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Home telemonitoring for heart failure cuts mortality
MUNICH – A comprehensive home telemonitoring program paid off big for selected patients with heart failure in a large, German nationwide masked randomization trial.
First, TIM-HF2 didn’t rely on passive monitoring of the patients’ daily electronically submitted home data. Instead, the data went straight to a central telemonitoring center staffed 24/7 by physicians and nurses with heart failure expertise. There, the information was immediately analyzed using proprietary telemedical analytic software known as the Fontane system. The software employs individually tailored, self-adapting algorithms in order to alert staff when trouble is brewing.
But the telemonitoring intervention doesn’t merely detect early clinical deterioration. It’s also a vehicle for ongoing patient education, outpatient adjustment of drugs, management of major comorbid conditions, and hospital admissions as needed. The patient’s local primary care physician was also plugged into the remote monitoring system and kept abreast of the patient’s condition.
Second, TIM-HF2 focused on a carefully selected subgroup of heart failure patients whom prior studies suggested were particularly likely to benefit from home telemedical management. All participants were NYHA class II or III with a left ventricular ejection fraction of 45% or less, a hospitalization for heart failure within 12 months prior to randomization, and free of moderate or severe depression as evidenced by a baseline Patient Health Questionnaire-9 score of 9 or less, explained Dr. Koehler, head of the center for cardiovascular telemedicine at Charite University in Berlin.
Why exclude patients with depression?
“In this concept, with wholistic remote patient management, we need an active patient who is able to measure every day, who is able to communicate with the telemedical center, and who is able to communicate in this network created between the telemedical center and local caregivers. If someone is really depressed, unable to act, lying in bed saying it makes no sense to take drugs or do anything, then we cannot help. That is for us, I think, the most important thing. We’ve seen it now in two trials,” according to the cardiologist.
The all-cause mortality rate was 7.86 per 100 person-years in the home-telemonitoring group versus 11.34 in usual-care controls. Patients in the active intervention arm lost a mean of 17.8 days per year because of unplanned cardiovascular hospital admissions, compared with 24.2 days per year in controls.
Importantly, outcomes were equally good in the remote patient-management group regardless of whether patients were among the 40% of participants living in urban Germany or the 60% in rural areas. Thus, the telemonitoring intervention eliminated the geographic disparity in health care outcomes which is a prominent issue in Germany, as well as the United States.
A formal cost-benefit analysis of the TIM-HF2 results is in the works, Dr. Koehler said.
Simultaneous with his presentation in Munich, the TIM-HF2 study was published online in the Lancet.
In an accompanying editorial, two prominent heart failure experts – John F.G. Cleland, MD, of the University of Glasgow and Robin A. Clark, MD, of Flinders University in Adelaide – hailed TIM-HF2 as a major advance and indicated in sharp terms that it’s time for guideline writers to sit up and take notice.
“Despite much clinical skepticism and feeble support from most guidelines, in our view the growing weight of evidence suggests that home telemonitoring does reduce mortality for patients with heart failure, and this effect might be substantial. These and other trials also show that the emphasis placed on hospital admission for heart failure might be misplaced, at least from a patient’s perspective, because the proportion of days lost due to hospital admission is small, compared with those lost to death,” the physicians wrote in the editorial.
They also noted that, even though the between-group difference in the number of days during which patients were hospitalized for cardiovascular causes was relatively small, it’s clear that home telemonitoring triggered some potentially life-saving hospitalizations. “Home telemonitoring puts the patient back in the center of health care, ensuring that they know what the health professional is trying to achieve and that they agree with those aims. Ultimately, patients and their families are a large and relatively untapped health care resource,” they wrote.
The TIM-HF 2 trial was funded by the German Federal Ministry of Education and Research. Dr. Koehler reported receiving speaking and/or consultant fees from Novartis, Abbott, and Medtronic.
[email protected]
SOURCE: Koehler F et al. ESC Congress 2018. Lancet. 2018 Sep 22;392(10152):1047-57.
MUNICH – A comprehensive home telemonitoring program paid off big for selected patients with heart failure in a large, German nationwide masked randomization trial.
First, TIM-HF2 didn’t rely on passive monitoring of the patients’ daily electronically submitted home data. Instead, the data went straight to a central telemonitoring center staffed 24/7 by physicians and nurses with heart failure expertise. There, the information was immediately analyzed using proprietary telemedical analytic software known as the Fontane system. The software employs individually tailored, self-adapting algorithms in order to alert staff when trouble is brewing.
But the telemonitoring intervention doesn’t merely detect early clinical deterioration. It’s also a vehicle for ongoing patient education, outpatient adjustment of drugs, management of major comorbid conditions, and hospital admissions as needed. The patient’s local primary care physician was also plugged into the remote monitoring system and kept abreast of the patient’s condition.
Second, TIM-HF2 focused on a carefully selected subgroup of heart failure patients whom prior studies suggested were particularly likely to benefit from home telemedical management. All participants were NYHA class II or III with a left ventricular ejection fraction of 45% or less, a hospitalization for heart failure within 12 months prior to randomization, and free of moderate or severe depression as evidenced by a baseline Patient Health Questionnaire-9 score of 9 or less, explained Dr. Koehler, head of the center for cardiovascular telemedicine at Charite University in Berlin.
Why exclude patients with depression?
“In this concept, with wholistic remote patient management, we need an active patient who is able to measure every day, who is able to communicate with the telemedical center, and who is able to communicate in this network created between the telemedical center and local caregivers. If someone is really depressed, unable to act, lying in bed saying it makes no sense to take drugs or do anything, then we cannot help. That is for us, I think, the most important thing. We’ve seen it now in two trials,” according to the cardiologist.
The all-cause mortality rate was 7.86 per 100 person-years in the home-telemonitoring group versus 11.34 in usual-care controls. Patients in the active intervention arm lost a mean of 17.8 days per year because of unplanned cardiovascular hospital admissions, compared with 24.2 days per year in controls.
Importantly, outcomes were equally good in the remote patient-management group regardless of whether patients were among the 40% of participants living in urban Germany or the 60% in rural areas. Thus, the telemonitoring intervention eliminated the geographic disparity in health care outcomes which is a prominent issue in Germany, as well as the United States.
A formal cost-benefit analysis of the TIM-HF2 results is in the works, Dr. Koehler said.
Simultaneous with his presentation in Munich, the TIM-HF2 study was published online in the Lancet.
In an accompanying editorial, two prominent heart failure experts – John F.G. Cleland, MD, of the University of Glasgow and Robin A. Clark, MD, of Flinders University in Adelaide – hailed TIM-HF2 as a major advance and indicated in sharp terms that it’s time for guideline writers to sit up and take notice.
“Despite much clinical skepticism and feeble support from most guidelines, in our view the growing weight of evidence suggests that home telemonitoring does reduce mortality for patients with heart failure, and this effect might be substantial. These and other trials also show that the emphasis placed on hospital admission for heart failure might be misplaced, at least from a patient’s perspective, because the proportion of days lost due to hospital admission is small, compared with those lost to death,” the physicians wrote in the editorial.
They also noted that, even though the between-group difference in the number of days during which patients were hospitalized for cardiovascular causes was relatively small, it’s clear that home telemonitoring triggered some potentially life-saving hospitalizations. “Home telemonitoring puts the patient back in the center of health care, ensuring that they know what the health professional is trying to achieve and that they agree with those aims. Ultimately, patients and their families are a large and relatively untapped health care resource,” they wrote.
The TIM-HF 2 trial was funded by the German Federal Ministry of Education and Research. Dr. Koehler reported receiving speaking and/or consultant fees from Novartis, Abbott, and Medtronic.
[email protected]
SOURCE: Koehler F et al. ESC Congress 2018. Lancet. 2018 Sep 22;392(10152):1047-57.
MUNICH – A comprehensive home telemonitoring program paid off big for selected patients with heart failure in a large, German nationwide masked randomization trial.
First, TIM-HF2 didn’t rely on passive monitoring of the patients’ daily electronically submitted home data. Instead, the data went straight to a central telemonitoring center staffed 24/7 by physicians and nurses with heart failure expertise. There, the information was immediately analyzed using proprietary telemedical analytic software known as the Fontane system. The software employs individually tailored, self-adapting algorithms in order to alert staff when trouble is brewing.
But the telemonitoring intervention doesn’t merely detect early clinical deterioration. It’s also a vehicle for ongoing patient education, outpatient adjustment of drugs, management of major comorbid conditions, and hospital admissions as needed. The patient’s local primary care physician was also plugged into the remote monitoring system and kept abreast of the patient’s condition.
Second, TIM-HF2 focused on a carefully selected subgroup of heart failure patients whom prior studies suggested were particularly likely to benefit from home telemedical management. All participants were NYHA class II or III with a left ventricular ejection fraction of 45% or less, a hospitalization for heart failure within 12 months prior to randomization, and free of moderate or severe depression as evidenced by a baseline Patient Health Questionnaire-9 score of 9 or less, explained Dr. Koehler, head of the center for cardiovascular telemedicine at Charite University in Berlin.
Why exclude patients with depression?
“In this concept, with wholistic remote patient management, we need an active patient who is able to measure every day, who is able to communicate with the telemedical center, and who is able to communicate in this network created between the telemedical center and local caregivers. If someone is really depressed, unable to act, lying in bed saying it makes no sense to take drugs or do anything, then we cannot help. That is for us, I think, the most important thing. We’ve seen it now in two trials,” according to the cardiologist.
The all-cause mortality rate was 7.86 per 100 person-years in the home-telemonitoring group versus 11.34 in usual-care controls. Patients in the active intervention arm lost a mean of 17.8 days per year because of unplanned cardiovascular hospital admissions, compared with 24.2 days per year in controls.
Importantly, outcomes were equally good in the remote patient-management group regardless of whether patients were among the 40% of participants living in urban Germany or the 60% in rural areas. Thus, the telemonitoring intervention eliminated the geographic disparity in health care outcomes which is a prominent issue in Germany, as well as the United States.
A formal cost-benefit analysis of the TIM-HF2 results is in the works, Dr. Koehler said.
Simultaneous with his presentation in Munich, the TIM-HF2 study was published online in the Lancet.
In an accompanying editorial, two prominent heart failure experts – John F.G. Cleland, MD, of the University of Glasgow and Robin A. Clark, MD, of Flinders University in Adelaide – hailed TIM-HF2 as a major advance and indicated in sharp terms that it’s time for guideline writers to sit up and take notice.
“Despite much clinical skepticism and feeble support from most guidelines, in our view the growing weight of evidence suggests that home telemonitoring does reduce mortality for patients with heart failure, and this effect might be substantial. These and other trials also show that the emphasis placed on hospital admission for heart failure might be misplaced, at least from a patient’s perspective, because the proportion of days lost due to hospital admission is small, compared with those lost to death,” the physicians wrote in the editorial.
They also noted that, even though the between-group difference in the number of days during which patients were hospitalized for cardiovascular causes was relatively small, it’s clear that home telemonitoring triggered some potentially life-saving hospitalizations. “Home telemonitoring puts the patient back in the center of health care, ensuring that they know what the health professional is trying to achieve and that they agree with those aims. Ultimately, patients and their families are a large and relatively untapped health care resource,” they wrote.
The TIM-HF 2 trial was funded by the German Federal Ministry of Education and Research. Dr. Koehler reported receiving speaking and/or consultant fees from Novartis, Abbott, and Medtronic.
[email protected]
SOURCE: Koehler F et al. ESC Congress 2018. Lancet. 2018 Sep 22;392(10152):1047-57.
REPORTING FROM THE ESC CONGRESS 2018
Key clinical point: Comprehensive home-telemonitoring program for heart failure saves lives.
Major finding: All-cause mortality was reduced by 30% at 1 year with a comprehensive home-telemonitoring program.
Study details: This prospective, masked randomization study included 1,538 German heart failure patients.
Disclosures: The TIM-HF2 trial was funded by the German Federal Ministry of Education and Research.
Source: Koehler F. ESC Congress 2018. Lancet. 2018 Sep 22;392(10152):1047-57.
Pulmonary artery denervation boosts walking capacity in left heart failure
SAN DIEGO – Pulmonary artery denervation is efficacious for treating combined pre- and postcapillary pulmonary hypertension attributable to left heart failure, based on results of the Chinese PADN-5 trial reported at the Transcatheter Cardiovascular Therapeutics annual meeting.
This ablative treatment has been studied among patients with pulmonary hypertension attributable to other etiologies, but not in randomized fashion among this population, noted lead investigator Shao-Liang Chen, MD, of Nanjing (China) First Hospital, Nanjing Medical University. The treatment is an attractive one, as medications recommended for pulmonary arterial hypertension are not recommended for joint pre- and postcapillary pulmonary hypertension (group II pulmonary hypertension).
In PADN-5, 98 patients were randomized to pulmonary artery denervation or to sham denervation plus open-label sildenafil (Viagra), which at the time of trial initiation was thought to be safe and potentially beneficial.
The trial’s main outcome, 6-minute walk distance at 6 months, improved in both groups, according to data reported at the meeting and simultaneously published in JACC Cardiovascular Interventions. But the improvement was about four times greater in the pulmonary artery denervation group. Secondary efficacy outcomes also favored that group, and the rate of fatal pulmonary embolism did not differ for the two groups.
“The PADN-5 trial demonstrates the benefits of pulmonary artery denervation for patients with combined pre- and postcapillary pulmonary hypertension. Patients with preserved and with reduced ejection fraction equally benefited,” summarized Dr. Chen, who pioneered this procedure about 7 years ago. “There was no sign of any harm of sildenafil in patients with combined pre- and postcapillary pulmonary hypertension.”
Trial critique
“This is a very difficult study to conduct, being able to recruit patients and actually have these procedures done,” commented press conference moderator Ori Ben-Yehuda, MD, professor of clinical medicine and director, coronary care unit, UC San Diego Medical Center.
At the same time, he expressed some reservations about the trial. “Sildenafil in the control group might actually be expected to ... decrease your effect size. Also, particularly in men, perhaps even in women, it might unblind them to which group they are in and undermine your sham design,” he noted. In addition, some hemodynamic changes after pulmonary artery denervation – a decrease in wedge pressure and an increase in ejection fraction – were puzzling.
“We need a lot more data here. There are some issues with this trial in terms of design, and we haven’t even gotten into the issue of whether there were core labs, whether the echoes, the hemodynamics, were read blindly,” Dr. Ben-Yehuda maintained. “This issue of secondary or group II pulmonary hypertension due to left heart failure is one that has been very frustrating in terms of actual PA-specific therapies. So this is an important step further, but it needs confirmation in truly sham-controlled trials that have no potential for unblinding.”
The catheter used in PADN-5 is available in China but has not received clearance in the United States, he pointed out. “There are alternative or competing technologies, one using ultrasound, for example, that has a very similar approach. … We’ll have to see how it ends up [performing].”
Trial details
Patients in the PADN-5 pulmonary artery denervation group underwent ablation only in the periconjunctional area between the distal main trunk and the left ostial branch with a multifunction catheter having premounted electrodes. Those in the control group underwent a sham procedure, with catheter positioning at the target sites and connection to a generator but no ablation, and were given open-label sildenafil. All additionally received standard heart failure medical therapy. (No sildenafil placebo was used in the denervation group.)
Trial results reported at the meeting, which is sponsored by the Cardiovascular Research Foundation, showed that most echocardiographic and hemodynamic measures improved more in the pulmonary artery denervation group.
The greater improvement in 6-minute walk test with denervation versus sham sildenafil at 6 months was evident in a variety of measures: absolute median distance walked (432.5 m vs. 358 m) and mean distance walked (434.6 m vs. 359.4 m), and absolute increase (80 m vs. 17.5 m) and relative increase (21.4% vs. 4.9%) The difference was significant for all measures at P less than .001.
The denervation group had a comparatively greater reduction of pulmonary vascular resistance (29.8% vs. 3.4%; P less than .001) and were less likely to experience clinical worsening (16.7% vs. 40.0%; P = .014).
There was a single fatal pulmonary embolism in each treatment group. Of the seven total deaths, two occurred in the denervation group (one attributable to pump failure, one a sudden death) and five occurred in the sham sildenafil group (all but one attributable to pump failure).
Dr. Chen disclosed that he had no relevant conflicts of interest. The trial was sponsored by Nanjing First Hospital, Nanjing Medical University.
SOURCE: Chen S-J et al. TCT 2018. JACC Cardiovasc Interv. 2018 Sep 23.
SAN DIEGO – Pulmonary artery denervation is efficacious for treating combined pre- and postcapillary pulmonary hypertension attributable to left heart failure, based on results of the Chinese PADN-5 trial reported at the Transcatheter Cardiovascular Therapeutics annual meeting.
This ablative treatment has been studied among patients with pulmonary hypertension attributable to other etiologies, but not in randomized fashion among this population, noted lead investigator Shao-Liang Chen, MD, of Nanjing (China) First Hospital, Nanjing Medical University. The treatment is an attractive one, as medications recommended for pulmonary arterial hypertension are not recommended for joint pre- and postcapillary pulmonary hypertension (group II pulmonary hypertension).
In PADN-5, 98 patients were randomized to pulmonary artery denervation or to sham denervation plus open-label sildenafil (Viagra), which at the time of trial initiation was thought to be safe and potentially beneficial.
The trial’s main outcome, 6-minute walk distance at 6 months, improved in both groups, according to data reported at the meeting and simultaneously published in JACC Cardiovascular Interventions. But the improvement was about four times greater in the pulmonary artery denervation group. Secondary efficacy outcomes also favored that group, and the rate of fatal pulmonary embolism did not differ for the two groups.
“The PADN-5 trial demonstrates the benefits of pulmonary artery denervation for patients with combined pre- and postcapillary pulmonary hypertension. Patients with preserved and with reduced ejection fraction equally benefited,” summarized Dr. Chen, who pioneered this procedure about 7 years ago. “There was no sign of any harm of sildenafil in patients with combined pre- and postcapillary pulmonary hypertension.”
Trial critique
“This is a very difficult study to conduct, being able to recruit patients and actually have these procedures done,” commented press conference moderator Ori Ben-Yehuda, MD, professor of clinical medicine and director, coronary care unit, UC San Diego Medical Center.
At the same time, he expressed some reservations about the trial. “Sildenafil in the control group might actually be expected to ... decrease your effect size. Also, particularly in men, perhaps even in women, it might unblind them to which group they are in and undermine your sham design,” he noted. In addition, some hemodynamic changes after pulmonary artery denervation – a decrease in wedge pressure and an increase in ejection fraction – were puzzling.
