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M. Alexander Otto began his reporting career early in 1999 covering the pharmaceutical industry for a national pharmacists' magazine and freelancing for the Washington Post and other newspapers. He then joined BNA, now part of Bloomberg News, covering health law and the protection of people and animals in medical research. Alex next worked for the McClatchy Company. Based on his work, Alex won a year-long Knight Science Journalism Fellowship to MIT in 2008-2009. He joined the company shortly thereafter. Alex has a newspaper journalism degree from Syracuse (N.Y.) University and a master's degree in medical science -- a physician assistant degree -- from George Washington University. Alex is based in Seattle.
FOLFOXIRI tops doublets as bevacizumab backbone for mCRC
investigators reported in the Journal of Clinical Oncology.
In analyzing data from five clinical trials, the investigators found a 4.4-month increase in median overall survival and an 11.6% increase in estimated 5-year overall survival with FOLFOXIRI versus doublets. The trade-off was a higher incidence of grade 3-4 adverse events with FOLFOXIRI.
FOLFOXIRI plus bevacizumab is already included among first-line options in most clinical guidelines and recommendations, but there was no “proper estimation of the magnitude of the overall survival benefit” because trials had other primary endpoints, according to study author Chiara Cremolini, MD, PhD, of University of Pisa (Italy), and colleagues.
“To fully appreciate the cost/benefit balance of this option,” the investigators wanted to see how the numbers played out when overall survival was the primary endpoint, so they pooled individual patient data from the CHARTA, OLIVIA, STEAM, TRIBE, and TRIBE2 trials.
Patient characteristics and treatment
The analysis included 1,697 patients. The median age was 61 years (range, 53-67 years).
About 99% of patients had an Eastern Cooperative Oncology Group performance score of 0 or 1. About 20% had left-sided RAS and BRAF wild-type tumors because of the increased use of anti–epidermal growth factor receptor antibodies as first-line therapy for that indication in recent years.
In all, 846 patients were randomized to FOLFOXIRI plus bevacizumab and 851 to bevacizumab with doublets: 69.9% to FOLFOX (leucovorin, fluorouracil, and oxaliplatin) and 30.1% to FOLFIRI (fluorouracil, leucovorin, and irinotecan).
The duration of induction in all five trials ranged from 4 to 6 months. It was followed by maintenance with a fluoropyrimidine (fluorouracil and leucovorin or capecitabine) plus bevacizumab.
Efficacy and safety
At a median follow-up of 39.9 months, the median overall survival was 28.9 months in the FOLFOXIRI group and 24.5 months in the doublet group (P < .001). The estimated 5-year overall survival rate was 22.3% and 10.7%, respectively.
The median progression-free survival was 12.2 months in the FOLFOXIRI group and 9.9 months in the doublet group (P < .001).
The objective response rate was higher with FOLFOXIRI (64.5% vs. 53.6%, P < .001), as was R0 resection rate (16.4% vs. 11.8%, P = .007).
The FOLFOXIRI group also had a higher incidence of grade 3-4 adverse events, including neutropenia (45.8% vs. 21.5%; P < .001), febrile neutropenia (6.3% vs. 3.7%; P = .019), nausea (5.5% vs. 3.0%; P = .016), mucositis (5.1% vs. 2.9%; P = .024), and diarrhea (17.8% vs. 8.4%; P < .001).
Even so, FOLFOXIRI plus bevacizumab was not associated with a significant increase in toxic deaths (2.3% vs. 1.4%; P = .277).
Patient selection is ‘critical’
Based on their findings, the investigators said the best candidates for first-line FOLFOXIRI plus bevacizumab may be younger patients with an ECOG performance status of 0 or 1 and right-sided and/or RAS-mutated tumors not exposed to a previous oxaliplatin-based adjuvant regimen.
FOLFOXIRI plus bevacizumab did not provide any additional benefit in patients with BRAF-mutant tumors, so the combination shouldn’t be the first choice in this group, the investigators wrote. “FOLFOX plus bevacizumab seems the preferable upfront option.”
For left-sided RAS and BRAF wild-type tumors, a chemotherapy doublet with an anti–epidermal growth factor receptor remains the preferred option, according to the investigators.
“The study does support the use of FOLFOXIRI and bevacizumab as a valuable first-line option, but patient selection is critical because there is a toxicity cost; this efficacy versus toxicity will constantly be a seesaw for us,” commented Aparna Parikh, MD, of Massachusetts General Hospital in Boston, when the study was presented at the American Society of Clinical Oncology annual meeting earlier this year.
There was no external funding for this analysis. Three of the original five trials were sponsored by Roche. The study authors had numerous industry ties. Among others, Dr. Cremolini is a consultant for and reported honoraria and travel expenses from Roche. One author was a Genentech employee. Dr. Parikh disclosed relationships with Lilly, Genentech, and other companies.
SOURCE: Cremolini C et al. J Clin Oncol. 2020 Aug 20. doi: 10.1200/JCO.20.01225.
investigators reported in the Journal of Clinical Oncology.
In analyzing data from five clinical trials, the investigators found a 4.4-month increase in median overall survival and an 11.6% increase in estimated 5-year overall survival with FOLFOXIRI versus doublets. The trade-off was a higher incidence of grade 3-4 adverse events with FOLFOXIRI.
FOLFOXIRI plus bevacizumab is already included among first-line options in most clinical guidelines and recommendations, but there was no “proper estimation of the magnitude of the overall survival benefit” because trials had other primary endpoints, according to study author Chiara Cremolini, MD, PhD, of University of Pisa (Italy), and colleagues.
“To fully appreciate the cost/benefit balance of this option,” the investigators wanted to see how the numbers played out when overall survival was the primary endpoint, so they pooled individual patient data from the CHARTA, OLIVIA, STEAM, TRIBE, and TRIBE2 trials.
Patient characteristics and treatment
The analysis included 1,697 patients. The median age was 61 years (range, 53-67 years).
About 99% of patients had an Eastern Cooperative Oncology Group performance score of 0 or 1. About 20% had left-sided RAS and BRAF wild-type tumors because of the increased use of anti–epidermal growth factor receptor antibodies as first-line therapy for that indication in recent years.
In all, 846 patients were randomized to FOLFOXIRI plus bevacizumab and 851 to bevacizumab with doublets: 69.9% to FOLFOX (leucovorin, fluorouracil, and oxaliplatin) and 30.1% to FOLFIRI (fluorouracil, leucovorin, and irinotecan).
The duration of induction in all five trials ranged from 4 to 6 months. It was followed by maintenance with a fluoropyrimidine (fluorouracil and leucovorin or capecitabine) plus bevacizumab.
Efficacy and safety
At a median follow-up of 39.9 months, the median overall survival was 28.9 months in the FOLFOXIRI group and 24.5 months in the doublet group (P < .001). The estimated 5-year overall survival rate was 22.3% and 10.7%, respectively.
The median progression-free survival was 12.2 months in the FOLFOXIRI group and 9.9 months in the doublet group (P < .001).
The objective response rate was higher with FOLFOXIRI (64.5% vs. 53.6%, P < .001), as was R0 resection rate (16.4% vs. 11.8%, P = .007).
The FOLFOXIRI group also had a higher incidence of grade 3-4 adverse events, including neutropenia (45.8% vs. 21.5%; P < .001), febrile neutropenia (6.3% vs. 3.7%; P = .019), nausea (5.5% vs. 3.0%; P = .016), mucositis (5.1% vs. 2.9%; P = .024), and diarrhea (17.8% vs. 8.4%; P < .001).
Even so, FOLFOXIRI plus bevacizumab was not associated with a significant increase in toxic deaths (2.3% vs. 1.4%; P = .277).
Patient selection is ‘critical’
Based on their findings, the investigators said the best candidates for first-line FOLFOXIRI plus bevacizumab may be younger patients with an ECOG performance status of 0 or 1 and right-sided and/or RAS-mutated tumors not exposed to a previous oxaliplatin-based adjuvant regimen.
FOLFOXIRI plus bevacizumab did not provide any additional benefit in patients with BRAF-mutant tumors, so the combination shouldn’t be the first choice in this group, the investigators wrote. “FOLFOX plus bevacizumab seems the preferable upfront option.”
For left-sided RAS and BRAF wild-type tumors, a chemotherapy doublet with an anti–epidermal growth factor receptor remains the preferred option, according to the investigators.
“The study does support the use of FOLFOXIRI and bevacizumab as a valuable first-line option, but patient selection is critical because there is a toxicity cost; this efficacy versus toxicity will constantly be a seesaw for us,” commented Aparna Parikh, MD, of Massachusetts General Hospital in Boston, when the study was presented at the American Society of Clinical Oncology annual meeting earlier this year.
There was no external funding for this analysis. Three of the original five trials were sponsored by Roche. The study authors had numerous industry ties. Among others, Dr. Cremolini is a consultant for and reported honoraria and travel expenses from Roche. One author was a Genentech employee. Dr. Parikh disclosed relationships with Lilly, Genentech, and other companies.
SOURCE: Cremolini C et al. J Clin Oncol. 2020 Aug 20. doi: 10.1200/JCO.20.01225.
investigators reported in the Journal of Clinical Oncology.
In analyzing data from five clinical trials, the investigators found a 4.4-month increase in median overall survival and an 11.6% increase in estimated 5-year overall survival with FOLFOXIRI versus doublets. The trade-off was a higher incidence of grade 3-4 adverse events with FOLFOXIRI.
FOLFOXIRI plus bevacizumab is already included among first-line options in most clinical guidelines and recommendations, but there was no “proper estimation of the magnitude of the overall survival benefit” because trials had other primary endpoints, according to study author Chiara Cremolini, MD, PhD, of University of Pisa (Italy), and colleagues.
“To fully appreciate the cost/benefit balance of this option,” the investigators wanted to see how the numbers played out when overall survival was the primary endpoint, so they pooled individual patient data from the CHARTA, OLIVIA, STEAM, TRIBE, and TRIBE2 trials.
Patient characteristics and treatment
The analysis included 1,697 patients. The median age was 61 years (range, 53-67 years).
About 99% of patients had an Eastern Cooperative Oncology Group performance score of 0 or 1. About 20% had left-sided RAS and BRAF wild-type tumors because of the increased use of anti–epidermal growth factor receptor antibodies as first-line therapy for that indication in recent years.
In all, 846 patients were randomized to FOLFOXIRI plus bevacizumab and 851 to bevacizumab with doublets: 69.9% to FOLFOX (leucovorin, fluorouracil, and oxaliplatin) and 30.1% to FOLFIRI (fluorouracil, leucovorin, and irinotecan).
The duration of induction in all five trials ranged from 4 to 6 months. It was followed by maintenance with a fluoropyrimidine (fluorouracil and leucovorin or capecitabine) plus bevacizumab.
Efficacy and safety
At a median follow-up of 39.9 months, the median overall survival was 28.9 months in the FOLFOXIRI group and 24.5 months in the doublet group (P < .001). The estimated 5-year overall survival rate was 22.3% and 10.7%, respectively.
The median progression-free survival was 12.2 months in the FOLFOXIRI group and 9.9 months in the doublet group (P < .001).
The objective response rate was higher with FOLFOXIRI (64.5% vs. 53.6%, P < .001), as was R0 resection rate (16.4% vs. 11.8%, P = .007).
The FOLFOXIRI group also had a higher incidence of grade 3-4 adverse events, including neutropenia (45.8% vs. 21.5%; P < .001), febrile neutropenia (6.3% vs. 3.7%; P = .019), nausea (5.5% vs. 3.0%; P = .016), mucositis (5.1% vs. 2.9%; P = .024), and diarrhea (17.8% vs. 8.4%; P < .001).
Even so, FOLFOXIRI plus bevacizumab was not associated with a significant increase in toxic deaths (2.3% vs. 1.4%; P = .277).
Patient selection is ‘critical’
Based on their findings, the investigators said the best candidates for first-line FOLFOXIRI plus bevacizumab may be younger patients with an ECOG performance status of 0 or 1 and right-sided and/or RAS-mutated tumors not exposed to a previous oxaliplatin-based adjuvant regimen.
FOLFOXIRI plus bevacizumab did not provide any additional benefit in patients with BRAF-mutant tumors, so the combination shouldn’t be the first choice in this group, the investigators wrote. “FOLFOX plus bevacizumab seems the preferable upfront option.”
For left-sided RAS and BRAF wild-type tumors, a chemotherapy doublet with an anti–epidermal growth factor receptor remains the preferred option, according to the investigators.
“The study does support the use of FOLFOXIRI and bevacizumab as a valuable first-line option, but patient selection is critical because there is a toxicity cost; this efficacy versus toxicity will constantly be a seesaw for us,” commented Aparna Parikh, MD, of Massachusetts General Hospital in Boston, when the study was presented at the American Society of Clinical Oncology annual meeting earlier this year.
There was no external funding for this analysis. Three of the original five trials were sponsored by Roche. The study authors had numerous industry ties. Among others, Dr. Cremolini is a consultant for and reported honoraria and travel expenses from Roche. One author was a Genentech employee. Dr. Parikh disclosed relationships with Lilly, Genentech, and other companies.
SOURCE: Cremolini C et al. J Clin Oncol. 2020 Aug 20. doi: 10.1200/JCO.20.01225.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Atezolizumab TNBC indication ‘in jeopardy’ because of phase 3 results
The FDA said the phase 3 IMpassion131 trial showed that atezolizumab plus paclitaxel did not significantly reduce the risk of cancer progression and death, when compared with paclitaxel plus placebo, in programmed death-ligand 1 (PD-L1)–positive patients.
“Additionally, interim overall survival results favored paclitaxel plus placebo over paclitaxel plus atezolizumab in both the PD-L1-positive population and total population,” the FDA noted.
As a result, “health care professionals should not replace paclitaxel protein-bound (Abraxane) with paclitaxel in clinical practice,” the FDA advised.
Atezolizumab is approved for use in combination with protein-bound paclitaxel, also known as nanoparticle albumin–bound paclitaxel (nab-paclitaxel), to treat patients with unresectable, locally advanced, or metastatic TNBC whose tumors express PD-L1, as detected by an FDA-approved test. The combination was granted accelerated approval for this indication last year.
Atezolizumab plus nab-paclitaxel is the combination most often used in PD-L1-positive TNBC, as opposed to atezolizumab and unbound paclitaxel, said Melinda L. Telli, MD, an associate professor of medicine and director of the Stanford Cancer Institute Breast Cancer Program at Stanford (Calif.) University.
However, as the FDA noted, “continued approval of atezolizumab in combination with [nab-paclitaxel] may be contingent on proven benefit of the treatment in additional trials.”
Dr. Telli explained that atezolizumab was granted accelerated approval for the treatment of PD-L1-positive TNBC based on results of the phase 3 IMpassion130 trial, which compared nab-paclitaxel plus atezolizumab with nab-paclitaxel plus placebo.
“Additional data from IMpassion131 was hoped to be used to support the conversion of the accelerated approval to a full approval. Since IMpassion131 was negative, it unfortunately places the status of atezolizumab in [TNBC] in jeopardy as the benefits were not corroborated. The FDA may move to revoke the approval of atezolizumab for [TNBC],” Dr. Telli said.
In its alert, the FDA stated that it “will review the findings of IMpassion131 and will communicate new information regarding the IMpassion131 results and any potential changes to prescribing information.”
“We need to wait for full presentation and publication of the study results, but, in my assessment, the negative results in IMpassion131 are most likely due to differences in patient selection [from IMpassion130],” Dr. Telli said.
Results from IMpassion131 are scheduled to be presented at the ESMO Virtual Congress 2020.
The IMpassion trials were funded by Roche, maker of atezolizumab. Dr. Telli disclosed relationships with AbbVie, AstraZeneca, Merck, PharmaMar, Pfizer, and Tesaro.
The FDA said the phase 3 IMpassion131 trial showed that atezolizumab plus paclitaxel did not significantly reduce the risk of cancer progression and death, when compared with paclitaxel plus placebo, in programmed death-ligand 1 (PD-L1)–positive patients.
“Additionally, interim overall survival results favored paclitaxel plus placebo over paclitaxel plus atezolizumab in both the PD-L1-positive population and total population,” the FDA noted.
As a result, “health care professionals should not replace paclitaxel protein-bound (Abraxane) with paclitaxel in clinical practice,” the FDA advised.
Atezolizumab is approved for use in combination with protein-bound paclitaxel, also known as nanoparticle albumin–bound paclitaxel (nab-paclitaxel), to treat patients with unresectable, locally advanced, or metastatic TNBC whose tumors express PD-L1, as detected by an FDA-approved test. The combination was granted accelerated approval for this indication last year.
Atezolizumab plus nab-paclitaxel is the combination most often used in PD-L1-positive TNBC, as opposed to atezolizumab and unbound paclitaxel, said Melinda L. Telli, MD, an associate professor of medicine and director of the Stanford Cancer Institute Breast Cancer Program at Stanford (Calif.) University.
However, as the FDA noted, “continued approval of atezolizumab in combination with [nab-paclitaxel] may be contingent on proven benefit of the treatment in additional trials.”
