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Ulipristal reduces bleeding with contraceptive implant
Ulipristal acetate reduces breakthrough bleeding in women with etonogestrel implants, according to new findings.
After 30 days, patients treated with ulipristal were more satisfied with their bleeding profiles than were those given placebo, reported Rachel E. Zigler, MD, of the department of obstetrics and gynecology at Washington University in St. Louis and her colleagues.
About half of women experience unscheduled bleeding within the first 6 months of etonogestrel implantation, causing many to discontinue treatment. The etiology of this phenomenon is poorly understood.
“One leading theory is that sustained exposure to a progestin can lead to endometrial angiogenesis disruption, resulting in the development of a dense venous network that is fragile and prone to bleeding,” the researchers wrote in Obstetrics & Gynecology.
Ulipristal acetate is a selective progesterone receptor modulator approved for emergency contraception in the United States. Outside the United States, it is used to treat abnormal uterine bleeding in cases of uterine leiomyoma. Ulipristal acts directly upon myometrial and endometrial tissue and “may also displace local progestin within the uterus to counteract bleeding secondary to … a dense, fragile venous network.”
The double-blind, placebo-controlled study included 65 women aged 18-45 years with etonogestrel implants. Eligibility required that implants be in place for more than 90 days and less than 3 years and that participants experienced more than one bleeding episode over a 24-day time frame.
Patients received either 15 mg ulipristal (n = 32) or placebo (n = 33) daily for 7 days. From the first day of treatment until 30 days, patients self-reported bleeding events. Weekly phone questionnaires also were conducted to determine satisfaction with medication and side effects.
Ten days after starting treatment, bleeding resolved in 34% of patients treated with ulipristal versus 10% of patients given placebo (P = .03).
The ulipristal group reported a median of 5 fewer bleeding days, compared with the placebo group, over the month-long evaluation (7 vs. 12; P = .002). Treatment satisfaction rates were also better in the ulipristal group, with nearly three-quarters (72%) “very happy” with results versus about one-quarter (27%) of women who received placebo.
Consequently, more ulipristal patients desired to keep their implants, compared with placebo patients. All patients receiving ulipristal would consider ulipristal for breakthrough bleeding in the future, compared with two-thirds of patients in the placebo group.
Side effects were uncommon for both groups; the most common side effect was headache, reported in 9% in the ulipristal group and 19% in the placebo group.
“Increased satisfaction with the etonogestrel implant may lead to a decrease in discontinuation rates and potentially a decrease in unintended pregnancy rates in this population,” the researchers wrote.
Study funding was provided by the Society of Family Planning Research Fund, the Washington University Institute of Clinical and Translational Sciences, and the National Center for Advancing Translational Sciences. The authors reported financial disclosures related to Bayer and Merck.
SOURCE: Zigler RE et al. Obstet Gynecol. 2018;132:888-94.
The recent trial by Zigler et al. showed that ulipristal acetate may reduce bleeding days in contraceptive implant users, but larger studies are needed, and concerns about logistics, dose, and toxicity must be addressed before clinical roll out, according to Eve Espey, MD.
The FDA halted the present trial after another ulipristal study overseas detected liver toxicity. The overseas study (for uterine leiomyoma) involved daily administration of ulipristal (5 mg) for 3 months, which is significantly longer than the present study for breakthrough bleeding. The European Medicines Agency has since determined that women with liver issues should not receive ulipristal and that others should have close liver monitoring before, during, and after ulipristal therapy.
Despite the above concerns, ulipristal still holds promise for a common clinical problem.
“This study contributes to the literature on management of bothersome bleeding with the contraceptive implant,” Dr. Espey said. “It is an important area because bothersome bleeding leads both to dissatisfaction and method discontinuation. As a recent Cochrane review pointed out, although several different medications have been used, studies are small and not yet conclusive. Despite these caveats, the findings were promising, similar to findings of prior work with a similar compound, mifepristone. Future directions would include clinical trials utilizing ulipristal acetate in a larger population powered for discontinuation.”
Dr. Espey is a professor in and chair of the department of obstetrics and gynecology and the family planning fellowship director at the University of New Mexico, Albuquerque. These comments are adapted from an interview. Dr. Espey said she had no relevant financial disclosures.
The recent trial by Zigler et al. showed that ulipristal acetate may reduce bleeding days in contraceptive implant users, but larger studies are needed, and concerns about logistics, dose, and toxicity must be addressed before clinical roll out, according to Eve Espey, MD.
The FDA halted the present trial after another ulipristal study overseas detected liver toxicity. The overseas study (for uterine leiomyoma) involved daily administration of ulipristal (5 mg) for 3 months, which is significantly longer than the present study for breakthrough bleeding. The European Medicines Agency has since determined that women with liver issues should not receive ulipristal and that others should have close liver monitoring before, during, and after ulipristal therapy.
Despite the above concerns, ulipristal still holds promise for a common clinical problem.
“This study contributes to the literature on management of bothersome bleeding with the contraceptive implant,” Dr. Espey said. “It is an important area because bothersome bleeding leads both to dissatisfaction and method discontinuation. As a recent Cochrane review pointed out, although several different medications have been used, studies are small and not yet conclusive. Despite these caveats, the findings were promising, similar to findings of prior work with a similar compound, mifepristone. Future directions would include clinical trials utilizing ulipristal acetate in a larger population powered for discontinuation.”
Dr. Espey is a professor in and chair of the department of obstetrics and gynecology and the family planning fellowship director at the University of New Mexico, Albuquerque. These comments are adapted from an interview. Dr. Espey said she had no relevant financial disclosures.
The recent trial by Zigler et al. showed that ulipristal acetate may reduce bleeding days in contraceptive implant users, but larger studies are needed, and concerns about logistics, dose, and toxicity must be addressed before clinical roll out, according to Eve Espey, MD.
The FDA halted the present trial after another ulipristal study overseas detected liver toxicity. The overseas study (for uterine leiomyoma) involved daily administration of ulipristal (5 mg) for 3 months, which is significantly longer than the present study for breakthrough bleeding. The European Medicines Agency has since determined that women with liver issues should not receive ulipristal and that others should have close liver monitoring before, during, and after ulipristal therapy.
Despite the above concerns, ulipristal still holds promise for a common clinical problem.
“This study contributes to the literature on management of bothersome bleeding with the contraceptive implant,” Dr. Espey said. “It is an important area because bothersome bleeding leads both to dissatisfaction and method discontinuation. As a recent Cochrane review pointed out, although several different medications have been used, studies are small and not yet conclusive. Despite these caveats, the findings were promising, similar to findings of prior work with a similar compound, mifepristone. Future directions would include clinical trials utilizing ulipristal acetate in a larger population powered for discontinuation.”
Dr. Espey is a professor in and chair of the department of obstetrics and gynecology and the family planning fellowship director at the University of New Mexico, Albuquerque. These comments are adapted from an interview. Dr. Espey said she had no relevant financial disclosures.
Ulipristal acetate reduces breakthrough bleeding in women with etonogestrel implants, according to new findings.
After 30 days, patients treated with ulipristal were more satisfied with their bleeding profiles than were those given placebo, reported Rachel E. Zigler, MD, of the department of obstetrics and gynecology at Washington University in St. Louis and her colleagues.
About half of women experience unscheduled bleeding within the first 6 months of etonogestrel implantation, causing many to discontinue treatment. The etiology of this phenomenon is poorly understood.
“One leading theory is that sustained exposure to a progestin can lead to endometrial angiogenesis disruption, resulting in the development of a dense venous network that is fragile and prone to bleeding,” the researchers wrote in Obstetrics & Gynecology.
Ulipristal acetate is a selective progesterone receptor modulator approved for emergency contraception in the United States. Outside the United States, it is used to treat abnormal uterine bleeding in cases of uterine leiomyoma. Ulipristal acts directly upon myometrial and endometrial tissue and “may also displace local progestin within the uterus to counteract bleeding secondary to … a dense, fragile venous network.”
The double-blind, placebo-controlled study included 65 women aged 18-45 years with etonogestrel implants. Eligibility required that implants be in place for more than 90 days and less than 3 years and that participants experienced more than one bleeding episode over a 24-day time frame.
Patients received either 15 mg ulipristal (n = 32) or placebo (n = 33) daily for 7 days. From the first day of treatment until 30 days, patients self-reported bleeding events. Weekly phone questionnaires also were conducted to determine satisfaction with medication and side effects.
Ten days after starting treatment, bleeding resolved in 34% of patients treated with ulipristal versus 10% of patients given placebo (P = .03).
The ulipristal group reported a median of 5 fewer bleeding days, compared with the placebo group, over the month-long evaluation (7 vs. 12; P = .002). Treatment satisfaction rates were also better in the ulipristal group, with nearly three-quarters (72%) “very happy” with results versus about one-quarter (27%) of women who received placebo.
Consequently, more ulipristal patients desired to keep their implants, compared with placebo patients. All patients receiving ulipristal would consider ulipristal for breakthrough bleeding in the future, compared with two-thirds of patients in the placebo group.
Side effects were uncommon for both groups; the most common side effect was headache, reported in 9% in the ulipristal group and 19% in the placebo group.
“Increased satisfaction with the etonogestrel implant may lead to a decrease in discontinuation rates and potentially a decrease in unintended pregnancy rates in this population,” the researchers wrote.
Study funding was provided by the Society of Family Planning Research Fund, the Washington University Institute of Clinical and Translational Sciences, and the National Center for Advancing Translational Sciences. The authors reported financial disclosures related to Bayer and Merck.
SOURCE: Zigler RE et al. Obstet Gynecol. 2018;132:888-94.
Ulipristal acetate reduces breakthrough bleeding in women with etonogestrel implants, according to new findings.
After 30 days, patients treated with ulipristal were more satisfied with their bleeding profiles than were those given placebo, reported Rachel E. Zigler, MD, of the department of obstetrics and gynecology at Washington University in St. Louis and her colleagues.
About half of women experience unscheduled bleeding within the first 6 months of etonogestrel implantation, causing many to discontinue treatment. The etiology of this phenomenon is poorly understood.
“One leading theory is that sustained exposure to a progestin can lead to endometrial angiogenesis disruption, resulting in the development of a dense venous network that is fragile and prone to bleeding,” the researchers wrote in Obstetrics & Gynecology.
Ulipristal acetate is a selective progesterone receptor modulator approved for emergency contraception in the United States. Outside the United States, it is used to treat abnormal uterine bleeding in cases of uterine leiomyoma. Ulipristal acts directly upon myometrial and endometrial tissue and “may also displace local progestin within the uterus to counteract bleeding secondary to … a dense, fragile venous network.”
The double-blind, placebo-controlled study included 65 women aged 18-45 years with etonogestrel implants. Eligibility required that implants be in place for more than 90 days and less than 3 years and that participants experienced more than one bleeding episode over a 24-day time frame.
Patients received either 15 mg ulipristal (n = 32) or placebo (n = 33) daily for 7 days. From the first day of treatment until 30 days, patients self-reported bleeding events. Weekly phone questionnaires also were conducted to determine satisfaction with medication and side effects.
Ten days after starting treatment, bleeding resolved in 34% of patients treated with ulipristal versus 10% of patients given placebo (P = .03).
The ulipristal group reported a median of 5 fewer bleeding days, compared with the placebo group, over the month-long evaluation (7 vs. 12; P = .002). Treatment satisfaction rates were also better in the ulipristal group, with nearly three-quarters (72%) “very happy” with results versus about one-quarter (27%) of women who received placebo.
Consequently, more ulipristal patients desired to keep their implants, compared with placebo patients. All patients receiving ulipristal would consider ulipristal for breakthrough bleeding in the future, compared with two-thirds of patients in the placebo group.
Side effects were uncommon for both groups; the most common side effect was headache, reported in 9% in the ulipristal group and 19% in the placebo group.
“Increased satisfaction with the etonogestrel implant may lead to a decrease in discontinuation rates and potentially a decrease in unintended pregnancy rates in this population,” the researchers wrote.
Study funding was provided by the Society of Family Planning Research Fund, the Washington University Institute of Clinical and Translational Sciences, and the National Center for Advancing Translational Sciences. The authors reported financial disclosures related to Bayer and Merck.
SOURCE: Zigler RE et al. Obstet Gynecol. 2018;132:888-94.
FROM OBSTETRICS & GYNECOLOGY
Key clinical point:
Major finding: Treatment with ulipristal was associated with 5 fewer bleeding days per month, compared with placebo (P = .002).
Study details: The double-blind, placebo-controlled trial involved 65 women with etonogestrel implants who reported more than one bleeding episode in a 24-day time frame.
Disclosures: The study was funded by the Society of Family Planning Research Fund, the Washington University Institute of Clinical and Translational Sciences, and the National Center for Advancing Translational Sciences (NCATS). The authors reported financial disclosures related to Bayer and Merck.
Source: Zigler RE et al. Obstet Gynecol. 2018;132:888-94.
Guideline-recommended tests’ prognostic ability affirmed in prostanoid-treated PAH
The results of guideline-recommended prognostic tests that measure mortality risk in patients with pulmonary arterial hypertension (PAH) are strongly associated with survival in those who are receiving a parenteral prostanoid, according to a recent study.
Patients with no lower-risk findings or at least two higher-risk findings had the worst outcomes, reported lead author Sonja Bartolome, MD, of the University of Texas Southwestern Medical Center in Dallas, and her colleagues.
Prostanoids are the most effective therapy for advanced PAH. However, patients may respond inadequately, so guidelines recommend lung transplant evaluation 3 months after starting a prostanoid.
The current study relied upon the 2015 European Society of Cardiology and European Respiratory Society (ESC/ERS) consensus guidelines. The guidelines recommend several tests to determine adequate response to therapy, including invasive hemodynamic measures, brain natriuretic peptide (BNP) level, N-terminal BNP (NT-proBNP) level, 6-minute walk distance (6MWD), and functional class (FC). Results of these tests are sorted into three hazard ratios for mortality: lower, intermediate, or higher risk.
It is commonly accepted that these risk categories can predict survival. For example, a patient with several higher-risk results and no lower-risk results would have a poor prognosis. However, the reliability of this method is poorly studied.