“We need a lot more data here. There are some issues with this trial in terms of design, and we haven’t even gotten into the issue of whether there were core labs, whether the echoes, the hemodynamics, were read blindly,” Dr. Ben-Yehuda maintained. “This issue of secondary or group II pulmonary hypertension due to left heart failure is one that has been very frustrating in terms of actual PA-specific therapies. So this is an important step further, but it needs confirmation in truly sham-controlled trials that have no potential for unblinding.”
The catheter used in PADN-5 is available in China but has not received clearance in the United States, he pointed out. “There are alternative or competing technologies, one using ultrasound, for example, that has a very similar approach. … We’ll have to see how it ends up [performing].”
Trial details
Patients in the PADN-5 pulmonary artery denervation group underwent ablation only in the periconjunctional area between the distal main trunk and the left ostial branch with a multifunction catheter having premounted electrodes. Those in the control group underwent a sham procedure, with catheter positioning at the target sites and connection to a generator but no ablation, and were given open-label sildenafil. All additionally received standard heart failure medical therapy. (No sildenafil placebo was used in the denervation group.)
Trial results reported at the meeting, which is sponsored by the Cardiovascular Research Foundation, showed that most echocardiographic and hemodynamic measures improved more in the pulmonary artery denervation group.
The greater improvement in 6-minute walk test with denervation versus sham sildenafil at 6 months was evident in a variety of measures: absolute median distance walked (432.5 m vs. 358 m) and mean distance walked (434.6 m vs. 359.4 m), and absolute increase (80 m vs. 17.5 m) and relative increase (21.4% vs. 4.9%) The difference was significant for all measures at P less than .001.
The denervation group had a comparatively greater reduction of pulmonary vascular resistance (29.8% vs. 3.4%; P less than .001) and were less likely to experience clinical worsening (16.7% vs. 40.0%; P = .014).
There was a single fatal pulmonary embolism in each treatment group. Of the seven total deaths, two occurred in the denervation group (one attributable to pump failure, one a sudden death) and five occurred in the sham sildenafil group (all but one attributable to pump failure).
Dr. Chen disclosed that he had no relevant conflicts of interest. The trial was sponsored by Nanjing First Hospital, Nanjing Medical University.
SOURCE: Chen S-J et al. TCT 2018. JACC Cardiovasc Interv. 2018 Sep 23.
SAN DIEGO – Pulmonary artery denervation is efficacious for treating combined pre- and postcapillary pulmonary hypertension attributable to left heart failure, based on results of the Chinese PADN-5 trial reported at the Transcatheter Cardiovascular Therapeutics annual meeting.
This ablative treatment has been studied among patients with pulmonary hypertension attributable to other etiologies, but not in randomized fashion among this population, noted lead investigator Shao-Liang Chen, MD, of Nanjing (China) First Hospital, Nanjing Medical University. The treatment is an attractive one, as medications recommended for pulmonary arterial hypertension are not recommended for joint pre- and postcapillary pulmonary hypertension (group II pulmonary hypertension).
In PADN-5, 98 patients were randomized to pulmonary artery denervation or to sham denervation plus open-label sildenafil (Viagra), which at the time of trial initiation was thought to be safe and potentially beneficial.
The trial’s main outcome, 6-minute walk distance at 6 months, improved in both groups, according to data reported at the meeting and simultaneously published in JACC Cardiovascular Interventions. But the improvement was about four times greater in the pulmonary artery denervation group. Secondary efficacy outcomes also favored that group, and the rate of fatal pulmonary embolism did not differ for the two groups.
“The PADN-5 trial demonstrates the benefits of pulmonary artery denervation for patients with combined pre- and postcapillary pulmonary hypertension. Patients with preserved and with reduced ejection fraction equally benefited,” summarized Dr. Chen, who pioneered this procedure about 7 years ago. “There was no sign of any harm of sildenafil in patients with combined pre- and postcapillary pulmonary hypertension.”
Trial critique
“This is a very difficult study to conduct, being able to recruit patients and actually have these procedures done,” commented press conference moderator Ori Ben-Yehuda, MD, professor of clinical medicine and director, coronary care unit, UC San Diego Medical Center.
At the same time, he expressed some reservations about the trial. “Sildenafil in the control group might actually be expected to ... decrease your effect size. Also, particularly in men, perhaps even in women, it might unblind them to which group they are in and undermine your sham design,” he noted. In addition, some hemodynamic changes after pulmonary artery denervation – a decrease in wedge pressure and an increase in ejection fraction – were puzzling.
“We need a lot more data here. There are some issues with this trial in terms of design, and we haven’t even gotten into the issue of whether there were core labs, whether the echoes, the hemodynamics, were read blindly,” Dr. Ben-Yehuda maintained. “This issue of secondary or group II pulmonary hypertension due to left heart failure is one that has been very frustrating in terms of actual PA-specific therapies. So this is an important step further, but it needs confirmation in truly sham-controlled trials that have no potential for unblinding.”
The catheter used in PADN-5 is available in China but has not received clearance in the United States, he pointed out. “There are alternative or competing technologies, one using ultrasound, for example, that has a very similar approach. … We’ll have to see how it ends up [performing].”
Trial details
Patients in the PADN-5 pulmonary artery denervation group underwent ablation only in the periconjunctional area between the distal main trunk and the left ostial branch with a multifunction catheter having premounted electrodes. Those in the control group underwent a sham procedure, with catheter positioning at the target sites and connection to a generator but no ablation, and were given open-label sildenafil. All additionally received standard heart failure medical therapy. (No sildenafil placebo was used in the denervation group.)
Trial results reported at the meeting, which is sponsored by the Cardiovascular Research Foundation, showed that most echocardiographic and hemodynamic measures improved more in the pulmonary artery denervation group.
The greater improvement in 6-minute walk test with denervation versus sham sildenafil at 6 months was evident in a variety of measures: absolute median distance walked (432.5 m vs. 358 m) and mean distance walked (434.6 m vs. 359.4 m), and absolute increase (80 m vs. 17.5 m) and relative increase (21.4% vs. 4.9%) The difference was significant for all measures at P less than .001.
The denervation group had a comparatively greater reduction of pulmonary vascular resistance (29.8% vs. 3.4%; P less than .001) and were less likely to experience clinical worsening (16.7% vs. 40.0%; P = .014).
There was a single fatal pulmonary embolism in each treatment group. Of the seven total deaths, two occurred in the denervation group (one attributable to pump failure, one a sudden death) and five occurred in the sham sildenafil group (all but one attributable to pump failure).
Dr. Chen disclosed that he had no relevant conflicts of interest. The trial was sponsored by Nanjing First Hospital, Nanjing Medical University.
SOURCE: Chen S-J et al. TCT 2018. JACC Cardiovasc Interv. 2018 Sep 23.
REPORTING FROM TCT 2018
Key clinical point: Pulmonary artery denervation is efficacious for treating pulmonary hypertension related to heart failure.
Major finding: Improvement in 6-minute walk distance was greater with pulmonary artery denervation than with sham denervation plus sildenafil (21.4% vs. 4.9%; P less than .001).
Study details: PADN-5 is a randomized controlled trial among 98 patients with combined pre- and postcapillary pulmonary hypertension secondary to left heart failure (group II pulmonary hypertension).
Disclosures: Dr. Chen disclosed that he had no relevant conflicts of interest. The trial was sponsored by Nanjing First Hospital, Nanjing Medical University.
Source: Chen S-L et al. TCT 2018. JACC Cardiovasc Interv. 2018 Sep 23.
FDA approves cemiplimab for advanced cutaneous squamous cell carcinoma
The U.S. Food and Drug Administration has approved cemiplimab-rwlc (Libtayo) for the treatment of metastatic or locally advanced cutaneous squamous cell carcinoma, the agency announced in a press release.
The approval was granted based on data from two open-label clinical trials involving a total of 108 patients: the phase 2 EMPOWER-CSCC-1 trial (NCT02760498) and two expansion cohorts from an open-label, nonrandomized phase 1 trial.
These trials, which included 75 patients with metastatic disease and 33 with locally advanced disease, found an overall response rate of 47.2%, and most of those patients still showed ongoing responses at the time of data analysis. Among patients with metastatic disease, 5% had a complete response, according to a press release from the manufacturer, Sanofi.
This is the sixth FDA approval for a checkpoint inhibitor targeting the PD-1/PD-L1 pathway. The drug was evaluated under the FDA’s Priority Review program for drugs that represent significant improvements in the safety or effectiveness of treatments for serious conditions. Manufacturer Sanofi was granted Breakthrough Therapy designation for cemiplimab in 2017 for advanced cutaneous squamous cell carcinoma, and the drug is also being reviewed by the European Medicines Agency.
Cemiplimab is administered as a 350-mg intravenous therapy every 3 weeks – costing $9,100 per treatment – until the disease progresses or patients experience unacceptable toxicity, according to the manufacturer. The most common side effects include fatigue, rash and diarrhea, but more serious adverse events can include immune-mediated reactions such as pneumonitis, colitis, hepatitis, endocrinopathies, and skin and kidney problems.
The U.S. Food and Drug Administration has approved cemiplimab-rwlc (Libtayo) for the treatment of metastatic or locally advanced cutaneous squamous cell carcinoma, the agency announced in a press release.
The approval was granted based on data from two open-label clinical trials involving a total of 108 patients: the phase 2 EMPOWER-CSCC-1 trial (NCT02760498) and two expansion cohorts from an open-label, nonrandomized phase 1 trial.
These trials, which included 75 patients with metastatic disease and 33 with locally advanced disease, found an overall response rate of 47.2%, and most of those patients still showed ongoing responses at the time of data analysis. Among patients with metastatic disease, 5% had a complete response, according to a press release from the manufacturer, Sanofi.
This is the sixth FDA approval for a checkpoint inhibitor targeting the PD-1/PD-L1 pathway. The drug was evaluated under the FDA’s Priority Review program for drugs that represent significant improvements in the safety or effectiveness of treatments for serious conditions. Manufacturer Sanofi was granted Breakthrough Therapy designation for cemiplimab in 2017 for advanced cutaneous squamous cell carcinoma, and the drug is also being reviewed by the European Medicines Agency.
Cemiplimab is administered as a 350-mg intravenous therapy every 3 weeks – costing $9,100 per treatment – until the disease progresses or patients experience unacceptable toxicity, according to the manufacturer. The most common side effects include fatigue, rash and diarrhea, but more serious adverse events can include immune-mediated reactions such as pneumonitis, colitis, hepatitis, endocrinopathies, and skin and kidney problems.
The U.S. Food and Drug Administration has approved cemiplimab-rwlc (Libtayo) for the treatment of metastatic or locally advanced cutaneous squamous cell carcinoma, the agency announced in a press release.
The approval was granted based on data from two open-label clinical trials involving a total of 108 patients: the phase 2 EMPOWER-CSCC-1 trial (NCT02760498) and two expansion cohorts from an open-label, nonrandomized phase 1 trial.
These trials, which included 75 patients with metastatic disease and 33 with locally advanced disease, found an overall response rate of 47.2%, and most of those patients still showed ongoing responses at the time of data analysis. Among patients with metastatic disease, 5% had a complete response, according to a press release from the manufacturer, Sanofi.
This is the sixth FDA approval for a checkpoint inhibitor targeting the PD-1/PD-L1 pathway. The drug was evaluated under the FDA’s Priority Review program for drugs that represent significant improvements in the safety or effectiveness of treatments for serious conditions. Manufacturer Sanofi was granted Breakthrough Therapy designation for cemiplimab in 2017 for advanced cutaneous squamous cell carcinoma, and the drug is also being reviewed by the European Medicines Agency.
Cemiplimab is administered as a 350-mg intravenous therapy every 3 weeks – costing $9,100 per treatment – until the disease progresses or patients experience unacceptable toxicity, according to the manufacturer. The most common side effects include fatigue, rash and diarrhea, but more serious adverse events can include immune-mediated reactions such as pneumonitis, colitis, hepatitis, endocrinopathies, and skin and kidney problems.
ASPREE: What to do now about aspirin for healthy elderly people
Across-the-board use of aspirin for primary prevention is “not justified” based on the results of ASPREE as well as the equivocal results from other recent primary prevention trials, according to Prakash C. Deedwania, MD, clinical professor of medicine and chief of the cardiology division at the Veterans Affairs Medical Center/University of California San Francisco Program in Fresno.
The importance of interpreting these studies lies in the recognition that while low-risk people don’t benefit, patients who are at mid to high cardiovascular (CV) risk clearly might. Aspirin’s role in secondary prevention after an initial CV event is clearly established, Dr. Deedwania added.
In ASPREE, a randomized, double-blind, placebo-controlled trial including nearly 20,000 participants, daily aspirin increased rates of major hemorrhage and did not significantly decrease risks of cardiovascular events, death, or other outcomes in healthy elderly individuals.
Aspirin did not prolong disability-free survival, a composite endpoint that included death, dementia, and permanent physical disability, according to one of three separate reports on ASPREE that were published in the New England Journal of Medicine.
Cardiovascular disease rates were likewise not significantly different between aspirin and placebo, with a hazard ratio that ruled out the possibility of a major protective effect, lead author John J. McNeil, MBBS, PhD, of Monash University, Melbourne, said in a second report on ASPREE.
All-cause mortality was actually higher in the aspirin arm versus the placebo arm, attributable largely to an excess of cancer-related deaths, Dr. McNeil and colleagues said in their third full report in the journal. However, that mortality finding needs to be interpreted with caution, they noted, given that previous investigations have shown a protective effect of aspirin on cancer-related death.
Potential harms of “innocuous” drug
The ASPREE (Aspirin in Reducing Events in the Elderly) study evaluated the use of aspirin as primary prevention in 19,114 healthy subjects, with a median age of 74 years, enrolled at 34 centers in Australia and the United States between 2010 and 2014.
The patients, who did not have cardiovascular disease, dementia, or disability at baseline, were randomized to daily 100-mg enteric-coated aspirin or placebo.
The rate of death, dementia, or disability was 21.5 events per 1,000 person-years in the aspirin group, and 21.2 events per 1,000 person-years in the placebo group, with a hazard ratio of 1.01 (95% confidence interval, 0.92-1.11; P = .79), Dr. McNeil and colleagues reported.
The rate of major hemorrhage was 8.6 events per 1,000 person-years for aspirin versus 6.2 events per 1,000 person years for placebo (HR, 1.38; 95% CI, 1.18-1.62; P less than .001), investigators found.
Cardiovascular outcomes: expectations vs. reality
Investigators said they thought they might see a significant cardiovascular benefit of aspirin in ASPREE based on earlier studies and meta-analyses that suggested a benefit in other populations. However, the rate of cardiovascular disease at 4.7 years of follow-up was 10.7 events per 1,000 person-years for aspirin, and 11.3 per 1,000 person years for placebo (HR, 0.95; 95% CI, 0.83-1.08).
That hazard ratio “rules out the possibility of a major protective effect of aspirin but is compatible with a more modest lowering of risk of up to 17%,” Dr. McNeil and colleagues wrote.
The results are consistent with those of a recent meta-analysis including eight primary prevention trials, mainly in adults under 70 years of age. That analysis found a 17% reduction in nonfatal myocardial infarction risk, a 14% reduction in stroke risk, and a higher risk of serious bleeding for aspirin versus control groups.
Results of ASPREE have to be interpreted in light of event rates, which were much lower than the expected 22.4 events per 1,000 person-years, they added. The low event rate probably reflects both the relatively good health of the study subjects, and the declining rates of cardiovascular disease in recent years, they said.
“Because of these factors, the absolute benefit that results from any proportionally lower rate of cardiovascular disease may be less than the benefit observed in studies from previous decades and is less likely than it had been to outweigh the risk of adverse events from aspirin,” investigators said in their report.
Current guidelines state that the evidence is limited for use of aspirin as primary prevention of cardiovascular disease in the elderly. “Nevertheless, many millions of relatively healthy older persons in the United States and Australia take low-dose aspirin with the assumption that it will reduce the likelihood of future cardiovascular disease and stroke,” study authors said in a discussion of the results.
Excess deaths explored
There were also no significant differences between arms for the endpoints of death, dementia, or disability evaluated separately. However, the rate of death by any cause was numerically higher in the aspirin group versus the placebo group, at 12.7 and 11.1 events per 1,000 person-years, respectively (HR, 1.14; 95% CI, 1.01-1.29).
Cancer was the major contributor to the imbalance in deaths, ASPREE results show, at 1.6 excess deaths per 1,000 person-years. A total of 3.1% of patients in the aspirin group had cancer-related deaths, compared with 2.3% in the placebo arm of the trial (HR, 1.31; 95% CI, 1.10-1.56).
Mortality related to major hemorrhage contributed “only minimally” to the excess in deaths, investigators added in their report.
The finding of excess deaths in the aspirin arm of ASPREE contrasts with meta-analyses of previous prevention trials. According to investigators, those studies show a protective effect of aspirin on cancer-related death that is apparent after 4-5 years of continuous treatment.
Various cellular and molecular pathways relevant to cancer development, progression, and spread are influenced by aspirin, previous studies show.
“Questions may therefore arise about whether the biology of cancer differs among age groups with regard to the frequency of common molecular patterns, metastatic behavior, and treatment responses,” Dr. McNeil and coauthors wrote in their report.
Dr. McNeil reported nonfinancial support from Bayer received during the conduct of the study.
SOURCE: McNeil JJ et al. N Engl J Med. 2018 Sep 16.
Across-the-board use of aspirin for primary prevention is “not justified” based on the results of ASPREE as well as the equivocal results from other recent primary prevention trials, according to Prakash C. Deedwania, MD, clinical professor of medicine and chief of the cardiology division at the Veterans Affairs Medical Center/University of California San Francisco Program in Fresno.
The importance of interpreting these studies lies in the recognition that while low-risk people don’t benefit, patients who are at mid to high cardiovascular (CV) risk clearly might. Aspirin’s role in secondary prevention after an initial CV event is clearly established, Dr. Deedwania added.
In ASPREE, a randomized, double-blind, placebo-controlled trial including nearly 20,000 participants, daily aspirin increased rates of major hemorrhage and did not significantly decrease risks of cardiovascular events, death, or other outcomes in healthy elderly individuals.
Aspirin did not prolong disability-free survival, a composite endpoint that included death, dementia, and permanent physical disability, according to one of three separate reports on ASPREE that were published in the New England Journal of Medicine.
Cardiovascular disease rates were likewise not significantly different between aspirin and placebo, with a hazard ratio that ruled out the possibility of a major protective effect, lead author John J. McNeil, MBBS, PhD, of Monash University, Melbourne, said in a second report on ASPREE.