Dr. Telli explained that atezolizumab was granted accelerated approval for the treatment of PD-L1-positive TNBC based on results of the phase 3 IMpassion130 trial, which compared nab-paclitaxel plus atezolizumab with nab-paclitaxel plus placebo.
“Additional data from IMpassion131 was hoped to be used to support the conversion of the accelerated approval to a full approval. Since IMpassion131 was negative, it unfortunately places the status of atezolizumab in [TNBC] in jeopardy as the benefits were not corroborated. The FDA may move to revoke the approval of atezolizumab for [TNBC],” Dr. Telli said.
In its alert, the FDA stated that it “will review the findings of IMpassion131 and will communicate new information regarding the IMpassion131 results and any potential changes to prescribing information.”
“We need to wait for full presentation and publication of the study results, but, in my assessment, the negative results in IMpassion131 are most likely due to differences in patient selection [from IMpassion130],” Dr. Telli said.
Results from IMpassion131 are scheduled to be presented at the ESMO Virtual Congress 2020.
The IMpassion trials were funded by Roche, maker of atezolizumab. Dr. Telli disclosed relationships with AbbVie, AstraZeneca, Merck, PharmaMar, Pfizer, and Tesaro.
The FDA said the phase 3 IMpassion131 trial showed that atezolizumab plus paclitaxel did not significantly reduce the risk of cancer progression and death, when compared with paclitaxel plus placebo, in programmed death-ligand 1 (PD-L1)–positive patients.
“Additionally, interim overall survival results favored paclitaxel plus placebo over paclitaxel plus atezolizumab in both the PD-L1-positive population and total population,” the FDA noted.
As a result, “health care professionals should not replace paclitaxel protein-bound (Abraxane) with paclitaxel in clinical practice,” the FDA advised.
Atezolizumab is approved for use in combination with protein-bound paclitaxel, also known as nanoparticle albumin–bound paclitaxel (nab-paclitaxel), to treat patients with unresectable, locally advanced, or metastatic TNBC whose tumors express PD-L1, as detected by an FDA-approved test. The combination was granted accelerated approval for this indication last year.
Atezolizumab plus nab-paclitaxel is the combination most often used in PD-L1-positive TNBC, as opposed to atezolizumab and unbound paclitaxel, said Melinda L. Telli, MD, an associate professor of medicine and director of the Stanford Cancer Institute Breast Cancer Program at Stanford (Calif.) University.
However, as the FDA noted, “continued approval of atezolizumab in combination with [nab-paclitaxel] may be contingent on proven benefit of the treatment in additional trials.”
Dr. Telli explained that atezolizumab was granted accelerated approval for the treatment of PD-L1-positive TNBC based on results of the phase 3 IMpassion130 trial, which compared nab-paclitaxel plus atezolizumab with nab-paclitaxel plus placebo.
“Additional data from IMpassion131 was hoped to be used to support the conversion of the accelerated approval to a full approval. Since IMpassion131 was negative, it unfortunately places the status of atezolizumab in [TNBC] in jeopardy as the benefits were not corroborated. The FDA may move to revoke the approval of atezolizumab for [TNBC],” Dr. Telli said.
In its alert, the FDA stated that it “will review the findings of IMpassion131 and will communicate new information regarding the IMpassion131 results and any potential changes to prescribing information.”
“We need to wait for full presentation and publication of the study results, but, in my assessment, the negative results in IMpassion131 are most likely due to differences in patient selection [from IMpassion130],” Dr. Telli said.
Results from IMpassion131 are scheduled to be presented at the ESMO Virtual Congress 2020.
The IMpassion trials were funded by Roche, maker of atezolizumab. Dr. Telli disclosed relationships with AbbVie, AstraZeneca, Merck, PharmaMar, Pfizer, and Tesaro.
Beyond baseline, DBT no better than mammography for dense breasts
In women with extremely dense breasts, digital breast tomosynthesis (DBT) does not outperform digital mammography (DM) after the baseline exam, according to a review of nearly 1.6 million screenings.
At baseline, DBT improved recall and cancer detection rates for all women. On subsequent exams, differences in screening performance between DBT and DM varied by age and density subgroups. However, there were no significant differences in recall or cancer detection rates among women with extremely dense breasts in any age group.
Kathryn Lowry, MD, of the University of Washington in Seattle, and colleagues reported these findings in JAMA Network Open.
“Our findings suggest that density likely should not be used as a criterion to triage use of DBT for routine screening in settings where DBT is not universally available, as has been reported in physician surveys,” the authors wrote. “The largest absolute improvements of DBT screening were achieved on the baseline screening examination, suggesting that women presenting for their first screening examination are particularly important to prioritize for DBT,” regardless of breast density or age.
Study details
Dr. Lowry and colleagues reviewed 1,584,079 screenings in women aged 40-79 years. The exams were done from January 2010 to April 2018 at Breast Cancer Surveillance Consortium facilities across the United States.
Sixty-five percent of the exams were in White, non-Hispanic women, 25.2% were in women younger than 50 years, and 42.4% were in women with heterogeneously dense or extremely dense breasts. Subjects had no history of breast cancer, mastectomy, or breast augmentation.
The investigators compared the performance of 1,273,492 DMs with 310,587 DBTs across the four Breast Imaging Reporting and Database System density types: almost entirely fatty, scattered fibroglandular density, heterogeneously dense, and extremely dense.
Findings were adjusted for race, family breast cancer history, and other potential confounders.
Recall and cancer detection rates
At baseline, recall and cancer detection rates were better with DBT than with DM, regardless of breast density subtype or patient age.
For instance, in women aged 50-59 years, screening recalls per 1,000 exams dropped from 241 with DM to 204 with DBT (relative risk, 0.84; 95% confidence interval, 0.73-0.98). Cancer detection rates per 1,000 exams in this age group increased from 5.9 with DM to 8.8 with DBT (RR, 1.50; 95% CI, 1.10-2.08).
On follow-up exams, recall rates were lower with DBT for women with scattered fibroglandular density and heterogeneously dense breasts in all age groups, as well as in women with almost entirely fatty breasts aged 50-79 years.
“By contrast, there were no significant differences in recall rates in women with extremely dense breasts in any age group,” the authors wrote.
Cancer detection rates on follow-up exams varied by age and breast density.
Cancer detection rates were higher with DBT than with DM in women with heterogeneously dense breasts in all age groups and in women with scattered fibroglandular density at 50-59 years of age and 60-79 years of age. However, cancer detection rates were not significantly different with DBT or DM for women with almost entirely fatty breasts or extremely dense breasts of any age.
Implications and next steps
Dr. Lowry and colleagues noted that use of DBT has increased steadily since it was approved by the Food and Drug Administration in 2011, driven by studies demonstrating, among other things, earlier detection of invasive cancers.
The problem has been that previous investigations “largely dichotomized dense (heterogeneously dense and extremely dense) and nondense (almost entirely fat and scattered fibroglandular densities) categories,” the authors wrote. Therefore, the nuance of benefit across density subtypes hasn’t been clear.
The finding that “screening benefits of DBT differ for women with heterogeneously dense breasts [versus] extremely dense breasts is especially important in the current landscape of density legislation and demand for supplemental screening tests beyond mammography. To date, most state mandates and ... proposed federal legislation have uniformly grouped women with heterogeneously dense breasts and those with extremely dense breasts as a single population,” the authors wrote.
As the new findings suggest, “there are important differences in performance that may not be appreciated by combining density categories,” the authors added.
The results “suggest that women with extremely dense breast tissue may benefit more from additional screening than women with heterogeneously dense breasts who undergo tomosynthesis mammography,” Catherine Tuite, MD, of Fox Chase Cancer Center in Philadelphia, and colleagues wrote in a related editorial.
“Research to determine density and risk-specific outcomes for supplemental screening methods, such as magnetic resonance imaging ... molecular breast imaging, or ultrasonography is necessary to understand which screening method beyond DBT is best for average-risk women with heterogeneous or extremely dense breasts,” the editorialists wrote.
This research was funded by the National Cancer Institute and the Patient-Centered Outcomes Research Institute through the Breast Cancer Surveillance Consortium. Dr. Lowry reported grants from GE Healthcare outside the submitted work. The editorialists didn’t have any disclosures.
SOURCE: Lowry K et al. JAMA Netw Open. 2020 Jul 1;3(7):e2011792.
In women with extremely dense breasts, digital breast tomosynthesis (DBT) does not outperform digital mammography (DM) after the baseline exam, according to a review of nearly 1.6 million screenings.
At baseline, DBT improved recall and cancer detection rates for all women. On subsequent exams, differences in screening performance between DBT and DM varied by age and density subgroups. However, there were no significant differences in recall or cancer detection rates among women with extremely dense breasts in any age group.
Kathryn Lowry, MD, of the University of Washington in Seattle, and colleagues reported these findings in JAMA Network Open.
“Our findings suggest that density likely should not be used as a criterion to triage use of DBT for routine screening in settings where DBT is not universally available, as has been reported in physician surveys,” the authors wrote. “The largest absolute improvements of DBT screening were achieved on the baseline screening examination, suggesting that women presenting for their first screening examination are particularly important to prioritize for DBT,” regardless of breast density or age.
Study details
Dr. Lowry and colleagues reviewed 1,584,079 screenings in women aged 40-79 years. The exams were done from January 2010 to April 2018 at Breast Cancer Surveillance Consortium facilities across the United States.
Sixty-five percent of the exams were in White, non-Hispanic women, 25.2% were in women younger than 50 years, and 42.4% were in women with heterogeneously dense or extremely dense breasts. Subjects had no history of breast cancer, mastectomy, or breast augmentation.
The investigators compared the performance of 1,273,492 DMs with 310,587 DBTs across the four Breast Imaging Reporting and Database System density types: almost entirely fatty, scattered fibroglandular density, heterogeneously dense, and extremely dense.
Findings were adjusted for race, family breast cancer history, and other potential confounders.
Recall and cancer detection rates
At baseline, recall and cancer detection rates were better with DBT than with DM, regardless of breast density subtype or patient age.
For instance, in women aged 50-59 years, screening recalls per 1,000 exams dropped from 241 with DM to 204 with DBT (relative risk, 0.84; 95% confidence interval, 0.73-0.98). Cancer detection rates per 1,000 exams in this age group increased from 5.9 with DM to 8.8 with DBT (RR, 1.50; 95% CI, 1.10-2.08).
On follow-up exams, recall rates were lower with DBT for women with scattered fibroglandular density and heterogeneously dense breasts in all age groups, as well as in women with almost entirely fatty breasts aged 50-79 years.
“By contrast, there were no significant differences in recall rates in women with extremely dense breasts in any age group,” the authors wrote.
Cancer detection rates on follow-up exams varied by age and breast density.
Cancer detection rates were higher with DBT than with DM in women with heterogeneously dense breasts in all age groups and in women with scattered fibroglandular density at 50-59 years of age and 60-79 years of age. However, cancer detection rates were not significantly different with DBT or DM for women with almost entirely fatty breasts or extremely dense breasts of any age.
Implications and next steps
Dr. Lowry and colleagues noted that use of DBT has increased steadily since it was approved by the Food and Drug Administration in 2011, driven by studies demonstrating, among other things, earlier detection of invasive cancers.
The problem has been that previous investigations “largely dichotomized dense (heterogeneously dense and extremely dense) and nondense (almost entirely fat and scattered fibroglandular densities) categories,” the authors wrote. Therefore, the nuance of benefit across density subtypes hasn’t been clear.
The finding that “screening benefits of DBT differ for women with heterogeneously dense breasts [versus] extremely dense breasts is especially important in the current landscape of density legislation and demand for supplemental screening tests beyond mammography. To date, most state mandates and ... proposed federal legislation have uniformly grouped women with heterogeneously dense breasts and those with extremely dense breasts as a single population,” the authors wrote.
As the new findings suggest, “there are important differences in performance that may not be appreciated by combining density categories,” the authors added.
The results “suggest that women with extremely dense breast tissue may benefit more from additional screening than women with heterogeneously dense breasts who undergo tomosynthesis mammography,” Catherine Tuite, MD, of Fox Chase Cancer Center in Philadelphia, and colleagues wrote in a related editorial.
“Research to determine density and risk-specific outcomes for supplemental screening methods, such as magnetic resonance imaging ... molecular breast imaging, or ultrasonography is necessary to understand which screening method beyond DBT is best for average-risk women with heterogeneous or extremely dense breasts,” the editorialists wrote.
This research was funded by the National Cancer Institute and the Patient-Centered Outcomes Research Institute through the Breast Cancer Surveillance Consortium. Dr. Lowry reported grants from GE Healthcare outside the submitted work. The editorialists didn’t have any disclosures.
SOURCE: Lowry K et al. JAMA Netw Open. 2020 Jul 1;3(7):e2011792.
In women with extremely dense breasts, digital breast tomosynthesis (DBT) does not outperform digital mammography (DM) after the baseline exam, according to a review of nearly 1.6 million screenings.
At baseline, DBT improved recall and cancer detection rates for all women. On subsequent exams, differences in screening performance between DBT and DM varied by age and density subgroups. However, there were no significant differences in recall or cancer detection rates among women with extremely dense breasts in any age group.
Kathryn Lowry, MD, of the University of Washington in Seattle, and colleagues reported these findings in JAMA Network Open.
“Our findings suggest that density likely should not be used as a criterion to triage use of DBT for routine screening in settings where DBT is not universally available, as has been reported in physician surveys,” the authors wrote. “The largest absolute improvements of DBT screening were achieved on the baseline screening examination, suggesting that women presenting for their first screening examination are particularly important to prioritize for DBT,” regardless of breast density or age.
Study details
Dr. Lowry and colleagues reviewed 1,584,079 screenings in women aged 40-79 years. The exams were done from January 2010 to April 2018 at Breast Cancer Surveillance Consortium facilities across the United States.
Sixty-five percent of the exams were in White, non-Hispanic women, 25.2% were in women younger than 50 years, and 42.4% were in women with heterogeneously dense or extremely dense breasts. Subjects had no history of breast cancer, mastectomy, or breast augmentation.
The investigators compared the performance of 1,273,492 DMs with 310,587 DBTs across the four Breast Imaging Reporting and Database System density types: almost entirely fatty, scattered fibroglandular density, heterogeneously dense, and extremely dense.
Findings were adjusted for race, family breast cancer history, and other potential confounders.
Recall and cancer detection rates
At baseline, recall and cancer detection rates were better with DBT than with DM, regardless of breast density subtype or patient age.
For instance, in women aged 50-59 years, screening recalls per 1,000 exams dropped from 241 with DM to 204 with DBT (relative risk, 0.84; 95% confidence interval, 0.73-0.98). Cancer detection rates per 1,000 exams in this age group increased from 5.9 with DM to 8.8 with DBT (RR, 1.50; 95% CI, 1.10-2.08).
On follow-up exams, recall rates were lower with DBT for women with scattered fibroglandular density and heterogeneously dense breasts in all age groups, as well as in women with almost entirely fatty breasts aged 50-79 years.
“By contrast, there were no significant differences in recall rates in women with extremely dense breasts in any age group,” the authors wrote.
Cancer detection rates on follow-up exams varied by age and breast density.
Cancer detection rates were higher with DBT than with DM in women with heterogeneously dense breasts in all age groups and in women with scattered fibroglandular density at 50-59 years of age and 60-79 years of age. However, cancer detection rates were not significantly different with DBT or DM for women with almost entirely fatty breasts or extremely dense breasts of any age.
Implications and next steps
Dr. Lowry and colleagues noted that use of DBT has increased steadily since it was approved by the Food and Drug Administration in 2011, driven by studies demonstrating, among other things, earlier detection of invasive cancers.
The problem has been that previous investigations “largely dichotomized dense (heterogeneously dense and extremely dense) and nondense (almost entirely fat and scattered fibroglandular densities) categories,” the authors wrote. Therefore, the nuance of benefit across density subtypes hasn’t been clear.
The finding that “screening benefits of DBT differ for women with heterogeneously dense breasts [versus] extremely dense breasts is especially important in the current landscape of density legislation and demand for supplemental screening tests beyond mammography. To date, most state mandates and ... proposed federal legislation have uniformly grouped women with heterogeneously dense breasts and those with extremely dense breasts as a single population,” the authors wrote.
As the new findings suggest, “there are important differences in performance that may not be appreciated by combining density categories,” the authors added.
The results “suggest that women with extremely dense breast tissue may benefit more from additional screening than women with heterogeneously dense breasts who undergo tomosynthesis mammography,” Catherine Tuite, MD, of Fox Chase Cancer Center in Philadelphia, and colleagues wrote in a related editorial.
“Research to determine density and risk-specific outcomes for supplemental screening methods, such as magnetic resonance imaging ... molecular breast imaging, or ultrasonography is necessary to understand which screening method beyond DBT is best for average-risk women with heterogeneous or extremely dense breasts,” the editorialists wrote.
This research was funded by the National Cancer Institute and the Patient-Centered Outcomes Research Institute through the Breast Cancer Surveillance Consortium. Dr. Lowry reported grants from GE Healthcare outside the submitted work. The editorialists didn’t have any disclosures.
