INDIANAPOLIS – Adolescents with nonsegmental vitiligo achieved substantial repigmentation with ruxolitinib cream, compared with those in a vehicle group at week 24, and a higher proportion responded at week 52, results from a pooled analysis of phase 3 data showed.

Currently, there is no treatment approved by the Food and Drug Administration to repigment patients with vitiligo, but the cream formulation of the Janus kinase inhibitor ruxolitinib was shown to be effective and have a favorable safety profile in patients aged 12 years and up in the phase 3 clinical trials, TRuE-V1 and TruE-V2. “We know that about half of patients will develop vitiligo by the age of 20, so there is a significant need to have treatments available for the pediatric population,” lead study author David Rosmarin, MD, told this news organization in advance of the annual meeting of the Society for Pediatric Dermatology.

In September 2021, topical ruxolitinib (Opzelura) was approved by the FDA for treating atopic dermatitis in nonimmunocompromised patients aged 12 years and older. The manufacturer, Incyte, has submitted an application for approval to the agency for treating vitiligo in patients ages 12 years and older based on 24-week results; the FDA is expected to make a decision by July 18.

For the current study, presented during a poster session at the meeting, Dr. Rosmarin, of the department of dermatology at Tufts Medical Center, Boston, and colleagues pooled efficacy and safety data for adolescent patients aged 12-17 years from the TRuE-V studies, which enrolled patients 12 years of age and older diagnosed with nonsegmental vitiligo with depigmentation covering up to 10% of total body surface area (BSA), including facial and total Vitiligo Area Scoring Index (F-VASI/T-VASI) scores of ≥ 0.5/≥ 3. Investigators randomized patients 2:1 to twice-daily 1.5% ruxolitinib cream or vehicle for 24 weeks, after which all patients could apply 1.5% ruxolitinib cream through week 52. Efficacy endpoints included the proportions of patients who achieved at least 75%, 50%, and 90% improvement from baseline in F-VASI scores (F-VASI75, F-VASI50, F-VASI90); the proportion of patients who achieved at least a 50% improvement from baseline in T-VASI (T-VASI50); the proportion of patients who achieved a Vitiligo Noticeability Scale (VNS) rating of 4 or 5; and percentage change from baseline in facial BSA (F-BSA). Safety and tolerability were also assessed.

For the pooled analysis, Dr. Rosmarin and colleagues reported results on 72 adolescents: 55 who received ruxolitinib cream and 17 who received vehicle. At week 24, 32.1% of adolescents treated with ruxolitinib cream achieved F-VASI75, compared with none of those in the vehicle group. Further, response rates at week 52 for patients who applied ruxolitinib cream from day 1 were as follows: F-VASI75, 48.0%; F-VASI50, 70.0%; F-VASI90, 24.0%; T-VASI50, 60.0%; VNS score of 4/5, 56.0%; and F-BSA mean percentage change from baseline, –41.9%.

Efficacy at week 52 among crossover patients (after 28 weeks of ruxolitinib cream) was consistent with week 24 data in patients who applied ruxolitinib cream from day 1.

“As we know that repigmentation takes time, about half of the patients achieved the F-VASI75 at the 52-week endpoint,” said Dr. Rosmarin, who is also vice-chair for research and education at Tufts Medical Center, Boston. “Particularly remarkable is that 60% of adolescents achieved a T-VASI50 [50% or more repigmentation of the whole body at the year mark] and over half the patients described their vitiligo as a lot less noticeable or no longer noticeable at the year mark.”

In terms of safety, treatment-related adverse events occurred in 12.9% of patients treated with ruxolitinib (no information was available on the specific events). Serious adverse events occurred in 1.4% of patients; none were considered related to treatment.

“Overall, these results are quite impressive,” Dr. Rosmarin said. “While it can be very challenging to repigment patients with vitiligo, ruxolitinib cream provides an effective option which can help many of my patients.” He acknowledged certain limitations of the analysis, including the fact that the TRuE-V studies were conducted during the COVID-19 pandemic, “which may have contributed to patients being lost to follow-up. Also, the majority of the patients had skin phototypes 1-3.”

Carrie C. Coughlin, MD, who was asked to comment on the study, said that patients with vitiligo need treatment options that are well-studied and covered by insurance. “This study is a great step forward in developing medications for this underserved patient population,” said Dr. Coughlin, who directs the section of pediatric dermatology at Washington University/St. Louis Children’s Hospital.

However, she continued, “the authors mention approximately 13% of patients had a treatment-related adverse reaction, but the abstract does not delineate these reactions.” In addition, the study was limited to children who had less than or equal to 10% body surface area involvement of vitiligo, she noted, adding that “more work is needed to learn about safety of application to larger surface areas.”

Going forward, “it will be important to learn the durability of response,” said Dr. Coughlin, who is also assistant professor of dermatology at Washington University in St. Louis. “Does the vitiligo return if patients stop applying the ruxolitinib cream?”

Dr. Rosmarin disclosed that he has received honoraria as a consultant for Incyte, AbbVie, Abcuro, AltruBio, Arena, Boehringer Ingelheim, Bristol Meyers Squibb, Celgene, Concert, CSL Behring, Dermavant, Dermira, Janssen, Kyowa Kirin, Lilly, Novartis, Pfizer, Regeneron, Revolo Biotherapeutics, Sanofi, Sun Pharmaceuticals, UCB, and VielaBio. He has also received research support from Incyte, AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Dermira, Galderma, Janssen, Lilly, Merck, Novartis, Pfizer, and Regeneron; and has served as a paid speaker for Incyte, AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Incyte, Janssen, Lilly, Novartis, Pfizer, Regeneron, and Sanofi. Dr. Coughlin is on the board of the Pediatric Dermatology Research Alliance and the International Immunosuppression and Transplant Skin Cancer Collaborative.

INDIANAPOLIS – Adolescents with nonsegmental vitiligo achieved substantial repigmentation with ruxolitinib cream, compared with those in a vehicle group at week 24, and a higher proportion responded at week 52, results from a pooled analysis of phase 3 data showed.

Currently, there is no treatment approved by the Food and Drug Administration to repigment patients with vitiligo, but the cream formulation of the Janus kinase inhibitor ruxolitinib was shown to be effective and have a favorable safety profile in patients aged 12 years and up in the phase 3 clinical trials, TRuE-V1 and TruE-V2. “We know that about half of patients will develop vitiligo by the age of 20, so there is a significant need to have treatments available for the pediatric population,” lead study author David Rosmarin, MD, told this news organization in advance of the annual meeting of the Society for Pediatric Dermatology.

In September 2021, topical ruxolitinib (Opzelura) was approved by the FDA for treating atopic dermatitis in nonimmunocompromised patients aged 12 years and older. The manufacturer, Incyte, has submitted an application for approval to the agency for treating vitiligo in patients ages 12 years and older based on 24-week results; the FDA is expected to make a decision by July 18.

For the current study, presented during a poster session at the meeting, Dr. Rosmarin, of the department of dermatology at Tufts Medical Center, Boston, and colleagues pooled efficacy and safety data for adolescent patients aged 12-17 years from the TRuE-V studies, which enrolled patients 12 years of age and older diagnosed with nonsegmental vitiligo with depigmentation covering up to 10% of total body surface area (BSA), including facial and total Vitiligo Area Scoring Index (F-VASI/T-VASI) scores of ≥ 0.5/≥ 3. Investigators randomized patients 2:1 to twice-daily 1.5% ruxolitinib cream or vehicle for 24 weeks, after which all patients could apply 1.5% ruxolitinib cream through week 52. Efficacy endpoints included the proportions of patients who achieved at least 75%, 50%, and 90% improvement from baseline in F-VASI scores (F-VASI75, F-VASI50, F-VASI90); the proportion of patients who achieved at least a 50% improvement from baseline in T-VASI (T-VASI50); the proportion of patients who achieved a Vitiligo Noticeability Scale (VNS) rating of 4 or 5; and percentage change from baseline in facial BSA (F-BSA). Safety and tolerability were also assessed.

For the pooled analysis, Dr. Rosmarin and colleagues reported results on 72 adolescents: 55 who received ruxolitinib cream and 17 who received vehicle. At week 24, 32.1% of adolescents treated with ruxolitinib cream achieved F-VASI75, compared with none of those in the vehicle group. Further, response rates at week 52 for patients who applied ruxolitinib cream from day 1 were as follows: F-VASI75, 48.0%; F-VASI50, 70.0%; F-VASI90, 24.0%; T-VASI50, 60.0%; VNS score of 4/5, 56.0%; and F-BSA mean percentage change from baseline, –41.9%.

Efficacy at week 52 among crossover patients (after 28 weeks of ruxolitinib cream) was consistent with week 24 data in patients who applied ruxolitinib cream from day 1.

“As we know that repigmentation takes time, about half of the patients achieved the F-VASI75 at the 52-week endpoint,” said Dr. Rosmarin, who is also vice-chair for research and education at Tufts Medical Center, Boston. “Particularly remarkable is that 60% of adolescents achieved a T-VASI50 [50% or more repigmentation of the whole body at the year mark] and over half the patients described their vitiligo as a lot less noticeable or no longer noticeable at the year mark.”

In terms of safety, treatment-related adverse events occurred in 12.9% of patients treated with ruxolitinib (no information was available on the specific events). Serious adverse events occurred in 1.4% of patients; none were considered related to treatment.

“Overall, these results are quite impressive,” Dr. Rosmarin said. “While it can be very challenging to repigment patients with vitiligo, ruxolitinib cream provides an effective option which can help many of my patients.” He acknowledged certain limitations of the analysis, including the fact that the TRuE-V studies were conducted during the COVID-19 pandemic, “which may have contributed to patients being lost to follow-up. Also, the majority of the patients had skin phototypes 1-3.”

Carrie C. Coughlin, MD, who was asked to comment on the study, said that patients with vitiligo need treatment options that are well-studied and covered by insurance. “This study is a great step forward in developing medications for this underserved patient population,” said Dr. Coughlin, who directs the section of pediatric dermatology at Washington University/St. Louis Children’s Hospital.

However, she continued, “the authors mention approximately 13% of patients had a treatment-related adverse reaction, but the abstract does not delineate these reactions.” In addition, the study was limited to children who had less than or equal to 10% body surface area involvement of vitiligo, she noted, adding that “more work is needed to learn about safety of application to larger surface areas.”

Going forward, “it will be important to learn the durability of response,” said Dr. Coughlin, who is also assistant professor of dermatology at Washington University in St. Louis. “Does the vitiligo return if patients stop applying the ruxolitinib cream?”

Dr. Rosmarin disclosed that he has received honoraria as a consultant for Incyte, AbbVie, Abcuro, AltruBio, Arena, Boehringer Ingelheim, Bristol Meyers Squibb, Celgene, Concert, CSL Behring, Dermavant, Dermira, Janssen, Kyowa Kirin, Lilly, Novartis, Pfizer, Regeneron, Revolo Biotherapeutics, Sanofi, Sun Pharmaceuticals, UCB, and VielaBio. He has also received research support from Incyte, AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Dermira, Galderma, Janssen, Lilly, Merck, Novartis, Pfizer, and Regeneron; and has served as a paid speaker for Incyte, AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Incyte, Janssen, Lilly, Novartis, Pfizer, Regeneron, and Sanofi. Dr. Coughlin is on the board of the Pediatric Dermatology Research Alliance and the International Immunosuppression and Transplant Skin Cancer Collaborative.

INDIANAPOLIS – Adolescents with nonsegmental vitiligo achieved substantial repigmentation with ruxolitinib cream, compared with those in a vehicle group at week 24, and a higher proportion responded at week 52, results from a pooled analysis of phase 3 data showed.

Currently, there is no treatment approved by the Food and Drug Administration to repigment patients with vitiligo, but the cream formulation of the Janus kinase inhibitor ruxolitinib was shown to be effective and have a favorable safety profile in patients aged 12 years and up in the phase 3 clinical trials, TRuE-V1 and TruE-V2. “We know that about half of patients will develop vitiligo by the age of 20, so there is a significant need to have treatments available for the pediatric population,” lead study author David Rosmarin, MD, told this news organization in advance of the annual meeting of the Society for Pediatric Dermatology.

In September 2021, topical ruxolitinib (Opzelura) was approved by the FDA for treating atopic dermatitis in nonimmunocompromised patients aged 12 years and older. The manufacturer, Incyte, has submitted an application for approval to the agency for treating vitiligo in patients ages 12 years and older based on 24-week results; the FDA is expected to make a decision by July 18.

For the current study, presented during a poster session at the meeting, Dr. Rosmarin, of the department of dermatology at Tufts Medical Center, Boston, and colleagues pooled efficacy and safety data for adolescent patients aged 12-17 years from the TRuE-V studies, which enrolled patients 12 years of age and older diagnosed with nonsegmental vitiligo with depigmentation covering up to 10% of total body surface area (BSA), including facial and total Vitiligo Area Scoring Index (F-VASI/T-VASI) scores of ≥ 0.5/≥ 3. Investigators randomized patients 2:1 to twice-daily 1.5% ruxolitinib cream or vehicle for 24 weeks, after which all patients could apply 1.5% ruxolitinib cream through week 52. Efficacy endpoints included the proportions of patients who achieved at least 75%, 50%, and 90% improvement from baseline in F-VASI scores (F-VASI75, F-VASI50, F-VASI90); the proportion of patients who achieved at least a 50% improvement from baseline in T-VASI (T-VASI50); the proportion of patients who achieved a Vitiligo Noticeability Scale (VNS) rating of 4 or 5; and percentage change from baseline in facial BSA (F-BSA). Safety and tolerability were also assessed.

For the pooled analysis, Dr. Rosmarin and colleagues reported results on 72 adolescents: 55 who received ruxolitinib cream and 17 who received vehicle. At week 24, 32.1% of adolescents treated with ruxolitinib cream achieved F-VASI75, compared with none of those in the vehicle group. Further, response rates at week 52 for patients who applied ruxolitinib cream from day 1 were as follows: F-VASI75, 48.0%; F-VASI50, 70.0%; F-VASI90, 24.0%; T-VASI50, 60.0%; VNS score of 4/5, 56.0%; and F-BSA mean percentage change from baseline, –41.9%.

Efficacy at week 52 among crossover patients (after 28 weeks of ruxolitinib cream) was consistent with week 24 data in patients who applied ruxolitinib cream from day 1.

“As we know that repigmentation takes time, about half of the patients achieved the F-VASI75 at the 52-week endpoint,” said Dr. Rosmarin, who is also vice-chair for research and education at Tufts Medical Center, Boston. “Particularly remarkable is that 60% of adolescents achieved a T-VASI50 [50% or more repigmentation of the whole body at the year mark] and over half the patients described their vitiligo as a lot less noticeable or no longer noticeable at the year mark.”

In terms of safety, treatment-related adverse events occurred in 12.9% of patients treated with ruxolitinib (no information was available on the specific events). Serious adverse events occurred in 1.4% of patients; none were considered related to treatment.

“Overall, these results are quite impressive,” Dr. Rosmarin said. “While it can be very challenging to repigment patients with vitiligo, ruxolitinib cream provides an effective option which can help many of my patients.” He acknowledged certain limitations of the analysis, including the fact that the TRuE-V studies were conducted during the COVID-19 pandemic, “which may have contributed to patients being lost to follow-up. Also, the majority of the patients had skin phototypes 1-3.”

Carrie C. Coughlin, MD, who was asked to comment on the study, said that patients with vitiligo need treatment options that are well-studied and covered by insurance. “This study is a great step forward in developing medications for this underserved patient population,” said Dr. Coughlin, who directs the section of pediatric dermatology at Washington University/St. Louis Children’s Hospital.

However, she continued, “the authors mention approximately 13% of patients had a treatment-related adverse reaction, but the abstract does not delineate these reactions.” In addition, the study was limited to children who had less than or equal to 10% body surface area involvement of vitiligo, she noted, adding that “more work is needed to learn about safety of application to larger surface areas.”

Going forward, “it will be important to learn the durability of response,” said Dr. Coughlin, who is also assistant professor of dermatology at Washington University in St. Louis. “Does the vitiligo return if patients stop applying the ruxolitinib cream?”

Dr. Rosmarin disclosed that he has received honoraria as a consultant for Incyte, AbbVie, Abcuro, AltruBio, Arena, Boehringer Ingelheim, Bristol Meyers Squibb, Celgene, Concert, CSL Behring, Dermavant, Dermira, Janssen, Kyowa Kirin, Lilly, Novartis, Pfizer, Regeneron, Revolo Biotherapeutics, Sanofi, Sun Pharmaceuticals, UCB, and VielaBio. He has also received research support from Incyte, AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Dermira, Galderma, Janssen, Lilly, Merck, Novartis, Pfizer, and Regeneron; and has served as a paid speaker for Incyte, AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Incyte, Janssen, Lilly, Novartis, Pfizer, Regeneron, and Sanofi. Dr. Coughlin is on the board of the Pediatric Dermatology Research Alliance and the International Immunosuppression and Transplant Skin Cancer Collaborative.

Only a small number of research clinical trials for cancer drugs actually show benefit in quality of life, according to a study published in JAMA Oncology.

The study found trials that failed to show improved quality of life often reported their quality of life outcomes more favorably. Non–immunotherapy-targeted drugs were found to lead to worse quality of life outcomes more often than did cytotoxic agents. And, while there is an association between quality of life benefit and overall survival, no such association was found with progression-free survival.

“In this study, we evaluated the outcomes of cancer drug trials with regard to patients’ quality of life and found that only a quarter of phase 3 cancer drug trials in the advanced-disease setting demonstrated improved quality of life,” wrote authors who were led by Bishal Gyawali, MD, PhD, of the Cancer Research Institute, Queen’s University, Kingston, Ont.

“Improved quality of life outcomes were associated with improved overall survival but not with improved progression-free survival. Importantly, almost half of the cancer drugs drug trials that showed improved progression-free survival showed no improved overall survival or quality of life (i.e., PFS-only benefit). Some reports included conclusions regarding quality of life (QOL) findings that were not directly supported by the trial data, particularly for inferior or non–statistically significant QOL outcomes, thereby framing the findings in a favorable light or downplaying detrimental effects of the study intervention on QOL. Furthermore, contrary to common perception, inferior QOL outcomes were more common with targeted drugs than cytotoxic drugs. Taken together, these findings have important policy implications,” the authors wrote.

These findings are based on the results of a cohort study of 45 phase 3 research clinical trials of 24,806 patients. Only a small percentage of patients showed QOL benefits. The study found that industry-funded clinical trial reports often framed QOL findings more favorably than was warranted by the data.

