclosures.

[email protected]

SOURCE: Guterman E et al. AES 2019, Abstract 1.394.

BALTIMORE – Investigators from the University of California, San Francisco, are working with medical directors across the state to update county emergency medical services protocols to ensure patients in status epilepticus get 10 mg IM midazolam in the field, per national treatment guidelines from the American Epilepsy Society.

The work comes in the wake of a recent research letter in JAMA where the UCSF team reported that, across 33 emergency medical services (EMS) in California, only 2 included 10 mg midazolam IM per the guidelines, advice based on randomized, controlled clinical trials that found it to be safe and effective for stopping prehospital seizures in adults.

“Making people aware of the problem [is having] an impact,” said investigator Elan Guterman, MD, a neurology hospitalist and assistant professor of neurology at the university.

In a follow-up review at the annual meeting of the American Epilepsy Society, the team took a deep dive into the situation in Alameda County, just east of San Francisco and including the city of Oakland, as an indicator of what’s been going on across the state.

Patients had to have an EMS record of active seizures, meaning more than two within 5 minutes or a single seizure lasting more than 5 minutes. Alameda ambulance crews, like most, carry intramuscular midazolam because it’s more shelf stable than the two other first-line options, lorazepam and diazepam, and doesn’t require an intravenous line.

Among the 2,494 adults treated for status epilepticus from 2013 to 2018, just 62% received intramuscular midazolam, and only 39% got a dose of 5 mg or more. Not a single patient received the recommended 10-mg IM injection.

In short, “at the time when it’s the most important to act quickly, patients were not receiving the care they needed,” and the problem isn’t likely limited to California, Dr. Guterman said.

When patients did get 5 mg or more, they were less likely to reseize and require additional doses (adjusted odds ratio, 0.59; 95% CI, 0.4-0.86). Also – and counterintuitively given the concern about benzodiazepines and respiratory depression – the team found that higher initial doses of 5 mg or more were actually associated with a lower need for respiratory support, including intubation (OR, 0.81; 95% CI, 0.67-0.99).

It’s possible ambulance crews were erring on the side of caution. People who got midazolam were more likely to have an established diagnosis of epilepsy (68% vs. 62%; P less than .01) and less likely to have been abusing drugs or alcohol (12.5% vs. 16.3%; P less than .01).

But an abundance of caution doesn’t fully explain it; even among people known to have epilepsy, many weren’t treated with midazolam and none at the appropriate dose.

Dr. Guterman thinks the bigger issue is what was reported in the research letter: Local EMS protocols simply haven’t been updated to include current best practices. EMS services might not even be aware of them, which is why she and her colleagues have been meeting with county medical directors.

“The first step is making sure the EMS world is aware of this gap in care, and motivating them to address it,” she said.

Patients in the study were a mean of 53 years old, and just over half were men.

There was no industry funding for the study, and Dr. Guterman didn’t report any relevant disclosures.

[email protected]

SOURCE: Guterman E et al. AES 2019, Abstract 1.394.

BALTIMORE – Investigators from the University of California, San Francisco, are working with medical directors across the state to update county emergency medical services protocols to ensure patients in status epilepticus get 10 mg IM midazolam in the field, per national treatment guidelines from the American Epilepsy Society.

The work comes in the wake of a recent research letter in JAMA where the UCSF team reported that, across 33 emergency medical services (EMS) in California, only 2 included 10 mg midazolam IM per the guidelines, advice based on randomized, controlled clinical trials that found it to be safe and effective for stopping prehospital seizures in adults.

“Making people aware of the problem [is having] an impact,” said investigator Elan Guterman, MD, a neurology hospitalist and assistant professor of neurology at the university.

In a follow-up review at the annual meeting of the American Epilepsy Society, the team took a deep dive into the situation in Alameda County, just east of San Francisco and including the city of Oakland, as an indicator of what’s been going on across the state.

Patients had to have an EMS record of active seizures, meaning more than two within 5 minutes or a single seizure lasting more than 5 minutes. Alameda ambulance crews, like most, carry intramuscular midazolam because it’s more shelf stable than the two other first-line options, lorazepam and diazepam, and doesn’t require an intravenous line.

Among the 2,494 adults treated for status epilepticus from 2013 to 2018, just 62% received intramuscular midazolam, and only 39% got a dose of 5 mg or more. Not a single patient received the recommended 10-mg IM injection.

In short, “at the time when it’s the most important to act quickly, patients were not receiving the care they needed,” and the problem isn’t likely limited to California, Dr. Guterman said.

When patients did get 5 mg or more, they were less likely to reseize and require additional doses (adjusted odds ratio, 0.59; 95% CI, 0.4-0.86). Also – and counterintuitively given the concern about benzodiazepines and respiratory depression – the team found that higher initial doses of 5 mg or more were actually associated with a lower need for respiratory support, including intubation (OR, 0.81; 95% CI, 0.67-0.99).

It’s possible ambulance crews were erring on the side of caution. People who got midazolam were more likely to have an established diagnosis of epilepsy (68% vs. 62%; P less than .01) and less likely to have been abusing drugs or alcohol (12.5% vs. 16.3%; P less than .01).

But an abundance of caution doesn’t fully explain it; even among people known to have epilepsy, many weren’t treated with midazolam and none at the appropriate dose.

Dr. Guterman thinks the bigger issue is what was reported in the research letter: Local EMS protocols simply haven’t been updated to include current best practices. EMS services might not even be aware of them, which is why she and her colleagues have been meeting with county medical directors.

“The first step is making sure the EMS world is aware of this gap in care, and motivating them to address it,” she said.

Patients in the study were a mean of 53 years old, and just over half were men.

There was no industry funding for the study, and Dr. Guterman didn’t report any relevant disclosures.

[email protected]

SOURCE: Guterman E et al. AES 2019, Abstract 1.394.

I practice in Seattle, where many of my patients are interested in natural treatment options. I am always puzzled that so many people assume that natural treatment options would be safer than prescription medications. Tsunamis, wildfires, flooding, and earthquakes are all natural and are deadly. There are certainly many natural poisons. There are a number of natural treatments that are very helpful, and recommending them are an important part of my practice. I want to share a few with you.

A useful vein pursuit?

Case: A 60-year-old woman presents to clinic with increasing pain in her left leg. She had a deep vein thrombosis in her left leg 2 years ago, which involved a large portion of her superficial femoral vein. She has noticed edema over the past few weeks, and pain has been more severe over the past 3 months. On exam, varicosities on left lower extremity with grade 2+ edema. Duplex of the lower extremity does not show deep vein thrombosis, but does show a great deal of venous valvular incompetence. She has tried compression stockings for the past 2 weeks. What is the best treatment option?

