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How aging affects melanoma development and treatment response
There are several mechanisms by which the aging microenvironment can drive cancer and influence response to therapy, according to a plenary presentation at the AACR virtual meeting II.
Ashani T. Weeraratna, PhD, highlighted research showing how the aging microenvironment affects tumor cell metabolism, angiogenesis, and treatment resistance in melanoma.
Dr. Weeraratna, of Johns Hopkins Bloomberg School of Public Health in Baltimore, first described a study showing how fibroblasts in the aged microenvironment contribute to tumor progression in models of melanoma (Nature. 2016 Apr 14;532[7598]:250-4).
Dr. Weeraratna and colleagues isolated dermal fibroblasts from young human donors (aged 25-35 years) and older donors (55-65 years) and used these cells to produce artificial skin.
Melanoma cells placed in the artificial skin created with young fibroblasts remained “very tightly nested at the surface,” Dr. Weeraratna said. On the other hand, melanoma cells migrated “very rapidly” through the artificial dermis created from aged fibroblasts.
In mouse models of melanoma, tumors grew much faster in young mice (6-8 weeks) than in old mice (12-18 months). However, tumors metastasized to the lung at a “much greater rate in the aged mice than in the young mice,” Dr. Weeraratna said.
Angiogenesis, SFRP2, and VEGF
Dr. Weeraratna went on to explain how a member of her lab conducted proteomic analyses of young and aged lung fibroblasts. The results were compared with results from prior analyses of young and aged skin fibroblasts.
The results showed that aged skin fibroblasts promote noncanonical WNT signaling via expression of SFRP2, SERPINE2, DKK1, Wnt5A, and ROR2. On the other hand, aged lung fibroblasts promote canonical WNT signaling via some of the same family members, including SFRP1, DKK3, and ROR1.
Research by another group showed that SFRP2 stimulates angiogenesis via a calcineurin/NFAT signaling pathway (Cancer Res. 2009 Jun 1;69[11]:4621-8).
Research in Dr. Weeraratna’s lab showed that SFRP2 and VEGF are inversely correlated with aging. Tumors in aged mice had an abundance of SFRP2 but little VEGF. Tumors in young mice had an abundance of VEGF but little SFRP2.
Dr. Weeraratna’s team wanted to determine if results would be similar in melanoma patients, so the researchers analyzed data from the TCGA database. They found that VEGF and two of its key receptors are decreased in older melanoma patients, in comparison with younger melanoma patients.
The clinical relevancy of this finding is reflected in an analysis of data from the AVAST-M study (Ann Oncol. 2019;30[12]:2013-4). When compared with observation, bevacizumab did not improve survival overall or for older patients, but the EGFR inhibitor was associated with longer survival in patients younger than 45 years.
Dr. Weeraratna said this finding and her group’s prior findings suggest younger melanoma patients have more VEGF but less angiogenesis than older patients. The older patients have less VEGF and more SFRP2, which drives angiogenesis.
Dr. Weeraratna’s lab then conducted experiments in young mice, which suggested that an anti-VEGF antibody can reduce angiogenesis, but not in the presence of SFRP2.
Lipid metabolism and treatment resistance
A recently published study by Dr. Weeraratna and colleagues tied changes in aged fibroblast lipid metabolism to treatment resistance in melanoma (Cancer Discov. 2020 Jun 4;CD-20-0329).
The research showed that melanoma cells accumulate lipids when incubated with aged, rather than young, fibroblasts in vitro.
Lipid uptake is mediated by fatty acid transporters (FATPs), and the researchers found that most FATPs were unchanged by age. However, FATP2 was elevated in melanoma cells exposed to aged media, aged mice, and melanoma patients older than 50 years of age.
When melanoma cells were incubated with conditioned media from aged fibroblasts and a FATP2 inhibitor, they no longer took up lipids.
When FATP2 was knocked down in aged mice with melanoma, BRAF and MEK inhibitors (which are not very effective ordinarily) caused dramatic and prolonged tumor regression. These effects were not seen with FATP2 inhibition in young mice.
These results suggest FATP2 is a key transporter of lipids in the aged microenvironment, and inhibiting FATP2 can delay the onset of treatment resistance.
Striving to understand a complex system
For many years, the dogma was that cancer cells behaved like unwelcome invaders, co-opting the metabolic machinery of the sites of spread, with crowding of the normal structures within those organs.
To say that concept was primitive is an understatement. Clearly, the relationship between tumor cells and the surrounding stroma is complex. Changes that occur in an aging microenvironment can influence cancer outcomes in older adults.
Dr. Weeraratna’s presentation adds further impetus to efforts to broaden eligibility criteria for clinical trials so the median age and the metabolic milieu of trial participants more closely parallels the general population.
She highlighted the importance of data analysis by age cohorts and the need to design preclinical studies so that investigators can study the microenvironment of cancer cells in in vitro models and in young and older laboratory animals.
As management expert W. Edwards Deming is believed to have said, “Every system is perfectly designed to get the results it gets.” Cancer is likely not an independent, hostile invader, overtaking the failing machinery of aging cells. To understand the intersection of cancer and aging, we need a more perfect understanding of the system in which tumors develop and are treated.
Dr. Weeraratna reported having no disclosures.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Weeraratna A. AACR 2020. Age against the machine: How the aging microenvironment governs response to therapy.
There are several mechanisms by which the aging microenvironment can drive cancer and influence response to therapy, according to a plenary presentation at the AACR virtual meeting II.
Ashani T. Weeraratna, PhD, highlighted research showing how the aging microenvironment affects tumor cell metabolism, angiogenesis, and treatment resistance in melanoma.
Dr. Weeraratna, of Johns Hopkins Bloomberg School of Public Health in Baltimore, first described a study showing how fibroblasts in the aged microenvironment contribute to tumor progression in models of melanoma (Nature. 2016 Apr 14;532[7598]:250-4).
Dr. Weeraratna and colleagues isolated dermal fibroblasts from young human donors (aged 25-35 years) and older donors (55-65 years) and used these cells to produce artificial skin.
Melanoma cells placed in the artificial skin created with young fibroblasts remained “very tightly nested at the surface,” Dr. Weeraratna said. On the other hand, melanoma cells migrated “very rapidly” through the artificial dermis created from aged fibroblasts.
In mouse models of melanoma, tumors grew much faster in young mice (6-8 weeks) than in old mice (12-18 months). However, tumors metastasized to the lung at a “much greater rate in the aged mice than in the young mice,” Dr. Weeraratna said.
Angiogenesis, SFRP2, and VEGF
Dr. Weeraratna went on to explain how a member of her lab conducted proteomic analyses of young and aged lung fibroblasts. The results were compared with results from prior analyses of young and aged skin fibroblasts.
The results showed that aged skin fibroblasts promote noncanonical WNT signaling via expression of SFRP2, SERPINE2, DKK1, Wnt5A, and ROR2. On the other hand, aged lung fibroblasts promote canonical WNT signaling via some of the same family members, including SFRP1, DKK3, and ROR1.
Research by another group showed that SFRP2 stimulates angiogenesis via a calcineurin/NFAT signaling pathway (Cancer Res. 2009 Jun 1;69[11]:4621-8).
Research in Dr. Weeraratna’s lab showed that SFRP2 and VEGF are inversely correlated with aging. Tumors in aged mice had an abundance of SFRP2 but little VEGF. Tumors in young mice had an abundance of VEGF but little SFRP2.
Dr. Weeraratna’s team wanted to determine if results would be similar in melanoma patients, so the researchers analyzed data from the TCGA database. They found that VEGF and two of its key receptors are decreased in older melanoma patients, in comparison with younger melanoma patients.
The clinical relevancy of this finding is reflected in an analysis of data from the AVAST-M study (Ann Oncol. 2019;30[12]:2013-4). When compared with observation, bevacizumab did not improve survival overall or for older patients, but the EGFR inhibitor was associated with longer survival in patients younger than 45 years.
Dr. Weeraratna said this finding and her group’s prior findings suggest younger melanoma patients have more VEGF but less angiogenesis than older patients. The older patients have less VEGF and more SFRP2, which drives angiogenesis.
Dr. Weeraratna’s lab then conducted experiments in young mice, which suggested that an anti-VEGF antibody can reduce angiogenesis, but not in the presence of SFRP2.
Lipid metabolism and treatment resistance
A recently published study by Dr. Weeraratna and colleagues tied changes in aged fibroblast lipid metabolism to treatment resistance in melanoma (Cancer Discov. 2020 Jun 4;CD-20-0329).
The research showed that melanoma cells accumulate lipids when incubated with aged, rather than young, fibroblasts in vitro.
Lipid uptake is mediated by fatty acid transporters (FATPs), and the researchers found that most FATPs were unchanged by age. However, FATP2 was elevated in melanoma cells exposed to aged media, aged mice, and melanoma patients older than 50 years of age.
When melanoma cells were incubated with conditioned media from aged fibroblasts and a FATP2 inhibitor, they no longer took up lipids.
When FATP2 was knocked down in aged mice with melanoma, BRAF and MEK inhibitors (which are not very effective ordinarily) caused dramatic and prolonged tumor regression. These effects were not seen with FATP2 inhibition in young mice.
These results suggest FATP2 is a key transporter of lipids in the aged microenvironment, and inhibiting FATP2 can delay the onset of treatment resistance.
Striving to understand a complex system
For many years, the dogma was that cancer cells behaved like unwelcome invaders, co-opting the metabolic machinery of the sites of spread, with crowding of the normal structures within those organs.
To say that concept was primitive is an understatement. Clearly, the relationship between tumor cells and the surrounding stroma is complex. Changes that occur in an aging microenvironment can influence cancer outcomes in older adults.
Dr. Weeraratna’s presentation adds further impetus to efforts to broaden eligibility criteria for clinical trials so the median age and the metabolic milieu of trial participants more closely parallels the general population.
She highlighted the importance of data analysis by age cohorts and the need to design preclinical studies so that investigators can study the microenvironment of cancer cells in in vitro models and in young and older laboratory animals.
As management expert W. Edwards Deming is believed to have said, “Every system is perfectly designed to get the results it gets.” Cancer is likely not an independent, hostile invader, overtaking the failing machinery of aging cells. To understand the intersection of cancer and aging, we need a more perfect understanding of the system in which tumors develop and are treated.
Dr. Weeraratna reported having no disclosures.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Weeraratna A. AACR 2020. Age against the machine: How the aging microenvironment governs response to therapy.
There are several mechanisms by which the aging microenvironment can drive cancer and influence response to therapy, according to a plenary presentation at the AACR virtual meeting II.
Ashani T. Weeraratna, PhD, highlighted research showing how the aging microenvironment affects tumor cell metabolism, angiogenesis, and treatment resistance in melanoma.
Dr. Weeraratna, of Johns Hopkins Bloomberg School of Public Health in Baltimore, first described a study showing how fibroblasts in the aged microenvironment contribute to tumor progression in models of melanoma (Nature. 2016 Apr 14;532[7598]:250-4).
Dr. Weeraratna and colleagues isolated dermal fibroblasts from young human donors (aged 25-35 years) and older donors (55-65 years) and used these cells to produce artificial skin.
Melanoma cells placed in the artificial skin created with young fibroblasts remained “very tightly nested at the surface,” Dr. Weeraratna said. On the other hand, melanoma cells migrated “very rapidly” through the artificial dermis created from aged fibroblasts.
In mouse models of melanoma, tumors grew much faster in young mice (6-8 weeks) than in old mice (12-18 months). However, tumors metastasized to the lung at a “much greater rate in the aged mice than in the young mice,” Dr. Weeraratna said.
Angiogenesis, SFRP2, and VEGF
Dr. Weeraratna went on to explain how a member of her lab conducted proteomic analyses of young and aged lung fibroblasts. The results were compared with results from prior analyses of young and aged skin fibroblasts.
The results showed that aged skin fibroblasts promote noncanonical WNT signaling via expression of SFRP2, SERPINE2, DKK1, Wnt5A, and ROR2. On the other hand, aged lung fibroblasts promote canonical WNT signaling via some of the same family members, including SFRP1, DKK3, and ROR1.
Research by another group showed that SFRP2 stimulates angiogenesis via a calcineurin/NFAT signaling pathway (Cancer Res. 2009 Jun 1;69[11]:4621-8).
Research in Dr. Weeraratna’s lab showed that SFRP2 and VEGF are inversely correlated with aging. Tumors in aged mice had an abundance of SFRP2 but little VEGF. Tumors in young mice had an abundance of VEGF but little SFRP2.
