Journal of Clinical Outcomes Management

Testing for HER2 in patients with colorectal cancer (CRC) should become a new standard of care, say experts discussing new results from a phase 2 trial showing benefit with trastuzumab deruxtecan (T-DXd, marketed as Enhertu, AstraZeneca/Daiichi Sankyo).

This drug is approved in the United States for use in the treatment of unresectable or metastatic HER2-positive breast cancer in patients who have already received two or more prior anti–HER2-based regimens in the metastatic setting.

Results come from a phase 2 study, dubbed DESTINY-CRC01, in patients with previously treated HER2+ advanced CRC.

The results show that, in patients with the highest degree of HER2 positivity, T-DXd was associated with an objective response rate of over 45% and a median progression-free survival (PFS) of almost 7 months.

They “demonstrate, in our opinion, the potential of T-DXd as a treatment option” for patients with advanced HER2-positive colorectal cancer that is refractory to standard therapies, said lead investigator Salvatore Siena, MD, from Niguarda Cancer Center, in Milan, Italy.

He presented the results at the 2020 annual meeting of the American Society of Clinical Oncology, held virtually because of the coronavirus pandemic.

At the same time, results from another study, this time in gastric cancer patients, were published online in the New England Journal of Medicine.
 

Interstitial lung disease as adverse event

The safety profile of T-DXd seen in the colorectal trial “is consistent with what has been previously reported,” said Siena, adding that most of the adverse events were low grade. But he noted there was also a serious adverse effect – interstitial lung disease (ILD). This occurred in 6% of patients, two of whom died. This is “an important risk and requires careful monitoring and proper intervention,” he emphasized.

The ILD adverse effect in this study is “a concern…and something to consider,” commented discussant for the study Michael S. Lee, MD, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill. But he added that these are the “the best data so far for subsequent anti-HER2 therapy in colorectal cancer”.

Also, the dose of drug used in this trial was higher than that approved for breast cancer, and the incidence of ILD “begs the question of whether we should be using a lower dose in this patient population,” said Autumn J. McRee, MD, also from Lineberger, in a highlights session at the meeting.

“The question here really is whether an HER2-specific approach is superior to what we would offer to these patients in the standard of care setting,” McRee said.

She noted that the patients in DESTINY-CRC01 were “heavily pretreated…and if you think about what our options are in the refractory setting, we do have two approved treatments: regorafenib [Stivarga, Bayer] and TAS-102 [Lonsurf, Taiho Oncology].”

The current data suggest, however, that T-DXd is associated with a trend toward higher response rates and improved survival outcomes, as well as lower monthly costs.

“Without a doubt, this trial is clinically relevant,” she said, adding that it’s “important not to miss these patients.”

“They are rare…but I would argue that testing for HER2 amplification in colorectal cancer should be considered standard of care,” she said.

She added that, based on the current evidence, the trial “may be” practice changing, although it is “still to be determined how to sequence HER2 targeted therapies.”
 

Study details

The trial was conducted in 78 patients with previously treated unresectable and/or metastatic CRC that was HER2 expressing, RAS/BRAF wild type, and patients had to have received at least two prior regimens, including prior anti-HER2 treatment. Patients with current or suspected ILD were excluded.

Patients were divided into three cohorts based on the degree of HER2 positivity:

• HER2+ with immunohistochemistry (IHC) scoring 3+ or IHC2+/in-situ-hybridization (ISH)+ (cohort A, n = 53)
• HER2 IHC2+/ISH– (cohort B, n = 7)
• HER2 IHC1+ (cohort C, n = 18)

All patients received T-DXd at 6.4 mg/kg intravenously every 3 weeks until progression or intolerable toxicity.

Across the three cohorts, the median age was 58.5 years, and nearly half (47.4%) of patients were female. The vast majority (98.7%) of patents had ECOG performance status 0 or 1, and the primary tumor site was the left colon or rectum in 89.7%.

Siena noted that “the median number of prior lines of standard therapies was four, ranging from two to 11.” All patients had previously received irinotecan and oxaliplatin, and 20.5% had received an anti-HER2 drug.

At the data cutoff on August 9, 2019, 38.5% of patients remained on treatment. The reason for discontinuation was progressive disease in 41%, and clinical progression in 9%.

Siena reported that the overall response rate, as confirmed by independent central review, was 45.3% in cohort A, with all but one of the 24 responders having a partial response. No responses were recorded in cohorts B and C.

Stable disease was seen in 37.7% of cohort A patients, giving a disease control rate of 83%. The median duration of response was not reached.

Median PFS was 6.9 months in cohort A, and the medial overall survival was not reached.

In terms of safety, 50.9% of patients in cohort A and 48.7% patients overall experienced drug-related treatment emergent adverse events, with 22.6% and 17.9%, respectively, having serious drug-related events.

The most common treatment-emergent adverse events were nausea, anemia, reduced neutrophil count, fatigue, and decreased appetite.

There were two deaths related to the study drug, as determined by investigator assessment: one from pneumonitis and one as a result of ILD, with both occurring in cohort A.

Looking specifically at ILD, Siena said there were five events – two grade 2, one grade 3, and two grade 5 – at a median time to reported onset of 80 days. All patients received corticosteroids, as per the study protocol, and two recovered.

Study discussant Lee commented that biomarker testing, such as for HER2, “is part of our standard of care for colorectal cancer,” although studies such as the current one are providing new data to “better refine” treatment approaches.

Lee said that, overall, T-DXd had a response rate and PFS survival “that looked similar to prior data from previous single arm phase 2 studies,” with response rates generally ranging from 30% to 50%, “and this compares favorably with other standard of care options” for chemotherapy-refractory patients.

Nevertheless, there are several ongoing questions related to the treatment of HER2 amplified metastatic CRC patients, some of which are being addressed in the ongoing SWOG S1613 study.

Lee said that, for now, he would recommend that patients with HER2 amplification enroll in a clinical trial, if possible. “However, if that’s not feasible, there are a range of options to consider,” including trastuzumab plus lapatinib (Tykerb, Novartis), or trastuzumab plus pembrolizumab (Keytruda, Merck).

However, “none of these options are FDA approved so there will be issues potentially with financial toxicity and other regulatory issues,” he said.

The study was funded by Daiichi Sankyo Co, Ltd.

Siena reports stock and other ownership interests with Guardant Health and Myriad Genetics; a consulting or advisory role with Amgen, Bayer, Bristol-Myers Squibb, CheckmAb, Clovis Oncology, Daiichi Sankyo, Incyte, Merck, Novartis, Roche/Genentech, Seattle Genetics; research funding from MSD Oncology (Inst); patents, royalties, and other intellectual property from Amgen; and travel, accommodations, expenses from Amgen, Bayer, and Roche. Other coauthors report potential conflicts of interest. The full list can be found with the original article.

Lee reports: Research Funding – Amgen (Inst); Bristol-Myers Squibb (Inst); EMD Serono (Inst); Exelixis (Inst); Genentech/Roche (Inst); Pfizer (Inst); Travel, Accommodations, Expenses – Genentech/Roche.

McRee reports honoraria from Cor2Ed and Onc Live; research funding from AstraZeneca (Inst), BioMed Valley Discoveries (Inst), Boston Biomedical (Inst), Inovio Pharmaceuticals (Inst), Merck (Inst), Novartis (Inst), Rgenix (Inst), and Takeda (Inst); and travel, accommodations, expenses from Cor2Ed.

This article first appeared on Medscape.com.

Testing for HER2 in patients with colorectal cancer (CRC) should become a new standard of care, say experts discussing new results from a phase 2 trial showing benefit with trastuzumab deruxtecan (T-DXd, marketed as Enhertu, AstraZeneca/Daiichi Sankyo).

This drug is approved in the United States for use in the treatment of unresectable or metastatic HER2-positive breast cancer in patients who have already received two or more prior anti–HER2-based regimens in the metastatic setting.

Results come from a phase 2 study, dubbed DESTINY-CRC01, in patients with previously treated HER2+ advanced CRC.

The results show that, in patients with the highest degree of HER2 positivity, T-DXd was associated with an objective response rate of over 45% and a median progression-free survival (PFS) of almost 7 months.

They “demonstrate, in our opinion, the potential of T-DXd as a treatment option” for patients with advanced HER2-positive colorectal cancer that is refractory to standard therapies, said lead investigator Salvatore Siena, MD, from Niguarda Cancer Center, in Milan, Italy.

He presented the results at the 2020 annual meeting of the American Society of Clinical Oncology, held virtually because of the coronavirus pandemic.

At the same time, results from another study, this time in gastric cancer patients, were published online in the New England Journal of Medicine.
 

Interstitial lung disease as adverse event

The safety profile of T-DXd seen in the colorectal trial “is consistent with what has been previously reported,” said Siena, adding that most of the adverse events were low grade. But he noted there was also a serious adverse effect – interstitial lung disease (ILD). This occurred in 6% of patients, two of whom died. This is “an important risk and requires careful monitoring and proper intervention,” he emphasized.

The ILD adverse effect in this study is “a concern…and something to consider,” commented discussant for the study Michael S. Lee, MD, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill. But he added that these are the “the best data so far for subsequent anti-HER2 therapy in colorectal cancer”.

Also, the dose of drug used in this trial was higher than that approved for breast cancer, and the incidence of ILD “begs the question of whether we should be using a lower dose in this patient population,” said Autumn J. McRee, MD, also from Lineberger, in a highlights session at the meeting.

“The question here really is whether an HER2-specific approach is superior to what we would offer to these patients in the standard of care setting,” McRee said.

She noted that the patients in DESTINY-CRC01 were “heavily pretreated…and if you think about what our options are in the refractory setting, we do have two approved treatments: regorafenib [Stivarga, Bayer] and TAS-102 [Lonsurf, Taiho Oncology].”

The current data suggest, however, that T-DXd is associated with a trend toward higher response rates and improved survival outcomes, as well as lower monthly costs.

“Without a doubt, this trial is clinically relevant,” she said, adding that it’s “important not to miss these patients.”

“They are rare…but I would argue that testing for HER2 amplification in colorectal cancer should be considered standard of care,” she said.

She added that, based on the current evidence, the trial “may be” practice changing, although it is “still to be determined how to sequence HER2 targeted therapies.”
 

Study details

The trial was conducted in 78 patients with previously treated unresectable and/or metastatic CRC that was HER2 expressing, RAS/BRAF wild type, and patients had to have received at least two prior regimens, including prior anti-HER2 treatment. Patients with current or suspected ILD were excluded.

Patients were divided into three cohorts based on the degree of HER2 positivity:

• HER2+ with immunohistochemistry (IHC) scoring 3+ or IHC2+/in-situ-hybridization (ISH)+ (cohort A, n = 53)
• HER2 IHC2+/ISH– (cohort B, n = 7)
• HER2 IHC1+ (cohort C, n = 18)

All patients received T-DXd at 6.4 mg/kg intravenously every 3 weeks until progression or intolerable toxicity.

Across the three cohorts, the median age was 58.5 years, and nearly half (47.4%) of patients were female. The vast majority (98.7%) of patents had ECOG performance status 0 or 1, and the primary tumor site was the left colon or rectum in 89.7%.

Siena noted that “the median number of prior lines of standard therapies was four, ranging from two to 11.” All patients had previously received irinotecan and oxaliplatin, and 20.5% had received an anti-HER2 drug.

At the data cutoff on August 9, 2019, 38.5% of patients remained on treatment. The reason for discontinuation was progressive disease in 41%, and clinical progression in 9%.

Siena reported that the overall response rate, as confirmed by independent central review, was 45.3% in cohort A, with all but one of the 24 responders having a partial response. No responses were recorded in cohorts B and C.

Stable disease was seen in 37.7% of cohort A patients, giving a disease control rate of 83%. The median duration of response was not reached.

Median PFS was 6.9 months in cohort A, and the medial overall survival was not reached.

In terms of safety, 50.9% of patients in cohort A and 48.7% patients overall experienced drug-related treatment emergent adverse events, with 22.6% and 17.9%, respectively, having serious drug-related events.

The most common treatment-emergent adverse events were nausea, anemia, reduced neutrophil count, fatigue, and decreased appetite.

There were two deaths related to the study drug, as determined by investigator assessment: one from pneumonitis and one as a result of ILD, with both occurring in cohort A.

Looking specifically at ILD, Siena said there were five events – two grade 2, one grade 3, and two grade 5 – at a median time to reported onset of 80 days. All patients received corticosteroids, as per the study protocol, and two recovered.

Study discussant Lee commented that biomarker testing, such as for HER2, “is part of our standard of care for colorectal cancer,” although studies such as the current one are providing new data to “better refine” treatment approaches.

Lee said that, overall, T-DXd had a response rate and PFS survival “that looked similar to prior data from previous single arm phase 2 studies,” with response rates generally ranging from 30% to 50%, “and this compares favorably with other standard of care options” for chemotherapy-refractory patients.

Nevertheless, there are several ongoing questions related to the treatment of HER2 amplified metastatic CRC patients, some of which are being addressed in the ongoing SWOG S1613 study.

Lee said that, for now, he would recommend that patients with HER2 amplification enroll in a clinical trial, if possible. “However, if that’s not feasible, there are a range of options to consider,” including trastuzumab plus lapatinib (Tykerb, Novartis), or trastuzumab plus pembrolizumab (Keytruda, Merck).

However, “none of these options are FDA approved so there will be issues potentially with financial toxicity and other regulatory issues,” he said.

The study was funded by Daiichi Sankyo Co, Ltd.

Siena reports stock and other ownership interests with Guardant Health and Myriad Genetics; a consulting or advisory role with Amgen, Bayer, Bristol-Myers Squibb, CheckmAb, Clovis Oncology, Daiichi Sankyo, Incyte, Merck, Novartis, Roche/Genentech, Seattle Genetics; research funding from MSD Oncology (Inst); patents, royalties, and other intellectual property from Amgen; and travel, accommodations, expenses from Amgen, Bayer, and Roche. Other coauthors report potential conflicts of interest. The full list can be found with the original article.

Lee reports: Research Funding – Amgen (Inst); Bristol-Myers Squibb (Inst); EMD Serono (Inst); Exelixis (Inst); Genentech/Roche (Inst); Pfizer (Inst); Travel, Accommodations, Expenses – Genentech/Roche.

McRee reports honoraria from Cor2Ed and Onc Live; research funding from AstraZeneca (Inst), BioMed Valley Discoveries (Inst), Boston Biomedical (Inst), Inovio Pharmaceuticals (Inst), Merck (Inst), Novartis (Inst), Rgenix (Inst), and Takeda (Inst); and travel, accommodations, expenses from Cor2Ed.

This article first appeared on Medscape.com.

Testing for HER2 in patients with colorectal cancer (CRC) should become a new standard of care, say experts discussing new results from a phase 2 trial showing benefit with trastuzumab deruxtecan (T-DXd, marketed as Enhertu, AstraZeneca/Daiichi Sankyo).

This drug is approved in the United States for use in the treatment of unresectable or metastatic HER2-positive breast cancer in patients who have already received two or more prior anti–HER2-based regimens in the metastatic setting.

Results come from a phase 2 study, dubbed DESTINY-CRC01, in patients with previously treated HER2+ advanced CRC.

The results show that, in patients with the highest degree of HER2 positivity, T-DXd was associated with an objective response rate of over 45% and a median progression-free survival (PFS) of almost 7 months.

They “demonstrate, in our opinion, the potential of T-DXd as a treatment option” for patients with advanced HER2-positive colorectal cancer that is refractory to standard therapies, said lead investigator Salvatore Siena, MD, from Niguarda Cancer Center, in Milan, Italy.

He presented the results at the 2020 annual meeting of the American Society of Clinical Oncology, held virtually because of the coronavirus pandemic.

At the same time, results from another study, this time in gastric cancer patients, were published online in the New England Journal of Medicine.
 

Interstitial lung disease as adverse event

The safety profile of T-DXd seen in the colorectal trial “is consistent with what has been previously reported,” said Siena, adding that most of the adverse events were low grade. But he noted there was also a serious adverse effect – interstitial lung disease (ILD). This occurred in 6% of patients, two of whom died. This is “an important risk and requires careful monitoring and proper intervention,” he emphasized.

The ILD adverse effect in this study is “a concern…and something to consider,” commented discussant for the study Michael S. Lee, MD, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill. But he added that these are the “the best data so far for subsequent anti-HER2 therapy in colorectal cancer”.

Also, the dose of drug used in this trial was higher than that approved for breast cancer, and the incidence of ILD “begs the question of whether we should be using a lower dose in this patient population,” said Autumn J. McRee, MD, also from Lineberger, in a highlights session at the meeting.

“The question here really is whether an HER2-specific approach is superior to what we would offer to these patients in the standard of care setting,” McRee said.

She noted that the patients in DESTINY-CRC01 were “heavily pretreated…and if you think about what our options are in the refractory setting, we do have two approved treatments: regorafenib [Stivarga, Bayer] and TAS-102 [Lonsurf, Taiho Oncology].”

The current data suggest, however, that T-DXd is associated with a trend toward higher response rates and improved survival outcomes, as well as lower monthly costs.

“Without a doubt, this trial is clinically relevant,” she said, adding that it’s “important not to miss these patients.”

“They are rare…but I would argue that testing for HER2 amplification in colorectal cancer should be considered standard of care,” she said.