A) Turmeric

B) Amitriptyline

C) Vitamin B12

D) Horse chestnut

The treatment option with positive data for this problem is horse chestnut. What is horse chestnut? Horse chestnut is a kind of tree, and the seed extract contains aescin which is believed to be the active ingredient. Diehm et al. studied horse chestnut seed extract (HCSE), compared with compression stockings and placebo for edema from chronic venous insufficiency in a study of 240 patients.¹ Lower-leg volume decreased by 43 mL with HCSE, 46 mL with compression stockings, and increased by 9 mL with placebo (P less than .005 for HCSE and P less than .002 for compression). In a Cochrane review, HCSE was considered efficacious and safe for the short-term therapy for chronic venous insufficiency.² Studies have shown both an improvement in pain as well as swelling in patients with chronic venous insufficiency.

The question of UTIs

Probably the most popular natural treatment for prevention and treatment of urinary tract infections (UTIs) in women is cranberry juice (or cranberry extract). Unfortunately, there is little evidence that this treatment is helpful. In a Cochrane analysis, the conclusion was, based on current evidence, cranberry juice cannot currently be recommended for the prevention of UTIs.³ A natural product that appears to be more promising is the sugar D-mannose. Kranjčec et al. studied 308 women with acute UTI who had a history of recurrent UTI.⁴ All the women were treated for their symptomatic infection with ciprofloxacin (500 mg twice daily for 1 week). The women were allocated equally to three groups for 6 months: D-mannose 2 g daily, nitrofurantoin 50 mg daily, or no prophylaxis. About 60% of the women who received no prophylaxis had a UTI during the study period, compared with 20% in the nitrofurantoin group and 15% in the D-mannose group. The relative risk for D-mannose, compared with no prophylaxis, was 0.24 and for nitrofurantoin was 0.34 (P less than .0001), compared with no prophylaxis.

Made for migraines?

Migraine prophylaxis is challenging because all medications that are commonly used have side effects that often limit patient adherence. Tricyclic antidepressants (dry mouth, dizziness and weight gain), beta-blockers (fatigue, decreased exercise tolerance), valproate (weight gain and fatigue), and topiramate (parasthesias and mental slowing) all have troubling side effects. Riboflavin is a vitamin with evidence of effectiveness for migraine prophylaxis. It is extremely well tolerated. In a recent study in children with migraines, Talebian et al. studied 90 children with migraines who were randomized to three groups (200 mg of riboflavin a day, 100 mg of riboflavin a day, or placebo) after observation during a 1-month baseline period.⁵ There was a significant reduction in migraine frequency and duration in patients receiving 200 mg of riboflavin daily, compared with placebo. Rahimdel et al. published an interesting study comparing high-dose riboflavin with valproate for migraine prophylaxis. A total of 90 patients were randomized to receive 400 mg of riboflavin or 500 mg of valproate over a 12-month study.⁶ Both treatments resulted in marked reduction in frequency, duration, and severity of migraines (not statistically significantly different from each other). The reduction in migraine frequency for the riboflavin group was from 9.2 headache days per month to 2.4. The American Academy of Neurology rates the level of evidence for riboflavin as B.

Pearl

Horse chestnut, D-mannose, and riboflavin are safe alternative therapies that can be helpful for several common problems we see frequently in primary care.

References

1. Diehm C et al. Lancet. 1996;347(8997):292-4.

2. Pittler MH, Ernst E. Cochrane Database Syst Rev. 2012 Nov 14;11:CD003230.

3. Jepson RG et al. Cochrane Database Syst Rev. 2012;10:CD001321.

4. Kranjčec B et al. World J Urol. 2014 Feb;32(1):79-84.

5. Talebian A et al. Electron Physician. Feb 25;10(2):6279-85.

6. Rahimdel A et al. Electron Physician. 2015 Oct 19;7(6):1344-8.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

I practice in Seattle, where many of my patients are interested in natural treatment options. I am always puzzled that so many people assume that natural treatment options would be safer than prescription medications. Tsunamis, wildfires, flooding, and earthquakes are all natural and are deadly. There are certainly many natural poisons. There are a number of natural treatments that are very helpful, and recommending them are an important part of my practice. I want to share a few with you.

A useful vein pursuit?

Case: A 60-year-old woman presents to clinic with increasing pain in her left leg. She had a deep vein thrombosis in her left leg 2 years ago, which involved a large portion of her superficial femoral vein. She has noticed edema over the past few weeks, and pain has been more severe over the past 3 months. On exam, varicosities on left lower extremity with grade 2+ edema. Duplex of the lower extremity does not show deep vein thrombosis, but does show a great deal of venous valvular incompetence. She has tried compression stockings for the past 2 weeks. What is the best treatment option?

A) Turmeric

B) Amitriptyline

C) Vitamin B12

D) Horse chestnut

The treatment option with positive data for this problem is horse chestnut. What is horse chestnut? Horse chestnut is a kind of tree, and the seed extract contains aescin which is believed to be the active ingredient. Diehm et al. studied horse chestnut seed extract (HCSE), compared with compression stockings and placebo for edema from chronic venous insufficiency in a study of 240 patients.¹ Lower-leg volume decreased by 43 mL with HCSE, 46 mL with compression stockings, and increased by 9 mL with placebo (P less than .005 for HCSE and P less than .002 for compression). In a Cochrane review, HCSE was considered efficacious and safe for the short-term therapy for chronic venous insufficiency.² Studies have shown both an improvement in pain as well as swelling in patients with chronic venous insufficiency.

The question of UTIs

Probably the most popular natural treatment for prevention and treatment of urinary tract infections (UTIs) in women is cranberry juice (or cranberry extract). Unfortunately, there is little evidence that this treatment is helpful. In a Cochrane analysis, the conclusion was, based on current evidence, cranberry juice cannot currently be recommended for the prevention of UTIs.³ A natural product that appears to be more promising is the sugar D-mannose. Kranjčec et al. studied 308 women with acute UTI who had a history of recurrent UTI.⁴ All the women were treated for their symptomatic infection with ciprofloxacin (500 mg twice daily for 1 week). The women were allocated equally to three groups for 6 months: D-mannose 2 g daily, nitrofurantoin 50 mg daily, or no prophylaxis. About 60% of the women who received no prophylaxis had a UTI during the study period, compared with 20% in the nitrofurantoin group and 15% in the D-mannose group. The relative risk for D-mannose, compared with no prophylaxis, was 0.24 and for nitrofurantoin was 0.34 (P less than .0001), compared with no prophylaxis.

Made for migraines?

Migraine prophylaxis is challenging because all medications that are commonly used have side effects that often limit patient adherence. Tricyclic antidepressants (dry mouth, dizziness and weight gain), beta-blockers (fatigue, decreased exercise tolerance), valproate (weight gain and fatigue), and topiramate (parasthesias and mental slowing) all have troubling side effects. Riboflavin is a vitamin with evidence of effectiveness for migraine prophylaxis. It is extremely well tolerated. In a recent study in children with migraines, Talebian et al. studied 90 children with migraines who were randomized to three groups (200 mg of riboflavin a day, 100 mg of riboflavin a day, or placebo) after observation during a 1-month baseline period.⁵ There was a significant reduction in migraine frequency and duration in patients receiving 200 mg of riboflavin daily, compared with placebo. Rahimdel et al. published an interesting study comparing high-dose riboflavin with valproate for migraine prophylaxis. A total of 90 patients were randomized to receive 400 mg of riboflavin or 500 mg of valproate over a 12-month study.⁶ Both treatments resulted in marked reduction in frequency, duration, and severity of migraines (not statistically significantly different from each other). The reduction in migraine frequency for the riboflavin group was from 9.2 headache days per month to 2.4. The American Academy of Neurology rates the level of evidence for riboflavin as B.