All-cause mortality was actually higher in the aspirin arm versus the placebo arm, attributable largely to an excess of cancer-related deaths, Dr. McNeil and colleagues said in their third full report in the journal. However, that mortality finding needs to be interpreted with caution, they noted, given that previous investigations have shown a protective effect of aspirin on cancer-related death.
Potential harms of “innocuous” drug
The ASPREE (Aspirin in Reducing Events in the Elderly) study evaluated the use of aspirin as primary prevention in 19,114 healthy subjects, with a median age of 74 years, enrolled at 34 centers in Australia and the United States between 2010 and 2014.
The patients, who did not have cardiovascular disease, dementia, or disability at baseline, were randomized to daily 100-mg enteric-coated aspirin or placebo.
The rate of death, dementia, or disability was 21.5 events per 1,000 person-years in the aspirin group, and 21.2 events per 1,000 person-years in the placebo group, with a hazard ratio of 1.01 (95% confidence interval, 0.92-1.11; P = .79), Dr. McNeil and colleagues reported.
The rate of major hemorrhage was 8.6 events per 1,000 person-years for aspirin versus 6.2 events per 1,000 person years for placebo (HR, 1.38; 95% CI, 1.18-1.62; P less than .001), investigators found.
Cardiovascular outcomes: expectations vs. reality
Investigators said they thought they might see a significant cardiovascular benefit of aspirin in ASPREE based on earlier studies and meta-analyses that suggested a benefit in other populations. However, the rate of cardiovascular disease at 4.7 years of follow-up was 10.7 events per 1,000 person-years for aspirin, and 11.3 per 1,000 person years for placebo (HR, 0.95; 95% CI, 0.83-1.08).
That hazard ratio “rules out the possibility of a major protective effect of aspirin but is compatible with a more modest lowering of risk of up to 17%,” Dr. McNeil and colleagues wrote.
The results are consistent with those of a recent meta-analysis including eight primary prevention trials, mainly in adults under 70 years of age. That analysis found a 17% reduction in nonfatal myocardial infarction risk, a 14% reduction in stroke risk, and a higher risk of serious bleeding for aspirin versus control groups.
Results of ASPREE have to be interpreted in light of event rates, which were much lower than the expected 22.4 events per 1,000 person-years, they added. The low event rate probably reflects both the relatively good health of the study subjects, and the declining rates of cardiovascular disease in recent years, they said.
“Because of these factors, the absolute benefit that results from any proportionally lower rate of cardiovascular disease may be less than the benefit observed in studies from previous decades and is less likely than it had been to outweigh the risk of adverse events from aspirin,” investigators said in their report.
Current guidelines state that the evidence is limited for use of aspirin as primary prevention of cardiovascular disease in the elderly. “Nevertheless, many millions of relatively healthy older persons in the United States and Australia take low-dose aspirin with the assumption that it will reduce the likelihood of future cardiovascular disease and stroke,” study authors said in a discussion of the results.
Excess deaths explored
There were also no significant differences between arms for the endpoints of death, dementia, or disability evaluated separately. However, the rate of death by any cause was numerically higher in the aspirin group versus the placebo group, at 12.7 and 11.1 events per 1,000 person-years, respectively (HR, 1.14; 95% CI, 1.01-1.29).
Cancer was the major contributor to the imbalance in deaths, ASPREE results show, at 1.6 excess deaths per 1,000 person-years. A total of 3.1% of patients in the aspirin group had cancer-related deaths, compared with 2.3% in the placebo arm of the trial (HR, 1.31; 95% CI, 1.10-1.56).
Mortality related to major hemorrhage contributed “only minimally” to the excess in deaths, investigators added in their report.
The finding of excess deaths in the aspirin arm of ASPREE contrasts with meta-analyses of previous prevention trials. According to investigators, those studies show a protective effect of aspirin on cancer-related death that is apparent after 4-5 years of continuous treatment.
Various cellular and molecular pathways relevant to cancer development, progression, and spread are influenced by aspirin, previous studies show.
“Questions may therefore arise about whether the biology of cancer differs among age groups with regard to the frequency of common molecular patterns, metastatic behavior, and treatment responses,” Dr. McNeil and coauthors wrote in their report.
Dr. McNeil reported nonfinancial support from Bayer received during the conduct of the study.
SOURCE: McNeil JJ et al. N Engl J Med. 2018 Sep 16.
Across-the-board use of aspirin for primary prevention is “not justified” based on the results of ASPREE as well as the equivocal results from other recent primary prevention trials, according to Prakash C. Deedwania, MD, clinical professor of medicine and chief of the cardiology division at the Veterans Affairs Medical Center/University of California San Francisco Program in Fresno.
The importance of interpreting these studies lies in the recognition that while low-risk people don’t benefit, patients who are at mid to high cardiovascular (CV) risk clearly might. Aspirin’s role in secondary prevention after an initial CV event is clearly established, Dr. Deedwania added.
In ASPREE, a randomized, double-blind, placebo-controlled trial including nearly 20,000 participants, daily aspirin increased rates of major hemorrhage and did not significantly decrease risks of cardiovascular events, death, or other outcomes in healthy elderly individuals.
Aspirin did not prolong disability-free survival, a composite endpoint that included death, dementia, and permanent physical disability, according to one of three separate reports on ASPREE that were published in the New England Journal of Medicine.
Cardiovascular disease rates were likewise not significantly different between aspirin and placebo, with a hazard ratio that ruled out the possibility of a major protective effect, lead author John J. McNeil, MBBS, PhD, of Monash University, Melbourne, said in a second report on ASPREE.
All-cause mortality was actually higher in the aspirin arm versus the placebo arm, attributable largely to an excess of cancer-related deaths, Dr. McNeil and colleagues said in their third full report in the journal. However, that mortality finding needs to be interpreted with caution, they noted, given that previous investigations have shown a protective effect of aspirin on cancer-related death.
Potential harms of “innocuous” drug
The ASPREE (Aspirin in Reducing Events in the Elderly) study evaluated the use of aspirin as primary prevention in 19,114 healthy subjects, with a median age of 74 years, enrolled at 34 centers in Australia and the United States between 2010 and 2014.
The patients, who did not have cardiovascular disease, dementia, or disability at baseline, were randomized to daily 100-mg enteric-coated aspirin or placebo.
The rate of death, dementia, or disability was 21.5 events per 1,000 person-years in the aspirin group, and 21.2 events per 1,000 person-years in the placebo group, with a hazard ratio of 1.01 (95% confidence interval, 0.92-1.11; P = .79), Dr. McNeil and colleagues reported.
The rate of major hemorrhage was 8.6 events per 1,000 person-years for aspirin versus 6.2 events per 1,000 person years for placebo (HR, 1.38; 95% CI, 1.18-1.62; P less than .001), investigators found.
Cardiovascular outcomes: expectations vs. reality
Investigators said they thought they might see a significant cardiovascular benefit of aspirin in ASPREE based on earlier studies and meta-analyses that suggested a benefit in other populations. However, the rate of cardiovascular disease at 4.7 years of follow-up was 10.7 events per 1,000 person-years for aspirin, and 11.3 per 1,000 person years for placebo (HR, 0.95; 95% CI, 0.83-1.08).
That hazard ratio “rules out the possibility of a major protective effect of aspirin but is compatible with a more modest lowering of risk of up to 17%,” Dr. McNeil and colleagues wrote.
The results are consistent with those of a recent meta-analysis including eight primary prevention trials, mainly in adults under 70 years of age. That analysis found a 17% reduction in nonfatal myocardial infarction risk, a 14% reduction in stroke risk, and a higher risk of serious bleeding for aspirin versus control groups.
Results of ASPREE have to be interpreted in light of event rates, which were much lower than the expected 22.4 events per 1,000 person-years, they added. The low event rate probably reflects both the relatively good health of the study subjects, and the declining rates of cardiovascular disease in recent years, they said.
“Because of these factors, the absolute benefit that results from any proportionally lower rate of cardiovascular disease may be less than the benefit observed in studies from previous decades and is less likely than it had been to outweigh the risk of adverse events from aspirin,” investigators said in their report.
Current guidelines state that the evidence is limited for use of aspirin as primary prevention of cardiovascular disease in the elderly. “Nevertheless, many millions of relatively healthy older persons in the United States and Australia take low-dose aspirin with the assumption that it will reduce the likelihood of future cardiovascular disease and stroke,” study authors said in a discussion of the results.
Excess deaths explored
There were also no significant differences between arms for the endpoints of death, dementia, or disability evaluated separately. However, the rate of death by any cause was numerically higher in the aspirin group versus the placebo group, at 12.7 and 11.1 events per 1,000 person-years, respectively (HR, 1.14; 95% CI, 1.01-1.29).
Cancer was the major contributor to the imbalance in deaths, ASPREE results show, at 1.6 excess deaths per 1,000 person-years. A total of 3.1% of patients in the aspirin group had cancer-related deaths, compared with 2.3% in the placebo arm of the trial (HR, 1.31; 95% CI, 1.10-1.56).
Mortality related to major hemorrhage contributed “only minimally” to the excess in deaths, investigators added in their report.
The finding of excess deaths in the aspirin arm of ASPREE contrasts with meta-analyses of previous prevention trials. According to investigators, those studies show a protective effect of aspirin on cancer-related death that is apparent after 4-5 years of continuous treatment.
Various cellular and molecular pathways relevant to cancer development, progression, and spread are influenced by aspirin, previous studies show.
“Questions may therefore arise about whether the biology of cancer differs among age groups with regard to the frequency of common molecular patterns, metastatic behavior, and treatment responses,” Dr. McNeil and coauthors wrote in their report.
Dr. McNeil reported nonfinancial support from Bayer received during the conduct of the study.
SOURCE: McNeil JJ et al. N Engl J Med. 2018 Sep 16.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Did psychiatry take a wrong turn?
Maybe it is just me. It probably is. It seems I must have taken a wrong turn in practicing psychiatry somewhere along the line.
For whatever reason, I never truly saw and appreciated the seamlessness between the psychiatric problems children, adults, and the elderly have plaguing them. Of course, I always marveled at how a child who had honest-to-goodness autism could become a full-grown adult and have an adult psychiatrist diagnose that individual as having schizophrenia; why not an adult with autism? But that was the extent of my understanding of the seamlessness between childhood and adult diagnoses. Maybe it is because I was poorly trained and never bothered to get a childhood developmental from my adult psychiatric patients. When I would present a case to supervisors as an adult psychiatric resident, I recall never presenting a child developmental history as a part of the patient’s trajectory. It was as though since there was adult psychiatry and child psychiatry, then the disorders of adults and children should be separated as well.
I know many adult psychiatrists never ask their adult patients, “How old were you when you graduated high school?” although an answer of “I never graduated,” or I graduated at 19-20” should raise questions. When I was in community psychiatry residency, I had some training at the Institute for Juvenile Research (birthplace of child psychiatry), so I understood something about children and the problems they had. Of course, back then, child psychiatric diagnoses were not that good, but with the advent of the DSM-5, children’s psychiatric diagnoses became more precise. This was probably because of research and better epidemiologic data about the prevalence of the six major neurodevelopmental disorders (intellectual disability, attention-deficit/hyperactivity disorder, speech and language disorders, autism spectrum disorders, specific learning disorders, and motor disorders). Maybe I am too old to remember, but I don’t remember anyone with a serious focus on what happens to psychiatrically ill children when they grow up to be adults or what psychiatric problems adult psychiatric patients had when they were children.
In a brilliant article in the September issue of the American Journal of Psychiatry, Avshalom Caspi, PhD, and Terrie E. Moffitt, PhD, propose that there is a single dimension of psychopathology, or “p.”
The authors perceptively remind us that we characterize children’s psychopathology as internalizing and externalizing disorders (with a slight nod to psychotic disorders in children), but these features do not seem prominent or ubiquitous in adult psychiatry’s thinking about adult psychiatric patients. They do a great job at pointing out there is ample evidence of a great deal of comorbidity between “discrete” children’s and adults’ psychiatric disorders. We certainly learned this from the findings of the DSM-5’s Personality and Personality Disorders Work Group.
Their p suggests a common thread between various childhood psychiatric disorders and adult psychiatric disorders. Furthermore, Dr. Caspi’s and Dr. Moffitt’s assertion that longitudinal research identifying “poor childhood self-control” (a symptom of affect dysregulation) and poor executive functioning as a salient early developmental predictor of their p sounds a lot like fetal alcohol exposure to me (Fetal Alcohol Exposure Among African Americans). So does their declaration that individuals with higher levels of p have difficulty with attention, concentration, mental control, and visual-motor problems.
Maybe I have confirmational bias, as I have seen the common thread of fetal alcohol exposure run from childhood to adults, but many of my residents and students see it as well.
Accordingly, I think we have made mistakes in psychiatry when we ask (if we ask) the mother of our patients was she drinking when she was pregnant, and “Was the patient born low-birth weight and/or premature?” We should be asking – “When did you realize you were pregnant?” “Were you doing any social drinking before you knew you were pregnant?” Thus, we miss the common thread of fetal alcohol exposure in child and adult psychopathology.
I realize that a great many competing interests are trying to get our time and attention, and there is a lot to read and figure out. In our efforts to do no harm, do psychiatrists try to take their time to fully understand things before we act? Some aspects of our understanding seem to be “no brainers,” and the continuation of child neurodevelopmental disorders morphing into adult mental disorders should be obvious. But maybe we took a wrong turn – which is why it took me 45 years to figure out that fetal alcohol exposure in utero has a significant impact on adult psychiatric disorders.
Dr. Bell is staff psychiatrist at Jackson Park Hospital’s surgical-medical/psychiatric inpatient unit; clinical professor emeritus, department of psychiatry, University of Illinois at Chicago; former director of the Institute for Juvenile Research; and former president/CEO of the Community Mental Health Council, all in Chicago. He also serves as chair of psychiatry at Windsor University, St. Kitts.
Maybe it is just me. It probably is. It seems I must have taken a wrong turn in practicing psychiatry somewhere along the line.
For whatever reason, I never truly saw and appreciated the seamlessness between the psychiatric problems children, adults, and the elderly have plaguing them. Of course, I always marveled at how a child who had honest-to-goodness autism could become a full-grown adult and have an adult psychiatrist diagnose that individual as having schizophrenia; why not an adult with autism? But that was the extent of my understanding of the seamlessness between childhood and adult diagnoses. Maybe it is because I was poorly trained and never bothered to get a childhood developmental from my adult psychiatric patients. When I would present a case to supervisors as an adult psychiatric resident, I recall never presenting a child developmental history as a part of the patient’s trajectory. It was as though since there was adult psychiatry and child psychiatry, then the disorders of adults and children should be separated as well.
I know many adult psychiatrists never ask their adult patients, “How old were you when you graduated high school?” although an answer of “I never graduated,” or I graduated at 19-20” should raise questions. When I was in community psychiatry residency, I had some training at the Institute for Juvenile Research (birthplace of child psychiatry), so I understood something about children and the problems they had. Of course, back then, child psychiatric diagnoses were not that good, but with the advent of the DSM-5, children’s psychiatric diagnoses became more precise. This was probably because of research and better epidemiologic data about the prevalence of the six major neurodevelopmental disorders (intellectual disability, attention-deficit/hyperactivity disorder, speech and language disorders, autism spectrum disorders, specific learning disorders, and motor disorders). Maybe I am too old to remember, but I don’t remember anyone with a serious focus on what happens to psychiatrically ill children when they grow up to be adults or what psychiatric problems adult psychiatric patients had when they were children.
In a brilliant article in the September issue of the American Journal of Psychiatry, Avshalom Caspi, PhD, and Terrie E. Moffitt, PhD, propose that there is a single dimension of psychopathology, or “p.”
The authors perceptively remind us that we characterize children’s psychopathology as internalizing and externalizing disorders (with a slight nod to psychotic disorders in children), but these features do not seem prominent or ubiquitous in adult psychiatry’s thinking about adult psychiatric patients. They do a great job at pointing out there is ample evidence of a great deal of comorbidity between “discrete” children’s and adults’ psychiatric disorders. We certainly learned this from the findings of the DSM-5’s Personality and Personality Disorders Work Group.
Their p suggests a common thread between various childhood psychiatric disorders and adult psychiatric disorders. Furthermore, Dr. Caspi’s and Dr. Moffitt’s assertion that longitudinal research identifying “poor childhood self-control” (a symptom of affect dysregulation) and poor executive functioning as a salient early developmental predictor of their p sounds a lot like fetal alcohol exposure to me (Fetal Alcohol Exposure Among African Americans). So does their declaration that individuals with higher levels of p have difficulty with attention, concentration, mental control, and visual-motor problems.
Maybe I have confirmational bias, as I have seen the common thread of fetal alcohol exposure run from childhood to adults, but many of my residents and students see it as well.
Accordingly, I think we have made mistakes in psychiatry when we ask (if we ask) the mother of our patients was she drinking when she was pregnant, and “Was the patient born low-birth weight and/or premature?” We should be asking – “When did you realize you were pregnant?” “Were you doing any social drinking before you knew you were pregnant?” Thus, we miss the common thread of fetal alcohol exposure in child and adult psychopathology.
I realize that a great many competing interests are trying to get our time and attention, and there is a lot to read and figure out. In our efforts to do no harm, do psychiatrists try to take their time to fully understand things before we act? Some aspects of our understanding seem to be “no brainers,” and the continuation of child neurodevelopmental disorders morphing into adult mental disorders should be obvious. But maybe we took a wrong turn – which is why it took me 45 years to figure out that fetal alcohol exposure in utero has a significant impact on adult psychiatric disorders.
Dr. Bell is staff psychiatrist at Jackson Park Hospital’s surgical-medical/psychiatric inpatient unit; clinical professor emeritus, department of psychiatry, University of Illinois at Chicago; former director of the Institute for Juvenile Research; and former president/CEO of the Community Mental Health Council, all in Chicago. He also serves as chair of psychiatry at Windsor University, St. Kitts.
Maybe it is just me. It probably is. It seems I must have taken a wrong turn in practicing psychiatry somewhere along the line.
For whatever reason, I never truly saw and appreciated the seamlessness between the psychiatric problems children, adults, and the elderly have plaguing them. Of course, I always marveled at how a child who had honest-to-goodness autism could become a full-grown adult and have an adult psychiatrist diagnose that individual as having schizophrenia; why not an adult with autism? But that was the extent of my understanding of the seamlessness between childhood and adult diagnoses. Maybe it is because I was poorly trained and never bothered to get a childhood developmental from my adult psychiatric patients. When I would present a case to supervisors as an adult psychiatric resident, I recall never presenting a child developmental history as a part of the patient’s trajectory. It was as though since there was adult psychiatry and child psychiatry, then the disorders of adults and children should be separated as well.