Dr. Weeraratna’s team wanted to determine if results would be similar in melanoma patients, so the researchers analyzed data from the TCGA database. They found that VEGF and two of its key receptors are decreased in older melanoma patients, in comparison with younger melanoma patients.
The clinical relevancy of this finding is reflected in an analysis of data from the AVAST-M study (Ann Oncol. 2019;30[12]:2013-4). When compared with observation, bevacizumab did not improve survival overall or for older patients, but the EGFR inhibitor was associated with longer survival in patients younger than 45 years.
Dr. Weeraratna said this finding and her group’s prior findings suggest younger melanoma patients have more VEGF but less angiogenesis than older patients. The older patients have less VEGF and more SFRP2, which drives angiogenesis.
Dr. Weeraratna’s lab then conducted experiments in young mice, which suggested that an anti-VEGF antibody can reduce angiogenesis, but not in the presence of SFRP2.
Lipid metabolism and treatment resistance
A recently published study by Dr. Weeraratna and colleagues tied changes in aged fibroblast lipid metabolism to treatment resistance in melanoma (Cancer Discov. 2020 Jun 4;CD-20-0329).
The research showed that melanoma cells accumulate lipids when incubated with aged, rather than young, fibroblasts in vitro.
Lipid uptake is mediated by fatty acid transporters (FATPs), and the researchers found that most FATPs were unchanged by age. However, FATP2 was elevated in melanoma cells exposed to aged media, aged mice, and melanoma patients older than 50 years of age.
When melanoma cells were incubated with conditioned media from aged fibroblasts and a FATP2 inhibitor, they no longer took up lipids.
When FATP2 was knocked down in aged mice with melanoma, BRAF and MEK inhibitors (which are not very effective ordinarily) caused dramatic and prolonged tumor regression. These effects were not seen with FATP2 inhibition in young mice.
These results suggest FATP2 is a key transporter of lipids in the aged microenvironment, and inhibiting FATP2 can delay the onset of treatment resistance.
Striving to understand a complex system
For many years, the dogma was that cancer cells behaved like unwelcome invaders, co-opting the metabolic machinery of the sites of spread, with crowding of the normal structures within those organs.
To say that concept was primitive is an understatement. Clearly, the relationship between tumor cells and the surrounding stroma is complex. Changes that occur in an aging microenvironment can influence cancer outcomes in older adults.
Dr. Weeraratna’s presentation adds further impetus to efforts to broaden eligibility criteria for clinical trials so the median age and the metabolic milieu of trial participants more closely parallels the general population.
She highlighted the importance of data analysis by age cohorts and the need to design preclinical studies so that investigators can study the microenvironment of cancer cells in in vitro models and in young and older laboratory animals.
As management expert W. Edwards Deming is believed to have said, “Every system is perfectly designed to get the results it gets.” Cancer is likely not an independent, hostile invader, overtaking the failing machinery of aging cells. To understand the intersection of cancer and aging, we need a more perfect understanding of the system in which tumors develop and are treated.
Dr. Weeraratna reported having no disclosures.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Weeraratna A. AACR 2020. Age against the machine: How the aging microenvironment governs response to therapy.
FROM AACR 2020
Endothelial injury may play a major role in COVID-19–associated coagulopathy
A striking clinical feature of illness from SARS-CoV-2 is a marked increase in thrombotic and microvascular complications, or COVID-19–associated coagulopathy (CAC).
A new study suggests endothelial cell injury plays a major role in the pathogenesis of CAC, and blood levels of soluble thrombomodulin correlate with mortality.
George Goshua, MD, of Yale University, New Haven, Conn., presented this study as a late-breaking abstract at the virtual annual congress of the European Hematology Association.
Dr. Goshua cited past research showing CAC to be highly prevalent among hospitalized patients. Venous thromboembolism was found in 17% to 69% of patients, despite thromboprophylaxis.1-4 Arterial thrombosis has been seen in 3.6% to 4.0% of patients,1-3 and autopsy findings have shown microvascular thrombosis in as many as 87% of patients.5-7
For their study, Dr. Goshua and colleagues assessed endothelial cell damage, platelet activation, and hemostatic and fibrinolytic cascade effects of CAC.
The investigators measured markers of endothelial cell injury and platelet activation, plasminogen activation inhibitor 1 (PAI-1), and coagulation factors in stable and critically ill patients hospitalized with COVID-19. In addition, the team sought to identify biomarkers of mortality in hospitalized patients.
Dr. Goshua and colleagues studied 68 adults hospitalized for suspected COVID-19 – 48 in the ICU and 20 outside the ICU. Patients in the ICU received mechanical ventilation, while the non-ICU patients required supplemental oxygen (≤3 L/min per nasal cannula).
There were more men than women (69% vs. 31%) in the ICU population but not in the non-ICU population (40% vs. 60%). There were no statistically significant differences in age or comorbid conditions between the ICU and non-ICU patients.
Results and interpretation
Consistent with augmentation of the coagulation cascade – and as expected – D-dimer and thrombin-antithrombin levels were high in both the ICU and non-ICU populations, but levels were significantly higher (P < .001) among the ICU patients.
Endogenous anticoagulants (antithrombin and proteins C and S) and fibrinolytic enzymes (alpha 2-antiplasmin) were preserved, verifying that CAC is distinct from disseminated intravascular coagulation. Classic fibrinolysis did not occur, as PAI-1 was high in ICU and non-ICU patients, and lysis-30 was normal in nearly all ICU patients (96%).
Von Willebrand factor antigen and activity levels and factor VIII levels were markedly elevated in non-ICU and ICU patients, but they were significantly higher (P < .001) in the ICU cohort. This supports the hypothesis that endothelial cell damage and platelet activation play major roles in CAC.
Similarly, soluble P-selectin, which is shed from endothelial cells and platelets, was dramatically elevated in ICU patients in comparison with controls and non-ICU patients (P < .001 for both comparisons).
Levels of soluble thrombomodulin, which is released from endothelial cells, were not significantly different in ICU patients and controls. However, given thrombomodulin’s significant role in the coagulation cascade, Dr. Goshua and colleagues plotted receiver operating curves to see if soluble thrombomodulin levels were predictive of mortality.
The results showed that soluble thrombomodulin correlated with the probability of survival, both overall and in ICU patients. Soluble thrombomodulin levels greater than 3.26 ng/mL were associated with significantly worse survival in all patients (P = .0087) and ICU patients (P = .0309).
Influence on therapy
Laboratory perturbations were detected in both ICU and non-ICU patients, and otherwise healthy outpatients have exhibited potentially life-threatening CAC, according to Dr. Goshua.
These findings suggest the prothrombotic state occurs early in the pathogenesis of SARS-CoV-2 infection, is driven by platelet activation and endotheliopathy, and becomes more pronounced with worsening severity of infection.
The results of this study prompted a change in how Yale–New Haven Hospital manages COVID-19 patients. Patients without a clinical contraindication now receive aspirin at 81 mg daily in addition to the anticoagulation regimen typically used for all hospitalized COVID-19 patients.
Investigations regarding other medications that can influence platelet-endothelial cell interactions and modulate endothelial cell damage in CAC – such as dipyridamole, defibrotide, and eculizumab – are planned.
Challenges and unanswered questions
Virchow’s triad was described by the eminent German physician, Rudolf Virchow, MD, in the 19th century. It refers to the three broad categories of factors that can predispose patients to thrombosis — circulatory stasis, hypercoagulability, and endothelial injury.
Although all of these elements could be operative in CAC, the current study suggests platelet activation and endothelial cell injury in CAC may be of primary importance.
Because of the limited ability to test critically ill patients and concerns regarding exposure of additional hospital personnel to COVID-19 patients, the current report lacked clarity about the relationship of the detected laboratory abnormalities to confirmed thrombotic events.
It is unknown whether endothelial cells in different organs are damaged uniformly. It is also unclear if the laboratory abnormalities identified in this analysis can be used to monitor response to therapy, to guide follow-up management of discharged patients with CAC, or to identify infected outpatients who should receive prophylactic anticoagulation.
The mechanism by which SARS-CoV-2 injures endothelial cells is not explained by these data. Neutrophil defensins and other prothrombotic peptides or markers of inflammation could play key roles in pathogenesis, assessment of disease severity, or monitoring for therapeutic efficacy.
Today, we have more sophisticated diagnostic tools than Dr. Virchow had. We also have the ability to record and rapidly disseminate information globally. Still, with regard to the COVID-19 pandemic, clinicians face many of the same challenges that confronted Dr. Virchow in his era.
The analysis conducted by Dr. Goshua and colleagues goes a long way toward elucidating some of the mechanisms and therapeutic targets to meet these challenges.
Dr. Goshua disclosed no conflicts of interest.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Goshua G et al. EHA Congress. Abstract LB2605.
References
1. Klok FA et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis. Thromb Res. 2020;191:148-50. doi: 10.1016/j.thromres.2020.04.041.
2. Thomas W et al. Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom. Thromb Res. 2020;191:76-7. doi: 10.1016/j.thromres.2020.04.028
3. Lodigiani C et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res. 2020;191:9-14. doi: 10.1016/j.thromres.2020.04.024
4. Llitjos JF et al. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients [published online ahead of print, 2020 Apr 22]. J Thromb Haemost. 2020;10.1111/jth.14869. doi: 10.1111/jth.14869
5. Carsana L et al. Pulmonary post-mortem findings in a large series of COVID-19 cases from Northern Italy. medRxiv 2020.04.19.20054262; doi: 10.1101/2020.04.19.20054262v1.
6. Menter T et al. Post-mortem examination of COVID19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction [published online ahead of print, 2020 May 4]. Histopathology. 2020;10.1111/his.14134. doi: 10.1111/his.14134
7. Lax SF, et al. Pulmonary arterial thrombosis in COVID-19 with fatal outcome: Results from a prospective, single-center, clinicopathologic case series [published online ahead of print, 2020 May 14]. Ann Intern Med. 2020;M20-2566. doi: 10.7326/M20-2566.
A striking clinical feature of illness from SARS-CoV-2 is a marked increase in thrombotic and microvascular complications, or COVID-19–associated coagulopathy (CAC).
A new study suggests endothelial cell injury plays a major role in the pathogenesis of CAC, and blood levels of soluble thrombomodulin correlate with mortality.
George Goshua, MD, of Yale University, New Haven, Conn., presented this study as a late-breaking abstract at the virtual annual congress of the European Hematology Association.
Dr. Goshua cited past research showing CAC to be highly prevalent among hospitalized patients. Venous thromboembolism was found in 17% to 69% of patients, despite thromboprophylaxis.1-4 Arterial thrombosis has been seen in 3.6% to 4.0% of patients,1-3 and autopsy findings have shown microvascular thrombosis in as many as 87% of patients.5-7
For their study, Dr. Goshua and colleagues assessed endothelial cell damage, platelet activation, and hemostatic and fibrinolytic cascade effects of CAC.
The investigators measured markers of endothelial cell injury and platelet activation, plasminogen activation inhibitor 1 (PAI-1), and coagulation factors in stable and critically ill patients hospitalized with COVID-19. In addition, the team sought to identify biomarkers of mortality in hospitalized patients.
Dr. Goshua and colleagues studied 68 adults hospitalized for suspected COVID-19 – 48 in the ICU and 20 outside the ICU. Patients in the ICU received mechanical ventilation, while the non-ICU patients required supplemental oxygen (≤3 L/min per nasal cannula).
There were more men than women (69% vs. 31%) in the ICU population but not in the non-ICU population (40% vs. 60%). There were no statistically significant differences in age or comorbid conditions between the ICU and non-ICU patients.
Results and interpretation
Consistent with augmentation of the coagulation cascade – and as expected – D-dimer and thrombin-antithrombin levels were high in both the ICU and non-ICU populations, but levels were significantly higher (P < .001) among the ICU patients.
Endogenous anticoagulants (antithrombin and proteins C and S) and fibrinolytic enzymes (alpha 2-antiplasmin) were preserved, verifying that CAC is distinct from disseminated intravascular coagulation. Classic fibrinolysis did not occur, as PAI-1 was high in ICU and non-ICU patients, and lysis-30 was normal in nearly all ICU patients (96%).
Von Willebrand factor antigen and activity levels and factor VIII levels were markedly elevated in non-ICU and ICU patients, but they were significantly higher (P < .001) in the ICU cohort. This supports the hypothesis that endothelial cell damage and platelet activation play major roles in CAC.