She added that, based on the current evidence, the trial “may be” practice changing, although it is “still to be determined how to sequence HER2 targeted therapies.”
 

Study details

The trial was conducted in 78 patients with previously treated unresectable and/or metastatic CRC that was HER2 expressing, RAS/BRAF wild type, and patients had to have received at least two prior regimens, including prior anti-HER2 treatment. Patients with current or suspected ILD were excluded.

Patients were divided into three cohorts based on the degree of HER2 positivity:

• HER2+ with immunohistochemistry (IHC) scoring 3+ or IHC2+/in-situ-hybridization (ISH)+ (cohort A, n = 53)
• HER2 IHC2+/ISH– (cohort B, n = 7)
• HER2 IHC1+ (cohort C, n = 18)

All patients received T-DXd at 6.4 mg/kg intravenously every 3 weeks until progression or intolerable toxicity.

Across the three cohorts, the median age was 58.5 years, and nearly half (47.4%) of patients were female. The vast majority (98.7%) of patents had ECOG performance status 0 or 1, and the primary tumor site was the left colon or rectum in 89.7%.

Siena noted that “the median number of prior lines of standard therapies was four, ranging from two to 11.” All patients had previously received irinotecan and oxaliplatin, and 20.5% had received an anti-HER2 drug.

At the data cutoff on August 9, 2019, 38.5% of patients remained on treatment. The reason for discontinuation was progressive disease in 41%, and clinical progression in 9%.

Siena reported that the overall response rate, as confirmed by independent central review, was 45.3% in cohort A, with all but one of the 24 responders having a partial response. No responses were recorded in cohorts B and C.

Stable disease was seen in 37.7% of cohort A patients, giving a disease control rate of 83%. The median duration of response was not reached.

Median PFS was 6.9 months in cohort A, and the medial overall survival was not reached.

In terms of safety, 50.9% of patients in cohort A and 48.7% patients overall experienced drug-related treatment emergent adverse events, with 22.6% and 17.9%, respectively, having serious drug-related events.

The most common treatment-emergent adverse events were nausea, anemia, reduced neutrophil count, fatigue, and decreased appetite.

There were two deaths related to the study drug, as determined by investigator assessment: one from pneumonitis and one as a result of ILD, with both occurring in cohort A.

Looking specifically at ILD, Siena said there were five events – two grade 2, one grade 3, and two grade 5 – at a median time to reported onset of 80 days. All patients received corticosteroids, as per the study protocol, and two recovered.

Study discussant Lee commented that biomarker testing, such as for HER2, “is part of our standard of care for colorectal cancer,” although studies such as the current one are providing new data to “better refine” treatment approaches.

Lee said that, overall, T-DXd had a response rate and PFS survival “that looked similar to prior data from previous single arm phase 2 studies,” with response rates generally ranging from 30% to 50%, “and this compares favorably with other standard of care options” for chemotherapy-refractory patients.

Nevertheless, there are several ongoing questions related to the treatment of HER2 amplified metastatic CRC patients, some of which are being addressed in the ongoing SWOG S1613 study.

Lee said that, for now, he would recommend that patients with HER2 amplification enroll in a clinical trial, if possible. “However, if that’s not feasible, there are a range of options to consider,” including trastuzumab plus lapatinib (Tykerb, Novartis), or trastuzumab plus pembrolizumab (Keytruda, Merck).

However, “none of these options are FDA approved so there will be issues potentially with financial toxicity and other regulatory issues,” he said.

The study was funded by Daiichi Sankyo Co, Ltd.

Siena reports stock and other ownership interests with Guardant Health and Myriad Genetics; a consulting or advisory role with Amgen, Bayer, Bristol-Myers Squibb, CheckmAb, Clovis Oncology, Daiichi Sankyo, Incyte, Merck, Novartis, Roche/Genentech, Seattle Genetics; research funding from MSD Oncology (Inst); patents, royalties, and other intellectual property from Amgen; and travel, accommodations, expenses from Amgen, Bayer, and Roche. Other coauthors report potential conflicts of interest. The full list can be found with the original article.

Lee reports: Research Funding – Amgen (Inst); Bristol-Myers Squibb (Inst); EMD Serono (Inst); Exelixis (Inst); Genentech/Roche (Inst); Pfizer (Inst); Travel, Accommodations, Expenses – Genentech/Roche.

McRee reports honoraria from Cor2Ed and Onc Live; research funding from AstraZeneca (Inst), BioMed Valley Discoveries (Inst), Boston Biomedical (Inst), Inovio Pharmaceuticals (Inst), Merck (Inst), Novartis (Inst), Rgenix (Inst), and Takeda (Inst); and travel, accommodations, expenses from Cor2Ed.

This article first appeared on Medscape.com.

A study that claims to be the first review of all the available evidence of the effectiveness of physical distancing, face masks, and eye protection to prevent spread of COVID-19 and other respiratory diseases has quantified the effectiveness of these protective measures. The study found that greater physical distancing from an exposed person significantly reduces risk of transmission and that N95 masks, particularly for health care workers, are more effective than other face coverings.

The meta-analysis, published online in The Lancet (2020 Jun 2; doi.org/10.1016/ S0140-6736(20)31142-9) also marks the first evaluation of these protective measures in both community and health care settings for COVID-19, the study authors stated.

“The risk for infection is highly dependent on distance to the individual infected and the type of face mask and eye protection worn,” wrote Derek K. Chu, MD, PhD, of McMaster University in Hamilton, Ont., and colleagues, reporting on behalf of the COVID-19 Systematic Urgent Review Group Effort, or SURGE.

The study reported that physical distancing of at least 1 meter, or about a yard, “seems to be strongly associated with a large protective effect,” but that distancing of 2 meters or about 6 feet could be more effective.

The study involved a systematic review of 172 observational studies across six continents that evaluated distance measures, face masks, and eye protection to prevent transmission between patients with confirmed or probable COVID-19, other severe acute respiratory syndrome (SARS) disease, and Middle East respiratory syndrome (MERS), and their family members, caregivers and health care workers up to May 3, 2020. The meta-analysis involved pooled estimates from 44 comparative studies with 25,697 participants, including seven studies of COVID-19 with 6,674 participants. None of the studies included in the meta-analysis were randomized clinical trials.

A subanalysis of 29 unadjusted and 9 adjusted studies found that the absolute risk of infection in proximity to an exposed individual was 12.8% at 1 m and 2.6% at 2 m. The risk remained constant even when the six COVID-19 studies in this subanalysis were isolated and regardless of being in a health care or non–health-care setting. Each meter of increased distance resulted in a doubling in the change in relative risk (P = .041).

The study also identified what Dr. Chu and colleagues characterized as a “large reduction” in infection risk with the use of both N95 or similar respirators or face masks, with an adjusted risk of infection of 3.1% with a face covering vs. a 17.4% without. The researchers also found a stronger association in health care settings vs. non–health care settings, with a relative risk of 0.3 vs. 0.56, respectively (P = .049). The protective effect of N95 or similar respirators was greater than other masks, with adjusted odds ratios of 0.04 vs. 0.33 (P = .09).

Eye protection was found to reduce the risk of infection to 5.5% vs. 16% without eye protection.

The study also identified potential barriers to social distancing and use of masks and eye protection: discomfort, resource use “linked with potentially decreased equity,” less clear communication, and a perceived lack of empathy on the part of providers toward patients.

Dr. Chu and colleagues wrote that more “high-quality” research, including randomized trials of the optimal physical distance and evaluation of different mask types in non–health care settings “is urgently needed.” They added, “Policymakers at all levels should, therefore, strive to address equity implications for groups with currently limited access to face masks and eye protection.”

The goal of this study was to “inform WHO guidance documents,” the study noted. “Governments and the public health community can use our results to give clear advice for community settings and healthcare workers on these protective measures to reduce infection risk,” said study co-leader Holger Schünemann, MD, MSc, PhD, of McMaster University.

Prof. Raina MacIntyre, MBBS, PhD, head of the biosecurity research program at the Kirby Institute at the University of New South Wales in Sydney, who authored the comment that accompanied the article, said that this study provides evidence for stronger PPE guidelines.

“The Centers for Disease Control and Prevention initially recommended N95s for health workers treating COVID-19 patients, but later downgraded this to surgical masks and even cloth masks and bandannas when there was a supply shortage,” she said. “This study shows that N95s are superior masks and should prompt a review of guidelines that recommend anything less for health workers.”

Recommending anything less than N95 masks for health workers is like sending troops into battle “unarmed or with bows and arrows against a fully armed enemy,” she said. “We are not talking about a device that costs hundreds or thousands of dollars; a N95 costs less than a dollar to produce. All that is needed to address the supply shortage is political will.”

While the study has some shortcomings – namely that it didn’t provide a breakdown of positive tests among COVID-19 participants – it does provide important insight for physicians, Sachin Gupta, MD, a pulmonary and critical care specialist in San Francisco, said in an interview. “The strength of a meta-analysis is that you’re able to get a composite idea; that’s one up side to this,” he said. “They’re confirming what we knew: that distance matters; that more protective masks reduce risk of infection; and that eye protection has an important role.”

Dr. Chu and colleagues have no relevant financial relationships to disclose. One member of SURGE is participating in a clinical trial comparing medical masks and N95 respirators. The World Health Organization provided partial funding for the study.

SOURCE: Chu DK et al. Lancet. 2020 Jun 2; doi.org/10.1016/ S0140-6736(20)31142-9 .

A study that claims to be the first review of all the available evidence of the effectiveness of physical distancing, face masks, and eye protection to prevent spread of COVID-19 and other respiratory diseases has quantified the effectiveness of these protective measures. The study found that greater physical distancing from an exposed person significantly reduces risk of transmission and that N95 masks, particularly for health care workers, are more effective than other face coverings.

The meta-analysis, published online in The Lancet (2020 Jun 2; doi.org/10.1016/ S0140-6736(20)31142-9) also marks the first evaluation of these protective measures in both community and health care settings for COVID-19, the study authors stated.

“The risk for infection is highly dependent on distance to the individual infected and the type of face mask and eye protection worn,” wrote Derek K. Chu, MD, PhD, of McMaster University in Hamilton, Ont., and colleagues, reporting on behalf of the COVID-19 Systematic Urgent Review Group Effort, or SURGE.

The study reported that physical distancing of at least 1 meter, or about a yard, “seems to be strongly associated with a large protective effect,” but that distancing of 2 meters or about 6 feet could be more effective.

The study involved a systematic review of 172 observational studies across six continents that evaluated distance measures, face masks, and eye protection to prevent transmission between patients with confirmed or probable COVID-19, other severe acute respiratory syndrome (SARS) disease, and Middle East respiratory syndrome (MERS), and their family members, caregivers and health care workers up to May 3, 2020. The meta-analysis involved pooled estimates from 44 comparative studies with 25,697 participants, including seven studies of COVID-19 with 6,674 participants. None of the studies included in the meta-analysis were randomized clinical trials.

A subanalysis of 29 unadjusted and 9 adjusted studies found that the absolute risk of infection in proximity to an exposed individual was 12.8% at 1 m and 2.6% at 2 m. The risk remained constant even when the six COVID-19 studies in this subanalysis were isolated and regardless of being in a health care or non–health-care setting. Each meter of increased distance resulted in a doubling in the change in relative risk (P = .041).

The study also identified what Dr. Chu and colleagues characterized as a “large reduction” in infection risk with the use of both N95 or similar respirators or face masks, with an adjusted risk of infection of 3.1% with a face covering vs. a 17.4% without. The researchers also found a stronger association in health care settings vs. non–health care settings, with a relative risk of 0.3 vs. 0.56, respectively (P = .049). The protective effect of N95 or similar respirators was greater than other masks, with adjusted odds ratios of 0.04 vs. 0.33 (P = .09).

Eye protection was found to reduce the risk of infection to 5.5% vs. 16% without eye protection.

The study also identified potential barriers to social distancing and use of masks and eye protection: discomfort, resource use “linked with potentially decreased equity,” less clear communication, and a perceived lack of empathy on the part of providers toward patients.

Dr. Chu and colleagues wrote that more “high-quality” research, including randomized trials of the optimal physical distance and evaluation of different mask types in non–health care settings “is urgently needed.” They added, “Policymakers at all levels should, therefore, strive to address equity implications for groups with currently limited access to face masks and eye protection.”

The goal of this study was to “inform WHO guidance documents,” the study noted. “Governments and the public health community can use our results to give clear advice for community settings and healthcare workers on these protective measures to reduce infection risk,” said study co-leader Holger Schünemann, MD, MSc, PhD, of McMaster University.

Prof. Raina MacIntyre, MBBS, PhD, head of the biosecurity research program at the Kirby Institute at the University of New South Wales in Sydney, who authored the comment that accompanied the article, said that this study provides evidence for stronger PPE guidelines.

“The Centers for Disease Control and Prevention initially recommended N95s for health workers treating COVID-19 patients, but later downgraded this to surgical masks and even cloth masks and bandannas when there was a supply shortage,” she said. “This study shows that N95s are superior masks and should prompt a review of guidelines that recommend anything less for health workers.”

Recommending anything less than N95 masks for health workers is like sending troops into battle “unarmed or with bows and arrows against a fully armed enemy,” she said. “We are not talking about a device that costs hundreds or thousands of dollars; a N95 costs less than a dollar to produce. All that is needed to address the supply shortage is political will.”

While the study has some shortcomings – namely that it didn’t provide a breakdown of positive tests among COVID-19 participants – it does provide important insight for physicians, Sachin Gupta, MD, a pulmonary and critical care specialist in San Francisco, said in an interview. “The strength of a meta-analysis is that you’re able to get a composite idea; that’s one up side to this,” he said. “They’re confirming what we knew: that distance matters; that more protective masks reduce risk of infection; and that eye protection has an important role.”

Dr. Chu and colleagues have no relevant financial relationships to disclose. One member of SURGE is participating in a clinical trial comparing medical masks and N95 respirators. The World Health Organization provided partial funding for the study.

SOURCE: Chu DK et al. Lancet. 2020 Jun 2; doi.org/10.1016/ S0140-6736(20)31142-9 .

A study that claims to be the first review of all the available evidence of the effectiveness of physical distancing, face masks, and eye protection to prevent spread of COVID-19 and other respiratory diseases has quantified the effectiveness of these protective measures. The study found that greater physical distancing from an exposed person significantly reduces risk of transmission and that N95 masks, particularly for health care workers, are more effective than other face coverings.

The meta-analysis, published online in The Lancet (2020 Jun 2; doi.org/10.1016/ S0140-6736(20)31142-9) also marks the first evaluation of these protective measures in both community and health care settings for COVID-19, the study authors stated.

“The risk for infection is highly dependent on distance to the individual infected and the type of face mask and eye protection worn,” wrote Derek K. Chu, MD, PhD, of McMaster University in Hamilton, Ont., and colleagues, reporting on behalf of the COVID-19 Systematic Urgent Review Group Effort, or SURGE.

The study reported that physical distancing of at least 1 meter, or about a yard, “seems to be strongly associated with a large protective effect,” but that distancing of 2 meters or about 6 feet could be more effective.

The study involved a systematic review of 172 observational studies across six continents that evaluated distance measures, face masks, and eye protection to prevent transmission between patients with confirmed or probable COVID-19, other severe acute respiratory syndrome (SARS) disease, and Middle East respiratory syndrome (MERS), and their family members, caregivers and health care workers up to May 3, 2020. The meta-analysis involved pooled estimates from 44 comparative studies with 25,697 participants, including seven studies of COVID-19 with 6,674 participants. None of the studies included in the meta-analysis were randomized clinical trials.

A subanalysis of 29 unadjusted and 9 adjusted studies found that the absolute risk of infection in proximity to an exposed individual was 12.8% at 1 m and 2.6% at 2 m. The risk remained constant even when the six COVID-19 studies in this subanalysis were isolated and regardless of being in a health care or non–health-care setting. Each meter of increased distance resulted in a doubling in the change in relative risk (P = .041).

The study also identified what Dr. Chu and colleagues characterized as a “large reduction” in infection risk with the use of both N95 or similar respirators or face masks, with an adjusted risk of infection of 3.1% with a face covering vs. a 17.4% without. The researchers also found a stronger association in health care settings vs. non–health care settings, with a relative risk of 0.3 vs. 0.56, respectively (P = .049). The protective effect of N95 or similar respirators was greater than other masks, with adjusted odds ratios of 0.04 vs. 0.33 (P = .09).

Eye protection was found to reduce the risk of infection to 5.5% vs. 16% without eye protection.

The study also identified potential barriers to social distancing and use of masks and eye protection: discomfort, resource use “linked with potentially decreased equity,” less clear communication, and a perceived lack of empathy on the part of providers toward patients.

Dr. Chu and colleagues wrote that more “high-quality” research, including randomized trials of the optimal physical distance and evaluation of different mask types in non–health care settings “is urgently needed.” They added, “Policymakers at all levels should, therefore, strive to address equity implications for groups with currently limited access to face masks and eye protection.”

The goal of this study was to “inform WHO guidance documents,” the study noted. “Governments and the public health community can use our results to give clear advice for community settings and healthcare workers on these protective measures to reduce infection risk,” said study co-leader Holger Schünemann, MD, MSc, PhD, of McMaster University.