Pearl

Horse chestnut, D-mannose, and riboflavin are safe alternative therapies that can be helpful for several common problems we see frequently in primary care.

References

1. Diehm C et al. Lancet. 1996;347(8997):292-4.

2. Pittler MH, Ernst E. Cochrane Database Syst Rev. 2012 Nov 14;11:CD003230.

3. Jepson RG et al. Cochrane Database Syst Rev. 2012;10:CD001321.

4. Kranjčec B et al. World J Urol. 2014 Feb;32(1):79-84.

5. Talebian A et al. Electron Physician. Feb 25;10(2):6279-85.

6. Rahimdel A et al. Electron Physician. 2015 Oct 19;7(6):1344-8.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

I practice in Seattle, where many of my patients are interested in natural treatment options. I am always puzzled that so many people assume that natural treatment options would be safer than prescription medications. Tsunamis, wildfires, flooding, and earthquakes are all natural and are deadly. There are certainly many natural poisons. There are a number of natural treatments that are very helpful, and recommending them are an important part of my practice. I want to share a few with you.

A useful vein pursuit?

Case: A 60-year-old woman presents to clinic with increasing pain in her left leg. She had a deep vein thrombosis in her left leg 2 years ago, which involved a large portion of her superficial femoral vein. She has noticed edema over the past few weeks, and pain has been more severe over the past 3 months. On exam, varicosities on left lower extremity with grade 2+ edema. Duplex of the lower extremity does not show deep vein thrombosis, but does show a great deal of venous valvular incompetence. She has tried compression stockings for the past 2 weeks. What is the best treatment option?

A) Turmeric

B) Amitriptyline

C) Vitamin B12

D) Horse chestnut

The treatment option with positive data for this problem is horse chestnut. What is horse chestnut? Horse chestnut is a kind of tree, and the seed extract contains aescin which is believed to be the active ingredient. Diehm et al. studied horse chestnut seed extract (HCSE), compared with compression stockings and placebo for edema from chronic venous insufficiency in a study of 240 patients.¹ Lower-leg volume decreased by 43 mL with HCSE, 46 mL with compression stockings, and increased by 9 mL with placebo (P less than .005 for HCSE and P less than .002 for compression). In a Cochrane review, HCSE was considered efficacious and safe for the short-term therapy for chronic venous insufficiency.² Studies have shown both an improvement in pain as well as swelling in patients with chronic venous insufficiency.

The question of UTIs

Probably the most popular natural treatment for prevention and treatment of urinary tract infections (UTIs) in women is cranberry juice (or cranberry extract). Unfortunately, there is little evidence that this treatment is helpful. In a Cochrane analysis, the conclusion was, based on current evidence, cranberry juice cannot currently be recommended for the prevention of UTIs.³ A natural product that appears to be more promising is the sugar D-mannose. Kranjčec et al. studied 308 women with acute UTI who had a history of recurrent UTI.⁴ All the women were treated for their symptomatic infection with ciprofloxacin (500 mg twice daily for 1 week). The women were allocated equally to three groups for 6 months: D-mannose 2 g daily, nitrofurantoin 50 mg daily, or no prophylaxis. About 60% of the women who received no prophylaxis had a UTI during the study period, compared with 20% in the nitrofurantoin group and 15% in the D-mannose group. The relative risk for D-mannose, compared with no prophylaxis, was 0.24 and for nitrofurantoin was 0.34 (P less than .0001), compared with no prophylaxis.

Made for migraines?

Migraine prophylaxis is challenging because all medications that are commonly used have side effects that often limit patient adherence. Tricyclic antidepressants (dry mouth, dizziness and weight gain), beta-blockers (fatigue, decreased exercise tolerance), valproate (weight gain and fatigue), and topiramate (parasthesias and mental slowing) all have troubling side effects. Riboflavin is a vitamin with evidence of effectiveness for migraine prophylaxis. It is extremely well tolerated. In a recent study in children with migraines, Talebian et al. studied 90 children with migraines who were randomized to three groups (200 mg of riboflavin a day, 100 mg of riboflavin a day, or placebo) after observation during a 1-month baseline period.⁵ There was a significant reduction in migraine frequency and duration in patients receiving 200 mg of riboflavin daily, compared with placebo. Rahimdel et al. published an interesting study comparing high-dose riboflavin with valproate for migraine prophylaxis. A total of 90 patients were randomized to receive 400 mg of riboflavin or 500 mg of valproate over a 12-month study.⁶ Both treatments resulted in marked reduction in frequency, duration, and severity of migraines (not statistically significantly different from each other). The reduction in migraine frequency for the riboflavin group was from 9.2 headache days per month to 2.4. The American Academy of Neurology rates the level of evidence for riboflavin as B.

Pearl

Horse chestnut, D-mannose, and riboflavin are safe alternative therapies that can be helpful for several common problems we see frequently in primary care.

References

1. Diehm C et al. Lancet. 1996;347(8997):292-4.

2. Pittler MH, Ernst E. Cochrane Database Syst Rev. 2012 Nov 14;11:CD003230.

3. Jepson RG et al. Cochrane Database Syst Rev. 2012;10:CD001321.

4. Kranjčec B et al. World J Urol. 2014 Feb;32(1):79-84.

5. Talebian A et al. Electron Physician. Feb 25;10(2):6279-85.

6. Rahimdel A et al. Electron Physician. 2015 Oct 19;7(6):1344-8.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

To the Editor:

A 76-year-old woman with venous insufficiency presented with numerous thick, hyperkeratotic, confluent papules and plaques involving both legs and thighs as well as the lower back. She initially developed lesions on the distal legs, which progressed to involve the thighs and lower back, slowly enlarging over 7 years (Figure 1). The eruption was associated with pruritus and was profoundly malodorous. The patient had been unsuccessfully treated with triamcinolone ointment, bleach baths, and several courses of oral antibiotics. Her history was remarkable for marked venous insufficiency and mild anemia, with a hemoglobin level of 11.9 g/dL (reference range, 14.0–17.5 g/dL). She had no other abnormalities on a comprehensive blood test, basic metabolic panel, or liver function test.

A punch biopsy specimen from the left lower back was obtained and demonstrated papillomatous psoriasiform epidermal hyperplasia with broad parakeratosis, few intracorneal neutrophils, hypogranulosis, and suprapapillary thinning (Figure 2). She was initially treated with oral methotrexate (20 mg weekly), resulting in partial improvement of plaques and complete resolution of pruritus and malodor. After 15 months of treatment with methotrexate, low-dose methotrexate (10 mg weekly) in combination with acitretin 25 mg daily was started, resulting in further improvement of hyperkeratosis (Figure 3). The patient also was given a compounded corticosteroid ointment containing liquor carbonis detergens, salicylic acid, and fluocinonide ointment, achieving minor additional benefit. Comprehensive metabolic panel, lipid panel, and liver function tests were obtained quarterly. Hemoglobin levels remained low, similar to baseline (11.3–12.5 g/dL), while all other values were within reference range. The patient tolerated treatment well, reporting mild dryness of lips on review of systems, which was attributed to acitretin and was treated with emollients.