SOURCE: Lowry K et al. JAMA Netw Open. 2020 Jul 1;3(7):e2011792.
FROM THE JAMA OPEN NETWORK
AI improves diagnostic accuracy in cervical cancer
This could allow some women to avoid surgery and be treated with chemotherapy instead, suggested researchers.
The model mined tumor information from pelvic sagittal contrast-enhanced T1-weighted MRIs and combined this with clinical MRI lymph node status.
It was 90.62% sensitive and 87.16% specific for predicting lymph node metastases (LNMs) in a validation cohort of women who underwent surgery for cervical cancer.
The area under the curve was 0.933. The approach was significantly associated with disease-free survival (hazard ratio, 4.59; 95% confidence interval, 2.04-10.31; P < .001).
The study was published online on July 24 in JAMA Network Open.
“The findings of this study suggest that deep learning can be used as a preoperative noninvasive tool to diagnose lymph node metastasis in cervical cancer ... This model might be used preoperatively to help gynecologists make decisions,” said investigators led by Qingxia Wu, PhD, of the Northeastern University College of Medicine and Biomedical Information Engineering in Shenyang, China.
“Studies like these suggest that deep learning has the potential to improve the way we care for our patients,” but there’s much to be done “before these types of algorithms will be commonplace,” commented Christiaan Rees, MD, PhD, an internal medicine resident at Brigham and Women’s Hospital, Boston, who has a doctorate in quantitative biomedical sciences.
Next steps include repeated validation across multiple control groups, he said in an interview, as well as “finding ways to effectively integrate these tools into the radiologist’s day-to-day practice. One possibility would be for direct integration of the algorithm into the electronic health record.”
Accurate prediction could lead to skipping surgery
Chemotherapy, rather than surgery, is an option for women with positive lymph nodes (LNs), so accurate prediction can help them avoid an operation and its risks, the authors said.
The problem is that “the traditional methods for assessing LN status in cervical cancer, which rely mainly on assessing the size of LNs on MRI, have limited sensitivity in diagnosing LNM in cervical cancer and might lead to inappropriate treatment decisions,” they wrote.
“Although sentinel LN dissection ... shows good sensitivity and specificity, its application is limited by available facilities and experts,” the team said.
DL is an advanced form of artificial intelligence in which a computer program continuously improves on a given task as it incorporates more data – in Dr. Wu’s study, more than 14 million images. Deep learning has recently shown promise in several imaging tasks, such as diagnosing Alzheimer’s disease and screening for breast cancer.
Once adapted for cervical cancer, DL “does not require precise tumor delineation, making it an easy-to-use method in clinical practice. In many tumor analysis tasks, DL outperforms traditional radiomic features,” the team noted.
The study involved 479 women – 338 during model development, and 141 in the validation cohorts. The mean age of the participants was 49.1 years. They had undergone radical hysterectomy with pelvic lymphadenectomy for stage IB-IIB cervical cancer within 2 weeks of a pelvic MRI. Pathology reports were used to check the accuracy of the model’s predictions.
Specificity, sensitivity, and area under the curve were a little better in the study’s development cohort than its validation group, for whom median disease-free survival was 23 months versus 31 months among the patients in the development cohort. Nodes were positive on lymphadenectomy in a little more than 20% of women in both groups.
Incorporation of both intratumoral and peritumoral regions on contrast-enhanced T1-weighted MRIs versus axial T2-weighted and axial diffusion-weighted imaging, produced the highest sensitivity. Adding MRI-LN status – defined as positive when the short-axis diameter of the largest LN on MRI was ≥1 cm – improved the model’s specificity.
To understand how the model reached its conclusions, the team analyzed how it extracted features from tumor images. “In the shallow convolution layers, the DL model extracted simple tumor edge features ... while in deeper convolution layers, it extracted complex tumor texture information ... In the last convolution layer, the DL model extracted high-level abstract features (the fourteenth layer). Although these high-level features were so intricate that they were hard to interpret by general gross observation, they were associated with LN status,” the investigators said.
The team notes that “both intratumoral and peritumoral regions were necessary for the DL model to make decisions,” which “can probably be explained by the fact that higher lymphatic vessel density in peritumoral regions might lead to higher regional LNM.”
Commenting on the study, Dr. Rees said that “the authors did a [good] job of essentially deconstructing their neural network to see what the algorithm was actually picking up on to make its decision.
“One of the nice features of deep learning is that once the algorithm has been developed and validated, the end user doesn’t need any experience in deep learning in order to use it,” he added.
Even so, “while these resources can be incredibly powerful tools, they should not function in a vacuum without human judgment,” Dr. Rees said.
The work was funded by the National Natural Science Foundation of China, among others. The investigators have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
This could allow some women to avoid surgery and be treated with chemotherapy instead, suggested researchers.
The model mined tumor information from pelvic sagittal contrast-enhanced T1-weighted MRIs and combined this with clinical MRI lymph node status.
It was 90.62% sensitive and 87.16% specific for predicting lymph node metastases (LNMs) in a validation cohort of women who underwent surgery for cervical cancer.
The area under the curve was 0.933. The approach was significantly associated with disease-free survival (hazard ratio, 4.59; 95% confidence interval, 2.04-10.31; P < .001).
The study was published online on July 24 in JAMA Network Open.
“The findings of this study suggest that deep learning can be used as a preoperative noninvasive tool to diagnose lymph node metastasis in cervical cancer ... This model might be used preoperatively to help gynecologists make decisions,” said investigators led by Qingxia Wu, PhD, of the Northeastern University College of Medicine and Biomedical Information Engineering in Shenyang, China.
“Studies like these suggest that deep learning has the potential to improve the way we care for our patients,” but there’s much to be done “before these types of algorithms will be commonplace,” commented Christiaan Rees, MD, PhD, an internal medicine resident at Brigham and Women’s Hospital, Boston, who has a doctorate in quantitative biomedical sciences.
Next steps include repeated validation across multiple control groups, he said in an interview, as well as “finding ways to effectively integrate these tools into the radiologist’s day-to-day practice. One possibility would be for direct integration of the algorithm into the electronic health record.”
Accurate prediction could lead to skipping surgery
Chemotherapy, rather than surgery, is an option for women with positive lymph nodes (LNs), so accurate prediction can help them avoid an operation and its risks, the authors said.
The problem is that “the traditional methods for assessing LN status in cervical cancer, which rely mainly on assessing the size of LNs on MRI, have limited sensitivity in diagnosing LNM in cervical cancer and might lead to inappropriate treatment decisions,” they wrote.
“Although sentinel LN dissection ... shows good sensitivity and specificity, its application is limited by available facilities and experts,” the team said.
DL is an advanced form of artificial intelligence in which a computer program continuously improves on a given task as it incorporates more data – in Dr. Wu’s study, more than 14 million images. Deep learning has recently shown promise in several imaging tasks, such as diagnosing Alzheimer’s disease and screening for breast cancer.
Once adapted for cervical cancer, DL “does not require precise tumor delineation, making it an easy-to-use method in clinical practice. In many tumor analysis tasks, DL outperforms traditional radiomic features,” the team noted.
The study involved 479 women – 338 during model development, and 141 in the validation cohorts. The mean age of the participants was 49.1 years. They had undergone radical hysterectomy with pelvic lymphadenectomy for stage IB-IIB cervical cancer within 2 weeks of a pelvic MRI. Pathology reports were used to check the accuracy of the model’s predictions.
Specificity, sensitivity, and area under the curve were a little better in the study’s development cohort than its validation group, for whom median disease-free survival was 23 months versus 31 months among the patients in the development cohort. Nodes were positive on lymphadenectomy in a little more than 20% of women in both groups.
Incorporation of both intratumoral and peritumoral regions on contrast-enhanced T1-weighted MRIs versus axial T2-weighted and axial diffusion-weighted imaging, produced the highest sensitivity. Adding MRI-LN status – defined as positive when the short-axis diameter of the largest LN on MRI was ≥1 cm – improved the model’s specificity.
To understand how the model reached its conclusions, the team analyzed how it extracted features from tumor images. “In the shallow convolution layers, the DL model extracted simple tumor edge features ... while in deeper convolution layers, it extracted complex tumor texture information ... In the last convolution layer, the DL model extracted high-level abstract features (the fourteenth layer). Although these high-level features were so intricate that they were hard to interpret by general gross observation, they were associated with LN status,” the investigators said.
The team notes that “both intratumoral and peritumoral regions were necessary for the DL model to make decisions,” which “can probably be explained by the fact that higher lymphatic vessel density in peritumoral regions might lead to higher regional LNM.”
Commenting on the study, Dr. Rees said that “the authors did a [good] job of essentially deconstructing their neural network to see what the algorithm was actually picking up on to make its decision.
“One of the nice features of deep learning is that once the algorithm has been developed and validated, the end user doesn’t need any experience in deep learning in order to use it,” he added.
Even so, “while these resources can be incredibly powerful tools, they should not function in a vacuum without human judgment,” Dr. Rees said.
The work was funded by the National Natural Science Foundation of China, among others. The investigators have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
This could allow some women to avoid surgery and be treated with chemotherapy instead, suggested researchers.
The model mined tumor information from pelvic sagittal contrast-enhanced T1-weighted MRIs and combined this with clinical MRI lymph node status.
It was 90.62% sensitive and 87.16% specific for predicting lymph node metastases (LNMs) in a validation cohort of women who underwent surgery for cervical cancer.
The area under the curve was 0.933. The approach was significantly associated with disease-free survival (hazard ratio, 4.59; 95% confidence interval, 2.04-10.31; P < .001).
The study was published online on July 24 in JAMA Network Open.
“The findings of this study suggest that deep learning can be used as a preoperative noninvasive tool to diagnose lymph node metastasis in cervical cancer ... This model might be used preoperatively to help gynecologists make decisions,” said investigators led by Qingxia Wu, PhD, of the Northeastern University College of Medicine and Biomedical Information Engineering in Shenyang, China.
“Studies like these suggest that deep learning has the potential to improve the way we care for our patients,” but there’s much to be done “before these types of algorithms will be commonplace,” commented Christiaan Rees, MD, PhD, an internal medicine resident at Brigham and Women’s Hospital, Boston, who has a doctorate in quantitative biomedical sciences.
Next steps include repeated validation across multiple control groups, he said in an interview, as well as “finding ways to effectively integrate these tools into the radiologist’s day-to-day practice. One possibility would be for direct integration of the algorithm into the electronic health record.”
Accurate prediction could lead to skipping surgery
Chemotherapy, rather than surgery, is an option for women with positive lymph nodes (LNs), so accurate prediction can help them avoid an operation and its risks, the authors said.
The problem is that “the traditional methods for assessing LN status in cervical cancer, which rely mainly on assessing the size of LNs on MRI, have limited sensitivity in diagnosing LNM in cervical cancer and might lead to inappropriate treatment decisions,” they wrote.
“Although sentinel LN dissection ... shows good sensitivity and specificity, its application is limited by available facilities and experts,” the team said.
DL is an advanced form of artificial intelligence in which a computer program continuously improves on a given task as it incorporates more data – in Dr. Wu’s study, more than 14 million images. Deep learning has recently shown promise in several imaging tasks, such as diagnosing Alzheimer’s disease and screening for breast cancer.
Once adapted for cervical cancer, DL “does not require precise tumor delineation, making it an easy-to-use method in clinical practice. In many tumor analysis tasks, DL outperforms traditional radiomic features,” the team noted.
The study involved 479 women – 338 during model development, and 141 in the validation cohorts. The mean age of the participants was 49.1 years. They had undergone radical hysterectomy with pelvic lymphadenectomy for stage IB-IIB cervical cancer within 2 weeks of a pelvic MRI. Pathology reports were used to check the accuracy of the model’s predictions.
Specificity, sensitivity, and area under the curve were a little better in the study’s development cohort than its validation group, for whom median disease-free survival was 23 months versus 31 months among the patients in the development cohort. Nodes were positive on lymphadenectomy in a little more than 20% of women in both groups.
Incorporation of both intratumoral and peritumoral regions on contrast-enhanced T1-weighted MRIs versus axial T2-weighted and axial diffusion-weighted imaging, produced the highest sensitivity. Adding MRI-LN status – defined as positive when the short-axis diameter of the largest LN on MRI was ≥1 cm – improved the model’s specificity.
To understand how the model reached its conclusions, the team analyzed how it extracted features from tumor images. “In the shallow convolution layers, the DL model extracted simple tumor edge features ... while in deeper convolution layers, it extracted complex tumor texture information ... In the last convolution layer, the DL model extracted high-level abstract features (the fourteenth layer). Although these high-level features were so intricate that they were hard to interpret by general gross observation, they were associated with LN status,” the investigators said.
The team notes that “both intratumoral and peritumoral regions were necessary for the DL model to make decisions,” which “can probably be explained by the fact that higher lymphatic vessel density in peritumoral regions might lead to higher regional LNM.”
Commenting on the study, Dr. Rees said that “the authors did a [good] job of essentially deconstructing their neural network to see what the algorithm was actually picking up on to make its decision.
“One of the nice features of deep learning is that once the algorithm has been developed and validated, the end user doesn’t need any experience in deep learning in order to use it,” he added.
Even so, “while these resources can be incredibly powerful tools, they should not function in a vacuum without human judgment,” Dr. Rees said.
The work was funded by the National Natural Science Foundation of China, among others. The investigators have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
PEGPH20 strikeout raises doubts about stroma-targeting agents in pancreatic cancer
The median overall survival was 11.2 months with PEGPH20 plus AG and 11.5 months with placebo plus AG. The median progression-free survival was 7.1 months in both treatment arms.
Eric Van Cutsem, MD, PhD, of University Hospitals Gasthuisberg Leuven and KU Leuven in Belgium, and colleagues reported these findings in the Journal of Clinical Oncology.
The authors explained that, in pancreatic ductal adenocarcinoma, “a dense fibrotic stroma (i.e., desmoplasia) surrounds the growing tumor mass, which can compress tumor vasculature within the microenvironment and increase interstitial pressure, impeding perfusion and delivery of systemic agents.”
PEGPH20 is an enzyme that degrades hyaluronan, a major component of the stroma. The researchers’ hypothesis was that PEGPH20 would weaken the stromal barrier and facilitate greater penetration of the AG combination into the tumor.
However, PEGPH20 failed to improve upon results with AG in this trial, which led Halozyme Therapeutics to halt further development of PEGPH20.
The negative findings in this trial, as well as the failure of other stroma-remodeling agents in pancreatic ductal adenocarcinoma, “collectively indicates the need to reevaluate this treatment strategy,” Dr. Van Cutsem and colleagues wrote.
“More preclinical and retrospective analyses are needed to better understand the failures of tumor stroma remodeling and whether and how it should continue to be pursued,” the authors added.
Phase 3 results
The intent-to-treat analysis included 492 adults with previously untreated metastatic pancreatic ductal adenocarcinoma. All patients expressed high hyaluronan levels, as defined by at least 50% hyaluronan staining in the extracellular matrix from tumor samples.
There were 165 subjects randomized to receive placebo plus AG and 327 randomized to receive PEGPH20 plus AG. Baseline characteristics were similar between the treatment arms.
The overall response rate was 47% with PEGPH20-AG and 36% with placebo-AG. The median duration of response was 6.1 months and 7.4 months, respectively.
The overall survival analysis was performed after 330 deaths. There were no significant differences between the PEGPH20 and placebo arms with regard to median overall survival (11.2 months and 11.5 months, respectively; hazard ratio, 1.00, P = .97) or progression-free survival (7.1 months in both arms; HR, 0.97).
All patients experienced at least one treatment-emergent adverse event (AE). The most common AEs of any grade that were more frequent in the PEGPH20 arm than in the placebo arm (≥ 2%) were peripheral edema (61.8% vs. 33.3%), muscle spasms (51.4% vs. 9.6%), myalgia (28.9% vs. 14.7%), and arthralgia (19.4% vs. 11.5%).
Grade 3 or higher AEs that were more common with PEGPH20 (≥ 2%) included fatigue (16.0% vs. 9.6%), muscle spasms (6.5% vs. 0.6%), and hyponatremia (8.0% vs. 3.8%).
“[T]here were no apparent safety signals that affected study treatment exposure or survival,” the investigators noted.
Two failed trials
“We now have two failed clinical trials for PEGPH20. Could it be perhaps that our theory of targeting the desmoplastic response is simply not enough?” Nausheen Hakim, DO, of Northwell Health Cancer Institute in New York, and colleagues wrote in a commentary shortly after Halozyme released topline results from the phase 3 trial (Pancreas [Fairfax]. 2019;3[1]:e1-e4. doi: 10.17140/POJ-3-e010).
The second study the editorialists were referring to is a phase 1b/2 trial of PEGPH20 added to fluorouracil, leucovorin, irinotecan, and oxaliplatin (J Clin Oncol. 2019 May 1;37[13]:1062-9).
In this trial, the median overall survival was worse with PEGPH20 than without it, at 7.7 months and 14.4 months, respectively. The difference was probably due to the increased toxicity with the PEGPH20 regimen, which led to subjects receiving only half the number of chemotherapy cycles as the control group, Dr. Hakim and colleagues wrote.