Prof. Raina MacIntyre, MBBS, PhD, head of the biosecurity research program at the Kirby Institute at the University of New South Wales in Sydney, who authored the comment that accompanied the article, said that this study provides evidence for stronger PPE guidelines.

“The Centers for Disease Control and Prevention initially recommended N95s for health workers treating COVID-19 patients, but later downgraded this to surgical masks and even cloth masks and bandannas when there was a supply shortage,” she said. “This study shows that N95s are superior masks and should prompt a review of guidelines that recommend anything less for health workers.”

Recommending anything less than N95 masks for health workers is like sending troops into battle “unarmed or with bows and arrows against a fully armed enemy,” she said. “We are not talking about a device that costs hundreds or thousands of dollars; a N95 costs less than a dollar to produce. All that is needed to address the supply shortage is political will.”

While the study has some shortcomings – namely that it didn’t provide a breakdown of positive tests among COVID-19 participants – it does provide important insight for physicians, Sachin Gupta, MD, a pulmonary and critical care specialist in San Francisco, said in an interview. “The strength of a meta-analysis is that you’re able to get a composite idea; that’s one up side to this,” he said. “They’re confirming what we knew: that distance matters; that more protective masks reduce risk of infection; and that eye protection has an important role.”

Dr. Chu and colleagues have no relevant financial relationships to disclose. One member of SURGE is participating in a clinical trial comparing medical masks and N95 respirators. The World Health Organization provided partial funding for the study.

SOURCE: Chu DK et al. Lancet. 2020 Jun 2; doi.org/10.1016/ S0140-6736(20)31142-9 .

The Navajo people have dealt with adversity that has tested our strength and resilience since our creation. In Navajo culture, the Holy People or gods challenged us with Naayee (monsters). We endured and learned from each Naayee, hunger, and death to name a few adversities. The COVID-19 pandemic, or “Big Cough” (Dikos Nitsaa’igii -19 in Navajo language) is a monster confronting the Navajo today. It has had significant impact on our nation and people.

The Navajo have the most cases of the COVID-19 virus of any tribe in the United States, and numbers as of May 31, 2020, are 5,348, with 246 confirmed deaths.¹ The Navajo Nation, which once lagged behind New York, has reported the largest per-capita infection rate in the United States.

These devastating numbers, which might be leveling off, are associated with Navajo people having higher-than-average numbers of diabetes, heart disease, and cancer. This is compounded with 30%-40% of homes having no electricity or running water, and a poverty rate of about 38%.²

Geographical and cultural factors also contribute to the inability to gain a foothold in mitigating the number of cases. The Navajo Nation is the largest tribe in the United States, covering 27,000 square miles over an arid, red rock expanse with canyons and mountains. The population is over 250,000,³ and Navajo have traditionally lived in matrilineal clan units throughout the reservation, the size of West Virginia. The family traditional dwelling, called a “hogan,” often is clustered together. Multiple generations live together in these units. The COVID-19 virus inflicted many Navajo and rapidly spread to the elderly in these close-proximity living quarters.

Most Navajo live away from services and grocery stores and travel back and forth for food and water, which contributes to the virus rapidly being transmitted among the community members. Education aimed at curbing travel and spread of the virus was issued with curfews, commands to stay at home and keep social distance, and protect elders. The Navajo leadership and traditional medicine people, meanwhile, advised the people to follow their cultural values by caring for family and community members and providing a safe environment.
 

Resources are spread out

There are only 13 stores in this expansive reservation,⁴ so tribal members rely on traveling to border towns, such as Farmington and Gallup, N.M., Families usually travel to these towns on weekends to replenish food and supplies. There has been a cluster of cases in Gallup, N.M., so to reduce the numbers, the town shut itself off from outsiders – including the Navajo people coming to buy food, do laundry, and get water and feed for livestock. This has affected and stressed the Navajo further in attempting to access necessities.

Access to health care is already challenging because of lack of transportation and distance. This has made it more difficult to access COVID-19 testing and more challenging to get the results back. The Indian Health Service has been the designated health care system for the Navajo since 1955. The Treaty of Bosque Redondo, signed by the Navajo in 1868, included the provision of health care, as well as education in exchange for tracts of land, that included the Navajo homeland or Dinetah.⁵

The Indian Health Service provides care with hospitals and clinics throughout the reservation. Some of the IHS facilities have been taken over by the Navajo, so there are four Navajo tribally controlled hospitals, along with one private hospital. Coordination of care for a pandemic is, therefore, more challenging to coordinate. This contributes to problems with coordination of the health care, establishing alternate care sites, accessing personal protective equipment, and providing testing sites. The Navajo Nation Council is working hard to equitably distribute the $600 million from the CARES Act.⁶

Dealing with the pandemic is compromised by chronic underfunding from the U.S. government. The treaty obligation of the U.S. government is to provide health care to all federally recognized Native Americans. The IHS, which has been designated to provide that care for a tribal person, gets one-third the Medicare dollars for health care provided for a person in the general population.⁷ Health factors have led to the public health issues of poorly controlled diabetes, obesity, and coronary artery disease, which is related to this underfunding and the high rate of COVID-19 cases. Parts of the reservation are also exposed to high levels of pollution from oil and gas wells from the coal-fueled power plants. Those exposed to these high levels of pollutions have a higher than average number of cases of COVID-19, higher than in areas where the pollution is markedly lower.⁸

The Navajo are having to rely on the strength and resilience of traditional Navajo culture and philosophy to confront this monster, Dikos Nitsaa’igii’ 19. We have relied on Western medicine and its limited resources but now need to empower the strength from our traditional ways of knowing. We have used this knowledge in times of adversity for hundreds of years. The Navajo elders and medicine people have reminded us we have dealt with monsters and know how to endure hardship and be resilient. This helps to ameliorate mental health conditions, but there are still issues that remain challenging.

Those having the virus go through times of shortness of breath, which produces anxiety and panic. The risk of death adds further stress, and for a family-oriented culture, the need to isolate from family adds further stress. For the elderly and young people with more serious disease having to go to the hospital alone without family, often far from home, is so challenging. Connecting family by phone or social media with those stricken is essential to decrease anxiety and isolation. Those infected with the virus can learn breathing exercises, which can help the damage from the virus and decrease emotional activation and triggers. Specific breathing techniques can be taught by medical providers. An effective breathing technique to reduce anxiety is coherent breathing, which is done by inhaling 6 seconds and exhaling for 6 seconds without holding your breath. Behavioral health practitioners are available in the tribal and IHS mental health clinics to refer patients to therapy support to manage anxiety and are available by telemedicine. Many of these programs are offering social media informational sessions for the Navajo community. Navajo people often access traditional healing for protection prayers and ceremonies. Some of the tribal and IHS programs provide traditional counselors to talk to. The Navajo access healing that focuses on restoring balance to the body, mind, and spirit.

Taking action against the virus by social distancing, hand washing, and wearing masks can go a long way in reducing anxiety and fear about getting the virus. Resources to help the Navajo Nation are coming from all over the world, from as far as Ireland,⁹ Doctors Without Borders, ¹⁰ and University of San Francisco.¹¹

Two resources that provide relief on the reservation are the Navajo Relief Fund and United Natives.
 

References

1. Navaho Times. 2020 May 27.

2. Ingalls A et al. BMC Obes. 2019 May 6. doi: 10.1186/s40608-019-0233-9.

3. U.S. Census 2010, as reported by discovernavajo.com.

4. Gould C et al. “Addressing food insecurity on the Navajo reservation through sustainable greenhouses.” 2018 Aug.

5. Native Knowledge 360. Smithsonian Institution. “Bosque Redondo.”

6. Personal communication, Carl Roessel Slater, Navajo Nation Council delegate.

7. IHS Profile Fact Sheet.

8. Wu X et al. medRxiv. 2020 Apr 27.

9. Carroll R. ”Irish support for Native American COVID-19 relief highlights historic bond.” The Guardian. 2020 May 9.

10. Capatides C. “Doctors Without Borders dispatches team to the Navajo Nation” CBS News. 2020 May 11.

11. Weiler N. “UCSF sends second wave of health workers to Navajo Nation.” UCSF.edu. 2020 May 21.
 

Dr. Roessel is a Navajo board-certified psychiatrist practicing in Santa Fe, N.M., working with the local indigenous population. She has special expertise in cultural psychiatry; her childhood was spent growing up in the Navajo Nation with her grandfather, who was a Navajo medicine man. Her psychiatric practice focuses on integrating indigenous knowledge and principles. Dr. Roessel is a distinguished fellow of the American Psychiatric Association. She has no disclosures.

The Navajo people have dealt with adversity that has tested our strength and resilience since our creation. In Navajo culture, the Holy People or gods challenged us with Naayee (monsters). We endured and learned from each Naayee, hunger, and death to name a few adversities. The COVID-19 pandemic, or “Big Cough” (Dikos Nitsaa’igii -19 in Navajo language) is a monster confronting the Navajo today. It has had significant impact on our nation and people.

The Navajo have the most cases of the COVID-19 virus of any tribe in the United States, and numbers as of May 31, 2020, are 5,348, with 246 confirmed deaths.¹ The Navajo Nation, which once lagged behind New York, has reported the largest per-capita infection rate in the United States.

These devastating numbers, which might be leveling off, are associated with Navajo people having higher-than-average numbers of diabetes, heart disease, and cancer. This is compounded with 30%-40% of homes having no electricity or running water, and a poverty rate of about 38%.²

Geographical and cultural factors also contribute to the inability to gain a foothold in mitigating the number of cases. The Navajo Nation is the largest tribe in the United States, covering 27,000 square miles over an arid, red rock expanse with canyons and mountains. The population is over 250,000,³ and Navajo have traditionally lived in matrilineal clan units throughout the reservation, the size of West Virginia. The family traditional dwelling, called a “hogan,” often is clustered together. Multiple generations live together in these units. The COVID-19 virus inflicted many Navajo and rapidly spread to the elderly in these close-proximity living quarters.

Most Navajo live away from services and grocery stores and travel back and forth for food and water, which contributes to the virus rapidly being transmitted among the community members. Education aimed at curbing travel and spread of the virus was issued with curfews, commands to stay at home and keep social distance, and protect elders. The Navajo leadership and traditional medicine people, meanwhile, advised the people to follow their cultural values by caring for family and community members and providing a safe environment.
 

Resources are spread out

There are only 13 stores in this expansive reservation,⁴ so tribal members rely on traveling to border towns, such as Farmington and Gallup, N.M., Families usually travel to these towns on weekends to replenish food and supplies. There has been a cluster of cases in Gallup, N.M., so to reduce the numbers, the town shut itself off from outsiders – including the Navajo people coming to buy food, do laundry, and get water and feed for livestock. This has affected and stressed the Navajo further in attempting to access necessities.

Access to health care is already challenging because of lack of transportation and distance. This has made it more difficult to access COVID-19 testing and more challenging to get the results back. The Indian Health Service has been the designated health care system for the Navajo since 1955. The Treaty of Bosque Redondo, signed by the Navajo in 1868, included the provision of health care, as well as education in exchange for tracts of land, that included the Navajo homeland or Dinetah.⁵

The Indian Health Service provides care with hospitals and clinics throughout the reservation. Some of the IHS facilities have been taken over by the Navajo, so there are four Navajo tribally controlled hospitals, along with one private hospital. Coordination of care for a pandemic is, therefore, more challenging to coordinate. This contributes to problems with coordination of the health care, establishing alternate care sites, accessing personal protective equipment, and providing testing sites. The Navajo Nation Council is working hard to equitably distribute the $600 million from the CARES Act.⁶

Dealing with the pandemic is compromised by chronic underfunding from the U.S. government. The treaty obligation of the U.S. government is to provide health care to all federally recognized Native Americans. The IHS, which has been designated to provide that care for a tribal person, gets one-third the Medicare dollars for health care provided for a person in the general population.⁷ Health factors have led to the public health issues of poorly controlled diabetes, obesity, and coronary artery disease, which is related to this underfunding and the high rate of COVID-19 cases. Parts of the reservation are also exposed to high levels of pollution from oil and gas wells from the coal-fueled power plants. Those exposed to these high levels of pollutions have a higher than average number of cases of COVID-19, higher than in areas where the pollution is markedly lower.⁸

The Navajo are having to rely on the strength and resilience of traditional Navajo culture and philosophy to confront this monster, Dikos Nitsaa’igii’ 19. We have relied on Western medicine and its limited resources but now need to empower the strength from our traditional ways of knowing. We have used this knowledge in times of adversity for hundreds of years. The Navajo elders and medicine people have reminded us we have dealt with monsters and know how to endure hardship and be resilient. This helps to ameliorate mental health conditions, but there are still issues that remain challenging.

Those having the virus go through times of shortness of breath, which produces anxiety and panic. The risk of death adds further stress, and for a family-oriented culture, the need to isolate from family adds further stress. For the elderly and young people with more serious disease having to go to the hospital alone without family, often far from home, is so challenging. Connecting family by phone or social media with those stricken is essential to decrease anxiety and isolation. Those infected with the virus can learn breathing exercises, which can help the damage from the virus and decrease emotional activation and triggers. Specific breathing techniques can be taught by medical providers. An effective breathing technique to reduce anxiety is coherent breathing, which is done by inhaling 6 seconds and exhaling for 6 seconds without holding your breath. Behavioral health practitioners are available in the tribal and IHS mental health clinics to refer patients to therapy support to manage anxiety and are available by telemedicine. Many of these programs are offering social media informational sessions for the Navajo community. Navajo people often access traditional healing for protection prayers and ceremonies. Some of the tribal and IHS programs provide traditional counselors to talk to. The Navajo access healing that focuses on restoring balance to the body, mind, and spirit.

Taking action against the virus by social distancing, hand washing, and wearing masks can go a long way in reducing anxiety and fear about getting the virus. Resources to help the Navajo Nation are coming from all over the world, from as far as Ireland,⁹ Doctors Without Borders, ¹⁰ and University of San Francisco.¹¹

Two resources that provide relief on the reservation are the Navajo Relief Fund and United Natives.
 

References

1. Navaho Times. 2020 May 27.

2. Ingalls A et al. BMC Obes. 2019 May 6. doi: 10.1186/s40608-019-0233-9.

3. U.S. Census 2010, as reported by discovernavajo.com.

4. Gould C et al. “Addressing food insecurity on the Navajo reservation through sustainable greenhouses.” 2018 Aug.

5. Native Knowledge 360. Smithsonian Institution. “Bosque Redondo.”

6. Personal communication, Carl Roessel Slater, Navajo Nation Council delegate.

7. IHS Profile Fact Sheet.

8. Wu X et al. medRxiv. 2020 Apr 27.

9. Carroll R. ”Irish support for Native American COVID-19 relief highlights historic bond.” The Guardian. 2020 May 9.

10. Capatides C. “Doctors Without Borders dispatches team to the Navajo Nation” CBS News. 2020 May 11.

11. Weiler N. “UCSF sends second wave of health workers to Navajo Nation.” UCSF.edu. 2020 May 21.
 

Dr. Roessel is a Navajo board-certified psychiatrist practicing in Santa Fe, N.M., working with the local indigenous population. She has special expertise in cultural psychiatry; her childhood was spent growing up in the Navajo Nation with her grandfather, who was a Navajo medicine man. Her psychiatric practice focuses on integrating indigenous knowledge and principles. Dr. Roessel is a distinguished fellow of the American Psychiatric Association. She has no disclosures.

The Navajo people have dealt with adversity that has tested our strength and resilience since our creation. In Navajo culture, the Holy People or gods challenged us with Naayee (monsters). We endured and learned from each Naayee, hunger, and death to name a few adversities. The COVID-19 pandemic, or “Big Cough” (Dikos Nitsaa’igii -19 in Navajo language) is a monster confronting the Navajo today. It has had significant impact on our nation and people.

The Navajo have the most cases of the COVID-19 virus of any tribe in the United States, and numbers as of May 31, 2020, are 5,348, with 246 confirmed deaths.¹ The Navajo Nation, which once lagged behind New York, has reported the largest per-capita infection rate in the United States.

These devastating numbers, which might be leveling off, are associated with Navajo people having higher-than-average numbers of diabetes, heart disease, and cancer. This is compounded with 30%-40% of homes having no electricity or running water, and a poverty rate of about 38%.²

Geographical and cultural factors also contribute to the inability to gain a foothold in mitigating the number of cases. The Navajo Nation is the largest tribe in the United States, covering 27,000 square miles over an arid, red rock expanse with canyons and mountains. The population is over 250,000,³ and Navajo have traditionally lived in matrilineal clan units throughout the reservation, the size of West Virginia. The family traditional dwelling, called a “hogan,” often is clustered together. Multiple generations live together in these units. The COVID-19 virus inflicted many Navajo and rapidly spread to the elderly in these close-proximity living quarters.

Most Navajo live away from services and grocery stores and travel back and forth for food and water, which contributes to the virus rapidly being transmitted among the community members. Education aimed at curbing travel and spread of the virus was issued with curfews, commands to stay at home and keep social distance, and protect elders. The Navajo leadership and traditional medicine people, meanwhile, advised the people to follow their cultural values by caring for family and community members and providing a safe environment.
 