I know many adult psychiatrists never ask their adult patients, “How old were you when you graduated high school?” although an answer of “I never graduated,” or I graduated at 19-20” should raise questions. When I was in community psychiatry residency, I had some training at the Institute for Juvenile Research (birthplace of child psychiatry), so I understood something about children and the problems they had. Of course, back then, child psychiatric diagnoses were not that good, but with the advent of the DSM-5, children’s psychiatric diagnoses became more precise. This was probably because of research and better epidemiologic data about the prevalence of the six major neurodevelopmental disorders (intellectual disability, attention-deficit/hyperactivity disorder, speech and language disorders, autism spectrum disorders, specific learning disorders, and motor disorders). Maybe I am too old to remember, but I don’t remember anyone with a serious focus on what happens to psychiatrically ill children when they grow up to be adults or what psychiatric problems adult psychiatric patients had when they were children.
In a brilliant article in the September issue of the American Journal of Psychiatry, Avshalom Caspi, PhD, and Terrie E. Moffitt, PhD, propose that there is a single dimension of psychopathology, or “p.”
The authors perceptively remind us that we characterize children’s psychopathology as internalizing and externalizing disorders (with a slight nod to psychotic disorders in children), but these features do not seem prominent or ubiquitous in adult psychiatry’s thinking about adult psychiatric patients. They do a great job at pointing out there is ample evidence of a great deal of comorbidity between “discrete” children’s and adults’ psychiatric disorders. We certainly learned this from the findings of the DSM-5’s Personality and Personality Disorders Work Group.
Their p suggests a common thread between various childhood psychiatric disorders and adult psychiatric disorders. Furthermore, Dr. Caspi’s and Dr. Moffitt’s assertion that longitudinal research identifying “poor childhood self-control” (a symptom of affect dysregulation) and poor executive functioning as a salient early developmental predictor of their p sounds a lot like fetal alcohol exposure to me (Fetal Alcohol Exposure Among African Americans). So does their declaration that individuals with higher levels of p have difficulty with attention, concentration, mental control, and visual-motor problems.
Maybe I have confirmational bias, as I have seen the common thread of fetal alcohol exposure run from childhood to adults, but many of my residents and students see it as well.
Accordingly, I think we have made mistakes in psychiatry when we ask (if we ask) the mother of our patients was she drinking when she was pregnant, and “Was the patient born low-birth weight and/or premature?” We should be asking – “When did you realize you were pregnant?” “Were you doing any social drinking before you knew you were pregnant?” Thus, we miss the common thread of fetal alcohol exposure in child and adult psychopathology.
I realize that a great many competing interests are trying to get our time and attention, and there is a lot to read and figure out. In our efforts to do no harm, do psychiatrists try to take their time to fully understand things before we act? Some aspects of our understanding seem to be “no brainers,” and the continuation of child neurodevelopmental disorders morphing into adult mental disorders should be obvious. But maybe we took a wrong turn – which is why it took me 45 years to figure out that fetal alcohol exposure in utero has a significant impact on adult psychiatric disorders.
Dr. Bell is staff psychiatrist at Jackson Park Hospital’s surgical-medical/psychiatric inpatient unit; clinical professor emeritus, department of psychiatry, University of Illinois at Chicago; former director of the Institute for Juvenile Research; and former president/CEO of the Community Mental Health Council, all in Chicago. He also serves as chair of psychiatry at Windsor University, St. Kitts.
FDA authorizes ClonoSEQ to detect MRD in ALL, myeloma
, the U.S. Food and Drug Administration announced. Marketing authorization of the ClonoSEQ assay was granted to Adaptive Biotechnologies.
The ClonoSEQ assay is an in vitro diagnostic test that uses multiplex polymerase chain reaction and next-generation sequencing to identify and quantify certain gene sequences in DNA extracted from the bone marrow from patients with ALL or multiple myeloma. This is a single-site assay collected by the patient’s provider and sent to Adaptive Biotechnologies for evaluation.
The ClonoSEQ assay is capable of detecting minimal residual disease at levels below 1 in 1 million cells. Currently, providers test for MRD using flow cytometry assays or polymerase chain reaction–based assays. Those methods are usually capable of measuring MRD down to 1 in 10,000 or 1 in 100,000 cells.
“Determining whether a patient has residual cancer cells remaining after treatment provides information on how well a patient has responded to therapy and how long remission may last. Having a highly sensitive test available to measure minimal residual disease in ALL or multiple myeloma patients can help providers manage their patients’ care,” FDA Commissioner Scott Gottlieb, MD, said in a press release.
Along with this authorization, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the accuracy, reliability, and effectiveness of tests intended to be used as an aid to measure MRD to assess the change in burden of disease during and after treatment. These special controls, when met along with general controls, provide a reasonable assurance of safety and effectiveness for these tests, the agency said in the release. This action also creates a new regulatory classification, which means that subsequent devices of the same type with the same intended use may go through the FDA’s 510(k) process, whereby devices can obtain marketing authorization by demonstrating substantial equivalence to a previously approved device.
“The FDA is applying novel regulatory approaches to make sure that these rapidly evolving [next-generation sequencing] tests are accurate and reliable. At the same time, we’re seeing more and more laboratory-developed tests seek marketing authorization from the FDA,” he said, adding that the agency has put forward a plan to modernize the regulatory framework for all in vitro clinical tests.
The FDA evaluated data to demonstrate clinical validity from a retrospective analysis of samples obtained from three previously conducted clinical studies including 273 patients with ALL, an ongoing study of 323 patients with multiple myeloma, and a study of 706 patients with multiple myeloma, according to the FDA release.
For patients with ALL, the ClonoSEQ assay was used to assess MRD at various disease burden thresholds to show that the MRD level correlated with event-free survival – the length of time, after treatment, that the patient remains free of certain complications or events. Patients whose ClonoSEQ assay result was MRD negative had longer event-free survival, while patients with higher MRD assay results had lower event-free survival. Similar patterns of results were seen for progression-free and disease-free survival in patients with multiple myeloma.
, the U.S. Food and Drug Administration announced. Marketing authorization of the ClonoSEQ assay was granted to Adaptive Biotechnologies.
The ClonoSEQ assay is an in vitro diagnostic test that uses multiplex polymerase chain reaction and next-generation sequencing to identify and quantify certain gene sequences in DNA extracted from the bone marrow from patients with ALL or multiple myeloma. This is a single-site assay collected by the patient’s provider and sent to Adaptive Biotechnologies for evaluation.
The ClonoSEQ assay is capable of detecting minimal residual disease at levels below 1 in 1 million cells. Currently, providers test for MRD using flow cytometry assays or polymerase chain reaction–based assays. Those methods are usually capable of measuring MRD down to 1 in 10,000 or 1 in 100,000 cells.
“Determining whether a patient has residual cancer cells remaining after treatment provides information on how well a patient has responded to therapy and how long remission may last. Having a highly sensitive test available to measure minimal residual disease in ALL or multiple myeloma patients can help providers manage their patients’ care,” FDA Commissioner Scott Gottlieb, MD, said in a press release.
Along with this authorization, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the accuracy, reliability, and effectiveness of tests intended to be used as an aid to measure MRD to assess the change in burden of disease during and after treatment. These special controls, when met along with general controls, provide a reasonable assurance of safety and effectiveness for these tests, the agency said in the release. This action also creates a new regulatory classification, which means that subsequent devices of the same type with the same intended use may go through the FDA’s 510(k) process, whereby devices can obtain marketing authorization by demonstrating substantial equivalence to a previously approved device.
“The FDA is applying novel regulatory approaches to make sure that these rapidly evolving [next-generation sequencing] tests are accurate and reliable. At the same time, we’re seeing more and more laboratory-developed tests seek marketing authorization from the FDA,” he said, adding that the agency has put forward a plan to modernize the regulatory framework for all in vitro clinical tests.
The FDA evaluated data to demonstrate clinical validity from a retrospective analysis of samples obtained from three previously conducted clinical studies including 273 patients with ALL, an ongoing study of 323 patients with multiple myeloma, and a study of 706 patients with multiple myeloma, according to the FDA release.
For patients with ALL, the ClonoSEQ assay was used to assess MRD at various disease burden thresholds to show that the MRD level correlated with event-free survival – the length of time, after treatment, that the patient remains free of certain complications or events. Patients whose ClonoSEQ assay result was MRD negative had longer event-free survival, while patients with higher MRD assay results had lower event-free survival. Similar patterns of results were seen for progression-free and disease-free survival in patients with multiple myeloma.
, the U.S. Food and Drug Administration announced. Marketing authorization of the ClonoSEQ assay was granted to Adaptive Biotechnologies.
The ClonoSEQ assay is an in vitro diagnostic test that uses multiplex polymerase chain reaction and next-generation sequencing to identify and quantify certain gene sequences in DNA extracted from the bone marrow from patients with ALL or multiple myeloma. This is a single-site assay collected by the patient’s provider and sent to Adaptive Biotechnologies for evaluation.
The ClonoSEQ assay is capable of detecting minimal residual disease at levels below 1 in 1 million cells. Currently, providers test for MRD using flow cytometry assays or polymerase chain reaction–based assays. Those methods are usually capable of measuring MRD down to 1 in 10,000 or 1 in 100,000 cells.
“Determining whether a patient has residual cancer cells remaining after treatment provides information on how well a patient has responded to therapy and how long remission may last. Having a highly sensitive test available to measure minimal residual disease in ALL or multiple myeloma patients can help providers manage their patients’ care,” FDA Commissioner Scott Gottlieb, MD, said in a press release.
Along with this authorization, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the accuracy, reliability, and effectiveness of tests intended to be used as an aid to measure MRD to assess the change in burden of disease during and after treatment. These special controls, when met along with general controls, provide a reasonable assurance of safety and effectiveness for these tests, the agency said in the release. This action also creates a new regulatory classification, which means that subsequent devices of the same type with the same intended use may go through the FDA’s 510(k) process, whereby devices can obtain marketing authorization by demonstrating substantial equivalence to a previously approved device.
“The FDA is applying novel regulatory approaches to make sure that these rapidly evolving [next-generation sequencing] tests are accurate and reliable. At the same time, we’re seeing more and more laboratory-developed tests seek marketing authorization from the FDA,” he said, adding that the agency has put forward a plan to modernize the regulatory framework for all in vitro clinical tests.
The FDA evaluated data to demonstrate clinical validity from a retrospective analysis of samples obtained from three previously conducted clinical studies including 273 patients with ALL, an ongoing study of 323 patients with multiple myeloma, and a study of 706 patients with multiple myeloma, according to the FDA release.
For patients with ALL, the ClonoSEQ assay was used to assess MRD at various disease burden thresholds to show that the MRD level correlated with event-free survival – the length of time, after treatment, that the patient remains free of certain complications or events. Patients whose ClonoSEQ assay result was MRD negative had longer event-free survival, while patients with higher MRD assay results had lower event-free survival. Similar patterns of results were seen for progression-free and disease-free survival in patients with multiple myeloma.
First NGS assay approved for MRD detection in ALL or MM
The U.S. Food and Drug Administration has authorized the first next-generation sequencing (NGS)-based assay to be marketed for minimal residual disease (MRD) testing in patients with acute lymphoblastic leukemia (ALL) or multiple myeloma (MM).
The assay, called clonoSEQ®, uses both polymerase chain reaction (PCR) and NGS to identify and quantify gene sequences in DNA from patients’ bone marrow.
ClonoSEQ Assay can detect MRD levels below 1 in 1 million cells. By comparison flow cytometry assays or PCR-based assays are capable of measuring MRD down to 1 in 10,000 or 1 in 100,000 cells.
The clonoSEQ Assay is marketed by Adaptive Biotechnologies.
The FDA based its authorization on data from three clinical studies, one with 273 ALL patients, an ongoing study of 323 MM patients, and another MM trial with 706 patients.
Validation in ALL
As described in the clonoSEQ Assay Technical Information, a subset of 273 patients originally enrolled in the Children’s Oncology Group AALL0232 (NCT00075725) and AALL0331 (NCT00103285) studies had left-over bone marrow specimens to evaluate the performance of the clonoSEQ Assay.
MRD as determined by MRD negativity at less than 10-4 predicted improved event-free survival (EFS) irrespective of age. MRD-positive patients had a 2.74 higher event risk compared to MRD-negative patients.
Similar findings between MRD negativity and EFS in pediatric ALL using an earlier version of the assay were published in Blood.
Validation in MM
The ongoing phase 3 DFCI Study 10-106 (NCT01208662) is comparing conventional treatment with lenalidomide, bortezomib and dexamethasone to high-dose treatment with stem cell transplant as initial management of MM patients less than 65 years.
According to clonoSEQ’s technical information, bone marrow samples from 323 of the 720 patients originally enrolled were available and evaluable for MRD assessment.
ClonoSEQ measurements demonstrated that MRD status at a threshold of 10-5 significantly predicts progression-free survival (PFS) in all patients (P=0.027).
And samples from 75 patients who had achieved complete remission (CR) showed a modest association with disease-free survival (DFS) and lower MRD levels (P=0.064).
In the phase 3 ALCYONE trial, investigators randomly assigned 706 treatment-naïve MM patients ineligible for hematopoietic stem cell transplant to bortezomib, melphalan, and prednisone with or without daratumumab.
MRD assessments were made using the clonoSEQ Assay at screening, at confirmation of CR or stringent CR, and at intervals after patients achieved a CR.
Patients who did not achieve CR were considered MRD positive. The threshold for the MRD analysis was 10-5.
Investigators found that patients who were MRD negative by the clonoSEQ Assay had longer PFS compared to MRD-positive patients, regardless of treatment group.
For additional information on the clonoSEQ Assay consult the Technical Information available online.
The U.S. Food and Drug Administration has authorized the first next-generation sequencing (NGS)-based assay to be marketed for minimal residual disease (MRD) testing in patients with acute lymphoblastic leukemia (ALL) or multiple myeloma (MM).
The assay, called clonoSEQ®, uses both polymerase chain reaction (PCR) and NGS to identify and quantify gene sequences in DNA from patients’ bone marrow.
ClonoSEQ Assay can detect MRD levels below 1 in 1 million cells. By comparison flow cytometry assays or PCR-based assays are capable of measuring MRD down to 1 in 10,000 or 1 in 100,000 cells.
The clonoSEQ Assay is marketed by Adaptive Biotechnologies.
The FDA based its authorization on data from three clinical studies, one with 273 ALL patients, an ongoing study of 323 MM patients, and another MM trial with 706 patients.
Validation in ALL
As described in the clonoSEQ Assay Technical Information, a subset of 273 patients originally enrolled in the Children’s Oncology Group AALL0232 (NCT00075725) and AALL0331 (NCT00103285) studies had left-over bone marrow specimens to evaluate the performance of the clonoSEQ Assay.
MRD as determined by MRD negativity at less than 10-4 predicted improved event-free survival (EFS) irrespective of age. MRD-positive patients had a 2.74 higher event risk compared to MRD-negative patients.
Similar findings between MRD negativity and EFS in pediatric ALL using an earlier version of the assay were published in Blood.
Validation in MM
The ongoing phase 3 DFCI Study 10-106 (NCT01208662) is comparing conventional treatment with lenalidomide, bortezomib and dexamethasone to high-dose treatment with stem cell transplant as initial management of MM patients less than 65 years.
According to clonoSEQ’s technical information, bone marrow samples from 323 of the 720 patients originally enrolled were available and evaluable for MRD assessment.
ClonoSEQ measurements demonstrated that MRD status at a threshold of 10-5 significantly predicts progression-free survival (PFS) in all patients (P=0.027).
And samples from 75 patients who had achieved complete remission (CR) showed a modest association with disease-free survival (DFS) and lower MRD levels (P=0.064).
In the phase 3 ALCYONE trial, investigators randomly assigned 706 treatment-naïve MM patients ineligible for hematopoietic stem cell transplant to bortezomib, melphalan, and prednisone with or without daratumumab.
MRD assessments were made using the clonoSEQ Assay at screening, at confirmation of CR or stringent CR, and at intervals after patients achieved a CR.
Patients who did not achieve CR were considered MRD positive. The threshold for the MRD analysis was 10-5.
Investigators found that patients who were MRD negative by the clonoSEQ Assay had longer PFS compared to MRD-positive patients, regardless of treatment group.
For additional information on the clonoSEQ Assay consult the Technical Information available online.
The U.S. Food and Drug Administration has authorized the first next-generation sequencing (NGS)-based assay to be marketed for minimal residual disease (MRD) testing in patients with acute lymphoblastic leukemia (ALL) or multiple myeloma (MM).
The assay, called clonoSEQ®, uses both polymerase chain reaction (PCR) and NGS to identify and quantify gene sequences in DNA from patients’ bone marrow.
ClonoSEQ Assay can detect MRD levels below 1 in 1 million cells. By comparison flow cytometry assays or PCR-based assays are capable of measuring MRD down to 1 in 10,000 or 1 in 100,000 cells.
The clonoSEQ Assay is marketed by Adaptive Biotechnologies.
The FDA based its authorization on data from three clinical studies, one with 273 ALL patients, an ongoing study of 323 MM patients, and another MM trial with 706 patients.
Validation in ALL
As described in the clonoSEQ Assay Technical Information, a subset of 273 patients originally enrolled in the Children’s Oncology Group AALL0232 (NCT00075725) and AALL0331 (NCT00103285) studies had left-over bone marrow specimens to evaluate the performance of the clonoSEQ Assay.
MRD as determined by MRD negativity at less than 10-4 predicted improved event-free survival (EFS) irrespective of age. MRD-positive patients had a 2.74 higher event risk compared to MRD-negative patients.
Similar findings between MRD negativity and EFS in pediatric ALL using an earlier version of the assay were published in Blood.
Validation in MM
The ongoing phase 3 DFCI Study 10-106 (NCT01208662) is comparing conventional treatment with lenalidomide, bortezomib and dexamethasone to high-dose treatment with stem cell transplant as initial management of MM patients less than 65 years.
According to clonoSEQ’s technical information, bone marrow samples from 323 of the 720 patients originally enrolled were available and evaluable for MRD assessment.
ClonoSEQ measurements demonstrated that MRD status at a threshold of 10-5 significantly predicts progression-free survival (PFS) in all patients (P=0.027).
And samples from 75 patients who had achieved complete remission (CR) showed a modest association with disease-free survival (DFS) and lower MRD levels (P=0.064).