The etiology of this entity is unknown. An association with diabetes mellitus, pulmonary disease, lymphatic circulation disorders, and immunosuppression has been proposed. Others have reported repeated trauma as contributing to the pathogenesis.¹ For our patient, trauma secondary to scratching, long-standing venous insufficiency, and neglect likely contributed to the development of verrucous plaques.

The diagnosis of verrucous psoriasis can be challenging because of its similarity to several other entities, including verruca vulgaris; epidermal nevus; and squamous cell carcinoma, particularly verrucous carcinoma.^4,6,7 The diagnosis has been less challenging in areas where prior typical psoriatic lesions evolved into a verrucous morphology. Our patient presented a diagnostic challenge and draws attention to this unique variant of psoriasis that could easily be misdiagnosed and lead to inappropriate treatment.

Verrucous psoriasis can be recalcitrant to therapy. Although studies addressing treatment modalities are lacking, several recommendations can be derived from case reports and our patient. The use of topical therapies, including topical corticosteroids (eg, fluocinonide, clobetasol, halobetasol), keratolytic agents (eg, urea, salicylic acid), and calcipotriene, provide only minimal improvement when used as monotherapy.¹ Better success has been reported with systemic therapies, mainly methotrexate and acitretin, with anecdotal reports favoring the use of oral retinoids.^1,6 Conversely, biologic medications such as etanercept, ustekinumab, adalimumab, and infliximab have only provided a partial response.¹ Combination therapies including intralesional triamcinolone plus methotrexate⁴ or methotrexate plus acitretin, as in our patient, seem to provide additional benefit. Methotrexate and acitretin combination therapy has traditionally been avoided because of the risk for hepatotoxicity. However, a case series has demonstrated a moderate safety profile with concurrent use of these drugs in treatment-resistant psoriasis.⁸ In our case, clinical response was most pronounced with combination therapy of methotrexate 10 mg weekly and acitretin 25 mg daily. Thus, strong consideration should be given for combination methotrexate-acitretin therapy in patients with recalcitrant verrucous psoriasis who lack comorbid conditions.

We present a case of verrucous psoriasis, a variant of psoriasis characterized by hypertrophic plaques. We propose that venous insufficiency and long-standing untreated disease was instrumental to the development of these lesions. Furthermore, retinoids, particularly in combination with methotrexate, provided the most benefit for our patient.

Acknowledgment
We thank Stephen Somach, MD (Cleveland, Ohio), for his help interpreting the microscopic findings in our biopsy specimen. He received no compensation.

To the Editor:

A 76-year-old woman with venous insufficiency presented with numerous thick, hyperkeratotic, confluent papules and plaques involving both legs and thighs as well as the lower back. She initially developed lesions on the distal legs, which progressed to involve the thighs and lower back, slowly enlarging over 7 years (Figure 1). The eruption was associated with pruritus and was profoundly malodorous. The patient had been unsuccessfully treated with triamcinolone ointment, bleach baths, and several courses of oral antibiotics. Her history was remarkable for marked venous insufficiency and mild anemia, with a hemoglobin level of 11.9 g/dL (reference range, 14.0–17.5 g/dL). She had no other abnormalities on a comprehensive blood test, basic metabolic panel, or liver function test.

A punch biopsy specimen from the left lower back was obtained and demonstrated papillomatous psoriasiform epidermal hyperplasia with broad parakeratosis, few intracorneal neutrophils, hypogranulosis, and suprapapillary thinning (Figure 2). She was initially treated with oral methotrexate (20 mg weekly), resulting in partial improvement of plaques and complete resolution of pruritus and malodor. After 15 months of treatment with methotrexate, low-dose methotrexate (10 mg weekly) in combination with acitretin 25 mg daily was started, resulting in further improvement of hyperkeratosis (Figure 3). The patient also was given a compounded corticosteroid ointment containing liquor carbonis detergens, salicylic acid, and fluocinonide ointment, achieving minor additional benefit. Comprehensive metabolic panel, lipid panel, and liver function tests were obtained quarterly. Hemoglobin levels remained low, similar to baseline (11.3–12.5 g/dL), while all other values were within reference range. The patient tolerated treatment well, reporting mild dryness of lips on review of systems, which was attributed to acitretin and was treated with emollients.

The etiology of this entity is unknown. An association with diabetes mellitus, pulmonary disease, lymphatic circulation disorders, and immunosuppression has been proposed. Others have reported repeated trauma as contributing to the pathogenesis.¹ For our patient, trauma secondary to scratching, long-standing venous insufficiency, and neglect likely contributed to the development of verrucous plaques.

The diagnosis of verrucous psoriasis can be challenging because of its similarity to several other entities, including verruca vulgaris; epidermal nevus; and squamous cell carcinoma, particularly verrucous carcinoma.^4,6,7 The diagnosis has been less challenging in areas where prior typical psoriatic lesions evolved into a verrucous morphology. Our patient presented a diagnostic challenge and draws attention to this unique variant of psoriasis that could easily be misdiagnosed and lead to inappropriate treatment.

Verrucous psoriasis can be recalcitrant to therapy. Although studies addressing treatment modalities are lacking, several recommendations can be derived from case reports and our patient. The use of topical therapies, including topical corticosteroids (eg, fluocinonide, clobetasol, halobetasol), keratolytic agents (eg, urea, salicylic acid), and calcipotriene, provide only minimal improvement when used as monotherapy.¹ Better success has been reported with systemic therapies, mainly methotrexate and acitretin, with anecdotal reports favoring the use of oral retinoids.^1,6 Conversely, biologic medications such as etanercept, ustekinumab, adalimumab, and infliximab have only provided a partial response.¹ Combination therapies including intralesional triamcinolone plus methotrexate⁴ or methotrexate plus acitretin, as in our patient, seem to provide additional benefit. Methotrexate and acitretin combination therapy has traditionally been avoided because of the risk for hepatotoxicity. However, a case series has demonstrated a moderate safety profile with concurrent use of these drugs in treatment-resistant psoriasis.⁸ In our case, clinical response was most pronounced with combination therapy of methotrexate 10 mg weekly and acitretin 25 mg daily. Thus, strong consideration should be given for combination methotrexate-acitretin therapy in patients with recalcitrant verrucous psoriasis who lack comorbid conditions.

We present a case of verrucous psoriasis, a variant of psoriasis characterized by hypertrophic plaques. We propose that venous insufficiency and long-standing untreated disease was instrumental to the development of these lesions. Furthermore, retinoids, particularly in combination with methotrexate, provided the most benefit for our patient.

Acknowledgment
We thank Stephen Somach, MD (Cleveland, Ohio), for his help interpreting the microscopic findings in our biopsy specimen. He received no compensation.