The study found improved QOL with experimental agents in 11 of 45 randomized controlled trials (24.4%). Studies that reported improved QOL were more likely to also show improved overall survival as compared with trials in which quality of life was not improved (7 of 11 [64%] versus 10 of 34 [29%] trials). For improved progression-free survival, however, there was no positive association (6 of 11 [55%] trials versus 17 of 34 [50%] trials without improved QOL). Among six trials reporting worsening QOL, three (50%) were trials of targeted drugs. Among 11 trials reporting improved QOL, 6 (55%) were trials of immunotherapy drugs. Among the 34 trials in which QOL was not improved compared with controls, the findings were framed favorably (versus neutrally or negatively) in the abstract or conclusions in 16 (47%), an observation that was statistically significantly associated with industry funding (chi-squared = 6.35; P = .01).

“It is important to clearly understand and communicate the effects of cancer drugs”

To fulfill the obligation to inform patients about proposed treatments, the authors wrote that it is important to clearly understand and communicate the effects of cancer drugs on patient quality of life alongside their effects on overall survival and intermediate end points such as progression-free survival. “Patients with advanced cancer expect treatment to help them live longer or have better lives,” the authors wrote. In that respect, in clinical trials of cancer medicines, overall survival and quality of life are the most important measures. Toxicity profiles and disease progression delays do not reliably predict quality of life, and studies have shown poor correlations between quality of life, overall survival, and progression-free survival. This raises the question of validity of progression-free survival as a surrogate endpoint. “Progression-free survival is meaningless without overall survival or quality of life gains,” Dr. Gyawali said in an interview.

Writing in The Lancet Oncology in March, Dr. Gyawali stated that, because progression free survival “does not directly measure how a patient feels or functions, or how long a patient lives, progression-free survival was not intended to inform clinical practice or establish whether a new therapy provides clinically meaningful benefits for patients. However, over the past 2 decades, it has become the most common primary endpoint in oncology clinical trials. We are deeply worried about how the term survival in this phrase can influence clinical practice and patient choices. We propose replacing the phrase progression-free survival with a less ambiguous term: progression-free interval.”

In JAMA Oncology, Dr. Gyawali aimed to elucidate relationships between QOL, overall survival, and progression-free survival, and to assess, as well, how QOL results are framed, especially in industry-sponsored research. When drug trials they analyzed showed no change in QOL but reported that QOL did not worsen or QOL was maintained rather than stating that QOL did not improve, or if there was downplaying of worse QOL outcomes, the study had favorable interpretation, Dr. Gyawali and associates wrote. The expectation of patients receiving cancer drugs would be improved QOL rather than “not worse” QOL, Dr. Gyawali said.

Regarding the finding that QOL outcomes were described as favorable in 47% of trials with unimproved QOL outcomes, Dr. Gyawali said, “the bias in reporting should be corrected by the reviewers and editors of journals. Also, quality of life reporting should be made mandatory. Without unbiased quality of life information, informed decision making on whether or not to use a certain drug is impossible. Patients and physicians need to know that information. Regulators can demand that this should be mandatory in all trials in noncurative settings.”

He remarked further on the worsening QOL in some targeted drug trials, “People tout chemo-free regimens as automatically having better quality of life, but that doesn’t seem to be the case. Targeted drugs can have a severe impact on quality of life, probably due to prolonged duration of side effects. Quality of life should be measured and reported for all drugs.”

Dr. Gyawali and associates noted the limitation in that several studies with negative QOL results are not published at all or are published after a considerable delay, so the present observations may understate the issues that have been raised.

Dr. Gyawali declared that he received no funding and disclosed no conflicts of interest for this study.

Only a small number of research clinical trials for cancer drugs actually show benefit in quality of life, according to a study published in JAMA Oncology.

The study found trials that failed to show improved quality of life often reported their quality of life outcomes more favorably. Non–immunotherapy-targeted drugs were found to lead to worse quality of life outcomes more often than did cytotoxic agents. And, while there is an association between quality of life benefit and overall survival, no such association was found with progression-free survival.

“In this study, we evaluated the outcomes of cancer drug trials with regard to patients’ quality of life and found that only a quarter of phase 3 cancer drug trials in the advanced-disease setting demonstrated improved quality of life,” wrote authors who were led by Bishal Gyawali, MD, PhD, of the Cancer Research Institute, Queen’s University, Kingston, Ont.

“Improved quality of life outcomes were associated with improved overall survival but not with improved progression-free survival. Importantly, almost half of the cancer drugs drug trials that showed improved progression-free survival showed no improved overall survival or quality of life (i.e., PFS-only benefit). Some reports included conclusions regarding quality of life (QOL) findings that were not directly supported by the trial data, particularly for inferior or non–statistically significant QOL outcomes, thereby framing the findings in a favorable light or downplaying detrimental effects of the study intervention on QOL. Furthermore, contrary to common perception, inferior QOL outcomes were more common with targeted drugs than cytotoxic drugs. Taken together, these findings have important policy implications,” the authors wrote.

These findings are based on the results of a cohort study of 45 phase 3 research clinical trials of 24,806 patients. Only a small percentage of patients showed QOL benefits. The study found that industry-funded clinical trial reports often framed QOL findings more favorably than was warranted by the data.

The study found improved QOL with experimental agents in 11 of 45 randomized controlled trials (24.4%). Studies that reported improved QOL were more likely to also show improved overall survival as compared with trials in which quality of life was not improved (7 of 11 [64%] versus 10 of 34 [29%] trials). For improved progression-free survival, however, there was no positive association (6 of 11 [55%] trials versus 17 of 34 [50%] trials without improved QOL). Among six trials reporting worsening QOL, three (50%) were trials of targeted drugs. Among 11 trials reporting improved QOL, 6 (55%) were trials of immunotherapy drugs. Among the 34 trials in which QOL was not improved compared with controls, the findings were framed favorably (versus neutrally or negatively) in the abstract or conclusions in 16 (47%), an observation that was statistically significantly associated with industry funding (chi-squared = 6.35; P = .01).

“It is important to clearly understand and communicate the effects of cancer drugs”

To fulfill the obligation to inform patients about proposed treatments, the authors wrote that it is important to clearly understand and communicate the effects of cancer drugs on patient quality of life alongside their effects on overall survival and intermediate end points such as progression-free survival. “Patients with advanced cancer expect treatment to help them live longer or have better lives,” the authors wrote. In that respect, in clinical trials of cancer medicines, overall survival and quality of life are the most important measures. Toxicity profiles and disease progression delays do not reliably predict quality of life, and studies have shown poor correlations between quality of life, overall survival, and progression-free survival. This raises the question of validity of progression-free survival as a surrogate endpoint. “Progression-free survival is meaningless without overall survival or quality of life gains,” Dr. Gyawali said in an interview.

Writing in The Lancet Oncology in March, Dr. Gyawali stated that, because progression free survival “does not directly measure how a patient feels or functions, or how long a patient lives, progression-free survival was not intended to inform clinical practice or establish whether a new therapy provides clinically meaningful benefits for patients. However, over the past 2 decades, it has become the most common primary endpoint in oncology clinical trials. We are deeply worried about how the term survival in this phrase can influence clinical practice and patient choices. We propose replacing the phrase progression-free survival with a less ambiguous term: progression-free interval.”

In JAMA Oncology, Dr. Gyawali aimed to elucidate relationships between QOL, overall survival, and progression-free survival, and to assess, as well, how QOL results are framed, especially in industry-sponsored research. When drug trials they analyzed showed no change in QOL but reported that QOL did not worsen or QOL was maintained rather than stating that QOL did not improve, or if there was downplaying of worse QOL outcomes, the study had favorable interpretation, Dr. Gyawali and associates wrote. The expectation of patients receiving cancer drugs would be improved QOL rather than “not worse” QOL, Dr. Gyawali said.

Regarding the finding that QOL outcomes were described as favorable in 47% of trials with unimproved QOL outcomes, Dr. Gyawali said, “the bias in reporting should be corrected by the reviewers and editors of journals. Also, quality of life reporting should be made mandatory. Without unbiased quality of life information, informed decision making on whether or not to use a certain drug is impossible. Patients and physicians need to know that information. Regulators can demand that this should be mandatory in all trials in noncurative settings.”

He remarked further on the worsening QOL in some targeted drug trials, “People tout chemo-free regimens as automatically having better quality of life, but that doesn’t seem to be the case. Targeted drugs can have a severe impact on quality of life, probably due to prolonged duration of side effects. Quality of life should be measured and reported for all drugs.”

Dr. Gyawali and associates noted the limitation in that several studies with negative QOL results are not published at all or are published after a considerable delay, so the present observations may understate the issues that have been raised.

Dr. Gyawali declared that he received no funding and disclosed no conflicts of interest for this study.

Only a small number of research clinical trials for cancer drugs actually show benefit in quality of life, according to a study published in JAMA Oncology.

The study found trials that failed to show improved quality of life often reported their quality of life outcomes more favorably. Non–immunotherapy-targeted drugs were found to lead to worse quality of life outcomes more often than did cytotoxic agents. And, while there is an association between quality of life benefit and overall survival, no such association was found with progression-free survival.

“In this study, we evaluated the outcomes of cancer drug trials with regard to patients’ quality of life and found that only a quarter of phase 3 cancer drug trials in the advanced-disease setting demonstrated improved quality of life,” wrote authors who were led by Bishal Gyawali, MD, PhD, of the Cancer Research Institute, Queen’s University, Kingston, Ont.

“Improved quality of life outcomes were associated with improved overall survival but not with improved progression-free survival. Importantly, almost half of the cancer drugs drug trials that showed improved progression-free survival showed no improved overall survival or quality of life (i.e., PFS-only benefit). Some reports included conclusions regarding quality of life (QOL) findings that were not directly supported by the trial data, particularly for inferior or non–statistically significant QOL outcomes, thereby framing the findings in a favorable light or downplaying detrimental effects of the study intervention on QOL. Furthermore, contrary to common perception, inferior QOL outcomes were more common with targeted drugs than cytotoxic drugs. Taken together, these findings have important policy implications,” the authors wrote.

These findings are based on the results of a cohort study of 45 phase 3 research clinical trials of 24,806 patients. Only a small percentage of patients showed QOL benefits. The study found that industry-funded clinical trial reports often framed QOL findings more favorably than was warranted by the data.

The study found improved QOL with experimental agents in 11 of 45 randomized controlled trials (24.4%). Studies that reported improved QOL were more likely to also show improved overall survival as compared with trials in which quality of life was not improved (7 of 11 [64%] versus 10 of 34 [29%] trials). For improved progression-free survival, however, there was no positive association (6 of 11 [55%] trials versus 17 of 34 [50%] trials without improved QOL). Among six trials reporting worsening QOL, three (50%) were trials of targeted drugs. Among 11 trials reporting improved QOL, 6 (55%) were trials of immunotherapy drugs. Among the 34 trials in which QOL was not improved compared with controls, the findings were framed favorably (versus neutrally or negatively) in the abstract or conclusions in 16 (47%), an observation that was statistically significantly associated with industry funding (chi-squared = 6.35; P = .01).

“It is important to clearly understand and communicate the effects of cancer drugs”

To fulfill the obligation to inform patients about proposed treatments, the authors wrote that it is important to clearly understand and communicate the effects of cancer drugs on patient quality of life alongside their effects on overall survival and intermediate end points such as progression-free survival. “Patients with advanced cancer expect treatment to help them live longer or have better lives,” the authors wrote. In that respect, in clinical trials of cancer medicines, overall survival and quality of life are the most important measures. Toxicity profiles and disease progression delays do not reliably predict quality of life, and studies have shown poor correlations between quality of life, overall survival, and progression-free survival. This raises the question of validity of progression-free survival as a surrogate endpoint. “Progression-free survival is meaningless without overall survival or quality of life gains,” Dr. Gyawali said in an interview.

Writing in The Lancet Oncology in March, Dr. Gyawali stated that, because progression free survival “does not directly measure how a patient feels or functions, or how long a patient lives, progression-free survival was not intended to inform clinical practice or establish whether a new therapy provides clinically meaningful benefits for patients. However, over the past 2 decades, it has become the most common primary endpoint in oncology clinical trials. We are deeply worried about how the term survival in this phrase can influence clinical practice and patient choices. We propose replacing the phrase progression-free survival with a less ambiguous term: progression-free interval.”

In JAMA Oncology, Dr. Gyawali aimed to elucidate relationships between QOL, overall survival, and progression-free survival, and to assess, as well, how QOL results are framed, especially in industry-sponsored research. When drug trials they analyzed showed no change in QOL but reported that QOL did not worsen or QOL was maintained rather than stating that QOL did not improve, or if there was downplaying of worse QOL outcomes, the study had favorable interpretation, Dr. Gyawali and associates wrote. The expectation of patients receiving cancer drugs would be improved QOL rather than “not worse” QOL, Dr. Gyawali said.

Regarding the finding that QOL outcomes were described as favorable in 47% of trials with unimproved QOL outcomes, Dr. Gyawali said, “the bias in reporting should be corrected by the reviewers and editors of journals. Also, quality of life reporting should be made mandatory. Without unbiased quality of life information, informed decision making on whether or not to use a certain drug is impossible. Patients and physicians need to know that information. Regulators can demand that this should be mandatory in all trials in noncurative settings.”

He remarked further on the worsening QOL in some targeted drug trials, “People tout chemo-free regimens as automatically having better quality of life, but that doesn’t seem to be the case. Targeted drugs can have a severe impact on quality of life, probably due to prolonged duration of side effects. Quality of life should be measured and reported for all drugs.”

Dr. Gyawali and associates noted the limitation in that several studies with negative QOL results are not published at all or are published after a considerable delay, so the present observations may understate the issues that have been raised.

Dr. Gyawali declared that he received no funding and disclosed no conflicts of interest for this study.

A family’s decision to vaccinate their child is best made jointly with a trusted medical provider who knows the child and family. The American Academy of Pediatrics created a toolkit with resources for answering questions about the recently authorized SARS-CoV-2 mRNA vaccines (Pfizer and Moderna) for 6-month- to 5-year-olds with science-backed vaccine facts, including links to other useful AAP information websites, talking points, graphics, and videos.¹

SARS-CoV-2 seasonality

SARS-CoV-2 is now endemic, not a once-a-year seasonal virus. Seasons (aka surges) will occur whenever a new variant arises (twice yearly since 2020, Omicron BA.4/BA.5 currently), or when enough vaccine holdouts, newborns, and/or those with waning of prior immunity (vaccine or infection induced) accrue.

Emergency use authorization submission data for mRNA vaccine responses in young children^2,3

Moderna in 6-month- through 5-year-olds. Two 25-mcg doses given 4-8 weeks apart produced 37.8% (95% confidence interval, 20.9%-51.1%) protection against symptomatic Omicron SARS-CoV-2 infections through 3 months of follow-up. Immunobridging analysis of antibody responses compared to 18- to 25-year-olds (100-mcg doses) showed the children’s responses were noninferior. Thus, the committee inferred that vaccine effectiveness in children should be similar to that in 18- to 25-year-olds. Fever, irritability, or local reaction/pain occurred in two-thirds after the second dose. Grade 3 reactions were noted in less than 5%.

Pfizer in 6-month- through 4-year-olds. Three 3-mcg doses, two doses 3-8 weeks apart and the third dose at least 8 weeks later (median 16 weeks), produced 80.3% (95% CI, 13.9%-96.7%) protection against symptomatic COVID-19 during the 6 weeks after the third dose. Local and systemic reactions occurred in 63.8%; less than 5% had grade 3 reactions (fever in about 3%, irritability in 1.3%, fatigue in 0.8%) mostly after second dose.

Neither duration of follow-up is very long. The Moderna data tell me that a third primary dose would have been better but restarting the trial to evaluate third doses would have delayed Moderna’s EUA another 4-6 months. The three-dose Pfizer data look better but may not have been as good with another 6 weeks of follow-up.

Additional post-EUA data will be collected. Boosters will be needed when immunity from both vaccines wanes (one estimate is about 6 months after the primary series). The Advisory Committee on Immunization Practices noted in their deliberations that vaccine-induced antibody responses are higher and cross-neutralize variants (even Omicron) better than infection-induced immunity.⁴

Are there downsides to the vaccines? Naysayers question vaccinating children less than 5 years old with reasons containing enough “truth” that they catch people’s attention, for example, “young children don’t get very sick with COVID-19,” “most have been infected already,” “RNA for the spike protein stays in the body for months,” or “myocarditis.” Naysayers can quote references in reputable journals but seem to spin selected data out of context or quote unconfirmed data from the Vaccine Adverse Event Reporting System.
 

Reasons to vaccinate

• While children have milder disease than adults, mid-June 2022 surveillance indicated 50 hospitalizations and 1 pediatric death each day from SARS-CoV-2.⁵
• Vaccinating young children endows a foundation of vaccine-induced SARS-CoV-2 immunity that is superior to infection-induced immunity.⁴
• Long-term effects of large numbers of SARS-CoV-2 particles that enter every organ of a developing child have not been determined.
• Viral loads are lowered by prior vaccine; fewer viral replications lessen chances for newer variants to arise.
• Transmission is less in breakthrough infections than infections in the unvaccinated.
• Thirty percent of 5- to 11-year-olds hospitalized for SARS-CoV-2 had no underlying conditions;⁶ hospitalization rates in newborn to 4-year-olds have been the highest in the Omicron surge.⁷
• No myocarditis or pericarditis episodes have been detected in 6-month- to 11-year-old trials.
• The AAP and ACIP recommend the mRNA vaccines.

My thoughts are that SARS-CoV-2 vaccine is just another “routine” childhood vaccine that prepares children for healthier futures, pandemic or not, and the vaccines are as safe as other routine vaccines.

And like other pediatric vaccines, it should be no surprise that boosters will be needed, even if no newer variants than Omicron BA.4/BA.5 arise. But we know newer variants will arise and, similar to influenza vaccine, new formulations, perhaps with multiple SARS-CoV-2 strain antigens, will be needed every year or so. Everyone will get SARS-CoV-2 multiple times in their lives no matter how careful they are. So isn’t it good medical practice to establish early the best available foundation for maintaining lifelong SARS-CoV-2 immunity?

To me it is like pertussis. Most pertussis-infected children are sick enough to be hospitalized; very few die. They are miserable with illnesses that take weeks to months to subside. The worst disease usually occurs in unvaccinated young children or those with underlying conditions. Reactogenicity was reduced with acellular vaccine but resulted in less immunogenicity, so we give boosters at intervals that best match waning immunity. Circulating strains can be different than the vaccine strain, so protection against infection is 80%. Finally, even the safest vaccine may very rarely have sequelae. That is why The National Vaccine Injury Compensation Program was created. Yet the benefit-to-harm ratio for children and society favors universal pertussis vaccine use. And we vaccinate even those who have had pertussis because even infection-based immunity is incomplete and protection wanes. If arguments similar to those by SARS-CoV-2 vaccine naysayers were applied to acellular pertussis vaccine, it seems they would argue against pertussis vaccine for young children.