Similarly, soluble P-selectin, which is shed from endothelial cells and platelets, was dramatically elevated in ICU patients in comparison with controls and non-ICU patients (P < .001 for both comparisons).
Levels of soluble thrombomodulin, which is released from endothelial cells, were not significantly different in ICU patients and controls. However, given thrombomodulin’s significant role in the coagulation cascade, Dr. Goshua and colleagues plotted receiver operating curves to see if soluble thrombomodulin levels were predictive of mortality.
The results showed that soluble thrombomodulin correlated with the probability of survival, both overall and in ICU patients. Soluble thrombomodulin levels greater than 3.26 ng/mL were associated with significantly worse survival in all patients (P = .0087) and ICU patients (P = .0309).
Influence on therapy
Laboratory perturbations were detected in both ICU and non-ICU patients, and otherwise healthy outpatients have exhibited potentially life-threatening CAC, according to Dr. Goshua.
These findings suggest the prothrombotic state occurs early in the pathogenesis of SARS-CoV-2 infection, is driven by platelet activation and endotheliopathy, and becomes more pronounced with worsening severity of infection.
The results of this study prompted a change in how Yale–New Haven Hospital manages COVID-19 patients. Patients without a clinical contraindication now receive aspirin at 81 mg daily in addition to the anticoagulation regimen typically used for all hospitalized COVID-19 patients.
Investigations regarding other medications that can influence platelet-endothelial cell interactions and modulate endothelial cell damage in CAC – such as dipyridamole, defibrotide, and eculizumab – are planned.
Challenges and unanswered questions
Virchow’s triad was described by the eminent German physician, Rudolf Virchow, MD, in the 19th century. It refers to the three broad categories of factors that can predispose patients to thrombosis — circulatory stasis, hypercoagulability, and endothelial injury.
Although all of these elements could be operative in CAC, the current study suggests platelet activation and endothelial cell injury in CAC may be of primary importance.
Because of the limited ability to test critically ill patients and concerns regarding exposure of additional hospital personnel to COVID-19 patients, the current report lacked clarity about the relationship of the detected laboratory abnormalities to confirmed thrombotic events.
It is unknown whether endothelial cells in different organs are damaged uniformly. It is also unclear if the laboratory abnormalities identified in this analysis can be used to monitor response to therapy, to guide follow-up management of discharged patients with CAC, or to identify infected outpatients who should receive prophylactic anticoagulation.
The mechanism by which SARS-CoV-2 injures endothelial cells is not explained by these data. Neutrophil defensins and other prothrombotic peptides or markers of inflammation could play key roles in pathogenesis, assessment of disease severity, or monitoring for therapeutic efficacy.
Today, we have more sophisticated diagnostic tools than Dr. Virchow had. We also have the ability to record and rapidly disseminate information globally. Still, with regard to the COVID-19 pandemic, clinicians face many of the same challenges that confronted Dr. Virchow in his era.
The analysis conducted by Dr. Goshua and colleagues goes a long way toward elucidating some of the mechanisms and therapeutic targets to meet these challenges.
Dr. Goshua disclosed no conflicts of interest.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Goshua G et al. EHA Congress. Abstract LB2605.
References
1. Klok FA et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis. Thromb Res. 2020;191:148-50. doi: 10.1016/j.thromres.2020.04.041.
2. Thomas W et al. Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom. Thromb Res. 2020;191:76-7. doi: 10.1016/j.thromres.2020.04.028
3. Lodigiani C et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res. 2020;191:9-14. doi: 10.1016/j.thromres.2020.04.024
4. Llitjos JF et al. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients [published online ahead of print, 2020 Apr 22]. J Thromb Haemost. 2020;10.1111/jth.14869. doi: 10.1111/jth.14869
5. Carsana L et al. Pulmonary post-mortem findings in a large series of COVID-19 cases from Northern Italy. medRxiv 2020.04.19.20054262; doi: 10.1101/2020.04.19.20054262v1.
6. Menter T et al. Post-mortem examination of COVID19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction [published online ahead of print, 2020 May 4]. Histopathology. 2020;10.1111/his.14134. doi: 10.1111/his.14134
7. Lax SF, et al. Pulmonary arterial thrombosis in COVID-19 with fatal outcome: Results from a prospective, single-center, clinicopathologic case series [published online ahead of print, 2020 May 14]. Ann Intern Med. 2020;M20-2566. doi: 10.7326/M20-2566.
A striking clinical feature of illness from SARS-CoV-2 is a marked increase in thrombotic and microvascular complications, or COVID-19–associated coagulopathy (CAC).
A new study suggests endothelial cell injury plays a major role in the pathogenesis of CAC, and blood levels of soluble thrombomodulin correlate with mortality.
George Goshua, MD, of Yale University, New Haven, Conn., presented this study as a late-breaking abstract at the virtual annual congress of the European Hematology Association.
Dr. Goshua cited past research showing CAC to be highly prevalent among hospitalized patients. Venous thromboembolism was found in 17% to 69% of patients, despite thromboprophylaxis.1-4 Arterial thrombosis has been seen in 3.6% to 4.0% of patients,1-3 and autopsy findings have shown microvascular thrombosis in as many as 87% of patients.5-7
For their study, Dr. Goshua and colleagues assessed endothelial cell damage, platelet activation, and hemostatic and fibrinolytic cascade effects of CAC.
The investigators measured markers of endothelial cell injury and platelet activation, plasminogen activation inhibitor 1 (PAI-1), and coagulation factors in stable and critically ill patients hospitalized with COVID-19. In addition, the team sought to identify biomarkers of mortality in hospitalized patients.
Dr. Goshua and colleagues studied 68 adults hospitalized for suspected COVID-19 – 48 in the ICU and 20 outside the ICU. Patients in the ICU received mechanical ventilation, while the non-ICU patients required supplemental oxygen (≤3 L/min per nasal cannula).
There were more men than women (69% vs. 31%) in the ICU population but not in the non-ICU population (40% vs. 60%). There were no statistically significant differences in age or comorbid conditions between the ICU and non-ICU patients.
Results and interpretation
Consistent with augmentation of the coagulation cascade – and as expected – D-dimer and thrombin-antithrombin levels were high in both the ICU and non-ICU populations, but levels were significantly higher (P < .001) among the ICU patients.
Endogenous anticoagulants (antithrombin and proteins C and S) and fibrinolytic enzymes (alpha 2-antiplasmin) were preserved, verifying that CAC is distinct from disseminated intravascular coagulation. Classic fibrinolysis did not occur, as PAI-1 was high in ICU and non-ICU patients, and lysis-30 was normal in nearly all ICU patients (96%).
Von Willebrand factor antigen and activity levels and factor VIII levels were markedly elevated in non-ICU and ICU patients, but they were significantly higher (P < .001) in the ICU cohort. This supports the hypothesis that endothelial cell damage and platelet activation play major roles in CAC.
Similarly, soluble P-selectin, which is shed from endothelial cells and platelets, was dramatically elevated in ICU patients in comparison with controls and non-ICU patients (P < .001 for both comparisons).
Levels of soluble thrombomodulin, which is released from endothelial cells, were not significantly different in ICU patients and controls. However, given thrombomodulin’s significant role in the coagulation cascade, Dr. Goshua and colleagues plotted receiver operating curves to see if soluble thrombomodulin levels were predictive of mortality.
The results showed that soluble thrombomodulin correlated with the probability of survival, both overall and in ICU patients. Soluble thrombomodulin levels greater than 3.26 ng/mL were associated with significantly worse survival in all patients (P = .0087) and ICU patients (P = .0309).
Influence on therapy
Laboratory perturbations were detected in both ICU and non-ICU patients, and otherwise healthy outpatients have exhibited potentially life-threatening CAC, according to Dr. Goshua.
These findings suggest the prothrombotic state occurs early in the pathogenesis of SARS-CoV-2 infection, is driven by platelet activation and endotheliopathy, and becomes more pronounced with worsening severity of infection.
The results of this study prompted a change in how Yale–New Haven Hospital manages COVID-19 patients. Patients without a clinical contraindication now receive aspirin at 81 mg daily in addition to the anticoagulation regimen typically used for all hospitalized COVID-19 patients.
Investigations regarding other medications that can influence platelet-endothelial cell interactions and modulate endothelial cell damage in CAC – such as dipyridamole, defibrotide, and eculizumab – are planned.
Challenges and unanswered questions
Virchow’s triad was described by the eminent German physician, Rudolf Virchow, MD, in the 19th century. It refers to the three broad categories of factors that can predispose patients to thrombosis — circulatory stasis, hypercoagulability, and endothelial injury.
Although all of these elements could be operative in CAC, the current study suggests platelet activation and endothelial cell injury in CAC may be of primary importance.
Because of the limited ability to test critically ill patients and concerns regarding exposure of additional hospital personnel to COVID-19 patients, the current report lacked clarity about the relationship of the detected laboratory abnormalities to confirmed thrombotic events.
It is unknown whether endothelial cells in different organs are damaged uniformly. It is also unclear if the laboratory abnormalities identified in this analysis can be used to monitor response to therapy, to guide follow-up management of discharged patients with CAC, or to identify infected outpatients who should receive prophylactic anticoagulation.
The mechanism by which SARS-CoV-2 injures endothelial cells is not explained by these data. Neutrophil defensins and other prothrombotic peptides or markers of inflammation could play key roles in pathogenesis, assessment of disease severity, or monitoring for therapeutic efficacy.
Today, we have more sophisticated diagnostic tools than Dr. Virchow had. We also have the ability to record and rapidly disseminate information globally. Still, with regard to the COVID-19 pandemic, clinicians face many of the same challenges that confronted Dr. Virchow in his era.
The analysis conducted by Dr. Goshua and colleagues goes a long way toward elucidating some of the mechanisms and therapeutic targets to meet these challenges.
Dr. Goshua disclosed no conflicts of interest.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Goshua G et al. EHA Congress. Abstract LB2605.
References
1. Klok FA et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis. Thromb Res. 2020;191:148-50. doi: 10.1016/j.thromres.2020.04.041.
2. Thomas W et al. Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom. Thromb Res. 2020;191:76-7. doi: 10.1016/j.thromres.2020.04.028
3. Lodigiani C et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res. 2020;191:9-14. doi: 10.1016/j.thromres.2020.04.024
4. Llitjos JF et al. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients [published online ahead of print, 2020 Apr 22]. J Thromb Haemost. 2020;10.1111/jth.14869. doi: 10.1111/jth.14869
5. Carsana L et al. Pulmonary post-mortem findings in a large series of COVID-19 cases from Northern Italy. medRxiv 2020.04.19.20054262; doi: 10.1101/2020.04.19.20054262v1.
6. Menter T et al. Post-mortem examination of COVID19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction [published online ahead of print, 2020 May 4]. Histopathology. 2020;10.1111/his.14134. doi: 10.1111/his.14134
7. Lax SF, et al. Pulmonary arterial thrombosis in COVID-19 with fatal outcome: Results from a prospective, single-center, clinicopathologic case series [published online ahead of print, 2020 May 14]. Ann Intern Med. 2020;M20-2566. doi: 10.7326/M20-2566.
FROM EHA CONGRESS
CheckMate 9LA: ‘Doing better’ for stage IV/recurrent NSCLC
Data from the CheckMate 9LA study suggest the combination amplifies the rapid response expected from chemotherapy and the long-term benefit from immunotherapy. Furthermore, the very limited exposure to chemotherapy appears to mitigate long-term risks.
Martin Reck, MD, PhD, of LungenClinic Grosshansdorf in Germany, reported the data as part of the American Society of Clinical Oncology virtual scientific program (Abstract 9501).
A prior trial, CheckMate 227, demonstrated that nivolumab plus ipilimumab improved overall survival (OS) and durability of response in comparison with conventional chemotherapy in advanced NSCLC, regardless of PD-L1 expression (N Engl J Med 2019; 381:2020-31).
In CheckMate 9LA, researchers tested whether adding a limited course of chemotherapy – just two cycles – could improve outcomes further. Dr. Reck reported that, at the first preplanned interim analysis, the combination met its primary goal of improving OS as well as meeting multiple secondary endpoints.
Details of CheckMate 9LA
CheckMate 9LA included 719 treatment-naive patients with histologically confirmed stage IV or recurrent NSCLC and no known sensitizing alterations in EGFR or ALK. All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1.
Patients received either nivolumab plus ipilimumab at standard NSCLC doses plus two cycles of chemotherapy or chemotherapy alone for four cycles.