In the phase 3 ALCYONE trial, investigators randomly assigned 706 treatment-naïve MM patients ineligible for hematopoietic stem cell transplant to bortezomib, melphalan, and prednisone with or without daratumumab.
MRD assessments were made using the clonoSEQ Assay at screening, at confirmation of CR or stringent CR, and at intervals after patients achieved a CR.
Patients who did not achieve CR were considered MRD positive. The threshold for the MRD analysis was 10-5.
Investigators found that patients who were MRD negative by the clonoSEQ Assay had longer PFS compared to MRD-positive patients, regardless of treatment group.
For additional information on the clonoSEQ Assay consult the Technical Information available online.
Behavioral checklist IDs children at risk of depressive, anxiety disorders
disorders in later adolescent or adult life, according to research published in the Journal of Pediatrics.
“If confirmed, this observation could have very significant clinical and public health implications in the identification of children at the highest risk for the development of major depressive disorder,” Mai Uchida, MD, of the department of psychiatry at Massachusetts General Hospital in Boston, and colleagues wrote. “Early identification is the first step toward effectively allocating limited societal resources to help prevent illness progression and its associated impairments in children most in need.”
Dr. Uchida and her colleagues analyzed a sample of 537 children aged 6-17 years from two longitudinal studies of children and their parents with and without ADHD, excluding the ADHD probands in their analysis. Parents answered the CBCL, which consisted of behavioral questions translated into scores for subscales involving being anxious and/or depressed, withdrawn and/or depressed, social problems, thought problems, aggressive behavior, rule-breaking behavior, attention problems, and somatic complaints.
The sample was then divided into four groups; there were 172 children with parents who had a mood disorder but the children did not have CBCL anxiety/depression subsyndromal elevations (high risk group); 22 children without a parental history of mood disorder but had CBCL anxiety/depression subsyndromal elevations (subsyndromal major depressive disorder); 22 children with a parental history of mood disorder and CBCL anxiety/depression subsyndromal elevations (high-risk and subsyndromal major depressive disorder); and 186 children in a control group with no parental history of mood disorder or CBCL anxiety/depression subsyndromal elevations.
Compared with the control group, children with a history of parental mood disorders and children with baseline CBCL anxiety/depression subsyndromal elevations had intermediate risk of developing major depression and anxiety disorders. However, the highest risk was among children with both a parental history of mood disorder and baseline CBCL anxiety/depression subsyndromal elevations.
Using data from two previously collected longitudinal studies was a potential limitation of the study, Dr. Uchida and her associates said, but they noted the CBCL scale has predictive utility for identifying anxiety and depressive disorders in children later in life.
“Considering its simplicity, strong psychometric properties, and limited cost, the CBCL scale lends itself to be used by health professionals and educators in the community,” they wrote.
This study was partly supported by National Institutes of Health and the Massachusetts General Hospital Pediatric Psychopharmacology Council Fund. Joseph Biederman, MD, received research support from Lundbeck AS, Neurocentria, Pfizer, Shire, Sunovion, and others, and has relationships with multiple other associations and pharmaceutical companies. The other authors have no relevant financial disclosures.
SOURCE: Uchida M et al. J Pediatr. 2018 Oct;201:252-8.
disorders in later adolescent or adult life, according to research published in the Journal of Pediatrics.
“If confirmed, this observation could have very significant clinical and public health implications in the identification of children at the highest risk for the development of major depressive disorder,” Mai Uchida, MD, of the department of psychiatry at Massachusetts General Hospital in Boston, and colleagues wrote. “Early identification is the first step toward effectively allocating limited societal resources to help prevent illness progression and its associated impairments in children most in need.”
Dr. Uchida and her colleagues analyzed a sample of 537 children aged 6-17 years from two longitudinal studies of children and their parents with and without ADHD, excluding the ADHD probands in their analysis. Parents answered the CBCL, which consisted of behavioral questions translated into scores for subscales involving being anxious and/or depressed, withdrawn and/or depressed, social problems, thought problems, aggressive behavior, rule-breaking behavior, attention problems, and somatic complaints.
The sample was then divided into four groups; there were 172 children with parents who had a mood disorder but the children did not have CBCL anxiety/depression subsyndromal elevations (high risk group); 22 children without a parental history of mood disorder but had CBCL anxiety/depression subsyndromal elevations (subsyndromal major depressive disorder); 22 children with a parental history of mood disorder and CBCL anxiety/depression subsyndromal elevations (high-risk and subsyndromal major depressive disorder); and 186 children in a control group with no parental history of mood disorder or CBCL anxiety/depression subsyndromal elevations.
Compared with the control group, children with a history of parental mood disorders and children with baseline CBCL anxiety/depression subsyndromal elevations had intermediate risk of developing major depression and anxiety disorders. However, the highest risk was among children with both a parental history of mood disorder and baseline CBCL anxiety/depression subsyndromal elevations.
Using data from two previously collected longitudinal studies was a potential limitation of the study, Dr. Uchida and her associates said, but they noted the CBCL scale has predictive utility for identifying anxiety and depressive disorders in children later in life.
“Considering its simplicity, strong psychometric properties, and limited cost, the CBCL scale lends itself to be used by health professionals and educators in the community,” they wrote.
This study was partly supported by National Institutes of Health and the Massachusetts General Hospital Pediatric Psychopharmacology Council Fund. Joseph Biederman, MD, received research support from Lundbeck AS, Neurocentria, Pfizer, Shire, Sunovion, and others, and has relationships with multiple other associations and pharmaceutical companies. The other authors have no relevant financial disclosures.
SOURCE: Uchida M et al. J Pediatr. 2018 Oct;201:252-8.
disorders in later adolescent or adult life, according to research published in the Journal of Pediatrics.
“If confirmed, this observation could have very significant clinical and public health implications in the identification of children at the highest risk for the development of major depressive disorder,” Mai Uchida, MD, of the department of psychiatry at Massachusetts General Hospital in Boston, and colleagues wrote. “Early identification is the first step toward effectively allocating limited societal resources to help prevent illness progression and its associated impairments in children most in need.”
Dr. Uchida and her colleagues analyzed a sample of 537 children aged 6-17 years from two longitudinal studies of children and their parents with and without ADHD, excluding the ADHD probands in their analysis. Parents answered the CBCL, which consisted of behavioral questions translated into scores for subscales involving being anxious and/or depressed, withdrawn and/or depressed, social problems, thought problems, aggressive behavior, rule-breaking behavior, attention problems, and somatic complaints.
The sample was then divided into four groups; there were 172 children with parents who had a mood disorder but the children did not have CBCL anxiety/depression subsyndromal elevations (high risk group); 22 children without a parental history of mood disorder but had CBCL anxiety/depression subsyndromal elevations (subsyndromal major depressive disorder); 22 children with a parental history of mood disorder and CBCL anxiety/depression subsyndromal elevations (high-risk and subsyndromal major depressive disorder); and 186 children in a control group with no parental history of mood disorder or CBCL anxiety/depression subsyndromal elevations.
Compared with the control group, children with a history of parental mood disorders and children with baseline CBCL anxiety/depression subsyndromal elevations had intermediate risk of developing major depression and anxiety disorders. However, the highest risk was among children with both a parental history of mood disorder and baseline CBCL anxiety/depression subsyndromal elevations.
Using data from two previously collected longitudinal studies was a potential limitation of the study, Dr. Uchida and her associates said, but they noted the CBCL scale has predictive utility for identifying anxiety and depressive disorders in children later in life.
“Considering its simplicity, strong psychometric properties, and limited cost, the CBCL scale lends itself to be used by health professionals and educators in the community,” they wrote.
This study was partly supported by National Institutes of Health and the Massachusetts General Hospital Pediatric Psychopharmacology Council Fund. Joseph Biederman, MD, received research support from Lundbeck AS, Neurocentria, Pfizer, Shire, Sunovion, and others, and has relationships with multiple other associations and pharmaceutical companies. The other authors have no relevant financial disclosures.
SOURCE: Uchida M et al. J Pediatr. 2018 Oct;201:252-8.
FROM THE JOURNAL OF PEDIATRICS
Key clinical point: Children with elevated CBCL anxiety/depression scale scores at baseline as well as a parent with a major depressive disorder were at risk of developing a major depressive disorder or anxiety disorder at 10-year follow-up.
Major finding:
Study details: An analysis of 537 children in a sample from two longitudinal case studies of families with and without child and parental history of ADHD.
Disclosures: This study was partly supported by National Institutes of Health and the Massachusetts General Hospital Pediatric Psychopharmacology Council Fund. Joseph Biederman, MD, received research support from Neurocentria, Pfizer, Shire, Sunovion, and others, and has relationships with multiple other associations and pharmaceutical companies. The other authors have no relevant financial disclosures.
Source: Uchida M et al. J Pediatr. 2018 Oct;201:252-8.
Admission eosinopenia predicted severe CDI outcomes
For patients with even in the absence of hypotension and tachycardia, researchers wrote in JAMA Surgery.
“In animal models, peripheral eosinopenia is a biologically plausible predictive factor for adverse outcomes, and human data from this study indicate that this frequent addition to an admission complete blood cell count is an inexpensive, widely available risk index in the treatment of C. difficile infection,” wrote Audrey S. Kulaylat, MD, of Penn State University, Hershey, and her associates.
In their cohort study of 2,065 patients admitted to two tertiary referral centers with C. difficile infection, undetectable eosinophil counts at hospital admission were associated with significantly increased odds of in-hospital mortality in both a training dataset (odds ratio, 2.01; 95% confidence interval, 1.08-3.73; P = .03) and a validation dataset (OR, 2.26; 95% CI, 1.33-3.83; P = .002). Undetectable eosinophil counts also were associated with elevated odds of severe disease requiring intensive care, vasopressor use, and emergency total colectomy. Besides eosinopenia, significant predictors of mortality included having more comorbidities and lower systolic blood pressure at admission. Strikingly, when patients had no initial hypotension or tachycardia, an undetectable eosinophil count was the only identifiable predictor of in-hospital death (OR, 5.76; 95% CI, 1.99-16.64). An elevated white blood cell count was not a significant predictor of mortality in this subgroup.
Dr. Kulaylat and her associates are studying the microbiome in C. difficile infection. Their work has identified a host immune reaction marked by an “exaggerated inflammasome response” and peripheral eosinopenia, they explained. Two recent murine models have produced similar results.
Admission eosinophil counts “allow for an immediate assessment of mortality risk at admission that is inexpensive and part of a differential for a standard complete blood count available at any hospital,” they concluded. They are now prospectively evaluating a prognostic score for C. difficile infection that includes eosinopenia and other easily discernible admission factors. The National Institutes of Health supported the work. The researchers reported having no conflicts of interest.
SOURCE: Kulaylat AS et al. JAMA Surg. 2018 Sep 12. doi: 10.1001/jamasurg.2018.3174.
For patients with even in the absence of hypotension and tachycardia, researchers wrote in JAMA Surgery.
“In animal models, peripheral eosinopenia is a biologically plausible predictive factor for adverse outcomes, and human data from this study indicate that this frequent addition to an admission complete blood cell count is an inexpensive, widely available risk index in the treatment of C. difficile infection,” wrote Audrey S. Kulaylat, MD, of Penn State University, Hershey, and her associates.
In their cohort study of 2,065 patients admitted to two tertiary referral centers with C. difficile infection, undetectable eosinophil counts at hospital admission were associated with significantly increased odds of in-hospital mortality in both a training dataset (odds ratio, 2.01; 95% confidence interval, 1.08-3.73; P = .03) and a validation dataset (OR, 2.26; 95% CI, 1.33-3.83; P = .002). Undetectable eosinophil counts also were associated with elevated odds of severe disease requiring intensive care, vasopressor use, and emergency total colectomy. Besides eosinopenia, significant predictors of mortality included having more comorbidities and lower systolic blood pressure at admission. Strikingly, when patients had no initial hypotension or tachycardia, an undetectable eosinophil count was the only identifiable predictor of in-hospital death (OR, 5.76; 95% CI, 1.99-16.64). An elevated white blood cell count was not a significant predictor of mortality in this subgroup.
Dr. Kulaylat and her associates are studying the microbiome in C. difficile infection. Their work has identified a host immune reaction marked by an “exaggerated inflammasome response” and peripheral eosinopenia, they explained. Two recent murine models have produced similar results.
Admission eosinophil counts “allow for an immediate assessment of mortality risk at admission that is inexpensive and part of a differential for a standard complete blood count available at any hospital,” they concluded. They are now prospectively evaluating a prognostic score for C. difficile infection that includes eosinopenia and other easily discernible admission factors. The National Institutes of Health supported the work. The researchers reported having no conflicts of interest.
SOURCE: Kulaylat AS et al. JAMA Surg. 2018 Sep 12. doi: 10.1001/jamasurg.2018.3174.
For patients with even in the absence of hypotension and tachycardia, researchers wrote in JAMA Surgery.
“In animal models, peripheral eosinopenia is a biologically plausible predictive factor for adverse outcomes, and human data from this study indicate that this frequent addition to an admission complete blood cell count is an inexpensive, widely available risk index in the treatment of C. difficile infection,” wrote Audrey S. Kulaylat, MD, of Penn State University, Hershey, and her associates.
In their cohort study of 2,065 patients admitted to two tertiary referral centers with C. difficile infection, undetectable eosinophil counts at hospital admission were associated with significantly increased odds of in-hospital mortality in both a training dataset (odds ratio, 2.01; 95% confidence interval, 1.08-3.73; P = .03) and a validation dataset (OR, 2.26; 95% CI, 1.33-3.83; P = .002). Undetectable eosinophil counts also were associated with elevated odds of severe disease requiring intensive care, vasopressor use, and emergency total colectomy. Besides eosinopenia, significant predictors of mortality included having more comorbidities and lower systolic blood pressure at admission. Strikingly, when patients had no initial hypotension or tachycardia, an undetectable eosinophil count was the only identifiable predictor of in-hospital death (OR, 5.76; 95% CI, 1.99-16.64). An elevated white blood cell count was not a significant predictor of mortality in this subgroup.
Dr. Kulaylat and her associates are studying the microbiome in C. difficile infection. Their work has identified a host immune reaction marked by an “exaggerated inflammasome response” and peripheral eosinopenia, they explained. Two recent murine models have produced similar results.
Admission eosinophil counts “allow for an immediate assessment of mortality risk at admission that is inexpensive and part of a differential for a standard complete blood count available at any hospital,” they concluded. They are now prospectively evaluating a prognostic score for C. difficile infection that includes eosinopenia and other easily discernible admission factors. The National Institutes of Health supported the work. The researchers reported having no conflicts of interest.
SOURCE: Kulaylat AS et al. JAMA Surg. 2018 Sep 12. doi: 10.1001/jamasurg.2018.3174.
FROM JAMA SURGERY
Key clinical point: Undetectable peripheral eosinophils predicted severe outcomes in patients admitted with Clostridium difficile infection.
Major finding: In the training and validation datasets, odds of in-hospital mortality were 2.01 (95% CI, 1.08-3.73) and 2.26 (95% CI, 1.33-3.83), respectively.
Study details: Two-hospital cohort study of 2,065 patients admitted with C. difficile infection.
Disclosures: The National Institutes of Health supported the work. The researchers reported having no conflicts of interest.
Source: Kulaylat A et al. JAMA Surg. 2018 Sep 12. doi: 10.1001/jamasurg.2018.3174.
Advances in precision medicine help refine – and redefine – cancer care
Among the groundbreaking findings presented at this year’s annual meeting of the American Society of Clinical Oncology were those showing that most women with HR-positive, HER2-negative, early-stage breast cancer who have an intermediate recurrence score can safely skip adjuvant chemotherapy, and that upfront pembrolizumab for patients with NSCLC expressing PD-L1 on at least 1% of tumor cells can not only significantly improve overall survival, but do so with less toxicity than standard chemotherapy.
TAILORx marks major advance for precision medicine in breast cancer
Key clinical point The majority of women with HR-positive, HER2-negative, node-negative early-stage breast cancer who have an intermediate recurrence score can safely skip adjuvant chemotherapy. Major finding In women with an Oncotype DX Recurrence Score in the midrange (11-25), invasive DFS with endocrine therapy alone was not inferior to that with chemotherapy plus endocrine therapy (HR, 1.08; P = .26). Study details A phase 3 trial in 10,273 women with HR-positive, HER2-negative, node-negative, early-stage breast cancer, with a noninferiority randomized component in the 6,711 women with a midrange recurrence score (TAILORx trial). Funding This study received funding primarily from the National Cancer Institute, National Institutes of Health. Additional support was provided by the Breast Cancer Research Foundation, Komen Foundation, and US Postal Service Breast Cancer Stamp. Disclosures Dr Sparano disclosed that he has a consulting or advisory role with Genentech/Roche, Novartis, AstraZeneca, Celgene, Lilly, Celldex, Pfizer, Prescient Therapeutics, Juno Therapeutics, and Merrimack; has stock or other ownership interests with MetaStat; and receives research funding (institutional) from Prescient Therapeutics, Deciphera, Genentech/Roche, Merck, Novartis, and Merrimack. Source Sparano et al. ASCO 2018 Abstract LBA1: https://meetinglibrary.asco.org/record/161490/abstract
Use of the 21-tumor gene expression assay (Oncotype DX Recurrence Score) allows nearly 70% of women with hormone receptor-positive, HER2-negative, node-negative, early-stage breast cancer to safely forgo adjuvant chemotherapy, sparing them adverse effects and preventing overtreatment, TAILORx trial results show.
The findings, which were reported in the plenary session at the meeting and simultaneously published in the New England Journal of Medicine (N Engl J Med. 2018; 379:111-121; [behind paywall]), mark a major advance in precision medicine.
“The rationale for the TAILORx precision medicine trial is that we are really trying to ‘thread the needle,’ “ lead study author Joseph A Sparano, MD, commented in a press briefing. Oncologists typically recommend adjuvant chemotherapy for the half of all breast cancers that are hormone receptor positive, HER2 negative, and node negative, even though its absolute benefit in reducing recurrences in this population is small. “This results in most patients being overtreated because endocrine therapy alone is adequate. But some are undertreated: They do not receive chemotherapy although they could have benefited from it,” he noted.
The recurrence score is known to be prognostic and predictive of benefit from adding chemotherapy to endocrine therapy, Dr Sparano said. “But there was a major gap: There was uncertain benefit for patients who had a midrange score, which is about two-thirds of all patients who are treated,” said Dr Sparano, the associate director for clinical research at Albert Einstein Cancer Center and Montefiore Health System in New York, and vice-chair of the ECOG-ACRIN Cancer Research Group.