Resources are spread out

There are only 13 stores in this expansive reservation,⁴ so tribal members rely on traveling to border towns, such as Farmington and Gallup, N.M., Families usually travel to these towns on weekends to replenish food and supplies. There has been a cluster of cases in Gallup, N.M., so to reduce the numbers, the town shut itself off from outsiders – including the Navajo people coming to buy food, do laundry, and get water and feed for livestock. This has affected and stressed the Navajo further in attempting to access necessities.

Access to health care is already challenging because of lack of transportation and distance. This has made it more difficult to access COVID-19 testing and more challenging to get the results back. The Indian Health Service has been the designated health care system for the Navajo since 1955. The Treaty of Bosque Redondo, signed by the Navajo in 1868, included the provision of health care, as well as education in exchange for tracts of land, that included the Navajo homeland or Dinetah.⁵

The Indian Health Service provides care with hospitals and clinics throughout the reservation. Some of the IHS facilities have been taken over by the Navajo, so there are four Navajo tribally controlled hospitals, along with one private hospital. Coordination of care for a pandemic is, therefore, more challenging to coordinate. This contributes to problems with coordination of the health care, establishing alternate care sites, accessing personal protective equipment, and providing testing sites. The Navajo Nation Council is working hard to equitably distribute the $600 million from the CARES Act.⁶

Dealing with the pandemic is compromised by chronic underfunding from the U.S. government. The treaty obligation of the U.S. government is to provide health care to all federally recognized Native Americans. The IHS, which has been designated to provide that care for a tribal person, gets one-third the Medicare dollars for health care provided for a person in the general population.⁷ Health factors have led to the public health issues of poorly controlled diabetes, obesity, and coronary artery disease, which is related to this underfunding and the high rate of COVID-19 cases. Parts of the reservation are also exposed to high levels of pollution from oil and gas wells from the coal-fueled power plants. Those exposed to these high levels of pollutions have a higher than average number of cases of COVID-19, higher than in areas where the pollution is markedly lower.⁸

The Navajo are having to rely on the strength and resilience of traditional Navajo culture and philosophy to confront this monster, Dikos Nitsaa’igii’ 19. We have relied on Western medicine and its limited resources but now need to empower the strength from our traditional ways of knowing. We have used this knowledge in times of adversity for hundreds of years. The Navajo elders and medicine people have reminded us we have dealt with monsters and know how to endure hardship and be resilient. This helps to ameliorate mental health conditions, but there are still issues that remain challenging.

Those having the virus go through times of shortness of breath, which produces anxiety and panic. The risk of death adds further stress, and for a family-oriented culture, the need to isolate from family adds further stress. For the elderly and young people with more serious disease having to go to the hospital alone without family, often far from home, is so challenging. Connecting family by phone or social media with those stricken is essential to decrease anxiety and isolation. Those infected with the virus can learn breathing exercises, which can help the damage from the virus and decrease emotional activation and triggers. Specific breathing techniques can be taught by medical providers. An effective breathing technique to reduce anxiety is coherent breathing, which is done by inhaling 6 seconds and exhaling for 6 seconds without holding your breath. Behavioral health practitioners are available in the tribal and IHS mental health clinics to refer patients to therapy support to manage anxiety and are available by telemedicine. Many of these programs are offering social media informational sessions for the Navajo community. Navajo people often access traditional healing for protection prayers and ceremonies. Some of the tribal and IHS programs provide traditional counselors to talk to. The Navajo access healing that focuses on restoring balance to the body, mind, and spirit.

Taking action against the virus by social distancing, hand washing, and wearing masks can go a long way in reducing anxiety and fear about getting the virus. Resources to help the Navajo Nation are coming from all over the world, from as far as Ireland,⁹ Doctors Without Borders, ¹⁰ and University of San Francisco.¹¹

Two resources that provide relief on the reservation are the Navajo Relief Fund and United Natives.
 

References

1. Navaho Times. 2020 May 27.

2. Ingalls A et al. BMC Obes. 2019 May 6. doi: 10.1186/s40608-019-0233-9.

3. U.S. Census 2010, as reported by discovernavajo.com.

4. Gould C et al. “Addressing food insecurity on the Navajo reservation through sustainable greenhouses.” 2018 Aug.

5. Native Knowledge 360. Smithsonian Institution. “Bosque Redondo.”

6. Personal communication, Carl Roessel Slater, Navajo Nation Council delegate.

7. IHS Profile Fact Sheet.

8. Wu X et al. medRxiv. 2020 Apr 27.

9. Carroll R. ”Irish support for Native American COVID-19 relief highlights historic bond.” The Guardian. 2020 May 9.

10. Capatides C. “Doctors Without Borders dispatches team to the Navajo Nation” CBS News. 2020 May 11.

11. Weiler N. “UCSF sends second wave of health workers to Navajo Nation.” UCSF.edu. 2020 May 21.
 

Dr. Roessel is a Navajo board-certified psychiatrist practicing in Santa Fe, N.M., working with the local indigenous population. She has special expertise in cultural psychiatry; her childhood was spent growing up in the Navajo Nation with her grandfather, who was a Navajo medicine man. Her psychiatric practice focuses on integrating indigenous knowledge and principles. Dr. Roessel is a distinguished fellow of the American Psychiatric Association. She has no disclosures.

The Food and Drug Administration has approved atezolizumab (Tecentriq) in combination with bevacizumab (Avastin) to treat patients with unresectable or metastatic hepatocellular carcinoma who have not received prior systemic therapy.

The approval was supported by results from the IMbrave150 trial (N Engl J Med. 2020;382:1894-1905). This phase 3 trial enrolled 501 patients with hepatocellular carcinoma who were randomized to receive either sorafenib or atezolizumab plus bevacizumab.



The median overall survival was not reached in patients who received atezolizumab plus bevacizumab, but it was 13.2 months in patients who received sorafenib (hazard ratio, 0.58; 95% confidence interval, 0.42-0.79; P = .0006). The median progression-free survival was 6.8 months in patients who received atezolizumab plus bevacizumab and 4.3 months for those who received sorafenib.

The most common adverse events seen in the atezolizumab-bevacizumab arm were hypertension, fatigue, and proteinuria.

The recommended atezolizumab dose is 1,200 mg, followed by 15 mg/kg bevacizumab on the same day every 3 weeks.

The FDA collaborated with regulatory agencies from Canada, Australia, and Singapore on the review of the atezolizumab application, as part of Project Orbis. The FDA approved the application ahead of schedule. It is still under review for the other agencies.

[email protected]

The Food and Drug Administration has approved atezolizumab (Tecentriq) in combination with bevacizumab (Avastin) to treat patients with unresectable or metastatic hepatocellular carcinoma who have not received prior systemic therapy.

The approval was supported by results from the IMbrave150 trial (N Engl J Med. 2020;382:1894-1905). This phase 3 trial enrolled 501 patients with hepatocellular carcinoma who were randomized to receive either sorafenib or atezolizumab plus bevacizumab.



The median overall survival was not reached in patients who received atezolizumab plus bevacizumab, but it was 13.2 months in patients who received sorafenib (hazard ratio, 0.58; 95% confidence interval, 0.42-0.79; P = .0006). The median progression-free survival was 6.8 months in patients who received atezolizumab plus bevacizumab and 4.3 months for those who received sorafenib.

The most common adverse events seen in the atezolizumab-bevacizumab arm were hypertension, fatigue, and proteinuria.

The recommended atezolizumab dose is 1,200 mg, followed by 15 mg/kg bevacizumab on the same day every 3 weeks.

The FDA collaborated with regulatory agencies from Canada, Australia, and Singapore on the review of the atezolizumab application, as part of Project Orbis. The FDA approved the application ahead of schedule. It is still under review for the other agencies.

[email protected]

The Food and Drug Administration has approved atezolizumab (Tecentriq) in combination with bevacizumab (Avastin) to treat patients with unresectable or metastatic hepatocellular carcinoma who have not received prior systemic therapy.

The approval was supported by results from the IMbrave150 trial (N Engl J Med. 2020;382:1894-1905). This phase 3 trial enrolled 501 patients with hepatocellular carcinoma who were randomized to receive either sorafenib or atezolizumab plus bevacizumab.



The median overall survival was not reached in patients who received atezolizumab plus bevacizumab, but it was 13.2 months in patients who received sorafenib (hazard ratio, 0.58; 95% confidence interval, 0.42-0.79; P = .0006). The median progression-free survival was 6.8 months in patients who received atezolizumab plus bevacizumab and 4.3 months for those who received sorafenib.

The most common adverse events seen in the atezolizumab-bevacizumab arm were hypertension, fatigue, and proteinuria.

The recommended atezolizumab dose is 1,200 mg, followed by 15 mg/kg bevacizumab on the same day every 3 weeks.

The FDA collaborated with regulatory agencies from Canada, Australia, and Singapore on the review of the atezolizumab application, as part of Project Orbis. The FDA approved the application ahead of schedule. It is still under review for the other agencies.

[email protected]

More than 1 in 10 people with diabetes hospitalized with COVID-19 die within a week, while nearly a third require mechanical ventilation, new research shows.

Data from the CORONADO (French Coronavirus SARS-CoV-2 and Diabetes Outcomes) study also revealed that body mass index (BMI) was independently associated with death or intubation at 7 days, while A_1c and use of renin-angiotensin-aldosterone system (RAAS) blockers and dipeptidyl peptidase–4 inhibitors were not.

The presence of diabetes-related complications and older age also increased the risk of death.

The findings were published online Diabetologia by Bertrand Cariou, MD, PhD, of the department of endocrinology at the Hôpital Guillaume et René Laennec in Nantes, France, and colleagues.
 

First study to examine specific characteristics at time of admission

Previous studies have linked diabetes to worse outcomes in COVID-19, but this is the first to examine specific characteristics before and at the time of hospital admission that predict worse outcomes among people with diabetes, study coauthor Samy Hadjadj, MD, PhD, said in an interview.

“Before the CORONADO study it was ‘all diabetes [patients] are the same.’ Now we can surely consider more precisely the risk, taking age, sex, BMI, complications, and [obstructive sleep apnea] as clear ‘very high-risk situations,’” said Dr. Hadjadj, of the same institution as Dr. Cariou.

Another clinical message, Dr. Hadjadj said, is that, “even in diabetes, each increase in BMI is associated with an increase in the risk of intubation and/or death in the 7 days following admission for COVID-19. So let’s target this population as a really important population to keep social distancing and stay alert on avoiding the virus.”

But he urged caution regarding the A_1c finding. “A_1c might be associated with admission to hospital but other factors far beyond A_1c drive the prognosis as soon as a patient is admitted. It’s surprising but reasonable speculation can explain this.”

And Dr. Hadjadj said that no obvious signals were identified with regard to medication use.

“Insulin is not suspected of having adverse effects closely related to COVID-19. RAAS blockers are not deleterious but indicative of hypertension, which is a comorbidity even in diabetes patients,” he said. (None of the patients studied were taking sodium-glucose cotransporter 2 inhibitors or glucagonlike peptide receptor agonists.)
 

_{Yet again, high BMI emerges as a major risk factor}

The study included 1,317 patients with diabetes and confirmed COVID-19 admitted to 53 French hospitals during March 10-31, 2020. Participants included 88.5% with type 2 diabetes, 3% with type 1 diabetes, and 3.1% newly diagnosed on admission. Mean age was 69.8 years.

Diabetes-related disorders on admission were reported in 11.1% of participants overall. These included 132 episodes of severe hyperglycemia, including 40 of ketosis, of which 19 were ketoacidosis, and 14 hypoglycemic events. Severe anorexia was reported in 6.3%.

The composite primary endpoint, tracheal intubation for mechanical ventilation and/or death within 7 days of admission, occurred in 29% of patients (n = 382).

Of the secondary outcomes, 31.1% (n = 410) were admitted to ICUs within 7 days of hospital admission, including 20.3% (n = 267) who required tracheal intubation for mechanical ventilation.

On day 7, 10.6% (n = 140) had died and 18.0% (n = 237) were discharged.

In the univariate analysis, the primary outcome was more frequent in men (69.1% vs. 63.2%; P = .0420) and those taking RAAS blockers (61.5% vs. 55.3%; P = .0386). Median BMI was significantly higher in those in whom the primary outcome occurred (29.1 vs 28.1 kg/m²; P = .0009),

Other characteristics prior to admission associated with risk of death on day 7 included age, hypertension, micro- and macrovascular diabetes-related complications, and comorbidities such as heart failure and treated obstructive sleep apnea.

Over 40% of those admitted had such complications. Of the patients analyzed, microvascular complications (eye, kidney, and neuropathy) were present in 47% and macrovascular complications (arteries of the heart, brain, and legs) were present in 41%.

Encouragingly, there were no deaths in patients aged under 65 years with type 1 diabetes, but only 39 participants had type 1 diabetes. Other work is ongoing to establish the effect of COVID-19 in this specific population, the researchers wrote.

Among prior medications, metformin use was lower in people who died, while insulin use, RAAS blockers, beta-blockers, loop diuretics, and mineralocorticoid-receptor antagonists were associated with death on day 7. The medication findings didn’t reach statistical significance, however.

When asked about the hint of a protective effect of metformin (odds ratio, 0.80; P = .4532), given that some experts have advised stopping it in the setting of COVID-19 because of the risk of lactic acidosis, Dr. Hadjadj said he wouldn’t necessarily stop it in all patients with COVID-19, but said, “let’s stop it in cases of severe condition.”
 

Analysis ongoing, ‘some new messages might pop up’

After adjustment for age and sex, BMI was significantly and positively associated with the primary outcome (P = .0001) but not with death on day 7 (P = .1488), and A_1c wasn’t associated with either outcome.

In a multivariable analysis that included characteristics prior to admission, BMI remained the only independent preadmission predictor associated with the primary outcome (adjusted odds ratio, 1.28), while factors independently associated with risk of death on day 7 included age, diabetes complication history, and treated obstructive sleep apnea.

And after adjustment for age and sex, admission plasma glucose level was significantly and positively associated with both the primary outcome (P = .0001) and death on day 7 (P = .0059).

In the multivariate analysis, admission characteristics that predicted the primary outcome were dyspnea, lymphopenia, increased AST, and increased C-reactive protein.

Dr. Hadjadj said his team is now “focusing on specific risk factors such as obesity, age, vascular complications, medications ... to perform some deeper analyses.”

“We look forward to analyzing the data on in-hospital stay up to day 28 after admission. Some new messages might well pop up,” he added.

But in the meantime, “Elderly populations with long-term diabetes with advanced diabetes-related complications and/or treated obstructive sleep apnea were particularly at risk of early death and might require specific management to avoid infection with the novel coronavirus,” the researchers stressed.

The study received funding from the Fondation Francophone de Recherche sur le Diabète and was supported by Novo Nordisk, MSD, Abbott, AstraZeneca, Lilly, and the Fédération Française des Diabétiques; Société Francophone du Diabète; and Air Liquide Healthcare International. Dr. Hadjadj reported receiving grants, personal fees, and/or nonfinancial support from AstraZeneca, Bayer, Boehringer Ingelheim, Dinno Santé, Eli Lilly, LVL, MSD, Novartis, Pierre Fabre Santé, Sanofi, Servier, and Valbiotis.

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

More than 1 in 10 people with diabetes hospitalized with COVID-19 die within a week, while nearly a third require mechanical ventilation, new research shows.

Data from the CORONADO (French Coronavirus SARS-CoV-2 and Diabetes Outcomes) study also revealed that body mass index (BMI) was independently associated with death or intubation at 7 days, while A_1c and use of renin-angiotensin-aldosterone system (RAAS) blockers and dipeptidyl peptidase–4 inhibitors were not.

The presence of diabetes-related complications and older age also increased the risk of death.

The findings were published online Diabetologia by Bertrand Cariou, MD, PhD, of the department of endocrinology at the Hôpital Guillaume et René Laennec in Nantes, France, and colleagues.
 

First study to examine specific characteristics at time of admission

Previous studies have linked diabetes to worse outcomes in COVID-19, but this is the first to examine specific characteristics before and at the time of hospital admission that predict worse outcomes among people with diabetes, study coauthor Samy Hadjadj, MD, PhD, said in an interview.

“Before the CORONADO study it was ‘all diabetes [patients] are the same.’ Now we can surely consider more precisely the risk, taking age, sex, BMI, complications, and [obstructive sleep apnea] as clear ‘very high-risk situations,’” said Dr. Hadjadj, of the same institution as Dr. Cariou.

Another clinical message, Dr. Hadjadj said, is that, “even in diabetes, each increase in BMI is associated with an increase in the risk of intubation and/or death in the 7 days following admission for COVID-19. So let’s target this population as a really important population to keep social distancing and stay alert on avoiding the virus.”

But he urged caution regarding the A_1c finding. “A_1c might be associated with admission to hospital but other factors far beyond A_1c drive the prognosis as soon as a patient is admitted. It’s surprising but reasonable speculation can explain this.”

And Dr. Hadjadj said that no obvious signals were identified with regard to medication use.

“Insulin is not suspected of having adverse effects closely related to COVID-19. RAAS blockers are not deleterious but indicative of hypertension, which is a comorbidity even in diabetes patients,” he said. (None of the patients studied were taking sodium-glucose cotransporter 2 inhibitors or glucagonlike peptide receptor agonists.)
 