The chemotherapy regimen was tailored by histology. Pemetrexed plus either cisplatin or carboplatin, with optional pemetrexed maintenance, was administered to patients with non-squamous histology. Paclitaxel plus carboplatin was chosen for patients with squamous disease.
If there was no disease progression or unacceptable toxicity, patients receiving nivolumab plus ipilimumab could continue immunotherapy for up to 2 years.
Patients were stratified by PD-L1 expression (< 1% vs. ≥ 1%), gender, and histology (squamous vs. non-squamous). Tumor and clinical characteristics were balanced across the trial arms.
The primary endpoint was OS, with secondary endpoints of progression-free survival, objective response rate by blinded independent central review, and efficacy by PD-L1 subgroups. Exploratory endpoints included safety/tolerability.
Results prompt FDA approval
Dr. Reck and colleagues found significantly better OS with nivolumab-ipilimumab plus chemotherapy, in comparison with chemotherapy alone (hazard ratio, 0.69; P = .0006).
With longer follow-up (minimum 12.7 months), nivolumab-ipilimumab plus chemotherapy continued to provide longer OS compared with chemotherapy alone. The median OS was 15.6 months and 10.9 months, respectively (HR, 0.66).
Despite more patients receiving subsequent systemic therapy in the chemotherapy-alone arm (34% of whom eventually received an immune checkpoint inhibitor), the immunotherapy-chemotherapy arm still yielded superior OS in the overall population.
One-year OS rates were 63% in the immunotherapy arm and 47% in the chemotherapy-alone arm.
Statistically significant improvements in progression-free survival and objective response rate were seen. The median response duration was 11.3 months in the immunotherapy arm and 5.6 months in the chemotherapy-alone arm.
Benefit was consistent by all efficacy measures and in all subgroups, including by PD-L1 expression and histology.
Based on the strength of these results, in May, the Food and Drug Administration approved nivolumab plus ipilimumab and two cycles of platinum-doublet chemotherapy for the frontline treatment of patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations.
Challenges to overcome
In the forest plots for OS, the 70 patients who were 75 years of age and older had inferior survival with the combination regimen, compared with chemotherapy alone.
Grade 3-4 treatment-related toxicity was reported in 47% of patients in the immunotherapy arm and 38% of those in the chemotherapy-alone arm.
With nivolumab-ipilimumab plus chemotherapy, more adverse events were considered serious (25.4% vs. 15%). Furthermore, grade 3-4 adverse events led to a higher rate of treatment discontinuation in the immunotherapy arm than in the chemotherapy-alone arm (16% vs. 5%).
Although cross-trial comparisons are treacherous, in CheckMate 227, only 12% of patients receiving nivolumab plus ipilimumab stopped treatment because of a grade 3-4 adverse event.
Better by design
In the updated analysis of CheckMate 227 (ASCO 2020, Abstract 9500), the nivolumab-ipilimumab regimen showed inferior OS results for the first 6 months of treatment, with more disease progression during that time. However, at 6 months, the OS curves crossed over to become consistently superior for the immunotherapy regimen thereafter.
Platinum-based chemotherapy is thought to augment antitumor immunity by inducing immunogenic cell death, increasing tumor neoantigen expression, and disturbing the immunosuppressive tumor microenvironment that prevents immune detection.
Therefore, CheckMate 9LA incorporated a short exposure to chemotherapy for the patients receiving nivolumab-ipilimumab in an effort to attain rapid disease control and retain the durable OS benefit that was seen with dual immunotherapy in CheckMate 227.
Indeed, in CheckMate 9LA, the Kaplan-Meier curves in both the initial and follow-up OS analyses diverged early in favor of the nivolumab-ipilimumab plus chemotherapy regimen and never crossed the curve for chemotherapy alone. Progressive disease was observed in fewer patients with the immunotherapy combination than with chemotherapy alone.
Longer follow-up needed
In recent years, a large number of treatment options for stage IV NSCLC patients have emerged. In the current report of CheckMate 9LA, the OS curve extended only to 27 months.
As was noted by invited discussant Benjamin Levy, MD, of Johns Hopkins University in Baltimore, it may be premature to put the regimen of two cycles of chemotherapy plus dual checkpoint/CTLA4 blockade in its proper context until follow-up extends for 3-5 years.
It would be ideal to know whether the tail of the OS curve will flatten out.
Do the best you can
Clinical investigators have a responsibility to retain the successes of prior regimens while overcoming the challenges of adverse events. New regimens also need to be practical when applied in general oncology practice.
In 2014, the American poet Maya Angelou advised, “Do the best you can until you know better. Then, when you know better, do better.” In many regards, the immunotherapy-chemotherapy combination tested in CheckMate 9LA appears to do better than preceding regimens.
Further refinements in dose, schedule, and supportive care, as well as real-time reporting of and response to patient-reported outcomes, will likely help us build on the CheckMate 9LA regimen and do even better.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Reck M et al. ASCO 2020, Abstract 9501.
Data from the CheckMate 9LA study suggest the combination amplifies the rapid response expected from chemotherapy and the long-term benefit from immunotherapy. Furthermore, the very limited exposure to chemotherapy appears to mitigate long-term risks.
Martin Reck, MD, PhD, of LungenClinic Grosshansdorf in Germany, reported the data as part of the American Society of Clinical Oncology virtual scientific program (Abstract 9501).
A prior trial, CheckMate 227, demonstrated that nivolumab plus ipilimumab improved overall survival (OS) and durability of response in comparison with conventional chemotherapy in advanced NSCLC, regardless of PD-L1 expression (N Engl J Med 2019; 381:2020-31).
In CheckMate 9LA, researchers tested whether adding a limited course of chemotherapy – just two cycles – could improve outcomes further. Dr. Reck reported that, at the first preplanned interim analysis, the combination met its primary goal of improving OS as well as meeting multiple secondary endpoints.
Details of CheckMate 9LA
CheckMate 9LA included 719 treatment-naive patients with histologically confirmed stage IV or recurrent NSCLC and no known sensitizing alterations in EGFR or ALK. All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1.
Patients received either nivolumab plus ipilimumab at standard NSCLC doses plus two cycles of chemotherapy or chemotherapy alone for four cycles.
The chemotherapy regimen was tailored by histology. Pemetrexed plus either cisplatin or carboplatin, with optional pemetrexed maintenance, was administered to patients with non-squamous histology. Paclitaxel plus carboplatin was chosen for patients with squamous disease.
If there was no disease progression or unacceptable toxicity, patients receiving nivolumab plus ipilimumab could continue immunotherapy for up to 2 years.
Patients were stratified by PD-L1 expression (< 1% vs. ≥ 1%), gender, and histology (squamous vs. non-squamous). Tumor and clinical characteristics were balanced across the trial arms.
The primary endpoint was OS, with secondary endpoints of progression-free survival, objective response rate by blinded independent central review, and efficacy by PD-L1 subgroups. Exploratory endpoints included safety/tolerability.
Results prompt FDA approval
Dr. Reck and colleagues found significantly better OS with nivolumab-ipilimumab plus chemotherapy, in comparison with chemotherapy alone (hazard ratio, 0.69; P = .0006).
With longer follow-up (minimum 12.7 months), nivolumab-ipilimumab plus chemotherapy continued to provide longer OS compared with chemotherapy alone. The median OS was 15.6 months and 10.9 months, respectively (HR, 0.66).
Despite more patients receiving subsequent systemic therapy in the chemotherapy-alone arm (34% of whom eventually received an immune checkpoint inhibitor), the immunotherapy-chemotherapy arm still yielded superior OS in the overall population.
One-year OS rates were 63% in the immunotherapy arm and 47% in the chemotherapy-alone arm.
Statistically significant improvements in progression-free survival and objective response rate were seen. The median response duration was 11.3 months in the immunotherapy arm and 5.6 months in the chemotherapy-alone arm.
Benefit was consistent by all efficacy measures and in all subgroups, including by PD-L1 expression and histology.
Based on the strength of these results, in May, the Food and Drug Administration approved nivolumab plus ipilimumab and two cycles of platinum-doublet chemotherapy for the frontline treatment of patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations.
Challenges to overcome
In the forest plots for OS, the 70 patients who were 75 years of age and older had inferior survival with the combination regimen, compared with chemotherapy alone.
Grade 3-4 treatment-related toxicity was reported in 47% of patients in the immunotherapy arm and 38% of those in the chemotherapy-alone arm.
With nivolumab-ipilimumab plus chemotherapy, more adverse events were considered serious (25.4% vs. 15%). Furthermore, grade 3-4 adverse events led to a higher rate of treatment discontinuation in the immunotherapy arm than in the chemotherapy-alone arm (16% vs. 5%).
Although cross-trial comparisons are treacherous, in CheckMate 227, only 12% of patients receiving nivolumab plus ipilimumab stopped treatment because of a grade 3-4 adverse event.
Better by design
In the updated analysis of CheckMate 227 (ASCO 2020, Abstract 9500), the nivolumab-ipilimumab regimen showed inferior OS results for the first 6 months of treatment, with more disease progression during that time. However, at 6 months, the OS curves crossed over to become consistently superior for the immunotherapy regimen thereafter.
Platinum-based chemotherapy is thought to augment antitumor immunity by inducing immunogenic cell death, increasing tumor neoantigen expression, and disturbing the immunosuppressive tumor microenvironment that prevents immune detection.
Therefore, CheckMate 9LA incorporated a short exposure to chemotherapy for the patients receiving nivolumab-ipilimumab in an effort to attain rapid disease control and retain the durable OS benefit that was seen with dual immunotherapy in CheckMate 227.
Indeed, in CheckMate 9LA, the Kaplan-Meier curves in both the initial and follow-up OS analyses diverged early in favor of the nivolumab-ipilimumab plus chemotherapy regimen and never crossed the curve for chemotherapy alone. Progressive disease was observed in fewer patients with the immunotherapy combination than with chemotherapy alone.
Longer follow-up needed
In recent years, a large number of treatment options for stage IV NSCLC patients have emerged. In the current report of CheckMate 9LA, the OS curve extended only to 27 months.
As was noted by invited discussant Benjamin Levy, MD, of Johns Hopkins University in Baltimore, it may be premature to put the regimen of two cycles of chemotherapy plus dual checkpoint/CTLA4 blockade in its proper context until follow-up extends for 3-5 years.
It would be ideal to know whether the tail of the OS curve will flatten out.
Do the best you can
Clinical investigators have a responsibility to retain the successes of prior regimens while overcoming the challenges of adverse events. New regimens also need to be practical when applied in general oncology practice.
In 2014, the American poet Maya Angelou advised, “Do the best you can until you know better. Then, when you know better, do better.” In many regards, the immunotherapy-chemotherapy combination tested in CheckMate 9LA appears to do better than preceding regimens.
Further refinements in dose, schedule, and supportive care, as well as real-time reporting of and response to patient-reported outcomes, will likely help us build on the CheckMate 9LA regimen and do even better.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Reck M et al. ASCO 2020, Abstract 9501.
Data from the CheckMate 9LA study suggest the combination amplifies the rapid response expected from chemotherapy and the long-term benefit from immunotherapy. Furthermore, the very limited exposure to chemotherapy appears to mitigate long-term risks.
Martin Reck, MD, PhD, of LungenClinic Grosshansdorf in Germany, reported the data as part of the American Society of Clinical Oncology virtual scientific program (Abstract 9501).
A prior trial, CheckMate 227, demonstrated that nivolumab plus ipilimumab improved overall survival (OS) and durability of response in comparison with conventional chemotherapy in advanced NSCLC, regardless of PD-L1 expression (N Engl J Med 2019; 381:2020-31).
In CheckMate 9LA, researchers tested whether adding a limited course of chemotherapy – just two cycles – could improve outcomes further. Dr. Reck reported that, at the first preplanned interim analysis, the combination met its primary goal of improving OS as well as meeting multiple secondary endpoints.
Details of CheckMate 9LA
CheckMate 9LA included 719 treatment-naive patients with histologically confirmed stage IV or recurrent NSCLC and no known sensitizing alterations in EGFR or ALK. All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1.
Patients received either nivolumab plus ipilimumab at standard NSCLC doses plus two cycles of chemotherapy or chemotherapy alone for four cycles.
The chemotherapy regimen was tailored by histology. Pemetrexed plus either cisplatin or carboplatin, with optional pemetrexed maintenance, was administered to patients with non-squamous histology. Paclitaxel plus carboplatin was chosen for patients with squamous disease.