The phase 3 TAILORx trial registered 10,273 women with hormone receptor-positive, HER2-negative, node-negative, early-stage breast cancer, making it the largest adjuvant breast cancer trial to date. Analyses focused on the 6,711 evaluable women with a midrange recurrence score (defined as 11 through 25 in the trial), who were randomized to receive endocrine therapy alone or adjuvant chemotherapy plus endocrine therapy, with a noninferiority design. Of note is that contemporary drugs and regimens were used.
Results at a median follow-up of 7.5 years showed that the trial met its primary endpoint: the risk of invasive disease-free survival (DFS) events (invasive disease recurrence, second primary cancer, or death) was not inferior for women given endocrine therapy alone compared with counterparts given chemotherapy plus endocrine therapy (hazard ratio [HR], 1.08; P = .26), Dr Sparano reported.
The groups were also on par, with absolute differences of no more than 1% between rates, with respect to a variety of other efficacy outcomes: freedom from distant recurrence and any recurrence, and overall survival (OS).
Findings were similar across most subgroups. But analyses suggested that women aged 50 years and younger and who had a recurrence score of 16-25 fared better when they received chemotherapy. “Though exploratory from a statistical perspective, this is a highly clinically relevant observation,” Dr Sparano said. “It suggests ... that chemotherapy should be spared with caution in this subgroup, after a careful discussion of potential benefits and risks in a shared decision process.”
In other findings, analyses of the trial’s nonrandomized groups confirmed excellent outcomes in women with a low recurrence score (0-10) who were given endocrine therapy alone, and at the other end of the spectrum, there was need for a more aggressive approach, including chemotherapy, in women with a high recurrence score (26-100).
Ultimately, application of the recurrence score allowed 69% of the trial population to skip chemotherapy: all of the women with a score of 0-10 (16% of the trial population), those older than 50 years with a score of 11-25 (45%), and those aged 50 years or younger with a score of 11-15 (8%).
An ongoing companion phase 3 trial, RxPONDER, is assessing the benefit of applying the recurrence score in women who are similar but ihave node-positive disease.
Study details
All of the women with hormone receptor-positive, HER2-negative, node-negative, early-stage breast cancer enrolled in TAILORx met National Comprehensive Cancer Network guidelines for receiving adjuvant chemotherapy. About 69% had an intermediate recurrence score (11-25) and were randomized. All of the 17% with a low recurrence score (0-10) were given only endocrine therapy, and all of the 14% with a high recurrence score (26-100) were given both adjuvant chemotherapy and endocrine therapy.
Of note, the recurrence scores used to define midrange were adjusted downward from those conventionally used to account for exclusion of patients with higher-risk HER2-positive disease and to minimize potential for undertreatment, Dr Sparano explained.
In the women with midrange scores who were randomized, the hazard ratio of 1.08 for invasive DFS with endocrine therapy alone compared with chemotherapy plus endocrine therapy fell well within the predefined hazard ratio for noninferiority (1.322). The 9-year rate of invasive DFS was 83.3% with endocrine therapy and 84.3% with chemotherapy plus endocrine therapy.
The groups had similar rates of freedom from distant recurrence (94.5% vs 95.0%; HR, 1.10; P = .48) and distant or locoregional recurrence (92.2% vs 92.9%; HR, 1.11; P = .33), and similar OSs (93.9% vs 93.8%; HR for death, 0.99; P = .89).
In exploratory analyses, there was an interaction of age and recurrence score (P = .004) whereby women aged 50 years or younger derived some benefit from chemotherapy if they had a recurrence score of 16-20 (9% fewer invasive DFS events, including 2% fewer distant recurrences) or a recurrence score 21-25 (6% fewer invasive DFS events, mainly distant recurrences). “This is information that could drive some younger women who have a recurrence score in this range to accept chemotherapy,” Dr Sparano said.
The 9-year rate of distant recurrence averaged 5% in women with midrange scores overall. It was 3% in those with a low recurrence score given endocrine therapy alone, but it was still 13% in those with a high recurrence score despite receiving both endocrine therapy and chemotherapy. The latter finding may “indicate the need to explore potentially more effective therapies in this setting,” he proposed.
Tailoring treatment: ‘not too much and not too little’
“These are important data because this is the most common form of breast cancer in the United States and other developed countries, and the most challenging decision we make with these patients is whether or not to recommend adjuvant chemotherapy with all its side effects and potential benefits,” said ASCO expert Harold Burstein, MD, PhD, FASCO. “The data show that the majority of women who have this test performed on their tumor can be told that they don’t need chemotherapy, and that can be said with tremendous confidence and reassurance.”
The recurrence score has been used for a decade, but the trial was necessary because the score was originally developed in patients who were receiving older chemotherapy regimens and older endocrine therapies, and because there have been few data to guide decision making in the large group of patients with midrange scores, he said. “Now we can say with confidence ... that the patients got contemporary chemo regimens and still saw no benefit from chemotherapy.
“This is not so much about de-escalation ... the goal of this study was not to just use less treatment but to tailor treatment. The investigators chose the title very aptly,” said Dr Burstein, a medical oncologist at the Dana-Farber Cancer Institute and associate professor of medicine at the Harvard Medical School, Boston.
“This is extraordinary data for breast cancer doctors and women who have breast cancer. It allows you to individualize treatment based on extraordinary science, which now has tremendous prospective validation,” he said. Overall, “women with breast cancer who are getting modern therapy are doing well, and this test shows us how to tailor that management so that they get exactly the right amount of treatment – not too much and not too little.”
— Susan London
First-line immunotherapy boosts survival in NSCLC patients
Key clinical point Many patients with previously untreated NSCLC could benefit from first-line therapy with the checkpoint inhibitor pembrolizumab. Major finding In all patients with expression of PD-L1 on 1% or more of tumor cells, OS was 16.7 months with pembrolizumab, compared with 12.1 months for chemotherapy. Study details Randomized phase 3 trial of 1,274 patients with advanced or metastatic NSCLC. Funding Merck, the maker of the study drug, funded the study. Disclosures Dr Lopes disclosed institutional research funding from Merck Sharp & Dohme, EMD Serono, and AstraZeneca. Dr Heymach disclosed stock/ownership in Bio-Tree and Cardinal Spine, a consulting or advisory role for Abbvie, ARIAD, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Calithera Biosciences, Genentech, Medivation, Novartis, Oncomed, and Synta, and institutional research funding from AstraZeneca. Dr Gandhi reported having no relevant disclosures. Source Lopes G et al. ASCO 2018, abstract LBA4. https://meetinglibrary.asco.org/record/165950/abstract
Pembrolizumab as first-line treatment of advanced non–small-cell lung cancer (NSCLC) offered longer OS with better tolerability compared with chemotherapy, results of the Keynote-042 phase 3 randomized trial show.
In 1,274 patients with advanced, previously untreated NSCLC with expression of the PD-L1 on 1% or more of tumor cells, median OS after a median follow-up of 12.8 months was 16.7 months for patients treated with pembrolizumab monotherapy, compared with 12.1 months for patients treated with either paclitaxel or pemetrexed plus carboplatin, reported lead author Gilberto Lopes, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami.
The survival benefit for immunotherapy was even greater for patients with higher levels of PD-L1 expression: 20 versus 12.2 months for patients with PD-L1 expression of 50% or greater, and 17.7 versus 13 months for patients with PD-L1 expression of 20% or greater, Dr Lopes noted.
For all 3 PD-L1 expression groups, the median duration of response was 20.2 months, compared with 10.8-8.3 months for patients in the chemotherapy arm.
“These are responses that are unlike anything that we have seen with chemotherapy in the past for non–small-cell lung cancer,” Dr Lopes said at a briefing before his presentation. “In addition to that, and probably more importantly, patients had fewer adverse events [with pembrolizumab]. Overall, about 60% had any treatment-related adverse event with pembrolizumab, versus 90% with chemotherapy,” he added.
‘A true milestone’
ASCO expert John Heymach, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, said at the briefing that the study was “a true milestone for the field, because now, for the first time, we can say that in non–small-cell lung cancer patients receiving first-line therapy, the vast majority can receive immunotherapy with pembrolizumab instead of chemotherapy.”
He noted that an earlier study, Keynote-024, showed that pembrolizumab significantly improved progression-free survival in patients with tumors expressing PD-L1 on at least 50% of cells compared with standard platinum-based chemotherapy (10.3 vs 6 months).
“This more than doubles that population that can start immunotherapy as a first-line treatment, assuming the [Food and Drug Administration] modifies the label in accordance with this study,” he added.
The Keynote-042 investigators enrolled 1,274 patients with locally advanced or metastatic NSCLC, and randomly assigned them to receive either a maximum of 35 cycles of pembrolizumab 200 mg every 3 weeks, or the investigators’ choice of not more than 6 cycles of either paclitaxel–carboplatin or pemetrexed–carboplatin, with optional pemetrexed maintenance for patients with nonsquamous histologies only.
The randomization was stratified by region (Asia vs non-East Asia), Eastern Cooperative Oncology Group performance status 0 or 1, squamous versus nonsquamous histology, and PD-L1 expression, or TPS (tumor proportion score) greater than 50% versus 1%-49%.
As noted before, the primary endpoint of OS in all patients with a TPS of 1% or greater was met, with respective median OS in the pembrolizumab versus chemotherapy groups of 16.7 and 12.1 months, translating into an HR favoring pembrolizumab of 0.81 (P = .0018). Respective hazard ratios for the TPS 20% or greater and TPS 50% or greater groups were 0.77 (P = .0020) and 0.69 (P = .0003).
At 12.8 months of median follow-up, 13% of patients assigned to pembrolizumab were still on the drug, and 4.3% of patients were receiving maintenance pemetrexed.
Treatment-related adverse events of any grade occurred in 399 of 636 patients assigned to pembrolizumab (62.7%), compared with 553 of 615 patients assigned to chemotherapy (89.9%). Grade 3 or greater events occurred in 17.8% and 41% of patients, respectively. There were 13 deaths related to therapy in the pembrolizumab arm (2.0%), and 14 in the chemotherapy arm (2.3%). Adverse events leading to discontinuation were similar between the groups, at 9% and 9.4%, respectively.
There were more immune-mediated adverse events in the pembrolizumab arm than in the chemotherapy arm (27.8% vs 7.2%, respectively), and of those, grade 3 or higher events occurred in 8% and 1.5% of patients. There was 1 immune-mediated death, from pneumonitis, in the immunotherapy arm; there were no deaths related to immune-mediated side effects in the chemotherapy arm.
“I really view this as a ‘double whammy’ for patients,” Dr Heymach said at the briefing. “Often advances in survival for our lung cancer patients come at the cost of significant toxicities. Here, by contrast, not only are patients living longer and having a much higher likelihood of prolonged survival in years, often instead of months, but they’re also receiving a treatment that has substantially less toxicity across virtually all measures, and this really impacts the day-to-day life of these patients.”
Leena Gandhi, MD, PhD, of the Perlmutter Cancer Center at New York University, the invited discussant at the plenary, agreed that pembrolizumab improves survival, compared with chemotherapy patients with PD-L1 expression levels greater than 1%, but noted that most of the benefit – as also seen in Keynote-024 – was in those patients whose tumors had high levels of PD-L1 expression.
She emphasized that although PD-L1 is an imperfect biomarker, it should still be used to help select patients for therapy and it may be complementary with tumor mutational burden for more precise treatment selection.
“What we know, and what this study adds to, is that PD-L1 really does define a patient population that could receive benefit from pembrolizumab over chemotherapy. Patients with low or no PD-L1 expression likely should get some type of combination therapy,” she said. “This study extends what we’ve seen from other recent studies, which is that chemotherapy alone is no longer a first-line standard of care in non–small-cell lung cancer.”
— Neil Osterweil
Maintenance chemo improves survival in youth with rhabdomyosarcoma
Key clinical point 6 months of maintenance chemotherapy improves survival in youth with high-risk rhabdomyosarcoma. Major finding Patients given maintenance low-dose vinorelbine and cyclophosphamide had better 5-year OS compared with those not receiving any additional treatment (86.5% vs 73.7%; HR, 0.52). Study details A phase 3 randomized controlled trial in 371 patients aged 0-21 years with high-risk rhabdomyosarcoma who had had a complete response to standard intensive therapy. Funding The study received funding from Fondazione Città della Speranza, Italy. Disclosures Dr Bisogno disclosed that he has a consulting or advisory role with Clinigen Group, and receives travel, accommodations, and/or expenses from Jazz Pharmaceuticals. Source Bisogno et al. ASCO 2018, Abstract LBA2. https://meetinglibrary.asco.org/record/161695/abstract
Six months of maintenance chemotherapy prolongs OS in youth with high-risk rhabdomyosarcoma, finds a phase 3 randomized controlled trial of the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG).
Rhabdomyosarcoma is a rare but highly aggressive tumor, lead study author Gianni Bisogno, MD, PhD, a professor at the University Hospital of Padova, Italy, and chair of the EpSSG, noted in a press briefing at the meeting, where the findings were reported. In pediatric patients who achieve complete response to standard therapy, “we know that after 1 or 2 years, one-third of these children relapse, and most of them die,” he said.
The EpSSG trial, which took about 10 years to conduct, enrolled 371 patients aged 0-21 years with high-risk rhabdomyosarcoma who had had a complete response to standard intensive therapy. They were randomized evenly to stop treatment or to receive 6 months of maintenance treatment consisting of low-dose vinorelbine and cyclophosphamide.
Results reported in the meeting’s plenary session showed that giving maintenance chemotherapy improved the 5-year OS rate by an absolute 12.8%, which translated to a near halving of the risk of death. And the maintenance regimen used was generally well tolerated.
“At the end of this long, not-easy study, we concluded that maintenance chemotherapy is an effective and well tolerated treatment for children with high-risk rhabdomyosarcoma,” Dr Bisogno said.
There are three possibilities for its efficacy, he speculated. “It may be the duration, the type of drugs used, or the metronomic approach. Maybe altogether, these three different actions have a benefit to increase survival.
“Our group has decided this is the new standard treatment for patients. At least in Europe, we give standard intensive therapy and then we continue with 6 more months of low-dose chemotherapy,” Dr Bisogno concluded. “We think that this approach – a new way of using old drugs – can be of interest also for other pediatric tumors.”
The trial is noteworthy in that it shows “how to successfully conduct large and important trials in rare diseases,” said ASCO expert Warren Chow, MD.
The standard therapy for rhabdomyosarcomas is somewhat different in the United States, typically a regimen containing vincristine, actinomycin D, cyclophosphamide, and (more recently) irinotecan, he noted. “We have not been traditionally using maintenance chemo for any of the pediatric sarcomas, so this is a paradigm shift. These results will need to be tested with US-based protocols before becoming standard of care in the United States. Also, we will need to determine if these results are applicable to patients older than 21 years of age who are considered high risk based solely on their age.
“Even with these caveats, this is the first significant treatment advance in this rare cancer in more than 30 years,” concluded Dr Chow, a medical oncologist and clinical professor at City of Hope, Duarte, Calif. “No doubt, this trial was a home run.”
Study details
Patients enrolled in the EpSSG trial had had a complete response to the standard intensive therapy used in Europe: high-dose chemotherapy (ifosfamide, vincristine, and actinomycin D, with or without doxorubicin), radiation therapy, and surgery.
The maintenance chemotherapy consisted of a combination of low-dose intravenous vinorelbine given weekly and oral cyclophosphamide given daily. The 6-month duration was somewhat arbitrary, according to Dr Bisogno. “We had to start somewhere. So when we started, we decided to use 6 months because there was some evidence in the past for regimens that long. In our next European trial, we are going to test different kinds and durations of maintenance because this is very important.”
The maintenance regimen was well tolerated compared with the regimen given during standard intensive therapy, with, for example, lower rates of grade 3 and 4 anemia (8.9% vs 48.9%), neutropenia (80.6% vs 91.6%), and thrombocytopenia (0.6% vs 26.0%), which translated to less of a need for transfusions, and a lower rate of grade 3 or 4 infection (29.4% vs 56.4%), Dr Bisogno reported. There were no cases of grade 3 or 4 cardiac, hepatobiliary/pancreatic, or renal toxicity.
Relative to peers who stopped treatment after standard intensive therapy, patients who received maintenance treatment tended to have better DFS (77.6% vs 69.8%; HR, 0.68; P = .0613) and had significantly better OS (86.5% vs 73.7%; HR, 0.52; P = .0111).
— Susan London
Among the groundbreaking findings presented at this year’s annual meeting of the American Society of Clinical Oncology were those showing that most women with HR-positive, HER2-negative, early-stage breast cancer who have an intermediate recurrence score can safely skip adjuvant chemotherapy, and that upfront pembrolizumab for patients with NSCLC expressing PD-L1 on at least 1% of tumor cells can not only significantly improve overall survival, but do so with less toxicity than standard chemotherapy.
TAILORx marks major advance for precision medicine in breast cancer
Key clinical point The majority of women with HR-positive, HER2-negative, node-negative early-stage breast cancer who have an intermediate recurrence score can safely skip adjuvant chemotherapy. Major finding In women with an Oncotype DX Recurrence Score in the midrange (11-25), invasive DFS with endocrine therapy alone was not inferior to that with chemotherapy plus endocrine therapy (HR, 1.08; P = .26). Study details A phase 3 trial in 10,273 women with HR-positive, HER2-negative, node-negative, early-stage breast cancer, with a noninferiority randomized component in the 6,711 women with a midrange recurrence score (TAILORx trial). Funding This study received funding primarily from the National Cancer Institute, National Institutes of Health. Additional support was provided by the Breast Cancer Research Foundation, Komen Foundation, and US Postal Service Breast Cancer Stamp. Disclosures Dr Sparano disclosed that he has a consulting or advisory role with Genentech/Roche, Novartis, AstraZeneca, Celgene, Lilly, Celldex, Pfizer, Prescient Therapeutics, Juno Therapeutics, and Merrimack; has stock or other ownership interests with MetaStat; and receives research funding (institutional) from Prescient Therapeutics, Deciphera, Genentech/Roche, Merck, Novartis, and Merrimack. Source Sparano et al. ASCO 2018 Abstract LBA1: https://meetinglibrary.asco.org/record/161490/abstract
Use of the 21-tumor gene expression assay (Oncotype DX Recurrence Score) allows nearly 70% of women with hormone receptor-positive, HER2-negative, node-negative, early-stage breast cancer to safely forgo adjuvant chemotherapy, sparing them adverse effects and preventing overtreatment, TAILORx trial results show.