_{Yet again, high BMI emerges as a major risk factor}

The study included 1,317 patients with diabetes and confirmed COVID-19 admitted to 53 French hospitals during March 10-31, 2020. Participants included 88.5% with type 2 diabetes, 3% with type 1 diabetes, and 3.1% newly diagnosed on admission. Mean age was 69.8 years.

Diabetes-related disorders on admission were reported in 11.1% of participants overall. These included 132 episodes of severe hyperglycemia, including 40 of ketosis, of which 19 were ketoacidosis, and 14 hypoglycemic events. Severe anorexia was reported in 6.3%.

The composite primary endpoint, tracheal intubation for mechanical ventilation and/or death within 7 days of admission, occurred in 29% of patients (n = 382).

Of the secondary outcomes, 31.1% (n = 410) were admitted to ICUs within 7 days of hospital admission, including 20.3% (n = 267) who required tracheal intubation for mechanical ventilation.

On day 7, 10.6% (n = 140) had died and 18.0% (n = 237) were discharged.

In the univariate analysis, the primary outcome was more frequent in men (69.1% vs. 63.2%; P = .0420) and those taking RAAS blockers (61.5% vs. 55.3%; P = .0386). Median BMI was significantly higher in those in whom the primary outcome occurred (29.1 vs 28.1 kg/m²; P = .0009),

Other characteristics prior to admission associated with risk of death on day 7 included age, hypertension, micro- and macrovascular diabetes-related complications, and comorbidities such as heart failure and treated obstructive sleep apnea.

Over 40% of those admitted had such complications. Of the patients analyzed, microvascular complications (eye, kidney, and neuropathy) were present in 47% and macrovascular complications (arteries of the heart, brain, and legs) were present in 41%.

Encouragingly, there were no deaths in patients aged under 65 years with type 1 diabetes, but only 39 participants had type 1 diabetes. Other work is ongoing to establish the effect of COVID-19 in this specific population, the researchers wrote.

Among prior medications, metformin use was lower in people who died, while insulin use, RAAS blockers, beta-blockers, loop diuretics, and mineralocorticoid-receptor antagonists were associated with death on day 7. The medication findings didn’t reach statistical significance, however.

When asked about the hint of a protective effect of metformin (odds ratio, 0.80; P = .4532), given that some experts have advised stopping it in the setting of COVID-19 because of the risk of lactic acidosis, Dr. Hadjadj said he wouldn’t necessarily stop it in all patients with COVID-19, but said, “let’s stop it in cases of severe condition.”
 

Analysis ongoing, ‘some new messages might pop up’

After adjustment for age and sex, BMI was significantly and positively associated with the primary outcome (P = .0001) but not with death on day 7 (P = .1488), and A_1c wasn’t associated with either outcome.

In a multivariable analysis that included characteristics prior to admission, BMI remained the only independent preadmission predictor associated with the primary outcome (adjusted odds ratio, 1.28), while factors independently associated with risk of death on day 7 included age, diabetes complication history, and treated obstructive sleep apnea.

And after adjustment for age and sex, admission plasma glucose level was significantly and positively associated with both the primary outcome (P = .0001) and death on day 7 (P = .0059).

In the multivariate analysis, admission characteristics that predicted the primary outcome were dyspnea, lymphopenia, increased AST, and increased C-reactive protein.

Dr. Hadjadj said his team is now “focusing on specific risk factors such as obesity, age, vascular complications, medications ... to perform some deeper analyses.”

“We look forward to analyzing the data on in-hospital stay up to day 28 after admission. Some new messages might well pop up,” he added.

But in the meantime, “Elderly populations with long-term diabetes with advanced diabetes-related complications and/or treated obstructive sleep apnea were particularly at risk of early death and might require specific management to avoid infection with the novel coronavirus,” the researchers stressed.

The study received funding from the Fondation Francophone de Recherche sur le Diabète and was supported by Novo Nordisk, MSD, Abbott, AstraZeneca, Lilly, and the Fédération Française des Diabétiques; Société Francophone du Diabète; and Air Liquide Healthcare International. Dr. Hadjadj reported receiving grants, personal fees, and/or nonfinancial support from AstraZeneca, Bayer, Boehringer Ingelheim, Dinno Santé, Eli Lilly, LVL, MSD, Novartis, Pierre Fabre Santé, Sanofi, Servier, and Valbiotis.

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

More than 1 in 10 people with diabetes hospitalized with COVID-19 die within a week, while nearly a third require mechanical ventilation, new research shows.

Data from the CORONADO (French Coronavirus SARS-CoV-2 and Diabetes Outcomes) study also revealed that body mass index (BMI) was independently associated with death or intubation at 7 days, while A_1c and use of renin-angiotensin-aldosterone system (RAAS) blockers and dipeptidyl peptidase–4 inhibitors were not.

The presence of diabetes-related complications and older age also increased the risk of death.

The findings were published online Diabetologia by Bertrand Cariou, MD, PhD, of the department of endocrinology at the Hôpital Guillaume et René Laennec in Nantes, France, and colleagues.
 

First study to examine specific characteristics at time of admission

Previous studies have linked diabetes to worse outcomes in COVID-19, but this is the first to examine specific characteristics before and at the time of hospital admission that predict worse outcomes among people with diabetes, study coauthor Samy Hadjadj, MD, PhD, said in an interview.

“Before the CORONADO study it was ‘all diabetes [patients] are the same.’ Now we can surely consider more precisely the risk, taking age, sex, BMI, complications, and [obstructive sleep apnea] as clear ‘very high-risk situations,’” said Dr. Hadjadj, of the same institution as Dr. Cariou.

Another clinical message, Dr. Hadjadj said, is that, “even in diabetes, each increase in BMI is associated with an increase in the risk of intubation and/or death in the 7 days following admission for COVID-19. So let’s target this population as a really important population to keep social distancing and stay alert on avoiding the virus.”

But he urged caution regarding the A_1c finding. “A_1c might be associated with admission to hospital but other factors far beyond A_1c drive the prognosis as soon as a patient is admitted. It’s surprising but reasonable speculation can explain this.”

And Dr. Hadjadj said that no obvious signals were identified with regard to medication use.

“Insulin is not suspected of having adverse effects closely related to COVID-19. RAAS blockers are not deleterious but indicative of hypertension, which is a comorbidity even in diabetes patients,” he said. (None of the patients studied were taking sodium-glucose cotransporter 2 inhibitors or glucagonlike peptide receptor agonists.)
 

_{Yet again, high BMI emerges as a major risk factor}

The study included 1,317 patients with diabetes and confirmed COVID-19 admitted to 53 French hospitals during March 10-31, 2020. Participants included 88.5% with type 2 diabetes, 3% with type 1 diabetes, and 3.1% newly diagnosed on admission. Mean age was 69.8 years.

Diabetes-related disorders on admission were reported in 11.1% of participants overall. These included 132 episodes of severe hyperglycemia, including 40 of ketosis, of which 19 were ketoacidosis, and 14 hypoglycemic events. Severe anorexia was reported in 6.3%.

The composite primary endpoint, tracheal intubation for mechanical ventilation and/or death within 7 days of admission, occurred in 29% of patients (n = 382).

Of the secondary outcomes, 31.1% (n = 410) were admitted to ICUs within 7 days of hospital admission, including 20.3% (n = 267) who required tracheal intubation for mechanical ventilation.

On day 7, 10.6% (n = 140) had died and 18.0% (n = 237) were discharged.

In the univariate analysis, the primary outcome was more frequent in men (69.1% vs. 63.2%; P = .0420) and those taking RAAS blockers (61.5% vs. 55.3%; P = .0386). Median BMI was significantly higher in those in whom the primary outcome occurred (29.1 vs 28.1 kg/m²; P = .0009),

Other characteristics prior to admission associated with risk of death on day 7 included age, hypertension, micro- and macrovascular diabetes-related complications, and comorbidities such as heart failure and treated obstructive sleep apnea.

Over 40% of those admitted had such complications. Of the patients analyzed, microvascular complications (eye, kidney, and neuropathy) were present in 47% and macrovascular complications (arteries of the heart, brain, and legs) were present in 41%.

Encouragingly, there were no deaths in patients aged under 65 years with type 1 diabetes, but only 39 participants had type 1 diabetes. Other work is ongoing to establish the effect of COVID-19 in this specific population, the researchers wrote.

Among prior medications, metformin use was lower in people who died, while insulin use, RAAS blockers, beta-blockers, loop diuretics, and mineralocorticoid-receptor antagonists were associated with death on day 7. The medication findings didn’t reach statistical significance, however.

When asked about the hint of a protective effect of metformin (odds ratio, 0.80; P = .4532), given that some experts have advised stopping it in the setting of COVID-19 because of the risk of lactic acidosis, Dr. Hadjadj said he wouldn’t necessarily stop it in all patients with COVID-19, but said, “let’s stop it in cases of severe condition.”
 

Analysis ongoing, ‘some new messages might pop up’

After adjustment for age and sex, BMI was significantly and positively associated with the primary outcome (P = .0001) but not with death on day 7 (P = .1488), and A_1c wasn’t associated with either outcome.

In a multivariable analysis that included characteristics prior to admission, BMI remained the only independent preadmission predictor associated with the primary outcome (adjusted odds ratio, 1.28), while factors independently associated with risk of death on day 7 included age, diabetes complication history, and treated obstructive sleep apnea.

And after adjustment for age and sex, admission plasma glucose level was significantly and positively associated with both the primary outcome (P = .0001) and death on day 7 (P = .0059).

In the multivariate analysis, admission characteristics that predicted the primary outcome were dyspnea, lymphopenia, increased AST, and increased C-reactive protein.

Dr. Hadjadj said his team is now “focusing on specific risk factors such as obesity, age, vascular complications, medications ... to perform some deeper analyses.”

“We look forward to analyzing the data on in-hospital stay up to day 28 after admission. Some new messages might well pop up,” he added.

But in the meantime, “Elderly populations with long-term diabetes with advanced diabetes-related complications and/or treated obstructive sleep apnea were particularly at risk of early death and might require specific management to avoid infection with the novel coronavirus,” the researchers stressed.

The study received funding from the Fondation Francophone de Recherche sur le Diabète and was supported by Novo Nordisk, MSD, Abbott, AstraZeneca, Lilly, and the Fédération Française des Diabétiques; Société Francophone du Diabète; and Air Liquide Healthcare International. Dr. Hadjadj reported receiving grants, personal fees, and/or nonfinancial support from AstraZeneca, Bayer, Boehringer Ingelheim, Dinno Santé, Eli Lilly, LVL, MSD, Novartis, Pierre Fabre Santé, Sanofi, Servier, and Valbiotis.

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

As mass protests continued in large and small cities across the country, officials expressed concerns on Sunday news shows about a potential spike in coronavirus cases in coming days.

“There’s going to be a lot of issues coming out of what’s happened in the last week, but one of them is going to be that chains of transmission will have become lit from these gatherings,” said Scott Gottlieb, former FDA commissioner, on the CBS News show “Face the Nation.”

In Minnesota, he noted, COVID-19 cases and hospitalizations increased in recent days – even before the protests started.

“We still have pockets of spread in communities that aren’t under good control,” he said.

The protests generally have started peacefully with some demonstrators following physical distancing rules. But they have evolved into sometimes violent gatherings of hundreds or thousands of people where standing 6 feet apart is impossible.

Chanting, singing, and shouting may spread the virus through respiratory droplets. In addition, people who have the virus but don’t show symptoms may infect others without knowing it.

“If you were out protesting last night, you probably need to go get a COVID test this week,” Atlanta Mayor Keisha Lance Bottoms said Saturday, according to the Associated Press.

Gottlieb and Bottoms also spoke Sunday about the disproportionate effect of the coronavirus on black and Hispanic people, who are contracting and dying from the virus at higher rates. Socioeconomic factors such as low incomes, limited health care access, underlying conditions and overcrowded housing play a role in the greater risk, Gottlieb said.

“It’s a symptom of broader racial inequities in our country that we need to work to resolve,” he said.

Protests against racial injustice, sparked by the death of George Floyd in Minneapolis last week, could harm those communities experiencing the most severe outcomes of the coronavirus, Bottoms added.

“We know what’s already happening in our community with this virus. We’re going to see the other side of this in a couple of weeks,” Bottoms said on CNN’s “State of the Union.”

The protests may affect the pandemic in other ways. Los Angeles Mayor Eric Garcetti said the city’s coronavirus testing centers were closed on Saturday because of “safety worries across the city,” according to KTLA.

“We need to make sure, especially in communities that have less power, that we are able to make sure people don’t disproportionately die because of the color of their skin,” he said. “We can’t do that when the city breaks down.”

This article first appeared on WebMD.com.

As mass protests continued in large and small cities across the country, officials expressed concerns on Sunday news shows about a potential spike in coronavirus cases in coming days.

“There’s going to be a lot of issues coming out of what’s happened in the last week, but one of them is going to be that chains of transmission will have become lit from these gatherings,” said Scott Gottlieb, former FDA commissioner, on the CBS News show “Face the Nation.”

In Minnesota, he noted, COVID-19 cases and hospitalizations increased in recent days – even before the protests started.

“We still have pockets of spread in communities that aren’t under good control,” he said.

The protests generally have started peacefully with some demonstrators following physical distancing rules. But they have evolved into sometimes violent gatherings of hundreds or thousands of people where standing 6 feet apart is impossible.

Chanting, singing, and shouting may spread the virus through respiratory droplets. In addition, people who have the virus but don’t show symptoms may infect others without knowing it.

“If you were out protesting last night, you probably need to go get a COVID test this week,” Atlanta Mayor Keisha Lance Bottoms said Saturday, according to the Associated Press.

Gottlieb and Bottoms also spoke Sunday about the disproportionate effect of the coronavirus on black and Hispanic people, who are contracting and dying from the virus at higher rates. Socioeconomic factors such as low incomes, limited health care access, underlying conditions and overcrowded housing play a role in the greater risk, Gottlieb said.

“It’s a symptom of broader racial inequities in our country that we need to work to resolve,” he said.

Protests against racial injustice, sparked by the death of George Floyd in Minneapolis last week, could harm those communities experiencing the most severe outcomes of the coronavirus, Bottoms added.

“We know what’s already happening in our community with this virus. We’re going to see the other side of this in a couple of weeks,” Bottoms said on CNN’s “State of the Union.”

The protests may affect the pandemic in other ways. Los Angeles Mayor Eric Garcetti said the city’s coronavirus testing centers were closed on Saturday because of “safety worries across the city,” according to KTLA.

“We need to make sure, especially in communities that have less power, that we are able to make sure people don’t disproportionately die because of the color of their skin,” he said. “We can’t do that when the city breaks down.”

This article first appeared on WebMD.com.

As mass protests continued in large and small cities across the country, officials expressed concerns on Sunday news shows about a potential spike in coronavirus cases in coming days.

“There’s going to be a lot of issues coming out of what’s happened in the last week, but one of them is going to be that chains of transmission will have become lit from these gatherings,” said Scott Gottlieb, former FDA commissioner, on the CBS News show “Face the Nation.”

In Minnesota, he noted, COVID-19 cases and hospitalizations increased in recent days – even before the protests started.

“We still have pockets of spread in communities that aren’t under good control,” he said.

The protests generally have started peacefully with some demonstrators following physical distancing rules. But they have evolved into sometimes violent gatherings of hundreds or thousands of people where standing 6 feet apart is impossible.

Chanting, singing, and shouting may spread the virus through respiratory droplets. In addition, people who have the virus but don’t show symptoms may infect others without knowing it.

“If you were out protesting last night, you probably need to go get a COVID test this week,” Atlanta Mayor Keisha Lance Bottoms said Saturday, according to the Associated Press.

Gottlieb and Bottoms also spoke Sunday about the disproportionate effect of the coronavirus on black and Hispanic people, who are contracting and dying from the virus at higher rates. Socioeconomic factors such as low incomes, limited health care access, underlying conditions and overcrowded housing play a role in the greater risk, Gottlieb said.

“It’s a symptom of broader racial inequities in our country that we need to work to resolve,” he said.

Protests against racial injustice, sparked by the death of George Floyd in Minneapolis last week, could harm those communities experiencing the most severe outcomes of the coronavirus, Bottoms added.

“We know what’s already happening in our community with this virus. We’re going to see the other side of this in a couple of weeks,” Bottoms said on CNN’s “State of the Union.”

The protests may affect the pandemic in other ways. Los Angeles Mayor Eric Garcetti said the city’s coronavirus testing centers were closed on Saturday because of “safety worries across the city,” according to KTLA.

“We need to make sure, especially in communities that have less power, that we are able to make sure people don’t disproportionately die because of the color of their skin,” he said. “We can’t do that when the city breaks down.”

This article first appeared on WebMD.com.

Prior to the current crisis of COVID-19, I had a critical view of the direction of our psychiatric field. We have given up on complicated psychotherapies in favor of dispensing medications. We have given up on complicated diagnostic assessments in favor of simple self-rated symptoms questionnaires. Many of us even chose to give up on seeing patients face to face in favor of practicing telepsychiatry in the comfort of our homes. Some even promoted a future of psychiatry in which psychiatrists treated patients through large spreadsheets of evidence-based rating tools following evidence-based algorithms without even ever meeting the patients.