“In practicality the definition of an ‘inadequate response’ remains nebulous given that data on prognostic markers in patients on advanced therapy is limited,” the authors wrote. Their report was published in Chest®. “We therefore sought to evaluate whether consensus guidelines recommended prognostic measures associate with survival free from transplant in PAH patients initiating parenteral prostanoids.”
The retrospective study involved 195 patients with group 1 PAH at multiple treatment centers who received a parenteral prostanoid between 2007 and 2016. Diagnosis relied upon CT angiography, ventilation-perfusion scan, pulmonary function testing, cardiac catheterization, or echocardiogram. Eligible diagnoses were idiopathic PAH (n = 111), heritable PAH (n = 9), and PAH associated with connective tissue disease (n = 61), congenital heart disease (n = 12), and HIV (n = 2).
Patients received either IV epoprostenol (n = 132), SC treprostinil (n = 38), or IV treprostinil (n = 25). Routine prognostic testing was done prior to prostanoid therapy, and again at least 90 days later (with right heart catheterization). The investigators then analyzed the data for associations between test outcomes and survival.
Results showed that survival rates at 1, 2, and 3 years were 84%, 77%, and 67%, respectively. All major prognostic measures improved after patients started a prostanoid. Better SVO2, BNP, NT-proBNP, 6MWD, and FC were associated with survival, but cardiac index (CI) was not. Survival was least likely in patients who had at least two higher-risk measures or no lower-risk measures; of these patients, less than 50% were alive after 2 years.
“These findings are likely broadly applicable to PAH patients being treated with parenteral prostanoids,” the authors wrote, citing the fact that all patients in the study were newly started on either of the two parenteral prostanoids currently available in the United States (including patients who were treatment naive as well as those transitioning to parenteral therapy) and the study involved patients with multiple PAH subtypes. They also noted that 97% of patients were receiving combination therapy at first follow-up, “reflecting the more frequent use of combinations of medications in the modern era.”
However, not all of the prognostic measures were reliable, particularly CI.
Although CI is used as a major determinant for lung transplant, the authors noted that the lack of association between CI and survival suggests that “the strength and usefulness of some individual prognostic measures may differ for prostanoid-treated PAH patients.”
Some of the authors disclosed financial ties to United Therapeutics, which markets treprostinil for infusion (Remodulin), and Actelion, which markets epoprostenol for injection (Veletri), as well as other pharmaceutical companies.
Source: Bartolome S et al. Chest. 2018 Sep 1. doi: 10.1016/j.chest.2018.03.050
The results of guideline-recommended prognostic tests that measure mortality risk in patients with pulmonary arterial hypertension (PAH) are strongly associated with survival in those who are receiving a parenteral prostanoid, according to a recent study.
Patients with no lower-risk findings or at least two higher-risk findings had the worst outcomes, reported lead author Sonja Bartolome, MD, of the University of Texas Southwestern Medical Center in Dallas, and her colleagues.
Prostanoids are the most effective therapy for advanced PAH. However, patients may respond inadequately, so guidelines recommend lung transplant evaluation 3 months after starting a prostanoid.
The current study relied upon the 2015 European Society of Cardiology and European Respiratory Society (ESC/ERS) consensus guidelines. The guidelines recommend several tests to determine adequate response to therapy, including invasive hemodynamic measures, brain natriuretic peptide (BNP) level, N-terminal BNP (NT-proBNP) level, 6-minute walk distance (6MWD), and functional class (FC). Results of these tests are sorted into three hazard ratios for mortality: lower, intermediate, or higher risk.
It is commonly accepted that these risk categories can predict survival. For example, a patient with several higher-risk results and no lower-risk results would have a poor prognosis. However, the reliability of this method is poorly studied.
“In practicality the definition of an ‘inadequate response’ remains nebulous given that data on prognostic markers in patients on advanced therapy is limited,” the authors wrote. Their report was published in Chest®. “We therefore sought to evaluate whether consensus guidelines recommended prognostic measures associate with survival free from transplant in PAH patients initiating parenteral prostanoids.”
The retrospective study involved 195 patients with group 1 PAH at multiple treatment centers who received a parenteral prostanoid between 2007 and 2016. Diagnosis relied upon CT angiography, ventilation-perfusion scan, pulmonary function testing, cardiac catheterization, or echocardiogram. Eligible diagnoses were idiopathic PAH (n = 111), heritable PAH (n = 9), and PAH associated with connective tissue disease (n = 61), congenital heart disease (n = 12), and HIV (n = 2).
Patients received either IV epoprostenol (n = 132), SC treprostinil (n = 38), or IV treprostinil (n = 25). Routine prognostic testing was done prior to prostanoid therapy, and again at least 90 days later (with right heart catheterization). The investigators then analyzed the data for associations between test outcomes and survival.
Results showed that survival rates at 1, 2, and 3 years were 84%, 77%, and 67%, respectively. All major prognostic measures improved after patients started a prostanoid. Better SVO2, BNP, NT-proBNP, 6MWD, and FC were associated with survival, but cardiac index (CI) was not. Survival was least likely in patients who had at least two higher-risk measures or no lower-risk measures; of these patients, less than 50% were alive after 2 years.
“These findings are likely broadly applicable to PAH patients being treated with parenteral prostanoids,” the authors wrote, citing the fact that all patients in the study were newly started on either of the two parenteral prostanoids currently available in the United States (including patients who were treatment naive as well as those transitioning to parenteral therapy) and the study involved patients with multiple PAH subtypes. They also noted that 97% of patients were receiving combination therapy at first follow-up, “reflecting the more frequent use of combinations of medications in the modern era.”
However, not all of the prognostic measures were reliable, particularly CI.
Although CI is used as a major determinant for lung transplant, the authors noted that the lack of association between CI and survival suggests that “the strength and usefulness of some individual prognostic measures may differ for prostanoid-treated PAH patients.”
Some of the authors disclosed financial ties to United Therapeutics, which markets treprostinil for infusion (Remodulin), and Actelion, which markets epoprostenol for injection (Veletri), as well as other pharmaceutical companies.
Source: Bartolome S et al. Chest. 2018 Sep 1. doi: 10.1016/j.chest.2018.03.050
The results of guideline-recommended prognostic tests that measure mortality risk in patients with pulmonary arterial hypertension (PAH) are strongly associated with survival in those who are receiving a parenteral prostanoid, according to a recent study.
Patients with no lower-risk findings or at least two higher-risk findings had the worst outcomes, reported lead author Sonja Bartolome, MD, of the University of Texas Southwestern Medical Center in Dallas, and her colleagues.
Prostanoids are the most effective therapy for advanced PAH. However, patients may respond inadequately, so guidelines recommend lung transplant evaluation 3 months after starting a prostanoid.
The current study relied upon the 2015 European Society of Cardiology and European Respiratory Society (ESC/ERS) consensus guidelines. The guidelines recommend several tests to determine adequate response to therapy, including invasive hemodynamic measures, brain natriuretic peptide (BNP) level, N-terminal BNP (NT-proBNP) level, 6-minute walk distance (6MWD), and functional class (FC). Results of these tests are sorted into three hazard ratios for mortality: lower, intermediate, or higher risk.
It is commonly accepted that these risk categories can predict survival. For example, a patient with several higher-risk results and no lower-risk results would have a poor prognosis. However, the reliability of this method is poorly studied.
“In practicality the definition of an ‘inadequate response’ remains nebulous given that data on prognostic markers in patients on advanced therapy is limited,” the authors wrote. Their report was published in Chest®. “We therefore sought to evaluate whether consensus guidelines recommended prognostic measures associate with survival free from transplant in PAH patients initiating parenteral prostanoids.”
The retrospective study involved 195 patients with group 1 PAH at multiple treatment centers who received a parenteral prostanoid between 2007 and 2016. Diagnosis relied upon CT angiography, ventilation-perfusion scan, pulmonary function testing, cardiac catheterization, or echocardiogram. Eligible diagnoses were idiopathic PAH (n = 111), heritable PAH (n = 9), and PAH associated with connective tissue disease (n = 61), congenital heart disease (n = 12), and HIV (n = 2).
Patients received either IV epoprostenol (n = 132), SC treprostinil (n = 38), or IV treprostinil (n = 25). Routine prognostic testing was done prior to prostanoid therapy, and again at least 90 days later (with right heart catheterization). The investigators then analyzed the data for associations between test outcomes and survival.
Results showed that survival rates at 1, 2, and 3 years were 84%, 77%, and 67%, respectively. All major prognostic measures improved after patients started a prostanoid. Better SVO2, BNP, NT-proBNP, 6MWD, and FC were associated with survival, but cardiac index (CI) was not. Survival was least likely in patients who had at least two higher-risk measures or no lower-risk measures; of these patients, less than 50% were alive after 2 years.
“These findings are likely broadly applicable to PAH patients being treated with parenteral prostanoids,” the authors wrote, citing the fact that all patients in the study were newly started on either of the two parenteral prostanoids currently available in the United States (including patients who were treatment naive as well as those transitioning to parenteral therapy) and the study involved patients with multiple PAH subtypes. They also noted that 97% of patients were receiving combination therapy at first follow-up, “reflecting the more frequent use of combinations of medications in the modern era.”
However, not all of the prognostic measures were reliable, particularly CI.
Although CI is used as a major determinant for lung transplant, the authors noted that the lack of association between CI and survival suggests that “the strength and usefulness of some individual prognostic measures may differ for prostanoid-treated PAH patients.”
Some of the authors disclosed financial ties to United Therapeutics, which markets treprostinil for infusion (Remodulin), and Actelion, which markets epoprostenol for injection (Veletri), as well as other pharmaceutical companies.
Source: Bartolome S et al. Chest. 2018 Sep 1. doi: 10.1016/j.chest.2018.03.050
FROM CHEST®
Key clinical point: Survival in patients with pulmonary arterial hypertension (PAH) who are receiving a parenteral prostanoid is closely associated with the results of most guideline-recommended prognostic tests that measure mortality risk.
Major finding:
Study details: A retrospective study of 195 patients with PAH at multiple treatment centers who received a parenteral prostanoid between 2007 and 2016.
Disclosures: Some of the authors disclosed financial ties to United Therapeutics, which markets treprostinil for infusion (Remodulin), and Actelion, which markets epoprostenol for injection (Veletri), as well as other pharmaceutical companies.
Source: Bartolome S et al. Chest. 2018 Sep 1. doi: 10.1016/j.chest.2018.03.050.
Guideline offers comprehensive approach for ICU clinicians
A new (PADIS).
The guideline builds upon the 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium (PAD) in Adult Patients in the ICU. Given the comprehensive nature of the PADIS guideline, an accompanying commentary was published simultaneously to help with implementation and interpretation. Both papers are the result of a large-scale, multicenter collaboration and were published in Critical Care Medicine.
A panel of 32 international experts, four methodologists, and four survivors of critical illness used the Grading of Recommendations Assessment, Development and Evaluation approach to develop the PADIS guideline.
“Thousands of hours were invested by these guidelines’ authors, who were in turn were supported by formal and informal collaborators, over the 3.5 years it took to produce this effort,” reported lead author John W. Devlin, PharmD, of the department of pharmacy and health systems sciences, Bouvé College of Health Sciences at Northeastern University, Boston, and his colleagues.
Compared with the 2013 PAD guideline, the PADIS guideline includes new sections regarding rehabilitation/mobility and sleep. “We sought to clarify conceptual definitions within these relatively new critical care research domains,” the panel wrote. “The recommendation rationales, fueled by debate and discussion, circled back to the bedside experience – and the perspective of what was best for patients – held by all panelists and methodology experts.”
The result is extensive and comprehensive, consisting of both broad and specific descriptions of current ICU practices and associated evidence; the guideline includes 37 recommendations, 32 ungraded, nonactionable statements, and two good practice statements. Of note, conditional recommendations far outnumber strong recommendations (34 vs. 3). Reasons for conditional rather than strong recommendations are discussed in rationale sections within the guideline and in the accompanying paper.
“Although our goal was to provide specific recommendations for each question, we suspect some guideline readers may be discouraged by the conditional nature of many recommendations and daunted by the breadth of topics discussed,” wrote Michele C. Balas, PhD, of the Ohio State University College of Nursing in Columbus, and her colleagues. Dr. Balas was on the guideline panel and is the lead author of the accompanying article intended to facilitate implementation and interpretation.
One of the more challenging recommendations surrounds the use of antipsychotics for delirious patients. Although this intervention has become relatively common, the guideline stands against it.
“It should be emphasized that there are few supportive data on ICU antipsychotic use and that the initiation of psychoactive medications during critical illness often results in their inappropriate continuation after ICU discharge,” wrote Dr. Balas and her coauthors.
Along with a hard look at existing practices, the panel actively sought to expand upon the 2013 guideline with new interventions. Discussions ranged from the less conventional, such as aromatherapy, to the more established, such as polypharmacy. Questions, recommendations, and rationale are clearly described for each topic, with clear supporting evidence. Where evidence is missing, the panel recommends future research possibilities.
“One example is the consideration of multiple pharmacologic and nonpharmacologic coanalgesic approaches to the ICU patient,” wrote Dr. Devlin and his coauthors. “When the published evidence was insufficient, limited to a narrow population or specific intervention (e.g., for procedural analgesia), or outright absent to answer the questions we posed, we structured evidence gap descriptors to inform clinicians where the uncertainty lay, and intended to provide sufficient information to apprise and invite researchers to address these gaps.”
The authors disclosed funding from AstraZeneca, Baxter, Covidien, and others.
SOURCE: Devlin JW et al. Crit Care Med. 2018 Sep 1. doi: 10.1097/CCM.0000000000003299; Balas MC et al. Crit Care Med. 2018 Sep 1. doi: 10.1097/CCM.0000000000003307.
A new (PADIS).
The guideline builds upon the 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium (PAD) in Adult Patients in the ICU. Given the comprehensive nature of the PADIS guideline, an accompanying commentary was published simultaneously to help with implementation and interpretation. Both papers are the result of a large-scale, multicenter collaboration and were published in Critical Care Medicine.
A panel of 32 international experts, four methodologists, and four survivors of critical illness used the Grading of Recommendations Assessment, Development and Evaluation approach to develop the PADIS guideline.