To the Editor:

A 76-year-old woman with venous insufficiency presented with numerous thick, hyperkeratotic, confluent papules and plaques involving both legs and thighs as well as the lower back. She initially developed lesions on the distal legs, which progressed to involve the thighs and lower back, slowly enlarging over 7 years (Figure 1). The eruption was associated with pruritus and was profoundly malodorous. The patient had been unsuccessfully treated with triamcinolone ointment, bleach baths, and several courses of oral antibiotics. Her history was remarkable for marked venous insufficiency and mild anemia, with a hemoglobin level of 11.9 g/dL (reference range, 14.0–17.5 g/dL). She had no other abnormalities on a comprehensive blood test, basic metabolic panel, or liver function test.

A punch biopsy specimen from the left lower back was obtained and demonstrated papillomatous psoriasiform epidermal hyperplasia with broad parakeratosis, few intracorneal neutrophils, hypogranulosis, and suprapapillary thinning (Figure 2). She was initially treated with oral methotrexate (20 mg weekly), resulting in partial improvement of plaques and complete resolution of pruritus and malodor. After 15 months of treatment with methotrexate, low-dose methotrexate (10 mg weekly) in combination with acitretin 25 mg daily was started, resulting in further improvement of hyperkeratosis (Figure 3). The patient also was given a compounded corticosteroid ointment containing liquor carbonis detergens, salicylic acid, and fluocinonide ointment, achieving minor additional benefit. Comprehensive metabolic panel, lipid panel, and liver function tests were obtained quarterly. Hemoglobin levels remained low, similar to baseline (11.3–12.5 g/dL), while all other values were within reference range. The patient tolerated treatment well, reporting mild dryness of lips on review of systems, which was attributed to acitretin and was treated with emollients.

The etiology of this entity is unknown. An association with diabetes mellitus, pulmonary disease, lymphatic circulation disorders, and immunosuppression has been proposed. Others have reported repeated trauma as contributing to the pathogenesis.¹ For our patient, trauma secondary to scratching, long-standing venous insufficiency, and neglect likely contributed to the development of verrucous plaques.

The diagnosis of verrucous psoriasis can be challenging because of its similarity to several other entities, including verruca vulgaris; epidermal nevus; and squamous cell carcinoma, particularly verrucous carcinoma.^4,6,7 The diagnosis has been less challenging in areas where prior typical psoriatic lesions evolved into a verrucous morphology. Our patient presented a diagnostic challenge and draws attention to this unique variant of psoriasis that could easily be misdiagnosed and lead to inappropriate treatment.

Verrucous psoriasis can be recalcitrant to therapy. Although studies addressing treatment modalities are lacking, several recommendations can be derived from case reports and our patient. The use of topical therapies, including topical corticosteroids (eg, fluocinonide, clobetasol, halobetasol), keratolytic agents (eg, urea, salicylic acid), and calcipotriene, provide only minimal improvement when used as monotherapy.¹ Better success has been reported with systemic therapies, mainly methotrexate and acitretin, with anecdotal reports favoring the use of oral retinoids.^1,6 Conversely, biologic medications such as etanercept, ustekinumab, adalimumab, and infliximab have only provided a partial response.¹ Combination therapies including intralesional triamcinolone plus methotrexate⁴ or methotrexate plus acitretin, as in our patient, seem to provide additional benefit. Methotrexate and acitretin combination therapy has traditionally been avoided because of the risk for hepatotoxicity. However, a case series has demonstrated a moderate safety profile with concurrent use of these drugs in treatment-resistant psoriasis.⁸ In our case, clinical response was most pronounced with combination therapy of methotrexate 10 mg weekly and acitretin 25 mg daily. Thus, strong consideration should be given for combination methotrexate-acitretin therapy in patients with recalcitrant verrucous psoriasis who lack comorbid conditions.

We present a case of verrucous psoriasis, a variant of psoriasis characterized by hypertrophic plaques. We propose that venous insufficiency and long-standing untreated disease was instrumental to the development of these lesions. Furthermore, retinoids, particularly in combination with methotrexate, provided the most benefit for our patient.

Acknowledgment
We thank Stephen Somach, MD (Cleveland, Ohio), for his help interpreting the microscopic findings in our biopsy specimen. He received no compensation.

SAN ANTONIO – An oral formulation of paclitaxel given with the P-glycoprotein pump inhibitor encequidar improved outcomes and reduced neuropathy risk, compared with intravenous paclitaxel, in women with metastatic breast cancer in a randomized, open-label, phase 3 study.

Sharon Worcester/MDedge News

The primary study endpoint of radiologically confirmed tumor response rate was 35.8% among 265 patients randomized to receive oral paclitaxel plus encequidar, compared with 23.4% among 137 who received intravenous paclitaxel – a statistically significant 12.4% difference, Gerardo Umanzor, MD, reported at the San Antonio Breast Cancer Symposium.

In the prespecified modified intent-to-treat (mITT) population of patients who had evaluable scans at baseline and who received at least seven doses of oral therapy or one dose of intravenous therapy, the corresponding confirmed tumor response rates were 40.4% and 25.5% (absolute improvement, 14.8%), said Dr. Umanzor, a medical oncologist with Liga Contra el Cancer in San Pedro Sulas, Honduras.

Tumor responses in all clinically important subgroups were consistent with the overall confirmed response profiles, he said, noting that the responses were durable, with ongoing analyses showing median response durations of 39.0 weeks versus 30.1 weeks with oral versus intravenous therapy.

Further, a higher percentage of oral versus intravenous paclitaxel recipients were receiving ongoing treatment at the time of the study endpoint (19% vs. 13%, respectively), he said.

Progression-free survival also showed a trend toward improved outcome with oral therapy in ongoing analyses in the mITT population (9.3 vs. 8.3 months, respectively), and an early analysis of overall survival also showed significant improvement (27.9 vs. 16.9 months; P = .035), he said.

Oral paclitaxel also was associated with a lower incidence of chemotherapy-induced peripheral neuropathy – a “highly debilitating side effect of IV paclitaxel,” he said, adding that “the difference between the arms is quite dramatic.”

The overall rates of neuropathy to week 23 were 17% versus 15% with oral versus intravenous therapy, and the rates of grade 3 neuropathy were 1% versus 8%, he said.

Alopecia incidence was reduced by about 50% with oral versus intravenous therapy, he added.

Toxicity was generally similar in the two groups, although the oral paclitaxel patients experienced higher rates of neutropenia and gastrointestinal effects. “These were low grade and manageable,” Dr. Umanzor said.

Study participants were patients with any type of metastatic breast cancer randomized 2:1 to receive a 15-mg tablet of encequidar followed by 205 mg/m² of oral paclitaxel (about 11 capsules, each containing 30 mg of solubilized paclitaxel) for 3 consecutive days each week for 3 weeks or intravenous paclitaxel at the labeled dose of 175 mg/m² over a 3-hour infusion every 3 weeks.

Confirmed tumor response rates were based on blinded assessment at two consecutive time points, 3-6 weeks apart, by study day 160.

The treatment groups were similar with respect to demographic characteristics and prior taxane therapy, he noted.