“Perhaps it is not solely the desmoplastic reaction that is the cause of chemoresistance of pancreatic cells but additional intrinsic factors at play,” the editorialists wrote. “It may indeed be a combination of stroma-modifying agents as well as other strategies to overcome chemoresistance to better fight pancreatic cancer. Further studies in molecular biology to better characterize the complex interaction between the microenvironment and cancer cells are warranted.”
The phase 3 study was funded by Halozyme Therapeutics. The authors disclosed relationships with Halozyme and many other companies. The editorialists disclosed no conflicts of interest.
SOURCE: Van Cutsem E et al. J Clin Oncol. 2020 Jul 24;JCO2000590. doi: 10.1200/JCO.20.00590.
The median overall survival was 11.2 months with PEGPH20 plus AG and 11.5 months with placebo plus AG. The median progression-free survival was 7.1 months in both treatment arms.
Eric Van Cutsem, MD, PhD, of University Hospitals Gasthuisberg Leuven and KU Leuven in Belgium, and colleagues reported these findings in the Journal of Clinical Oncology.
The authors explained that, in pancreatic ductal adenocarcinoma, “a dense fibrotic stroma (i.e., desmoplasia) surrounds the growing tumor mass, which can compress tumor vasculature within the microenvironment and increase interstitial pressure, impeding perfusion and delivery of systemic agents.”
PEGPH20 is an enzyme that degrades hyaluronan, a major component of the stroma. The researchers’ hypothesis was that PEGPH20 would weaken the stromal barrier and facilitate greater penetration of the AG combination into the tumor.
However, PEGPH20 failed to improve upon results with AG in this trial, which led Halozyme Therapeutics to halt further development of PEGPH20.
The negative findings in this trial, as well as the failure of other stroma-remodeling agents in pancreatic ductal adenocarcinoma, “collectively indicates the need to reevaluate this treatment strategy,” Dr. Van Cutsem and colleagues wrote.
“More preclinical and retrospective analyses are needed to better understand the failures of tumor stroma remodeling and whether and how it should continue to be pursued,” the authors added.
Phase 3 results
The intent-to-treat analysis included 492 adults with previously untreated metastatic pancreatic ductal adenocarcinoma. All patients expressed high hyaluronan levels, as defined by at least 50% hyaluronan staining in the extracellular matrix from tumor samples.
There were 165 subjects randomized to receive placebo plus AG and 327 randomized to receive PEGPH20 plus AG. Baseline characteristics were similar between the treatment arms.
The overall response rate was 47% with PEGPH20-AG and 36% with placebo-AG. The median duration of response was 6.1 months and 7.4 months, respectively.
The overall survival analysis was performed after 330 deaths. There were no significant differences between the PEGPH20 and placebo arms with regard to median overall survival (11.2 months and 11.5 months, respectively; hazard ratio, 1.00, P = .97) or progression-free survival (7.1 months in both arms; HR, 0.97).
All patients experienced at least one treatment-emergent adverse event (AE). The most common AEs of any grade that were more frequent in the PEGPH20 arm than in the placebo arm (≥ 2%) were peripheral edema (61.8% vs. 33.3%), muscle spasms (51.4% vs. 9.6%), myalgia (28.9% vs. 14.7%), and arthralgia (19.4% vs. 11.5%).
Grade 3 or higher AEs that were more common with PEGPH20 (≥ 2%) included fatigue (16.0% vs. 9.6%), muscle spasms (6.5% vs. 0.6%), and hyponatremia (8.0% vs. 3.8%).
“[T]here were no apparent safety signals that affected study treatment exposure or survival,” the investigators noted.
Two failed trials
“We now have two failed clinical trials for PEGPH20. Could it be perhaps that our theory of targeting the desmoplastic response is simply not enough?” Nausheen Hakim, DO, of Northwell Health Cancer Institute in New York, and colleagues wrote in a commentary shortly after Halozyme released topline results from the phase 3 trial (Pancreas [Fairfax]. 2019;3[1]:e1-e4. doi: 10.17140/POJ-3-e010).
The second study the editorialists were referring to is a phase 1b/2 trial of PEGPH20 added to fluorouracil, leucovorin, irinotecan, and oxaliplatin (J Clin Oncol. 2019 May 1;37[13]:1062-9).
In this trial, the median overall survival was worse with PEGPH20 than without it, at 7.7 months and 14.4 months, respectively. The difference was probably due to the increased toxicity with the PEGPH20 regimen, which led to subjects receiving only half the number of chemotherapy cycles as the control group, Dr. Hakim and colleagues wrote.
“Perhaps it is not solely the desmoplastic reaction that is the cause of chemoresistance of pancreatic cells but additional intrinsic factors at play,” the editorialists wrote. “It may indeed be a combination of stroma-modifying agents as well as other strategies to overcome chemoresistance to better fight pancreatic cancer. Further studies in molecular biology to better characterize the complex interaction between the microenvironment and cancer cells are warranted.”
The phase 3 study was funded by Halozyme Therapeutics. The authors disclosed relationships with Halozyme and many other companies. The editorialists disclosed no conflicts of interest.
SOURCE: Van Cutsem E et al. J Clin Oncol. 2020 Jul 24;JCO2000590. doi: 10.1200/JCO.20.00590.
The median overall survival was 11.2 months with PEGPH20 plus AG and 11.5 months with placebo plus AG. The median progression-free survival was 7.1 months in both treatment arms.
Eric Van Cutsem, MD, PhD, of University Hospitals Gasthuisberg Leuven and KU Leuven in Belgium, and colleagues reported these findings in the Journal of Clinical Oncology.
The authors explained that, in pancreatic ductal adenocarcinoma, “a dense fibrotic stroma (i.e., desmoplasia) surrounds the growing tumor mass, which can compress tumor vasculature within the microenvironment and increase interstitial pressure, impeding perfusion and delivery of systemic agents.”
PEGPH20 is an enzyme that degrades hyaluronan, a major component of the stroma. The researchers’ hypothesis was that PEGPH20 would weaken the stromal barrier and facilitate greater penetration of the AG combination into the tumor.
However, PEGPH20 failed to improve upon results with AG in this trial, which led Halozyme Therapeutics to halt further development of PEGPH20.
The negative findings in this trial, as well as the failure of other stroma-remodeling agents in pancreatic ductal adenocarcinoma, “collectively indicates the need to reevaluate this treatment strategy,” Dr. Van Cutsem and colleagues wrote.
“More preclinical and retrospective analyses are needed to better understand the failures of tumor stroma remodeling and whether and how it should continue to be pursued,” the authors added.
Phase 3 results
The intent-to-treat analysis included 492 adults with previously untreated metastatic pancreatic ductal adenocarcinoma. All patients expressed high hyaluronan levels, as defined by at least 50% hyaluronan staining in the extracellular matrix from tumor samples.
There were 165 subjects randomized to receive placebo plus AG and 327 randomized to receive PEGPH20 plus AG. Baseline characteristics were similar between the treatment arms.
The overall response rate was 47% with PEGPH20-AG and 36% with placebo-AG. The median duration of response was 6.1 months and 7.4 months, respectively.
The overall survival analysis was performed after 330 deaths. There were no significant differences between the PEGPH20 and placebo arms with regard to median overall survival (11.2 months and 11.5 months, respectively; hazard ratio, 1.00, P = .97) or progression-free survival (7.1 months in both arms; HR, 0.97).
All patients experienced at least one treatment-emergent adverse event (AE). The most common AEs of any grade that were more frequent in the PEGPH20 arm than in the placebo arm (≥ 2%) were peripheral edema (61.8% vs. 33.3%), muscle spasms (51.4% vs. 9.6%), myalgia (28.9% vs. 14.7%), and arthralgia (19.4% vs. 11.5%).
Grade 3 or higher AEs that were more common with PEGPH20 (≥ 2%) included fatigue (16.0% vs. 9.6%), muscle spasms (6.5% vs. 0.6%), and hyponatremia (8.0% vs. 3.8%).
“[T]here were no apparent safety signals that affected study treatment exposure or survival,” the investigators noted.
Two failed trials
“We now have two failed clinical trials for PEGPH20. Could it be perhaps that our theory of targeting the desmoplastic response is simply not enough?” Nausheen Hakim, DO, of Northwell Health Cancer Institute in New York, and colleagues wrote in a commentary shortly after Halozyme released topline results from the phase 3 trial (Pancreas [Fairfax]. 2019;3[1]:e1-e4. doi: 10.17140/POJ-3-e010).
The second study the editorialists were referring to is a phase 1b/2 trial of PEGPH20 added to fluorouracil, leucovorin, irinotecan, and oxaliplatin (J Clin Oncol. 2019 May 1;37[13]:1062-9).
In this trial, the median overall survival was worse with PEGPH20 than without it, at 7.7 months and 14.4 months, respectively. The difference was probably due to the increased toxicity with the PEGPH20 regimen, which led to subjects receiving only half the number of chemotherapy cycles as the control group, Dr. Hakim and colleagues wrote.
“Perhaps it is not solely the desmoplastic reaction that is the cause of chemoresistance of pancreatic cells but additional intrinsic factors at play,” the editorialists wrote. “It may indeed be a combination of stroma-modifying agents as well as other strategies to overcome chemoresistance to better fight pancreatic cancer. Further studies in molecular biology to better characterize the complex interaction between the microenvironment and cancer cells are warranted.”
The phase 3 study was funded by Halozyme Therapeutics. The authors disclosed relationships with Halozyme and many other companies. The editorialists disclosed no conflicts of interest.
SOURCE: Van Cutsem E et al. J Clin Oncol. 2020 Jul 24;JCO2000590. doi: 10.1200/JCO.20.00590.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
The fix is in: AIM bundles to combat maternal morbidity and mortality
“Anytime you have a maternal death, it sticks with you for life,” said Elliott Main, MD, a maternal fetal medicine specialist at Stanford (Calif.) University and one of the nation’s leaders in combating maternal mortality.
Dr. Main has had two maternal deaths in his career, years ago. One woman had a fatal stroke because of severe hypertension, and another died of cardiac complications. “We tried to do everything we possibly could, but you scrounge your memory for years and years [afterward]. To have a young healthy person go into labor and delivery and not come out is a tragedy at all levels. It charged me to not ever want to see that happen again,” he said.
Today, Dr. Main is the medical director of the California Maternal Quality Care Collaborative (CMQCC), a wide-ranging group of clinicians, state officials, hospitals, and others who have come together to address the issue. About 30 states have similar perinatal quality collaboratives (PQCs), and other states are forming them.
They work in collaboration with maternal mortality review committees (MMRCs), state-level groups that review maternal deaths, identify problems to address, and make recommendations to the quality collaboratives on how to prevent maternal deaths.
About 600-800 women die in the United States each year due to pregnancy-related complications, which ranks the United States behind other industrialized nations. Leading causes include hemorrhage and hemorrhagic strokes secondary to hypertension. It’s estimated that the majority of maternal deaths could be prevented with proper care.
To that end, states are enacting safety bundles from the Alliance for Innovation on Maternal Health (AIM), which was established by the American College of Obstetricians and Gynecologist several years ago. There are bundles that address obstetric hypertension, hemorrhage, mental health, venous thromboembolism, opioid use, racial disparities, and other problems. They were developed by experts in the field and published in multiple journals. California and other states have issued toolkits on how to implement them based on local circumstances.
Dr. Main said.
AIM bundle implementation is “what’s happening in New Mexico and a lot of states, mostly through the efforts of state level quality care collaboratives. Some [states] are further ahead than others,” said Eve Espey, MD, professor and chair of the department of obstetrics and gynecology at the University of New Mexico, Albuquerque, and president of the New Mexico PQC.
“Most states now have a [MMRC] that collects maternal mortality and near-miss data. Those data are used by the action arm,” which is the PQC. “If the review committee says” opioid use disorder is a significant contributor “like in our state, the collaborative rolls out the opioid use disorder bundle,” she said.
Beginning next January, the Joint Commission, formerly known as the Joint Commission on Accreditation of Healthcare Organizations, will require that accredited hospitals enact key elements of the AIM bundles for both obstetric hemorrhage and severe hypertension. “Everyone’s [now] motivated to get on that bandwagon,” Dr. Espey said.
“The bundles are here to stay,” and the Joint Commission requirements are “a really important step for sustainability and basic implementation. We really want to get them adopted everywhere,” said Dr. Main, who is also the national implementation director for the AIM initiative.
“The key thing is to work on implementing the hemorrhage and hypertension bundles in your hospital. I would suggest contacting [your] state” PQC, he said.
The California model
California, which has been working to reduce maternal mortality and morbidity since the mid 2000s, has produced among the strongest evidence to date that the efforts make a difference.
By 2013, the state had halved its maternal mortality rate to a 3-year average of 7 deaths per 100,000 live births, which is comparable with the average Western Europe rate of 7.2 deaths. Nationwide, the rate was about 17.4 deaths per 100,000 live births in 2018, according to the Centers for Disease Control and Prevention
The reasons are multifactorial, but “we think” the quality improvement efforts have been “an important contributor,” Dr. Main said.
Improvements especially for Black women
Among the success stories has been California’s implementation of the AIM obstetric hemorrhage bundle about 5 years ago. Among other steps, the 17 evidence-based recommendations included early recognition, immediate access to oxytocin and other medications, immediate access to a hemorrhage cart with instructions for intrauterine balloons and compression stitches, the establishment of a hemorrhage response protocol and team, and regular unit-based drills with debriefing sessions afterward.
Mentoring teams consisting of a physician and nurse with maternal quality improvement experience were created to help hospitals come on board, with each team working with five to eight hospitals. Efforts included monthly telephone calls and face-to-face meetings, and providers were held accountable for progress. Hospitals shared data and tips on implementation, under the aegis of the CMQCC.
When the baseline period of 2011-2014 to the postintervention period of October 2015 to December 2016 were compared, the rate of severe maternal morbidity from hemorrhage fell from 22.1% to 18.5% across 99 hospitals and 73,476 women.
The benefit among Black women exceeded that among White women, with a 9% absolute rate reduction versus 2.1%. “If you adjusted for risk factors, [we found] you could eliminate [racial differences] completely,” which is something that hadn’t been shown before. “This is a really big deal,” Dr. Main said, because the risk of maternal morbidity and mortality is three to four times higher among Black women, compared with White women.
Dr. Main and his team found that the biggest clinical risk factor that accounted for racial differences was a higher rate of cesarean deliveries among Black women, followed by higher rates of anemia at hospital admission. “If you have a C-section when you are anemic, you are going to have a transfusion,” he explained.
More recently, there’s been a push in California to reduce the rate of primary cesarean deliveries by enacting the associated AIM bundle with use of the same approach as with the hemorrhage bundle. Dr. Main and his team recently reported a rate reduction from 29.3% to 25% without compromising birth outcomes.
However, “some changes are easier than others. Hemorrhage was an easy one to change because it didn’t deal with physician autonomy as much, and you saw more immediate results” with fewer hemorrhages. Reducing cesarean delivery rates is “a bigger lift” because “it’s really changing the culture of labor and delivery. It involves more group pressure and more reinforcing, but we were able to do that,” he said.
Problems in the Show Me State
“We’ve patterned a lot” of what’s being done in New Mexico “after California,” Dr. Espey said.
The AIM hemorrhage bundle, for instance, is being rolled out to New Mexico hospitals, with the help of virtual meetings and mentoring programs, plus outreach to the Navajo and others reservations because, as with Black women, rates of maternal morbidity and mortality are higher among Native American women.
It’s been tougher going, however, in states such as Missouri, which recently ranked 44th in the country for maternal mortality.
“We started a little bit late, and we are a little bit behind,” said ob.gyn. Karen L. Florio, DO, at the University of Missouri–Kansas City and also a leader of the state MMRC and member of its PQC.
The main problem is money. California’s efforts are funded by the Centers for Disease Control and Prevention, the state health department, and hospitals, among others.
But Missouri is “not as well funded as California for our mortality review board, and our [PQC] is mostly not funded. If we could get that funding, we would have more resources to implement these AIM bundles,” she said.
In addition to the issue, Missouri didn’t expand Medicaid under the Accountable Care Act – something that’s been linked to reduced maternal morbidity and mortality – and there are entire rural areas with no maternity care. Plus after generations of mistreatment, “our African American population has a valid distrust of the medical system that contributes to maternal mortality,” she said.
Obesity-related heart disease is also prevalent in Missouri, even among young people. “I cannot tell you how many women I have had who have had a heart attack at the age of 30 and who have had stents placed,” Dr. Florio said.
Dr. Florio and her colleagues are currently using teleconferences and other means to roll out the AIM hypertension bundle but can do so only selectively. “We don’t have the resources to reach every single rural hospital all over the state,” she said; they are working to address the funding issues.
For rural hospitals, implementation is “daunting”
Meanwhile, rural hospitals have been a particular concern in South Dakota, said Kimberlee McKay, MD, an ob.gyn. who is the clinical vice president of the ob.gyn. service line at Avera Health, a hospital system based in Sioux Falls, S.D.