I do not view this problem as unique to psychiatry but rather as part of a larger trend in society. For the past couple of years, Vivek Murthy, MD, the former U.S. surgeon general, has popularized the idea that we are in a loneliness epidemic, saying, “We live in the most technologically connected age in the history of civilization, yet rates of loneliness have doubled since the 1980s.” Despite having enumerable means to reach other human beings, so many of us feel distant and out of touch with others. This loneliness has a measurable impact on our well-being with one study that states, “Actual and perceived social isolation are both associated with increased risk for early mortality.”

Then, seemingly out of nowhere, we were confronted with the largest challenge to our sense of connectedness in my lifetime. Throughout the past months, we have been asked to meet each other less frequently, do so through sterile means, and certainly not shake hands, hug, or embrace. The COVID-19 crisis has quickly made us all experts in telepsychiatry, remote work, and doing more with less. The COVID-19 crisis has asked many of us to put aside some of our human rituals like eating together, enjoying artistic experiences as a group, and touching, for the sake of saving lives.

For many, socially distancing has been a considerable added stressor – a stressor that continues to test humanity’s ability to be resilient. I am saddened by prior patients reaching out to seek comfort in these difficult times. I am touched by their desire to reconnect with someone they know, someone who feels familiar. I am surprised by the power of connection through phone and video calls. For some patients, despite the added burden, the current crisis has been an opportunity for their mental health and a reminder of the things that are important, including calling old friends and staying in touch with those who matter the most.

Yet, as the social restrictions continue, the stressors mount and the resilience becomes harder to find. Checking in on others can become a chore. The social norm to partake in fashion, and self-care, become harder to find. In some cases, even hygiene and our health take a side role. The weekly phone visits with a therapist can feel just as mundane and repetitive as life. Sleep becomes harder to find, and food loses its taste. At this point, we realize the humanity that we lost in all this.

In the past couple of months, we have all become much more aware of the fragility of connectedness. However, we should recognize that the impact was well on its way before the COVID-19 crisis. It is my opinion that psychiatry should champion the issue of human relations. I do not think that we need to wait for a new DSM diagnosis, an evidence-based paradigm, or a Food and Drug Administration–approved medication to do so. The COVID-19 crisis has rendered us all cognizant of the importance of relationships.

While it may be that psychiatry continues to foray in electronic means of communication, use of impersonal scales and diagnosis, as well as anonymized algorithmic treatment plans, we should also promote as much humanity as society and public health safety will permit. Getting dressed to see your psychiatrist, face to face, to have an open-ended conversation about the nature of one’s life has clearly become something precious and powerful that should be cherished and protected. My hope is the rules and mandates we are required to use during the pandemic today do not become a continued habit that result in further loneliness and disconnect. If we chose to, the lessons we learn today can, in fact, strengthen our appreciation and pursuit of human connection.
 

Dr. Badre is a forensic psychiatrist in San Diego and an expert in correctional mental health. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Among his writings is chapter 7 in the book “Critical Psychiatry: Controversies and Clinical Implications” (Springer, 2019). He has no disclosures.

Prior to the current crisis of COVID-19, I had a critical view of the direction of our psychiatric field. We have given up on complicated psychotherapies in favor of dispensing medications. We have given up on complicated diagnostic assessments in favor of simple self-rated symptoms questionnaires. Many of us even chose to give up on seeing patients face to face in favor of practicing telepsychiatry in the comfort of our homes. Some even promoted a future of psychiatry in which psychiatrists treated patients through large spreadsheets of evidence-based rating tools following evidence-based algorithms without even ever meeting the patients.

I do not view this problem as unique to psychiatry but rather as part of a larger trend in society. For the past couple of years, Vivek Murthy, MD, the former U.S. surgeon general, has popularized the idea that we are in a loneliness epidemic, saying, “We live in the most technologically connected age in the history of civilization, yet rates of loneliness have doubled since the 1980s.” Despite having enumerable means to reach other human beings, so many of us feel distant and out of touch with others. This loneliness has a measurable impact on our well-being with one study that states, “Actual and perceived social isolation are both associated with increased risk for early mortality.”

Then, seemingly out of nowhere, we were confronted with the largest challenge to our sense of connectedness in my lifetime. Throughout the past months, we have been asked to meet each other less frequently, do so through sterile means, and certainly not shake hands, hug, or embrace. The COVID-19 crisis has quickly made us all experts in telepsychiatry, remote work, and doing more with less. The COVID-19 crisis has asked many of us to put aside some of our human rituals like eating together, enjoying artistic experiences as a group, and touching, for the sake of saving lives.

For many, socially distancing has been a considerable added stressor – a stressor that continues to test humanity’s ability to be resilient. I am saddened by prior patients reaching out to seek comfort in these difficult times. I am touched by their desire to reconnect with someone they know, someone who feels familiar. I am surprised by the power of connection through phone and video calls. For some patients, despite the added burden, the current crisis has been an opportunity for their mental health and a reminder of the things that are important, including calling old friends and staying in touch with those who matter the most.

Yet, as the social restrictions continue, the stressors mount and the resilience becomes harder to find. Checking in on others can become a chore. The social norm to partake in fashion, and self-care, become harder to find. In some cases, even hygiene and our health take a side role. The weekly phone visits with a therapist can feel just as mundane and repetitive as life. Sleep becomes harder to find, and food loses its taste. At this point, we realize the humanity that we lost in all this.

In the past couple of months, we have all become much more aware of the fragility of connectedness. However, we should recognize that the impact was well on its way before the COVID-19 crisis. It is my opinion that psychiatry should champion the issue of human relations. I do not think that we need to wait for a new DSM diagnosis, an evidence-based paradigm, or a Food and Drug Administration–approved medication to do so. The COVID-19 crisis has rendered us all cognizant of the importance of relationships.

While it may be that psychiatry continues to foray in electronic means of communication, use of impersonal scales and diagnosis, as well as anonymized algorithmic treatment plans, we should also promote as much humanity as society and public health safety will permit. Getting dressed to see your psychiatrist, face to face, to have an open-ended conversation about the nature of one’s life has clearly become something precious and powerful that should be cherished and protected. My hope is the rules and mandates we are required to use during the pandemic today do not become a continued habit that result in further loneliness and disconnect. If we chose to, the lessons we learn today can, in fact, strengthen our appreciation and pursuit of human connection.
 

Dr. Badre is a forensic psychiatrist in San Diego and an expert in correctional mental health. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Among his writings is chapter 7 in the book “Critical Psychiatry: Controversies and Clinical Implications” (Springer, 2019). He has no disclosures.

Prior to the current crisis of COVID-19, I had a critical view of the direction of our psychiatric field. We have given up on complicated psychotherapies in favor of dispensing medications. We have given up on complicated diagnostic assessments in favor of simple self-rated symptoms questionnaires. Many of us even chose to give up on seeing patients face to face in favor of practicing telepsychiatry in the comfort of our homes. Some even promoted a future of psychiatry in which psychiatrists treated patients through large spreadsheets of evidence-based rating tools following evidence-based algorithms without even ever meeting the patients.

I do not view this problem as unique to psychiatry but rather as part of a larger trend in society. For the past couple of years, Vivek Murthy, MD, the former U.S. surgeon general, has popularized the idea that we are in a loneliness epidemic, saying, “We live in the most technologically connected age in the history of civilization, yet rates of loneliness have doubled since the 1980s.” Despite having enumerable means to reach other human beings, so many of us feel distant and out of touch with others. This loneliness has a measurable impact on our well-being with one study that states, “Actual and perceived social isolation are both associated with increased risk for early mortality.”

Then, seemingly out of nowhere, we were confronted with the largest challenge to our sense of connectedness in my lifetime. Throughout the past months, we have been asked to meet each other less frequently, do so through sterile means, and certainly not shake hands, hug, or embrace. The COVID-19 crisis has quickly made us all experts in telepsychiatry, remote work, and doing more with less. The COVID-19 crisis has asked many of us to put aside some of our human rituals like eating together, enjoying artistic experiences as a group, and touching, for the sake of saving lives.

For many, socially distancing has been a considerable added stressor – a stressor that continues to test humanity’s ability to be resilient. I am saddened by prior patients reaching out to seek comfort in these difficult times. I am touched by their desire to reconnect with someone they know, someone who feels familiar. I am surprised by the power of connection through phone and video calls. For some patients, despite the added burden, the current crisis has been an opportunity for their mental health and a reminder of the things that are important, including calling old friends and staying in touch with those who matter the most.

Yet, as the social restrictions continue, the stressors mount and the resilience becomes harder to find. Checking in on others can become a chore. The social norm to partake in fashion, and self-care, become harder to find. In some cases, even hygiene and our health take a side role. The weekly phone visits with a therapist can feel just as mundane and repetitive as life. Sleep becomes harder to find, and food loses its taste. At this point, we realize the humanity that we lost in all this.

In the past couple of months, we have all become much more aware of the fragility of connectedness. However, we should recognize that the impact was well on its way before the COVID-19 crisis. It is my opinion that psychiatry should champion the issue of human relations. I do not think that we need to wait for a new DSM diagnosis, an evidence-based paradigm, or a Food and Drug Administration–approved medication to do so. The COVID-19 crisis has rendered us all cognizant of the importance of relationships.

While it may be that psychiatry continues to foray in electronic means of communication, use of impersonal scales and diagnosis, as well as anonymized algorithmic treatment plans, we should also promote as much humanity as society and public health safety will permit. Getting dressed to see your psychiatrist, face to face, to have an open-ended conversation about the nature of one’s life has clearly become something precious and powerful that should be cherished and protected. My hope is the rules and mandates we are required to use during the pandemic today do not become a continued habit that result in further loneliness and disconnect. If we chose to, the lessons we learn today can, in fact, strengthen our appreciation and pursuit of human connection.
 

Dr. Badre is a forensic psychiatrist in San Diego and an expert in correctional mental health. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Among his writings is chapter 7 in the book “Critical Psychiatry: Controversies and Clinical Implications” (Springer, 2019). He has no disclosures.

In patients with newly diagnosed stage IV breast cancer and an intact primary tumor, locoregional therapy after optimal systemic therapy does not improve survival or quality of life, results of the phase 3 E2108 trial suggest.

Among 256 patients with stage IV breast cancer with intact primary tumors who had no disease progression for 4-8 months after the start of optimal systemic therapy, there were no significant differences in overall survival or progression-free survival between patients randomized to receive locoregional therapy and those who did not receive the locoregional treatment.

Although patients who did not receive locoregional treatment had a 150% higher rate of local recurrence/progression, health-related quality of life (HRQOL) was actually worse at 18 months among the patients who underwent locoregional therapy. There were no HRQOL differences at 6 months, 12 months, or 30 months of follow-up.

Seema A. Khan, MD, of Northwestern University, Chicago, reported these results during a plenary session broadcast as a part of the American Society of Clinical Oncology virtual scientific program.

“There is no hint here of an advantage in terms of survival with the use of early locoregional therapy for the primary site,” Dr. Khan said.

Although neither the E2108 trial nor similar trials showed an overall survival advantage for locoregional therapy, as many as 20% of patients who are treated with systemic therapy alone may need locoregional therapy with surgery and/or radiation at some point for palliation or progression, said invited discussant Julia R. White, MD, professor of radiation oncology at the Ohio State University, Columbus.

“Locoregional therapy should be reserved for these patients that become symptomatic or progress locally. There may be a role for routine locoregional therapy for de novo oligometastatic breast cancer in combination with systemic therapy plus ablative therapy” to secure long-term remission or cure, questions that are being addressed in ongoing clinical trials, Dr. White said.
 

Past data

An estimated 6% of newly diagnosed breast cancer patients present with stage IV disease and an intact primary tumor.

The rationale for locoregional therapy of the primary tumor in patients with metastatic disease is based on retrospective data suggesting a survival advantage. However, the studies were biased because of younger patient populations with small tumors, a higher proportion of estrogen receptor–positive disease, and a generally lower metastatic burden than that seen in the E2108 population, according to Dr. Khan.

She went on to cite two randomized trials with differing outcomes. One trial showed no survival advantage with locoregional therapy at 2 years (Lancet Oncol. 2015 Oct;16[13]:1380-8). The other showed an improvement in survival with locoregional therapy at 5 years (Ann Surg Oncol. 2018 Oct;25[11]:3141-9).
 

E2108 details

In the E2108 trial, patients first received optimal systemic therapy based on individual patient and disease features. Patients who had no disease progression or distant disease for at least 4-8 months of therapy were then randomized to additional therapy.

In one randomized arm, patients received continued systemic therapy alone. The other arm received early local therapy, which included complete tumor resection with free surgical margins and postoperative radiotherapy according to the standard of care.

A total of 390 patients were registered, and 256 went on to randomization. Of those subjects, 131 were randomized to the continued systemic therapy arm and 125 to the early local therapy arm. All patients in each arm were included in the efficacy analysis.

In all, 59.6% of randomized patients had hormone receptor–positive/HER2-negative disease, 8.2% had triple-negative disease, and 32.2% had HER2-positive disease. Metastases included bone-only disease in 37.9% of patients, visceral-only disease in 24.2%, and 40.9% in both sites.

Among the patients randomized to early local therapy, 14 did not have surgery for personal, clinical, or insurance reasons. Of the 109 who went on to surgery, 87 had clear surgical margins, and 74 received locoregional radiation therapy.
 

Survival, progression, and HRQOL

At a median follow-up of 53 months, the median overall survival was 54 months in each arm. There was no significant difference in survival between the study arms, with superimposable survival curves (hazard ratio, 1.09; P = .63).

An analysis of overall survival by tumor type showed that, for the 20 women with triple-negative disease, survival was worse with early local therapy (HR, 3.50). There were no differences in survival either for the 79 patients with HER2-positive disease or for the 137 patients with hormone receptor–positive/HER2-negative disease.

Locoregional progression occurred in 25.6% of patients assigned to continued systemic therapy, compared with 10.2% assigned to early local therapy. However, progression-free survival was virtually identical between the study arms (P = .40).

At most time points, there were no significant between-arm differences in HRQOL. The exception was at 18 months of follow-up, when the HRQOL was significantly lower among patients who had undergone early local therapy (P = .001).

“Based on available data, locoregional therapy for the primary tumor should not be offered to women with stage IV breast cancer with the expectation of a survival benefit. When systemic disease is well controlled with systemic therapy but the primary site is progressing, as does happen occasionally, locoregional treatment can be considered,” Dr. Khan concluded.

She noted there is an ongoing trial of similar design in Japan (JCOG-1017), with results expected in 2022.

The current trial was supported by the National Cancer Institute and Canadian Cancer Society. Dr. Khan reported no conflicts of interest. Dr. White reported institutional research funding from Intraop Medical.

SOURCE: Khan SA et al. ASCO 2020, Abstract LBA2.

In patients with newly diagnosed stage IV breast cancer and an intact primary tumor, locoregional therapy after optimal systemic therapy does not improve survival or quality of life, results of the phase 3 E2108 trial suggest.

Among 256 patients with stage IV breast cancer with intact primary tumors who had no disease progression for 4-8 months after the start of optimal systemic therapy, there were no significant differences in overall survival or progression-free survival between patients randomized to receive locoregional therapy and those who did not receive the locoregional treatment.

Although patients who did not receive locoregional treatment had a 150% higher rate of local recurrence/progression, health-related quality of life (HRQOL) was actually worse at 18 months among the patients who underwent locoregional therapy. There were no HRQOL differences at 6 months, 12 months, or 30 months of follow-up.

Seema A. Khan, MD, of Northwestern University, Chicago, reported these results during a plenary session broadcast as a part of the American Society of Clinical Oncology virtual scientific program.

“There is no hint here of an advantage in terms of survival with the use of early locoregional therapy for the primary site,” Dr. Khan said.

Although neither the E2108 trial nor similar trials showed an overall survival advantage for locoregional therapy, as many as 20% of patients who are treated with systemic therapy alone may need locoregional therapy with surgery and/or radiation at some point for palliation or progression, said invited discussant Julia R. White, MD, professor of radiation oncology at the Ohio State University, Columbus.

“Locoregional therapy should be reserved for these patients that become symptomatic or progress locally. There may be a role for routine locoregional therapy for de novo oligometastatic breast cancer in combination with systemic therapy plus ablative therapy” to secure long-term remission or cure, questions that are being addressed in ongoing clinical trials, Dr. White said.
 

Past data

An estimated 6% of newly diagnosed breast cancer patients present with stage IV disease and an intact primary tumor.

The rationale for locoregional therapy of the primary tumor in patients with metastatic disease is based on retrospective data suggesting a survival advantage. However, the studies were biased because of younger patient populations with small tumors, a higher proportion of estrogen receptor–positive disease, and a generally lower metastatic burden than that seen in the E2108 population, according to Dr. Khan.

She went on to cite two randomized trials with differing outcomes. One trial showed no survival advantage with locoregional therapy at 2 years (Lancet Oncol. 2015 Oct;16[13]:1380-8). The other showed an improvement in survival with locoregional therapy at 5 years (Ann Surg Oncol. 2018 Oct;25[11]:3141-9).
 

E2108 details

In the E2108 trial, patients first received optimal systemic therapy based on individual patient and disease features. Patients who had no disease progression or distant disease for at least 4-8 months of therapy were then randomized to additional therapy.

In one randomized arm, patients received continued systemic therapy alone. The other arm received early local therapy, which included complete tumor resection with free surgical margins and postoperative radiotherapy according to the standard of care.