The findings have important implications, because while intravenous paclitaxel is an efficacious chemotherapeutic agent against metastatic breast cancer and multiple other cancers, it is associated in some patients with neuropathy.

“As an oncologist, it has been very frustrating to have an effective chemotherapy like paclitaxel, which a lot of patients cannot tolerate,” Dr. Umanzor said, noting that, in addition to eliminating the need for intravenous access and the risk of infusion hypersensitivity reactions, oral administration offers a number of potential benefits – particularly patient convenience.

Hypothesizing that the lower peak concentration of oral paclitaxel might result in lower systemic toxicity, Dr. Umanzor and colleagues developed the orally administered paclitaxel regimen used in this study to test that hypothesis. The paclitaxel was made bioavailable through combination with the encequidar, which promotes paclitaxel absorption into the blood stream, he explained, noting that the pharmacokinetic exposure matches that of intravenous paclitaxel when given at 80 mg/m², but with peak concentrations that are approximately one-tenth of those seen with intravenous therapy.

In a phase 2 study of 26 patients with heavily pretreated metastatic breast cancer, the oral therapy was associated with an encouraging 42.3% partial response rate and a 46.2% stable disease rate, he said.

The oral paclitaxel plus encequidar combination used in this pivotal study is the first orally administered taxane to demonstrate improved and durable overall confirmed response rates with minimal clinically meaningful neuropathy, compared with intravenous paclitaxel given every 3 weeks, he said.

“Oral paclitaxel and encequidar provides an important oral therapeutic option for patients with metastatic breast cancer, representing a meaningful improvement in the clinical profile of paclitaxel,” he said.

He further noted in a press release that “[t]his oral form of paclitaxel provides a new therapeutic option for patients, in particular, for those who cannot easily travel. While blood counts still need to be monitored, oral administration allows patients to remain home during therapy, and avoid spending significant time in the chemotherapy unit.”

The next step will be testing the tolerability of oral paclitaxel in patients at high risk of developing peripheral neuropathy, he said, adding that the findings could also open the door for assessing this approach with other taxanes.

During a press briefing on the findings at the symposium, several attendees voiced concerns about patient compliance given the large number of capsules required for oral dosing, but Dr. Umanzor said “there were no complaints at all and no issues with adherence.”

“Patients were so excited that they were getting an oral treatment, and we had very good compliance,” he said.

The study was funded by Athenex, the maker of the oral form of paclitaxel. Dr. Umanzor reported having no conflicts of interest.

SOURCE: Umanzor G et al. SABCS 2019, Abstract GS6-01.

SAN ANTONIO – An oral formulation of paclitaxel given with the P-glycoprotein pump inhibitor encequidar improved outcomes and reduced neuropathy risk, compared with intravenous paclitaxel, in women with metastatic breast cancer in a randomized, open-label, phase 3 study.

Sharon Worcester/MDedge News

The primary study endpoint of radiologically confirmed tumor response rate was 35.8% among 265 patients randomized to receive oral paclitaxel plus encequidar, compared with 23.4% among 137 who received intravenous paclitaxel – a statistically significant 12.4% difference, Gerardo Umanzor, MD, reported at the San Antonio Breast Cancer Symposium.

In the prespecified modified intent-to-treat (mITT) population of patients who had evaluable scans at baseline and who received at least seven doses of oral therapy or one dose of intravenous therapy, the corresponding confirmed tumor response rates were 40.4% and 25.5% (absolute improvement, 14.8%), said Dr. Umanzor, a medical oncologist with Liga Contra el Cancer in San Pedro Sulas, Honduras.

Tumor responses in all clinically important subgroups were consistent with the overall confirmed response profiles, he said, noting that the responses were durable, with ongoing analyses showing median response durations of 39.0 weeks versus 30.1 weeks with oral versus intravenous therapy.

Further, a higher percentage of oral versus intravenous paclitaxel recipients were receiving ongoing treatment at the time of the study endpoint (19% vs. 13%, respectively), he said.

Progression-free survival also showed a trend toward improved outcome with oral therapy in ongoing analyses in the mITT population (9.3 vs. 8.3 months, respectively), and an early analysis of overall survival also showed significant improvement (27.9 vs. 16.9 months; P = .035), he said.

Oral paclitaxel also was associated with a lower incidence of chemotherapy-induced peripheral neuropathy – a “highly debilitating side effect of IV paclitaxel,” he said, adding that “the difference between the arms is quite dramatic.”

The overall rates of neuropathy to week 23 were 17% versus 15% with oral versus intravenous therapy, and the rates of grade 3 neuropathy were 1% versus 8%, he said.

Alopecia incidence was reduced by about 50% with oral versus intravenous therapy, he added.

Toxicity was generally similar in the two groups, although the oral paclitaxel patients experienced higher rates of neutropenia and gastrointestinal effects. “These were low grade and manageable,” Dr. Umanzor said.

Study participants were patients with any type of metastatic breast cancer randomized 2:1 to receive a 15-mg tablet of encequidar followed by 205 mg/m² of oral paclitaxel (about 11 capsules, each containing 30 mg of solubilized paclitaxel) for 3 consecutive days each week for 3 weeks or intravenous paclitaxel at the labeled dose of 175 mg/m² over a 3-hour infusion every 3 weeks.

Confirmed tumor response rates were based on blinded assessment at two consecutive time points, 3-6 weeks apart, by study day 160.

The treatment groups were similar with respect to demographic characteristics and prior taxane therapy, he noted.

The findings have important implications, because while intravenous paclitaxel is an efficacious chemotherapeutic agent against metastatic breast cancer and multiple other cancers, it is associated in some patients with neuropathy.

“As an oncologist, it has been very frustrating to have an effective chemotherapy like paclitaxel, which a lot of patients cannot tolerate,” Dr. Umanzor said, noting that, in addition to eliminating the need for intravenous access and the risk of infusion hypersensitivity reactions, oral administration offers a number of potential benefits – particularly patient convenience.

Hypothesizing that the lower peak concentration of oral paclitaxel might result in lower systemic toxicity, Dr. Umanzor and colleagues developed the orally administered paclitaxel regimen used in this study to test that hypothesis. The paclitaxel was made bioavailable through combination with the encequidar, which promotes paclitaxel absorption into the blood stream, he explained, noting that the pharmacokinetic exposure matches that of intravenous paclitaxel when given at 80 mg/m², but with peak concentrations that are approximately one-tenth of those seen with intravenous therapy.

In a phase 2 study of 26 patients with heavily pretreated metastatic breast cancer, the oral therapy was associated with an encouraging 42.3% partial response rate and a 46.2% stable disease rate, he said.

The oral paclitaxel plus encequidar combination used in this pivotal study is the first orally administered taxane to demonstrate improved and durable overall confirmed response rates with minimal clinically meaningful neuropathy, compared with intravenous paclitaxel given every 3 weeks, he said.

“Oral paclitaxel and encequidar provides an important oral therapeutic option for patients with metastatic breast cancer, representing a meaningful improvement in the clinical profile of paclitaxel,” he said.