“Thousands of hours were invested by these guidelines’ authors, who were in turn were supported by formal and informal collaborators, over the 3.5 years it took to produce this effort,” reported lead author John W. Devlin, PharmD, of the department of pharmacy and health systems sciences, Bouvé College of Health Sciences at Northeastern University, Boston, and his colleagues.
Compared with the 2013 PAD guideline, the PADIS guideline includes new sections regarding rehabilitation/mobility and sleep. “We sought to clarify conceptual definitions within these relatively new critical care research domains,” the panel wrote. “The recommendation rationales, fueled by debate and discussion, circled back to the bedside experience – and the perspective of what was best for patients – held by all panelists and methodology experts.”
The result is extensive and comprehensive, consisting of both broad and specific descriptions of current ICU practices and associated evidence; the guideline includes 37 recommendations, 32 ungraded, nonactionable statements, and two good practice statements. Of note, conditional recommendations far outnumber strong recommendations (34 vs. 3). Reasons for conditional rather than strong recommendations are discussed in rationale sections within the guideline and in the accompanying paper.
“Although our goal was to provide specific recommendations for each question, we suspect some guideline readers may be discouraged by the conditional nature of many recommendations and daunted by the breadth of topics discussed,” wrote Michele C. Balas, PhD, of the Ohio State University College of Nursing in Columbus, and her colleagues. Dr. Balas was on the guideline panel and is the lead author of the accompanying article intended to facilitate implementation and interpretation.
One of the more challenging recommendations surrounds the use of antipsychotics for delirious patients. Although this intervention has become relatively common, the guideline stands against it.
“It should be emphasized that there are few supportive data on ICU antipsychotic use and that the initiation of psychoactive medications during critical illness often results in their inappropriate continuation after ICU discharge,” wrote Dr. Balas and her coauthors.
Along with a hard look at existing practices, the panel actively sought to expand upon the 2013 guideline with new interventions. Discussions ranged from the less conventional, such as aromatherapy, to the more established, such as polypharmacy. Questions, recommendations, and rationale are clearly described for each topic, with clear supporting evidence. Where evidence is missing, the panel recommends future research possibilities.
“One example is the consideration of multiple pharmacologic and nonpharmacologic coanalgesic approaches to the ICU patient,” wrote Dr. Devlin and his coauthors. “When the published evidence was insufficient, limited to a narrow population or specific intervention (e.g., for procedural analgesia), or outright absent to answer the questions we posed, we structured evidence gap descriptors to inform clinicians where the uncertainty lay, and intended to provide sufficient information to apprise and invite researchers to address these gaps.”
The authors disclosed funding from AstraZeneca, Baxter, Covidien, and others.
SOURCE: Devlin JW et al. Crit Care Med. 2018 Sep 1. doi: 10.1097/CCM.0000000000003299; Balas MC et al. Crit Care Med. 2018 Sep 1. doi: 10.1097/CCM.0000000000003307.
A new (PADIS).
The guideline builds upon the 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium (PAD) in Adult Patients in the ICU. Given the comprehensive nature of the PADIS guideline, an accompanying commentary was published simultaneously to help with implementation and interpretation. Both papers are the result of a large-scale, multicenter collaboration and were published in Critical Care Medicine.
A panel of 32 international experts, four methodologists, and four survivors of critical illness used the Grading of Recommendations Assessment, Development and Evaluation approach to develop the PADIS guideline.
“Thousands of hours were invested by these guidelines’ authors, who were in turn were supported by formal and informal collaborators, over the 3.5 years it took to produce this effort,” reported lead author John W. Devlin, PharmD, of the department of pharmacy and health systems sciences, Bouvé College of Health Sciences at Northeastern University, Boston, and his colleagues.
Compared with the 2013 PAD guideline, the PADIS guideline includes new sections regarding rehabilitation/mobility and sleep. “We sought to clarify conceptual definitions within these relatively new critical care research domains,” the panel wrote. “The recommendation rationales, fueled by debate and discussion, circled back to the bedside experience – and the perspective of what was best for patients – held by all panelists and methodology experts.”
The result is extensive and comprehensive, consisting of both broad and specific descriptions of current ICU practices and associated evidence; the guideline includes 37 recommendations, 32 ungraded, nonactionable statements, and two good practice statements. Of note, conditional recommendations far outnumber strong recommendations (34 vs. 3). Reasons for conditional rather than strong recommendations are discussed in rationale sections within the guideline and in the accompanying paper.
“Although our goal was to provide specific recommendations for each question, we suspect some guideline readers may be discouraged by the conditional nature of many recommendations and daunted by the breadth of topics discussed,” wrote Michele C. Balas, PhD, of the Ohio State University College of Nursing in Columbus, and her colleagues. Dr. Balas was on the guideline panel and is the lead author of the accompanying article intended to facilitate implementation and interpretation.
One of the more challenging recommendations surrounds the use of antipsychotics for delirious patients. Although this intervention has become relatively common, the guideline stands against it.
“It should be emphasized that there are few supportive data on ICU antipsychotic use and that the initiation of psychoactive medications during critical illness often results in their inappropriate continuation after ICU discharge,” wrote Dr. Balas and her coauthors.
Along with a hard look at existing practices, the panel actively sought to expand upon the 2013 guideline with new interventions. Discussions ranged from the less conventional, such as aromatherapy, to the more established, such as polypharmacy. Questions, recommendations, and rationale are clearly described for each topic, with clear supporting evidence. Where evidence is missing, the panel recommends future research possibilities.
“One example is the consideration of multiple pharmacologic and nonpharmacologic coanalgesic approaches to the ICU patient,” wrote Dr. Devlin and his coauthors. “When the published evidence was insufficient, limited to a narrow population or specific intervention (e.g., for procedural analgesia), or outright absent to answer the questions we posed, we structured evidence gap descriptors to inform clinicians where the uncertainty lay, and intended to provide sufficient information to apprise and invite researchers to address these gaps.”
The authors disclosed funding from AstraZeneca, Baxter, Covidien, and others.
SOURCE: Devlin JW et al. Crit Care Med. 2018 Sep 1. doi: 10.1097/CCM.0000000000003299; Balas MC et al. Crit Care Med. 2018 Sep 1. doi: 10.1097/CCM.0000000000003307.
FROM CRITICAL CARE MEDICINE
Key clinical point: The 2018 PADIS guideline recommends intervention strategies for adult ICU patients with pain, agitation/sedation, delirium, immobility, and sleep disruption.
Major finding: The guideline includes 37 recommendations; 32 ungraded, nonactionable statements; and two good practice statements.
Study details: A clinical practice guideline was created by 32 international experts, four methodologists, and four survivors of critical illness.
Disclosures: The authors declared funding from AstraZeneca, Baxter, Covidien, and others.
Sources: Devlin JW et al. Crit Care Med. 2018 Sep 1. doi: 10.1097/CCM.0000000000003299; Balas MC et al. Crit Care Med. 2018 Sep 1. doi: 10.1097/CCM.0000000000003307.
PARP inhibitor plus trabectedin shows promise for sarcoma
A combination of trabectedin and the PARP inhibitor olaparib may be a safe and effective therapy for patients with sarcoma, the recent TOMAS trial found.
High PARP1 expression was associated with treatment response, reported Giovanni Grignani, MD, of the Medical Oncology_Sarcoma Unit at Istituto di Ricovero e Cura a Carattere Scientifico in Candiolo, Italy, and his colleagues.
PARP inhibitors prevent repair of DNA damage, suggesting potential synergisms with DNA-damaging anticancer agents. Preclinical models support this strategy; however, clinical trials have found that toxicities restrict doses below antitumor activity levels.
“In view of these findings, trabectedin could be an ideal drug to use in combination with PARP1/2 inhibitors for two reasons: its favourable haemopoietic toxicity profile and its unique mechanisms of action,” the authors wrote in The Lancet Oncology. Trabectedin bends the minor groove of DNA toward the major groove, which activates PARP1 in an attempt to repair the damage. Preclinical trials showed that a PARP inhibitor such as olaparib would block this PARP1 activation, ultimately resulting in a more robust response than with either drug alone.
The phase 1b, open-label TOMAS trial involved 50 patients with sarcoma who had experienced disease progression after standard therapy. The study was divided into two cohorts: dose-escalation and dose-expansion. Patients received a median of four cycles of therapy with a median follow-up of 10 months (some patients are still undergoing treatment). The primary endpoint was maximum tolerated dose. The investigators also evaluated pharmacokinetics, pharmacodynamics, and various response measures.
Although adverse events occurred, these were manageable, and the authors concluded that the combination is safe for further investigation. The most common grade 3 or higher adverse events were lymphopenia (64%), neutropenia (62%), thrombocytopenia (28%), anemia (26%), hypophosphatemia (40%), and alanine aminotransferase elevation (18%). The maximum tolerated dose (recommended phase 2 dose) was olaparib 150 mg twice daily and trabectedin 1.1 mg/m2 every 3 weeks.
“These doses allowed us to minimize the need for dose reductions and continue treatment for as long as tumour control was maintained,” the authors wrote. Previous treatments impacted tolerability. The researchers noted that “patients who had received more than two lines of therapy had a higher risk of developing dose-limiting toxicities than those patients who had been treated with only one line of therapy.”
Overall, 14% of patients responded to therapy. Six-month progression-free survival was more common in patients with soft tissue sarcoma (38%) than other tumor types. More patients with high PARP1 expression achieved 6-month PFS compared with patients who had low PARP1 expression (59% vs. 8%; P = .01).
“The combination of olaparib and trabectedin exploits the potential of two different first-in-class drugs and shows tolerability and activity in homologous repair-proficient tumors,” the authors concluded.
They are planning two phase 2 studies in the future; one “comparing trabectedin alone versus the combination of trabectedin and olaparib, stratifying patients according to PARP1 expression,” and an “after-platinum-failure study of patients with ovarian cancer regardless of patients’ BRCA1/2 and BRCAness status.”
The TOMAS trial was funded by the Italian Association for Cancer Research, the Foundation for Research on Musculoskeletal and Rare Tumors, the Italian Ministry of Health, and PharmaMar. The authors reported compensation from Lilly, Novartis, Bayer, Eisai, Amgen, and others.
SOURCE: Grignani et al. Lancet Oncol. 2018 Sep 11. doi: 10.1016/S1470-2045(18)30438-8.
The phase 1b TOMAS trial by Grignani et al. showed that PARP inhibitor combination therapy may be a safe and effective option for patients with sarcoma, and a phase 2 study is warranted, according to Benjamin A. Nacev, MD, and William D. Tap, MD.
PARP inhibitors mitigate DNA damage repair, suggesting potential for synergistic combinations with DNA-damaging anticancer agents. Unfortunately, previous combinations have revealed toxicity issues.
“The first clinical example of this approach was the combination of the alkylating drug temozolomide and the PARP inhibitor rucaparib, which was hampered by dose-limiting myelosuppression,” Dr. Nacev and Dr. Tap wrote in an editorial in The Lancet Oncology.
In the TOMAS trial, Grignani et al. assessed a combination of trabectedin and the PARP inhibitor olaparib. Preclinical data showed synergistic activity in sarcoma cell lines, and the authors predicted tolerable myelosuppression with trabectedin.
Their predictions yielded promising results: Approximately one-third of patients with soft-tissue sarcoma were progression free at 6 months. Although myelosuppression did occur, the adverse event profile was tolerable.
As drug synergisms are biologically complex, “a key success of the TOMAS trial is the effective use of exploratory pharmacodynamic endpoints including PARP1 expression, PARylation, and mutational status of the DNA damage repair pathway.”
“For example, efficacy in the TOMAS trial correlated with PARP1 expression, with greater 6-month progression-free survival in the high PARP1 expression group than the low expression group.”
“The TOMAS investigators should be commended for doing the important bench-to-bedside approach of rationally designing and testing a drug combination to leverage available active drugs. We agree with the authors’ call for further investigation of trabectedin and olaparib in a randomised phase 2 trial in soft tissue sarcoma.”
William D. Tap, MD is chief of the Sarcoma Medical Oncology Service and Benjamin A. Nacev, MD is a third-year medical oncology/hematology fellow at Memorial Sloan Kettering Cancer Center in New York. Dr. Tap reported personal fees from Eli Lilly, Novartis, Eisai, and others. These comments are adapted from their accompanying editorial .
The phase 1b TOMAS trial by Grignani et al. showed that PARP inhibitor combination therapy may be a safe and effective option for patients with sarcoma, and a phase 2 study is warranted, according to Benjamin A. Nacev, MD, and William D. Tap, MD.
PARP inhibitors mitigate DNA damage repair, suggesting potential for synergistic combinations with DNA-damaging anticancer agents. Unfortunately, previous combinations have revealed toxicity issues.
“The first clinical example of this approach was the combination of the alkylating drug temozolomide and the PARP inhibitor rucaparib, which was hampered by dose-limiting myelosuppression,” Dr. Nacev and Dr. Tap wrote in an editorial in The Lancet Oncology.
In the TOMAS trial, Grignani et al. assessed a combination of trabectedin and the PARP inhibitor olaparib. Preclinical data showed synergistic activity in sarcoma cell lines, and the authors predicted tolerable myelosuppression with trabectedin.
Their predictions yielded promising results: Approximately one-third of patients with soft-tissue sarcoma were progression free at 6 months. Although myelosuppression did occur, the adverse event profile was tolerable.
As drug synergisms are biologically complex, “a key success of the TOMAS trial is the effective use of exploratory pharmacodynamic endpoints including PARP1 expression, PARylation, and mutational status of the DNA damage repair pathway.”
“For example, efficacy in the TOMAS trial correlated with PARP1 expression, with greater 6-month progression-free survival in the high PARP1 expression group than the low expression group.”
“The TOMAS investigators should be commended for doing the important bench-to-bedside approach of rationally designing and testing a drug combination to leverage available active drugs. We agree with the authors’ call for further investigation of trabectedin and olaparib in a randomised phase 2 trial in soft tissue sarcoma.”
William D. Tap, MD is chief of the Sarcoma Medical Oncology Service and Benjamin A. Nacev, MD is a third-year medical oncology/hematology fellow at Memorial Sloan Kettering Cancer Center in New York. Dr. Tap reported personal fees from Eli Lilly, Novartis, Eisai, and others. These comments are adapted from their accompanying editorial .