A total of 390 patients were registered, and 256 went on to randomization. Of those subjects, 131 were randomized to the continued systemic therapy arm and 125 to the early local therapy arm. All patients in each arm were included in the efficacy analysis.

In all, 59.6% of randomized patients had hormone receptor–positive/HER2-negative disease, 8.2% had triple-negative disease, and 32.2% had HER2-positive disease. Metastases included bone-only disease in 37.9% of patients, visceral-only disease in 24.2%, and 40.9% in both sites.

Among the patients randomized to early local therapy, 14 did not have surgery for personal, clinical, or insurance reasons. Of the 109 who went on to surgery, 87 had clear surgical margins, and 74 received locoregional radiation therapy.
 

Survival, progression, and HRQOL

At a median follow-up of 53 months, the median overall survival was 54 months in each arm. There was no significant difference in survival between the study arms, with superimposable survival curves (hazard ratio, 1.09; P = .63).

An analysis of overall survival by tumor type showed that, for the 20 women with triple-negative disease, survival was worse with early local therapy (HR, 3.50). There were no differences in survival either for the 79 patients with HER2-positive disease or for the 137 patients with hormone receptor–positive/HER2-negative disease.

Locoregional progression occurred in 25.6% of patients assigned to continued systemic therapy, compared with 10.2% assigned to early local therapy. However, progression-free survival was virtually identical between the study arms (P = .40).

At most time points, there were no significant between-arm differences in HRQOL. The exception was at 18 months of follow-up, when the HRQOL was significantly lower among patients who had undergone early local therapy (P = .001).

“Based on available data, locoregional therapy for the primary tumor should not be offered to women with stage IV breast cancer with the expectation of a survival benefit. When systemic disease is well controlled with systemic therapy but the primary site is progressing, as does happen occasionally, locoregional treatment can be considered,” Dr. Khan concluded.

She noted there is an ongoing trial of similar design in Japan (JCOG-1017), with results expected in 2022.

The current trial was supported by the National Cancer Institute and Canadian Cancer Society. Dr. Khan reported no conflicts of interest. Dr. White reported institutional research funding from Intraop Medical.

SOURCE: Khan SA et al. ASCO 2020, Abstract LBA2.

In patients with newly diagnosed stage IV breast cancer and an intact primary tumor, locoregional therapy after optimal systemic therapy does not improve survival or quality of life, results of the phase 3 E2108 trial suggest.

Among 256 patients with stage IV breast cancer with intact primary tumors who had no disease progression for 4-8 months after the start of optimal systemic therapy, there were no significant differences in overall survival or progression-free survival between patients randomized to receive locoregional therapy and those who did not receive the locoregional treatment.

Although patients who did not receive locoregional treatment had a 150% higher rate of local recurrence/progression, health-related quality of life (HRQOL) was actually worse at 18 months among the patients who underwent locoregional therapy. There were no HRQOL differences at 6 months, 12 months, or 30 months of follow-up.

Seema A. Khan, MD, of Northwestern University, Chicago, reported these results during a plenary session broadcast as a part of the American Society of Clinical Oncology virtual scientific program.

“There is no hint here of an advantage in terms of survival with the use of early locoregional therapy for the primary site,” Dr. Khan said.

Although neither the E2108 trial nor similar trials showed an overall survival advantage for locoregional therapy, as many as 20% of patients who are treated with systemic therapy alone may need locoregional therapy with surgery and/or radiation at some point for palliation or progression, said invited discussant Julia R. White, MD, professor of radiation oncology at the Ohio State University, Columbus.

“Locoregional therapy should be reserved for these patients that become symptomatic or progress locally. There may be a role for routine locoregional therapy for de novo oligometastatic breast cancer in combination with systemic therapy plus ablative therapy” to secure long-term remission or cure, questions that are being addressed in ongoing clinical trials, Dr. White said.
 

Past data

An estimated 6% of newly diagnosed breast cancer patients present with stage IV disease and an intact primary tumor.

The rationale for locoregional therapy of the primary tumor in patients with metastatic disease is based on retrospective data suggesting a survival advantage. However, the studies were biased because of younger patient populations with small tumors, a higher proportion of estrogen receptor–positive disease, and a generally lower metastatic burden than that seen in the E2108 population, according to Dr. Khan.

She went on to cite two randomized trials with differing outcomes. One trial showed no survival advantage with locoregional therapy at 2 years (Lancet Oncol. 2015 Oct;16[13]:1380-8). The other showed an improvement in survival with locoregional therapy at 5 years (Ann Surg Oncol. 2018 Oct;25[11]:3141-9).
 

E2108 details

In the E2108 trial, patients first received optimal systemic therapy based on individual patient and disease features. Patients who had no disease progression or distant disease for at least 4-8 months of therapy were then randomized to additional therapy.

In one randomized arm, patients received continued systemic therapy alone. The other arm received early local therapy, which included complete tumor resection with free surgical margins and postoperative radiotherapy according to the standard of care.

A total of 390 patients were registered, and 256 went on to randomization. Of those subjects, 131 were randomized to the continued systemic therapy arm and 125 to the early local therapy arm. All patients in each arm were included in the efficacy analysis.

In all, 59.6% of randomized patients had hormone receptor–positive/HER2-negative disease, 8.2% had triple-negative disease, and 32.2% had HER2-positive disease. Metastases included bone-only disease in 37.9% of patients, visceral-only disease in 24.2%, and 40.9% in both sites.

Among the patients randomized to early local therapy, 14 did not have surgery for personal, clinical, or insurance reasons. Of the 109 who went on to surgery, 87 had clear surgical margins, and 74 received locoregional radiation therapy.
 

Survival, progression, and HRQOL

At a median follow-up of 53 months, the median overall survival was 54 months in each arm. There was no significant difference in survival between the study arms, with superimposable survival curves (hazard ratio, 1.09; P = .63).

An analysis of overall survival by tumor type showed that, for the 20 women with triple-negative disease, survival was worse with early local therapy (HR, 3.50). There were no differences in survival either for the 79 patients with HER2-positive disease or for the 137 patients with hormone receptor–positive/HER2-negative disease.

Locoregional progression occurred in 25.6% of patients assigned to continued systemic therapy, compared with 10.2% assigned to early local therapy. However, progression-free survival was virtually identical between the study arms (P = .40).

At most time points, there were no significant between-arm differences in HRQOL. The exception was at 18 months of follow-up, when the HRQOL was significantly lower among patients who had undergone early local therapy (P = .001).

“Based on available data, locoregional therapy for the primary tumor should not be offered to women with stage IV breast cancer with the expectation of a survival benefit. When systemic disease is well controlled with systemic therapy but the primary site is progressing, as does happen occasionally, locoregional treatment can be considered,” Dr. Khan concluded.

She noted there is an ongoing trial of similar design in Japan (JCOG-1017), with results expected in 2022.

The current trial was supported by the National Cancer Institute and Canadian Cancer Society. Dr. Khan reported no conflicts of interest. Dr. White reported institutional research funding from Intraop Medical.

SOURCE: Khan SA et al. ASCO 2020, Abstract LBA2.

Pembrolizumab treatment significantly improved progression-free survival versus brentuximab vedotin in a randomized, phase 3 trial including patients with relapsed or refractory classical Hodgkin lymphoma, an investigator has reported.

Median progression-free survival (PFS) was 13.2 versus 8.3 months in favor of pembrolizumab, according to the report on the KEYNOTE-204 trial, which included patients with classical Hodgkin lymphoma who either had relapsed after autologous stem cell transplant (SCT) or were ineligible for autologous SCT.

The PFS improvement was “statistically significant and clinically meaningful,” said investigator John Kuruvilla, MD, of Princess Margaret Cancer Centre in Toronto.

“This PFS benefit extended to key subgroups, including those ineligible for autologous transplant, patients with primary refractory disease, and patients who were brentuximab-vedotin naive,” Dr. Kuruvilla added in his presentation, which was part of the American Society of Clinical Oncology virtual scientific program.

Pneumonitis was more frequent in the pembrolizumab arm, but “appeared in general to be quite well managed” among patients who experienced this adverse event, according to Dr. Kuruvilla, who said that treatment with the programmed death–1 inhibitor should be considered “the preferred treatment option and the new standard of care” for patients with relapsed/refractory classic Hodgkin lymphoma who have relapsed after autologous SCT or are ineligible for it.

Although the pneumonitis findings are important to keep in mind, results of KEYNOTE-204 are indeed “practice defining” and immediately impactful, said Mark J. Roschewski, MD, clinical investigator in the lymphoid malignancies branch at the Center for Cancer Research, part of the National Cancer Institute, Bethesda, Md.

“I would select pembrolizumab over brentuximab for this patient population, particularly those that are refractory to chemotherapy,” he said in a commentary on the study also included in the virtual ASCO proceedings.

“There may be specific patient populations that I’d reconsider, such as those that might be at high risk for lung toxicity,” he added. “They may not be suitable for this, but it’s something to at least to be aware of.”

Although the antibody-drug conjugate brentuximab vedotin has been considered the standard of care for patients with relapse after autologous SCT, there has historically been no standard of care for patients who are ineligible for transplant because of chemorefractory disease, advanced age, or comorbidities, Dr. Kuruvilla said in his presentation.

In the KEYNOTE-204 study, 304 patients with relapsed/refractory classic Hodgkin lymphoma were randomized to receive either pembrolizumab 200 mg or brentuximab at 1.8 mg/kg intravenously every 3 weeks for up to 35 cycles.

The median age of patients was 36 years in the pembrolizumab arm and 35 years in the brentuximab vedotin arm, according to the report. Approximately 37% of the patients had previously undergone autologous SCT. About 40% had been refractory to frontline therapy, while 28% relapsed within 12 months of therapy and 32% relapsed later than 12 months.

Median PFS by blinded independent central review was 13.2 versus 8.3 months in the pembrolizumab and brentuximab arms, respectively (hazard ratio, 0.65; 95% confidence interval, 0.48-0.88; P = .00271), Dr. Kuruvilla reported.

The benefit extended to “key subgroups” in the trial, he added, including those who were ineligible for autologous SCT, those with primary refractory disease, and those who were naive to brentuximab vedotin, with HRs of 0.61, 0.52, and 0.67, respectively.

Pembrolizumab was also associated with more durable responses versus brentuximab vedotin, according to the investigator.

The overall response rate was 65.6% and 54.2%, respectively, for pembrolizumab and brentuximab, although this difference of approximately 11 percentage points did not meet criteria for statistical significance, he said. Duration of response was 20.7 months or pembrolizumab and 13.8 months for brentuximab.

The rate of serious treatment-related adverse events was similar between groups, according to Dr. Kuruvilla, who reported grade 3-5 events occurring in 19.6% and 25.0% of the pembrolizumab and brentuximab arms. Serious treatment-related adverse events were numerically more frequent in the pembrolizumab arm (16.2% vs. 10.5%) and there was one treatment-related death caused by pneumonia, seen in the pembrolizumab arm.

Pneumonitis occurred in 2.6% of the brentuximab-treated patients and in 10.8% of pembrolizumab-treated patients, of which half of cases were grade 3-4, according to the report.

In the pembrolizumab arm, pneumonitis was felt to be drug-related in 15 of 16 cases, according to Dr. Kuruvilla, who added that 15 of 16 patients required corticosteroid therapy. “This has led to the resolution of the pneumonitis in 12 of 16 patients, with ongoing resolution in one further patient.”

Research funding for KEYNOTE-204 came from Merck Sharp & Dohme. Dr. Kuruvilla provided disclosures related to Merck and a variety of other pharmaceutical companies. Dr. Roschewski said he had no relationships to disclose.

SOURCE: Kuruvilla J et al. ASCO 2020, Abstract 8005.

Pembrolizumab treatment significantly improved progression-free survival versus brentuximab vedotin in a randomized, phase 3 trial including patients with relapsed or refractory classical Hodgkin lymphoma, an investigator has reported.

Median progression-free survival (PFS) was 13.2 versus 8.3 months in favor of pembrolizumab, according to the report on the KEYNOTE-204 trial, which included patients with classical Hodgkin lymphoma who either had relapsed after autologous stem cell transplant (SCT) or were ineligible for autologous SCT.

The PFS improvement was “statistically significant and clinically meaningful,” said investigator John Kuruvilla, MD, of Princess Margaret Cancer Centre in Toronto.

“This PFS benefit extended to key subgroups, including those ineligible for autologous transplant, patients with primary refractory disease, and patients who were brentuximab-vedotin naive,” Dr. Kuruvilla added in his presentation, which was part of the American Society of Clinical Oncology virtual scientific program.

Pneumonitis was more frequent in the pembrolizumab arm, but “appeared in general to be quite well managed” among patients who experienced this adverse event, according to Dr. Kuruvilla, who said that treatment with the programmed death–1 inhibitor should be considered “the preferred treatment option and the new standard of care” for patients with relapsed/refractory classic Hodgkin lymphoma who have relapsed after autologous SCT or are ineligible for it.

Although the pneumonitis findings are important to keep in mind, results of KEYNOTE-204 are indeed “practice defining” and immediately impactful, said Mark J. Roschewski, MD, clinical investigator in the lymphoid malignancies branch at the Center for Cancer Research, part of the National Cancer Institute, Bethesda, Md.

“I would select pembrolizumab over brentuximab for this patient population, particularly those that are refractory to chemotherapy,” he said in a commentary on the study also included in the virtual ASCO proceedings.

“There may be specific patient populations that I’d reconsider, such as those that might be at high risk for lung toxicity,” he added. “They may not be suitable for this, but it’s something to at least to be aware of.”

Although the antibody-drug conjugate brentuximab vedotin has been considered the standard of care for patients with relapse after autologous SCT, there has historically been no standard of care for patients who are ineligible for transplant because of chemorefractory disease, advanced age, or comorbidities, Dr. Kuruvilla said in his presentation.

In the KEYNOTE-204 study, 304 patients with relapsed/refractory classic Hodgkin lymphoma were randomized to receive either pembrolizumab 200 mg or brentuximab at 1.8 mg/kg intravenously every 3 weeks for up to 35 cycles.

The median age of patients was 36 years in the pembrolizumab arm and 35 years in the brentuximab vedotin arm, according to the report. Approximately 37% of the patients had previously undergone autologous SCT. About 40% had been refractory to frontline therapy, while 28% relapsed within 12 months of therapy and 32% relapsed later than 12 months.

Median PFS by blinded independent central review was 13.2 versus 8.3 months in the pembrolizumab and brentuximab arms, respectively (hazard ratio, 0.65; 95% confidence interval, 0.48-0.88; P = .00271), Dr. Kuruvilla reported.

The benefit extended to “key subgroups” in the trial, he added, including those who were ineligible for autologous SCT, those with primary refractory disease, and those who were naive to brentuximab vedotin, with HRs of 0.61, 0.52, and 0.67, respectively.

Pembrolizumab was also associated with more durable responses versus brentuximab vedotin, according to the investigator.

The overall response rate was 65.6% and 54.2%, respectively, for pembrolizumab and brentuximab, although this difference of approximately 11 percentage points did not meet criteria for statistical significance, he said. Duration of response was 20.7 months or pembrolizumab and 13.8 months for brentuximab.

The rate of serious treatment-related adverse events was similar between groups, according to Dr. Kuruvilla, who reported grade 3-5 events occurring in 19.6% and 25.0% of the pembrolizumab and brentuximab arms. Serious treatment-related adverse events were numerically more frequent in the pembrolizumab arm (16.2% vs. 10.5%) and there was one treatment-related death caused by pneumonia, seen in the pembrolizumab arm.

Pneumonitis occurred in 2.6% of the brentuximab-treated patients and in 10.8% of pembrolizumab-treated patients, of which half of cases were grade 3-4, according to the report.

In the pembrolizumab arm, pneumonitis was felt to be drug-related in 15 of 16 cases, according to Dr. Kuruvilla, who added that 15 of 16 patients required corticosteroid therapy. “This has led to the resolution of the pneumonitis in 12 of 16 patients, with ongoing resolution in one further patient.”

Research funding for KEYNOTE-204 came from Merck Sharp & Dohme. Dr. Kuruvilla provided disclosures related to Merck and a variety of other pharmaceutical companies. Dr. Roschewski said he had no relationships to disclose.

SOURCE: Kuruvilla J et al. ASCO 2020, Abstract 8005.

Pembrolizumab treatment significantly improved progression-free survival versus brentuximab vedotin in a randomized, phase 3 trial including patients with relapsed or refractory classical Hodgkin lymphoma, an investigator has reported.

Median progression-free survival (PFS) was 13.2 versus 8.3 months in favor of pembrolizumab, according to the report on the KEYNOTE-204 trial, which included patients with classical Hodgkin lymphoma who either had relapsed after autologous stem cell transplant (SCT) or were ineligible for autologous SCT.

The PFS improvement was “statistically significant and clinically meaningful,” said investigator John Kuruvilla, MD, of Princess Margaret Cancer Centre in Toronto.

“This PFS benefit extended to key subgroups, including those ineligible for autologous transplant, patients with primary refractory disease, and patients who were brentuximab-vedotin naive,” Dr. Kuruvilla added in his presentation, which was part of the American Society of Clinical Oncology virtual scientific program.