Another major issue has been “safety concerns” about the vaccines’ small amount of mRNA for the spike protein encased in microscopic lipid bubbles injected in the arm or leg. This mRNA is picked up by human cells, and in the cytoplasm (not the nucleus where our DNA resides) produces a limited supply of spike protein that is then picked up by antigen-presenting cells for short-lived distribution (days to 2 weeks at most) to regional lymph nodes where immune-memory processes are jump-started. Contrast that to even asymptomatic SARS-CoV-2 infection where multibillions of virus particles are produced for up to 14 days with access to every bodily organ that contains ACE-2 receptors (they all do). Each virus particle hijacks a human cell producing thousands of mRNA for spike protein (and multiple other SARS-CoV-2 proteins), eventually releasing multibillions of lipid fragments from the ruptured cell. Comparing the amount of these components in the mRNA vaccines to those from infection is like comparing a campfire to the many-thousand-acre wildfire. So, if one is worried about the effects of spike protein and lipid fragments, the limited localized amounts in mRNA vaccines should make one much less concerned than the enormous amounts circulating throughout the body as a result of a SARS-CoV-2 infection.

My take is that children 6-months to 5-years-old deserve SARS-CoV-2–induced vaccine protection and we can and should strongly recommend it as medical providers and child advocates.
 

*Dr. Harrison is professor, University of Missouri Kansas City School of Medicine, department of medicine, infectious diseases section, Kansas City. Email him at [email protected].

References

1. AAP. 2022 Jun 21. As COVID-19 vaccines become available for children ages 6 months to 4 years, AAP urges families to reach out to pediatricians to ask questions and access vaccine. www.aap.org.

2. CDC. Grading of recommendations, assessment, development, and evaluation (GRADE): Moderna COVID-19 vaccine for children aged 6 months–5 years. www.cdc.gov.

3. CDC. ACIP evidence to recommendations for use of Moderna COVID-19 vaccine in children ages 6 months–5 years and Pfizer-BioNTech COVID-19 vaccine in children ages 6 months–4 years under an emergency use authorization. www.cdc.gov.

4. Tang J et al. Nat Commun. 2022;13:2979.

5. Children and COVID-19: State Data Report. 2022 Jun 30. www.aap.org.

6. Shi DS et al. MMWR Morb Mortal Wkly Rep. 2022;71:574-81.

7. Marks KJ et al. MMWR Morb Mortal Wkly Rep. 2022;71:429-36.
 

Other good resources for families are https://getvaccineanswers.org/ or www.mayoclinic.org/diseases-conditions/coronavirus/in-depth/coronavirus-in-babies-and-children/art-20484405.

*This story was updated on July 19, 2022.

A family’s decision to vaccinate their child is best made jointly with a trusted medical provider who knows the child and family. The American Academy of Pediatrics created a toolkit with resources for answering questions about the recently authorized SARS-CoV-2 mRNA vaccines (Pfizer and Moderna) for 6-month- to 5-year-olds with science-backed vaccine facts, including links to other useful AAP information websites, talking points, graphics, and videos.¹

SARS-CoV-2 seasonality

SARS-CoV-2 is now endemic, not a once-a-year seasonal virus. Seasons (aka surges) will occur whenever a new variant arises (twice yearly since 2020, Omicron BA.4/BA.5 currently), or when enough vaccine holdouts, newborns, and/or those with waning of prior immunity (vaccine or infection induced) accrue.

Emergency use authorization submission data for mRNA vaccine responses in young children^2,3

Moderna in 6-month- through 5-year-olds. Two 25-mcg doses given 4-8 weeks apart produced 37.8% (95% confidence interval, 20.9%-51.1%) protection against symptomatic Omicron SARS-CoV-2 infections through 3 months of follow-up. Immunobridging analysis of antibody responses compared to 18- to 25-year-olds (100-mcg doses) showed the children’s responses were noninferior. Thus, the committee inferred that vaccine effectiveness in children should be similar to that in 18- to 25-year-olds. Fever, irritability, or local reaction/pain occurred in two-thirds after the second dose. Grade 3 reactions were noted in less than 5%.

Pfizer in 6-month- through 4-year-olds. Three 3-mcg doses, two doses 3-8 weeks apart and the third dose at least 8 weeks later (median 16 weeks), produced 80.3% (95% CI, 13.9%-96.7%) protection against symptomatic COVID-19 during the 6 weeks after the third dose. Local and systemic reactions occurred in 63.8%; less than 5% had grade 3 reactions (fever in about 3%, irritability in 1.3%, fatigue in 0.8%) mostly after second dose.

Neither duration of follow-up is very long. The Moderna data tell me that a third primary dose would have been better but restarting the trial to evaluate third doses would have delayed Moderna’s EUA another 4-6 months. The three-dose Pfizer data look better but may not have been as good with another 6 weeks of follow-up.

Additional post-EUA data will be collected. Boosters will be needed when immunity from both vaccines wanes (one estimate is about 6 months after the primary series). The Advisory Committee on Immunization Practices noted in their deliberations that vaccine-induced antibody responses are higher and cross-neutralize variants (even Omicron) better than infection-induced immunity.⁴

Are there downsides to the vaccines? Naysayers question vaccinating children less than 5 years old with reasons containing enough “truth” that they catch people’s attention, for example, “young children don’t get very sick with COVID-19,” “most have been infected already,” “RNA for the spike protein stays in the body for months,” or “myocarditis.” Naysayers can quote references in reputable journals but seem to spin selected data out of context or quote unconfirmed data from the Vaccine Adverse Event Reporting System.
 

Reasons to vaccinate

• While children have milder disease than adults, mid-June 2022 surveillance indicated 50 hospitalizations and 1 pediatric death each day from SARS-CoV-2.⁵
• Vaccinating young children endows a foundation of vaccine-induced SARS-CoV-2 immunity that is superior to infection-induced immunity.⁴
• Long-term effects of large numbers of SARS-CoV-2 particles that enter every organ of a developing child have not been determined.
• Viral loads are lowered by prior vaccine; fewer viral replications lessen chances for newer variants to arise.
• Transmission is less in breakthrough infections than infections in the unvaccinated.
• Thirty percent of 5- to 11-year-olds hospitalized for SARS-CoV-2 had no underlying conditions;⁶ hospitalization rates in newborn to 4-year-olds have been the highest in the Omicron surge.⁷
• No myocarditis or pericarditis episodes have been detected in 6-month- to 11-year-old trials.
• The AAP and ACIP recommend the mRNA vaccines.

My thoughts are that SARS-CoV-2 vaccine is just another “routine” childhood vaccine that prepares children for healthier futures, pandemic or not, and the vaccines are as safe as other routine vaccines.

And like other pediatric vaccines, it should be no surprise that boosters will be needed, even if no newer variants than Omicron BA.4/BA.5 arise. But we know newer variants will arise and, similar to influenza vaccine, new formulations, perhaps with multiple SARS-CoV-2 strain antigens, will be needed every year or so. Everyone will get SARS-CoV-2 multiple times in their lives no matter how careful they are. So isn’t it good medical practice to establish early the best available foundation for maintaining lifelong SARS-CoV-2 immunity?

To me it is like pertussis. Most pertussis-infected children are sick enough to be hospitalized; very few die. They are miserable with illnesses that take weeks to months to subside. The worst disease usually occurs in unvaccinated young children or those with underlying conditions. Reactogenicity was reduced with acellular vaccine but resulted in less immunogenicity, so we give boosters at intervals that best match waning immunity. Circulating strains can be different than the vaccine strain, so protection against infection is 80%. Finally, even the safest vaccine may very rarely have sequelae. That is why The National Vaccine Injury Compensation Program was created. Yet the benefit-to-harm ratio for children and society favors universal pertussis vaccine use. And we vaccinate even those who have had pertussis because even infection-based immunity is incomplete and protection wanes. If arguments similar to those by SARS-CoV-2 vaccine naysayers were applied to acellular pertussis vaccine, it seems they would argue against pertussis vaccine for young children.

Another major issue has been “safety concerns” about the vaccines’ small amount of mRNA for the spike protein encased in microscopic lipid bubbles injected in the arm or leg. This mRNA is picked up by human cells, and in the cytoplasm (not the nucleus where our DNA resides) produces a limited supply of spike protein that is then picked up by antigen-presenting cells for short-lived distribution (days to 2 weeks at most) to regional lymph nodes where immune-memory processes are jump-started. Contrast that to even asymptomatic SARS-CoV-2 infection where multibillions of virus particles are produced for up to 14 days with access to every bodily organ that contains ACE-2 receptors (they all do). Each virus particle hijacks a human cell producing thousands of mRNA for spike protein (and multiple other SARS-CoV-2 proteins), eventually releasing multibillions of lipid fragments from the ruptured cell. Comparing the amount of these components in the mRNA vaccines to those from infection is like comparing a campfire to the many-thousand-acre wildfire. So, if one is worried about the effects of spike protein and lipid fragments, the limited localized amounts in mRNA vaccines should make one much less concerned than the enormous amounts circulating throughout the body as a result of a SARS-CoV-2 infection.

My take is that children 6-months to 5-years-old deserve SARS-CoV-2–induced vaccine protection and we can and should strongly recommend it as medical providers and child advocates.
 

*Dr. Harrison is professor, University of Missouri Kansas City School of Medicine, department of medicine, infectious diseases section, Kansas City. Email him at [email protected].

References

1. AAP. 2022 Jun 21. As COVID-19 vaccines become available for children ages 6 months to 4 years, AAP urges families to reach out to pediatricians to ask questions and access vaccine. www.aap.org.

2. CDC. Grading of recommendations, assessment, development, and evaluation (GRADE): Moderna COVID-19 vaccine for children aged 6 months–5 years. www.cdc.gov.

3. CDC. ACIP evidence to recommendations for use of Moderna COVID-19 vaccine in children ages 6 months–5 years and Pfizer-BioNTech COVID-19 vaccine in children ages 6 months–4 years under an emergency use authorization. www.cdc.gov.

4. Tang J et al. Nat Commun. 2022;13:2979.

5. Children and COVID-19: State Data Report. 2022 Jun 30. www.aap.org.

6. Shi DS et al. MMWR Morb Mortal Wkly Rep. 2022;71:574-81.

7. Marks KJ et al. MMWR Morb Mortal Wkly Rep. 2022;71:429-36.
 

Other good resources for families are https://getvaccineanswers.org/ or www.mayoclinic.org/diseases-conditions/coronavirus/in-depth/coronavirus-in-babies-and-children/art-20484405.

*This story was updated on July 19, 2022.

A family’s decision to vaccinate their child is best made jointly with a trusted medical provider who knows the child and family. The American Academy of Pediatrics created a toolkit with resources for answering questions about the recently authorized SARS-CoV-2 mRNA vaccines (Pfizer and Moderna) for 6-month- to 5-year-olds with science-backed vaccine facts, including links to other useful AAP information websites, talking points, graphics, and videos.¹

SARS-CoV-2 seasonality

SARS-CoV-2 is now endemic, not a once-a-year seasonal virus. Seasons (aka surges) will occur whenever a new variant arises (twice yearly since 2020, Omicron BA.4/BA.5 currently), or when enough vaccine holdouts, newborns, and/or those with waning of prior immunity (vaccine or infection induced) accrue.

Emergency use authorization submission data for mRNA vaccine responses in young children^2,3

Moderna in 6-month- through 5-year-olds. Two 25-mcg doses given 4-8 weeks apart produced 37.8% (95% confidence interval, 20.9%-51.1%) protection against symptomatic Omicron SARS-CoV-2 infections through 3 months of follow-up. Immunobridging analysis of antibody responses compared to 18- to 25-year-olds (100-mcg doses) showed the children’s responses were noninferior. Thus, the committee inferred that vaccine effectiveness in children should be similar to that in 18- to 25-year-olds. Fever, irritability, or local reaction/pain occurred in two-thirds after the second dose. Grade 3 reactions were noted in less than 5%.

Pfizer in 6-month- through 4-year-olds. Three 3-mcg doses, two doses 3-8 weeks apart and the third dose at least 8 weeks later (median 16 weeks), produced 80.3% (95% CI, 13.9%-96.7%) protection against symptomatic COVID-19 during the 6 weeks after the third dose. Local and systemic reactions occurred in 63.8%; less than 5% had grade 3 reactions (fever in about 3%, irritability in 1.3%, fatigue in 0.8%) mostly after second dose.

Neither duration of follow-up is very long. The Moderna data tell me that a third primary dose would have been better but restarting the trial to evaluate third doses would have delayed Moderna’s EUA another 4-6 months. The three-dose Pfizer data look better but may not have been as good with another 6 weeks of follow-up.

Additional post-EUA data will be collected. Boosters will be needed when immunity from both vaccines wanes (one estimate is about 6 months after the primary series). The Advisory Committee on Immunization Practices noted in their deliberations that vaccine-induced antibody responses are higher and cross-neutralize variants (even Omicron) better than infection-induced immunity.⁴

Are there downsides to the vaccines? Naysayers question vaccinating children less than 5 years old with reasons containing enough “truth” that they catch people’s attention, for example, “young children don’t get very sick with COVID-19,” “most have been infected already,” “RNA for the spike protein stays in the body for months,” or “myocarditis.” Naysayers can quote references in reputable journals but seem to spin selected data out of context or quote unconfirmed data from the Vaccine Adverse Event Reporting System.
 

Reasons to vaccinate

• While children have milder disease than adults, mid-June 2022 surveillance indicated 50 hospitalizations and 1 pediatric death each day from SARS-CoV-2.⁵
• Vaccinating young children endows a foundation of vaccine-induced SARS-CoV-2 immunity that is superior to infection-induced immunity.⁴
• Long-term effects of large numbers of SARS-CoV-2 particles that enter every organ of a developing child have not been determined.
• Viral loads are lowered by prior vaccine; fewer viral replications lessen chances for newer variants to arise.
• Transmission is less in breakthrough infections than infections in the unvaccinated.
• Thirty percent of 5- to 11-year-olds hospitalized for SARS-CoV-2 had no underlying conditions;⁶ hospitalization rates in newborn to 4-year-olds have been the highest in the Omicron surge.⁷
• No myocarditis or pericarditis episodes have been detected in 6-month- to 11-year-old trials.
• The AAP and ACIP recommend the mRNA vaccines.

My thoughts are that SARS-CoV-2 vaccine is just another “routine” childhood vaccine that prepares children for healthier futures, pandemic or not, and the vaccines are as safe as other routine vaccines.

And like other pediatric vaccines, it should be no surprise that boosters will be needed, even if no newer variants than Omicron BA.4/BA.5 arise. But we know newer variants will arise and, similar to influenza vaccine, new formulations, perhaps with multiple SARS-CoV-2 strain antigens, will be needed every year or so. Everyone will get SARS-CoV-2 multiple times in their lives no matter how careful they are. So isn’t it good medical practice to establish early the best available foundation for maintaining lifelong SARS-CoV-2 immunity?

To me it is like pertussis. Most pertussis-infected children are sick enough to be hospitalized; very few die. They are miserable with illnesses that take weeks to months to subside. The worst disease usually occurs in unvaccinated young children or those with underlying conditions. Reactogenicity was reduced with acellular vaccine but resulted in less immunogenicity, so we give boosters at intervals that best match waning immunity. Circulating strains can be different than the vaccine strain, so protection against infection is 80%. Finally, even the safest vaccine may very rarely have sequelae. That is why The National Vaccine Injury Compensation Program was created. Yet the benefit-to-harm ratio for children and society favors universal pertussis vaccine use. And we vaccinate even those who have had pertussis because even infection-based immunity is incomplete and protection wanes. If arguments similar to those by SARS-CoV-2 vaccine naysayers were applied to acellular pertussis vaccine, it seems they would argue against pertussis vaccine for young children.

Another major issue has been “safety concerns” about the vaccines’ small amount of mRNA for the spike protein encased in microscopic lipid bubbles injected in the arm or leg. This mRNA is picked up by human cells, and in the cytoplasm (not the nucleus where our DNA resides) produces a limited supply of spike protein that is then picked up by antigen-presenting cells for short-lived distribution (days to 2 weeks at most) to regional lymph nodes where immune-memory processes are jump-started. Contrast that to even asymptomatic SARS-CoV-2 infection where multibillions of virus particles are produced for up to 14 days with access to every bodily organ that contains ACE-2 receptors (they all do). Each virus particle hijacks a human cell producing thousands of mRNA for spike protein (and multiple other SARS-CoV-2 proteins), eventually releasing multibillions of lipid fragments from the ruptured cell. Comparing the amount of these components in the mRNA vaccines to those from infection is like comparing a campfire to the many-thousand-acre wildfire. So, if one is worried about the effects of spike protein and lipid fragments, the limited localized amounts in mRNA vaccines should make one much less concerned than the enormous amounts circulating throughout the body as a result of a SARS-CoV-2 infection.

My take is that children 6-months to 5-years-old deserve SARS-CoV-2–induced vaccine protection and we can and should strongly recommend it as medical providers and child advocates.
 

*Dr. Harrison is professor, University of Missouri Kansas City School of Medicine, department of medicine, infectious diseases section, Kansas City. Email him at [email protected].

References

1. AAP. 2022 Jun 21. As COVID-19 vaccines become available for children ages 6 months to 4 years, AAP urges families to reach out to pediatricians to ask questions and access vaccine. www.aap.org.

2. CDC. Grading of recommendations, assessment, development, and evaluation (GRADE): Moderna COVID-19 vaccine for children aged 6 months–5 years. www.cdc.gov.

3. CDC. ACIP evidence to recommendations for use of Moderna COVID-19 vaccine in children ages 6 months–5 years and Pfizer-BioNTech COVID-19 vaccine in children ages 6 months–4 years under an emergency use authorization. www.cdc.gov.

4. Tang J et al. Nat Commun. 2022;13:2979.

5. Children and COVID-19: State Data Report. 2022 Jun 30. www.aap.org.

6. Shi DS et al. MMWR Morb Mortal Wkly Rep. 2022;71:574-81.

7. Marks KJ et al. MMWR Morb Mortal Wkly Rep. 2022;71:429-36.
 

Other good resources for families are https://getvaccineanswers.org/ or www.mayoclinic.org/diseases-conditions/coronavirus/in-depth/coronavirus-in-babies-and-children/art-20484405.

*This story was updated on July 19, 2022.

Bulevirtide (Hepcludex) monotherapy significantly reduces the load of hepatitis delta virus (HDV) and is safe in difficult-to-treat patients with compensated cirrhosis and clinically significant portal hypertension, according to the results of an ongoing 1-year study.