The phase 1b TOMAS trial by Grignani et al. showed that PARP inhibitor combination therapy may be a safe and effective option for patients with sarcoma, and a phase 2 study is warranted, according to Benjamin A. Nacev, MD, and William D. Tap, MD.
PARP inhibitors mitigate DNA damage repair, suggesting potential for synergistic combinations with DNA-damaging anticancer agents. Unfortunately, previous combinations have revealed toxicity issues.
“The first clinical example of this approach was the combination of the alkylating drug temozolomide and the PARP inhibitor rucaparib, which was hampered by dose-limiting myelosuppression,” Dr. Nacev and Dr. Tap wrote in an editorial in The Lancet Oncology.
In the TOMAS trial, Grignani et al. assessed a combination of trabectedin and the PARP inhibitor olaparib. Preclinical data showed synergistic activity in sarcoma cell lines, and the authors predicted tolerable myelosuppression with trabectedin.
Their predictions yielded promising results: Approximately one-third of patients with soft-tissue sarcoma were progression free at 6 months. Although myelosuppression did occur, the adverse event profile was tolerable.
As drug synergisms are biologically complex, “a key success of the TOMAS trial is the effective use of exploratory pharmacodynamic endpoints including PARP1 expression, PARylation, and mutational status of the DNA damage repair pathway.”
“For example, efficacy in the TOMAS trial correlated with PARP1 expression, with greater 6-month progression-free survival in the high PARP1 expression group than the low expression group.”
“The TOMAS investigators should be commended for doing the important bench-to-bedside approach of rationally designing and testing a drug combination to leverage available active drugs. We agree with the authors’ call for further investigation of trabectedin and olaparib in a randomised phase 2 trial in soft tissue sarcoma.”
William D. Tap, MD is chief of the Sarcoma Medical Oncology Service and Benjamin A. Nacev, MD is a third-year medical oncology/hematology fellow at Memorial Sloan Kettering Cancer Center in New York. Dr. Tap reported personal fees from Eli Lilly, Novartis, Eisai, and others. These comments are adapted from their accompanying editorial .
A combination of trabectedin and the PARP inhibitor olaparib may be a safe and effective therapy for patients with sarcoma, the recent TOMAS trial found.
High PARP1 expression was associated with treatment response, reported Giovanni Grignani, MD, of the Medical Oncology_Sarcoma Unit at Istituto di Ricovero e Cura a Carattere Scientifico in Candiolo, Italy, and his colleagues.
PARP inhibitors prevent repair of DNA damage, suggesting potential synergisms with DNA-damaging anticancer agents. Preclinical models support this strategy; however, clinical trials have found that toxicities restrict doses below antitumor activity levels.
“In view of these findings, trabectedin could be an ideal drug to use in combination with PARP1/2 inhibitors for two reasons: its favourable haemopoietic toxicity profile and its unique mechanisms of action,” the authors wrote in The Lancet Oncology. Trabectedin bends the minor groove of DNA toward the major groove, which activates PARP1 in an attempt to repair the damage. Preclinical trials showed that a PARP inhibitor such as olaparib would block this PARP1 activation, ultimately resulting in a more robust response than with either drug alone.
The phase 1b, open-label TOMAS trial involved 50 patients with sarcoma who had experienced disease progression after standard therapy. The study was divided into two cohorts: dose-escalation and dose-expansion. Patients received a median of four cycles of therapy with a median follow-up of 10 months (some patients are still undergoing treatment). The primary endpoint was maximum tolerated dose. The investigators also evaluated pharmacokinetics, pharmacodynamics, and various response measures.
Although adverse events occurred, these were manageable, and the authors concluded that the combination is safe for further investigation. The most common grade 3 or higher adverse events were lymphopenia (64%), neutropenia (62%), thrombocytopenia (28%), anemia (26%), hypophosphatemia (40%), and alanine aminotransferase elevation (18%). The maximum tolerated dose (recommended phase 2 dose) was olaparib 150 mg twice daily and trabectedin 1.1 mg/m2 every 3 weeks.
“These doses allowed us to minimize the need for dose reductions and continue treatment for as long as tumour control was maintained,” the authors wrote. Previous treatments impacted tolerability. The researchers noted that “patients who had received more than two lines of therapy had a higher risk of developing dose-limiting toxicities than those patients who had been treated with only one line of therapy.”
Overall, 14% of patients responded to therapy. Six-month progression-free survival was more common in patients with soft tissue sarcoma (38%) than other tumor types. More patients with high PARP1 expression achieved 6-month PFS compared with patients who had low PARP1 expression (59% vs. 8%; P = .01).
“The combination of olaparib and trabectedin exploits the potential of two different first-in-class drugs and shows tolerability and activity in homologous repair-proficient tumors,” the authors concluded.
They are planning two phase 2 studies in the future; one “comparing trabectedin alone versus the combination of trabectedin and olaparib, stratifying patients according to PARP1 expression,” and an “after-platinum-failure study of patients with ovarian cancer regardless of patients’ BRCA1/2 and BRCAness status.”
The TOMAS trial was funded by the Italian Association for Cancer Research, the Foundation for Research on Musculoskeletal and Rare Tumors, the Italian Ministry of Health, and PharmaMar. The authors reported compensation from Lilly, Novartis, Bayer, Eisai, Amgen, and others.
SOURCE: Grignani et al. Lancet Oncol. 2018 Sep 11. doi: 10.1016/S1470-2045(18)30438-8.
A combination of trabectedin and the PARP inhibitor olaparib may be a safe and effective therapy for patients with sarcoma, the recent TOMAS trial found.
High PARP1 expression was associated with treatment response, reported Giovanni Grignani, MD, of the Medical Oncology_Sarcoma Unit at Istituto di Ricovero e Cura a Carattere Scientifico in Candiolo, Italy, and his colleagues.
PARP inhibitors prevent repair of DNA damage, suggesting potential synergisms with DNA-damaging anticancer agents. Preclinical models support this strategy; however, clinical trials have found that toxicities restrict doses below antitumor activity levels.
“In view of these findings, trabectedin could be an ideal drug to use in combination with PARP1/2 inhibitors for two reasons: its favourable haemopoietic toxicity profile and its unique mechanisms of action,” the authors wrote in The Lancet Oncology. Trabectedin bends the minor groove of DNA toward the major groove, which activates PARP1 in an attempt to repair the damage. Preclinical trials showed that a PARP inhibitor such as olaparib would block this PARP1 activation, ultimately resulting in a more robust response than with either drug alone.
The phase 1b, open-label TOMAS trial involved 50 patients with sarcoma who had experienced disease progression after standard therapy. The study was divided into two cohorts: dose-escalation and dose-expansion. Patients received a median of four cycles of therapy with a median follow-up of 10 months (some patients are still undergoing treatment). The primary endpoint was maximum tolerated dose. The investigators also evaluated pharmacokinetics, pharmacodynamics, and various response measures.
Although adverse events occurred, these were manageable, and the authors concluded that the combination is safe for further investigation. The most common grade 3 or higher adverse events were lymphopenia (64%), neutropenia (62%), thrombocytopenia (28%), anemia (26%), hypophosphatemia (40%), and alanine aminotransferase elevation (18%). The maximum tolerated dose (recommended phase 2 dose) was olaparib 150 mg twice daily and trabectedin 1.1 mg/m2 every 3 weeks.
“These doses allowed us to minimize the need for dose reductions and continue treatment for as long as tumour control was maintained,” the authors wrote. Previous treatments impacted tolerability. The researchers noted that “patients who had received more than two lines of therapy had a higher risk of developing dose-limiting toxicities than those patients who had been treated with only one line of therapy.”
Overall, 14% of patients responded to therapy. Six-month progression-free survival was more common in patients with soft tissue sarcoma (38%) than other tumor types. More patients with high PARP1 expression achieved 6-month PFS compared with patients who had low PARP1 expression (59% vs. 8%; P = .01).
“The combination of olaparib and trabectedin exploits the potential of two different first-in-class drugs and shows tolerability and activity in homologous repair-proficient tumors,” the authors concluded.
They are planning two phase 2 studies in the future; one “comparing trabectedin alone versus the combination of trabectedin and olaparib, stratifying patients according to PARP1 expression,” and an “after-platinum-failure study of patients with ovarian cancer regardless of patients’ BRCA1/2 and BRCAness status.”
The TOMAS trial was funded by the Italian Association for Cancer Research, the Foundation for Research on Musculoskeletal and Rare Tumors, the Italian Ministry of Health, and PharmaMar. The authors reported compensation from Lilly, Novartis, Bayer, Eisai, Amgen, and others.
SOURCE: Grignani et al. Lancet Oncol. 2018 Sep 11. doi: 10.1016/S1470-2045(18)30438-8.
FROM THE LANCET ONCOLOGY
Key clinical point: A combination of trabectedin and the PARP inhibitor olaparib may be a safe and effective therapy for patients with sarcoma.
Major finding: Of those with high PARP1 expression, 59% were progression free 6 months after treatment.
Study details: TOMAS was an open-label phase 1b trial involving 50 patients with sarcoma who had disease progression after standard therapy.
Disclosures: The study was funded by the Italian Association for Cancer Research, the Foundation for Research on Musculoskeletal and Rare Tumors, the Italian Ministry of Health, and PharmaMar. The authors reported compensation from Lilly, Novartis, Bayer, Eisai, Amgen, and others.
Source: Grignani et al. Lancet Oncol. 2018 Sep 11. doi: 10.1016/S1470-2045(18)30438-8.
Kymriah cost effectiveness depends on long-term outcomes
The cost-effectiveness of tisagenlecleucel (Kymriah) depends on long-term clinical outcomes, which are presently unknown, according to investigators.
If the long-term outcomes are more modest than clinical trials suggest, then payers may be unwilling to cover the costly therapy, reported John K. Lin, MD, of the Center for Primary Care and Outcomes Research at Stanford (Calif.) University, and his colleagues. Lowering the price or setting up an outcomes-based pricing structure may be necessary to get insurers to cover the therapy.
Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that was approved by the Food and Drug Administration in August 2017 for relapsed or refractory pediatric B-cell acute lymphoblastic leukemia (ALL). In 2018, the FDA expanded the indication for tisagenlecleucel to include adults with relapsed or refractory large B-cell lymphoma, though outcomes from lymphoma trials are not analyzed in the current study.
At a wholesale acquisition cost of $475,000 per infusion, it is the most expensive existing oncology therapy to date, and can be accompanied by expensive, potentially fatal adverse effects. However, clinical trials suggest that tisagenlecleucel can offer years of relapse-free remission, thereby allowing patients to forgo other expensive therapies such as hematopoietic stem cell transplantation (HSCT).
“Although tisagenlecleucel-induced remission rates are promising, compared with those of established therapies (greater than 80% vs. less than 50%), only short-term follow-up data currently exist,” the investigators wrote in the Journal of Clinical Oncology. “Given the high cost and broad applicability in other malignancies of tisagenlecleucel, a pressing question for policy makers, payers, patients, and clinicians is whether the cost of therapy represents reasonable value.”
The study used a Markov model to assess various long-term clinical outcome rates and cost thresholds of tisagenlecleucel. The lifetime cost of therapy was assessed and compared with costs of existing therapies.
The results showed that a 5-year relapse free survival rate of 40% would make the present cost ($475,000) of tisagenlecleucel economically reasonable. In this scenario, the increased life expectancy would be 12.1 years and would result in an additional 5.07 quality-adjusted life years (QALY) gained at a cost of $61,000 per QALY, compared with blinatumomab.
But if long-term outcomes are less favorable, tisagenlecleucel becomes much less cost effective. A 5-year relapse-free survival rate of 20% would drop increased life expectancy to 3.8 years, resulting in 1.80 QALYs gained and raising the cost to $151,000 per QALY.
“Our results suggest that at tisagenlecleucel’s current price and payment structure, its economic value is uncertain,” the investigators wrote.
They suggested a price drop to $200,000 or $350,000, which would allow the drug to remain cost effective even in a worse-case scenario, in which patients relapse and tisagenlecleucel is a bridge to transplant. Another option is to move to outcomes-based pricing. Making payment conditional on 7 months of remission would make the treatment cost effective, according to the analysis.
“Price reductions of tisagenlecleucel or payment only for longer-term remissions would favorably influence cost-effectiveness, even if long-term clinical outcomes are modest,” the investigators wrote.
The study was funded by a Veterans Affairs Office of Academic Affiliations advanced fellowship in health service and research development, and a National Center for Advancing Translational Science Clinical and Translational Science Award. One of the study coauthors reported consulting and research funding from Novartis.
SOURCE: Lin et al. J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642.
The cost-effectiveness of tisagenlecleucel (Kymriah) depends on long-term clinical outcomes, which are presently unknown, according to investigators.
If the long-term outcomes are more modest than clinical trials suggest, then payers may be unwilling to cover the costly therapy, reported John K. Lin, MD, of the Center for Primary Care and Outcomes Research at Stanford (Calif.) University, and his colleagues. Lowering the price or setting up an outcomes-based pricing structure may be necessary to get insurers to cover the therapy.
Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that was approved by the Food and Drug Administration in August 2017 for relapsed or refractory pediatric B-cell acute lymphoblastic leukemia (ALL). In 2018, the FDA expanded the indication for tisagenlecleucel to include adults with relapsed or refractory large B-cell lymphoma, though outcomes from lymphoma trials are not analyzed in the current study.
At a wholesale acquisition cost of $475,000 per infusion, it is the most expensive existing oncology therapy to date, and can be accompanied by expensive, potentially fatal adverse effects. However, clinical trials suggest that tisagenlecleucel can offer years of relapse-free remission, thereby allowing patients to forgo other expensive therapies such as hematopoietic stem cell transplantation (HSCT).
“Although tisagenlecleucel-induced remission rates are promising, compared with those of established therapies (greater than 80% vs. less than 50%), only short-term follow-up data currently exist,” the investigators wrote in the Journal of Clinical Oncology. “Given the high cost and broad applicability in other malignancies of tisagenlecleucel, a pressing question for policy makers, payers, patients, and clinicians is whether the cost of therapy represents reasonable value.”