If there was no disease progression or unacceptable toxicity, patients receiving nivolumab plus ipilimumab could continue immunotherapy for up to 2 years.
Patients were stratified by PD-L1 expression (< 1% vs. ≥ 1%), gender, and histology (squamous vs. non-squamous). Tumor and clinical characteristics were balanced across the trial arms.
The primary endpoint was OS, with secondary endpoints of progression-free survival, objective response rate by blinded independent central review, and efficacy by PD-L1 subgroups. Exploratory endpoints included safety/tolerability.
Results prompt FDA approval
Dr. Reck and colleagues found significantly better OS with nivolumab-ipilimumab plus chemotherapy, in comparison with chemotherapy alone (hazard ratio, 0.69; P = .0006).
With longer follow-up (minimum 12.7 months), nivolumab-ipilimumab plus chemotherapy continued to provide longer OS compared with chemotherapy alone. The median OS was 15.6 months and 10.9 months, respectively (HR, 0.66).
Despite more patients receiving subsequent systemic therapy in the chemotherapy-alone arm (34% of whom eventually received an immune checkpoint inhibitor), the immunotherapy-chemotherapy arm still yielded superior OS in the overall population.
One-year OS rates were 63% in the immunotherapy arm and 47% in the chemotherapy-alone arm.
Statistically significant improvements in progression-free survival and objective response rate were seen. The median response duration was 11.3 months in the immunotherapy arm and 5.6 months in the chemotherapy-alone arm.
Benefit was consistent by all efficacy measures and in all subgroups, including by PD-L1 expression and histology.
Based on the strength of these results, in May, the Food and Drug Administration approved nivolumab plus ipilimumab and two cycles of platinum-doublet chemotherapy for the frontline treatment of patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations.
Challenges to overcome
In the forest plots for OS, the 70 patients who were 75 years of age and older had inferior survival with the combination regimen, compared with chemotherapy alone.
Grade 3-4 treatment-related toxicity was reported in 47% of patients in the immunotherapy arm and 38% of those in the chemotherapy-alone arm.
With nivolumab-ipilimumab plus chemotherapy, more adverse events were considered serious (25.4% vs. 15%). Furthermore, grade 3-4 adverse events led to a higher rate of treatment discontinuation in the immunotherapy arm than in the chemotherapy-alone arm (16% vs. 5%).
Although cross-trial comparisons are treacherous, in CheckMate 227, only 12% of patients receiving nivolumab plus ipilimumab stopped treatment because of a grade 3-4 adverse event.
Better by design
In the updated analysis of CheckMate 227 (ASCO 2020, Abstract 9500), the nivolumab-ipilimumab regimen showed inferior OS results for the first 6 months of treatment, with more disease progression during that time. However, at 6 months, the OS curves crossed over to become consistently superior for the immunotherapy regimen thereafter.
Platinum-based chemotherapy is thought to augment antitumor immunity by inducing immunogenic cell death, increasing tumor neoantigen expression, and disturbing the immunosuppressive tumor microenvironment that prevents immune detection.
Therefore, CheckMate 9LA incorporated a short exposure to chemotherapy for the patients receiving nivolumab-ipilimumab in an effort to attain rapid disease control and retain the durable OS benefit that was seen with dual immunotherapy in CheckMate 227.
Indeed, in CheckMate 9LA, the Kaplan-Meier curves in both the initial and follow-up OS analyses diverged early in favor of the nivolumab-ipilimumab plus chemotherapy regimen and never crossed the curve for chemotherapy alone. Progressive disease was observed in fewer patients with the immunotherapy combination than with chemotherapy alone.
Longer follow-up needed
In recent years, a large number of treatment options for stage IV NSCLC patients have emerged. In the current report of CheckMate 9LA, the OS curve extended only to 27 months.
As was noted by invited discussant Benjamin Levy, MD, of Johns Hopkins University in Baltimore, it may be premature to put the regimen of two cycles of chemotherapy plus dual checkpoint/CTLA4 blockade in its proper context until follow-up extends for 3-5 years.
It would be ideal to know whether the tail of the OS curve will flatten out.
Do the best you can
Clinical investigators have a responsibility to retain the successes of prior regimens while overcoming the challenges of adverse events. New regimens also need to be practical when applied in general oncology practice.
In 2014, the American poet Maya Angelou advised, “Do the best you can until you know better. Then, when you know better, do better.” In many regards, the immunotherapy-chemotherapy combination tested in CheckMate 9LA appears to do better than preceding regimens.
Further refinements in dose, schedule, and supportive care, as well as real-time reporting of and response to patient-reported outcomes, will likely help us build on the CheckMate 9LA regimen and do even better.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Reck M et al. ASCO 2020, Abstract 9501.
FROM ASCO 2020
TILs and PET-CT can predict pCR in HER2-positive metastatic breast cancer
In an update of the PREDIX-HER2 trial, trastuzumab emtansine (T-DM1) remained equivalent to standard neoadjuvant chemotherapy plus dual-targeted HER2 therapy in producing pathologic complete remissions (pCRs) among patients with HER2-positive, metastatic breast cancer.
The new data also suggest tumor-infiltrating lymphocytes (TILs) and dramatic improvements in PET-CT scans can predict favorable outcomes in both treatment groups. Though these findings will be useful for research purposes, they likely won’t influence routine clinical practice.
Thomas Hatschek, MD, PhD, of Karolinska Institutet in Stockholm, presented the updated results from PREDIX-HER2 during the European Society for Medical Oncology: Breast Cancer virtual meeting.
PREDIX-HER2 included patients with HER2-positive breast cancer and tumor size greater than 20 mm or lymph node metastases.
Patients received neoadjuvant therapy (NAT) with docetaxel and trastuzumab plus pertuzumab (DTP) or T-DM1 every 3 weeks for a planned total of six courses. The protocol permitted switching to the competing treatment for progression, lack of response, or drug-related severe toxicity.
Postoperatively, all patients received triweekly epirubicin plus cyclophosphamide – four courses for the T-DM1 arm and two courses for the DTP arm. All patients then received triweekly adjuvant trastuzumab for 11 courses. The 62% of patients whose tumors were hormone receptor (HR)–positive received standard endocrine therapy postoperatively.
Updated results, predictors of pCR
At the 2019 ASCO annual meeting, PREDIX-HER2 investigators reported that, when compared with DTP, T-DM1 produced the same likelihood of pCR with less toxicity (ASCO 2019, Abstract 501). Updated data presented at ESMO Breast Cancer 2020 showed similar results.
The pCR rate was 45.5% in the DTP arm and 43.9% in the T-DM1 arm (P = .824). pCR rates were higher for HR-negative tumors – 63.6% in the DTP arm and 59% in the T-DM1 arm – than for HR-positive tumors – 36.4% in the DTP arm and 33.9% in the TDM-1 arm.
Three patients had disease progression with T-DM1, and none progressed with DTP. However, almost twice as many patients switched from DTP to T-DM1, compared with the other sequence.
Dr. Hatschek reported that the presence of at least 10% TILs predicted pCR in both treatment groups. Among patients who achieved a pCR, 52.2% had at least 10% TILs in baseline biopsies, and 30.4% had less than 10% TILs.
In addition, a decrease of FDG maximum standardized uptake value by more than 75% on protocol-required PET-CT scans was highly predictive of pCR. Among patients who achieved a pCR, 70.3% had a maximum standardized uptake value decrease of more than 75%, and 22.5% had a decrease of 75% or less.
At median follow-up of 28.5 months, event-free survival was similar between the treatment arms. Overall, there were 13 cases of progression, relapse, contralateral breast cancer, distant metastases, or death from any cause. There were five such events in the DTP arm and eight in the TDM-1 arm.
Dr. Hatschek concluded that neoadjuvant T-DM1 may be as effective as standard NAT in all clinical subgroups evaluated. Both TILs and PET-CT showed the potential to predict pCR and merit further study in the NAT setting.
An imperfect surrogate
By definition, a surrogate is “one appointed to act in place of another.” In the case of PREDIX-HER2 and most other NAT studies in HER2-positive breast cancer patients, pCR is a surrogate for the endpoint about which doctors and patients really care – cancer-free survival.
As such, pCR is not a perfect surrogate. Reproducibly, pCR has been highly predictive of disease-free survival and overall survival, especially in the HR-negative subset of HER2-positive patients.
However, despite improvements with dual targeting of HER2 in the TRYPHAENA trial (Eur J Cancer. 2018;89:27-35) and the use of T-DM1 for patients failing to achieve pCR in the immediately practice-changing KATHERINE trial (N Engl J Med. 2019;380:617-28), eventual relapse is seen in 10%-20% of patients in various clinical-pathologic subgroups.
In PREDIX-HER2, the pCR rate for node-positive patients was considerably lower with T-DM1 than with DTP (54.1% vs. 38%), noted Valentina Guarneri, MD, of the University of Padova (Italy), in her discussion of the trial at ESMO Breast Cancer 2020.
Patients with larger initial tumor size and multiple involved axillary nodes at diagnosis remain at increased risk of death because of cancer relapse.
Central nervous system relapse remains a vexing problem. Among patients with triple-positive breast cancer, relapses may occur late, despite pCR.
Patients whose tumors transform from HER2 positive to HER2 negative with NAT, seen in approximately 8% of cases in the KATHERINE trial (ESMO Breast Cancer 2020, Abstract 96O), may be another poor-risk group.
Clinical implications
PREDIX-HER2 is an important study. At the early time point of 2.4 years (especially early since most patients were HR-positive), if pCR is achieved, event-free survival is excellent with T-DM1 or an aggressive multiagent cytotoxic combination plus dual HER2 targeting followed by anthracyclines.
It is ideal to have clinical-pathologic tests to distinguish those patients destined to achieve the surrogate endpoint of pCR from those who will not achieve it.
Despite linkage of TILs to improved outcome for triple-negative and HER2-enriched molecular subtypes (Lancet Oncol. 2018 Jan;19[1]:40-50), analysis of TILs is not standard practice in HER2-positive breast cancer in community settings. Optimal cutoffs are not well established, and TILs have not been linked to the choice of particular treatment options.
Currently, PET-CT scans are not part of National Comprehensive Cancer Network guidelines for pretreatment evaluation, except in patients for whom there is clinical suspicion of distant disease.
For those reasons, the main results of PREDIX-HER2 remain research tools that will focus our attention on the clinical-pathologic correlations Dr. Hatschek highlighted, but the results should have no influence on routine clinical practice at this time.
PREDIX-HER2 was funded by the Swedish Cancer Society, Radiumhemmet of Karolinska Institutet, Region Stockholm, and Roche Sweden. Dr. Hatschek disclosed relationships with Roche Sweden, Pfizer Sweden, and Pierre Fabre Sweden. Dr. Guarneri disclosed relationships with Roche, Novartis, and Eli Lilly.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Hatschek T et al. ESMO Breast Cancer 2020, Abstract 97O.
In an update of the PREDIX-HER2 trial, trastuzumab emtansine (T-DM1) remained equivalent to standard neoadjuvant chemotherapy plus dual-targeted HER2 therapy in producing pathologic complete remissions (pCRs) among patients with HER2-positive, metastatic breast cancer.
The new data also suggest tumor-infiltrating lymphocytes (TILs) and dramatic improvements in PET-CT scans can predict favorable outcomes in both treatment groups. Though these findings will be useful for research purposes, they likely won’t influence routine clinical practice.
Thomas Hatschek, MD, PhD, of Karolinska Institutet in Stockholm, presented the updated results from PREDIX-HER2 during the European Society for Medical Oncology: Breast Cancer virtual meeting.
PREDIX-HER2 included patients with HER2-positive breast cancer and tumor size greater than 20 mm or lymph node metastases.
Patients received neoadjuvant therapy (NAT) with docetaxel and trastuzumab plus pertuzumab (DTP) or T-DM1 every 3 weeks for a planned total of six courses. The protocol permitted switching to the competing treatment for progression, lack of response, or drug-related severe toxicity.
Postoperatively, all patients received triweekly epirubicin plus cyclophosphamide – four courses for the T-DM1 arm and two courses for the DTP arm. All patients then received triweekly adjuvant trastuzumab for 11 courses. The 62% of patients whose tumors were hormone receptor (HR)–positive received standard endocrine therapy postoperatively.
Updated results, predictors of pCR
At the 2019 ASCO annual meeting, PREDIX-HER2 investigators reported that, when compared with DTP, T-DM1 produced the same likelihood of pCR with less toxicity (ASCO 2019, Abstract 501). Updated data presented at ESMO Breast Cancer 2020 showed similar results.