He further noted in a press release that “[t]his oral form of paclitaxel provides a new therapeutic option for patients, in particular, for those who cannot easily travel. While blood counts still need to be monitored, oral administration allows patients to remain home during therapy, and avoid spending significant time in the chemotherapy unit.”

The next step will be testing the tolerability of oral paclitaxel in patients at high risk of developing peripheral neuropathy, he said, adding that the findings could also open the door for assessing this approach with other taxanes.

During a press briefing on the findings at the symposium, several attendees voiced concerns about patient compliance given the large number of capsules required for oral dosing, but Dr. Umanzor said “there were no complaints at all and no issues with adherence.”

“Patients were so excited that they were getting an oral treatment, and we had very good compliance,” he said.

The study was funded by Athenex, the maker of the oral form of paclitaxel. Dr. Umanzor reported having no conflicts of interest.

SOURCE: Umanzor G et al. SABCS 2019, Abstract GS6-01.

SAN ANTONIO – An oral formulation of paclitaxel given with the P-glycoprotein pump inhibitor encequidar improved outcomes and reduced neuropathy risk, compared with intravenous paclitaxel, in women with metastatic breast cancer in a randomized, open-label, phase 3 study.

Sharon Worcester/MDedge News

The primary study endpoint of radiologically confirmed tumor response rate was 35.8% among 265 patients randomized to receive oral paclitaxel plus encequidar, compared with 23.4% among 137 who received intravenous paclitaxel – a statistically significant 12.4% difference, Gerardo Umanzor, MD, reported at the San Antonio Breast Cancer Symposium.

In the prespecified modified intent-to-treat (mITT) population of patients who had evaluable scans at baseline and who received at least seven doses of oral therapy or one dose of intravenous therapy, the corresponding confirmed tumor response rates were 40.4% and 25.5% (absolute improvement, 14.8%), said Dr. Umanzor, a medical oncologist with Liga Contra el Cancer in San Pedro Sulas, Honduras.

Tumor responses in all clinically important subgroups were consistent with the overall confirmed response profiles, he said, noting that the responses were durable, with ongoing analyses showing median response durations of 39.0 weeks versus 30.1 weeks with oral versus intravenous therapy.

Further, a higher percentage of oral versus intravenous paclitaxel recipients were receiving ongoing treatment at the time of the study endpoint (19% vs. 13%, respectively), he said.

Progression-free survival also showed a trend toward improved outcome with oral therapy in ongoing analyses in the mITT population (9.3 vs. 8.3 months, respectively), and an early analysis of overall survival also showed significant improvement (27.9 vs. 16.9 months; P = .035), he said.

Oral paclitaxel also was associated with a lower incidence of chemotherapy-induced peripheral neuropathy – a “highly debilitating side effect of IV paclitaxel,” he said, adding that “the difference between the arms is quite dramatic.”

The overall rates of neuropathy to week 23 were 17% versus 15% with oral versus intravenous therapy, and the rates of grade 3 neuropathy were 1% versus 8%, he said.

Alopecia incidence was reduced by about 50% with oral versus intravenous therapy, he added.

Toxicity was generally similar in the two groups, although the oral paclitaxel patients experienced higher rates of neutropenia and gastrointestinal effects. “These were low grade and manageable,” Dr. Umanzor said.

Study participants were patients with any type of metastatic breast cancer randomized 2:1 to receive a 15-mg tablet of encequidar followed by 205 mg/m² of oral paclitaxel (about 11 capsules, each containing 30 mg of solubilized paclitaxel) for 3 consecutive days each week for 3 weeks or intravenous paclitaxel at the labeled dose of 175 mg/m² over a 3-hour infusion every 3 weeks.

Confirmed tumor response rates were based on blinded assessment at two consecutive time points, 3-6 weeks apart, by study day 160.

The treatment groups were similar with respect to demographic characteristics and prior taxane therapy, he noted.

The findings have important implications, because while intravenous paclitaxel is an efficacious chemotherapeutic agent against metastatic breast cancer and multiple other cancers, it is associated in some patients with neuropathy.

“As an oncologist, it has been very frustrating to have an effective chemotherapy like paclitaxel, which a lot of patients cannot tolerate,” Dr. Umanzor said, noting that, in addition to eliminating the need for intravenous access and the risk of infusion hypersensitivity reactions, oral administration offers a number of potential benefits – particularly patient convenience.

Hypothesizing that the lower peak concentration of oral paclitaxel might result in lower systemic toxicity, Dr. Umanzor and colleagues developed the orally administered paclitaxel regimen used in this study to test that hypothesis. The paclitaxel was made bioavailable through combination with the encequidar, which promotes paclitaxel absorption into the blood stream, he explained, noting that the pharmacokinetic exposure matches that of intravenous paclitaxel when given at 80 mg/m², but with peak concentrations that are approximately one-tenth of those seen with intravenous therapy.

In a phase 2 study of 26 patients with heavily pretreated metastatic breast cancer, the oral therapy was associated with an encouraging 42.3% partial response rate and a 46.2% stable disease rate, he said.

The oral paclitaxel plus encequidar combination used in this pivotal study is the first orally administered taxane to demonstrate improved and durable overall confirmed response rates with minimal clinically meaningful neuropathy, compared with intravenous paclitaxel given every 3 weeks, he said.

“Oral paclitaxel and encequidar provides an important oral therapeutic option for patients with metastatic breast cancer, representing a meaningful improvement in the clinical profile of paclitaxel,” he said.

He further noted in a press release that “[t]his oral form of paclitaxel provides a new therapeutic option for patients, in particular, for those who cannot easily travel. While blood counts still need to be monitored, oral administration allows patients to remain home during therapy, and avoid spending significant time in the chemotherapy unit.”

The next step will be testing the tolerability of oral paclitaxel in patients at high risk of developing peripheral neuropathy, he said, adding that the findings could also open the door for assessing this approach with other taxanes.

During a press briefing on the findings at the symposium, several attendees voiced concerns about patient compliance given the large number of capsules required for oral dosing, but Dr. Umanzor said “there were no complaints at all and no issues with adherence.”

“Patients were so excited that they were getting an oral treatment, and we had very good compliance,” he said.

The study was funded by Athenex, the maker of the oral form of paclitaxel. Dr. Umanzor reported having no conflicts of interest.

SOURCE: Umanzor G et al. SABCS 2019, Abstract GS6-01.

A study of high-dose progesterone as a mifepristone antagonist to reverse medical abortion has been stopped early because of safety concerns, but the authors say mifepristone antagonization should not be considered impossible.

In Obstetrics & Gynecology, Mitchell D. Creinin, MD, of the University of California, Davis, and coauthors reported the outcomes of a double-blind, placebo-controlled trial investigating the efficacy and safety of high-dose oral progesterone as a mifepristone antagonist. The study intended to enroll more women at 44–63 days of gestation who were planning surgical abortion, but stopped enrolling after 12 patients because of hemorrhage concerns.

Women were given a 200-mg dose of oral mifepristone, then randomized to either 200 mg oral progesterone or placebo 24 hours later, taken twice daily for 3 days then once daily until their planned surgical abortion 14-16 days after enrollment.