The study used a Markov model to assess various long-term clinical outcome rates and cost thresholds of tisagenlecleucel. The lifetime cost of therapy was assessed and compared with costs of existing therapies.
The results showed that a 5-year relapse free survival rate of 40% would make the present cost ($475,000) of tisagenlecleucel economically reasonable. In this scenario, the increased life expectancy would be 12.1 years and would result in an additional 5.07 quality-adjusted life years (QALY) gained at a cost of $61,000 per QALY, compared with blinatumomab.
But if long-term outcomes are less favorable, tisagenlecleucel becomes much less cost effective. A 5-year relapse-free survival rate of 20% would drop increased life expectancy to 3.8 years, resulting in 1.80 QALYs gained and raising the cost to $151,000 per QALY.
“Our results suggest that at tisagenlecleucel’s current price and payment structure, its economic value is uncertain,” the investigators wrote.
They suggested a price drop to $200,000 or $350,000, which would allow the drug to remain cost effective even in a worse-case scenario, in which patients relapse and tisagenlecleucel is a bridge to transplant. Another option is to move to outcomes-based pricing. Making payment conditional on 7 months of remission would make the treatment cost effective, according to the analysis.
“Price reductions of tisagenlecleucel or payment only for longer-term remissions would favorably influence cost-effectiveness, even if long-term clinical outcomes are modest,” the investigators wrote.
The study was funded by a Veterans Affairs Office of Academic Affiliations advanced fellowship in health service and research development, and a National Center for Advancing Translational Science Clinical and Translational Science Award. One of the study coauthors reported consulting and research funding from Novartis.
SOURCE: Lin et al. J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642.
The cost-effectiveness of tisagenlecleucel (Kymriah) depends on long-term clinical outcomes, which are presently unknown, according to investigators.
If the long-term outcomes are more modest than clinical trials suggest, then payers may be unwilling to cover the costly therapy, reported John K. Lin, MD, of the Center for Primary Care and Outcomes Research at Stanford (Calif.) University, and his colleagues. Lowering the price or setting up an outcomes-based pricing structure may be necessary to get insurers to cover the therapy.
Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that was approved by the Food and Drug Administration in August 2017 for relapsed or refractory pediatric B-cell acute lymphoblastic leukemia (ALL). In 2018, the FDA expanded the indication for tisagenlecleucel to include adults with relapsed or refractory large B-cell lymphoma, though outcomes from lymphoma trials are not analyzed in the current study.
At a wholesale acquisition cost of $475,000 per infusion, it is the most expensive existing oncology therapy to date, and can be accompanied by expensive, potentially fatal adverse effects. However, clinical trials suggest that tisagenlecleucel can offer years of relapse-free remission, thereby allowing patients to forgo other expensive therapies such as hematopoietic stem cell transplantation (HSCT).
“Although tisagenlecleucel-induced remission rates are promising, compared with those of established therapies (greater than 80% vs. less than 50%), only short-term follow-up data currently exist,” the investigators wrote in the Journal of Clinical Oncology. “Given the high cost and broad applicability in other malignancies of tisagenlecleucel, a pressing question for policy makers, payers, patients, and clinicians is whether the cost of therapy represents reasonable value.”
The study used a Markov model to assess various long-term clinical outcome rates and cost thresholds of tisagenlecleucel. The lifetime cost of therapy was assessed and compared with costs of existing therapies.
The results showed that a 5-year relapse free survival rate of 40% would make the present cost ($475,000) of tisagenlecleucel economically reasonable. In this scenario, the increased life expectancy would be 12.1 years and would result in an additional 5.07 quality-adjusted life years (QALY) gained at a cost of $61,000 per QALY, compared with blinatumomab.
But if long-term outcomes are less favorable, tisagenlecleucel becomes much less cost effective. A 5-year relapse-free survival rate of 20% would drop increased life expectancy to 3.8 years, resulting in 1.80 QALYs gained and raising the cost to $151,000 per QALY.
“Our results suggest that at tisagenlecleucel’s current price and payment structure, its economic value is uncertain,” the investigators wrote.
They suggested a price drop to $200,000 or $350,000, which would allow the drug to remain cost effective even in a worse-case scenario, in which patients relapse and tisagenlecleucel is a bridge to transplant. Another option is to move to outcomes-based pricing. Making payment conditional on 7 months of remission would make the treatment cost effective, according to the analysis.
“Price reductions of tisagenlecleucel or payment only for longer-term remissions would favorably influence cost-effectiveness, even if long-term clinical outcomes are modest,” the investigators wrote.
The study was funded by a Veterans Affairs Office of Academic Affiliations advanced fellowship in health service and research development, and a National Center for Advancing Translational Science Clinical and Translational Science Award. One of the study coauthors reported consulting and research funding from Novartis.
SOURCE: Lin et al. J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642.
FROM JOURNAL OF CLINICAL ONCOLOGY
Key clinical point:
Major finding: If 40% of patients achieve 5-year remission without relapse, then tisagenlecleucel would cost $61,000 per quality-adjusted life year.
Study details: An economic analysis involving tisagenlecleucel costs and clinical trial outcomes.
Disclosures: The study was funded by a Veterans Affairs Office of Academic Affiliations advanced fellowship in health service and research development, and a National Center for Advancing Translational Science Clinical and Translational Science Award. One study coauthor reported consulting and research funding from Novartis.
Source: Lin JK et al. J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642.
Updated IPF guideline refines diagnostic criteria with HRCT
A recently updated guideline for idiopathic pulmonary fibrosis (IPF) provides refined diagnostic criteria in an effort to improve clinical application and diagnostic accuracy.
Of note, the guideline recommends that high-resolution CT (HRCT) patterns be used to dictate management course. The guideline also calls for detailed medical history, serological testing to exclude connective tissue disease, and multidisciplinary discussion. Serum biomarkers are recommended against as a means of distinguishing between IPF and other interstitial lung diseases (ILDs).
“Diagnosing IPF is challenging because these symptoms are nonspecific: They occur with all other interstitial lung diseases and with other respiratory problems,” Ganesh Raghu, MD, chair of the guideline committee and professor of medicine and director of the Center for Interstitial Lung Disease at the University of Washington, Seattle, said in a written statement. “Because drugs may slow the progression of IPF, an early and accurate diagnosis is essential for prompt and appropriate treatment for this fatal disease.”
The 2018 guideline represents a second collaborative effort from the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society. The guideline committee consisted of 29 clinicians, scientists, and a patient with IPF. They evaluated all IPF-related evidence and rated the quality of findings with the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. The first IPF guideline was published 7 years ago; the intervening time has revealed some clinical limitations that the 2018 guideline aims to fix.
“The 2011 guideline provided the first evidence-based, formal criteria for diagnosis of IPF and allowed patients with a well-defined diagnosis of IPF to participate in numerous clinical studies and randomized controlled trials that enhanced our understanding of the disease,” Dr. Raghu said. “However, it became clear that there were significant challenges in ascertaining the diagnosis per the 2011 criteria, and abundant evidence accumulated since then allowed the committee to refine the diagnostic criteria now.”
“This [updated] guideline is intended to help clinicians make an accurate diagnosis of IPF,” the authors wrote in the American Journal of Respiratory and Critical Care Medicine, “and to empower them to implement recommended courses of action in the context of individual patient values and preferences, particularly decisions regarding which diagnostic interventions to pursue.”
While the 2011 guideline did not distinguish between patients with different HRCT patterns, the 2018 guideline emphasizes the use of HRCT. It is now recommended that patients undergo HRCT to determine the pattern of usual interstitial pneumonia (UIP). Broadly, patients exhibit the UIP pattern or one of three possible non-UIP patterns (probable UIP, indeterminate UIP, or an alternative diagnosis). Recommendations are specific for UIP and non-UIP.
Patients with probable UIP, indeterminate UIP, or an alternative diagnosis should undergo bronchoalveolar lavage (BAL) and surgical lung biopsy (SLB). Transbronchial lung biopsy (TBBx) and lung cryobiopsy recommendations were not described in these patients because of a lack of evidence. However, patients with UIP should not undergo BAL, SLB, TBBx, or cryobiopsy.
For all patients, the 2018 guideline recommends that medical histories include environmental exposure and medication use, and that serological testing is performed to exclude connective tissue disease. Multidisciplinary discussion is conditionally recommended for diagnostic decision making, particularly when a patient has probable UIP, indeterminate UIP, or an alternative diagnosis.
Finally, the guideline recommends against the use of serum biomarkers as a means of distinguishing between IPF and other ILDs because of weak data on this point. “For the time being, the guideline panel dismissed serum biomarker measurement as an approach to distinguishing IPF from other ILDs because of the high false-positive and false-negative result rates,” the panel wrote.
“Our hope is that this new guideline will bridge the gap between the experienced IPF experts and general pulmonologists in making a prompt and accurate diagnosis of IPF for the individual unfortunately confronted with the disease,” Dr. Raghu said. “This will allow patients to make well-informed decisions about treatment options and participation in clinical trials.”
Looking to the future, the panel described an “urgent need to refine and validate diagnostic approaches to ILD. These needs can be roughly categorized as investigations into the roles of clinical observations, HRCT, bronchoscopy, histopathology, and biomarkers.” The authors also emphasized “the need to refine prognostic approaches, identify risk factors for the development of IPF, and determine the impact and approach to the diagnosis of comorbid illness in the patient with IPF.”
The authors reported funding from Bellerophon, Gilead, Roche, Sanofi, and others.
SOURCE: Raghu G et al. Am J Respir Crit Care Med. 2018 Sep 1. doi: 10.1164/rccm.201807-1255ST.
A recently updated guideline for idiopathic pulmonary fibrosis (IPF) provides refined diagnostic criteria in an effort to improve clinical application and diagnostic accuracy.
Of note, the guideline recommends that high-resolution CT (HRCT) patterns be used to dictate management course. The guideline also calls for detailed medical history, serological testing to exclude connective tissue disease, and multidisciplinary discussion. Serum biomarkers are recommended against as a means of distinguishing between IPF and other interstitial lung diseases (ILDs).
“Diagnosing IPF is challenging because these symptoms are nonspecific: They occur with all other interstitial lung diseases and with other respiratory problems,” Ganesh Raghu, MD, chair of the guideline committee and professor of medicine and director of the Center for Interstitial Lung Disease at the University of Washington, Seattle, said in a written statement. “Because drugs may slow the progression of IPF, an early and accurate diagnosis is essential for prompt and appropriate treatment for this fatal disease.”
The 2018 guideline represents a second collaborative effort from the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society. The guideline committee consisted of 29 clinicians, scientists, and a patient with IPF. They evaluated all IPF-related evidence and rated the quality of findings with the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. The first IPF guideline was published 7 years ago; the intervening time has revealed some clinical limitations that the 2018 guideline aims to fix.
“The 2011 guideline provided the first evidence-based, formal criteria for diagnosis of IPF and allowed patients with a well-defined diagnosis of IPF to participate in numerous clinical studies and randomized controlled trials that enhanced our understanding of the disease,” Dr. Raghu said. “However, it became clear that there were significant challenges in ascertaining the diagnosis per the 2011 criteria, and abundant evidence accumulated since then allowed the committee to refine the diagnostic criteria now.”
“This [updated] guideline is intended to help clinicians make an accurate diagnosis of IPF,” the authors wrote in the American Journal of Respiratory and Critical Care Medicine, “and to empower them to implement recommended courses of action in the context of individual patient values and preferences, particularly decisions regarding which diagnostic interventions to pursue.”
While the 2011 guideline did not distinguish between patients with different HRCT patterns, the 2018 guideline emphasizes the use of HRCT. It is now recommended that patients undergo HRCT to determine the pattern of usual interstitial pneumonia (UIP). Broadly, patients exhibit the UIP pattern or one of three possible non-UIP patterns (probable UIP, indeterminate UIP, or an alternative diagnosis). Recommendations are specific for UIP and non-UIP.
Patients with probable UIP, indeterminate UIP, or an alternative diagnosis should undergo bronchoalveolar lavage (BAL) and surgical lung biopsy (SLB). Transbronchial lung biopsy (TBBx) and lung cryobiopsy recommendations were not described in these patients because of a lack of evidence. However, patients with UIP should not undergo BAL, SLB, TBBx, or cryobiopsy.
For all patients, the 2018 guideline recommends that medical histories include environmental exposure and medication use, and that serological testing is performed to exclude connective tissue disease. Multidisciplinary discussion is conditionally recommended for diagnostic decision making, particularly when a patient has probable UIP, indeterminate UIP, or an alternative diagnosis.
Finally, the guideline recommends against the use of serum biomarkers as a means of distinguishing between IPF and other ILDs because of weak data on this point. “For the time being, the guideline panel dismissed serum biomarker measurement as an approach to distinguishing IPF from other ILDs because of the high false-positive and false-negative result rates,” the panel wrote.
“Our hope is that this new guideline will bridge the gap between the experienced IPF experts and general pulmonologists in making a prompt and accurate diagnosis of IPF for the individual unfortunately confronted with the disease,” Dr. Raghu said. “This will allow patients to make well-informed decisions about treatment options and participation in clinical trials.”
Looking to the future, the panel described an “urgent need to refine and validate diagnostic approaches to ILD. These needs can be roughly categorized as investigations into the roles of clinical observations, HRCT, bronchoscopy, histopathology, and biomarkers.” The authors also emphasized “the need to refine prognostic approaches, identify risk factors for the development of IPF, and determine the impact and approach to the diagnosis of comorbid illness in the patient with IPF.”
The authors reported funding from Bellerophon, Gilead, Roche, Sanofi, and others.
SOURCE: Raghu G et al. Am J Respir Crit Care Med. 2018 Sep 1. doi: 10.1164/rccm.201807-1255ST.
A recently updated guideline for idiopathic pulmonary fibrosis (IPF) provides refined diagnostic criteria in an effort to improve clinical application and diagnostic accuracy.
Of note, the guideline recommends that high-resolution CT (HRCT) patterns be used to dictate management course. The guideline also calls for detailed medical history, serological testing to exclude connective tissue disease, and multidisciplinary discussion. Serum biomarkers are recommended against as a means of distinguishing between IPF and other interstitial lung diseases (ILDs).