She’s been overseeing Avera’s implementation of the hypertension, hemorrhage, and venous thromboembolism bundles. “What’s hard is that” the AIM protocols come “out of academic centers. Implementation of complex algorithms is daunting” for hospitals that only do a couple hundred deliveries a year, she said.
For small hospitals, the approach she’s found that works is to first assess what they can offer, and then have them “do what’s reasonable” for their resources. The second part is making sure high-risk women get to a regional center – with an adequate blood supply, in the case of hemorrhage, for instance – for complications. Dr. McKay and colleagues are working on a system by which regional centers can monitor smaller hospitals for potential maternity problems, and contact them proactively before they emerge.
They’ve also made access to hemorrhage and hypertension drugs easier on labor and delivery units with the help of close-by dedicated medicine boxes, and standardized protocols and order sets across Avera. “We try to make the right thing the easy thing to do,” Dr. McKay said.
Dr. Espey is an editorial adviser for Ob.Gyn. News. The physicians have no relevant financial disclosures.
“Anytime you have a maternal death, it sticks with you for life,” said Elliott Main, MD, a maternal fetal medicine specialist at Stanford (Calif.) University and one of the nation’s leaders in combating maternal mortality.
Dr. Main has had two maternal deaths in his career, years ago. One woman had a fatal stroke because of severe hypertension, and another died of cardiac complications. “We tried to do everything we possibly could, but you scrounge your memory for years and years [afterward]. To have a young healthy person go into labor and delivery and not come out is a tragedy at all levels. It charged me to not ever want to see that happen again,” he said.
Today, Dr. Main is the medical director of the California Maternal Quality Care Collaborative (CMQCC), a wide-ranging group of clinicians, state officials, hospitals, and others who have come together to address the issue. About 30 states have similar perinatal quality collaboratives (PQCs), and other states are forming them.
They work in collaboration with maternal mortality review committees (MMRCs), state-level groups that review maternal deaths, identify problems to address, and make recommendations to the quality collaboratives on how to prevent maternal deaths.
About 600-800 women die in the United States each year due to pregnancy-related complications, which ranks the United States behind other industrialized nations. Leading causes include hemorrhage and hemorrhagic strokes secondary to hypertension. It’s estimated that the majority of maternal deaths could be prevented with proper care.
To that end, states are enacting safety bundles from the Alliance for Innovation on Maternal Health (AIM), which was established by the American College of Obstetricians and Gynecologist several years ago. There are bundles that address obstetric hypertension, hemorrhage, mental health, venous thromboembolism, opioid use, racial disparities, and other problems. They were developed by experts in the field and published in multiple journals. California and other states have issued toolkits on how to implement them based on local circumstances.
Dr. Main said.
AIM bundle implementation is “what’s happening in New Mexico and a lot of states, mostly through the efforts of state level quality care collaboratives. Some [states] are further ahead than others,” said Eve Espey, MD, professor and chair of the department of obstetrics and gynecology at the University of New Mexico, Albuquerque, and president of the New Mexico PQC.
“Most states now have a [MMRC] that collects maternal mortality and near-miss data. Those data are used by the action arm,” which is the PQC. “If the review committee says” opioid use disorder is a significant contributor “like in our state, the collaborative rolls out the opioid use disorder bundle,” she said.
Beginning next January, the Joint Commission, formerly known as the Joint Commission on Accreditation of Healthcare Organizations, will require that accredited hospitals enact key elements of the AIM bundles for both obstetric hemorrhage and severe hypertension. “Everyone’s [now] motivated to get on that bandwagon,” Dr. Espey said.
“The bundles are here to stay,” and the Joint Commission requirements are “a really important step for sustainability and basic implementation. We really want to get them adopted everywhere,” said Dr. Main, who is also the national implementation director for the AIM initiative.
“The key thing is to work on implementing the hemorrhage and hypertension bundles in your hospital. I would suggest contacting [your] state” PQC, he said.
The California model
California, which has been working to reduce maternal mortality and morbidity since the mid 2000s, has produced among the strongest evidence to date that the efforts make a difference.
By 2013, the state had halved its maternal mortality rate to a 3-year average of 7 deaths per 100,000 live births, which is comparable with the average Western Europe rate of 7.2 deaths. Nationwide, the rate was about 17.4 deaths per 100,000 live births in 2018, according to the Centers for Disease Control and Prevention
The reasons are multifactorial, but “we think” the quality improvement efforts have been “an important contributor,” Dr. Main said.
Improvements especially for Black women
Among the success stories has been California’s implementation of the AIM obstetric hemorrhage bundle about 5 years ago. Among other steps, the 17 evidence-based recommendations included early recognition, immediate access to oxytocin and other medications, immediate access to a hemorrhage cart with instructions for intrauterine balloons and compression stitches, the establishment of a hemorrhage response protocol and team, and regular unit-based drills with debriefing sessions afterward.
Mentoring teams consisting of a physician and nurse with maternal quality improvement experience were created to help hospitals come on board, with each team working with five to eight hospitals. Efforts included monthly telephone calls and face-to-face meetings, and providers were held accountable for progress. Hospitals shared data and tips on implementation, under the aegis of the CMQCC.
When the baseline period of 2011-2014 to the postintervention period of October 2015 to December 2016 were compared, the rate of severe maternal morbidity from hemorrhage fell from 22.1% to 18.5% across 99 hospitals and 73,476 women.
The benefit among Black women exceeded that among White women, with a 9% absolute rate reduction versus 2.1%. “If you adjusted for risk factors, [we found] you could eliminate [racial differences] completely,” which is something that hadn’t been shown before. “This is a really big deal,” Dr. Main said, because the risk of maternal morbidity and mortality is three to four times higher among Black women, compared with White women.
Dr. Main and his team found that the biggest clinical risk factor that accounted for racial differences was a higher rate of cesarean deliveries among Black women, followed by higher rates of anemia at hospital admission. “If you have a C-section when you are anemic, you are going to have a transfusion,” he explained.
More recently, there’s been a push in California to reduce the rate of primary cesarean deliveries by enacting the associated AIM bundle with use of the same approach as with the hemorrhage bundle. Dr. Main and his team recently reported a rate reduction from 29.3% to 25% without compromising birth outcomes.
However, “some changes are easier than others. Hemorrhage was an easy one to change because it didn’t deal with physician autonomy as much, and you saw more immediate results” with fewer hemorrhages. Reducing cesarean delivery rates is “a bigger lift” because “it’s really changing the culture of labor and delivery. It involves more group pressure and more reinforcing, but we were able to do that,” he said.
Problems in the Show Me State
“We’ve patterned a lot” of what’s being done in New Mexico “after California,” Dr. Espey said.
The AIM hemorrhage bundle, for instance, is being rolled out to New Mexico hospitals, with the help of virtual meetings and mentoring programs, plus outreach to the Navajo and others reservations because, as with Black women, rates of maternal morbidity and mortality are higher among Native American women.
It’s been tougher going, however, in states such as Missouri, which recently ranked 44th in the country for maternal mortality.
“We started a little bit late, and we are a little bit behind,” said ob.gyn. Karen L. Florio, DO, at the University of Missouri–Kansas City and also a leader of the state MMRC and member of its PQC.
The main problem is money. California’s efforts are funded by the Centers for Disease Control and Prevention, the state health department, and hospitals, among others.
But Missouri is “not as well funded as California for our mortality review board, and our [PQC] is mostly not funded. If we could get that funding, we would have more resources to implement these AIM bundles,” she said.
In addition to the issue, Missouri didn’t expand Medicaid under the Accountable Care Act – something that’s been linked to reduced maternal morbidity and mortality – and there are entire rural areas with no maternity care. Plus after generations of mistreatment, “our African American population has a valid distrust of the medical system that contributes to maternal mortality,” she said.
Obesity-related heart disease is also prevalent in Missouri, even among young people. “I cannot tell you how many women I have had who have had a heart attack at the age of 30 and who have had stents placed,” Dr. Florio said.
Dr. Florio and her colleagues are currently using teleconferences and other means to roll out the AIM hypertension bundle but can do so only selectively. “We don’t have the resources to reach every single rural hospital all over the state,” she said; they are working to address the funding issues.
For rural hospitals, implementation is “daunting”
Meanwhile, rural hospitals have been a particular concern in South Dakota, said Kimberlee McKay, MD, an ob.gyn. who is the clinical vice president of the ob.gyn. service line at Avera Health, a hospital system based in Sioux Falls, S.D.
She’s been overseeing Avera’s implementation of the hypertension, hemorrhage, and venous thromboembolism bundles. “What’s hard is that” the AIM protocols come “out of academic centers. Implementation of complex algorithms is daunting” for hospitals that only do a couple hundred deliveries a year, she said.
For small hospitals, the approach she’s found that works is to first assess what they can offer, and then have them “do what’s reasonable” for their resources. The second part is making sure high-risk women get to a regional center – with an adequate blood supply, in the case of hemorrhage, for instance – for complications. Dr. McKay and colleagues are working on a system by which regional centers can monitor smaller hospitals for potential maternity problems, and contact them proactively before they emerge.
They’ve also made access to hemorrhage and hypertension drugs easier on labor and delivery units with the help of close-by dedicated medicine boxes, and standardized protocols and order sets across Avera. “We try to make the right thing the easy thing to do,” Dr. McKay said.
Dr. Espey is an editorial adviser for Ob.Gyn. News. The physicians have no relevant financial disclosures.
“Anytime you have a maternal death, it sticks with you for life,” said Elliott Main, MD, a maternal fetal medicine specialist at Stanford (Calif.) University and one of the nation’s leaders in combating maternal mortality.
Dr. Main has had two maternal deaths in his career, years ago. One woman had a fatal stroke because of severe hypertension, and another died of cardiac complications. “We tried to do everything we possibly could, but you scrounge your memory for years and years [afterward]. To have a young healthy person go into labor and delivery and not come out is a tragedy at all levels. It charged me to not ever want to see that happen again,” he said.
Today, Dr. Main is the medical director of the California Maternal Quality Care Collaborative (CMQCC), a wide-ranging group of clinicians, state officials, hospitals, and others who have come together to address the issue. About 30 states have similar perinatal quality collaboratives (PQCs), and other states are forming them.
They work in collaboration with maternal mortality review committees (MMRCs), state-level groups that review maternal deaths, identify problems to address, and make recommendations to the quality collaboratives on how to prevent maternal deaths.
About 600-800 women die in the United States each year due to pregnancy-related complications, which ranks the United States behind other industrialized nations. Leading causes include hemorrhage and hemorrhagic strokes secondary to hypertension. It’s estimated that the majority of maternal deaths could be prevented with proper care.
To that end, states are enacting safety bundles from the Alliance for Innovation on Maternal Health (AIM), which was established by the American College of Obstetricians and Gynecologist several years ago. There are bundles that address obstetric hypertension, hemorrhage, mental health, venous thromboembolism, opioid use, racial disparities, and other problems. They were developed by experts in the field and published in multiple journals. California and other states have issued toolkits on how to implement them based on local circumstances.
Dr. Main said.
AIM bundle implementation is “what’s happening in New Mexico and a lot of states, mostly through the efforts of state level quality care collaboratives. Some [states] are further ahead than others,” said Eve Espey, MD, professor and chair of the department of obstetrics and gynecology at the University of New Mexico, Albuquerque, and president of the New Mexico PQC.
“Most states now have a [MMRC] that collects maternal mortality and near-miss data. Those data are used by the action arm,” which is the PQC. “If the review committee says” opioid use disorder is a significant contributor “like in our state, the collaborative rolls out the opioid use disorder bundle,” she said.
Beginning next January, the Joint Commission, formerly known as the Joint Commission on Accreditation of Healthcare Organizations, will require that accredited hospitals enact key elements of the AIM bundles for both obstetric hemorrhage and severe hypertension. “Everyone’s [now] motivated to get on that bandwagon,” Dr. Espey said.
“The bundles are here to stay,” and the Joint Commission requirements are “a really important step for sustainability and basic implementation. We really want to get them adopted everywhere,” said Dr. Main, who is also the national implementation director for the AIM initiative.
“The key thing is to work on implementing the hemorrhage and hypertension bundles in your hospital. I would suggest contacting [your] state” PQC, he said.
The California model
California, which has been working to reduce maternal mortality and morbidity since the mid 2000s, has produced among the strongest evidence to date that the efforts make a difference.
By 2013, the state had halved its maternal mortality rate to a 3-year average of 7 deaths per 100,000 live births, which is comparable with the average Western Europe rate of 7.2 deaths. Nationwide, the rate was about 17.4 deaths per 100,000 live births in 2018, according to the Centers for Disease Control and Prevention
The reasons are multifactorial, but “we think” the quality improvement efforts have been “an important contributor,” Dr. Main said.
Improvements especially for Black women
Among the success stories has been California’s implementation of the AIM obstetric hemorrhage bundle about 5 years ago. Among other steps, the 17 evidence-based recommendations included early recognition, immediate access to oxytocin and other medications, immediate access to a hemorrhage cart with instructions for intrauterine balloons and compression stitches, the establishment of a hemorrhage response protocol and team, and regular unit-based drills with debriefing sessions afterward.
Mentoring teams consisting of a physician and nurse with maternal quality improvement experience were created to help hospitals come on board, with each team working with five to eight hospitals. Efforts included monthly telephone calls and face-to-face meetings, and providers were held accountable for progress. Hospitals shared data and tips on implementation, under the aegis of the CMQCC.
When the baseline period of 2011-2014 to the postintervention period of October 2015 to December 2016 were compared, the rate of severe maternal morbidity from hemorrhage fell from 22.1% to 18.5% across 99 hospitals and 73,476 women.
The benefit among Black women exceeded that among White women, with a 9% absolute rate reduction versus 2.1%. “If you adjusted for risk factors, [we found] you could eliminate [racial differences] completely,” which is something that hadn’t been shown before. “This is a really big deal,” Dr. Main said, because the risk of maternal morbidity and mortality is three to four times higher among Black women, compared with White women.
Dr. Main and his team found that the biggest clinical risk factor that accounted for racial differences was a higher rate of cesarean deliveries among Black women, followed by higher rates of anemia at hospital admission. “If you have a C-section when you are anemic, you are going to have a transfusion,” he explained.
More recently, there’s been a push in California to reduce the rate of primary cesarean deliveries by enacting the associated AIM bundle with use of the same approach as with the hemorrhage bundle. Dr. Main and his team recently reported a rate reduction from 29.3% to 25% without compromising birth outcomes.
However, “some changes are easier than others. Hemorrhage was an easy one to change because it didn’t deal with physician autonomy as much, and you saw more immediate results” with fewer hemorrhages. Reducing cesarean delivery rates is “a bigger lift” because “it’s really changing the culture of labor and delivery. It involves more group pressure and more reinforcing, but we were able to do that,” he said.
Problems in the Show Me State
“We’ve patterned a lot” of what’s being done in New Mexico “after California,” Dr. Espey said.
The AIM hemorrhage bundle, for instance, is being rolled out to New Mexico hospitals, with the help of virtual meetings and mentoring programs, plus outreach to the Navajo and others reservations because, as with Black women, rates of maternal morbidity and mortality are higher among Native American women.
It’s been tougher going, however, in states such as Missouri, which recently ranked 44th in the country for maternal mortality.
“We started a little bit late, and we are a little bit behind,” said ob.gyn. Karen L. Florio, DO, at the University of Missouri–Kansas City and also a leader of the state MMRC and member of its PQC.
The main problem is money. California’s efforts are funded by the Centers for Disease Control and Prevention, the state health department, and hospitals, among others.
But Missouri is “not as well funded as California for our mortality review board, and our [PQC] is mostly not funded. If we could get that funding, we would have more resources to implement these AIM bundles,” she said.
In addition to the issue, Missouri didn’t expand Medicaid under the Accountable Care Act – something that’s been linked to reduced maternal morbidity and mortality – and there are entire rural areas with no maternity care. Plus after generations of mistreatment, “our African American population has a valid distrust of the medical system that contributes to maternal mortality,” she said.
Obesity-related heart disease is also prevalent in Missouri, even among young people. “I cannot tell you how many women I have had who have had a heart attack at the age of 30 and who have had stents placed,” Dr. Florio said.
Dr. Florio and her colleagues are currently using teleconferences and other means to roll out the AIM hypertension bundle but can do so only selectively. “We don’t have the resources to reach every single rural hospital all over the state,” she said; they are working to address the funding issues.
For rural hospitals, implementation is “daunting”
Meanwhile, rural hospitals have been a particular concern in South Dakota, said Kimberlee McKay, MD, an ob.gyn. who is the clinical vice president of the ob.gyn. service line at Avera Health, a hospital system based in Sioux Falls, S.D.
She’s been overseeing Avera’s implementation of the hypertension, hemorrhage, and venous thromboembolism bundles. “What’s hard is that” the AIM protocols come “out of academic centers. Implementation of complex algorithms is daunting” for hospitals that only do a couple hundred deliveries a year, she said.