The findings, which were reported in the plenary session at the meeting and simultaneously published in the New England Journal of Medicine (N Engl J Med. 2018; 379:111-121; [behind paywall]), mark a major advance in precision medicine.
“The rationale for the TAILORx precision medicine trial is that we are really trying to ‘thread the needle,’ “ lead study author Joseph A Sparano, MD, commented in a press briefing. Oncologists typically recommend adjuvant chemotherapy for the half of all breast cancers that are hormone receptor positive, HER2 negative, and node negative, even though its absolute benefit in reducing recurrences in this population is small. “This results in most patients being overtreated because endocrine therapy alone is adequate. But some are undertreated: They do not receive chemotherapy although they could have benefited from it,” he noted.
The recurrence score is known to be prognostic and predictive of benefit from adding chemotherapy to endocrine therapy, Dr Sparano said. “But there was a major gap: There was uncertain benefit for patients who had a midrange score, which is about two-thirds of all patients who are treated,” said Dr Sparano, the associate director for clinical research at Albert Einstein Cancer Center and Montefiore Health System in New York, and vice-chair of the ECOG-ACRIN Cancer Research Group.
The phase 3 TAILORx trial registered 10,273 women with hormone receptor-positive, HER2-negative, node-negative, early-stage breast cancer, making it the largest adjuvant breast cancer trial to date. Analyses focused on the 6,711 evaluable women with a midrange recurrence score (defined as 11 through 25 in the trial), who were randomized to receive endocrine therapy alone or adjuvant chemotherapy plus endocrine therapy, with a noninferiority design. Of note is that contemporary drugs and regimens were used.
Results at a median follow-up of 7.5 years showed that the trial met its primary endpoint: the risk of invasive disease-free survival (DFS) events (invasive disease recurrence, second primary cancer, or death) was not inferior for women given endocrine therapy alone compared with counterparts given chemotherapy plus endocrine therapy (hazard ratio [HR], 1.08; P = .26), Dr Sparano reported.
The groups were also on par, with absolute differences of no more than 1% between rates, with respect to a variety of other efficacy outcomes: freedom from distant recurrence and any recurrence, and overall survival (OS).
Findings were similar across most subgroups. But analyses suggested that women aged 50 years and younger and who had a recurrence score of 16-25 fared better when they received chemotherapy. “Though exploratory from a statistical perspective, this is a highly clinically relevant observation,” Dr Sparano said. “It suggests ... that chemotherapy should be spared with caution in this subgroup, after a careful discussion of potential benefits and risks in a shared decision process.”
In other findings, analyses of the trial’s nonrandomized groups confirmed excellent outcomes in women with a low recurrence score (0-10) who were given endocrine therapy alone, and at the other end of the spectrum, there was need for a more aggressive approach, including chemotherapy, in women with a high recurrence score (26-100).
Ultimately, application of the recurrence score allowed 69% of the trial population to skip chemotherapy: all of the women with a score of 0-10 (16% of the trial population), those older than 50 years with a score of 11-25 (45%), and those aged 50 years or younger with a score of 11-15 (8%).
An ongoing companion phase 3 trial, RxPONDER, is assessing the benefit of applying the recurrence score in women who are similar but ihave node-positive disease.
Study details
All of the women with hormone receptor-positive, HER2-negative, node-negative, early-stage breast cancer enrolled in TAILORx met National Comprehensive Cancer Network guidelines for receiving adjuvant chemotherapy. About 69% had an intermediate recurrence score (11-25) and were randomized. All of the 17% with a low recurrence score (0-10) were given only endocrine therapy, and all of the 14% with a high recurrence score (26-100) were given both adjuvant chemotherapy and endocrine therapy.
Of note, the recurrence scores used to define midrange were adjusted downward from those conventionally used to account for exclusion of patients with higher-risk HER2-positive disease and to minimize potential for undertreatment, Dr Sparano explained.
In the women with midrange scores who were randomized, the hazard ratio of 1.08 for invasive DFS with endocrine therapy alone compared with chemotherapy plus endocrine therapy fell well within the predefined hazard ratio for noninferiority (1.322). The 9-year rate of invasive DFS was 83.3% with endocrine therapy and 84.3% with chemotherapy plus endocrine therapy.
The groups had similar rates of freedom from distant recurrence (94.5% vs 95.0%; HR, 1.10; P = .48) and distant or locoregional recurrence (92.2% vs 92.9%; HR, 1.11; P = .33), and similar OSs (93.9% vs 93.8%; HR for death, 0.99; P = .89).
In exploratory analyses, there was an interaction of age and recurrence score (P = .004) whereby women aged 50 years or younger derived some benefit from chemotherapy if they had a recurrence score of 16-20 (9% fewer invasive DFS events, including 2% fewer distant recurrences) or a recurrence score 21-25 (6% fewer invasive DFS events, mainly distant recurrences). “This is information that could drive some younger women who have a recurrence score in this range to accept chemotherapy,” Dr Sparano said.
The 9-year rate of distant recurrence averaged 5% in women with midrange scores overall. It was 3% in those with a low recurrence score given endocrine therapy alone, but it was still 13% in those with a high recurrence score despite receiving both endocrine therapy and chemotherapy. The latter finding may “indicate the need to explore potentially more effective therapies in this setting,” he proposed.
Tailoring treatment: ‘not too much and not too little’
“These are important data because this is the most common form of breast cancer in the United States and other developed countries, and the most challenging decision we make with these patients is whether or not to recommend adjuvant chemotherapy with all its side effects and potential benefits,” said ASCO expert Harold Burstein, MD, PhD, FASCO. “The data show that the majority of women who have this test performed on their tumor can be told that they don’t need chemotherapy, and that can be said with tremendous confidence and reassurance.”
The recurrence score has been used for a decade, but the trial was necessary because the score was originally developed in patients who were receiving older chemotherapy regimens and older endocrine therapies, and because there have been few data to guide decision making in the large group of patients with midrange scores, he said. “Now we can say with confidence ... that the patients got contemporary chemo regimens and still saw no benefit from chemotherapy.
“This is not so much about de-escalation ... the goal of this study was not to just use less treatment but to tailor treatment. The investigators chose the title very aptly,” said Dr Burstein, a medical oncologist at the Dana-Farber Cancer Institute and associate professor of medicine at the Harvard Medical School, Boston.
“This is extraordinary data for breast cancer doctors and women who have breast cancer. It allows you to individualize treatment based on extraordinary science, which now has tremendous prospective validation,” he said. Overall, “women with breast cancer who are getting modern therapy are doing well, and this test shows us how to tailor that management so that they get exactly the right amount of treatment – not too much and not too little.”
— Susan London
First-line immunotherapy boosts survival in NSCLC patients
Key clinical point Many patients with previously untreated NSCLC could benefit from first-line therapy with the checkpoint inhibitor pembrolizumab. Major finding In all patients with expression of PD-L1 on 1% or more of tumor cells, OS was 16.7 months with pembrolizumab, compared with 12.1 months for chemotherapy. Study details Randomized phase 3 trial of 1,274 patients with advanced or metastatic NSCLC. Funding Merck, the maker of the study drug, funded the study. Disclosures Dr Lopes disclosed institutional research funding from Merck Sharp & Dohme, EMD Serono, and AstraZeneca. Dr Heymach disclosed stock/ownership in Bio-Tree and Cardinal Spine, a consulting or advisory role for Abbvie, ARIAD, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Calithera Biosciences, Genentech, Medivation, Novartis, Oncomed, and Synta, and institutional research funding from AstraZeneca. Dr Gandhi reported having no relevant disclosures. Source Lopes G et al. ASCO 2018, abstract LBA4. https://meetinglibrary.asco.org/record/165950/abstract
Pembrolizumab as first-line treatment of advanced non–small-cell lung cancer (NSCLC) offered longer OS with better tolerability compared with chemotherapy, results of the Keynote-042 phase 3 randomized trial show.
In 1,274 patients with advanced, previously untreated NSCLC with expression of the PD-L1 on 1% or more of tumor cells, median OS after a median follow-up of 12.8 months was 16.7 months for patients treated with pembrolizumab monotherapy, compared with 12.1 months for patients treated with either paclitaxel or pemetrexed plus carboplatin, reported lead author Gilberto Lopes, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami.
The survival benefit for immunotherapy was even greater for patients with higher levels of PD-L1 expression: 20 versus 12.2 months for patients with PD-L1 expression of 50% or greater, and 17.7 versus 13 months for patients with PD-L1 expression of 20% or greater, Dr Lopes noted.
For all 3 PD-L1 expression groups, the median duration of response was 20.2 months, compared with 10.8-8.3 months for patients in the chemotherapy arm.
“These are responses that are unlike anything that we have seen with chemotherapy in the past for non–small-cell lung cancer,” Dr Lopes said at a briefing before his presentation. “In addition to that, and probably more importantly, patients had fewer adverse events [with pembrolizumab]. Overall, about 60% had any treatment-related adverse event with pembrolizumab, versus 90% with chemotherapy,” he added.
‘A true milestone’
ASCO expert John Heymach, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, said at the briefing that the study was “a true milestone for the field, because now, for the first time, we can say that in non–small-cell lung cancer patients receiving first-line therapy, the vast majority can receive immunotherapy with pembrolizumab instead of chemotherapy.”
He noted that an earlier study, Keynote-024, showed that pembrolizumab significantly improved progression-free survival in patients with tumors expressing PD-L1 on at least 50% of cells compared with standard platinum-based chemotherapy (10.3 vs 6 months).
“This more than doubles that population that can start immunotherapy as a first-line treatment, assuming the [Food and Drug Administration] modifies the label in accordance with this study,” he added.
The Keynote-042 investigators enrolled 1,274 patients with locally advanced or metastatic NSCLC, and randomly assigned them to receive either a maximum of 35 cycles of pembrolizumab 200 mg every 3 weeks, or the investigators’ choice of not more than 6 cycles of either paclitaxel–carboplatin or pemetrexed–carboplatin, with optional pemetrexed maintenance for patients with nonsquamous histologies only.
The randomization was stratified by region (Asia vs non-East Asia), Eastern Cooperative Oncology Group performance status 0 or 1, squamous versus nonsquamous histology, and PD-L1 expression, or TPS (tumor proportion score) greater than 50% versus 1%-49%.
As noted before, the primary endpoint of OS in all patients with a TPS of 1% or greater was met, with respective median OS in the pembrolizumab versus chemotherapy groups of 16.7 and 12.1 months, translating into an HR favoring pembrolizumab of 0.81 (P = .0018). Respective hazard ratios for the TPS 20% or greater and TPS 50% or greater groups were 0.77 (P = .0020) and 0.69 (P = .0003).
At 12.8 months of median follow-up, 13% of patients assigned to pembrolizumab were still on the drug, and 4.3% of patients were receiving maintenance pemetrexed.
Treatment-related adverse events of any grade occurred in 399 of 636 patients assigned to pembrolizumab (62.7%), compared with 553 of 615 patients assigned to chemotherapy (89.9%). Grade 3 or greater events occurred in 17.8% and 41% of patients, respectively. There were 13 deaths related to therapy in the pembrolizumab arm (2.0%), and 14 in the chemotherapy arm (2.3%). Adverse events leading to discontinuation were similar between the groups, at 9% and 9.4%, respectively.
There were more immune-mediated adverse events in the pembrolizumab arm than in the chemotherapy arm (27.8% vs 7.2%, respectively), and of those, grade 3 or higher events occurred in 8% and 1.5% of patients. There was 1 immune-mediated death, from pneumonitis, in the immunotherapy arm; there were no deaths related to immune-mediated side effects in the chemotherapy arm.
“I really view this as a ‘double whammy’ for patients,” Dr Heymach said at the briefing. “Often advances in survival for our lung cancer patients come at the cost of significant toxicities. Here, by contrast, not only are patients living longer and having a much higher likelihood of prolonged survival in years, often instead of months, but they’re also receiving a treatment that has substantially less toxicity across virtually all measures, and this really impacts the day-to-day life of these patients.”
Leena Gandhi, MD, PhD, of the Perlmutter Cancer Center at New York University, the invited discussant at the plenary, agreed that pembrolizumab improves survival, compared with chemotherapy patients with PD-L1 expression levels greater than 1%, but noted that most of the benefit – as also seen in Keynote-024 – was in those patients whose tumors had high levels of PD-L1 expression.
She emphasized that although PD-L1 is an imperfect biomarker, it should still be used to help select patients for therapy and it may be complementary with tumor mutational burden for more precise treatment selection.
“What we know, and what this study adds to, is that PD-L1 really does define a patient population that could receive benefit from pembrolizumab over chemotherapy. Patients with low or no PD-L1 expression likely should get some type of combination therapy,” she said. “This study extends what we’ve seen from other recent studies, which is that chemotherapy alone is no longer a first-line standard of care in non–small-cell lung cancer.”
— Neil Osterweil
Maintenance chemo improves survival in youth with rhabdomyosarcoma
Key clinical point 6 months of maintenance chemotherapy improves survival in youth with high-risk rhabdomyosarcoma. Major finding Patients given maintenance low-dose vinorelbine and cyclophosphamide had better 5-year OS compared with those not receiving any additional treatment (86.5% vs 73.7%; HR, 0.52). Study details A phase 3 randomized controlled trial in 371 patients aged 0-21 years with high-risk rhabdomyosarcoma who had had a complete response to standard intensive therapy. Funding The study received funding from Fondazione Città della Speranza, Italy. Disclosures Dr Bisogno disclosed that he has a consulting or advisory role with Clinigen Group, and receives travel, accommodations, and/or expenses from Jazz Pharmaceuticals. Source Bisogno et al. ASCO 2018, Abstract LBA2. https://meetinglibrary.asco.org/record/161695/abstract
Six months of maintenance chemotherapy prolongs OS in youth with high-risk rhabdomyosarcoma, finds a phase 3 randomized controlled trial of the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG).
Rhabdomyosarcoma is a rare but highly aggressive tumor, lead study author Gianni Bisogno, MD, PhD, a professor at the University Hospital of Padova, Italy, and chair of the EpSSG, noted in a press briefing at the meeting, where the findings were reported. In pediatric patients who achieve complete response to standard therapy, “we know that after 1 or 2 years, one-third of these children relapse, and most of them die,” he said.
The EpSSG trial, which took about 10 years to conduct, enrolled 371 patients aged 0-21 years with high-risk rhabdomyosarcoma who had had a complete response to standard intensive therapy. They were randomized evenly to stop treatment or to receive 6 months of maintenance treatment consisting of low-dose vinorelbine and cyclophosphamide.
Results reported in the meeting’s plenary session showed that giving maintenance chemotherapy improved the 5-year OS rate by an absolute 12.8%, which translated to a near halving of the risk of death. And the maintenance regimen used was generally well tolerated.
“At the end of this long, not-easy study, we concluded that maintenance chemotherapy is an effective and well tolerated treatment for children with high-risk rhabdomyosarcoma,” Dr Bisogno said.
There are three possibilities for its efficacy, he speculated. “It may be the duration, the type of drugs used, or the metronomic approach. Maybe altogether, these three different actions have a benefit to increase survival.
“Our group has decided this is the new standard treatment for patients. At least in Europe, we give standard intensive therapy and then we continue with 6 more months of low-dose chemotherapy,” Dr Bisogno concluded. “We think that this approach – a new way of using old drugs – can be of interest also for other pediatric tumors.”
The trial is noteworthy in that it shows “how to successfully conduct large and important trials in rare diseases,” said ASCO expert Warren Chow, MD.
The standard therapy for rhabdomyosarcomas is somewhat different in the United States, typically a regimen containing vincristine, actinomycin D, cyclophosphamide, and (more recently) irinotecan, he noted. “We have not been traditionally using maintenance chemo for any of the pediatric sarcomas, so this is a paradigm shift. These results will need to be tested with US-based protocols before becoming standard of care in the United States. Also, we will need to determine if these results are applicable to patients older than 21 years of age who are considered high risk based solely on their age.
“Even with these caveats, this is the first significant treatment advance in this rare cancer in more than 30 years,” concluded Dr Chow, a medical oncologist and clinical professor at City of Hope, Duarte, Calif. “No doubt, this trial was a home run.”
Study details
Patients enrolled in the EpSSG trial had had a complete response to the standard intensive therapy used in Europe: high-dose chemotherapy (ifosfamide, vincristine, and actinomycin D, with or without doxorubicin), radiation therapy, and surgery.
The maintenance chemotherapy consisted of a combination of low-dose intravenous vinorelbine given weekly and oral cyclophosphamide given daily. The 6-month duration was somewhat arbitrary, according to Dr Bisogno. “We had to start somewhere. So when we started, we decided to use 6 months because there was some evidence in the past for regimens that long. In our next European trial, we are going to test different kinds and durations of maintenance because this is very important.”
The maintenance regimen was well tolerated compared with the regimen given during standard intensive therapy, with, for example, lower rates of grade 3 and 4 anemia (8.9% vs 48.9%), neutropenia (80.6% vs 91.6%), and thrombocytopenia (0.6% vs 26.0%), which translated to less of a need for transfusions, and a lower rate of grade 3 or 4 infection (29.4% vs 56.4%), Dr Bisogno reported. There were no cases of grade 3 or 4 cardiac, hepatobiliary/pancreatic, or renal toxicity.
Relative to peers who stopped treatment after standard intensive therapy, patients who received maintenance treatment tended to have better DFS (77.6% vs 69.8%; HR, 0.68; P = .0613) and had significantly better OS (86.5% vs 73.7%; HR, 0.52; P = .0111).
— Susan London
Among the groundbreaking findings presented at this year’s annual meeting of the American Society of Clinical Oncology were those showing that most women with HR-positive, HER2-negative, early-stage breast cancer who have an intermediate recurrence score can safely skip adjuvant chemotherapy, and that upfront pembrolizumab for patients with NSCLC expressing PD-L1 on at least 1% of tumor cells can not only significantly improve overall survival, but do so with less toxicity than standard chemotherapy.