“Diagnosing IPF is challenging because these symptoms are nonspecific: They occur with all other interstitial lung diseases and with other respiratory problems,” Ganesh Raghu, MD, chair of the guideline committee and professor of medicine and director of the Center for Interstitial Lung Disease at the University of Washington, Seattle, said in a written statement. “Because drugs may slow the progression of IPF, an early and accurate diagnosis is essential for prompt and appropriate treatment for this fatal disease.”
The 2018 guideline represents a second collaborative effort from the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society. The guideline committee consisted of 29 clinicians, scientists, and a patient with IPF. They evaluated all IPF-related evidence and rated the quality of findings with the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. The first IPF guideline was published 7 years ago; the intervening time has revealed some clinical limitations that the 2018 guideline aims to fix.
“The 2011 guideline provided the first evidence-based, formal criteria for diagnosis of IPF and allowed patients with a well-defined diagnosis of IPF to participate in numerous clinical studies and randomized controlled trials that enhanced our understanding of the disease,” Dr. Raghu said. “However, it became clear that there were significant challenges in ascertaining the diagnosis per the 2011 criteria, and abundant evidence accumulated since then allowed the committee to refine the diagnostic criteria now.”
“This [updated] guideline is intended to help clinicians make an accurate diagnosis of IPF,” the authors wrote in the American Journal of Respiratory and Critical Care Medicine, “and to empower them to implement recommended courses of action in the context of individual patient values and preferences, particularly decisions regarding which diagnostic interventions to pursue.”
While the 2011 guideline did not distinguish between patients with different HRCT patterns, the 2018 guideline emphasizes the use of HRCT. It is now recommended that patients undergo HRCT to determine the pattern of usual interstitial pneumonia (UIP). Broadly, patients exhibit the UIP pattern or one of three possible non-UIP patterns (probable UIP, indeterminate UIP, or an alternative diagnosis). Recommendations are specific for UIP and non-UIP.
Patients with probable UIP, indeterminate UIP, or an alternative diagnosis should undergo bronchoalveolar lavage (BAL) and surgical lung biopsy (SLB). Transbronchial lung biopsy (TBBx) and lung cryobiopsy recommendations were not described in these patients because of a lack of evidence. However, patients with UIP should not undergo BAL, SLB, TBBx, or cryobiopsy.
For all patients, the 2018 guideline recommends that medical histories include environmental exposure and medication use, and that serological testing is performed to exclude connective tissue disease. Multidisciplinary discussion is conditionally recommended for diagnostic decision making, particularly when a patient has probable UIP, indeterminate UIP, or an alternative diagnosis.
Finally, the guideline recommends against the use of serum biomarkers as a means of distinguishing between IPF and other ILDs because of weak data on this point. “For the time being, the guideline panel dismissed serum biomarker measurement as an approach to distinguishing IPF from other ILDs because of the high false-positive and false-negative result rates,” the panel wrote.
“Our hope is that this new guideline will bridge the gap between the experienced IPF experts and general pulmonologists in making a prompt and accurate diagnosis of IPF for the individual unfortunately confronted with the disease,” Dr. Raghu said. “This will allow patients to make well-informed decisions about treatment options and participation in clinical trials.”
Looking to the future, the panel described an “urgent need to refine and validate diagnostic approaches to ILD. These needs can be roughly categorized as investigations into the roles of clinical observations, HRCT, bronchoscopy, histopathology, and biomarkers.” The authors also emphasized “the need to refine prognostic approaches, identify risk factors for the development of IPF, and determine the impact and approach to the diagnosis of comorbid illness in the patient with IPF.”
The authors reported funding from Bellerophon, Gilead, Roche, Sanofi, and others.
SOURCE: Raghu G et al. Am J Respir Crit Care Med. 2018 Sep 1. doi: 10.1164/rccm.201807-1255ST.
FROM THE AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
SBRT controls oligometastatic RCC in majority of patients
Stereotactic body radiation therapy (SBRT) is a safe and effective treatment option for patients with oligometastatic renal cell carcinoma (RCC), according to investigators.
Patients with clear cell RCC who had previously received systemic therapy were more likely to achieve local control, reported Ciro Franzese, MD of Humanitas Clinical and Research Center in Milan, and his coauthors.
These findings contribute to a shifting landscape in RCC; modern techniques are opening doors once closed by disappointing historical results. Several recent SBRT studies have demonstrated local control rates of approximately 90%, compared with conventional RT rates of 20%.
“While the outcomes from conventional RT were quite poor, with SBRT, different biological mechanisms occur due to the use of higher doses per fraction,” the authors wrote in The Journal of Urology.
The present retrospective study involved 58 patients with oligometastatic RCC who were treated with SBRT between 2004 and 2006. Patients previously underwent primary tumor excision, had no greater than three distant extracranial metastases, and were not surgical candidates. Study endpoints included median overall survival (OS), progression-free survival (PFS), and in-field local control (LC). Stratified analysis was also performed in patients with clear cell RCC.
Just over 90% of patients achieved LC at 18 months. Slightly less than half (46.2%) were progression-free at 1 year, and this number dropped to one-third (35%) by 18 months. Median OS was just over 2 years (28 months). Although all patients (100%) were alive at 2 years, this rate dropped to 83% by the 5-year mark.
In patients with clear cell RCC, those treated with systemic therapy prior to SBRT were more likely to achieve LC compared with patients who did not receive systemic therapy (HR 0.15; P = .032).
Overall, SBRT was well tolerated. No grade 3 or higher adverse events occurred. The most common adverse events were pain, fatigue, nausea, and vomiting.
The authors concluded that SBRT is a safe and effective option for patients with oligometastatic RCC. They called for future research to address “the radiobiology of RCC” in order to “understand the role of SBRT and, particularly, its possible interaction with medical therapies.”
The authors reported no conflicts of interest.
SOURCE: Franzese et al. J Urol. 2018 Sep 1. doi: 10.1016/j.juro.2018.08.049.
Stereotactic body radiation therapy (SBRT) is a safe and effective treatment option for patients with oligometastatic renal cell carcinoma (RCC), according to investigators.
Patients with clear cell RCC who had previously received systemic therapy were more likely to achieve local control, reported Ciro Franzese, MD of Humanitas Clinical and Research Center in Milan, and his coauthors.
These findings contribute to a shifting landscape in RCC; modern techniques are opening doors once closed by disappointing historical results. Several recent SBRT studies have demonstrated local control rates of approximately 90%, compared with conventional RT rates of 20%.
“While the outcomes from conventional RT were quite poor, with SBRT, different biological mechanisms occur due to the use of higher doses per fraction,” the authors wrote in The Journal of Urology.
The present retrospective study involved 58 patients with oligometastatic RCC who were treated with SBRT between 2004 and 2006. Patients previously underwent primary tumor excision, had no greater than three distant extracranial metastases, and were not surgical candidates. Study endpoints included median overall survival (OS), progression-free survival (PFS), and in-field local control (LC). Stratified analysis was also performed in patients with clear cell RCC.
Just over 90% of patients achieved LC at 18 months. Slightly less than half (46.2%) were progression-free at 1 year, and this number dropped to one-third (35%) by 18 months. Median OS was just over 2 years (28 months). Although all patients (100%) were alive at 2 years, this rate dropped to 83% by the 5-year mark.
In patients with clear cell RCC, those treated with systemic therapy prior to SBRT were more likely to achieve LC compared with patients who did not receive systemic therapy (HR 0.15; P = .032).
Overall, SBRT was well tolerated. No grade 3 or higher adverse events occurred. The most common adverse events were pain, fatigue, nausea, and vomiting.
The authors concluded that SBRT is a safe and effective option for patients with oligometastatic RCC. They called for future research to address “the radiobiology of RCC” in order to “understand the role of SBRT and, particularly, its possible interaction with medical therapies.”
The authors reported no conflicts of interest.
SOURCE: Franzese et al. J Urol. 2018 Sep 1. doi: 10.1016/j.juro.2018.08.049.
Stereotactic body radiation therapy (SBRT) is a safe and effective treatment option for patients with oligometastatic renal cell carcinoma (RCC), according to investigators.
Patients with clear cell RCC who had previously received systemic therapy were more likely to achieve local control, reported Ciro Franzese, MD of Humanitas Clinical and Research Center in Milan, and his coauthors.
These findings contribute to a shifting landscape in RCC; modern techniques are opening doors once closed by disappointing historical results. Several recent SBRT studies have demonstrated local control rates of approximately 90%, compared with conventional RT rates of 20%.
“While the outcomes from conventional RT were quite poor, with SBRT, different biological mechanisms occur due to the use of higher doses per fraction,” the authors wrote in The Journal of Urology.
The present retrospective study involved 58 patients with oligometastatic RCC who were treated with SBRT between 2004 and 2006. Patients previously underwent primary tumor excision, had no greater than three distant extracranial metastases, and were not surgical candidates. Study endpoints included median overall survival (OS), progression-free survival (PFS), and in-field local control (LC). Stratified analysis was also performed in patients with clear cell RCC.
Just over 90% of patients achieved LC at 18 months. Slightly less than half (46.2%) were progression-free at 1 year, and this number dropped to one-third (35%) by 18 months. Median OS was just over 2 years (28 months). Although all patients (100%) were alive at 2 years, this rate dropped to 83% by the 5-year mark.
In patients with clear cell RCC, those treated with systemic therapy prior to SBRT were more likely to achieve LC compared with patients who did not receive systemic therapy (HR 0.15; P = .032).
Overall, SBRT was well tolerated. No grade 3 or higher adverse events occurred. The most common adverse events were pain, fatigue, nausea, and vomiting.
The authors concluded that SBRT is a safe and effective option for patients with oligometastatic RCC. They called for future research to address “the radiobiology of RCC” in order to “understand the role of SBRT and, particularly, its possible interaction with medical therapies.”
The authors reported no conflicts of interest.
SOURCE: Franzese et al. J Urol. 2018 Sep 1. doi: 10.1016/j.juro.2018.08.049.
FROM THE JOURNAL OF UROLOGY
Key clinical point: For patients with oligometastatic renal cell carcinoma (RCC), stereotactic body radiation therapy (SBRT) is a safe and effective treatment option.
Major finding: The local control rate 18 months after SBRT was 90.2%.
Study details: A retrospective study involving 58 patients with oligometastatic RCC who were treated with SBRT between 2004 and 2006.
Disclosures: None.
Source: Franzese et al. J Urol. 2018 Sep 1. doi: 10.1016/j.juro.2018.08.049.
Repeat MRI not useful in suspected axial spondyloarthritis
Patients with chronic back pain suspected of having axial spondyloarthritis (axSpA) should not undergo follow-up MRI of the sacroiliac joint (MRI-SI) within a year if they had a negative baseline MRI-SI, according to investigators.
It is very unlikely that a follow-up MRI-SI will yield new results, reported Pauline A. Bakker, MD, of the department of rheumatology at Leiden University Medical Centre, the Netherlands, and her colleagues.
Since gender and HLA-B27 status were closely associated with MRI-SI positivity, these factors should be considered when deciding to repeat an MRI-SI.
“Over the last decade, MRI rapidly gained ground and proved to be an important imaging technique in the diagnostic process of [nonradiographic] axial spondyloarthritis,” the investigators wrote in Arthritis and Rheumatology. “It has been shown that MRI can detect the early inflammatory stages of sacroiliitis months to years before structural damage can be detected on a conventional radiograph.”
Although MRI represents a diagnostic leap forward, questions of clinical application remain. “For example… if an MRI is completely normal and there is still a clinical suspicion of axSpA, should the MRI be repeated? And if so, after what period of follow-up? Or does this not contribute to the diagnostic process?”
To answer these questions, the investigators observed the “evolution of MRI lesions over a 3-month and 1-year time frame” in patients with early chronic back pain and suspected axSpA.
The prospective study involved 188 patients from the Spondyloarthritis Caught Early (SPACE) cohort. The authors commented that this is “an ideal cohort… since it includes a population of patients with back pain of short duration referred to rheumatologists with a suspicion of SpA [but without the mandatory presence of a single or multiple SpA features].”
Enrolled patients had chronic back pain lasting between 3 months and 2 years, with onset beginning between 16 and 45 years of age. Each underwent physical examination (including evaluation of other SpA features), MRI and radiographs of the sacroiliac joints, and HLA-B27 testing. If patients fulfilled axSpA criteria or had possible axSpA (at least one SpA feature), then they proceeded into the follow-up phase of the study, which included repeat MRI-SI at 3 months and 1 year.
Among enrolled patients, slightly more than one-third were male, almost half were HLA-B27 positive, and about three-quarters had Assessment of Spondyloarthritis International Society–defined inflammatory back pain. Mean age was 31 years; 31 (16.5%) patients were MRI-SI positive.
Of patients that were MRI-SI positive at baseline, 11.1% and 37.9% had a negative MRI-SI at 3 months and 1 year, respectively. The authors noted that this change “was partly induced by the start of anti-TNF [tumor necrosis factor] therapy.” In patients who were MRI-SI negative at baseline, 4.3% and 7.2% were positive at 3 months and 1 year, respectively.
“A very small percentage of patients become positive… which indicates that the usefulness of repeating an MRI-SI in the diagnostic process after 3 months or 1 year is very limited,” the authors wrote.
Gender and HLA-B27 status were independently associated with a positive MRI-SI at any point in time. About 43% of HLA-B27-positive men had a positive MRI-SI, compared with just 7% of HLA-B27-negative women. The investigators advised that these associations be considered when deciding upon repeat MRI-SI.
“If a clinical suspicion [of axSpA] remains [for example, a patient develops other SpA features] it might be worthwhile to consider redoing an MRI in HLA-B27 positive patients,” the investigators wrote. “Likewise, there is a statistically significant difference between male and female patients with a negative baseline MRI, namely that in male patients more often a positive MRI at follow-up is seen [difference: 12% in men, 3% in women].”
The researchers reported having no conflicts of interest.
SOURCE: Bakker PA et al. Arthritis Rheumatol. 2018 Sep 11. doi: 10.1002/art.40718.
Patients with chronic back pain suspected of having axial spondyloarthritis (axSpA) should not undergo follow-up MRI of the sacroiliac joint (MRI-SI) within a year if they had a negative baseline MRI-SI, according to investigators.