For small hospitals, the approach she’s found that works is to first assess what they can offer, and then have them “do what’s reasonable” for their resources. The second part is making sure high-risk women get to a regional center – with an adequate blood supply, in the case of hemorrhage, for instance – for complications. Dr. McKay and colleagues are working on a system by which regional centers can monitor smaller hospitals for potential maternity problems, and contact them proactively before they emerge.
They’ve also made access to hemorrhage and hypertension drugs easier on labor and delivery units with the help of close-by dedicated medicine boxes, and standardized protocols and order sets across Avera. “We try to make the right thing the easy thing to do,” Dr. McKay said.
Dr. Espey is an editorial adviser for Ob.Gyn. News. The physicians have no relevant financial disclosures.
Genetic differences by ancestry shouldn’t impact efficacy of prostate cancer therapies
, according to an analysis published in Clinical Cancer Research.
“[N]o significant differences were seen in clinically actionable DNA repair genes, MSI-high [microsatellite instability–high] status, and tumor mutation burden, suggesting that current therapeutic strategies may be equally beneficial in both populations,” wrote study author Yusuke Koga, of the Boston University, and colleagues.
“Since these findings suggest that the frequency of targetable genetic alterations is similar in patients of predominantly African versus European ancestry, offering comprehensive genomic profiling and biomarker-based therapies to all patients, including African American patients, is a critical component of promoting equity in the management of metastatic prostate cancer,” said Atish D. Choudhury, MD, PhD, of the Dana-Farber Cancer Institute in Boston, who was not involved in this study.
Mr. Koga and colleagues noted that, when compared with European-American men, African American men have a higher incidence of prostate cancer, present with more advanced disease at an earlier age, and have increased mortality. These differences persist even after adjustment for socioeconomic covariates. That raises the question of the role of genetics.
“There is emerging evidence that, across some clinical trials and equal-access health systems, outcomes between AFR [African-American] men and European-American men with prostate cancer are similar,” the investigators wrote. “Although these data suggest that disparities can be ameliorated, there is limited knowledge of the genomic alterations that differ between groups and that could impact clinical outcomes.”
Study details and results
To get a handle on the issue, the investigators performed a meta-analysis of tumors from 250 African American men and 611 European-American men to compare the frequencies of somatic alterations across datasets from the Cancer Genome Atlas, the African Ancestry prostate cancer cohort, and the Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets panel.
The team also compared prostate cancer sequencing data from a commercial platform, the Foundation Medicine assay, from 436 African-American men and 3,018 European-American men.
In the meta-analysis, mutations in ZFHX3 and focal deletions in ETV3 were more common in tumors from African American men than in tumors from European-American men. Both genes are putative prostate cancer tumor suppressors, the investigators noted.
TP53 mutations, meanwhile, were associated with increasing Gleason scores in both groups, suggesting “that if TP53 mutations are found in low-grade disease, they may potentially indicate a more aggressive clinical trajectory,” the investigators wrote.
In the analysis with the commercial assay, MYC amplifications were more frequent in African American men with metastatic disease, raising “the possibility that MYC amplifications may also contribute to high-risk disease in this population,” the team wrote.
Deletions in PTEN and rearrangements in TMPRSS2-ERG were less frequent in tumors from African American men, but KMT2D truncations and CCND1 amplifications were more frequent.
“Higher expression of CCND1 has been implicated with perineural invasion in prostate cancer, an aggressive histological feature in prostate cancer. Truncating mutations in KMT2D have been reported in both localized and metastatic prostate cancer patients with unclear clinical significance,” the investigators noted.
“The genomic differences seen in genes such as MYC, ZFHX3, PTEN, and TMPRSS2-ERG suggest that different pathways of carcinogenesis may be active in AFR [African American] men, which could lead to further disparities if targeted therapies for some of these alterations become available,” the team wrote.
They noted that the meta-analysis was limited by the fact that some cohorts lacked matched tumors from European-American men, which limited the investigators’ ability to control for differences in region, clinical setting, or sequencing assay. Furthermore, age, tumor stage, and Gleason grade were unavailable in the cohort analyzed with the commercial assay.
This research was funded by the Department of Defense, the National Cancer Institute, and the Prostate Cancer Foundation. Two authors are employees of Foundation Medicine.
SOURCE: Koga Y et al. Clin Cancer Res. 2020 Jul 10. doi: 10.1158/1078-0432.CCR-19-4112.
, according to an analysis published in Clinical Cancer Research.
“[N]o significant differences were seen in clinically actionable DNA repair genes, MSI-high [microsatellite instability–high] status, and tumor mutation burden, suggesting that current therapeutic strategies may be equally beneficial in both populations,” wrote study author Yusuke Koga, of the Boston University, and colleagues.
“Since these findings suggest that the frequency of targetable genetic alterations is similar in patients of predominantly African versus European ancestry, offering comprehensive genomic profiling and biomarker-based therapies to all patients, including African American patients, is a critical component of promoting equity in the management of metastatic prostate cancer,” said Atish D. Choudhury, MD, PhD, of the Dana-Farber Cancer Institute in Boston, who was not involved in this study.
Mr. Koga and colleagues noted that, when compared with European-American men, African American men have a higher incidence of prostate cancer, present with more advanced disease at an earlier age, and have increased mortality. These differences persist even after adjustment for socioeconomic covariates. That raises the question of the role of genetics.
“There is emerging evidence that, across some clinical trials and equal-access health systems, outcomes between AFR [African-American] men and European-American men with prostate cancer are similar,” the investigators wrote. “Although these data suggest that disparities can be ameliorated, there is limited knowledge of the genomic alterations that differ between groups and that could impact clinical outcomes.”
Study details and results
To get a handle on the issue, the investigators performed a meta-analysis of tumors from 250 African American men and 611 European-American men to compare the frequencies of somatic alterations across datasets from the Cancer Genome Atlas, the African Ancestry prostate cancer cohort, and the Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets panel.
The team also compared prostate cancer sequencing data from a commercial platform, the Foundation Medicine assay, from 436 African-American men and 3,018 European-American men.
In the meta-analysis, mutations in ZFHX3 and focal deletions in ETV3 were more common in tumors from African American men than in tumors from European-American men. Both genes are putative prostate cancer tumor suppressors, the investigators noted.
TP53 mutations, meanwhile, were associated with increasing Gleason scores in both groups, suggesting “that if TP53 mutations are found in low-grade disease, they may potentially indicate a more aggressive clinical trajectory,” the investigators wrote.
In the analysis with the commercial assay, MYC amplifications were more frequent in African American men with metastatic disease, raising “the possibility that MYC amplifications may also contribute to high-risk disease in this population,” the team wrote.
Deletions in PTEN and rearrangements in TMPRSS2-ERG were less frequent in tumors from African American men, but KMT2D truncations and CCND1 amplifications were more frequent.
“Higher expression of CCND1 has been implicated with perineural invasion in prostate cancer, an aggressive histological feature in prostate cancer. Truncating mutations in KMT2D have been reported in both localized and metastatic prostate cancer patients with unclear clinical significance,” the investigators noted.
“The genomic differences seen in genes such as MYC, ZFHX3, PTEN, and TMPRSS2-ERG suggest that different pathways of carcinogenesis may be active in AFR [African American] men, which could lead to further disparities if targeted therapies for some of these alterations become available,” the team wrote.
They noted that the meta-analysis was limited by the fact that some cohorts lacked matched tumors from European-American men, which limited the investigators’ ability to control for differences in region, clinical setting, or sequencing assay. Furthermore, age, tumor stage, and Gleason grade were unavailable in the cohort analyzed with the commercial assay.
This research was funded by the Department of Defense, the National Cancer Institute, and the Prostate Cancer Foundation. Two authors are employees of Foundation Medicine.
SOURCE: Koga Y et al. Clin Cancer Res. 2020 Jul 10. doi: 10.1158/1078-0432.CCR-19-4112.
, according to an analysis published in Clinical Cancer Research.
“[N]o significant differences were seen in clinically actionable DNA repair genes, MSI-high [microsatellite instability–high] status, and tumor mutation burden, suggesting that current therapeutic strategies may be equally beneficial in both populations,” wrote study author Yusuke Koga, of the Boston University, and colleagues.
“Since these findings suggest that the frequency of targetable genetic alterations is similar in patients of predominantly African versus European ancestry, offering comprehensive genomic profiling and biomarker-based therapies to all patients, including African American patients, is a critical component of promoting equity in the management of metastatic prostate cancer,” said Atish D. Choudhury, MD, PhD, of the Dana-Farber Cancer Institute in Boston, who was not involved in this study.
Mr. Koga and colleagues noted that, when compared with European-American men, African American men have a higher incidence of prostate cancer, present with more advanced disease at an earlier age, and have increased mortality. These differences persist even after adjustment for socioeconomic covariates. That raises the question of the role of genetics.
“There is emerging evidence that, across some clinical trials and equal-access health systems, outcomes between AFR [African-American] men and European-American men with prostate cancer are similar,” the investigators wrote. “Although these data suggest that disparities can be ameliorated, there is limited knowledge of the genomic alterations that differ between groups and that could impact clinical outcomes.”
Study details and results
To get a handle on the issue, the investigators performed a meta-analysis of tumors from 250 African American men and 611 European-American men to compare the frequencies of somatic alterations across datasets from the Cancer Genome Atlas, the African Ancestry prostate cancer cohort, and the Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets panel.
The team also compared prostate cancer sequencing data from a commercial platform, the Foundation Medicine assay, from 436 African-American men and 3,018 European-American men.
In the meta-analysis, mutations in ZFHX3 and focal deletions in ETV3 were more common in tumors from African American men than in tumors from European-American men. Both genes are putative prostate cancer tumor suppressors, the investigators noted.
TP53 mutations, meanwhile, were associated with increasing Gleason scores in both groups, suggesting “that if TP53 mutations are found in low-grade disease, they may potentially indicate a more aggressive clinical trajectory,” the investigators wrote.
In the analysis with the commercial assay, MYC amplifications were more frequent in African American men with metastatic disease, raising “the possibility that MYC amplifications may also contribute to high-risk disease in this population,” the team wrote.
Deletions in PTEN and rearrangements in TMPRSS2-ERG were less frequent in tumors from African American men, but KMT2D truncations and CCND1 amplifications were more frequent.
“Higher expression of CCND1 has been implicated with perineural invasion in prostate cancer, an aggressive histological feature in prostate cancer. Truncating mutations in KMT2D have been reported in both localized and metastatic prostate cancer patients with unclear clinical significance,” the investigators noted.
“The genomic differences seen in genes such as MYC, ZFHX3, PTEN, and TMPRSS2-ERG suggest that different pathways of carcinogenesis may be active in AFR [African American] men, which could lead to further disparities if targeted therapies for some of these alterations become available,” the team wrote.
They noted that the meta-analysis was limited by the fact that some cohorts lacked matched tumors from European-American men, which limited the investigators’ ability to control for differences in region, clinical setting, or sequencing assay. Furthermore, age, tumor stage, and Gleason grade were unavailable in the cohort analyzed with the commercial assay.
This research was funded by the Department of Defense, the National Cancer Institute, and the Prostate Cancer Foundation. Two authors are employees of Foundation Medicine.
SOURCE: Koga Y et al. Clin Cancer Res. 2020 Jul 10. doi: 10.1158/1078-0432.CCR-19-4112.
FROM CLINICAL CANCER RESEARCH
Intraventricular methotrexate may improve survival for medulloblastoma subtypes
according to research published in the Journal of Clinical Oncology.
Investigators conducted a prospective trial of 87 children diagnosed with nonmetastatic medulloblastoma before the age of 4 years who were treated from 2001-2011.
At 5 years after diagnosis, the 42 DMB/MBEN patients had a 93% progression-free survival (PFS) rate, a 100% overall survival (OS) rate, and a 93% craniospinal irradiation (CSI)–free survival rate.
“Our results suggest that ... poor outcomes of patients treated with systemic chemotherapy alone can be improved by the addition of intraventricular [methotrexate],” wrote Martin Mynarek, MD, of the University Medical Center Hamburg-Eppendorf (Germany), and colleagues.
However, it was a different story for the 45 patients with classic medulloblastoma (CMB) or large-cell/anaplastic medulloblastoma (CLA), in which outcomes are historically worse. At 5 years, the PFS was 37%, the OS was 62%, and the CSI-free survival was 39% in these patients.
In 2006, the CMB and CLA patients started receiving local radiotherapy in addition to chemotherapy and intraventricular methotrexate, but the radiotherapy did not seem to help with their disease.
“Because data suggest no effects, or even adverse effects, of local radiotherapy, additional development of this approach does not seem justified,” the investigators wrote.
“Interestingly, almost all patients with CMB/LCA had distant or combined relapses after local radiotherapy,” they added. “One might speculate that local radiotherapy reduced disease burden of the primary tumor and subclinical metastasis in the posterior fossa, leading to a survival advantage of distant subclinical metastasis over local residues.”
Treatment details
The 87 patients were enrolled in the BIS4 arm of the HIT 2000 trial (NCT00303810), which was designed to test six protocols and identify the optimal approach for treating young patients with medulloblastoma, supratentorial primitive neuroectodermal tumor, or ependymoma.
Patients started “HIT-SKK” chemotherapy within 2-4 weeks of surgery. They received three cycles of intravenous cyclophosphamide, vincristine, methotrexate (followed by leucovorin rescue after 42 hours), carboplatin, and etoposide, with concomitant intraventricular methotrexate, for a duration of 6 months (Neuro Oncol. 2011 Jun;13[6]:669-79).
Among patients who achieved a complete remission, treatment was ended after two additional cycles of chemotherapy. For other patients, secondary surgery, radiotherapy, and consolidation chemotherapy were recommended.
Starting in 2006, DMB and MBEN patients without complete remissions, as well as those with CMB or LCA, received 54 Gy of focal radiotherapy to the tumor bed after the first three treatment cycles.
SHH-I vs. SHH-II DMB/MBEN
DNA methylation profiling was available for 50 of the 87 patients in this analysis, 28 of whom had infantile sonic hedgehog (SHH)–activated DMB/MBEN. Data from these 28 patients – and 71 patients in a validation cohort – revealed no significant difference in 5-year PFS or OS based on methylation subtype.
The 5-year PFS was 73% in SHH-I patients and 83% in SHH-II patients (P = .25). The 5-year OS was 88% and 97%, respectively (P = .099).
“This suggests that the higher risk of relapse in the less favorable [SHH-I subtype] can be abrogated by the addition of intraventricular [methotrexate] to systemic chemotherapy,” the investigators wrote.
The results suggest SHH-I patients “markedly benefit” from the addition of intraventricular chemotherapy, according to the authors of a related editorial, Giles Robinson, MD, and Amar Gajjar, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn.
“However, cross-trial comparison of PFS among the SHH-II subtype does not suggest that SHH-II patients derive the same benefit,” the editorialists wrote.
These data divide SHH medulloblastoma into SHH-I, which benefits from chemotherapy with intraventricular methotrexate, and SHH-II, which can be cured without intraventricular methotrexate, high-dose chemotherapy, or focal radiotherapy, according to the editorialists.
This new information might prompt investigation of a risk-adapted approach. SHH-II patients would receive a reduced-intensity regimen with systemic chemotherapy only, and SHH-I patients would receive systemic chemotherapy combined with intraventricular methotrexate. This could avoid exposing young children to “more intensive therapy than necessary,” according to the editorialists.
Non-WNT/non-SHH disease
Patients with non-WNT/non-SHH medulloblastoma (CMB or LCA) were divided into molecularly defined subtypes group 3 (n = 14) and group 4 (n = 6). The patients in group 3 had lower survival rates than patients in group 4. The 5-year PFS rate was 36% and 83%, respectively (P < .001 ). The 5-year OS rate was 49% and 100%, respectively (P < .001).
“This represents the third recent publication to describe a poor PFS for group 3, and it signals a desperate need for better therapy,” the editorialists wrote. As for the “encouraging” survival rate for group 4 patients, there were only six subjects, which makes this finding “worthy of follow-up but not actionable.”
Even so, the investigators noted that “although poor survival has been reported for non-SHH CMB/LCA in almost every series of patients treated with CSI-sparing approaches, again, use of intraventricular [methotrexate] might be associated with slightly higher PFS, compared with conventional chemotherapy alone.”
As expected, IQ was significantly lower in patients who received CSI salvage. The mean IQ was 74 in patients who received CSI and 90 in patients who did not (P = .012). Neurocognitive outcomes were poor in general among CMB/LCA survivors, “which was closely related to use of radiotherapy,” according to the investigators.
“It is important to recognize that these studies were not designed to define outcome on the basis of molecular subgroup or subtype and that the sample size in all these studies is small,” Dr. Robinson and Dr. Gajjar wrote. “Thus, caution should be used when basing any treatment recommendation on these results, and it is our strong-held opinion that any treatment change be done on a well-planned and well-monitored clinical trial.”
This research was supported by the German Childhood Cancer Foundation, Styrian Childhood Cancer Foundation, and other organizations. Dr. Mynarek and colleagues disclosed relationships with Medac, Novartis, Eli Lilly, Bayer, Roche, and numerous other companies. Dr. Robinson disclosed relationships with Eli Lilly, Genentech, and Novartis. Dr. Gajjar reported relationships with Genentech and Kazia Therapeutics.