In presenting a poster with these findings at the annual International Liver Congress, sponsored by the European Association for the Study of the Liver, lead author Elisabetta Degasperi, MD, from the Grand Hospital Maggiore Policlinico in Milan, said that they were important “because they confirm the safety of this drug in real life.”

Dr. Degasperi and colleagues showed that bulevirtide leads to a significant viral response in 78% of patients by week 48, which was measured using the outcome of greater than 2 log decline in HDV RNA from baseline.

Dr. Degasperi added that the research still needed to assess the longer-term benefits, but “so far the 1-year results clearly show an initial benefit that is not only a good viral response but also one of disease control and a slight improvement in liver function.”
 

Addressing an immense, unmet therapeutic need

HDV requires the presence of hepatitis B virus to replicate. Bulevirtide blocks the entry of HDV and hepatitis B virus into hepatocytes.

In July 2020, it was conditionally approved in the European Economic Area for use to treat chronic HDV infection in adults with compensated liver disease upon confirmation of HDV RNA in the blood. It currently remains an investigational agent in the United States, as well as outside of the EEA.

The ongoing trial led by Dr. Degasperi is specifically conducted in patients with compensated cirrhosis who also have clinically significant portal hypertension, where safety and efficacy are unknown.

Dr. Degasperi said in an interview that, although HDV was rare, there is nonetheless an “immense” need for effective therapies against it, especially in young patients with advanced liver disease.

“We have a lot of patients with hepatitis D who have not responded to other antiviral treatment. Right now, the only other available treatment is pegylated interferon,” she said. “Unfortunately, rates of sustained viral response to pegylated interferon are extremely low at around 30% of patients.”

Chronic HDV is the most severe form of viral hepatitis and can have mortality rates as high as 50% within 5 years in patients with cirrhosis.

The management of hepatitis D is also complicated by the fact that patients with advanced cirrhosis and clinically significant portal hypertension cannot be treated with pegylated interferon owing to lack of efficacy and safety reasons, including a high risk for decompensation and liver-related complications. Pegylated interferon is contraindicated in these patients.
 

Bulevirtide at 48 weeks: A closer look at the findings

Eighteen patients with HDV, compensated cirrhosis, and clinically significant portal hypertension were consecutively enrolled in this single-center, longitudinal study.

All received bulevirtide monotherapy at 2 mg/day and underwent monitoring every 2 months. They were also treated with nucleotide analogs for their hepatitis B virus, which was suppressed when they began bulevirtide.

Clinical and virologic characteristics were collected at baseline, at weeks 4 and 8, and then every 8 weeks thereafter.

Bulevirtide led to a significant viral response such that by week 48, HDV RNA declined by 3.1 log IU/mL (range, 0.2-4.6 log IU/mL), was undetectable in six patients (33%), and was less than 100 IU/L in 50% of patients. Two patients were nonresponders. In addition, 78% of patients achieved at least an HDV RNA 2 log decline from baseline.

There was also a normalization of biochemical response in the majority of patients.

Alanine aminotransferase normalization was seen in 89% of patients and declined by a median of 34 U/L (range, 15-76 U/L) over 48 weeks. Aspartate aminotransferase declined to 39 U/L (range, 21-92 U/L). A combined response was seen in 72% of patients, reported Dr. Degasperi.

“Previously, we only had results from a phase 2 study, so we had no idea of the results over such a long treatment period,” said Dr. Degasperi. “It is also the first time we have been able to treat these patients with such advanced disease that is so difficult to manage.”

“Real-world results are typically inferior to those from clinical trials, but the viral decline is comparable to phase 2 trials, and the first report of the phase 3 trial,” said Dr. Degasperi.

Gamma-glutamyltransferase, alpha-fetoprotein, immunoglobulin G, and gamma-globulin levels also improved, whereas hepatitis B surface antigen, hepatitis B virus RNA, hepatitis B core-related antigen, platelet, and bilirubin values did not significantly change.

“All patients were Child-Pugh score A, so well-compensated [disease]. However, they increased a little bit in liver function by week 48,” Dr. Degasperi said. “This was important for this very advanced disease population.”

She added that the safety profile was very favorable, with no adverse events, including no injection-site reactions.

There was an asymptomatic increase in serum bile acids. “No patients complained about itching or pruritus,” Dr. Degasperi said.
 

What’s ahead for bulevirtide?

In a comment, Marc Bourlière, MD, from Saint Joseph Hospital in Marseilles, France, welcomed the decrease in viral load.

“This is known to be beneficial in terms of reducing morbidity and mortality in hepatitis D,” he said. “Remember that this disease is very difficult to treat, and until now, we have had no drug available. Pegylated interferon achieves cure in only 30% of patients, and half of these relapse, so actually only 15% have a meaningful response from pegylated interferon.”

“The main issue is its use as a daily subcutaneous injection. In clinical practice, it is a little bit complicated to set up, but once done, it is quite well accepted,” he said.

“I’m impressed with these results to date because there are no other compounds that have, as yet, achieved such results. This is impressive,” he added. “But whether it translates into a long-term response we don’t yet know.”

Dr. Bourlière also noted the meaningful 2-point log decline, noting that “HDV RNA negativity where treatment can be stopped would be really meaningful, but this endpoint is hard to obtain.”

Dr. Bourlière is awaiting results of the current ongoing phase 2/3 study, which would help determine a possible final treatment duration. He is also curious to settle the ongoing debate about whether bulevirtide should be used alone or in combination.

“We need to combine bulevirtide with pegylated interferon in less-advanced patients, because we know it is more potent and active against the HDV RNA,” he said.

Dr. Degasperi has previously declared she was on the advisory board for AbbVie and has spoken and taught for Gilead, MSD, and AbbVie. Dr. Bourlière declared interests with all companies involved in the R&D of liver therapies.

A version of this article first appeared on Medscape.com.

Bulevirtide (Hepcludex) monotherapy significantly reduces the load of hepatitis delta virus (HDV) and is safe in difficult-to-treat patients with compensated cirrhosis and clinically significant portal hypertension, according to the results of an ongoing 1-year study.

In presenting a poster with these findings at the annual International Liver Congress, sponsored by the European Association for the Study of the Liver, lead author Elisabetta Degasperi, MD, from the Grand Hospital Maggiore Policlinico in Milan, said that they were important “because they confirm the safety of this drug in real life.”

Dr. Degasperi and colleagues showed that bulevirtide leads to a significant viral response in 78% of patients by week 48, which was measured using the outcome of greater than 2 log decline in HDV RNA from baseline.

Dr. Degasperi added that the research still needed to assess the longer-term benefits, but “so far the 1-year results clearly show an initial benefit that is not only a good viral response but also one of disease control and a slight improvement in liver function.”
 

Addressing an immense, unmet therapeutic need

HDV requires the presence of hepatitis B virus to replicate. Bulevirtide blocks the entry of HDV and hepatitis B virus into hepatocytes.

In July 2020, it was conditionally approved in the European Economic Area for use to treat chronic HDV infection in adults with compensated liver disease upon confirmation of HDV RNA in the blood. It currently remains an investigational agent in the United States, as well as outside of the EEA.

The ongoing trial led by Dr. Degasperi is specifically conducted in patients with compensated cirrhosis who also have clinically significant portal hypertension, where safety and efficacy are unknown.

Dr. Degasperi said in an interview that, although HDV was rare, there is nonetheless an “immense” need for effective therapies against it, especially in young patients with advanced liver disease.

“We have a lot of patients with hepatitis D who have not responded to other antiviral treatment. Right now, the only other available treatment is pegylated interferon,” she said. “Unfortunately, rates of sustained viral response to pegylated interferon are extremely low at around 30% of patients.”

Chronic HDV is the most severe form of viral hepatitis and can have mortality rates as high as 50% within 5 years in patients with cirrhosis.

The management of hepatitis D is also complicated by the fact that patients with advanced cirrhosis and clinically significant portal hypertension cannot be treated with pegylated interferon owing to lack of efficacy and safety reasons, including a high risk for decompensation and liver-related complications. Pegylated interferon is contraindicated in these patients.
 

Bulevirtide at 48 weeks: A closer look at the findings

Eighteen patients with HDV, compensated cirrhosis, and clinically significant portal hypertension were consecutively enrolled in this single-center, longitudinal study.

All received bulevirtide monotherapy at 2 mg/day and underwent monitoring every 2 months. They were also treated with nucleotide analogs for their hepatitis B virus, which was suppressed when they began bulevirtide.

Clinical and virologic characteristics were collected at baseline, at weeks 4 and 8, and then every 8 weeks thereafter.

Bulevirtide led to a significant viral response such that by week 48, HDV RNA declined by 3.1 log IU/mL (range, 0.2-4.6 log IU/mL), was undetectable in six patients (33%), and was less than 100 IU/L in 50% of patients. Two patients were nonresponders. In addition, 78% of patients achieved at least an HDV RNA 2 log decline from baseline.

There was also a normalization of biochemical response in the majority of patients.

Alanine aminotransferase normalization was seen in 89% of patients and declined by a median of 34 U/L (range, 15-76 U/L) over 48 weeks. Aspartate aminotransferase declined to 39 U/L (range, 21-92 U/L). A combined response was seen in 72% of patients, reported Dr. Degasperi.

“Previously, we only had results from a phase 2 study, so we had no idea of the results over such a long treatment period,” said Dr. Degasperi. “It is also the first time we have been able to treat these patients with such advanced disease that is so difficult to manage.”

“Real-world results are typically inferior to those from clinical trials, but the viral decline is comparable to phase 2 trials, and the first report of the phase 3 trial,” said Dr. Degasperi.

Gamma-glutamyltransferase, alpha-fetoprotein, immunoglobulin G, and gamma-globulin levels also improved, whereas hepatitis B surface antigen, hepatitis B virus RNA, hepatitis B core-related antigen, platelet, and bilirubin values did not significantly change.

“All patients were Child-Pugh score A, so well-compensated [disease]. However, they increased a little bit in liver function by week 48,” Dr. Degasperi said. “This was important for this very advanced disease population.”

She added that the safety profile was very favorable, with no adverse events, including no injection-site reactions.

There was an asymptomatic increase in serum bile acids. “No patients complained about itching or pruritus,” Dr. Degasperi said.
 

What’s ahead for bulevirtide?

In a comment, Marc Bourlière, MD, from Saint Joseph Hospital in Marseilles, France, welcomed the decrease in viral load.

“This is known to be beneficial in terms of reducing morbidity and mortality in hepatitis D,” he said. “Remember that this disease is very difficult to treat, and until now, we have had no drug available. Pegylated interferon achieves cure in only 30% of patients, and half of these relapse, so actually only 15% have a meaningful response from pegylated interferon.”

“The main issue is its use as a daily subcutaneous injection. In clinical practice, it is a little bit complicated to set up, but once done, it is quite well accepted,” he said.

“I’m impressed with these results to date because there are no other compounds that have, as yet, achieved such results. This is impressive,” he added. “But whether it translates into a long-term response we don’t yet know.”

Dr. Bourlière also noted the meaningful 2-point log decline, noting that “HDV RNA negativity where treatment can be stopped would be really meaningful, but this endpoint is hard to obtain.”

Dr. Bourlière is awaiting results of the current ongoing phase 2/3 study, which would help determine a possible final treatment duration. He is also curious to settle the ongoing debate about whether bulevirtide should be used alone or in combination.

“We need to combine bulevirtide with pegylated interferon in less-advanced patients, because we know it is more potent and active against the HDV RNA,” he said.

Dr. Degasperi has previously declared she was on the advisory board for AbbVie and has spoken and taught for Gilead, MSD, and AbbVie. Dr. Bourlière declared interests with all companies involved in the R&D of liver therapies.

A version of this article first appeared on Medscape.com.

Bulevirtide (Hepcludex) monotherapy significantly reduces the load of hepatitis delta virus (HDV) and is safe in difficult-to-treat patients with compensated cirrhosis and clinically significant portal hypertension, according to the results of an ongoing 1-year study.

In presenting a poster with these findings at the annual International Liver Congress, sponsored by the European Association for the Study of the Liver, lead author Elisabetta Degasperi, MD, from the Grand Hospital Maggiore Policlinico in Milan, said that they were important “because they confirm the safety of this drug in real life.”

Dr. Degasperi and colleagues showed that bulevirtide leads to a significant viral response in 78% of patients by week 48, which was measured using the outcome of greater than 2 log decline in HDV RNA from baseline.

Dr. Degasperi added that the research still needed to assess the longer-term benefits, but “so far the 1-year results clearly show an initial benefit that is not only a good viral response but also one of disease control and a slight improvement in liver function.”
 

Addressing an immense, unmet therapeutic need

HDV requires the presence of hepatitis B virus to replicate. Bulevirtide blocks the entry of HDV and hepatitis B virus into hepatocytes.

In July 2020, it was conditionally approved in the European Economic Area for use to treat chronic HDV infection in adults with compensated liver disease upon confirmation of HDV RNA in the blood. It currently remains an investigational agent in the United States, as well as outside of the EEA.

The ongoing trial led by Dr. Degasperi is specifically conducted in patients with compensated cirrhosis who also have clinically significant portal hypertension, where safety and efficacy are unknown.

Dr. Degasperi said in an interview that, although HDV was rare, there is nonetheless an “immense” need for effective therapies against it, especially in young patients with advanced liver disease.

“We have a lot of patients with hepatitis D who have not responded to other antiviral treatment. Right now, the only other available treatment is pegylated interferon,” she said. “Unfortunately, rates of sustained viral response to pegylated interferon are extremely low at around 30% of patients.”

Chronic HDV is the most severe form of viral hepatitis and can have mortality rates as high as 50% within 5 years in patients with cirrhosis.

The management of hepatitis D is also complicated by the fact that patients with advanced cirrhosis and clinically significant portal hypertension cannot be treated with pegylated interferon owing to lack of efficacy and safety reasons, including a high risk for decompensation and liver-related complications. Pegylated interferon is contraindicated in these patients.
 

Bulevirtide at 48 weeks: A closer look at the findings

Eighteen patients with HDV, compensated cirrhosis, and clinically significant portal hypertension were consecutively enrolled in this single-center, longitudinal study.

All received bulevirtide monotherapy at 2 mg/day and underwent monitoring every 2 months. They were also treated with nucleotide analogs for their hepatitis B virus, which was suppressed when they began bulevirtide.

Clinical and virologic characteristics were collected at baseline, at weeks 4 and 8, and then every 8 weeks thereafter.

Bulevirtide led to a significant viral response such that by week 48, HDV RNA declined by 3.1 log IU/mL (range, 0.2-4.6 log IU/mL), was undetectable in six patients (33%), and was less than 100 IU/L in 50% of patients. Two patients were nonresponders. In addition, 78% of patients achieved at least an HDV RNA 2 log decline from baseline.

There was also a normalization of biochemical response in the majority of patients.

Alanine aminotransferase normalization was seen in 89% of patients and declined by a median of 34 U/L (range, 15-76 U/L) over 48 weeks. Aspartate aminotransferase declined to 39 U/L (range, 21-92 U/L). A combined response was seen in 72% of patients, reported Dr. Degasperi.

“Previously, we only had results from a phase 2 study, so we had no idea of the results over such a long treatment period,” said Dr. Degasperi. “It is also the first time we have been able to treat these patients with such advanced disease that is so difficult to manage.”

“Real-world results are typically inferior to those from clinical trials, but the viral decline is comparable to phase 2 trials, and the first report of the phase 3 trial,” said Dr. Degasperi.

Gamma-glutamyltransferase, alpha-fetoprotein, immunoglobulin G, and gamma-globulin levels also improved, whereas hepatitis B surface antigen, hepatitis B virus RNA, hepatitis B core-related antigen, platelet, and bilirubin values did not significantly change.

“All patients were Child-Pugh score A, so well-compensated [disease]. However, they increased a little bit in liver function by week 48,” Dr. Degasperi said. “This was important for this very advanced disease population.”

She added that the safety profile was very favorable, with no adverse events, including no injection-site reactions.

There was an asymptomatic increase in serum bile acids. “No patients complained about itching or pruritus,” Dr. Degasperi said.
 

What’s ahead for bulevirtide?

In a comment, Marc Bourlière, MD, from Saint Joseph Hospital in Marseilles, France, welcomed the decrease in viral load.

“This is known to be beneficial in terms of reducing morbidity and mortality in hepatitis D,” he said. “Remember that this disease is very difficult to treat, and until now, we have had no drug available. Pegylated interferon achieves cure in only 30% of patients, and half of these relapse, so actually only 15% have a meaningful response from pegylated interferon.”

“The main issue is its use as a daily subcutaneous injection. In clinical practice, it is a little bit complicated to set up, but once done, it is quite well accepted,” he said.

“I’m impressed with these results to date because there are no other compounds that have, as yet, achieved such results. This is impressive,” he added. “But whether it translates into a long-term response we don’t yet know.”

Dr. Bourlière also noted the meaningful 2-point log decline, noting that “HDV RNA negativity where treatment can be stopped would be really meaningful, but this endpoint is hard to obtain.”

Dr. Bourlière is awaiting results of the current ongoing phase 2/3 study, which would help determine a possible final treatment duration. He is also curious to settle the ongoing debate about whether bulevirtide should be used alone or in combination.

“We need to combine bulevirtide with pegylated interferon in less-advanced patients, because we know it is more potent and active against the HDV RNA,” he said.

Dr. Degasperi has previously declared she was on the advisory board for AbbVie and has spoken and taught for Gilead, MSD, and AbbVie. Dr. Bourlière declared interests with all companies involved in the R&D of liver therapies.

A version of this article first appeared on Medscape.com.

Ann Marco, 73, who was diagnosed with ovarian cancer in late 2018, credits her oncology team for saving her life. They treated her with chemotherapy, debulking surgery, and more chemotherapy. But it is her second and current care team that helped restore Ms. Marco’s quality of life, directing her toward such resources as palliative care, physical therapy and counseling for her and her husband.

“I can’t say enough about my palliative care doctor. She helped me manage pain, and the fatigue associated with chemotherapy. When she noticed that my leg was swollen she suspected a blood clot and sent me for an ultrasound,” Ms. Marco said.

The ultrasound revealed that she did indeed have a blood clot, for which she received, and continues to receive, medication. “Because with ovarian cancer, you always have blood clots. So little things like that, though they’re not that little, have really helped me in my journey with this cancer,” Ms. Marco said.

That journey has had its ups and downs. One chemotherapy regimen was so intolerable she decided to discontinue it, with full support of her oncologist. I told her, I just want to live my life, whether that’s only 6 more months or 3 years, but I don’t want to live it like this. And she said, ‘Ann, we’re going to do what you want to do.’”

Nine months later, when her cancer started growing again, Ms. Marco returned to chemotherapy. But this regimen has been much more tolerable, and it also appears to be doing its job. A recent CT scan showed that the tumors are shrinking.