It is very unlikely that a follow-up MRI-SI will yield new results, reported Pauline A. Bakker, MD, of the department of rheumatology at Leiden University Medical Centre, the Netherlands, and her colleagues.
Since gender and HLA-B27 status were closely associated with MRI-SI positivity, these factors should be considered when deciding to repeat an MRI-SI.
“Over the last decade, MRI rapidly gained ground and proved to be an important imaging technique in the diagnostic process of [nonradiographic] axial spondyloarthritis,” the investigators wrote in Arthritis and Rheumatology. “It has been shown that MRI can detect the early inflammatory stages of sacroiliitis months to years before structural damage can be detected on a conventional radiograph.”
Although MRI represents a diagnostic leap forward, questions of clinical application remain. “For example… if an MRI is completely normal and there is still a clinical suspicion of axSpA, should the MRI be repeated? And if so, after what period of follow-up? Or does this not contribute to the diagnostic process?”
To answer these questions, the investigators observed the “evolution of MRI lesions over a 3-month and 1-year time frame” in patients with early chronic back pain and suspected axSpA.
The prospective study involved 188 patients from the Spondyloarthritis Caught Early (SPACE) cohort. The authors commented that this is “an ideal cohort… since it includes a population of patients with back pain of short duration referred to rheumatologists with a suspicion of SpA [but without the mandatory presence of a single or multiple SpA features].”
Enrolled patients had chronic back pain lasting between 3 months and 2 years, with onset beginning between 16 and 45 years of age. Each underwent physical examination (including evaluation of other SpA features), MRI and radiographs of the sacroiliac joints, and HLA-B27 testing. If patients fulfilled axSpA criteria or had possible axSpA (at least one SpA feature), then they proceeded into the follow-up phase of the study, which included repeat MRI-SI at 3 months and 1 year.
Among enrolled patients, slightly more than one-third were male, almost half were HLA-B27 positive, and about three-quarters had Assessment of Spondyloarthritis International Society–defined inflammatory back pain. Mean age was 31 years; 31 (16.5%) patients were MRI-SI positive.
Of patients that were MRI-SI positive at baseline, 11.1% and 37.9% had a negative MRI-SI at 3 months and 1 year, respectively. The authors noted that this change “was partly induced by the start of anti-TNF [tumor necrosis factor] therapy.” In patients who were MRI-SI negative at baseline, 4.3% and 7.2% were positive at 3 months and 1 year, respectively.
“A very small percentage of patients become positive… which indicates that the usefulness of repeating an MRI-SI in the diagnostic process after 3 months or 1 year is very limited,” the authors wrote.
Gender and HLA-B27 status were independently associated with a positive MRI-SI at any point in time. About 43% of HLA-B27-positive men had a positive MRI-SI, compared with just 7% of HLA-B27-negative women. The investigators advised that these associations be considered when deciding upon repeat MRI-SI.
“If a clinical suspicion [of axSpA] remains [for example, a patient develops other SpA features] it might be worthwhile to consider redoing an MRI in HLA-B27 positive patients,” the investigators wrote. “Likewise, there is a statistically significant difference between male and female patients with a negative baseline MRI, namely that in male patients more often a positive MRI at follow-up is seen [difference: 12% in men, 3% in women].”
The researchers reported having no conflicts of interest.
SOURCE: Bakker PA et al. Arthritis Rheumatol. 2018 Sep 11. doi: 10.1002/art.40718.
Patients with chronic back pain suspected of having axial spondyloarthritis (axSpA) should not undergo follow-up MRI of the sacroiliac joint (MRI-SI) within a year if they had a negative baseline MRI-SI, according to investigators.
It is very unlikely that a follow-up MRI-SI will yield new results, reported Pauline A. Bakker, MD, of the department of rheumatology at Leiden University Medical Centre, the Netherlands, and her colleagues.
Since gender and HLA-B27 status were closely associated with MRI-SI positivity, these factors should be considered when deciding to repeat an MRI-SI.
“Over the last decade, MRI rapidly gained ground and proved to be an important imaging technique in the diagnostic process of [nonradiographic] axial spondyloarthritis,” the investigators wrote in Arthritis and Rheumatology. “It has been shown that MRI can detect the early inflammatory stages of sacroiliitis months to years before structural damage can be detected on a conventional radiograph.”
Although MRI represents a diagnostic leap forward, questions of clinical application remain. “For example… if an MRI is completely normal and there is still a clinical suspicion of axSpA, should the MRI be repeated? And if so, after what period of follow-up? Or does this not contribute to the diagnostic process?”
To answer these questions, the investigators observed the “evolution of MRI lesions over a 3-month and 1-year time frame” in patients with early chronic back pain and suspected axSpA.
The prospective study involved 188 patients from the Spondyloarthritis Caught Early (SPACE) cohort. The authors commented that this is “an ideal cohort… since it includes a population of patients with back pain of short duration referred to rheumatologists with a suspicion of SpA [but without the mandatory presence of a single or multiple SpA features].”
Enrolled patients had chronic back pain lasting between 3 months and 2 years, with onset beginning between 16 and 45 years of age. Each underwent physical examination (including evaluation of other SpA features), MRI and radiographs of the sacroiliac joints, and HLA-B27 testing. If patients fulfilled axSpA criteria or had possible axSpA (at least one SpA feature), then they proceeded into the follow-up phase of the study, which included repeat MRI-SI at 3 months and 1 year.
Among enrolled patients, slightly more than one-third were male, almost half were HLA-B27 positive, and about three-quarters had Assessment of Spondyloarthritis International Society–defined inflammatory back pain. Mean age was 31 years; 31 (16.5%) patients were MRI-SI positive.
Of patients that were MRI-SI positive at baseline, 11.1% and 37.9% had a negative MRI-SI at 3 months and 1 year, respectively. The authors noted that this change “was partly induced by the start of anti-TNF [tumor necrosis factor] therapy.” In patients who were MRI-SI negative at baseline, 4.3% and 7.2% were positive at 3 months and 1 year, respectively.
“A very small percentage of patients become positive… which indicates that the usefulness of repeating an MRI-SI in the diagnostic process after 3 months or 1 year is very limited,” the authors wrote.
Gender and HLA-B27 status were independently associated with a positive MRI-SI at any point in time. About 43% of HLA-B27-positive men had a positive MRI-SI, compared with just 7% of HLA-B27-negative women. The investigators advised that these associations be considered when deciding upon repeat MRI-SI.
“If a clinical suspicion [of axSpA] remains [for example, a patient develops other SpA features] it might be worthwhile to consider redoing an MRI in HLA-B27 positive patients,” the investigators wrote. “Likewise, there is a statistically significant difference between male and female patients with a negative baseline MRI, namely that in male patients more often a positive MRI at follow-up is seen [difference: 12% in men, 3% in women].”
The researchers reported having no conflicts of interest.
SOURCE: Bakker PA et al. Arthritis Rheumatol. 2018 Sep 11. doi: 10.1002/art.40718.
FROM ARTHRITIS & RHEUMATOLOGY
Key clinical point:
Major finding: In patients who had a negative baseline MRI of the sacroiliac joints, the maximum likelihood of a follow-up MRI being positive was 7%.
Study details: A prospective study involving 188 patients (from the Spondyloarthritis Caught Early cohort) with early chronic back pain suspected of axial spondyloarthritis.
Disclosures: The researchers reported having no financial disclosures.
Source: Bakker PA et al. Arthritis Rheumatol. 2018 Sep 11. doi: 10.1002/art.40718.
Outpatient costs soar for Medicare patients with chronic hepatitis B
The average cost of outpatient care for Medicare recipients with chronic hepatitis B (CH-B) rose by 400% from 2005 to 2014, according to investigators.
Inpatient costs also increased, although less dramatically, reported lead author Min Kim, MD, of the Inova Fairfax Hospital Center for Liver Diseases in Falls Church, Virginia, and her colleagues. The causes of these spending hikes may range from policy changes and expanded screening to an aging immigrant population.
“According to the National Health and Nutrition Examination Survey, from 1988 to 2012 most people with CH-B in the United States were foreign born and accounted for up to 70% of all CH-B infections,” the authors wrote in the Journal of Clinical Gastroenterology. “The Centers for Disease Control [and Prevention] estimates that Asians, who comprise 5% of the U.S. population, account for 50% of all chronic CH-B infections.” Despite these statistics, the clinical and economic impacts of an aging immigrant population are unknown. The investigators therefore assessed patient characteristics associated with increased 1-year mortality and the impact of demographic changes on Medicare costs.
The retrospective study began with a random sample of Medicare beneficiaries from 2005 to 2014. From this group, 18,603 patients with CH-B were identified by ICD-9 codes V02.61, 070.2, 070.3, 070.42, and 070.52. Patients with ICD-9-CM codes of 197.7, 155.1, or 155.2 were excluded, as were records containing insufficient information about year, region, or race. Patients were analyzed collectively and as inpatients (n = 6,550) or outpatients (n = 13,648).
Cost of care (per patient, per year) and 1-year mortality were evaluated. Patient characteristics included age, sex, race/ethnicity, geographic region, type of Medicare eligibility, length of stay, Charlson comorbidity index, presence of decompensated cirrhosis, and/or hepatocellular carcinoma (HCC).
Most dramatically, outpatient charges rose more than 400% during the study period, from $9,257 in 2005 to $47,864 in 2014 (P less than .001). Inpatient charges increased by almost 50%, from $66,610 to $94,221 (P less than .001). (All values converted to 2016 dollars.)
Although the increase in outpatient costs appears seismic, the authors noted that costs held steady from 2005 to 2010 before spiking dramatically, reaching a peak of $58,450 in 2013 before settling down to $47,864 the following year. This spike may be caused by changes in screening measures and policies. In 2009, the American Association for the Study of Liver Diseases expanded screening guidelines to include previously ineligible patients with CH-B, and in 2010, the Centers for Medicare & Medicaid Services expanded ICD-9 and ICD-10 codes for CH-B from 9 to 25.
“It seems plausible that the increase in CH-B prevalence, and its associated costs, might actually be a reflection of [these factors],” the authors noted. Still, “additional studies are needed to clarify this observation.”
Turning to patient characteristics, the authors reported that 1-year mortality was independently associated most strongly with decompensated cirrhosis (odds ratio, 3.02) and hepatocellular carcinoma (OR, 2.64). In comparison with white patients, Asians were less likely to die (OR, 0.47).
“It is possible that this can be explained through differences in transmission mode and disease progression of CH-B between these two demographics,” the authors wrote. “A majority of Asian Medicare recipients with CH-B likely acquired it perinatally and did not develop significant liver disease. In contrast, whites with CH-B generally acquired it in adulthood, increasing the chance of developing liver disease.”
Over the 10-year study period, Medicare beneficiaries with CH-B became more frequently Asian and less frequently male. While the number of outpatient visits and average Charlson comorbidity index increased, decreases were reported for length of stay, rates of 1-year mortality, hospitalization, and HCC – the latter of which is most closely associated with higher costs of care.
The investigators suggested that the decreased incidence of HCC was caused by “better screening programs for HCC and/or more widespread use of antiviral treatment for CH-B.”
“Although advances in antiviral treatment have effectively reduced hospitalization and disease progression,” the authors wrote, “vulnerable groups – especially immigrants and individuals living in poverty – present an important challenge for better identification of infected individuals and their linkage to care. In this context, it is vital to target these cohorts to reduce further mortality and resource utilization, as well as optimize long-term public health and financial benefits.”
Study funding was provided by Seattle Genetics. One coauthor reported compensation from Gilead Sciences, AbbVie, Intercept Pharmaceuticals, GlaxoSmithKline, and Bristol-Myers Squibb.
SOURCE: Kim M et al. J Clin Gastro. 2018 Aug 13. doi: 10.1097/MCG.0000000000001110.
The average cost of outpatient care for Medicare recipients with chronic hepatitis B (CH-B) rose by 400% from 2005 to 2014, according to investigators.
Inpatient costs also increased, although less dramatically, reported lead author Min Kim, MD, of the Inova Fairfax Hospital Center for Liver Diseases in Falls Church, Virginia, and her colleagues. The causes of these spending hikes may range from policy changes and expanded screening to an aging immigrant population.
“According to the National Health and Nutrition Examination Survey, from 1988 to 2012 most people with CH-B in the United States were foreign born and accounted for up to 70% of all CH-B infections,” the authors wrote in the Journal of Clinical Gastroenterology. “The Centers for Disease Control [and Prevention] estimates that Asians, who comprise 5% of the U.S. population, account for 50% of all chronic CH-B infections.” Despite these statistics, the clinical and economic impacts of an aging immigrant population are unknown. The investigators therefore assessed patient characteristics associated with increased 1-year mortality and the impact of demographic changes on Medicare costs.
The retrospective study began with a random sample of Medicare beneficiaries from 2005 to 2014. From this group, 18,603 patients with CH-B were identified by ICD-9 codes V02.61, 070.2, 070.3, 070.42, and 070.52. Patients with ICD-9-CM codes of 197.7, 155.1, or 155.2 were excluded, as were records containing insufficient information about year, region, or race. Patients were analyzed collectively and as inpatients (n = 6,550) or outpatients (n = 13,648).
Cost of care (per patient, per year) and 1-year mortality were evaluated. Patient characteristics included age, sex, race/ethnicity, geographic region, type of Medicare eligibility, length of stay, Charlson comorbidity index, presence of decompensated cirrhosis, and/or hepatocellular carcinoma (HCC).
Most dramatically, outpatient charges rose more than 400% during the study period, from $9,257 in 2005 to $47,864 in 2014 (P less than .001). Inpatient charges increased by almost 50%, from $66,610 to $94,221 (P less than .001). (All values converted to 2016 dollars.)
Although the increase in outpatient costs appears seismic, the authors noted that costs held steady from 2005 to 2010 before spiking dramatically, reaching a peak of $58,450 in 2013 before settling down to $47,864 the following year. This spike may be caused by changes in screening measures and policies. In 2009, the American Association for the Study of Liver Diseases expanded screening guidelines to include previously ineligible patients with CH-B, and in 2010, the Centers for Medicare & Medicaid Services expanded ICD-9 and ICD-10 codes for CH-B from 9 to 25.