SOURCE: Mynarek M et al. J Clin Oncol. 2020 Jun 20;38(18):2028-40.
according to research published in the Journal of Clinical Oncology.
Investigators conducted a prospective trial of 87 children diagnosed with nonmetastatic medulloblastoma before the age of 4 years who were treated from 2001-2011.
At 5 years after diagnosis, the 42 DMB/MBEN patients had a 93% progression-free survival (PFS) rate, a 100% overall survival (OS) rate, and a 93% craniospinal irradiation (CSI)–free survival rate.
“Our results suggest that ... poor outcomes of patients treated with systemic chemotherapy alone can be improved by the addition of intraventricular [methotrexate],” wrote Martin Mynarek, MD, of the University Medical Center Hamburg-Eppendorf (Germany), and colleagues.
However, it was a different story for the 45 patients with classic medulloblastoma (CMB) or large-cell/anaplastic medulloblastoma (CLA), in which outcomes are historically worse. At 5 years, the PFS was 37%, the OS was 62%, and the CSI-free survival was 39% in these patients.
In 2006, the CMB and CLA patients started receiving local radiotherapy in addition to chemotherapy and intraventricular methotrexate, but the radiotherapy did not seem to help with their disease.
“Because data suggest no effects, or even adverse effects, of local radiotherapy, additional development of this approach does not seem justified,” the investigators wrote.
“Interestingly, almost all patients with CMB/LCA had distant or combined relapses after local radiotherapy,” they added. “One might speculate that local radiotherapy reduced disease burden of the primary tumor and subclinical metastasis in the posterior fossa, leading to a survival advantage of distant subclinical metastasis over local residues.”
Treatment details
The 87 patients were enrolled in the BIS4 arm of the HIT 2000 trial (NCT00303810), which was designed to test six protocols and identify the optimal approach for treating young patients with medulloblastoma, supratentorial primitive neuroectodermal tumor, or ependymoma.
Patients started “HIT-SKK” chemotherapy within 2-4 weeks of surgery. They received three cycles of intravenous cyclophosphamide, vincristine, methotrexate (followed by leucovorin rescue after 42 hours), carboplatin, and etoposide, with concomitant intraventricular methotrexate, for a duration of 6 months (Neuro Oncol. 2011 Jun;13[6]:669-79).
Among patients who achieved a complete remission, treatment was ended after two additional cycles of chemotherapy. For other patients, secondary surgery, radiotherapy, and consolidation chemotherapy were recommended.
Starting in 2006, DMB and MBEN patients without complete remissions, as well as those with CMB or LCA, received 54 Gy of focal radiotherapy to the tumor bed after the first three treatment cycles.
SHH-I vs. SHH-II DMB/MBEN
DNA methylation profiling was available for 50 of the 87 patients in this analysis, 28 of whom had infantile sonic hedgehog (SHH)–activated DMB/MBEN. Data from these 28 patients – and 71 patients in a validation cohort – revealed no significant difference in 5-year PFS or OS based on methylation subtype.
The 5-year PFS was 73% in SHH-I patients and 83% in SHH-II patients (P = .25). The 5-year OS was 88% and 97%, respectively (P = .099).
“This suggests that the higher risk of relapse in the less favorable [SHH-I subtype] can be abrogated by the addition of intraventricular [methotrexate] to systemic chemotherapy,” the investigators wrote.
The results suggest SHH-I patients “markedly benefit” from the addition of intraventricular chemotherapy, according to the authors of a related editorial, Giles Robinson, MD, and Amar Gajjar, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn.
“However, cross-trial comparison of PFS among the SHH-II subtype does not suggest that SHH-II patients derive the same benefit,” the editorialists wrote.
These data divide SHH medulloblastoma into SHH-I, which benefits from chemotherapy with intraventricular methotrexate, and SHH-II, which can be cured without intraventricular methotrexate, high-dose chemotherapy, or focal radiotherapy, according to the editorialists.
This new information might prompt investigation of a risk-adapted approach. SHH-II patients would receive a reduced-intensity regimen with systemic chemotherapy only, and SHH-I patients would receive systemic chemotherapy combined with intraventricular methotrexate. This could avoid exposing young children to “more intensive therapy than necessary,” according to the editorialists.
Non-WNT/non-SHH disease
Patients with non-WNT/non-SHH medulloblastoma (CMB or LCA) were divided into molecularly defined subtypes group 3 (n = 14) and group 4 (n = 6). The patients in group 3 had lower survival rates than patients in group 4. The 5-year PFS rate was 36% and 83%, respectively (P < .001 ). The 5-year OS rate was 49% and 100%, respectively (P < .001).
“This represents the third recent publication to describe a poor PFS for group 3, and it signals a desperate need for better therapy,” the editorialists wrote. As for the “encouraging” survival rate for group 4 patients, there were only six subjects, which makes this finding “worthy of follow-up but not actionable.”
Even so, the investigators noted that “although poor survival has been reported for non-SHH CMB/LCA in almost every series of patients treated with CSI-sparing approaches, again, use of intraventricular [methotrexate] might be associated with slightly higher PFS, compared with conventional chemotherapy alone.”
As expected, IQ was significantly lower in patients who received CSI salvage. The mean IQ was 74 in patients who received CSI and 90 in patients who did not (P = .012). Neurocognitive outcomes were poor in general among CMB/LCA survivors, “which was closely related to use of radiotherapy,” according to the investigators.
“It is important to recognize that these studies were not designed to define outcome on the basis of molecular subgroup or subtype and that the sample size in all these studies is small,” Dr. Robinson and Dr. Gajjar wrote. “Thus, caution should be used when basing any treatment recommendation on these results, and it is our strong-held opinion that any treatment change be done on a well-planned and well-monitored clinical trial.”
This research was supported by the German Childhood Cancer Foundation, Styrian Childhood Cancer Foundation, and other organizations. Dr. Mynarek and colleagues disclosed relationships with Medac, Novartis, Eli Lilly, Bayer, Roche, and numerous other companies. Dr. Robinson disclosed relationships with Eli Lilly, Genentech, and Novartis. Dr. Gajjar reported relationships with Genentech and Kazia Therapeutics.
SOURCE: Mynarek M et al. J Clin Oncol. 2020 Jun 20;38(18):2028-40.
according to research published in the Journal of Clinical Oncology.
Investigators conducted a prospective trial of 87 children diagnosed with nonmetastatic medulloblastoma before the age of 4 years who were treated from 2001-2011.
At 5 years after diagnosis, the 42 DMB/MBEN patients had a 93% progression-free survival (PFS) rate, a 100% overall survival (OS) rate, and a 93% craniospinal irradiation (CSI)–free survival rate.
“Our results suggest that ... poor outcomes of patients treated with systemic chemotherapy alone can be improved by the addition of intraventricular [methotrexate],” wrote Martin Mynarek, MD, of the University Medical Center Hamburg-Eppendorf (Germany), and colleagues.
However, it was a different story for the 45 patients with classic medulloblastoma (CMB) or large-cell/anaplastic medulloblastoma (CLA), in which outcomes are historically worse. At 5 years, the PFS was 37%, the OS was 62%, and the CSI-free survival was 39% in these patients.
In 2006, the CMB and CLA patients started receiving local radiotherapy in addition to chemotherapy and intraventricular methotrexate, but the radiotherapy did not seem to help with their disease.
“Because data suggest no effects, or even adverse effects, of local radiotherapy, additional development of this approach does not seem justified,” the investigators wrote.
“Interestingly, almost all patients with CMB/LCA had distant or combined relapses after local radiotherapy,” they added. “One might speculate that local radiotherapy reduced disease burden of the primary tumor and subclinical metastasis in the posterior fossa, leading to a survival advantage of distant subclinical metastasis over local residues.”
Treatment details
The 87 patients were enrolled in the BIS4 arm of the HIT 2000 trial (NCT00303810), which was designed to test six protocols and identify the optimal approach for treating young patients with medulloblastoma, supratentorial primitive neuroectodermal tumor, or ependymoma.
Patients started “HIT-SKK” chemotherapy within 2-4 weeks of surgery. They received three cycles of intravenous cyclophosphamide, vincristine, methotrexate (followed by leucovorin rescue after 42 hours), carboplatin, and etoposide, with concomitant intraventricular methotrexate, for a duration of 6 months (Neuro Oncol. 2011 Jun;13[6]:669-79).
Among patients who achieved a complete remission, treatment was ended after two additional cycles of chemotherapy. For other patients, secondary surgery, radiotherapy, and consolidation chemotherapy were recommended.
Starting in 2006, DMB and MBEN patients without complete remissions, as well as those with CMB or LCA, received 54 Gy of focal radiotherapy to the tumor bed after the first three treatment cycles.
SHH-I vs. SHH-II DMB/MBEN
DNA methylation profiling was available for 50 of the 87 patients in this analysis, 28 of whom had infantile sonic hedgehog (SHH)–activated DMB/MBEN. Data from these 28 patients – and 71 patients in a validation cohort – revealed no significant difference in 5-year PFS or OS based on methylation subtype.
The 5-year PFS was 73% in SHH-I patients and 83% in SHH-II patients (P = .25). The 5-year OS was 88% and 97%, respectively (P = .099).
“This suggests that the higher risk of relapse in the less favorable [SHH-I subtype] can be abrogated by the addition of intraventricular [methotrexate] to systemic chemotherapy,” the investigators wrote.
The results suggest SHH-I patients “markedly benefit” from the addition of intraventricular chemotherapy, according to the authors of a related editorial, Giles Robinson, MD, and Amar Gajjar, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn.
“However, cross-trial comparison of PFS among the SHH-II subtype does not suggest that SHH-II patients derive the same benefit,” the editorialists wrote.
These data divide SHH medulloblastoma into SHH-I, which benefits from chemotherapy with intraventricular methotrexate, and SHH-II, which can be cured without intraventricular methotrexate, high-dose chemotherapy, or focal radiotherapy, according to the editorialists.
This new information might prompt investigation of a risk-adapted approach. SHH-II patients would receive a reduced-intensity regimen with systemic chemotherapy only, and SHH-I patients would receive systemic chemotherapy combined with intraventricular methotrexate. This could avoid exposing young children to “more intensive therapy than necessary,” according to the editorialists.
Non-WNT/non-SHH disease
Patients with non-WNT/non-SHH medulloblastoma (CMB or LCA) were divided into molecularly defined subtypes group 3 (n = 14) and group 4 (n = 6). The patients in group 3 had lower survival rates than patients in group 4. The 5-year PFS rate was 36% and 83%, respectively (P < .001 ). The 5-year OS rate was 49% and 100%, respectively (P < .001).
“This represents the third recent publication to describe a poor PFS for group 3, and it signals a desperate need for better therapy,” the editorialists wrote. As for the “encouraging” survival rate for group 4 patients, there were only six subjects, which makes this finding “worthy of follow-up but not actionable.”
Even so, the investigators noted that “although poor survival has been reported for non-SHH CMB/LCA in almost every series of patients treated with CSI-sparing approaches, again, use of intraventricular [methotrexate] might be associated with slightly higher PFS, compared with conventional chemotherapy alone.”
As expected, IQ was significantly lower in patients who received CSI salvage. The mean IQ was 74 in patients who received CSI and 90 in patients who did not (P = .012). Neurocognitive outcomes were poor in general among CMB/LCA survivors, “which was closely related to use of radiotherapy,” according to the investigators.
“It is important to recognize that these studies were not designed to define outcome on the basis of molecular subgroup or subtype and that the sample size in all these studies is small,” Dr. Robinson and Dr. Gajjar wrote. “Thus, caution should be used when basing any treatment recommendation on these results, and it is our strong-held opinion that any treatment change be done on a well-planned and well-monitored clinical trial.”
This research was supported by the German Childhood Cancer Foundation, Styrian Childhood Cancer Foundation, and other organizations. Dr. Mynarek and colleagues disclosed relationships with Medac, Novartis, Eli Lilly, Bayer, Roche, and numerous other companies. Dr. Robinson disclosed relationships with Eli Lilly, Genentech, and Novartis. Dr. Gajjar reported relationships with Genentech and Kazia Therapeutics.
SOURCE: Mynarek M et al. J Clin Oncol. 2020 Jun 20;38(18):2028-40.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Early data support further study of ivosidenib in mIDH1 glioma
The median progression-free survival was 13.6 months for patients with nonenhancing tumors and 1.4 months for patients with enhancing tumors in a study of 66 adults with mIDH1 advanced glioma.
“On the basis of these data, additional clinical development of mIDH inhibitors for mIDH low-grade gliomas is warranted,” Ingo Mellinghoff, MD, of Memorial Sloan Kettering Cancer Center in New York, and colleagues wrote in the Journal of Clinical Oncology.
“This is not a home run but is of interest to the community,” said Lawrence Recht, MD, of Stanford (Calif.) University, who was not involved in this study. “Other companies are also developing agents like this.”
Considering that the ivosidenib study “is uncontrolled, one cannot say for sure that this wasn’t just the natural history of the disease,” Dr. Recht continued. “This type of tumor can behave very indolently, and patients can survive years without treatment, so this is rather a short interval to make a long-time statement. I think the authors are a bit overenthusiastic.”
The authors tested ivosidenib in 66 adults with mIDH1 glioma – 35 with nonenhancing glioma and 31 with enhancing glioma. Tumors had recurred after, or did not respond to, initial surgery, radiation, or chemotherapy.
The patients’ median age was 41 years (range, 21-71 years), and 25 patients (37.9%) were women. The most common tumor type at screening was oligodendroglioma in 23 patients (34.8%).
Patients received ivosidenib at doses ranging from 100 mg twice a day to 900 mg once a day. A total of 50 patients received the phase 2 recommended dose – 500 mg once a day. There were no dose-limiting toxicities, and there was no maximum-tolerated dose.
Adverse events of grade 3 or higher occurred in 19.7% of patients and included headache, seizure, hyperglycemia, neutropenia, and hypophosphatemia. Grade 3 or higher treatment-related adverse events occurred in two patients.
A total of 30 patients with nonenhancing tumors (85.7%) and 14 with enhancing tumors (45.2%) had a best response of stable disease. There was one partial response in a nonenhancing patient on 500 mg/day. The rest of the subjects had a best response of progressive disease.
The median treatment duration was 18.4 months among patients with nonenhancing tumors and 1.9 months among those with enhancing tumors. Discontinuation was caused byo progression in all but one case.
Among patients with measurable disease, tumor measurements decreased from baseline in 22 nonenhancing tumors (66.7%) and in 9 enhancing tumors (33.3%).
“Despite the heterogeneous patient population in our trial, the nonrandomized design, and the lack of central pathology review, the data from our trial suggest that ivosidenib has greater activity against nonenhancing gliomas than against enhancing gliomas,” the investigators wrote. “This finding may seem surprising because the absence of contrast enhancement is typically associated with impaired drug delivery.
“We hypothesize that ivosidenib may be more effective in nonenhancing gliomas because these tumors represent an earlier disease stage with fewer genetic alterations, reminiscent of the greater antitumor activity of the BCR-ABL inhibitor imatinib in earlier stages of chronic myeloid leukemia,” the investigators wrote.
The team also noted that the median progression-free survival for patients with nonenhancing gliomas in the current study “compares favorably to that reported for temozolomide” in advanced mIDH1 low-grade glioma, which was approximately 7 months.
This research was funded by Agios Pharmaceuticals, the company developing ivosidenib. Dr. Mellinghoff receives travel compensation from and is an adviser to the company. Several other investigators are employees. Dr. Recht disclosed no conflicts of interest.
SOURCE: Mellinghoff I et al. J Clin Oncol. 2020 Jun 12. doi: 10.1200/JCO.19.03327
The median progression-free survival was 13.6 months for patients with nonenhancing tumors and 1.4 months for patients with enhancing tumors in a study of 66 adults with mIDH1 advanced glioma.
“On the basis of these data, additional clinical development of mIDH inhibitors for mIDH low-grade gliomas is warranted,” Ingo Mellinghoff, MD, of Memorial Sloan Kettering Cancer Center in New York, and colleagues wrote in the Journal of Clinical Oncology.
“This is not a home run but is of interest to the community,” said Lawrence Recht, MD, of Stanford (Calif.) University, who was not involved in this study. “Other companies are also developing agents like this.”
Considering that the ivosidenib study “is uncontrolled, one cannot say for sure that this wasn’t just the natural history of the disease,” Dr. Recht continued. “This type of tumor can behave very indolently, and patients can survive years without treatment, so this is rather a short interval to make a long-time statement. I think the authors are a bit overenthusiastic.”
The authors tested ivosidenib in 66 adults with mIDH1 glioma – 35 with nonenhancing glioma and 31 with enhancing glioma. Tumors had recurred after, or did not respond to, initial surgery, radiation, or chemotherapy.
The patients’ median age was 41 years (range, 21-71 years), and 25 patients (37.9%) were women. The most common tumor type at screening was oligodendroglioma in 23 patients (34.8%).