“They’ll never go away. I have metastatic cancer. But they’re smaller, and I was really thrilled about that. It’s the best news I’ve had in more than 3 years,” Ms. Marco said.
 

End-of-life aggressive care still common

Despite clinical guidelines advising against intensive or invasive end-of-life care, more than half of women with terminal ovarian cancer receive at least one aggressive intervention, shows a study published in JCO Oncology Practice.

“We have good evidence that the types of aggressive end-of-life care we looked at in this paper are generally related to a lower quality of life for patients, poorer bereavement outcomes for their families, and even shorter duration survivals,” said lead author Megan A. Mullins, PhD, MPH, a postdoctoral research fellow at the University of Michigan in Ann Arbor. “This suggests there’s a disconnect between what people think aggressive care might do and what it’s doing.”

In their evaluation of variation in end-of-life care, Dr. Mullins and her colleagues analyzed SEER-Medicare data on 6,288 women with ovarian cancer who died between 2016 and 2020. They found that 51% of those women received some form of aggressive cancer care. The most common forms were not being admitted to hospice (28.9%), receiving an invasive procedure (20.7%) and being admitted to an intensive care unit (18.6%).

Dr. Mullins noted that since palliative care was officially recognized as a specialty in 2006, there has been increasing guidance for earlier integration of palliative care and reducing the aggressiveness of end-of-life care; both ASCO and the National Quality Form have standards advising against aggressive end-of-life care.

“But there are a lot of complicated factors that I think make it hard to move the needle in this area,” she said. “For one thing, particularly with ovarian cancer, women tend to have recurrences. I’ve spoken with physicians who got their patients through a difficult patch; they rebounded and they did fine. You don’t know for sure if that’s going to happen again if you try something else. Prognostication is not an exact science.”

Also, end-of-life discussions can be challenging conversations. “Nobody wants to take hope away from their patients. But there’s evidence to show that these conversations don’t actually reduce patients’ hopes – that’s a misconception,” Dr. Mullins said.

“It’s challenging. In the United States, we don’t like to talk about death and dying. But I think having these conversations earlier and more often can help make them a more regular part of care,” she said.

Brittany A. Davidson, MD, a gynecologic oncologist with Duke Health in Durham, N.C., who wrote an accompanying editorial, acknowledges that end-of-life can be fraught with fear, anxiety, and a lot of emotion. But she finds helping patients and their families navigate the ups and downs of their cancer one of the most rewarding aspects of her career as a physician.

“We want to help patients and their family members make these transitions as smoothly as possible,” she said.

A proponent of communications skills training for physicians in general, Dr. Brittany said doctors can learn to identify cues that patients are ready to have conversations about their end-of-life care.

“Those cues will help us facilitate conversations sooner rather than later so we’re not waiting until the very end,” she said.

What these conversations consist of varies depending on where the patient is in her cancer trajectory. In a patient with recurrent ovarian or recurrent uterine cancer, this might start with making sure the patient understands that while their cancer is treatable, it is very unlikely to be curable.

“I have often had patients who have been treated for cancer for several years and didn’t know their cancer wasn’t curable. How many missed opportunities have we overlooked?” Dr. Davidson said.

Then the conversation can turn to the goals of treatment. What’s important to the patient? “Are there events they want to be around for? Symptoms they want to avoid? Some patients really want to know what it’s going to be like to die. I try to take the lead from the patient. Ask what kind of information is helpful to them. Is it numbers? Is it symptoms? It’s really different for everybody,” Dr. Davidson said.

Although Dr. Mullins’s research and Dr. Davidson’s editorial suggest there’s room for improvement toward achieving goal-concordant care in gynecological cancers, Dr. Davidson suspects these patients might be faring a bit better than patients with other types of cancer based on her own anecdotal observations.

“One of the unique things about gynecologic oncology is that we have an amazing longitudinal relationship with our patients – we are not only their surgeons, we’re their oncologists. In other solid tumors, care is fractionated.

“That’s one of the reasons I love gynecologic oncology. I have the opportunity to know my patients through all the stages they experience as part of their cancer. I’d like to think that allows me a better opportunity to get to know them and help them recognize the value of palliative care,” Dr. Mullins said.

Ann Marco, 73, who was diagnosed with ovarian cancer in late 2018, credits her oncology team for saving her life. They treated her with chemotherapy, debulking surgery, and more chemotherapy. But it is her second and current care team that helped restore Ms. Marco’s quality of life, directing her toward such resources as palliative care, physical therapy and counseling for her and her husband.

“I can’t say enough about my palliative care doctor. She helped me manage pain, and the fatigue associated with chemotherapy. When she noticed that my leg was swollen she suspected a blood clot and sent me for an ultrasound,” Ms. Marco said.

The ultrasound revealed that she did indeed have a blood clot, for which she received, and continues to receive, medication. “Because with ovarian cancer, you always have blood clots. So little things like that, though they’re not that little, have really helped me in my journey with this cancer,” Ms. Marco said.

That journey has had its ups and downs. One chemotherapy regimen was so intolerable she decided to discontinue it, with full support of her oncologist. I told her, I just want to live my life, whether that’s only 6 more months or 3 years, but I don’t want to live it like this. And she said, ‘Ann, we’re going to do what you want to do.’”

Nine months later, when her cancer started growing again, Ms. Marco returned to chemotherapy. But this regimen has been much more tolerable, and it also appears to be doing its job. A recent CT scan showed that the tumors are shrinking.

“They’ll never go away. I have metastatic cancer. But they’re smaller, and I was really thrilled about that. It’s the best news I’ve had in more than 3 years,” Ms. Marco said.
 

End-of-life aggressive care still common

Despite clinical guidelines advising against intensive or invasive end-of-life care, more than half of women with terminal ovarian cancer receive at least one aggressive intervention, shows a study published in JCO Oncology Practice.

“We have good evidence that the types of aggressive end-of-life care we looked at in this paper are generally related to a lower quality of life for patients, poorer bereavement outcomes for their families, and even shorter duration survivals,” said lead author Megan A. Mullins, PhD, MPH, a postdoctoral research fellow at the University of Michigan in Ann Arbor. “This suggests there’s a disconnect between what people think aggressive care might do and what it’s doing.”

In their evaluation of variation in end-of-life care, Dr. Mullins and her colleagues analyzed SEER-Medicare data on 6,288 women with ovarian cancer who died between 2016 and 2020. They found that 51% of those women received some form of aggressive cancer care. The most common forms were not being admitted to hospice (28.9%), receiving an invasive procedure (20.7%) and being admitted to an intensive care unit (18.6%).

Dr. Mullins noted that since palliative care was officially recognized as a specialty in 2006, there has been increasing guidance for earlier integration of palliative care and reducing the aggressiveness of end-of-life care; both ASCO and the National Quality Form have standards advising against aggressive end-of-life care.

“But there are a lot of complicated factors that I think make it hard to move the needle in this area,” she said. “For one thing, particularly with ovarian cancer, women tend to have recurrences. I’ve spoken with physicians who got their patients through a difficult patch; they rebounded and they did fine. You don’t know for sure if that’s going to happen again if you try something else. Prognostication is not an exact science.”

Also, end-of-life discussions can be challenging conversations. “Nobody wants to take hope away from their patients. But there’s evidence to show that these conversations don’t actually reduce patients’ hopes – that’s a misconception,” Dr. Mullins said.

“It’s challenging. In the United States, we don’t like to talk about death and dying. But I think having these conversations earlier and more often can help make them a more regular part of care,” she said.

Brittany A. Davidson, MD, a gynecologic oncologist with Duke Health in Durham, N.C., who wrote an accompanying editorial, acknowledges that end-of-life can be fraught with fear, anxiety, and a lot of emotion. But she finds helping patients and their families navigate the ups and downs of their cancer one of the most rewarding aspects of her career as a physician.

“We want to help patients and their family members make these transitions as smoothly as possible,” she said.

A proponent of communications skills training for physicians in general, Dr. Brittany said doctors can learn to identify cues that patients are ready to have conversations about their end-of-life care.

“Those cues will help us facilitate conversations sooner rather than later so we’re not waiting until the very end,” she said.

What these conversations consist of varies depending on where the patient is in her cancer trajectory. In a patient with recurrent ovarian or recurrent uterine cancer, this might start with making sure the patient understands that while their cancer is treatable, it is very unlikely to be curable.

“I have often had patients who have been treated for cancer for several years and didn’t know their cancer wasn’t curable. How many missed opportunities have we overlooked?” Dr. Davidson said.

Then the conversation can turn to the goals of treatment. What’s important to the patient? “Are there events they want to be around for? Symptoms they want to avoid? Some patients really want to know what it’s going to be like to die. I try to take the lead from the patient. Ask what kind of information is helpful to them. Is it numbers? Is it symptoms? It’s really different for everybody,” Dr. Davidson said.

Although Dr. Mullins’s research and Dr. Davidson’s editorial suggest there’s room for improvement toward achieving goal-concordant care in gynecological cancers, Dr. Davidson suspects these patients might be faring a bit better than patients with other types of cancer based on her own anecdotal observations.

“One of the unique things about gynecologic oncology is that we have an amazing longitudinal relationship with our patients – we are not only their surgeons, we’re their oncologists. In other solid tumors, care is fractionated.

“That’s one of the reasons I love gynecologic oncology. I have the opportunity to know my patients through all the stages they experience as part of their cancer. I’d like to think that allows me a better opportunity to get to know them and help them recognize the value of palliative care,” Dr. Mullins said.

Ann Marco, 73, who was diagnosed with ovarian cancer in late 2018, credits her oncology team for saving her life. They treated her with chemotherapy, debulking surgery, and more chemotherapy. But it is her second and current care team that helped restore Ms. Marco’s quality of life, directing her toward such resources as palliative care, physical therapy and counseling for her and her husband.

“I can’t say enough about my palliative care doctor. She helped me manage pain, and the fatigue associated with chemotherapy. When she noticed that my leg was swollen she suspected a blood clot and sent me for an ultrasound,” Ms. Marco said.

The ultrasound revealed that she did indeed have a blood clot, for which she received, and continues to receive, medication. “Because with ovarian cancer, you always have blood clots. So little things like that, though they’re not that little, have really helped me in my journey with this cancer,” Ms. Marco said.

That journey has had its ups and downs. One chemotherapy regimen was so intolerable she decided to discontinue it, with full support of her oncologist. I told her, I just want to live my life, whether that’s only 6 more months or 3 years, but I don’t want to live it like this. And she said, ‘Ann, we’re going to do what you want to do.’”

Nine months later, when her cancer started growing again, Ms. Marco returned to chemotherapy. But this regimen has been much more tolerable, and it also appears to be doing its job. A recent CT scan showed that the tumors are shrinking.

“They’ll never go away. I have metastatic cancer. But they’re smaller, and I was really thrilled about that. It’s the best news I’ve had in more than 3 years,” Ms. Marco said.
 

End-of-life aggressive care still common

Despite clinical guidelines advising against intensive or invasive end-of-life care, more than half of women with terminal ovarian cancer receive at least one aggressive intervention, shows a study published in JCO Oncology Practice.

“We have good evidence that the types of aggressive end-of-life care we looked at in this paper are generally related to a lower quality of life for patients, poorer bereavement outcomes for their families, and even shorter duration survivals,” said lead author Megan A. Mullins, PhD, MPH, a postdoctoral research fellow at the University of Michigan in Ann Arbor. “This suggests there’s a disconnect between what people think aggressive care might do and what it’s doing.”

In their evaluation of variation in end-of-life care, Dr. Mullins and her colleagues analyzed SEER-Medicare data on 6,288 women with ovarian cancer who died between 2016 and 2020. They found that 51% of those women received some form of aggressive cancer care. The most common forms were not being admitted to hospice (28.9%), receiving an invasive procedure (20.7%) and being admitted to an intensive care unit (18.6%).

Dr. Mullins noted that since palliative care was officially recognized as a specialty in 2006, there has been increasing guidance for earlier integration of palliative care and reducing the aggressiveness of end-of-life care; both ASCO and the National Quality Form have standards advising against aggressive end-of-life care.

“But there are a lot of complicated factors that I think make it hard to move the needle in this area,” she said. “For one thing, particularly with ovarian cancer, women tend to have recurrences. I’ve spoken with physicians who got their patients through a difficult patch; they rebounded and they did fine. You don’t know for sure if that’s going to happen again if you try something else. Prognostication is not an exact science.”

Also, end-of-life discussions can be challenging conversations. “Nobody wants to take hope away from their patients. But there’s evidence to show that these conversations don’t actually reduce patients’ hopes – that’s a misconception,” Dr. Mullins said.

“It’s challenging. In the United States, we don’t like to talk about death and dying. But I think having these conversations earlier and more often can help make them a more regular part of care,” she said.

Brittany A. Davidson, MD, a gynecologic oncologist with Duke Health in Durham, N.C., who wrote an accompanying editorial, acknowledges that end-of-life can be fraught with fear, anxiety, and a lot of emotion. But she finds helping patients and their families navigate the ups and downs of their cancer one of the most rewarding aspects of her career as a physician.

“We want to help patients and their family members make these transitions as smoothly as possible,” she said.

A proponent of communications skills training for physicians in general, Dr. Brittany said doctors can learn to identify cues that patients are ready to have conversations about their end-of-life care.

“Those cues will help us facilitate conversations sooner rather than later so we’re not waiting until the very end,” she said.

What these conversations consist of varies depending on where the patient is in her cancer trajectory. In a patient with recurrent ovarian or recurrent uterine cancer, this might start with making sure the patient understands that while their cancer is treatable, it is very unlikely to be curable.

“I have often had patients who have been treated for cancer for several years and didn’t know their cancer wasn’t curable. How many missed opportunities have we overlooked?” Dr. Davidson said.

Then the conversation can turn to the goals of treatment. What’s important to the patient? “Are there events they want to be around for? Symptoms they want to avoid? Some patients really want to know what it’s going to be like to die. I try to take the lead from the patient. Ask what kind of information is helpful to them. Is it numbers? Is it symptoms? It’s really different for everybody,” Dr. Davidson said.

Although Dr. Mullins’s research and Dr. Davidson’s editorial suggest there’s room for improvement toward achieving goal-concordant care in gynecological cancers, Dr. Davidson suspects these patients might be faring a bit better than patients with other types of cancer based on her own anecdotal observations.

“One of the unique things about gynecologic oncology is that we have an amazing longitudinal relationship with our patients – we are not only their surgeons, we’re their oncologists. In other solid tumors, care is fractionated.

“That’s one of the reasons I love gynecologic oncology. I have the opportunity to know my patients through all the stages they experience as part of their cancer. I’d like to think that allows me a better opportunity to get to know them and help them recognize the value of palliative care,” Dr. Mullins said.

A 6-year-old girl presents with breast development. Her medical history is unremarkable. The parents are of average height, and the mother reports her thelarche was age 11 years. The girl is at the 97th percentile for her height and 90th percentile for her weight. She has Tanner stage 3 breast development and Tanner stage 2 pubic hair development. She has grown slightly more than 3 inches over the past year. How should she be evaluated and managed (N Engl J Med. 2008;358:2366-77)?

The premature onset of puberty, i.e., precocious puberty (PP), can be an emotionally traumatic event for the child and parents. Over the past century, improvements in public health and nutrition, and, more recently, increased obesity, have been associated with earlier puberty and the dominant factor has been attributed to genetics (Curr Opin Endocrinol Diabetes Obes. 2018;25[1]:49-54). This month’s article will focus on understanding what is considered “early” puberty, evaluating for causes, and managing precocious puberty.

More commonly seen in girls than boys, PP is defined as the onset of secondary sexual characteristics before age 7.5 years in Black and Hispanic girls, and prior to 8 years in White girls, which is 2-2.5 standard deviations below the average age of pubertal onset in healthy children (J Pediatr Adolesc Gynecol. 2019;32:455-9). As a comparison, PP is diagnosed with onset before age 9 years in boys. For White compared with Black girls, the average timing of thelarche is age 10 vs. 9.5 years, peak growth velocity is age 11.5, menarche is age 12.5 vs. 12, while completion of puberty is near age 14.5 vs. 13.5, respectively (J Pediatr. 1985;107:317). Fortunately, most girls with PP have common variants rather than serious pathology.
 

Classification: Central (CPP) vs. peripheral (PPP)

CPP is gonadotropin dependent, meaning the hypothalamic-pituitary-ovarian axis (HPO) is prematurely activated resulting in the normal progression of puberty.

PPP is gonadotropin independent, caused by sex steroid secretion from any source – ovaries, adrenal gland, exogenous or ectopic production, e.g., germ-cell tumor. This results in a disordered progression of pubertal milestones.

Whereas CPP is typically isosexual development, i.e., consistent with the child’s gender, PPP can be isosexual or contrasexual, e.g., virilization of girls. A third classification is “benign or nonprogressive pubertal variants” manifesting as isolated premature thelarche or adrenarche.
 

Causes (see table)

CPP. Idiopathic causes account for 80%-90% of presentations in girls and 25%-80% in boys. Remarkably, international and domestic adoption, as well as a family history of PP increases the likelihood of CPP in girls. Other etiologies include CNS lesions, e.g., hamartomas, which are the most common cause of PP in young children. MRI with contrast has been the traditional mode of diagnosis for CNS tumors, yet the yield is dubious in girls above age 6. Genetic causes are found in only a small percentage of PP cases. Rarely, CPP can result from gonadotropin-secreting tumors because of elevated luteinizing hormone levels.

McCune-Albright syndrome is rare and presents with the classic triad of PPP, skin pigmentation called café-au-lait, and fibrous dysplasia of bone. The pathophysiology of McCune-Albright syndrome is autoactivation of the G-protein leading to activation of ovarian tissue that results in formation of large ovarian cysts and extreme elevations in serum estradiol as well as the potential production of other hormones, e.g., thyrotoxicosis, excess growth hormone (acromegaly), and Cushing syndrome.

Premature thelarche. Premature thelarche typically occurs in girls between the ages of 1 and 3 years and is limited to breast enlargement. While no cause has been determined, the plausible explanations include partial activation of the HPO axis, endocrine-disrupting chemicals (EDCs), or a genetic origin. A small percentage of these girls progress to CPP.

EDCs have been considered as potential influencers of early puberty, but no consensus has been established. (Examples of EDCs in the environment include air, soil, or water supply along with food sources, personal care products, and manufactured products that can affect the endocrine system.)

Premature adenarche. Premature adrenarche presents with adult body odor and/or body hair (pubic and/or axillary) in girls who have an elevated body mass index, most commonly at the ages of 6-7 years. The presumed mechanism is normal maturation of the adrenal gland with resultant elevation of circulating androgens. Bone age may be mildly accelerated and DHEAS is prematurely elevated for age. These girls appear to be at increased risk for polycystic ovary syndrome.