Pneumonitis was more frequent in the pembrolizumab arm, but “appeared in general to be quite well managed” among patients who experienced this adverse event, according to Dr. Kuruvilla, who said that treatment with the programmed death–1 inhibitor should be considered “the preferred treatment option and the new standard of care” for patients with relapsed/refractory classic Hodgkin lymphoma who have relapsed after autologous SCT or are ineligible for it.

Although the pneumonitis findings are important to keep in mind, results of KEYNOTE-204 are indeed “practice defining” and immediately impactful, said Mark J. Roschewski, MD, clinical investigator in the lymphoid malignancies branch at the Center for Cancer Research, part of the National Cancer Institute, Bethesda, Md.

“I would select pembrolizumab over brentuximab for this patient population, particularly those that are refractory to chemotherapy,” he said in a commentary on the study also included in the virtual ASCO proceedings.

“There may be specific patient populations that I’d reconsider, such as those that might be at high risk for lung toxicity,” he added. “They may not be suitable for this, but it’s something to at least to be aware of.”

Although the antibody-drug conjugate brentuximab vedotin has been considered the standard of care for patients with relapse after autologous SCT, there has historically been no standard of care for patients who are ineligible for transplant because of chemorefractory disease, advanced age, or comorbidities, Dr. Kuruvilla said in his presentation.

In the KEYNOTE-204 study, 304 patients with relapsed/refractory classic Hodgkin lymphoma were randomized to receive either pembrolizumab 200 mg or brentuximab at 1.8 mg/kg intravenously every 3 weeks for up to 35 cycles.

The median age of patients was 36 years in the pembrolizumab arm and 35 years in the brentuximab vedotin arm, according to the report. Approximately 37% of the patients had previously undergone autologous SCT. About 40% had been refractory to frontline therapy, while 28% relapsed within 12 months of therapy and 32% relapsed later than 12 months.

Median PFS by blinded independent central review was 13.2 versus 8.3 months in the pembrolizumab and brentuximab arms, respectively (hazard ratio, 0.65; 95% confidence interval, 0.48-0.88; P = .00271), Dr. Kuruvilla reported.

The benefit extended to “key subgroups” in the trial, he added, including those who were ineligible for autologous SCT, those with primary refractory disease, and those who were naive to brentuximab vedotin, with HRs of 0.61, 0.52, and 0.67, respectively.

Pembrolizumab was also associated with more durable responses versus brentuximab vedotin, according to the investigator.

The overall response rate was 65.6% and 54.2%, respectively, for pembrolizumab and brentuximab, although this difference of approximately 11 percentage points did not meet criteria for statistical significance, he said. Duration of response was 20.7 months or pembrolizumab and 13.8 months for brentuximab.

The rate of serious treatment-related adverse events was similar between groups, according to Dr. Kuruvilla, who reported grade 3-5 events occurring in 19.6% and 25.0% of the pembrolizumab and brentuximab arms. Serious treatment-related adverse events were numerically more frequent in the pembrolizumab arm (16.2% vs. 10.5%) and there was one treatment-related death caused by pneumonia, seen in the pembrolizumab arm.

Pneumonitis occurred in 2.6% of the brentuximab-treated patients and in 10.8% of pembrolizumab-treated patients, of which half of cases were grade 3-4, according to the report.

In the pembrolizumab arm, pneumonitis was felt to be drug-related in 15 of 16 cases, according to Dr. Kuruvilla, who added that 15 of 16 patients required corticosteroid therapy. “This has led to the resolution of the pneumonitis in 12 of 16 patients, with ongoing resolution in one further patient.”

Research funding for KEYNOTE-204 came from Merck Sharp & Dohme. Dr. Kuruvilla provided disclosures related to Merck and a variety of other pharmaceutical companies. Dr. Roschewski said he had no relationships to disclose.

SOURCE: Kuruvilla J et al. ASCO 2020, Abstract 8005.

For patients with BRCA-like triple-negative breast cancer (TNBC), adding veliparib to cisplatin chemotherapy may extend survival, based on results from the phase 3 SWOG S1416 trial.

All patients with BRCA-like TNBC had a significant improvement in progression-free survival (PFS) when they received veliparib plus cisplatin. Previously untreated patients with BRCA-like TNBC had a significant improvement in overall survival (OS) as well.

The results are a “very positive step towards expanding the role of PARP inhibitors beyond germline BRCA in breast cancer,” reported lead author Priyanka Sharma, MD, of the University of Kansas Medical Center in Kansas City, who presented the findings as part of the American Society of Clinical Oncology virtual scientific program.

According to Dr. Sharma, PARP inhibitors have demonstrated efficacy for certain patients with BRCA wild-type ovarian cancer, such as those with homologous recombination deficiency, which also occurs in approximately half of patients with BRCA wild-type TNBC. In TNBC, homologous recombination deficiency and other aberrations lead to a BRCA-like disease phenotype, which may respond to PARP inhibitors.

Dr. Sharma noted that previous attempts to use PARP inhibitors for BRCA wild-type TNBC have revealed obstacles, such as the inefficacy of PARP inhibitor monotherapy and dose-limiting myelosuppression when PARP inhibitors were added to chemotherapy. The issue of bone marrow toxicity may be mitigated by veliparib, which has minimal PARP-trapping activity, she explained.

“A phase 1 trial has demonstrated that adequate doses of cisplatin can be delivered safely in combination with the near-maximal single-agent dose of veliparib in patients with metastatic TNBC,” Dr. Sharma said.

She and her colleagues put this finding to the test in a phase 3 trial that enrolled 335 patients with metastatic and/or loco-regionally recurrent TNBC or BRCA-associated HER2-negative breast cancer. Patients could be previously untreated or have received one prior cytotoxic chemotherapy for metastatic disease.

Of the patients enrolled, 321 met eligibility criteria, 294 had germline BRCA testing, and 209 had BRCA-like assessment.

Patients were divided into the following groups: germline BRCA-associated disease (n = 37), BRCA-like disease (n = 99), non-BRCA-like disease (n = 110), and unclassified (n = 75).

In each group, patients were randomized in a 1:1 ratio to receive cisplatin (75 mg/m²on day 1) plus veliparib (300 mg twice daily on days 1-14) every 3 weeks, or cisplatin with placebo. The primary endpoint was PFS.

Results

Among patients with BRCA-like disease, there was a significant improvement in PFS and a trend toward improved OS when veliparib was added to cisplatin. The median PFS was 5.9 months with veliparib and 4.2 months with placebo (P = .006). The median OS was 14.0 months and 12.1 months, respectively (P = .067).

Among patients with previously untreated BRCA-like disease, there were significant improvements in both PFS and OS.

The median PFS in this group was 6.1 months with veliparib and 4.2 months with placebo (P = .008). The 12-month PFS rates were 23% and 3%, respectively.

The median OS in this group was 17.8 months with veliparib and 10.3 months with placebo (P = .048). The 24-month OS rates were 43% and 20%, respectively.

There were no survival benefits with veliparib among patients with unclassified disease, non-BRCA-like disease, or BRCA-associated disease.

Dr. Sharma noted that the lack of significant improvement in the BRCA-associated group was likely due to the small sample size. “FDA approval of PARP inhibitors for treatment of germline BRCA-associated metastatic breast cancer during the course of this trial impacted accrual to this group,” she said.

Veliparib was associated with a higher rate of grade 3-4 hematologic toxicities, including neutropenia (46% vs. 19%), leukopenia (27% vs. 7%), anemia (23% vs. 7%), and thrombocytopenia (19% vs. 3%).

Dr. Sharma said results from this trial should prompt further research. “The combination of veliparib plus cisplatin warrants further evaluation in larger randomized trials for patients with BRCA-like phenotype TNBC,” she said.

Invited discussant Catherine M. Kelly, MB BCh, of Mater Misericordiae University Hospital in Dublin, called the trial “an ambitious study” that has created a “valuable tissue bank” for future translational research. She agreed that more work is necessary.

“Further research is needed to identify the optimal homologous recombination deficiency biomarkers critical in the early treatment-naive and in the advanced treatment-exposed disease settings,” Dr. Kelly said.

SWOG S1416 was funded by the National Institutes of Health and AbbVie. Dr. Sharma disclosed relationships with AstraZeneca, Merck, Novartis, and other companies. Dr. Kelly reported affiliations with Pfizer, Novartis, Roche, and MSD Oncology.

SOURCE: Sharma et al. ASCO 2020, Abstract 1001.

For patients with BRCA-like triple-negative breast cancer (TNBC), adding veliparib to cisplatin chemotherapy may extend survival, based on results from the phase 3 SWOG S1416 trial.

All patients with BRCA-like TNBC had a significant improvement in progression-free survival (PFS) when they received veliparib plus cisplatin. Previously untreated patients with BRCA-like TNBC had a significant improvement in overall survival (OS) as well.

The results are a “very positive step towards expanding the role of PARP inhibitors beyond germline BRCA in breast cancer,” reported lead author Priyanka Sharma, MD, of the University of Kansas Medical Center in Kansas City, who presented the findings as part of the American Society of Clinical Oncology virtual scientific program.

According to Dr. Sharma, PARP inhibitors have demonstrated efficacy for certain patients with BRCA wild-type ovarian cancer, such as those with homologous recombination deficiency, which also occurs in approximately half of patients with BRCA wild-type TNBC. In TNBC, homologous recombination deficiency and other aberrations lead to a BRCA-like disease phenotype, which may respond to PARP inhibitors.

Dr. Sharma noted that previous attempts to use PARP inhibitors for BRCA wild-type TNBC have revealed obstacles, such as the inefficacy of PARP inhibitor monotherapy and dose-limiting myelosuppression when PARP inhibitors were added to chemotherapy. The issue of bone marrow toxicity may be mitigated by veliparib, which has minimal PARP-trapping activity, she explained.

“A phase 1 trial has demonstrated that adequate doses of cisplatin can be delivered safely in combination with the near-maximal single-agent dose of veliparib in patients with metastatic TNBC,” Dr. Sharma said.

She and her colleagues put this finding to the test in a phase 3 trial that enrolled 335 patients with metastatic and/or loco-regionally recurrent TNBC or BRCA-associated HER2-negative breast cancer. Patients could be previously untreated or have received one prior cytotoxic chemotherapy for metastatic disease.

Of the patients enrolled, 321 met eligibility criteria, 294 had germline BRCA testing, and 209 had BRCA-like assessment.

Patients were divided into the following groups: germline BRCA-associated disease (n = 37), BRCA-like disease (n = 99), non-BRCA-like disease (n = 110), and unclassified (n = 75).

In each group, patients were randomized in a 1:1 ratio to receive cisplatin (75 mg/m²on day 1) plus veliparib (300 mg twice daily on days 1-14) every 3 weeks, or cisplatin with placebo. The primary endpoint was PFS.

Results

Among patients with BRCA-like disease, there was a significant improvement in PFS and a trend toward improved OS when veliparib was added to cisplatin. The median PFS was 5.9 months with veliparib and 4.2 months with placebo (P = .006). The median OS was 14.0 months and 12.1 months, respectively (P = .067).

Among patients with previously untreated BRCA-like disease, there were significant improvements in both PFS and OS.

The median PFS in this group was 6.1 months with veliparib and 4.2 months with placebo (P = .008). The 12-month PFS rates were 23% and 3%, respectively.

The median OS in this group was 17.8 months with veliparib and 10.3 months with placebo (P = .048). The 24-month OS rates were 43% and 20%, respectively.

There were no survival benefits with veliparib among patients with unclassified disease, non-BRCA-like disease, or BRCA-associated disease.

Dr. Sharma noted that the lack of significant improvement in the BRCA-associated group was likely due to the small sample size. “FDA approval of PARP inhibitors for treatment of germline BRCA-associated metastatic breast cancer during the course of this trial impacted accrual to this group,” she said.

Veliparib was associated with a higher rate of grade 3-4 hematologic toxicities, including neutropenia (46% vs. 19%), leukopenia (27% vs. 7%), anemia (23% vs. 7%), and thrombocytopenia (19% vs. 3%).

Dr. Sharma said results from this trial should prompt further research. “The combination of veliparib plus cisplatin warrants further evaluation in larger randomized trials for patients with BRCA-like phenotype TNBC,” she said.

Invited discussant Catherine M. Kelly, MB BCh, of Mater Misericordiae University Hospital in Dublin, called the trial “an ambitious study” that has created a “valuable tissue bank” for future translational research. She agreed that more work is necessary.

“Further research is needed to identify the optimal homologous recombination deficiency biomarkers critical in the early treatment-naive and in the advanced treatment-exposed disease settings,” Dr. Kelly said.

SWOG S1416 was funded by the National Institutes of Health and AbbVie. Dr. Sharma disclosed relationships with AstraZeneca, Merck, Novartis, and other companies. Dr. Kelly reported affiliations with Pfizer, Novartis, Roche, and MSD Oncology.

SOURCE: Sharma et al. ASCO 2020, Abstract 1001.

For patients with BRCA-like triple-negative breast cancer (TNBC), adding veliparib to cisplatin chemotherapy may extend survival, based on results from the phase 3 SWOG S1416 trial.

All patients with BRCA-like TNBC had a significant improvement in progression-free survival (PFS) when they received veliparib plus cisplatin. Previously untreated patients with BRCA-like TNBC had a significant improvement in overall survival (OS) as well.

The results are a “very positive step towards expanding the role of PARP inhibitors beyond germline BRCA in breast cancer,” reported lead author Priyanka Sharma, MD, of the University of Kansas Medical Center in Kansas City, who presented the findings as part of the American Society of Clinical Oncology virtual scientific program.

According to Dr. Sharma, PARP inhibitors have demonstrated efficacy for certain patients with BRCA wild-type ovarian cancer, such as those with homologous recombination deficiency, which also occurs in approximately half of patients with BRCA wild-type TNBC. In TNBC, homologous recombination deficiency and other aberrations lead to a BRCA-like disease phenotype, which may respond to PARP inhibitors.

Dr. Sharma noted that previous attempts to use PARP inhibitors for BRCA wild-type TNBC have revealed obstacles, such as the inefficacy of PARP inhibitor monotherapy and dose-limiting myelosuppression when PARP inhibitors were added to chemotherapy. The issue of bone marrow toxicity may be mitigated by veliparib, which has minimal PARP-trapping activity, she explained.

“A phase 1 trial has demonstrated that adequate doses of cisplatin can be delivered safely in combination with the near-maximal single-agent dose of veliparib in patients with metastatic TNBC,” Dr. Sharma said.

She and her colleagues put this finding to the test in a phase 3 trial that enrolled 335 patients with metastatic and/or loco-regionally recurrent TNBC or BRCA-associated HER2-negative breast cancer. Patients could be previously untreated or have received one prior cytotoxic chemotherapy for metastatic disease.

Of the patients enrolled, 321 met eligibility criteria, 294 had germline BRCA testing, and 209 had BRCA-like assessment.

Patients were divided into the following groups: germline BRCA-associated disease (n = 37), BRCA-like disease (n = 99), non-BRCA-like disease (n = 110), and unclassified (n = 75).

In each group, patients were randomized in a 1:1 ratio to receive cisplatin (75 mg/m²on day 1) plus veliparib (300 mg twice daily on days 1-14) every 3 weeks, or cisplatin with placebo. The primary endpoint was PFS.

Results

Among patients with BRCA-like disease, there was a significant improvement in PFS and a trend toward improved OS when veliparib was added to cisplatin. The median PFS was 5.9 months with veliparib and 4.2 months with placebo (P = .006). The median OS was 14.0 months and 12.1 months, respectively (P = .067).

Among patients with previously untreated BRCA-like disease, there were significant improvements in both PFS and OS.

The median PFS in this group was 6.1 months with veliparib and 4.2 months with placebo (P = .008). The 12-month PFS rates were 23% and 3%, respectively.

The median OS in this group was 17.8 months with veliparib and 10.3 months with placebo (P = .048). The 24-month OS rates were 43% and 20%, respectively.

There were no survival benefits with veliparib among patients with unclassified disease, non-BRCA-like disease, or BRCA-associated disease.

Dr. Sharma noted that the lack of significant improvement in the BRCA-associated group was likely due to the small sample size. “FDA approval of PARP inhibitors for treatment of germline BRCA-associated metastatic breast cancer during the course of this trial impacted accrual to this group,” she said.

Veliparib was associated with a higher rate of grade 3-4 hematologic toxicities, including neutropenia (46% vs. 19%), leukopenia (27% vs. 7%), anemia (23% vs. 7%), and thrombocytopenia (19% vs. 3%).

Dr. Sharma said results from this trial should prompt further research. “The combination of veliparib plus cisplatin warrants further evaluation in larger randomized trials for patients with BRCA-like phenotype TNBC,” she said.

Invited discussant Catherine M. Kelly, MB BCh, of Mater Misericordiae University Hospital in Dublin, called the trial “an ambitious study” that has created a “valuable tissue bank” for future translational research. She agreed that more work is necessary.

“Further research is needed to identify the optimal homologous recombination deficiency biomarkers critical in the early treatment-naive and in the advanced treatment-exposed disease settings,” Dr. Kelly said.

SWOG S1416 was funded by the National Institutes of Health and AbbVie. Dr. Sharma disclosed relationships with AstraZeneca, Merck, Novartis, and other companies. Dr. Kelly reported affiliations with Pfizer, Novartis, Roche, and MSD Oncology.

SOURCE: Sharma et al. ASCO 2020, Abstract 1001.