TAILORx marks major advance for precision medicine in breast cancer
Key clinical point The majority of women with HR-positive, HER2-negative, node-negative early-stage breast cancer who have an intermediate recurrence score can safely skip adjuvant chemotherapy. Major finding In women with an Oncotype DX Recurrence Score in the midrange (11-25), invasive DFS with endocrine therapy alone was not inferior to that with chemotherapy plus endocrine therapy (HR, 1.08; P = .26). Study details A phase 3 trial in 10,273 women with HR-positive, HER2-negative, node-negative, early-stage breast cancer, with a noninferiority randomized component in the 6,711 women with a midrange recurrence score (TAILORx trial). Funding This study received funding primarily from the National Cancer Institute, National Institutes of Health. Additional support was provided by the Breast Cancer Research Foundation, Komen Foundation, and US Postal Service Breast Cancer Stamp. Disclosures Dr Sparano disclosed that he has a consulting or advisory role with Genentech/Roche, Novartis, AstraZeneca, Celgene, Lilly, Celldex, Pfizer, Prescient Therapeutics, Juno Therapeutics, and Merrimack; has stock or other ownership interests with MetaStat; and receives research funding (institutional) from Prescient Therapeutics, Deciphera, Genentech/Roche, Merck, Novartis, and Merrimack. Source Sparano et al. ASCO 2018 Abstract LBA1: https://meetinglibrary.asco.org/record/161490/abstract
Use of the 21-tumor gene expression assay (Oncotype DX Recurrence Score) allows nearly 70% of women with hormone receptor-positive, HER2-negative, node-negative, early-stage breast cancer to safely forgo adjuvant chemotherapy, sparing them adverse effects and preventing overtreatment, TAILORx trial results show.
The findings, which were reported in the plenary session at the meeting and simultaneously published in the New England Journal of Medicine (N Engl J Med. 2018; 379:111-121; [behind paywall]), mark a major advance in precision medicine.
“The rationale for the TAILORx precision medicine trial is that we are really trying to ‘thread the needle,’ “ lead study author Joseph A Sparano, MD, commented in a press briefing. Oncologists typically recommend adjuvant chemotherapy for the half of all breast cancers that are hormone receptor positive, HER2 negative, and node negative, even though its absolute benefit in reducing recurrences in this population is small. “This results in most patients being overtreated because endocrine therapy alone is adequate. But some are undertreated: They do not receive chemotherapy although they could have benefited from it,” he noted.
The recurrence score is known to be prognostic and predictive of benefit from adding chemotherapy to endocrine therapy, Dr Sparano said. “But there was a major gap: There was uncertain benefit for patients who had a midrange score, which is about two-thirds of all patients who are treated,” said Dr Sparano, the associate director for clinical research at Albert Einstein Cancer Center and Montefiore Health System in New York, and vice-chair of the ECOG-ACRIN Cancer Research Group.
The phase 3 TAILORx trial registered 10,273 women with hormone receptor-positive, HER2-negative, node-negative, early-stage breast cancer, making it the largest adjuvant breast cancer trial to date. Analyses focused on the 6,711 evaluable women with a midrange recurrence score (defined as 11 through 25 in the trial), who were randomized to receive endocrine therapy alone or adjuvant chemotherapy plus endocrine therapy, with a noninferiority design. Of note is that contemporary drugs and regimens were used.
Results at a median follow-up of 7.5 years showed that the trial met its primary endpoint: the risk of invasive disease-free survival (DFS) events (invasive disease recurrence, second primary cancer, or death) was not inferior for women given endocrine therapy alone compared with counterparts given chemotherapy plus endocrine therapy (hazard ratio [HR], 1.08; P = .26), Dr Sparano reported.
The groups were also on par, with absolute differences of no more than 1% between rates, with respect to a variety of other efficacy outcomes: freedom from distant recurrence and any recurrence, and overall survival (OS).
Findings were similar across most subgroups. But analyses suggested that women aged 50 years and younger and who had a recurrence score of 16-25 fared better when they received chemotherapy. “Though exploratory from a statistical perspective, this is a highly clinically relevant observation,” Dr Sparano said. “It suggests ... that chemotherapy should be spared with caution in this subgroup, after a careful discussion of potential benefits and risks in a shared decision process.”
In other findings, analyses of the trial’s nonrandomized groups confirmed excellent outcomes in women with a low recurrence score (0-10) who were given endocrine therapy alone, and at the other end of the spectrum, there was need for a more aggressive approach, including chemotherapy, in women with a high recurrence score (26-100).
Ultimately, application of the recurrence score allowed 69% of the trial population to skip chemotherapy: all of the women with a score of 0-10 (16% of the trial population), those older than 50 years with a score of 11-25 (45%), and those aged 50 years or younger with a score of 11-15 (8%).
An ongoing companion phase 3 trial, RxPONDER, is assessing the benefit of applying the recurrence score in women who are similar but ihave node-positive disease.
Study details
All of the women with hormone receptor-positive, HER2-negative, node-negative, early-stage breast cancer enrolled in TAILORx met National Comprehensive Cancer Network guidelines for receiving adjuvant chemotherapy. About 69% had an intermediate recurrence score (11-25) and were randomized. All of the 17% with a low recurrence score (0-10) were given only endocrine therapy, and all of the 14% with a high recurrence score (26-100) were given both adjuvant chemotherapy and endocrine therapy.
Of note, the recurrence scores used to define midrange were adjusted downward from those conventionally used to account for exclusion of patients with higher-risk HER2-positive disease and to minimize potential for undertreatment, Dr Sparano explained.
In the women with midrange scores who were randomized, the hazard ratio of 1.08 for invasive DFS with endocrine therapy alone compared with chemotherapy plus endocrine therapy fell well within the predefined hazard ratio for noninferiority (1.322). The 9-year rate of invasive DFS was 83.3% with endocrine therapy and 84.3% with chemotherapy plus endocrine therapy.
The groups had similar rates of freedom from distant recurrence (94.5% vs 95.0%; HR, 1.10; P = .48) and distant or locoregional recurrence (92.2% vs 92.9%; HR, 1.11; P = .33), and similar OSs (93.9% vs 93.8%; HR for death, 0.99; P = .89).
In exploratory analyses, there was an interaction of age and recurrence score (P = .004) whereby women aged 50 years or younger derived some benefit from chemotherapy if they had a recurrence score of 16-20 (9% fewer invasive DFS events, including 2% fewer distant recurrences) or a recurrence score 21-25 (6% fewer invasive DFS events, mainly distant recurrences). “This is information that could drive some younger women who have a recurrence score in this range to accept chemotherapy,” Dr Sparano said.
The 9-year rate of distant recurrence averaged 5% in women with midrange scores overall. It was 3% in those with a low recurrence score given endocrine therapy alone, but it was still 13% in those with a high recurrence score despite receiving both endocrine therapy and chemotherapy. The latter finding may “indicate the need to explore potentially more effective therapies in this setting,” he proposed.
Tailoring treatment: ‘not too much and not too little’
“These are important data because this is the most common form of breast cancer in the United States and other developed countries, and the most challenging decision we make with these patients is whether or not to recommend adjuvant chemotherapy with all its side effects and potential benefits,” said ASCO expert Harold Burstein, MD, PhD, FASCO. “The data show that the majority of women who have this test performed on their tumor can be told that they don’t need chemotherapy, and that can be said with tremendous confidence and reassurance.”
The recurrence score has been used for a decade, but the trial was necessary because the score was originally developed in patients who were receiving older chemotherapy regimens and older endocrine therapies, and because there have been few data to guide decision making in the large group of patients with midrange scores, he said. “Now we can say with confidence ... that the patients got contemporary chemo regimens and still saw no benefit from chemotherapy.
“This is not so much about de-escalation ... the goal of this study was not to just use less treatment but to tailor treatment. The investigators chose the title very aptly,” said Dr Burstein, a medical oncologist at the Dana-Farber Cancer Institute and associate professor of medicine at the Harvard Medical School, Boston.
“This is extraordinary data for breast cancer doctors and women who have breast cancer. It allows you to individualize treatment based on extraordinary science, which now has tremendous prospective validation,” he said. Overall, “women with breast cancer who are getting modern therapy are doing well, and this test shows us how to tailor that management so that they get exactly the right amount of treatment – not too much and not too little.”
— Susan London
First-line immunotherapy boosts survival in NSCLC patients
Key clinical point Many patients with previously untreated NSCLC could benefit from first-line therapy with the checkpoint inhibitor pembrolizumab. Major finding In all patients with expression of PD-L1 on 1% or more of tumor cells, OS was 16.7 months with pembrolizumab, compared with 12.1 months for chemotherapy. Study details Randomized phase 3 trial of 1,274 patients with advanced or metastatic NSCLC. Funding Merck, the maker of the study drug, funded the study. Disclosures Dr Lopes disclosed institutional research funding from Merck Sharp & Dohme, EMD Serono, and AstraZeneca. Dr Heymach disclosed stock/ownership in Bio-Tree and Cardinal Spine, a consulting or advisory role for Abbvie, ARIAD, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Calithera Biosciences, Genentech, Medivation, Novartis, Oncomed, and Synta, and institutional research funding from AstraZeneca. Dr Gandhi reported having no relevant disclosures. Source Lopes G et al. ASCO 2018, abstract LBA4. https://meetinglibrary.asco.org/record/165950/abstract
Pembrolizumab as first-line treatment of advanced non–small-cell lung cancer (NSCLC) offered longer OS with better tolerability compared with chemotherapy, results of the Keynote-042 phase 3 randomized trial show.
In 1,274 patients with advanced, previously untreated NSCLC with expression of the PD-L1 on 1% or more of tumor cells, median OS after a median follow-up of 12.8 months was 16.7 months for patients treated with pembrolizumab monotherapy, compared with 12.1 months for patients treated with either paclitaxel or pemetrexed plus carboplatin, reported lead author Gilberto Lopes, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami.
The survival benefit for immunotherapy was even greater for patients with higher levels of PD-L1 expression: 20 versus 12.2 months for patients with PD-L1 expression of 50% or greater, and 17.7 versus 13 months for patients with PD-L1 expression of 20% or greater, Dr Lopes noted.
For all 3 PD-L1 expression groups, the median duration of response was 20.2 months, compared with 10.8-8.3 months for patients in the chemotherapy arm.
“These are responses that are unlike anything that we have seen with chemotherapy in the past for non–small-cell lung cancer,” Dr Lopes said at a briefing before his presentation. “In addition to that, and probably more importantly, patients had fewer adverse events [with pembrolizumab]. Overall, about 60% had any treatment-related adverse event with pembrolizumab, versus 90% with chemotherapy,” he added.
‘A true milestone’
ASCO expert John Heymach, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, said at the briefing that the study was “a true milestone for the field, because now, for the first time, we can say that in non–small-cell lung cancer patients receiving first-line therapy, the vast majority can receive immunotherapy with pembrolizumab instead of chemotherapy.”
He noted that an earlier study, Keynote-024, showed that pembrolizumab significantly improved progression-free survival in patients with tumors expressing PD-L1 on at least 50% of cells compared with standard platinum-based chemotherapy (10.3 vs 6 months).
“This more than doubles that population that can start immunotherapy as a first-line treatment, assuming the [Food and Drug Administration] modifies the label in accordance with this study,” he added.
The Keynote-042 investigators enrolled 1,274 patients with locally advanced or metastatic NSCLC, and randomly assigned them to receive either a maximum of 35 cycles of pembrolizumab 200 mg every 3 weeks, or the investigators’ choice of not more than 6 cycles of either paclitaxel–carboplatin or pemetrexed–carboplatin, with optional pemetrexed maintenance for patients with nonsquamous histologies only.
The randomization was stratified by region (Asia vs non-East Asia), Eastern Cooperative Oncology Group performance status 0 or 1, squamous versus nonsquamous histology, and PD-L1 expression, or TPS (tumor proportion score) greater than 50% versus 1%-49%.
As noted before, the primary endpoint of OS in all patients with a TPS of 1% or greater was met, with respective median OS in the pembrolizumab versus chemotherapy groups of 16.7 and 12.1 months, translating into an HR favoring pembrolizumab of 0.81 (P = .0018). Respective hazard ratios for the TPS 20% or greater and TPS 50% or greater groups were 0.77 (P = .0020) and 0.69 (P = .0003).
At 12.8 months of median follow-up, 13% of patients assigned to pembrolizumab were still on the drug, and 4.3% of patients were receiving maintenance pemetrexed.
Treatment-related adverse events of any grade occurred in 399 of 636 patients assigned to pembrolizumab (62.7%), compared with 553 of 615 patients assigned to chemotherapy (89.9%). Grade 3 or greater events occurred in 17.8% and 41% of patients, respectively. There were 13 deaths related to therapy in the pembrolizumab arm (2.0%), and 14 in the chemotherapy arm (2.3%). Adverse events leading to discontinuation were similar between the groups, at 9% and 9.4%, respectively.
There were more immune-mediated adverse events in the pembrolizumab arm than in the chemotherapy arm (27.8% vs 7.2%, respectively), and of those, grade 3 or higher events occurred in 8% and 1.5% of patients. There was 1 immune-mediated death, from pneumonitis, in the immunotherapy arm; there were no deaths related to immune-mediated side effects in the chemotherapy arm.
“I really view this as a ‘double whammy’ for patients,” Dr Heymach said at the briefing. “Often advances in survival for our lung cancer patients come at the cost of significant toxicities. Here, by contrast, not only are patients living longer and having a much higher likelihood of prolonged survival in years, often instead of months, but they’re also receiving a treatment that has substantially less toxicity across virtually all measures, and this really impacts the day-to-day life of these patients.”
Leena Gandhi, MD, PhD, of the Perlmutter Cancer Center at New York University, the invited discussant at the plenary, agreed that pembrolizumab improves survival, compared with chemotherapy patients with PD-L1 expression levels greater than 1%, but noted that most of the benefit – as also seen in Keynote-024 – was in those patients whose tumors had high levels of PD-L1 expression.
She emphasized that although PD-L1 is an imperfect biomarker, it should still be used to help select patients for therapy and it may be complementary with tumor mutational burden for more precise treatment selection.
“What we know, and what this study adds to, is that PD-L1 really does define a patient population that could receive benefit from pembrolizumab over chemotherapy. Patients with low or no PD-L1 expression likely should get some type of combination therapy,” she said. “This study extends what we’ve seen from other recent studies, which is that chemotherapy alone is no longer a first-line standard of care in non–small-cell lung cancer.”
— Neil Osterweil
Maintenance chemo improves survival in youth with rhabdomyosarcoma
Key clinical point 6 months of maintenance chemotherapy improves survival in youth with high-risk rhabdomyosarcoma. Major finding Patients given maintenance low-dose vinorelbine and cyclophosphamide had better 5-year OS compared with those not receiving any additional treatment (86.5% vs 73.7%; HR, 0.52). Study details A phase 3 randomized controlled trial in 371 patients aged 0-21 years with high-risk rhabdomyosarcoma who had had a complete response to standard intensive therapy. Funding The study received funding from Fondazione Città della Speranza, Italy. Disclosures Dr Bisogno disclosed that he has a consulting or advisory role with Clinigen Group, and receives travel, accommodations, and/or expenses from Jazz Pharmaceuticals. Source Bisogno et al. ASCO 2018, Abstract LBA2. https://meetinglibrary.asco.org/record/161695/abstract
Six months of maintenance chemotherapy prolongs OS in youth with high-risk rhabdomyosarcoma, finds a phase 3 randomized controlled trial of the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG).
Rhabdomyosarcoma is a rare but highly aggressive tumor, lead study author Gianni Bisogno, MD, PhD, a professor at the University Hospital of Padova, Italy, and chair of the EpSSG, noted in a press briefing at the meeting, where the findings were reported. In pediatric patients who achieve complete response to standard therapy, “we know that after 1 or 2 years, one-third of these children relapse, and most of them die,” he said.
The EpSSG trial, which took about 10 years to conduct, enrolled 371 patients aged 0-21 years with high-risk rhabdomyosarcoma who had had a complete response to standard intensive therapy. They were randomized evenly to stop treatment or to receive 6 months of maintenance treatment consisting of low-dose vinorelbine and cyclophosphamide.
Results reported in the meeting’s plenary session showed that giving maintenance chemotherapy improved the 5-year OS rate by an absolute 12.8%, which translated to a near halving of the risk of death. And the maintenance regimen used was generally well tolerated.
“At the end of this long, not-easy study, we concluded that maintenance chemotherapy is an effective and well tolerated treatment for children with high-risk rhabdomyosarcoma,” Dr Bisogno said.
There are three possibilities for its efficacy, he speculated. “It may be the duration, the type of drugs used, or the metronomic approach. Maybe altogether, these three different actions have a benefit to increase survival.
“Our group has decided this is the new standard treatment for patients. At least in Europe, we give standard intensive therapy and then we continue with 6 more months of low-dose chemotherapy,” Dr Bisogno concluded. “We think that this approach – a new way of using old drugs – can be of interest also for other pediatric tumors.”
The trial is noteworthy in that it shows “how to successfully conduct large and important trials in rare diseases,” said ASCO expert Warren Chow, MD.
The standard therapy for rhabdomyosarcomas is somewhat different in the United States, typically a regimen containing vincristine, actinomycin D, cyclophosphamide, and (more recently) irinotecan, he noted. “We have not been traditionally using maintenance chemo for any of the pediatric sarcomas, so this is a paradigm shift. These results will need to be tested with US-based protocols before becoming standard of care in the United States. Also, we will need to determine if these results are applicable to patients older than 21 years of age who are considered high risk based solely on their age.
“Even with these caveats, this is the first significant treatment advance in this rare cancer in more than 30 years,” concluded Dr Chow, a medical oncologist and clinical professor at City of Hope, Duarte, Calif. “No doubt, this trial was a home run.”
Study details
Patients enrolled in the EpSSG trial had had a complete response to the standard intensive therapy used in Europe: high-dose chemotherapy (ifosfamide, vincristine, and actinomycin D, with or without doxorubicin), radiation therapy, and surgery.
The maintenance chemotherapy consisted of a combination of low-dose intravenous vinorelbine given weekly and oral cyclophosphamide given daily. The 6-month duration was somewhat arbitrary, according to Dr Bisogno. “We had to start somewhere. So when we started, we decided to use 6 months because there was some evidence in the past for regimens that long. In our next European trial, we are going to test different kinds and durations of maintenance because this is very important.”
The maintenance regimen was well tolerated compared with the regimen given during standard intensive therapy, with, for example, lower rates of grade 3 and 4 anemia (8.9% vs 48.9%), neutropenia (80.6% vs 91.6%), and thrombocytopenia (0.6% vs 26.0%), which translated to less of a need for transfusions, and a lower rate of grade 3 or 4 infection (29.4% vs 56.4%), Dr Bisogno reported. There were no cases of grade 3 or 4 cardiac, hepatobiliary/pancreatic, or renal toxicity.
Relative to peers who stopped treatment after standard intensive therapy, patients who received maintenance treatment tended to have better DFS (77.6% vs 69.8%; HR, 0.68; P = .0613) and had significantly better OS (86.5% vs 73.7%; HR, 0.52; P = .0111).
— Susan London