Evaluation

The initial step in the evaluation of PP is to determine whether the cause is CPP or PPP; the latter includes distinguishing isosexual from contrasexual development. A thorough history (growth, headaches, behavior or visual change, seizures, abdominal pain), physical exam, including Tanner staging, and bone age is required. However, with isolated premature thelarche or adrenarche, a bone age may not be necessary, as initial close clinical observation for pubertal progression is likely sufficient.

For CPP, the diagnosis is based on serum LH, whether random levels or elevations follow GnRH stimulation. Puberty milestones progress normally although adrenarche is not consistently apparent. For girls younger than age 6, a brain MRI is recommended but not in asymptomatic older girls with CPP. LH and FSH along with estradiol or testosterone, the latter especially in boys, are the first line of serum testing. Serum TSH is recommended for suspicion of primary hypothyroidism. In girls with premature adrenarche, a bone age, testosterone, DHEAS, and 17-OHP to rule out adrenal hyperplasia should be obtained. Pelvic ultrasound may be a useful adjunct to assess uterine volume and/or ovarian cysts/tumors.

Rapidity of onset can also lead the evaluation since a normal growth chart and skeletal maturation suggests a benign pubertal variant whereas a more rapid rate can signal CPP or PPP. Of note, health care providers should ensure prescription, over-the-counter oral or topical sources of hormones, and EDCs are ruled out.
 

Consequences

An association between childhood sexual abuse and earlier pubertal onset has been cited. These girls may be at increased risk for psychosocial difficulties, menstrual and fertility problems, and even reproductive cancers because of prolonged exposure to sex hormones (J Adolesc Health. 2016;60[1]:65-71).

Treatment

The mainstay of CPP treatment is maximizing adult height, typically through the use of a GnRH agonist for HPO suppression from pituitary downregulation. For girls above age 8 years, attempts at improving adult height have not shown a benefit.

In girls with PPP, treatment is directed at the prevailing pathology. Interestingly, early PPP can activate the HPO axis thereby converting to “secondary” CPP. In PPP, McCune-Albright syndrome treatment targets reducing circulating estrogens through letrozole or tamoxifen as well as addressing other autoactivated hormone production. Ovarian and adrenal tumors, albeit rare, can cause PP; therefore, surgical excision is the goal of treatment.

PP should be approached with equal concerns about the physical and emotional effects while including the family to help them understand the pathophysiology and psychosocial risks.
 

Dr. Mark P. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.

A 6-year-old girl presents with breast development. Her medical history is unremarkable. The parents are of average height, and the mother reports her thelarche was age 11 years. The girl is at the 97th percentile for her height and 90th percentile for her weight. She has Tanner stage 3 breast development and Tanner stage 2 pubic hair development. She has grown slightly more than 3 inches over the past year. How should she be evaluated and managed (N Engl J Med. 2008;358:2366-77)?

The premature onset of puberty, i.e., precocious puberty (PP), can be an emotionally traumatic event for the child and parents. Over the past century, improvements in public health and nutrition, and, more recently, increased obesity, have been associated with earlier puberty and the dominant factor has been attributed to genetics (Curr Opin Endocrinol Diabetes Obes. 2018;25[1]:49-54). This month’s article will focus on understanding what is considered “early” puberty, evaluating for causes, and managing precocious puberty.

More commonly seen in girls than boys, PP is defined as the onset of secondary sexual characteristics before age 7.5 years in Black and Hispanic girls, and prior to 8 years in White girls, which is 2-2.5 standard deviations below the average age of pubertal onset in healthy children (J Pediatr Adolesc Gynecol. 2019;32:455-9). As a comparison, PP is diagnosed with onset before age 9 years in boys. For White compared with Black girls, the average timing of thelarche is age 10 vs. 9.5 years, peak growth velocity is age 11.5, menarche is age 12.5 vs. 12, while completion of puberty is near age 14.5 vs. 13.5, respectively (J Pediatr. 1985;107:317). Fortunately, most girls with PP have common variants rather than serious pathology.
 

Classification: Central (CPP) vs. peripheral (PPP)

CPP is gonadotropin dependent, meaning the hypothalamic-pituitary-ovarian axis (HPO) is prematurely activated resulting in the normal progression of puberty.

PPP is gonadotropin independent, caused by sex steroid secretion from any source – ovaries, adrenal gland, exogenous or ectopic production, e.g., germ-cell tumor. This results in a disordered progression of pubertal milestones.

Whereas CPP is typically isosexual development, i.e., consistent with the child’s gender, PPP can be isosexual or contrasexual, e.g., virilization of girls. A third classification is “benign or nonprogressive pubertal variants” manifesting as isolated premature thelarche or adrenarche.
 

Causes (see table)

CPP. Idiopathic causes account for 80%-90% of presentations in girls and 25%-80% in boys. Remarkably, international and domestic adoption, as well as a family history of PP increases the likelihood of CPP in girls. Other etiologies include CNS lesions, e.g., hamartomas, which are the most common cause of PP in young children. MRI with contrast has been the traditional mode of diagnosis for CNS tumors, yet the yield is dubious in girls above age 6. Genetic causes are found in only a small percentage of PP cases. Rarely, CPP can result from gonadotropin-secreting tumors because of elevated luteinizing hormone levels.

McCune-Albright syndrome is rare and presents with the classic triad of PPP, skin pigmentation called café-au-lait, and fibrous dysplasia of bone. The pathophysiology of McCune-Albright syndrome is autoactivation of the G-protein leading to activation of ovarian tissue that results in formation of large ovarian cysts and extreme elevations in serum estradiol as well as the potential production of other hormones, e.g., thyrotoxicosis, excess growth hormone (acromegaly), and Cushing syndrome.

Premature thelarche. Premature thelarche typically occurs in girls between the ages of 1 and 3 years and is limited to breast enlargement. While no cause has been determined, the plausible explanations include partial activation of the HPO axis, endocrine-disrupting chemicals (EDCs), or a genetic origin. A small percentage of these girls progress to CPP.

EDCs have been considered as potential influencers of early puberty, but no consensus has been established. (Examples of EDCs in the environment include air, soil, or water supply along with food sources, personal care products, and manufactured products that can affect the endocrine system.)

Premature adenarche. Premature adrenarche presents with adult body odor and/or body hair (pubic and/or axillary) in girls who have an elevated body mass index, most commonly at the ages of 6-7 years. The presumed mechanism is normal maturation of the adrenal gland with resultant elevation of circulating androgens. Bone age may be mildly accelerated and DHEAS is prematurely elevated for age. These girls appear to be at increased risk for polycystic ovary syndrome.

Evaluation

The initial step in the evaluation of PP is to determine whether the cause is CPP or PPP; the latter includes distinguishing isosexual from contrasexual development. A thorough history (growth, headaches, behavior or visual change, seizures, abdominal pain), physical exam, including Tanner staging, and bone age is required. However, with isolated premature thelarche or adrenarche, a bone age may not be necessary, as initial close clinical observation for pubertal progression is likely sufficient.

For CPP, the diagnosis is based on serum LH, whether random levels or elevations follow GnRH stimulation. Puberty milestones progress normally although adrenarche is not consistently apparent. For girls younger than age 6, a brain MRI is recommended but not in asymptomatic older girls with CPP. LH and FSH along with estradiol or testosterone, the latter especially in boys, are the first line of serum testing. Serum TSH is recommended for suspicion of primary hypothyroidism. In girls with premature adrenarche, a bone age, testosterone, DHEAS, and 17-OHP to rule out adrenal hyperplasia should be obtained. Pelvic ultrasound may be a useful adjunct to assess uterine volume and/or ovarian cysts/tumors.

Rapidity of onset can also lead the evaluation since a normal growth chart and skeletal maturation suggests a benign pubertal variant whereas a more rapid rate can signal CPP or PPP. Of note, health care providers should ensure prescription, over-the-counter oral or topical sources of hormones, and EDCs are ruled out.
 

Consequences

An association between childhood sexual abuse and earlier pubertal onset has been cited. These girls may be at increased risk for psychosocial difficulties, menstrual and fertility problems, and even reproductive cancers because of prolonged exposure to sex hormones (J Adolesc Health. 2016;60[1]:65-71).

Treatment

The mainstay of CPP treatment is maximizing adult height, typically through the use of a GnRH agonist for HPO suppression from pituitary downregulation. For girls above age 8 years, attempts at improving adult height have not shown a benefit.

In girls with PPP, treatment is directed at the prevailing pathology. Interestingly, early PPP can activate the HPO axis thereby converting to “secondary” CPP. In PPP, McCune-Albright syndrome treatment targets reducing circulating estrogens through letrozole or tamoxifen as well as addressing other autoactivated hormone production. Ovarian and adrenal tumors, albeit rare, can cause PP; therefore, surgical excision is the goal of treatment.

PP should be approached with equal concerns about the physical and emotional effects while including the family to help them understand the pathophysiology and psychosocial risks.
 

Dr. Mark P. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.

A 6-year-old girl presents with breast development. Her medical history is unremarkable. The parents are of average height, and the mother reports her thelarche was age 11 years. The girl is at the 97th percentile for her height and 90th percentile for her weight. She has Tanner stage 3 breast development and Tanner stage 2 pubic hair development. She has grown slightly more than 3 inches over the past year. How should she be evaluated and managed (N Engl J Med. 2008;358:2366-77)?

The premature onset of puberty, i.e., precocious puberty (PP), can be an emotionally traumatic event for the child and parents. Over the past century, improvements in public health and nutrition, and, more recently, increased obesity, have been associated with earlier puberty and the dominant factor has been attributed to genetics (Curr Opin Endocrinol Diabetes Obes. 2018;25[1]:49-54). This month’s article will focus on understanding what is considered “early” puberty, evaluating for causes, and managing precocious puberty.

More commonly seen in girls than boys, PP is defined as the onset of secondary sexual characteristics before age 7.5 years in Black and Hispanic girls, and prior to 8 years in White girls, which is 2-2.5 standard deviations below the average age of pubertal onset in healthy children (J Pediatr Adolesc Gynecol. 2019;32:455-9). As a comparison, PP is diagnosed with onset before age 9 years in boys. For White compared with Black girls, the average timing of thelarche is age 10 vs. 9.5 years, peak growth velocity is age 11.5, menarche is age 12.5 vs. 12, while completion of puberty is near age 14.5 vs. 13.5, respectively (J Pediatr. 1985;107:317). Fortunately, most girls with PP have common variants rather than serious pathology.
 

Classification: Central (CPP) vs. peripheral (PPP)

CPP is gonadotropin dependent, meaning the hypothalamic-pituitary-ovarian axis (HPO) is prematurely activated resulting in the normal progression of puberty.

PPP is gonadotropin independent, caused by sex steroid secretion from any source – ovaries, adrenal gland, exogenous or ectopic production, e.g., germ-cell tumor. This results in a disordered progression of pubertal milestones.

Whereas CPP is typically isosexual development, i.e., consistent with the child’s gender, PPP can be isosexual or contrasexual, e.g., virilization of girls. A third classification is “benign or nonprogressive pubertal variants” manifesting as isolated premature thelarche or adrenarche.
 

Causes (see table)

CPP. Idiopathic causes account for 80%-90% of presentations in girls and 25%-80% in boys. Remarkably, international and domestic adoption, as well as a family history of PP increases the likelihood of CPP in girls. Other etiologies include CNS lesions, e.g., hamartomas, which are the most common cause of PP in young children. MRI with contrast has been the traditional mode of diagnosis for CNS tumors, yet the yield is dubious in girls above age 6. Genetic causes are found in only a small percentage of PP cases. Rarely, CPP can result from gonadotropin-secreting tumors because of elevated luteinizing hormone levels.

McCune-Albright syndrome is rare and presents with the classic triad of PPP, skin pigmentation called café-au-lait, and fibrous dysplasia of bone. The pathophysiology of McCune-Albright syndrome is autoactivation of the G-protein leading to activation of ovarian tissue that results in formation of large ovarian cysts and extreme elevations in serum estradiol as well as the potential production of other hormones, e.g., thyrotoxicosis, excess growth hormone (acromegaly), and Cushing syndrome.

Premature thelarche. Premature thelarche typically occurs in girls between the ages of 1 and 3 years and is limited to breast enlargement. While no cause has been determined, the plausible explanations include partial activation of the HPO axis, endocrine-disrupting chemicals (EDCs), or a genetic origin. A small percentage of these girls progress to CPP.

EDCs have been considered as potential influencers of early puberty, but no consensus has been established. (Examples of EDCs in the environment include air, soil, or water supply along with food sources, personal care products, and manufactured products that can affect the endocrine system.)

Premature adenarche. Premature adrenarche presents with adult body odor and/or body hair (pubic and/or axillary) in girls who have an elevated body mass index, most commonly at the ages of 6-7 years. The presumed mechanism is normal maturation of the adrenal gland with resultant elevation of circulating androgens. Bone age may be mildly accelerated and DHEAS is prematurely elevated for age. These girls appear to be at increased risk for polycystic ovary syndrome.

Evaluation

The initial step in the evaluation of PP is to determine whether the cause is CPP or PPP; the latter includes distinguishing isosexual from contrasexual development. A thorough history (growth, headaches, behavior or visual change, seizures, abdominal pain), physical exam, including Tanner staging, and bone age is required. However, with isolated premature thelarche or adrenarche, a bone age may not be necessary, as initial close clinical observation for pubertal progression is likely sufficient.

For CPP, the diagnosis is based on serum LH, whether random levels or elevations follow GnRH stimulation. Puberty milestones progress normally although adrenarche is not consistently apparent. For girls younger than age 6, a brain MRI is recommended but not in asymptomatic older girls with CPP. LH and FSH along with estradiol or testosterone, the latter especially in boys, are the first line of serum testing. Serum TSH is recommended for suspicion of primary hypothyroidism. In girls with premature adrenarche, a bone age, testosterone, DHEAS, and 17-OHP to rule out adrenal hyperplasia should be obtained. Pelvic ultrasound may be a useful adjunct to assess uterine volume and/or ovarian cysts/tumors.

Rapidity of onset can also lead the evaluation since a normal growth chart and skeletal maturation suggests a benign pubertal variant whereas a more rapid rate can signal CPP or PPP. Of note, health care providers should ensure prescription, over-the-counter oral or topical sources of hormones, and EDCs are ruled out.
 

Consequences

An association between childhood sexual abuse and earlier pubertal onset has been cited. These girls may be at increased risk for psychosocial difficulties, menstrual and fertility problems, and even reproductive cancers because of prolonged exposure to sex hormones (J Adolesc Health. 2016;60[1]:65-71).

Treatment

The mainstay of CPP treatment is maximizing adult height, typically through the use of a GnRH agonist for HPO suppression from pituitary downregulation. For girls above age 8 years, attempts at improving adult height have not shown a benefit.

In girls with PPP, treatment is directed at the prevailing pathology. Interestingly, early PPP can activate the HPO axis thereby converting to “secondary” CPP. In PPP, McCune-Albright syndrome treatment targets reducing circulating estrogens through letrozole or tamoxifen as well as addressing other autoactivated hormone production. Ovarian and adrenal tumors, albeit rare, can cause PP; therefore, surgical excision is the goal of treatment.

PP should be approached with equal concerns about the physical and emotional effects while including the family to help them understand the pathophysiology and psychosocial risks.
 

Dr. Mark P. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.

Opioids remain a staple in pain management for cancer, but there is little guidance around how to treat patients who have a history of opioid misuse.

Recently, a group of palliative and addiction medicine specialists developed strategies to help frontline clinicians manage patients with advanced cancer-related pain and opioid use disorder.

“There is a tendency to ignore treatment of opioid use disorder in advanced cancer patients because people think: ‘Oh, this person has bigger fish to fry,’ but that’s not a very patient-centric way of looking at things,” senior author Jessica Merlin, MD, PhD, with the University of Pittsburgh, said in a news release.

“We know that opioid use disorder is a really important factor in quality of life, so addressing opioid addiction and prescription opioid misuse in people with advanced cancer is really critical,” Dr. Merlin added.

The study was published online in JAMA Oncology.

To improve care for people with advanced cancer and cancer-related pain, the researchers first assessed how clinicians currently treat patients with opioid complexity.

Using an online Delphi platform, the team invited 120 clinicians with expertise in palliative care, pain management, and addiction medicine to weigh in on three common clinical scenarios – a patient with a recent history of untreated opioid use disorder, a patient taking more opioids than prescribed, and a patient using nonprescribed benzodiazepines.

For a patient with cancer and a recent history of untreated opioid use disorder, regardless of prognosis, the panel deemed it appropriate to begin treatment with buprenorphine/naloxone for pain but inappropriate to refer the patient to a methadone clinic. The panel felt that going to a methadone clinic would be too burdensome for a patient with advanced cancer and not possible for those with limited prognoses.

“This underscores the importance of access to [opioid use disorder] treatment in cancer treatment settings, including non–addiction specialists waivered to prescribe buprenorphine/naloxone and addiction specialists for more complex cases,” the authors wrote.

For a patient with untreated opioid use disorder, the panel deemed split-dose methadone (two to three times daily) appropriate in those with limited prognosis of weeks to months but was uncertain about the suitability of this approach for patients with longer prognoses of a year or longer.

The appropriateness of initiating treatment with a full-agonist opioid was considered uncertain for a patient with limited prognosis and inappropriate for a patient with longer prognosis.

For a patient with cancer pain and no medical history of opioid use disorder but taking more opioids than prescribed, regardless of prognosis, the panel felt it was appropriate to increase monitoring and inappropriate to taper opioids. The panel was not certain about whether to increase opioids based on the patient’s account of what they need or transition to buprenorphine/naloxone.

For a patient with no history of opioid use disorder who was prescribed traditional opioids for pain and had a positive urine drug test for nonprescribed benzodiazepines, regardless of prognosis, the panel felt it was appropriate to continue opioids with close monitoring and inappropriate to taper opioids or transition to buprenorphine/naloxone.

The researchers said that improving education around buprenorphine and cancer pain management in the context of opioid use disorder or misuse is needed.

In a related editorial, two experts noted that the patients considered in this “important article” require considerable time and expertise from an interdisciplinary team.

“It is important that cancer centers establish and fund such teams mainly as a safety measure for these patients and also as a major contribution to the care of all patients with cancer,” wrote Joseph Arthur, MD, and Eduardo Bruera, MD, with the University of Texas MD Anderson Cancer Center, Houston.

In the wider context, Dr. Arthur and Dr. Bruera highlighted how treatments for patients with advanced cancer have evolved over the past 3 decades, yet patients have continued to be given opioids to address cancer-related pain. Developing more sophisticated drugs that relieve pain without significant side effects or addictive properties is imperative.