“It seems plausible that the increase in CH-B prevalence, and its associated costs, might actually be a reflection of [these factors],” the authors noted. Still, “additional studies are needed to clarify this observation.”
Turning to patient characteristics, the authors reported that 1-year mortality was independently associated most strongly with decompensated cirrhosis (odds ratio, 3.02) and hepatocellular carcinoma (OR, 2.64). In comparison with white patients, Asians were less likely to die (OR, 0.47).
“It is possible that this can be explained through differences in transmission mode and disease progression of CH-B between these two demographics,” the authors wrote. “A majority of Asian Medicare recipients with CH-B likely acquired it perinatally and did not develop significant liver disease. In contrast, whites with CH-B generally acquired it in adulthood, increasing the chance of developing liver disease.”
Over the 10-year study period, Medicare beneficiaries with CH-B became more frequently Asian and less frequently male. While the number of outpatient visits and average Charlson comorbidity index increased, decreases were reported for length of stay, rates of 1-year mortality, hospitalization, and HCC – the latter of which is most closely associated with higher costs of care.
The investigators suggested that the decreased incidence of HCC was caused by “better screening programs for HCC and/or more widespread use of antiviral treatment for CH-B.”
“Although advances in antiviral treatment have effectively reduced hospitalization and disease progression,” the authors wrote, “vulnerable groups – especially immigrants and individuals living in poverty – present an important challenge for better identification of infected individuals and their linkage to care. In this context, it is vital to target these cohorts to reduce further mortality and resource utilization, as well as optimize long-term public health and financial benefits.”
Study funding was provided by Seattle Genetics. One coauthor reported compensation from Gilead Sciences, AbbVie, Intercept Pharmaceuticals, GlaxoSmithKline, and Bristol-Myers Squibb.
SOURCE: Kim M et al. J Clin Gastro. 2018 Aug 13. doi: 10.1097/MCG.0000000000001110.
The average cost of outpatient care for Medicare recipients with chronic hepatitis B (CH-B) rose by 400% from 2005 to 2014, according to investigators.
Inpatient costs also increased, although less dramatically, reported lead author Min Kim, MD, of the Inova Fairfax Hospital Center for Liver Diseases in Falls Church, Virginia, and her colleagues. The causes of these spending hikes may range from policy changes and expanded screening to an aging immigrant population.
“According to the National Health and Nutrition Examination Survey, from 1988 to 2012 most people with CH-B in the United States were foreign born and accounted for up to 70% of all CH-B infections,” the authors wrote in the Journal of Clinical Gastroenterology. “The Centers for Disease Control [and Prevention] estimates that Asians, who comprise 5% of the U.S. population, account for 50% of all chronic CH-B infections.” Despite these statistics, the clinical and economic impacts of an aging immigrant population are unknown. The investigators therefore assessed patient characteristics associated with increased 1-year mortality and the impact of demographic changes on Medicare costs.
The retrospective study began with a random sample of Medicare beneficiaries from 2005 to 2014. From this group, 18,603 patients with CH-B were identified by ICD-9 codes V02.61, 070.2, 070.3, 070.42, and 070.52. Patients with ICD-9-CM codes of 197.7, 155.1, or 155.2 were excluded, as were records containing insufficient information about year, region, or race. Patients were analyzed collectively and as inpatients (n = 6,550) or outpatients (n = 13,648).
Cost of care (per patient, per year) and 1-year mortality were evaluated. Patient characteristics included age, sex, race/ethnicity, geographic region, type of Medicare eligibility, length of stay, Charlson comorbidity index, presence of decompensated cirrhosis, and/or hepatocellular carcinoma (HCC).
Most dramatically, outpatient charges rose more than 400% during the study period, from $9,257 in 2005 to $47,864 in 2014 (P less than .001). Inpatient charges increased by almost 50%, from $66,610 to $94,221 (P less than .001). (All values converted to 2016 dollars.)
Although the increase in outpatient costs appears seismic, the authors noted that costs held steady from 2005 to 2010 before spiking dramatically, reaching a peak of $58,450 in 2013 before settling down to $47,864 the following year. This spike may be caused by changes in screening measures and policies. In 2009, the American Association for the Study of Liver Diseases expanded screening guidelines to include previously ineligible patients with CH-B, and in 2010, the Centers for Medicare & Medicaid Services expanded ICD-9 and ICD-10 codes for CH-B from 9 to 25.
“It seems plausible that the increase in CH-B prevalence, and its associated costs, might actually be a reflection of [these factors],” the authors noted. Still, “additional studies are needed to clarify this observation.”
Turning to patient characteristics, the authors reported that 1-year mortality was independently associated most strongly with decompensated cirrhosis (odds ratio, 3.02) and hepatocellular carcinoma (OR, 2.64). In comparison with white patients, Asians were less likely to die (OR, 0.47).
“It is possible that this can be explained through differences in transmission mode and disease progression of CH-B between these two demographics,” the authors wrote. “A majority of Asian Medicare recipients with CH-B likely acquired it perinatally and did not develop significant liver disease. In contrast, whites with CH-B generally acquired it in adulthood, increasing the chance of developing liver disease.”
Over the 10-year study period, Medicare beneficiaries with CH-B became more frequently Asian and less frequently male. While the number of outpatient visits and average Charlson comorbidity index increased, decreases were reported for length of stay, rates of 1-year mortality, hospitalization, and HCC – the latter of which is most closely associated with higher costs of care.
The investigators suggested that the decreased incidence of HCC was caused by “better screening programs for HCC and/or more widespread use of antiviral treatment for CH-B.”
“Although advances in antiviral treatment have effectively reduced hospitalization and disease progression,” the authors wrote, “vulnerable groups – especially immigrants and individuals living in poverty – present an important challenge for better identification of infected individuals and their linkage to care. In this context, it is vital to target these cohorts to reduce further mortality and resource utilization, as well as optimize long-term public health and financial benefits.”
Study funding was provided by Seattle Genetics. One coauthor reported compensation from Gilead Sciences, AbbVie, Intercept Pharmaceuticals, GlaxoSmithKline, and Bristol-Myers Squibb.
SOURCE: Kim M et al. J Clin Gastro. 2018 Aug 13. doi: 10.1097/MCG.0000000000001110.
FROM THE JOURNAL OF CLINICAL GASTROENTEROLOGY
Key clinical point: Outpatient care for patients with chronic hepatitis B is becoming more expensive; the trend may be tied to an aging immigrant population.
Major finding: The average Medicare charge for outpatient care per patient increased from $9,257 in 2005 to $47,864 in 2014 (P less than .001).
Study details: A retrospective study involving 18,603 Medicare recipients with chronic hepatitis B who filed claims between 2005 and 2014.
Disclosures: Study funding was provided by the Beatty Center for Integrated Research. One coauthor reported compensation from Gilead Sciences, AbbVie, Intercept Pharmaceuticals, GlaxoSmithKline, and Bristol-Myers Squibb.
Source: Kim M et al. J Clin Gastro. 2018 Aug 13. doi: 10.1097/MCG.0000000000001110.
HIV-associated Kaposi sarcoma responds to checkpoint inhibitors
Checkpoint inhibitor therapy is effective for patients with HIV-associated Kaposi sarcoma (KS), a recent study has found.
Partial or complete remission was achieved by a majority of patients; others currently have stable disease lasting longer than 6 months, reported Natalie Galanina, MD, of Rebecca and John Moores Cancer Center at the University of California, San Diego, and her colleagues. Earlier this year, investigators reported similar responses to checkpoint inhibitors in two patients with KS that wasn’t associated with HIV.
“An association has been demonstrated between chronic viral infection, malignancy, and up-regulation of programmed death receptor 1 (PD-1) on CD8+ cytotoxic T-lymphocytes,” the authors wrote in Cancer Immunology Research. In particular, “HIV-specific CD8+ T cells have increased PD-1 expression, which … promotes a cellular milieu conducive to oncogenesis.” These factors, together with the results from the previous study, have suggested that checkpoint inhibitors may be effective for patients with HIV-associated KS.
The retrospective study involved 320 patients treated with immunotherapy at Moores Cancer Center from August 2013 through December 2017. From this group, nine cases of HIV-associated KS were found. Median CD4 count was 256 cells/mcL and median viral load was 20 copies/mL. Eight patients were treated with nivolumab and one was treated with pembrolizumab. Median age was 44 years. All patients were male and receiving antiretroviral therapy.
Six patients (67%) achieved remission, with five attaining partial remission and one attaining complete remission (gastrointestinal disease). Of the remaining three patients, two currently have stable disease lasting longer than 6 months, and one has stable disease lasting longer than 3 months.
Muscle aches, pruritus, and low-grade fever were the most common adverse events. No grade 3 or higher drug-related adverse events occurred.
“Most of our patients received one to four prior lines of therapy but still responded to checkpoint blockade,” the authors wrote. “Our observations suggest that patients with HIV-associated KS have high [response rates] to PD-1 checkpoint blockade, without significant toxicity, even in the presence of low [tumor mutational burden] and/or lack of PD-L1 expression.”
Authors reported compensation from Incyte, Genentech, Merck, Pfizer, and others.
SOURCE: Galanina et al. Cancer Immunol Res. doi: 10.1158/2326-6066.CIR-18-0121.
Checkpoint inhibitor therapy is effective for patients with HIV-associated Kaposi sarcoma (KS), a recent study has found.
Partial or complete remission was achieved by a majority of patients; others currently have stable disease lasting longer than 6 months, reported Natalie Galanina, MD, of Rebecca and John Moores Cancer Center at the University of California, San Diego, and her colleagues. Earlier this year, investigators reported similar responses to checkpoint inhibitors in two patients with KS that wasn’t associated with HIV.
“An association has been demonstrated between chronic viral infection, malignancy, and up-regulation of programmed death receptor 1 (PD-1) on CD8+ cytotoxic T-lymphocytes,” the authors wrote in Cancer Immunology Research. In particular, “HIV-specific CD8+ T cells have increased PD-1 expression, which … promotes a cellular milieu conducive to oncogenesis.” These factors, together with the results from the previous study, have suggested that checkpoint inhibitors may be effective for patients with HIV-associated KS.
The retrospective study involved 320 patients treated with immunotherapy at Moores Cancer Center from August 2013 through December 2017. From this group, nine cases of HIV-associated KS were found. Median CD4 count was 256 cells/mcL and median viral load was 20 copies/mL. Eight patients were treated with nivolumab and one was treated with pembrolizumab. Median age was 44 years. All patients were male and receiving antiretroviral therapy.
Six patients (67%) achieved remission, with five attaining partial remission and one attaining complete remission (gastrointestinal disease). Of the remaining three patients, two currently have stable disease lasting longer than 6 months, and one has stable disease lasting longer than 3 months.
Muscle aches, pruritus, and low-grade fever were the most common adverse events. No grade 3 or higher drug-related adverse events occurred.
“Most of our patients received one to four prior lines of therapy but still responded to checkpoint blockade,” the authors wrote. “Our observations suggest that patients with HIV-associated KS have high [response rates] to PD-1 checkpoint blockade, without significant toxicity, even in the presence of low [tumor mutational burden] and/or lack of PD-L1 expression.”
Authors reported compensation from Incyte, Genentech, Merck, Pfizer, and others.
SOURCE: Galanina et al. Cancer Immunol Res. doi: 10.1158/2326-6066.CIR-18-0121.
Checkpoint inhibitor therapy is effective for patients with HIV-associated Kaposi sarcoma (KS), a recent study has found.
Partial or complete remission was achieved by a majority of patients; others currently have stable disease lasting longer than 6 months, reported Natalie Galanina, MD, of Rebecca and John Moores Cancer Center at the University of California, San Diego, and her colleagues. Earlier this year, investigators reported similar responses to checkpoint inhibitors in two patients with KS that wasn’t associated with HIV.
“An association has been demonstrated between chronic viral infection, malignancy, and up-regulation of programmed death receptor 1 (PD-1) on CD8+ cytotoxic T-lymphocytes,” the authors wrote in Cancer Immunology Research. In particular, “HIV-specific CD8+ T cells have increased PD-1 expression, which … promotes a cellular milieu conducive to oncogenesis.” These factors, together with the results from the previous study, have suggested that checkpoint inhibitors may be effective for patients with HIV-associated KS.
The retrospective study involved 320 patients treated with immunotherapy at Moores Cancer Center from August 2013 through December 2017. From this group, nine cases of HIV-associated KS were found. Median CD4 count was 256 cells/mcL and median viral load was 20 copies/mL. Eight patients were treated with nivolumab and one was treated with pembrolizumab. Median age was 44 years. All patients were male and receiving antiretroviral therapy.
Six patients (67%) achieved remission, with five attaining partial remission and one attaining complete remission (gastrointestinal disease). Of the remaining three patients, two currently have stable disease lasting longer than 6 months, and one has stable disease lasting longer than 3 months.
Muscle aches, pruritus, and low-grade fever were the most common adverse events. No grade 3 or higher drug-related adverse events occurred.
“Most of our patients received one to four prior lines of therapy but still responded to checkpoint blockade,” the authors wrote. “Our observations suggest that patients with HIV-associated KS have high [response rates] to PD-1 checkpoint blockade, without significant toxicity, even in the presence of low [tumor mutational burden] and/or lack of PD-L1 expression.”
Authors reported compensation from Incyte, Genentech, Merck, Pfizer, and others.
SOURCE: Galanina et al. Cancer Immunol Res. doi: 10.1158/2326-6066.CIR-18-0121.
FROM CANCER IMMUNOLOGY RESEARCH
Key clinical point: Checkpoint inhibitor therapy is effective for patients with HIV-associated Kaposi sarcoma.
Major finding: Two-thirds of patients (67%) with HIV-associated Kaposi sarcoma achieved partial or complete remission when treated with immune checkpoint blockade.
Study details: A retrospective study involving nine patients with Kaposi sarcoma treated with either nivolumab or pembrolizumab at the Rebecca and John Moores Cancer Center at the University of California, San Diego, (UCSD) from August 2013 through December 2017.
Disclosures: Authors reported compensation from Incyte, Genentech, Merck, Pfizer, and others.
Source: Galanina et al. Cancer Immunol Res. 2018 Sept 7. doi: 10.1158/2326-6066.CIR-18-0121.