The approved method of medical abortion in the United States involves a combination of mifepristone followed by the prostaglandin analogue misoprostol 24-48 hours later, a combination designed to improve efficacy of the treatment.

There have been reports of some patients changing their minds in between taking the mifepristone and the misoprostol. The fact that mifepristone binds strongly to the progesterone receptor has led to the idea that its action could be reversed with high-dose progesterone as an antagonist.

In this study, three women – two in the placebo group and one in the progesterone group – experienced severe bleeding requiring ambulance transport to the emergency department 2-3 days after taking the mifepristone.

The study found that four of the six patients in the progesterone group, and two of the six patients in the placebo group had continuing pregnancies at 2 weeks.

There were two patients – one in each group – who did not complete the study. One in the placebo group left after taking the mifepristone because of anxiety about bleeding, and had a suction aspiration. The second women completed two of the four doses of progesterone, then requested a suction aspiration.

Dr. Creinin and coauthors wrote that while the study ended early, they found that there were no significant differences in the side effects experienced by patients treated with progesterone, compared with those on placebo – apart from a worsening of some pregnancy symptoms such as vomiting and tiredness.

However, patients should be told of the risk of using mifepristone for medical abortion without using misoprostol, they said, as this was associated with severe hemorrhage even with progesterone treatment.

“Because of the potential dangers for patients who opt not to use misoprostol after mifepristone ingestion, any mifepristone antagonization treatment must be considered experimental,” Dr. Creinin and associates wrote.

The Society of Family Planning Research Fund supported the study. One author declared a consultancy with a laboratory providing medical consultation for clinicians regarding mifepristone, and a second author was an employee of Planned Parenthood. No other conflicts of interest were declared.

SOURCE: Creinin M et al. Obstet Gynecol 2019 Dec 5. doi: 10.1097/AOG.0000000000003620.

A study of high-dose progesterone as a mifepristone antagonist to reverse medical abortion has been stopped early because of safety concerns, but the authors say mifepristone antagonization should not be considered impossible.

In Obstetrics & Gynecology, Mitchell D. Creinin, MD, of the University of California, Davis, and coauthors reported the outcomes of a double-blind, placebo-controlled trial investigating the efficacy and safety of high-dose oral progesterone as a mifepristone antagonist. The study intended to enroll more women at 44–63 days of gestation who were planning surgical abortion, but stopped enrolling after 12 patients because of hemorrhage concerns.

Women were given a 200-mg dose of oral mifepristone, then randomized to either 200 mg oral progesterone or placebo 24 hours later, taken twice daily for 3 days then once daily until their planned surgical abortion 14-16 days after enrollment.

The approved method of medical abortion in the United States involves a combination of mifepristone followed by the prostaglandin analogue misoprostol 24-48 hours later, a combination designed to improve efficacy of the treatment.

There have been reports of some patients changing their minds in between taking the mifepristone and the misoprostol. The fact that mifepristone binds strongly to the progesterone receptor has led to the idea that its action could be reversed with high-dose progesterone as an antagonist.

In this study, three women – two in the placebo group and one in the progesterone group – experienced severe bleeding requiring ambulance transport to the emergency department 2-3 days after taking the mifepristone.

The study found that four of the six patients in the progesterone group, and two of the six patients in the placebo group had continuing pregnancies at 2 weeks.

There were two patients – one in each group – who did not complete the study. One in the placebo group left after taking the mifepristone because of anxiety about bleeding, and had a suction aspiration. The second women completed two of the four doses of progesterone, then requested a suction aspiration.

Dr. Creinin and coauthors wrote that while the study ended early, they found that there were no significant differences in the side effects experienced by patients treated with progesterone, compared with those on placebo – apart from a worsening of some pregnancy symptoms such as vomiting and tiredness.

However, patients should be told of the risk of using mifepristone for medical abortion without using misoprostol, they said, as this was associated with severe hemorrhage even with progesterone treatment.

“Because of the potential dangers for patients who opt not to use misoprostol after mifepristone ingestion, any mifepristone antagonization treatment must be considered experimental,” Dr. Creinin and associates wrote.

The Society of Family Planning Research Fund supported the study. One author declared a consultancy with a laboratory providing medical consultation for clinicians regarding mifepristone, and a second author was an employee of Planned Parenthood. No other conflicts of interest were declared.

SOURCE: Creinin M et al. Obstet Gynecol 2019 Dec 5. doi: 10.1097/AOG.0000000000003620.

A study of high-dose progesterone as a mifepristone antagonist to reverse medical abortion has been stopped early because of safety concerns, but the authors say mifepristone antagonization should not be considered impossible.

In Obstetrics & Gynecology, Mitchell D. Creinin, MD, of the University of California, Davis, and coauthors reported the outcomes of a double-blind, placebo-controlled trial investigating the efficacy and safety of high-dose oral progesterone as a mifepristone antagonist. The study intended to enroll more women at 44–63 days of gestation who were planning surgical abortion, but stopped enrolling after 12 patients because of hemorrhage concerns.

Women were given a 200-mg dose of oral mifepristone, then randomized to either 200 mg oral progesterone or placebo 24 hours later, taken twice daily for 3 days then once daily until their planned surgical abortion 14-16 days after enrollment.

The approved method of medical abortion in the United States involves a combination of mifepristone followed by the prostaglandin analogue misoprostol 24-48 hours later, a combination designed to improve efficacy of the treatment.

There have been reports of some patients changing their minds in between taking the mifepristone and the misoprostol. The fact that mifepristone binds strongly to the progesterone receptor has led to the idea that its action could be reversed with high-dose progesterone as an antagonist.

In this study, three women – two in the placebo group and one in the progesterone group – experienced severe bleeding requiring ambulance transport to the emergency department 2-3 days after taking the mifepristone.

The study found that four of the six patients in the progesterone group, and two of the six patients in the placebo group had continuing pregnancies at 2 weeks.

There were two patients – one in each group – who did not complete the study. One in the placebo group left after taking the mifepristone because of anxiety about bleeding, and had a suction aspiration. The second women completed two of the four doses of progesterone, then requested a suction aspiration.

Dr. Creinin and coauthors wrote that while the study ended early, they found that there were no significant differences in the side effects experienced by patients treated with progesterone, compared with those on placebo – apart from a worsening of some pregnancy symptoms such as vomiting and tiredness.

However, patients should be told of the risk of using mifepristone for medical abortion without using misoprostol, they said, as this was associated with severe hemorrhage even with progesterone treatment.

“Because of the potential dangers for patients who opt not to use misoprostol after mifepristone ingestion, any mifepristone antagonization treatment must be considered experimental,” Dr. Creinin and associates wrote.

The Society of Family Planning Research Fund supported the study. One author declared a consultancy with a laboratory providing medical consultation for clinicians regarding mifepristone, and a second author was an employee of Planned Parenthood. No other conflicts of interest were declared.

SOURCE: Creinin M et al. Obstet Gynecol 2019 Dec 5. doi: 10.1097/AOG.0000000000003620.