The pCR rate was 45.5% in the DTP arm and 43.9% in the T-DM1 arm (P = .824). pCR rates were higher for HR-negative tumors – 63.6% in the DTP arm and 59% in the T-DM1 arm – than for HR-positive tumors – 36.4% in the DTP arm and 33.9% in the TDM-1 arm.
Three patients had disease progression with T-DM1, and none progressed with DTP. However, almost twice as many patients switched from DTP to T-DM1, compared with the other sequence.
Dr. Hatschek reported that the presence of at least 10% TILs predicted pCR in both treatment groups. Among patients who achieved a pCR, 52.2% had at least 10% TILs in baseline biopsies, and 30.4% had less than 10% TILs.
In addition, a decrease of FDG maximum standardized uptake value by more than 75% on protocol-required PET-CT scans was highly predictive of pCR. Among patients who achieved a pCR, 70.3% had a maximum standardized uptake value decrease of more than 75%, and 22.5% had a decrease of 75% or less.
At median follow-up of 28.5 months, event-free survival was similar between the treatment arms. Overall, there were 13 cases of progression, relapse, contralateral breast cancer, distant metastases, or death from any cause. There were five such events in the DTP arm and eight in the TDM-1 arm.
Dr. Hatschek concluded that neoadjuvant T-DM1 may be as effective as standard NAT in all clinical subgroups evaluated. Both TILs and PET-CT showed the potential to predict pCR and merit further study in the NAT setting.
An imperfect surrogate
By definition, a surrogate is “one appointed to act in place of another.” In the case of PREDIX-HER2 and most other NAT studies in HER2-positive breast cancer patients, pCR is a surrogate for the endpoint about which doctors and patients really care – cancer-free survival.
As such, pCR is not a perfect surrogate. Reproducibly, pCR has been highly predictive of disease-free survival and overall survival, especially in the HR-negative subset of HER2-positive patients.
However, despite improvements with dual targeting of HER2 in the TRYPHAENA trial (Eur J Cancer. 2018;89:27-35) and the use of T-DM1 for patients failing to achieve pCR in the immediately practice-changing KATHERINE trial (N Engl J Med. 2019;380:617-28), eventual relapse is seen in 10%-20% of patients in various clinical-pathologic subgroups.
In PREDIX-HER2, the pCR rate for node-positive patients was considerably lower with T-DM1 than with DTP (54.1% vs. 38%), noted Valentina Guarneri, MD, of the University of Padova (Italy), in her discussion of the trial at ESMO Breast Cancer 2020.
Patients with larger initial tumor size and multiple involved axillary nodes at diagnosis remain at increased risk of death because of cancer relapse.
Central nervous system relapse remains a vexing problem. Among patients with triple-positive breast cancer, relapses may occur late, despite pCR.
Patients whose tumors transform from HER2 positive to HER2 negative with NAT, seen in approximately 8% of cases in the KATHERINE trial (ESMO Breast Cancer 2020, Abstract 96O), may be another poor-risk group.
Clinical implications
PREDIX-HER2 is an important study. At the early time point of 2.4 years (especially early since most patients were HR-positive), if pCR is achieved, event-free survival is excellent with T-DM1 or an aggressive multiagent cytotoxic combination plus dual HER2 targeting followed by anthracyclines.
It is ideal to have clinical-pathologic tests to distinguish those patients destined to achieve the surrogate endpoint of pCR from those who will not achieve it.
Despite linkage of TILs to improved outcome for triple-negative and HER2-enriched molecular subtypes (Lancet Oncol. 2018 Jan;19[1]:40-50), analysis of TILs is not standard practice in HER2-positive breast cancer in community settings. Optimal cutoffs are not well established, and TILs have not been linked to the choice of particular treatment options.
Currently, PET-CT scans are not part of National Comprehensive Cancer Network guidelines for pretreatment evaluation, except in patients for whom there is clinical suspicion of distant disease.
For those reasons, the main results of PREDIX-HER2 remain research tools that will focus our attention on the clinical-pathologic correlations Dr. Hatschek highlighted, but the results should have no influence on routine clinical practice at this time.
PREDIX-HER2 was funded by the Swedish Cancer Society, Radiumhemmet of Karolinska Institutet, Region Stockholm, and Roche Sweden. Dr. Hatschek disclosed relationships with Roche Sweden, Pfizer Sweden, and Pierre Fabre Sweden. Dr. Guarneri disclosed relationships with Roche, Novartis, and Eli Lilly.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Hatschek T et al. ESMO Breast Cancer 2020, Abstract 97O.
In an update of the PREDIX-HER2 trial, trastuzumab emtansine (T-DM1) remained equivalent to standard neoadjuvant chemotherapy plus dual-targeted HER2 therapy in producing pathologic complete remissions (pCRs) among patients with HER2-positive, metastatic breast cancer.
The new data also suggest tumor-infiltrating lymphocytes (TILs) and dramatic improvements in PET-CT scans can predict favorable outcomes in both treatment groups. Though these findings will be useful for research purposes, they likely won’t influence routine clinical practice.
Thomas Hatschek, MD, PhD, of Karolinska Institutet in Stockholm, presented the updated results from PREDIX-HER2 during the European Society for Medical Oncology: Breast Cancer virtual meeting.
PREDIX-HER2 included patients with HER2-positive breast cancer and tumor size greater than 20 mm or lymph node metastases.
Patients received neoadjuvant therapy (NAT) with docetaxel and trastuzumab plus pertuzumab (DTP) or T-DM1 every 3 weeks for a planned total of six courses. The protocol permitted switching to the competing treatment for progression, lack of response, or drug-related severe toxicity.
Postoperatively, all patients received triweekly epirubicin plus cyclophosphamide – four courses for the T-DM1 arm and two courses for the DTP arm. All patients then received triweekly adjuvant trastuzumab for 11 courses. The 62% of patients whose tumors were hormone receptor (HR)–positive received standard endocrine therapy postoperatively.
Updated results, predictors of pCR
At the 2019 ASCO annual meeting, PREDIX-HER2 investigators reported that, when compared with DTP, T-DM1 produced the same likelihood of pCR with less toxicity (ASCO 2019, Abstract 501). Updated data presented at ESMO Breast Cancer 2020 showed similar results.
The pCR rate was 45.5% in the DTP arm and 43.9% in the T-DM1 arm (P = .824). pCR rates were higher for HR-negative tumors – 63.6% in the DTP arm and 59% in the T-DM1 arm – than for HR-positive tumors – 36.4% in the DTP arm and 33.9% in the TDM-1 arm.
Three patients had disease progression with T-DM1, and none progressed with DTP. However, almost twice as many patients switched from DTP to T-DM1, compared with the other sequence.
Dr. Hatschek reported that the presence of at least 10% TILs predicted pCR in both treatment groups. Among patients who achieved a pCR, 52.2% had at least 10% TILs in baseline biopsies, and 30.4% had less than 10% TILs.
In addition, a decrease of FDG maximum standardized uptake value by more than 75% on protocol-required PET-CT scans was highly predictive of pCR. Among patients who achieved a pCR, 70.3% had a maximum standardized uptake value decrease of more than 75%, and 22.5% had a decrease of 75% or less.
At median follow-up of 28.5 months, event-free survival was similar between the treatment arms. Overall, there were 13 cases of progression, relapse, contralateral breast cancer, distant metastases, or death from any cause. There were five such events in the DTP arm and eight in the TDM-1 arm.
Dr. Hatschek concluded that neoadjuvant T-DM1 may be as effective as standard NAT in all clinical subgroups evaluated. Both TILs and PET-CT showed the potential to predict pCR and merit further study in the NAT setting.
An imperfect surrogate
By definition, a surrogate is “one appointed to act in place of another.” In the case of PREDIX-HER2 and most other NAT studies in HER2-positive breast cancer patients, pCR is a surrogate for the endpoint about which doctors and patients really care – cancer-free survival.
As such, pCR is not a perfect surrogate. Reproducibly, pCR has been highly predictive of disease-free survival and overall survival, especially in the HR-negative subset of HER2-positive patients.
However, despite improvements with dual targeting of HER2 in the TRYPHAENA trial (Eur J Cancer. 2018;89:27-35) and the use of T-DM1 for patients failing to achieve pCR in the immediately practice-changing KATHERINE trial (N Engl J Med. 2019;380:617-28), eventual relapse is seen in 10%-20% of patients in various clinical-pathologic subgroups.
In PREDIX-HER2, the pCR rate for node-positive patients was considerably lower with T-DM1 than with DTP (54.1% vs. 38%), noted Valentina Guarneri, MD, of the University of Padova (Italy), in her discussion of the trial at ESMO Breast Cancer 2020.
Patients with larger initial tumor size and multiple involved axillary nodes at diagnosis remain at increased risk of death because of cancer relapse.
Central nervous system relapse remains a vexing problem. Among patients with triple-positive breast cancer, relapses may occur late, despite pCR.
Patients whose tumors transform from HER2 positive to HER2 negative with NAT, seen in approximately 8% of cases in the KATHERINE trial (ESMO Breast Cancer 2020, Abstract 96O), may be another poor-risk group.
Clinical implications
PREDIX-HER2 is an important study. At the early time point of 2.4 years (especially early since most patients were HR-positive), if pCR is achieved, event-free survival is excellent with T-DM1 or an aggressive multiagent cytotoxic combination plus dual HER2 targeting followed by anthracyclines.
It is ideal to have clinical-pathologic tests to distinguish those patients destined to achieve the surrogate endpoint of pCR from those who will not achieve it.
Despite linkage of TILs to improved outcome for triple-negative and HER2-enriched molecular subtypes (Lancet Oncol. 2018 Jan;19[1]:40-50), analysis of TILs is not standard practice in HER2-positive breast cancer in community settings. Optimal cutoffs are not well established, and TILs have not been linked to the choice of particular treatment options.
Currently, PET-CT scans are not part of National Comprehensive Cancer Network guidelines for pretreatment evaluation, except in patients for whom there is clinical suspicion of distant disease.
For those reasons, the main results of PREDIX-HER2 remain research tools that will focus our attention on the clinical-pathologic correlations Dr. Hatschek highlighted, but the results should have no influence on routine clinical practice at this time.
PREDIX-HER2 was funded by the Swedish Cancer Society, Radiumhemmet of Karolinska Institutet, Region Stockholm, and Roche Sweden. Dr. Hatschek disclosed relationships with Roche Sweden, Pfizer Sweden, and Pierre Fabre Sweden. Dr. Guarneri disclosed relationships with Roche, Novartis, and Eli Lilly.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Hatschek T et al. ESMO Breast Cancer 2020, Abstract 97O.
FROM ESMO BREAST CANCER 2020
TERAVOLT data suggest high death rate in lung cancer patients with COVID-19
Registry data suggest an “unexpectedly high” mortality rate among patients with thoracic cancers who develop COVID-19, according to a presenter at the AACR virtual meeting I.
Data from the TERAVOLT registry showed a 34.6% mortality rate among 200 patients with COVID-19 and thoracic cancer, according to Marina Chiara Garassino, MD, of Fondazione IRCCS Instituto Nazionale dei Tumor in Milan, Italy, who presented the data at the meeting in a session on cancer and COVID-19.
Cancer patients infected with COVID-19 have been reported to be at increased risk of death, but the magnitude of increase is uncertain (Lancet Oncol. 2020 Mar;21[3]:335-7; JAMA. 2020 Mar 23. doi: 10.1001/jama.2020.4683).
Patients with thoracic cancer may be particularly vulnerable because of older age, tobacco use, preexisting cardiopulmonary comorbidities, and the immunosuppressive effects of treatment.
The global TERAVOLT registry was begun in late March 2020 to provide outcome data for coronavirus infections in thoracic cancer patients specifically. It is hoped that the data collected will guide patient management and define factors influencing morbidity and mortality.
Dr. Garassino said institutions from 21 countries have joined the TERAVOLT registry thus far. Currently, about 17 new patients with thoracic cancer and laboratory confirmed or clinically suspected COVID-19 are added to the registry each week.
As of April 12, 2020, there were 200 patients included in the registry. Their median age was 68 years, and 70.5% were men. Non–small cell lung cancer was the histology in 75.5% and small-cell lung cancer in 14.5% of patients. Most patients (73.5%) had stage IV disease. Approximately 27% of patients had at least three comorbid conditions.