Patients received ivosidenib at doses ranging from 100 mg twice a day to 900 mg once a day. A total of 50 patients received the phase 2 recommended dose – 500 mg once a day. There were no dose-limiting toxicities, and there was no maximum-tolerated dose.
Adverse events of grade 3 or higher occurred in 19.7% of patients and included headache, seizure, hyperglycemia, neutropenia, and hypophosphatemia. Grade 3 or higher treatment-related adverse events occurred in two patients.
A total of 30 patients with nonenhancing tumors (85.7%) and 14 with enhancing tumors (45.2%) had a best response of stable disease. There was one partial response in a nonenhancing patient on 500 mg/day. The rest of the subjects had a best response of progressive disease.
The median treatment duration was 18.4 months among patients with nonenhancing tumors and 1.9 months among those with enhancing tumors. Discontinuation was caused byo progression in all but one case.
Among patients with measurable disease, tumor measurements decreased from baseline in 22 nonenhancing tumors (66.7%) and in 9 enhancing tumors (33.3%).
“Despite the heterogeneous patient population in our trial, the nonrandomized design, and the lack of central pathology review, the data from our trial suggest that ivosidenib has greater activity against nonenhancing gliomas than against enhancing gliomas,” the investigators wrote. “This finding may seem surprising because the absence of contrast enhancement is typically associated with impaired drug delivery.
“We hypothesize that ivosidenib may be more effective in nonenhancing gliomas because these tumors represent an earlier disease stage with fewer genetic alterations, reminiscent of the greater antitumor activity of the BCR-ABL inhibitor imatinib in earlier stages of chronic myeloid leukemia,” the investigators wrote.
The team also noted that the median progression-free survival for patients with nonenhancing gliomas in the current study “compares favorably to that reported for temozolomide” in advanced mIDH1 low-grade glioma, which was approximately 7 months.
This research was funded by Agios Pharmaceuticals, the company developing ivosidenib. Dr. Mellinghoff receives travel compensation from and is an adviser to the company. Several other investigators are employees. Dr. Recht disclosed no conflicts of interest.
SOURCE: Mellinghoff I et al. J Clin Oncol. 2020 Jun 12. doi: 10.1200/JCO.19.03327
The median progression-free survival was 13.6 months for patients with nonenhancing tumors and 1.4 months for patients with enhancing tumors in a study of 66 adults with mIDH1 advanced glioma.
“On the basis of these data, additional clinical development of mIDH inhibitors for mIDH low-grade gliomas is warranted,” Ingo Mellinghoff, MD, of Memorial Sloan Kettering Cancer Center in New York, and colleagues wrote in the Journal of Clinical Oncology.
“This is not a home run but is of interest to the community,” said Lawrence Recht, MD, of Stanford (Calif.) University, who was not involved in this study. “Other companies are also developing agents like this.”
Considering that the ivosidenib study “is uncontrolled, one cannot say for sure that this wasn’t just the natural history of the disease,” Dr. Recht continued. “This type of tumor can behave very indolently, and patients can survive years without treatment, so this is rather a short interval to make a long-time statement. I think the authors are a bit overenthusiastic.”
The authors tested ivosidenib in 66 adults with mIDH1 glioma – 35 with nonenhancing glioma and 31 with enhancing glioma. Tumors had recurred after, or did not respond to, initial surgery, radiation, or chemotherapy.
The patients’ median age was 41 years (range, 21-71 years), and 25 patients (37.9%) were women. The most common tumor type at screening was oligodendroglioma in 23 patients (34.8%).
Patients received ivosidenib at doses ranging from 100 mg twice a day to 900 mg once a day. A total of 50 patients received the phase 2 recommended dose – 500 mg once a day. There were no dose-limiting toxicities, and there was no maximum-tolerated dose.
Adverse events of grade 3 or higher occurred in 19.7% of patients and included headache, seizure, hyperglycemia, neutropenia, and hypophosphatemia. Grade 3 or higher treatment-related adverse events occurred in two patients.
A total of 30 patients with nonenhancing tumors (85.7%) and 14 with enhancing tumors (45.2%) had a best response of stable disease. There was one partial response in a nonenhancing patient on 500 mg/day. The rest of the subjects had a best response of progressive disease.
The median treatment duration was 18.4 months among patients with nonenhancing tumors and 1.9 months among those with enhancing tumors. Discontinuation was caused byo progression in all but one case.
Among patients with measurable disease, tumor measurements decreased from baseline in 22 nonenhancing tumors (66.7%) and in 9 enhancing tumors (33.3%).
“Despite the heterogeneous patient population in our trial, the nonrandomized design, and the lack of central pathology review, the data from our trial suggest that ivosidenib has greater activity against nonenhancing gliomas than against enhancing gliomas,” the investigators wrote. “This finding may seem surprising because the absence of contrast enhancement is typically associated with impaired drug delivery.
“We hypothesize that ivosidenib may be more effective in nonenhancing gliomas because these tumors represent an earlier disease stage with fewer genetic alterations, reminiscent of the greater antitumor activity of the BCR-ABL inhibitor imatinib in earlier stages of chronic myeloid leukemia,” the investigators wrote.
The team also noted that the median progression-free survival for patients with nonenhancing gliomas in the current study “compares favorably to that reported for temozolomide” in advanced mIDH1 low-grade glioma, which was approximately 7 months.
This research was funded by Agios Pharmaceuticals, the company developing ivosidenib. Dr. Mellinghoff receives travel compensation from and is an adviser to the company. Several other investigators are employees. Dr. Recht disclosed no conflicts of interest.
SOURCE: Mellinghoff I et al. J Clin Oncol. 2020 Jun 12. doi: 10.1200/JCO.19.03327
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Breast density asymmetry might increase breast cancer risk
The 854 women in the study had been referred for biopsy after an abnormal mammogram.
Researchers used the mammograms to assess global bilateral asymmetry, which was the overall absolute difference in percent fibroglandular tissue volume (%FGV) between the ipsilateral (biopsied) breast and the contralateral (unaffected) breast.
The researchers also assessed local bilateral asymmetry, which was the perilesional %FGV difference in an area twice the size of, but excluding, the biopsy target, and the corresponding area in the unaffected breast.
The women were then divided into quartiles based on breast density asymmetry.
Most of the women had benign breast disease, including proliferative (43%) and nonproliferative (33%) disease, but 23% had carcinoma in situ or invasive breast cancer.
The trend for higher risk of in situ or invasive cancer with increasing breast density asymmetry was observed only in the local analysis. The odds ratio was 1.59 (95% confidence interval, 0.94-2.69) for women in the highest quartile of breast density asymmetry (absolute difference, > 8.23) versus those in the lowest quartile (absolute difference, ≤ –5.55; P = .067).
When compared with women who had proliferative benign disease, women with carcinoma in situ or invasive breast cancer “were more likely to be in the higher than lower quartiles,” said lead investigator Maeve Mullooly, PhD, a research fellow at the Royal College of Surgeons in Dublin.
There was no association between breast density asymmetry and traditional breast cancer risk factors such as age, body mass index, race, and hormone therapy. However, among women diagnosed with benign nonproliferative disease, women with a breast cancer family history were more likely to have higher overall breast density asymmetry.
Study rationale and details
Higher breast density is a known risk factor for breast cancer. Breast asymmetry also has been reported as a possible risk factor (Breast Cancer Res. 2006;8[2]:R14), and incorporation of breast density asymmetry into traditional risk factors in one study improved risk prediction (Breast Cancer Res. 2017 Mar 14;19[1]:29).
Building on that work, the goal of Dr. Mullooly’s study was to “learn how to better use breast density to inform breast cancer risk prediction,” she said.
To that end, her team turned to 854 women enrolled from 2007-2010 in the National Cancer Institute’s Breast Radiology Evaluation and Study of Tissues Project, a cross-sectional molecular epidemiologic study designed to understand how breast density measures are related to breast cancer etiology.
Most of the women were non-Hispanic white. The mean age was 51 years (range, 40-65), and the median body mass index was 25 kg/m2.
About three-quarters of the women (76%) had a breast density asymmetry of at least 2% on the global analysis, with 43% having higher %FGV in the biopsied breast and 33% having higher %FGV in the unaffected breast. In all, 89% of women had local breast density asymmetry, with higher density in the biopsied breast in 61% of women and higher density in the contralateral breast in 28%.
Next steps
This research is ongoing, and additional follow-up is planned, according to Dr. Mullooly. She said the researchers hope to apply more recent analytical techniques to the mammograms and to study the histologic differences in their breast biopsy specimens, among other steps, to see if stronger relationships with greater clinical utility emerge.
It was a “very well done study” with “very provocative data,” said presentation moderator Jennifer Wargo, MD, professor of genomic medicine and surgical oncology at the University of Texas MD Anderson Cancer Center in Houston.
She was interested in the planned next steps, particularly the histologic analysis of dense versus less dense breast tissue. There could be “differences in stroma or hormonal levels even at the microenvironmental level” that “represent a potential field defect, which later puts someone at risk,” she said, adding that it’s “great” that the work is continuing.
The National Cancer Institute funded the research. Dr. Mullooly reported no relevant disclosures. Dr. Wargo disclosed relationships with Bristol-Myers Squibb, Roche/Genentech, Novartis, GlaxoSmithKline, AstraZeneca, Imedex, Dava Oncology, Omniprex, Illumina, Gilead, PeerView, Physician Education Resource, MedImmune, Merck, Biothera Pharmaceuticals, and Microbiome DX.
SOURCE: Mullooly M et al. AACR 2020, Abstract NG15.
The 854 women in the study had been referred for biopsy after an abnormal mammogram.
Researchers used the mammograms to assess global bilateral asymmetry, which was the overall absolute difference in percent fibroglandular tissue volume (%FGV) between the ipsilateral (biopsied) breast and the contralateral (unaffected) breast.
The researchers also assessed local bilateral asymmetry, which was the perilesional %FGV difference in an area twice the size of, but excluding, the biopsy target, and the corresponding area in the unaffected breast.
The women were then divided into quartiles based on breast density asymmetry.
Most of the women had benign breast disease, including proliferative (43%) and nonproliferative (33%) disease, but 23% had carcinoma in situ or invasive breast cancer.
The trend for higher risk of in situ or invasive cancer with increasing breast density asymmetry was observed only in the local analysis. The odds ratio was 1.59 (95% confidence interval, 0.94-2.69) for women in the highest quartile of breast density asymmetry (absolute difference, > 8.23) versus those in the lowest quartile (absolute difference, ≤ –5.55; P = .067).
When compared with women who had proliferative benign disease, women with carcinoma in situ or invasive breast cancer “were more likely to be in the higher than lower quartiles,” said lead investigator Maeve Mullooly, PhD, a research fellow at the Royal College of Surgeons in Dublin.
There was no association between breast density asymmetry and traditional breast cancer risk factors such as age, body mass index, race, and hormone therapy. However, among women diagnosed with benign nonproliferative disease, women with a breast cancer family history were more likely to have higher overall breast density asymmetry.
Study rationale and details
Higher breast density is a known risk factor for breast cancer. Breast asymmetry also has been reported as a possible risk factor (Breast Cancer Res. 2006;8[2]:R14), and incorporation of breast density asymmetry into traditional risk factors in one study improved risk prediction (Breast Cancer Res. 2017 Mar 14;19[1]:29).
Building on that work, the goal of Dr. Mullooly’s study was to “learn how to better use breast density to inform breast cancer risk prediction,” she said.
To that end, her team turned to 854 women enrolled from 2007-2010 in the National Cancer Institute’s Breast Radiology Evaluation and Study of Tissues Project, a cross-sectional molecular epidemiologic study designed to understand how breast density measures are related to breast cancer etiology.
Most of the women were non-Hispanic white. The mean age was 51 years (range, 40-65), and the median body mass index was 25 kg/m2.
About three-quarters of the women (76%) had a breast density asymmetry of at least 2% on the global analysis, with 43% having higher %FGV in the biopsied breast and 33% having higher %FGV in the unaffected breast. In all, 89% of women had local breast density asymmetry, with higher density in the biopsied breast in 61% of women and higher density in the contralateral breast in 28%.
Next steps
This research is ongoing, and additional follow-up is planned, according to Dr. Mullooly. She said the researchers hope to apply more recent analytical techniques to the mammograms and to study the histologic differences in their breast biopsy specimens, among other steps, to see if stronger relationships with greater clinical utility emerge.
It was a “very well done study” with “very provocative data,” said presentation moderator Jennifer Wargo, MD, professor of genomic medicine and surgical oncology at the University of Texas MD Anderson Cancer Center in Houston.
She was interested in the planned next steps, particularly the histologic analysis of dense versus less dense breast tissue. There could be “differences in stroma or hormonal levels even at the microenvironmental level” that “represent a potential field defect, which later puts someone at risk,” she said, adding that it’s “great” that the work is continuing.
The National Cancer Institute funded the research. Dr. Mullooly reported no relevant disclosures. Dr. Wargo disclosed relationships with Bristol-Myers Squibb, Roche/Genentech, Novartis, GlaxoSmithKline, AstraZeneca, Imedex, Dava Oncology, Omniprex, Illumina, Gilead, PeerView, Physician Education Resource, MedImmune, Merck, Biothera Pharmaceuticals, and Microbiome DX.
SOURCE: Mullooly M et al. AACR 2020, Abstract NG15.
The 854 women in the study had been referred for biopsy after an abnormal mammogram.
Researchers used the mammograms to assess global bilateral asymmetry, which was the overall absolute difference in percent fibroglandular tissue volume (%FGV) between the ipsilateral (biopsied) breast and the contralateral (unaffected) breast.
The researchers also assessed local bilateral asymmetry, which was the perilesional %FGV difference in an area twice the size of, but excluding, the biopsy target, and the corresponding area in the unaffected breast.
The women were then divided into quartiles based on breast density asymmetry.
Most of the women had benign breast disease, including proliferative (43%) and nonproliferative (33%) disease, but 23% had carcinoma in situ or invasive breast cancer.
The trend for higher risk of in situ or invasive cancer with increasing breast density asymmetry was observed only in the local analysis. The odds ratio was 1.59 (95% confidence interval, 0.94-2.69) for women in the highest quartile of breast density asymmetry (absolute difference, > 8.23) versus those in the lowest quartile (absolute difference, ≤ –5.55; P = .067).
When compared with women who had proliferative benign disease, women with carcinoma in situ or invasive breast cancer “were more likely to be in the higher than lower quartiles,” said lead investigator Maeve Mullooly, PhD, a research fellow at the Royal College of Surgeons in Dublin.
There was no association between breast density asymmetry and traditional breast cancer risk factors such as age, body mass index, race, and hormone therapy. However, among women diagnosed with benign nonproliferative disease, women with a breast cancer family history were more likely to have higher overall breast density asymmetry.
Study rationale and details
Higher breast density is a known risk factor for breast cancer. Breast asymmetry also has been reported as a possible risk factor (Breast Cancer Res. 2006;8[2]:R14), and incorporation of breast density asymmetry into traditional risk factors in one study improved risk prediction (Breast Cancer Res. 2017 Mar 14;19[1]:29).
Building on that work, the goal of Dr. Mullooly’s study was to “learn how to better use breast density to inform breast cancer risk prediction,” she said.
To that end, her team turned to 854 women enrolled from 2007-2010 in the National Cancer Institute’s Breast Radiology Evaluation and Study of Tissues Project, a cross-sectional molecular epidemiologic study designed to understand how breast density measures are related to breast cancer etiology.
Most of the women were non-Hispanic white. The mean age was 51 years (range, 40-65), and the median body mass index was 25 kg/m2.
About three-quarters of the women (76%) had a breast density asymmetry of at least 2% on the global analysis, with 43% having higher %FGV in the biopsied breast and 33% having higher %FGV in the unaffected breast. In all, 89% of women had local breast density asymmetry, with higher density in the biopsied breast in 61% of women and higher density in the contralateral breast in 28%.
Next steps
This research is ongoing, and additional follow-up is planned, according to Dr. Mullooly. She said the researchers hope to apply more recent analytical techniques to the mammograms and to study the histologic differences in their breast biopsy specimens, among other steps, to see if stronger relationships with greater clinical utility emerge.
It was a “very well done study” with “very provocative data,” said presentation moderator Jennifer Wargo, MD, professor of genomic medicine and surgical oncology at the University of Texas MD Anderson Cancer Center in Houston.
She was interested in the planned next steps, particularly the histologic analysis of dense versus less dense breast tissue. There could be “differences in stroma or hormonal levels even at the microenvironmental level” that “represent a potential field defect, which later puts someone at risk,” she said, adding that it’s “great” that the work is continuing.
The National Cancer Institute funded the research. Dr. Mullooly reported no relevant disclosures. Dr. Wargo disclosed relationships with Bristol-Myers Squibb, Roche/Genentech, Novartis, GlaxoSmithKline, AstraZeneca, Imedex, Dava Oncology, Omniprex, Illumina, Gilead, PeerView, Physician Education Resource, MedImmune, Merck, Biothera Pharmaceuticals, and Microbiome DX.
SOURCE: Mullooly M et al. AACR 2020, Abstract NG15.
FROM AACR 2020