Dr. Arthur and Dr. Bruera said the study authors “appropriately emphasize the value of delivering compassionate and expert care for these particularly complex cases and the importance of conducting research on the best ways to alleviate the suffering in this rapidly growing patient population.”

This research was supported by Cambia Health Foundation and the National Institute of Nursing Research. Dr. Merlin, Dr. Arthur, and Dr. Bruera reported no relevant disclosures.

A version of this article first appeared on Medscape.com.

Opioids remain a staple in pain management for cancer, but there is little guidance around how to treat patients who have a history of opioid misuse.

Recently, a group of palliative and addiction medicine specialists developed strategies to help frontline clinicians manage patients with advanced cancer-related pain and opioid use disorder.

“There is a tendency to ignore treatment of opioid use disorder in advanced cancer patients because people think: ‘Oh, this person has bigger fish to fry,’ but that’s not a very patient-centric way of looking at things,” senior author Jessica Merlin, MD, PhD, with the University of Pittsburgh, said in a news release.

“We know that opioid use disorder is a really important factor in quality of life, so addressing opioid addiction and prescription opioid misuse in people with advanced cancer is really critical,” Dr. Merlin added.

The study was published online in JAMA Oncology.

To improve care for people with advanced cancer and cancer-related pain, the researchers first assessed how clinicians currently treat patients with opioid complexity.

Using an online Delphi platform, the team invited 120 clinicians with expertise in palliative care, pain management, and addiction medicine to weigh in on three common clinical scenarios – a patient with a recent history of untreated opioid use disorder, a patient taking more opioids than prescribed, and a patient using nonprescribed benzodiazepines.

For a patient with cancer and a recent history of untreated opioid use disorder, regardless of prognosis, the panel deemed it appropriate to begin treatment with buprenorphine/naloxone for pain but inappropriate to refer the patient to a methadone clinic. The panel felt that going to a methadone clinic would be too burdensome for a patient with advanced cancer and not possible for those with limited prognoses.

“This underscores the importance of access to [opioid use disorder] treatment in cancer treatment settings, including non–addiction specialists waivered to prescribe buprenorphine/naloxone and addiction specialists for more complex cases,” the authors wrote.

For a patient with untreated opioid use disorder, the panel deemed split-dose methadone (two to three times daily) appropriate in those with limited prognosis of weeks to months but was uncertain about the suitability of this approach for patients with longer prognoses of a year or longer.

The appropriateness of initiating treatment with a full-agonist opioid was considered uncertain for a patient with limited prognosis and inappropriate for a patient with longer prognosis.

For a patient with cancer pain and no medical history of opioid use disorder but taking more opioids than prescribed, regardless of prognosis, the panel felt it was appropriate to increase monitoring and inappropriate to taper opioids. The panel was not certain about whether to increase opioids based on the patient’s account of what they need or transition to buprenorphine/naloxone.

For a patient with no history of opioid use disorder who was prescribed traditional opioids for pain and had a positive urine drug test for nonprescribed benzodiazepines, regardless of prognosis, the panel felt it was appropriate to continue opioids with close monitoring and inappropriate to taper opioids or transition to buprenorphine/naloxone.

The researchers said that improving education around buprenorphine and cancer pain management in the context of opioid use disorder or misuse is needed.

In a related editorial, two experts noted that the patients considered in this “important article” require considerable time and expertise from an interdisciplinary team.

“It is important that cancer centers establish and fund such teams mainly as a safety measure for these patients and also as a major contribution to the care of all patients with cancer,” wrote Joseph Arthur, MD, and Eduardo Bruera, MD, with the University of Texas MD Anderson Cancer Center, Houston.

In the wider context, Dr. Arthur and Dr. Bruera highlighted how treatments for patients with advanced cancer have evolved over the past 3 decades, yet patients have continued to be given opioids to address cancer-related pain. Developing more sophisticated drugs that relieve pain without significant side effects or addictive properties is imperative.

Dr. Arthur and Dr. Bruera said the study authors “appropriately emphasize the value of delivering compassionate and expert care for these particularly complex cases and the importance of conducting research on the best ways to alleviate the suffering in this rapidly growing patient population.”

This research was supported by Cambia Health Foundation and the National Institute of Nursing Research. Dr. Merlin, Dr. Arthur, and Dr. Bruera reported no relevant disclosures.

A version of this article first appeared on Medscape.com.

Opioids remain a staple in pain management for cancer, but there is little guidance around how to treat patients who have a history of opioid misuse.

Recently, a group of palliative and addiction medicine specialists developed strategies to help frontline clinicians manage patients with advanced cancer-related pain and opioid use disorder.

“There is a tendency to ignore treatment of opioid use disorder in advanced cancer patients because people think: ‘Oh, this person has bigger fish to fry,’ but that’s not a very patient-centric way of looking at things,” senior author Jessica Merlin, MD, PhD, with the University of Pittsburgh, said in a news release.

“We know that opioid use disorder is a really important factor in quality of life, so addressing opioid addiction and prescription opioid misuse in people with advanced cancer is really critical,” Dr. Merlin added.

The study was published online in JAMA Oncology.

To improve care for people with advanced cancer and cancer-related pain, the researchers first assessed how clinicians currently treat patients with opioid complexity.

Using an online Delphi platform, the team invited 120 clinicians with expertise in palliative care, pain management, and addiction medicine to weigh in on three common clinical scenarios – a patient with a recent history of untreated opioid use disorder, a patient taking more opioids than prescribed, and a patient using nonprescribed benzodiazepines.

For a patient with cancer and a recent history of untreated opioid use disorder, regardless of prognosis, the panel deemed it appropriate to begin treatment with buprenorphine/naloxone for pain but inappropriate to refer the patient to a methadone clinic. The panel felt that going to a methadone clinic would be too burdensome for a patient with advanced cancer and not possible for those with limited prognoses.

“This underscores the importance of access to [opioid use disorder] treatment in cancer treatment settings, including non–addiction specialists waivered to prescribe buprenorphine/naloxone and addiction specialists for more complex cases,” the authors wrote.

For a patient with untreated opioid use disorder, the panel deemed split-dose methadone (two to three times daily) appropriate in those with limited prognosis of weeks to months but was uncertain about the suitability of this approach for patients with longer prognoses of a year or longer.

The appropriateness of initiating treatment with a full-agonist opioid was considered uncertain for a patient with limited prognosis and inappropriate for a patient with longer prognosis.

For a patient with cancer pain and no medical history of opioid use disorder but taking more opioids than prescribed, regardless of prognosis, the panel felt it was appropriate to increase monitoring and inappropriate to taper opioids. The panel was not certain about whether to increase opioids based on the patient’s account of what they need or transition to buprenorphine/naloxone.

For a patient with no history of opioid use disorder who was prescribed traditional opioids for pain and had a positive urine drug test for nonprescribed benzodiazepines, regardless of prognosis, the panel felt it was appropriate to continue opioids with close monitoring and inappropriate to taper opioids or transition to buprenorphine/naloxone.

The researchers said that improving education around buprenorphine and cancer pain management in the context of opioid use disorder or misuse is needed.

In a related editorial, two experts noted that the patients considered in this “important article” require considerable time and expertise from an interdisciplinary team.

“It is important that cancer centers establish and fund such teams mainly as a safety measure for these patients and also as a major contribution to the care of all patients with cancer,” wrote Joseph Arthur, MD, and Eduardo Bruera, MD, with the University of Texas MD Anderson Cancer Center, Houston.

In the wider context, Dr. Arthur and Dr. Bruera highlighted how treatments for patients with advanced cancer have evolved over the past 3 decades, yet patients have continued to be given opioids to address cancer-related pain. Developing more sophisticated drugs that relieve pain without significant side effects or addictive properties is imperative.

Dr. Arthur and Dr. Bruera said the study authors “appropriately emphasize the value of delivering compassionate and expert care for these particularly complex cases and the importance of conducting research on the best ways to alleviate the suffering in this rapidly growing patient population.”

This research was supported by Cambia Health Foundation and the National Institute of Nursing Research. Dr. Merlin, Dr. Arthur, and Dr. Bruera reported no relevant disclosures.

A version of this article first appeared on Medscape.com.

Findings from a cohort study highlight a potential role of tumor grade for predicting mucosal head and neck squamous cell carcinoma response to immunotherapy, researchers report in JAMA Otolaryngology–Head & Neck Surgery.

The analysis, which was among patients with either high-grade or low-grade recurrent or metastatic mucosal head and neck squamous cell carcinoma (HNSCC) tumors, revealed that tumor grade was independently associated with immunotherapy response.

“Generally, one would expect high-grade tumors to do worse because they are more aggressive,” said Rajarsi Mandal, MD, the study’s lead author. “But it’s thought that high-grade tumors have higher degrees of chromosomal instability with a lot more mutations generated throughout the genome of these tumors ... and we know that higher mutation rates correlate with higher responses to immunotherapy.”

Researchers found that the proportion of patients having a beneficial response to immunotherapy was larger for patients with high grade tumors (12 of 35; 34.3%) than those with low grade tumors (2 of 25, 8.0%) (difference, 26.3%; 95% confidence interval, 7.3%-45.3%). The odds of having a clinically beneficial response to immunotherapy was increased 5.35-fold (95% CI, 1.04-27.37) in patients with high-grade tumors. Among four patients with low-grade tumors and eight patients with high-grade tumors with available tumor mutational burden data, the mean tumor mutational burden was greater for patients with high-grade tumors (mean [standard deviation], 8.6 [5.4] mut/Mb; n = 8) than for patients with low grade tumors (mean [SD], 3.6 [1.1] mut/Mb; n = 4) (difference, 5.0 mut/Mb; 95% CI, −1.4 to 11.4 mut/Mb; Cohen d, 1.2).

“High tumor grade is not a guarantee but it possibly provides an easy biomarker and a good rationale to say that there’s a better chance the patient will respond to immune checkpoint inhibition,” said Dr. Mandal who is a head and neck cancer surgeon with the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore.

Previous studies of HNSCC tumors that are refractory to traditional therapies, including surgery, chemotherapy, and radiation therapy, have demonstrated a clinically beneficial response to immune checkpoint inhibitors (ICIs). An association between increased tumor mutational burden and beneficial response to ICIs has been shown in other cancers.

Researchers hypothesized that tumor histological grade may be associated with responses to immune checkpoint blockade, and designed their study to examine the association between tumor grade and immunotherapy response in patients treated with ICIs for recurrent or metastatic mucosal HNSCC.

In a single-center retrospective cohort study, investigators reviewed the medical records of 60 adult patients (mean age, 64.6 years; 85% male) with a primary mucosal HNSCC tumor treated with an immune checkpoint inhibitor (pembrolizumab, nivolumab, ipilimumab, or durvalumab) treated between July 1, 2015, and Jan. 22, 2020. They stratified them into those with low grade tumors (well differentiated and moderately differentiated) and those with high grade tumors (poorly differentiated). A clinically beneficial immunotherapy response, defined as complete response or partial response was the primary outcome.

Thirty-eight patients in the study cohort were current or former smokers. The most common primary tumor sight was at the oropharynx. Outcomes among those with high-grade tumors were improved, compared with those with low-grade tumors, for median progression-free survival (5.9 months vs. 3.3 months), median overall survival (16.6 months vs. 15.0 months, and risk of death (hazard ratio, 0.94).

The study’s main limitation was its small sample size and small number of patients who had a clinically beneficial immunotherapy response.

Dr. Mandal had no conflicts of interest to disclose.

Findings from a cohort study highlight a potential role of tumor grade for predicting mucosal head and neck squamous cell carcinoma response to immunotherapy, researchers report in JAMA Otolaryngology–Head & Neck Surgery.

The analysis, which was among patients with either high-grade or low-grade recurrent or metastatic mucosal head and neck squamous cell carcinoma (HNSCC) tumors, revealed that tumor grade was independently associated with immunotherapy response.

“Generally, one would expect high-grade tumors to do worse because they are more aggressive,” said Rajarsi Mandal, MD, the study’s lead author. “But it’s thought that high-grade tumors have higher degrees of chromosomal instability with a lot more mutations generated throughout the genome of these tumors ... and we know that higher mutation rates correlate with higher responses to immunotherapy.”

Researchers found that the proportion of patients having a beneficial response to immunotherapy was larger for patients with high grade tumors (12 of 35; 34.3%) than those with low grade tumors (2 of 25, 8.0%) (difference, 26.3%; 95% confidence interval, 7.3%-45.3%). The odds of having a clinically beneficial response to immunotherapy was increased 5.35-fold (95% CI, 1.04-27.37) in patients with high-grade tumors. Among four patients with low-grade tumors and eight patients with high-grade tumors with available tumor mutational burden data, the mean tumor mutational burden was greater for patients with high-grade tumors (mean [standard deviation], 8.6 [5.4] mut/Mb; n = 8) than for patients with low grade tumors (mean [SD], 3.6 [1.1] mut/Mb; n = 4) (difference, 5.0 mut/Mb; 95% CI, −1.4 to 11.4 mut/Mb; Cohen d, 1.2).

“High tumor grade is not a guarantee but it possibly provides an easy biomarker and a good rationale to say that there’s a better chance the patient will respond to immune checkpoint inhibition,” said Dr. Mandal who is a head and neck cancer surgeon with the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore.

Previous studies of HNSCC tumors that are refractory to traditional therapies, including surgery, chemotherapy, and radiation therapy, have demonstrated a clinically beneficial response to immune checkpoint inhibitors (ICIs). An association between increased tumor mutational burden and beneficial response to ICIs has been shown in other cancers.

Researchers hypothesized that tumor histological grade may be associated with responses to immune checkpoint blockade, and designed their study to examine the association between tumor grade and immunotherapy response in patients treated with ICIs for recurrent or metastatic mucosal HNSCC.

In a single-center retrospective cohort study, investigators reviewed the medical records of 60 adult patients (mean age, 64.6 years; 85% male) with a primary mucosal HNSCC tumor treated with an immune checkpoint inhibitor (pembrolizumab, nivolumab, ipilimumab, or durvalumab) treated between July 1, 2015, and Jan. 22, 2020. They stratified them into those with low grade tumors (well differentiated and moderately differentiated) and those with high grade tumors (poorly differentiated). A clinically beneficial immunotherapy response, defined as complete response or partial response was the primary outcome.

Thirty-eight patients in the study cohort were current or former smokers. The most common primary tumor sight was at the oropharynx. Outcomes among those with high-grade tumors were improved, compared with those with low-grade tumors, for median progression-free survival (5.9 months vs. 3.3 months), median overall survival (16.6 months vs. 15.0 months, and risk of death (hazard ratio, 0.94).

The study’s main limitation was its small sample size and small number of patients who had a clinically beneficial immunotherapy response.

Dr. Mandal had no conflicts of interest to disclose.

Findings from a cohort study highlight a potential role of tumor grade for predicting mucosal head and neck squamous cell carcinoma response to immunotherapy, researchers report in JAMA Otolaryngology–Head & Neck Surgery.

The analysis, which was among patients with either high-grade or low-grade recurrent or metastatic mucosal head and neck squamous cell carcinoma (HNSCC) tumors, revealed that tumor grade was independently associated with immunotherapy response.

“Generally, one would expect high-grade tumors to do worse because they are more aggressive,” said Rajarsi Mandal, MD, the study’s lead author. “But it’s thought that high-grade tumors have higher degrees of chromosomal instability with a lot more mutations generated throughout the genome of these tumors ... and we know that higher mutation rates correlate with higher responses to immunotherapy.”

Researchers found that the proportion of patients having a beneficial response to immunotherapy was larger for patients with high grade tumors (12 of 35; 34.3%) than those with low grade tumors (2 of 25, 8.0%) (difference, 26.3%; 95% confidence interval, 7.3%-45.3%). The odds of having a clinically beneficial response to immunotherapy was increased 5.35-fold (95% CI, 1.04-27.37) in patients with high-grade tumors. Among four patients with low-grade tumors and eight patients with high-grade tumors with available tumor mutational burden data, the mean tumor mutational burden was greater for patients with high-grade tumors (mean [standard deviation], 8.6 [5.4] mut/Mb; n = 8) than for patients with low grade tumors (mean [SD], 3.6 [1.1] mut/Mb; n = 4) (difference, 5.0 mut/Mb; 95% CI, −1.4 to 11.4 mut/Mb; Cohen d, 1.2).

“High tumor grade is not a guarantee but it possibly provides an easy biomarker and a good rationale to say that there’s a better chance the patient will respond to immune checkpoint inhibition,” said Dr. Mandal who is a head and neck cancer surgeon with the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore.

Previous studies of HNSCC tumors that are refractory to traditional therapies, including surgery, chemotherapy, and radiation therapy, have demonstrated a clinically beneficial response to immune checkpoint inhibitors (ICIs). An association between increased tumor mutational burden and beneficial response to ICIs has been shown in other cancers.

Researchers hypothesized that tumor histological grade may be associated with responses to immune checkpoint blockade, and designed their study to examine the association between tumor grade and immunotherapy response in patients treated with ICIs for recurrent or metastatic mucosal HNSCC.

In a single-center retrospective cohort study, investigators reviewed the medical records of 60 adult patients (mean age, 64.6 years; 85% male) with a primary mucosal HNSCC tumor treated with an immune checkpoint inhibitor (pembrolizumab, nivolumab, ipilimumab, or durvalumab) treated between July 1, 2015, and Jan. 22, 2020. They stratified them into those with low grade tumors (well differentiated and moderately differentiated) and those with high grade tumors (poorly differentiated). A clinically beneficial immunotherapy response, defined as complete response or partial response was the primary outcome.

Thirty-eight patients in the study cohort were current or former smokers. The most common primary tumor sight was at the oropharynx. Outcomes among those with high-grade tumors were improved, compared with those with low-grade tumors, for median progression-free survival (5.9 months vs. 3.3 months), median overall survival (16.6 months vs. 15.0 months, and risk of death (hazard ratio, 0.94).

The study’s main limitation was its small sample size and small number of patients who had a clinically beneficial immunotherapy response.

Dr. Mandal had no conflicts of interest to disclose.

An experimental cancer drug could be promising for some people hospitalized with COVID-19, a new study shows.

The medication, called sabizabulin and given as a pill, reduced by half the risk of death among participants. It could be more effective than other drugs for those severely sick with COVID-19, The New York Times reports.

The manufacturer, Veru, is seeking emergency use authorization from the Food and Drug Administration. Hospitalized COVID-19 patients currently have only a few pharmaceutical options.

Sabizabulin blocks cells from building molecular cables that carry material from one part of a cell to another. It was created to fight cancer, because tumor cells need those cables (called microtubules) to grow quickly.

Researchers tried it against COVID-19 2 years ago, because viral replication also requires microtubules to bring pieces of new viruses together.