About 74% of patients were on current cancer treatment, with 19% on tyrosine kinase inhibitors alone, 32.7% on chemotherapy alone, 23.1% on immunotherapy alone, and 13.6% on chemotherapy plus immunotherapy.
In all, 152 patients (76.0%) were hospitalized. However, 91.2% of patients were not admitted to the ICU, either because of a shortage of equipment or institutional policy.
The most common complications were pneumonia/pneumonitis (79.6%), acute respiratory distress syndrome (26.8%), multiorgan failure (7.6%), and sepsis (5.1%).
A total of 66 patients (34.6%) died. Most deaths were attributed to COVID-19 and not the underlying cancer, Dr. Garassino said.
A univariate analysis showed no association between cancer treatment and an increased risk of hospitalization or death. However, Dr. Garassino and colleagues are collecting more data to confirm these results.
In a multivariate analysis, no factors were associated with the risk of death, although data from a larger number of patients may shed more light on that issue.
TERAVOLT will continue to collect and provide data to identify characteristics associated with severe COVID-19–related illness, to guide physicians with information applicable to patients with thoracic malignancies, tailored to individual risk.
Like the COVID-19 and Cancer Consortium and the ESMO CoCare registry, TERAVOLT represents a way for the patient care and translational science communities to share lessons from the COVID-19 pandemic.
AACR plans to help share those lessons as well, in another session on COVID-19 and cancer at the AACR virtual meeting II in June and at a conference on COVID-19 and cancer in July, according to session moderator Antoni Ribas, MD, PhD, of the University of California, Los Angeles.
Dr. Garassino disclosed relationships with AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, and other companies.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
Registry data suggest an “unexpectedly high” mortality rate among patients with thoracic cancers who develop COVID-19, according to a presenter at the AACR virtual meeting I.
Data from the TERAVOLT registry showed a 34.6% mortality rate among 200 patients with COVID-19 and thoracic cancer, according to Marina Chiara Garassino, MD, of Fondazione IRCCS Instituto Nazionale dei Tumor in Milan, Italy, who presented the data at the meeting in a session on cancer and COVID-19.
Cancer patients infected with COVID-19 have been reported to be at increased risk of death, but the magnitude of increase is uncertain (Lancet Oncol. 2020 Mar;21[3]:335-7; JAMA. 2020 Mar 23. doi: 10.1001/jama.2020.4683).
Patients with thoracic cancer may be particularly vulnerable because of older age, tobacco use, preexisting cardiopulmonary comorbidities, and the immunosuppressive effects of treatment.
The global TERAVOLT registry was begun in late March 2020 to provide outcome data for coronavirus infections in thoracic cancer patients specifically. It is hoped that the data collected will guide patient management and define factors influencing morbidity and mortality.
Dr. Garassino said institutions from 21 countries have joined the TERAVOLT registry thus far. Currently, about 17 new patients with thoracic cancer and laboratory confirmed or clinically suspected COVID-19 are added to the registry each week.
As of April 12, 2020, there were 200 patients included in the registry. Their median age was 68 years, and 70.5% were men. Non–small cell lung cancer was the histology in 75.5% and small-cell lung cancer in 14.5% of patients. Most patients (73.5%) had stage IV disease. Approximately 27% of patients had at least three comorbid conditions.
About 74% of patients were on current cancer treatment, with 19% on tyrosine kinase inhibitors alone, 32.7% on chemotherapy alone, 23.1% on immunotherapy alone, and 13.6% on chemotherapy plus immunotherapy.
In all, 152 patients (76.0%) were hospitalized. However, 91.2% of patients were not admitted to the ICU, either because of a shortage of equipment or institutional policy.
The most common complications were pneumonia/pneumonitis (79.6%), acute respiratory distress syndrome (26.8%), multiorgan failure (7.6%), and sepsis (5.1%).
A total of 66 patients (34.6%) died. Most deaths were attributed to COVID-19 and not the underlying cancer, Dr. Garassino said.
A univariate analysis showed no association between cancer treatment and an increased risk of hospitalization or death. However, Dr. Garassino and colleagues are collecting more data to confirm these results.
In a multivariate analysis, no factors were associated with the risk of death, although data from a larger number of patients may shed more light on that issue.
TERAVOLT will continue to collect and provide data to identify characteristics associated with severe COVID-19–related illness, to guide physicians with information applicable to patients with thoracic malignancies, tailored to individual risk.
Like the COVID-19 and Cancer Consortium and the ESMO CoCare registry, TERAVOLT represents a way for the patient care and translational science communities to share lessons from the COVID-19 pandemic.
AACR plans to help share those lessons as well, in another session on COVID-19 and cancer at the AACR virtual meeting II in June and at a conference on COVID-19 and cancer in July, according to session moderator Antoni Ribas, MD, PhD, of the University of California, Los Angeles.
Dr. Garassino disclosed relationships with AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, and other companies.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
Registry data suggest an “unexpectedly high” mortality rate among patients with thoracic cancers who develop COVID-19, according to a presenter at the AACR virtual meeting I.
Data from the TERAVOLT registry showed a 34.6% mortality rate among 200 patients with COVID-19 and thoracic cancer, according to Marina Chiara Garassino, MD, of Fondazione IRCCS Instituto Nazionale dei Tumor in Milan, Italy, who presented the data at the meeting in a session on cancer and COVID-19.
Cancer patients infected with COVID-19 have been reported to be at increased risk of death, but the magnitude of increase is uncertain (Lancet Oncol. 2020 Mar;21[3]:335-7; JAMA. 2020 Mar 23. doi: 10.1001/jama.2020.4683).
Patients with thoracic cancer may be particularly vulnerable because of older age, tobacco use, preexisting cardiopulmonary comorbidities, and the immunosuppressive effects of treatment.
The global TERAVOLT registry was begun in late March 2020 to provide outcome data for coronavirus infections in thoracic cancer patients specifically. It is hoped that the data collected will guide patient management and define factors influencing morbidity and mortality.
Dr. Garassino said institutions from 21 countries have joined the TERAVOLT registry thus far. Currently, about 17 new patients with thoracic cancer and laboratory confirmed or clinically suspected COVID-19 are added to the registry each week.
As of April 12, 2020, there were 200 patients included in the registry. Their median age was 68 years, and 70.5% were men. Non–small cell lung cancer was the histology in 75.5% and small-cell lung cancer in 14.5% of patients. Most patients (73.5%) had stage IV disease. Approximately 27% of patients had at least three comorbid conditions.
About 74% of patients were on current cancer treatment, with 19% on tyrosine kinase inhibitors alone, 32.7% on chemotherapy alone, 23.1% on immunotherapy alone, and 13.6% on chemotherapy plus immunotherapy.
In all, 152 patients (76.0%) were hospitalized. However, 91.2% of patients were not admitted to the ICU, either because of a shortage of equipment or institutional policy.
The most common complications were pneumonia/pneumonitis (79.6%), acute respiratory distress syndrome (26.8%), multiorgan failure (7.6%), and sepsis (5.1%).
A total of 66 patients (34.6%) died. Most deaths were attributed to COVID-19 and not the underlying cancer, Dr. Garassino said.
A univariate analysis showed no association between cancer treatment and an increased risk of hospitalization or death. However, Dr. Garassino and colleagues are collecting more data to confirm these results.
In a multivariate analysis, no factors were associated with the risk of death, although data from a larger number of patients may shed more light on that issue.
TERAVOLT will continue to collect and provide data to identify characteristics associated with severe COVID-19–related illness, to guide physicians with information applicable to patients with thoracic malignancies, tailored to individual risk.
Like the COVID-19 and Cancer Consortium and the ESMO CoCare registry, TERAVOLT represents a way for the patient care and translational science communities to share lessons from the COVID-19 pandemic.
AACR plans to help share those lessons as well, in another session on COVID-19 and cancer at the AACR virtual meeting II in June and at a conference on COVID-19 and cancer in July, according to session moderator Antoni Ribas, MD, PhD, of the University of California, Los Angeles.
Dr. Garassino disclosed relationships with AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, and other companies.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
FROM AACR 2020
ESMO gets creative with guidelines for breast cancer care in the COVID-19 era
Like other agencies, the European Society for Medical Oncology has developed guidelines for managing breast cancer patients during the COVID-19 pandemic, recommending when care should be prioritized, delayed, or modified.
ESMO’s breast cancer guidelines expand upon guidelines issued by other groups, addressing a broad spectrum of patient profiles and providing a creative array of treatment options in COVID-19–era clinical practice.
As with ESMO’s other disease-focused COVID-19 guidelines, the breast cancer guidelines are organized by priority levels – high, medium, and low – which are applied to several domains of diagnosis and treatment.
High-priority recommendations apply to patients whose condition is either clinically unstable or whose cancer burden is immediately life-threatening.
Medium-priority recommendations apply to patients for whom delaying care beyond 6 weeks would probably lower the likelihood of a significant benefit from the intervention.
Low-priority recommendations apply to patients for whom services can be delayed for the duration of the COVID-19 pandemic.
Personalized care and high-priority situations
ESMO’s guidelines suggest that multidisciplinary tumor boards should guide decisions about the urgency of care for individual patients, given the complexity of breast cancer biology, the multiplicity of evidence-based treatments, and the possibility of cure or durable high-quality remissions.
The guidelines deliver a clear message that prepandemic discussions about delivering personalized care are even more important now.
ESMO prioritizes investigating high-risk screening mammography results (i.e., BIRADS 5), lumps noted on breast self-examination, clinical evidence of local-regional recurrence, and breast cancer in pregnant women.
Making these scenarios “high priority” will facilitate the best long-term outcomes in time-sensitive scenarios and improve patient satisfaction with care.
Modifications to consider
ESMO provides explicit options for treatment of common breast cancer profiles in which short-term modifications of standard management strategies can safely be considered. Given the generally long natural history of most breast cancer subtypes, these temporary modifications are unlikely to compromise long-term outcomes.
For patients with a new diagnosis of localized breast cancer, the guidelines recommend neoadjuvant chemotherapy, targeted therapy, or hormonal therapy to achieve optimal breast cancer outcomes and safely delay surgery or radiotherapy.
In the metastatic setting, ESMO advises providers to consider:
- Symptom-oriented testing, recognizing the arguable benefit of frequent imaging or serum tumor marker measurement (J Clin Oncol. 2016 Aug 20;34[24]:2820-6).
- Drug holidays, de-escalated maintenance therapy, and protracted schedules of bone-modifying agents.
- Avoiding mTOR and PI3KCA inhibitors as an addition to standard hormonal therapy because of pneumonitis, hyperglycemia, and immunosuppression risks. The guidelines suggest careful thought about adding CDK4/6 inhibitors to standard hormonal therapy because of the added burden of remote safety monitoring with the biologic agents.
ESMO makes suggestions about trimming the duration of adjuvant trastuzumab to 6 months, as in the PERSEPHONE study (Lancet. 2019 Jun 29;393[10191]:2599-612), and modifying the schedule of luteinizing hormone–releasing hormone agonist administration, in an effort to reduce patient exposure to health care personnel (and vice versa).
The guidelines recommend continuing clinical trials if benefits to patients outweigh risks and trials can be modified to enhance patient safety while preserving study endpoint evaluations.
Lower-priority situations
ESMO pointedly assigns a low priority to follow-up of patients who are at high risk of relapse but lack signs or symptoms of relapse.
Like other groups, ESMO recommends that patients with equivocal (i.e., BIRADS 3) screening mammograms should have 6-month follow-up imaging in preference to immediate core needle biopsy of the area(s) of concern.
ESMO uses age to assign priority for postponing adjuvant breast radiation in patients with low- to moderate-risk lesions. However, the guidelines stop surprisingly short of recommending that adjuvant radiation be withheld for older patients with low-risk, stage I, hormonally sensitive, HER2-negative breast cancers who receive endocrine therapy.
Bottom line
The pragmatic adjustments ESMO suggests address the challenges of evaluating and treating breast cancer patients during the COVID-19 pandemic. The guidelines protect each patient’s right to care and safety as well as protecting the safety of caregivers.
The guidelines will likely heighten patients’ satisfaction with care and decrease concern about adequacy of timely evaluation and treatment.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
Like other agencies, the European Society for Medical Oncology has developed guidelines for managing breast cancer patients during the COVID-19 pandemic, recommending when care should be prioritized, delayed, or modified.
ESMO’s breast cancer guidelines expand upon guidelines issued by other groups, addressing a broad spectrum of patient profiles and providing a creative array of treatment options in COVID-19–era clinical practice.