To participate in the small trial, patients had to be receiving oxygen or on a ventilator and at a high risk of dying from COVID-19, “with risk factors such as hypertension, advanced age or obesity,” the Times reported.

A total of 134 patients received the medicine; 70 got a placebo. Among those receiving sabizabulin, 20.2% died within 2 months; 45.1% of those who took the placebo died.

One infectious disease expert told the Times that the high mortality rate of those on the placebo could mean the study was too small to offer conclusive results.

“The 45% mortality rate in the control group jumps out at me as rather high,” said David Boulware, MD, of the University of Minnesota.

A version of this article first appeared on WebMD.com.

An experimental cancer drug could be promising for some people hospitalized with COVID-19, a new study shows.

The medication, called sabizabulin and given as a pill, reduced by half the risk of death among participants. It could be more effective than other drugs for those severely sick with COVID-19, The New York Times reports.

The manufacturer, Veru, is seeking emergency use authorization from the Food and Drug Administration. Hospitalized COVID-19 patients currently have only a few pharmaceutical options.

Sabizabulin blocks cells from building molecular cables that carry material from one part of a cell to another. It was created to fight cancer, because tumor cells need those cables (called microtubules) to grow quickly.

Researchers tried it against COVID-19 2 years ago, because viral replication also requires microtubules to bring pieces of new viruses together.

To participate in the small trial, patients had to be receiving oxygen or on a ventilator and at a high risk of dying from COVID-19, “with risk factors such as hypertension, advanced age or obesity,” the Times reported.

A total of 134 patients received the medicine; 70 got a placebo. Among those receiving sabizabulin, 20.2% died within 2 months; 45.1% of those who took the placebo died.

One infectious disease expert told the Times that the high mortality rate of those on the placebo could mean the study was too small to offer conclusive results.

“The 45% mortality rate in the control group jumps out at me as rather high,” said David Boulware, MD, of the University of Minnesota.

A version of this article first appeared on WebMD.com.

An experimental cancer drug could be promising for some people hospitalized with COVID-19, a new study shows.

The medication, called sabizabulin and given as a pill, reduced by half the risk of death among participants. It could be more effective than other drugs for those severely sick with COVID-19, The New York Times reports.

The manufacturer, Veru, is seeking emergency use authorization from the Food and Drug Administration. Hospitalized COVID-19 patients currently have only a few pharmaceutical options.

Sabizabulin blocks cells from building molecular cables that carry material from one part of a cell to another. It was created to fight cancer, because tumor cells need those cables (called microtubules) to grow quickly.

Researchers tried it against COVID-19 2 years ago, because viral replication also requires microtubules to bring pieces of new viruses together.

To participate in the small trial, patients had to be receiving oxygen or on a ventilator and at a high risk of dying from COVID-19, “with risk factors such as hypertension, advanced age or obesity,” the Times reported.

A total of 134 patients received the medicine; 70 got a placebo. Among those receiving sabizabulin, 20.2% died within 2 months; 45.1% of those who took the placebo died.

One infectious disease expert told the Times that the high mortality rate of those on the placebo could mean the study was too small to offer conclusive results.

“The 45% mortality rate in the control group jumps out at me as rather high,” said David Boulware, MD, of the University of Minnesota.

A version of this article first appeared on WebMD.com.

Fecal microbiota transplantation (FMT) resulted in sustained high response rates in patients with irritable bowel syndrome (IBS) and resulted in only mild side effects after 3 years, new data show.

Nearly three out of four people in a clinical trial experienced fewer symptoms and fatigue and a greater quality of life at both 2 years and 3 years after FMT in Norway. Those FMT-treated patients who relapsed subsequently responded to FMT upon retransplantation, reported the authors, who also correlated individual microbial profiles with clinical outcomes.

The study, led by Magdy El-Salhy, MD, PhD, department of medicine, Stord (Norway) Hospital, was published online in Gastroenterology.

An expert not involved with the study, Brian Lacy, MD, PhD, a gastroenterologist with the Mayo Clinic in Jacksonville, Fla., said that the results of the study are important, but he cautions against treating IBS with FMT outside clinical trials, at least until the protocol is validated, given demonstrated risks.

The new study included 125 patients (104 women, 21 men) in three groups: 38 received a placebo, 42 received 30 g of donor feces, and 45 received 60 g of donor feces. The feces – all from one male donor – was administered to the duodenum.

The response rates for those who received FMT were significantly higher than for those who received placebo. Those receiving 30 g of feces had a response rate of 69.1%, and those in the 60-g group had a response rate of 77.8%, whereas the response rate in the placebo group was 26.3%.

Patients provided a fecal sample and completed five questionnaires at the beginning of the study and at 2 and 3 years after FMT.

Patients in both treatment groups had significantly fewer IBS symptoms – such as abdominal pain, abdominal bloating, dissatisfaction with bowel habits, and quality-of-life interruption – and less fatigue compared with the placebo group, as well as higher quality of life scores at 2 and 3 years.

No long-term adverse effects were reported.

The dysbiosis index decreased only in the treatment group at years 2 and 3.
 

Microbial modifications correlate with IBS symptoms

In addition, the fluorescent signals of 10 bacteria that had changed after FMT were significantly correlated with improved IBS symptoms and fatigue in both treatment groups.

“Of the bacteria markers whose fluorescence signals changed in the 30-g and 60-g groups, but not in the placebo group, at both 2 and 3 years after FMT, nine were significantly correlated with the total IBS-SSS [IBS–Severity Scoring System] scores,” the authors wrote. One more bacterium with a changed fluorescence signal in the active treatment group also correlated with total fatigue.

Dr. El-Salhy told this news organization that those findings open the door for the select bacteria to be used, for example, in capsule form to treat IBS and fatigue.

The most surprising finding for the team was that the “majority of IBS patients [who] responded to FMT maintained response up to 3 years” or more, said Dr. El-Salhy, alluding to unpublished data up to 5 years.

“Furthermore, 80% of those who relapsed after 3 years responded to a new FMT,” he said.

Women had higher response rates than men at years 2 and 3 after FMT, but there were no differences between complete remission rates of women and men at years 2 and 3.
 

‘Impressive’ results, but caution warranted

“The results are impressive,” Dr. Lacy said. “I believe that this will help researchers around the world refine their techniques, as we learn more about FMT for the treatment of IBS. It also clearly plays up the importance of the gut microbiome in symptom generation in IBS patients.”

However, he said, until the results are replicated, and the protocol validated, FMT should not be used routinely to treat IBS because there are risks with the procedure.

Dr. Lacy pointed out there have been mixed results in the literature regarding FMT and IBS.

He cited a meta-analysis of four studies (n = 254) in 2019 that did not show a benefit for FMT in patients with IBS. However, a second meta-analysis of five studies (n = 267) did show some benefit, possibly owing to the type of donor and small-bowel infusion.

The authors added that, in the seven randomized, controlled trials investigating FMT for IBS, four concluded that FMT eased symptoms and improved quality of life in patients with IBS, whereas treatment was not effective in the other three.

The authors pointed to differences in protocols, donors, the cohort treated, FMT dose, and route of administration.

The longest response time previously studied in the randomized, controlled trials was 1 year, the authors pointed out. The new study was a 3-year follow-up of these authors’ previous randomly assigned placebo-controlled trial participants.
 

The ‘super-donor’ concept

The authors of the current study described the single chosen donor as “a healthy male aged 36 years with a normal BMI [body mass index] who was born via vaginal delivery, breastfed, a nonsmoker, was not taking any medication, was treated only a few times with antibiotics, exercised regularly, and consumed a sport-specific diet that was richer in protein, fiber, minerals, and vitamins than the average diet.”

The donor had high microbial diversity, and his fecal bacteria makeup was different from that of 254 healthy subjects for 14 of the 48 bacterial markers investigators tested.

Dr. Lacy said that the “super-donor” concept is noteworthy and an apparent key to success.

“Other studies have not done this,” Dr. Lacy noted.

Among the strengths of the study are that it included a relatively large cohort of patients with IBS, with three IBS subtypes and a single well-defined donor. However, it did not include the fourth IBS subtype, unsubtyped IBS, and it only investigated a part of the intestinal bacterial content, the authors acknowledged.

Most interesting, Dr. Lacy said, is that the IBS subtype did not seem to matter to FMT outcomes at 3 years and that all three subtypes responded better than placebo.

“That’s encouraging,” Dr. Lacy said.

The investigators received a grant from Helse Fonna. The study authors and Dr. Lacy reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Fecal microbiota transplantation (FMT) resulted in sustained high response rates in patients with irritable bowel syndrome (IBS) and resulted in only mild side effects after 3 years, new data show.

Nearly three out of four people in a clinical trial experienced fewer symptoms and fatigue and a greater quality of life at both 2 years and 3 years after FMT in Norway. Those FMT-treated patients who relapsed subsequently responded to FMT upon retransplantation, reported the authors, who also correlated individual microbial profiles with clinical outcomes.

The study, led by Magdy El-Salhy, MD, PhD, department of medicine, Stord (Norway) Hospital, was published online in Gastroenterology.

An expert not involved with the study, Brian Lacy, MD, PhD, a gastroenterologist with the Mayo Clinic in Jacksonville, Fla., said that the results of the study are important, but he cautions against treating IBS with FMT outside clinical trials, at least until the protocol is validated, given demonstrated risks.

The new study included 125 patients (104 women, 21 men) in three groups: 38 received a placebo, 42 received 30 g of donor feces, and 45 received 60 g of donor feces. The feces – all from one male donor – was administered to the duodenum.

The response rates for those who received FMT were significantly higher than for those who received placebo. Those receiving 30 g of feces had a response rate of 69.1%, and those in the 60-g group had a response rate of 77.8%, whereas the response rate in the placebo group was 26.3%.

Patients provided a fecal sample and completed five questionnaires at the beginning of the study and at 2 and 3 years after FMT.

Patients in both treatment groups had significantly fewer IBS symptoms – such as abdominal pain, abdominal bloating, dissatisfaction with bowel habits, and quality-of-life interruption – and less fatigue compared with the placebo group, as well as higher quality of life scores at 2 and 3 years.

No long-term adverse effects were reported.

The dysbiosis index decreased only in the treatment group at years 2 and 3.
 

Microbial modifications correlate with IBS symptoms

In addition, the fluorescent signals of 10 bacteria that had changed after FMT were significantly correlated with improved IBS symptoms and fatigue in both treatment groups.

“Of the bacteria markers whose fluorescence signals changed in the 30-g and 60-g groups, but not in the placebo group, at both 2 and 3 years after FMT, nine were significantly correlated with the total IBS-SSS [IBS–Severity Scoring System] scores,” the authors wrote. One more bacterium with a changed fluorescence signal in the active treatment group also correlated with total fatigue.

Dr. El-Salhy told this news organization that those findings open the door for the select bacteria to be used, for example, in capsule form to treat IBS and fatigue.

The most surprising finding for the team was that the “majority of IBS patients [who] responded to FMT maintained response up to 3 years” or more, said Dr. El-Salhy, alluding to unpublished data up to 5 years.

“Furthermore, 80% of those who relapsed after 3 years responded to a new FMT,” he said.

Women had higher response rates than men at years 2 and 3 after FMT, but there were no differences between complete remission rates of women and men at years 2 and 3.
 

‘Impressive’ results, but caution warranted

“The results are impressive,” Dr. Lacy said. “I believe that this will help researchers around the world refine their techniques, as we learn more about FMT for the treatment of IBS. It also clearly plays up the importance of the gut microbiome in symptom generation in IBS patients.”

However, he said, until the results are replicated, and the protocol validated, FMT should not be used routinely to treat IBS because there are risks with the procedure.

Dr. Lacy pointed out there have been mixed results in the literature regarding FMT and IBS.

He cited a meta-analysis of four studies (n = 254) in 2019 that did not show a benefit for FMT in patients with IBS. However, a second meta-analysis of five studies (n = 267) did show some benefit, possibly owing to the type of donor and small-bowel infusion.

The authors added that, in the seven randomized, controlled trials investigating FMT for IBS, four concluded that FMT eased symptoms and improved quality of life in patients with IBS, whereas treatment was not effective in the other three.

The authors pointed to differences in protocols, donors, the cohort treated, FMT dose, and route of administration.

The longest response time previously studied in the randomized, controlled trials was 1 year, the authors pointed out. The new study was a 3-year follow-up of these authors’ previous randomly assigned placebo-controlled trial participants.
 

The ‘super-donor’ concept

The authors of the current study described the single chosen donor as “a healthy male aged 36 years with a normal BMI [body mass index] who was born via vaginal delivery, breastfed, a nonsmoker, was not taking any medication, was treated only a few times with antibiotics, exercised regularly, and consumed a sport-specific diet that was richer in protein, fiber, minerals, and vitamins than the average diet.”

The donor had high microbial diversity, and his fecal bacteria makeup was different from that of 254 healthy subjects for 14 of the 48 bacterial markers investigators tested.

Dr. Lacy said that the “super-donor” concept is noteworthy and an apparent key to success.

“Other studies have not done this,” Dr. Lacy noted.

Among the strengths of the study are that it included a relatively large cohort of patients with IBS, with three IBS subtypes and a single well-defined donor. However, it did not include the fourth IBS subtype, unsubtyped IBS, and it only investigated a part of the intestinal bacterial content, the authors acknowledged.

Most interesting, Dr. Lacy said, is that the IBS subtype did not seem to matter to FMT outcomes at 3 years and that all three subtypes responded better than placebo.

“That’s encouraging,” Dr. Lacy said.

The investigators received a grant from Helse Fonna. The study authors and Dr. Lacy reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Fecal microbiota transplantation (FMT) resulted in sustained high response rates in patients with irritable bowel syndrome (IBS) and resulted in only mild side effects after 3 years, new data show.

Nearly three out of four people in a clinical trial experienced fewer symptoms and fatigue and a greater quality of life at both 2 years and 3 years after FMT in Norway. Those FMT-treated patients who relapsed subsequently responded to FMT upon retransplantation, reported the authors, who also correlated individual microbial profiles with clinical outcomes.

The study, led by Magdy El-Salhy, MD, PhD, department of medicine, Stord (Norway) Hospital, was published online in Gastroenterology.

An expert not involved with the study, Brian Lacy, MD, PhD, a gastroenterologist with the Mayo Clinic in Jacksonville, Fla., said that the results of the study are important, but he cautions against treating IBS with FMT outside clinical trials, at least until the protocol is validated, given demonstrated risks.

The new study included 125 patients (104 women, 21 men) in three groups: 38 received a placebo, 42 received 30 g of donor feces, and 45 received 60 g of donor feces. The feces – all from one male donor – was administered to the duodenum.

The response rates for those who received FMT were significantly higher than for those who received placebo. Those receiving 30 g of feces had a response rate of 69.1%, and those in the 60-g group had a response rate of 77.8%, whereas the response rate in the placebo group was 26.3%.

Patients provided a fecal sample and completed five questionnaires at the beginning of the study and at 2 and 3 years after FMT.

Patients in both treatment groups had significantly fewer IBS symptoms – such as abdominal pain, abdominal bloating, dissatisfaction with bowel habits, and quality-of-life interruption – and less fatigue compared with the placebo group, as well as higher quality of life scores at 2 and 3 years.

No long-term adverse effects were reported.

The dysbiosis index decreased only in the treatment group at years 2 and 3.
 

Microbial modifications correlate with IBS symptoms

In addition, the fluorescent signals of 10 bacteria that had changed after FMT were significantly correlated with improved IBS symptoms and fatigue in both treatment groups.

“Of the bacteria markers whose fluorescence signals changed in the 30-g and 60-g groups, but not in the placebo group, at both 2 and 3 years after FMT, nine were significantly correlated with the total IBS-SSS [IBS–Severity Scoring System] scores,” the authors wrote. One more bacterium with a changed fluorescence signal in the active treatment group also correlated with total fatigue.

Dr. El-Salhy told this news organization that those findings open the door for the select bacteria to be used, for example, in capsule form to treat IBS and fatigue.

The most surprising finding for the team was that the “majority of IBS patients [who] responded to FMT maintained response up to 3 years” or more, said Dr. El-Salhy, alluding to unpublished data up to 5 years.

“Furthermore, 80% of those who relapsed after 3 years responded to a new FMT,” he said.

Women had higher response rates than men at years 2 and 3 after FMT, but there were no differences between complete remission rates of women and men at years 2 and 3.
 

‘Impressive’ results, but caution warranted

“The results are impressive,” Dr. Lacy said. “I believe that this will help researchers around the world refine their techniques, as we learn more about FMT for the treatment of IBS. It also clearly plays up the importance of the gut microbiome in symptom generation in IBS patients.”

However, he said, until the results are replicated, and the protocol validated, FMT should not be used routinely to treat IBS because there are risks with the procedure.

Dr. Lacy pointed out there have been mixed results in the literature regarding FMT and IBS.

He cited a meta-analysis of four studies (n = 254) in 2019 that did not show a benefit for FMT in patients with IBS. However, a second meta-analysis of five studies (n = 267) did show some benefit, possibly owing to the type of donor and small-bowel infusion.

The authors added that, in the seven randomized, controlled trials investigating FMT for IBS, four concluded that FMT eased symptoms and improved quality of life in patients with IBS, whereas treatment was not effective in the other three.

The authors pointed to differences in protocols, donors, the cohort treated, FMT dose, and route of administration.

The longest response time previously studied in the randomized, controlled trials was 1 year, the authors pointed out. The new study was a 3-year follow-up of these authors’ previous randomly assigned placebo-controlled trial participants.
 

The ‘super-donor’ concept

The authors of the current study described the single chosen donor as “a healthy male aged 36 years with a normal BMI [body mass index] who was born via vaginal delivery, breastfed, a nonsmoker, was not taking any medication, was treated only a few times with antibiotics, exercised regularly, and consumed a sport-specific diet that was richer in protein, fiber, minerals, and vitamins than the average diet.”

The donor had high microbial diversity, and his fecal bacteria makeup was different from that of 254 healthy subjects for 14 of the 48 bacterial markers investigators tested.

Dr. Lacy said that the “super-donor” concept is noteworthy and an apparent key to success.

“Other studies have not done this,” Dr. Lacy noted.

Among the strengths of the study are that it included a relatively large cohort of patients with IBS, with three IBS subtypes and a single well-defined donor. However, it did not include the fourth IBS subtype, unsubtyped IBS, and it only investigated a part of the intestinal bacterial content, the authors acknowledged.

Most interesting, Dr. Lacy said, is that the IBS subtype did not seem to matter to FMT outcomes at 3 years and that all three subtypes responded better than placebo.

“That’s encouraging,” Dr. Lacy said.

The investigators received a grant from Helse Fonna. The study authors and Dr. Lacy reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.