As with ESMO’s other disease-focused COVID-19 guidelines, the breast cancer guidelines are organized by priority levels – high, medium, and low – which are applied to several domains of diagnosis and treatment.
High-priority recommendations apply to patients whose condition is either clinically unstable or whose cancer burden is immediately life-threatening.
Medium-priority recommendations apply to patients for whom delaying care beyond 6 weeks would probably lower the likelihood of a significant benefit from the intervention.
Low-priority recommendations apply to patients for whom services can be delayed for the duration of the COVID-19 pandemic.
Personalized care and high-priority situations
ESMO’s guidelines suggest that multidisciplinary tumor boards should guide decisions about the urgency of care for individual patients, given the complexity of breast cancer biology, the multiplicity of evidence-based treatments, and the possibility of cure or durable high-quality remissions.
The guidelines deliver a clear message that prepandemic discussions about delivering personalized care are even more important now.
ESMO prioritizes investigating high-risk screening mammography results (i.e., BIRADS 5), lumps noted on breast self-examination, clinical evidence of local-regional recurrence, and breast cancer in pregnant women.
Making these scenarios “high priority” will facilitate the best long-term outcomes in time-sensitive scenarios and improve patient satisfaction with care.
Modifications to consider
ESMO provides explicit options for treatment of common breast cancer profiles in which short-term modifications of standard management strategies can safely be considered. Given the generally long natural history of most breast cancer subtypes, these temporary modifications are unlikely to compromise long-term outcomes.
For patients with a new diagnosis of localized breast cancer, the guidelines recommend neoadjuvant chemotherapy, targeted therapy, or hormonal therapy to achieve optimal breast cancer outcomes and safely delay surgery or radiotherapy.
In the metastatic setting, ESMO advises providers to consider:
- Symptom-oriented testing, recognizing the arguable benefit of frequent imaging or serum tumor marker measurement (J Clin Oncol. 2016 Aug 20;34[24]:2820-6).
- Drug holidays, de-escalated maintenance therapy, and protracted schedules of bone-modifying agents.
- Avoiding mTOR and PI3KCA inhibitors as an addition to standard hormonal therapy because of pneumonitis, hyperglycemia, and immunosuppression risks. The guidelines suggest careful thought about adding CDK4/6 inhibitors to standard hormonal therapy because of the added burden of remote safety monitoring with the biologic agents.
ESMO makes suggestions about trimming the duration of adjuvant trastuzumab to 6 months, as in the PERSEPHONE study (Lancet. 2019 Jun 29;393[10191]:2599-612), and modifying the schedule of luteinizing hormone–releasing hormone agonist administration, in an effort to reduce patient exposure to health care personnel (and vice versa).
The guidelines recommend continuing clinical trials if benefits to patients outweigh risks and trials can be modified to enhance patient safety while preserving study endpoint evaluations.
Lower-priority situations
ESMO pointedly assigns a low priority to follow-up of patients who are at high risk of relapse but lack signs or symptoms of relapse.
Like other groups, ESMO recommends that patients with equivocal (i.e., BIRADS 3) screening mammograms should have 6-month follow-up imaging in preference to immediate core needle biopsy of the area(s) of concern.
ESMO uses age to assign priority for postponing adjuvant breast radiation in patients with low- to moderate-risk lesions. However, the guidelines stop surprisingly short of recommending that adjuvant radiation be withheld for older patients with low-risk, stage I, hormonally sensitive, HER2-negative breast cancers who receive endocrine therapy.
Bottom line
The pragmatic adjustments ESMO suggests address the challenges of evaluating and treating breast cancer patients during the COVID-19 pandemic. The guidelines protect each patient’s right to care and safety as well as protecting the safety of caregivers.
The guidelines will likely heighten patients’ satisfaction with care and decrease concern about adequacy of timely evaluation and treatment.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
Like other agencies, the European Society for Medical Oncology has developed guidelines for managing breast cancer patients during the COVID-19 pandemic, recommending when care should be prioritized, delayed, or modified.
ESMO’s breast cancer guidelines expand upon guidelines issued by other groups, addressing a broad spectrum of patient profiles and providing a creative array of treatment options in COVID-19–era clinical practice.
As with ESMO’s other disease-focused COVID-19 guidelines, the breast cancer guidelines are organized by priority levels – high, medium, and low – which are applied to several domains of diagnosis and treatment.
High-priority recommendations apply to patients whose condition is either clinically unstable or whose cancer burden is immediately life-threatening.
Medium-priority recommendations apply to patients for whom delaying care beyond 6 weeks would probably lower the likelihood of a significant benefit from the intervention.
Low-priority recommendations apply to patients for whom services can be delayed for the duration of the COVID-19 pandemic.
Personalized care and high-priority situations
ESMO’s guidelines suggest that multidisciplinary tumor boards should guide decisions about the urgency of care for individual patients, given the complexity of breast cancer biology, the multiplicity of evidence-based treatments, and the possibility of cure or durable high-quality remissions.
The guidelines deliver a clear message that prepandemic discussions about delivering personalized care are even more important now.
ESMO prioritizes investigating high-risk screening mammography results (i.e., BIRADS 5), lumps noted on breast self-examination, clinical evidence of local-regional recurrence, and breast cancer in pregnant women.
Making these scenarios “high priority” will facilitate the best long-term outcomes in time-sensitive scenarios and improve patient satisfaction with care.
Modifications to consider
ESMO provides explicit options for treatment of common breast cancer profiles in which short-term modifications of standard management strategies can safely be considered. Given the generally long natural history of most breast cancer subtypes, these temporary modifications are unlikely to compromise long-term outcomes.
For patients with a new diagnosis of localized breast cancer, the guidelines recommend neoadjuvant chemotherapy, targeted therapy, or hormonal therapy to achieve optimal breast cancer outcomes and safely delay surgery or radiotherapy.
In the metastatic setting, ESMO advises providers to consider:
- Symptom-oriented testing, recognizing the arguable benefit of frequent imaging or serum tumor marker measurement (J Clin Oncol. 2016 Aug 20;34[24]:2820-6).
- Drug holidays, de-escalated maintenance therapy, and protracted schedules of bone-modifying agents.
- Avoiding mTOR and PI3KCA inhibitors as an addition to standard hormonal therapy because of pneumonitis, hyperglycemia, and immunosuppression risks. The guidelines suggest careful thought about adding CDK4/6 inhibitors to standard hormonal therapy because of the added burden of remote safety monitoring with the biologic agents.
ESMO makes suggestions about trimming the duration of adjuvant trastuzumab to 6 months, as in the PERSEPHONE study (Lancet. 2019 Jun 29;393[10191]:2599-612), and modifying the schedule of luteinizing hormone–releasing hormone agonist administration, in an effort to reduce patient exposure to health care personnel (and vice versa).
The guidelines recommend continuing clinical trials if benefits to patients outweigh risks and trials can be modified to enhance patient safety while preserving study endpoint evaluations.
Lower-priority situations
ESMO pointedly assigns a low priority to follow-up of patients who are at high risk of relapse but lack signs or symptoms of relapse.
Like other groups, ESMO recommends that patients with equivocal (i.e., BIRADS 3) screening mammograms should have 6-month follow-up imaging in preference to immediate core needle biopsy of the area(s) of concern.
ESMO uses age to assign priority for postponing adjuvant breast radiation in patients with low- to moderate-risk lesions. However, the guidelines stop surprisingly short of recommending that adjuvant radiation be withheld for older patients with low-risk, stage I, hormonally sensitive, HER2-negative breast cancers who receive endocrine therapy.
Bottom line
The pragmatic adjustments ESMO suggests address the challenges of evaluating and treating breast cancer patients during the COVID-19 pandemic. The guidelines protect each patient’s right to care and safety as well as protecting the safety of caregivers.
The guidelines will likely heighten patients’ satisfaction with care and decrease concern about adequacy of timely evaluation and treatment.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
ESMO provides road map for lung cancer care in the COVID-19 era
The European Society for Medical Oncology (ESMO) has issued guidelines that provide a practical road map for managing lung cancer patients during the COVID-19 pandemic, but the guidelines don’t address some issues that may affect U.S. physicians.
ESMO’s lung cancer guidelines provide specific details on when to prioritize and when to delay care. However, the guidelines don’t provide recommendations for managing patients who cannot participate in telemedicine or patients who have seen their clinical trial halted because of the pandemic, two situations that may be familiar to U.S. physicians.
Prioritization
As with ESMO’s other disease-focused COVID-19 guidelines, the lung cancer guidelines are organized into three priority levels – high, medium, and low – which are applied to several domains of diagnosis and treatment.
High-priority recommendations apply to patients whose condition is either clinically unstable or whose cancer burden is immediately life-threatening. Medium-priority recommendations apply to patients in noncritical situations for whom delaying care beyond 6 weeks would likely lower the chance of a significant benefit from the intervention. Low-priority recommendations apply to patients whose condition is stable enough that services can be delayed for the duration of the COVID-19 pandemic.
ESMO applied the high-, medium-, and low-prioritization schema to clinically distinct domains of lung cancer management, including outpatient visits; imaging; surgical treatment and diagnostic intervention; radiation therapy; and medical oncology treatment of early, locally advanced, or metastatic lung cancer.
As an example, a high-priority outpatient visit would be a visit for a patient with a new diagnosis of lung cancer and disease-related symptoms, suspicion of advanced disease or small cell cancer, or a visit for treatment administration. Low-priority visits would be survivorship visits, follow-up for a patient with low or intermediate relapse risk, or a visit for psychological support alone. For each diagnostic and therapeutic domain, there are similarly explicit examples.
Strengths of the guidelines
Because of small cell lung cancer’s usually aggressive behavior, ESMO’s recommendations appropriately give high priority to the diagnosis and treatment of small cell lung cancer.
Regarding imaging of pulmonary nodules, ESMO’s guidelines are fairly faithful to the Fleischner Society’s 2017 recommendations (Radiographics. 2018 Sep-Oct;38[5]:1337-50).
Most importantly, ESMO urges oncologists to adjust their routines by amplifying telemedicine services, reducing clinic visits, delaying adjuvant radiation therapy, switching to oral therapies when possible, and taking minor liberties with the schedule and duration of immune-targeted therapy.
The guidelines contain advice on supportive therapies, particularly regarding more liberal use of myeloid growth factors for patients on cytotoxic chemotherapy and postponement of antiresorptive therapy when it is not needed urgently.
Unaddressed issues
ESMO’s guidelines do not suggest more liberal use of immune-targeted therapy alone for specific patient profiles, nor do the guidelines provide tips for enhancing mental and physical health of patients during this stressful time.
The guidelines put primacy on “patient safety.” However, Narjust Duma, MD, of the University of Wisconsin–Madison, noted that there may be other equally important considerations. The patient’s comfort level about management recommendations and the safety of family members are vital, especially those who are older or immunocompromised.
Dr. Duma also noted that access to care is an issue specific to the United States that is not specifically addressed in the ESMO guidelines.
Dr. Duma estimated that as many as 30%-40% of patients with lung cancer may have no access to the Internet, a smartphone, or the ability to set up a telemedicine encounter. A patient’s lack of health insurance, transportation, and shelter will also have a direct impact on a provider’s ability to implement the ESMO guidance.
In addition, ESMO’s lung cancer guidelines do not specifically address accrual of patients to research studies during the pandemic. In the United States, many institutions have decided to suspend recruitment of patients to clinical trials, and many developing studies have been put on hold.
Lung cancer management today
The COVID-19 pandemic poses unique challenges to cancer patient care, since cancer patients are at high risk of COVID-19-related mortality, but they also have a high risk of cancer progression and its associated morbidity and mortality. In an analysis of 355 Italian patients who died from COVID-19, 20% had active cancer (JAMA. 2020 Mar 23. doi: 10.1001/jama.2020.4683).
Patients with lung cancer may be particularly vulnerable to death from coronavirus infection caused by older age, comorbid conditions, and the frequent requirement for multiple modalities of treatment, including cytotoxic therapy. In China, among 18 patients with cancer and coronavirus infection, 28% had lung cancer, and those patients had a high risk of requiring ICU-level care (Lancet Oncol. 2020 Mar;21[3]:335-7).
Bearing these data in mind, even the most mundane aspects of lung cancer diagnosis, treatment, and follow-up require careful risk-benefit analysis before application to individual patients.
There are always gray areas, particularly in quantifying the risk of relapse or infection for individual patients. However, the articulation of the ESMO guidelines into the chosen domains should make them easy to apply in routine practice for many patients.
The holistic approach the ESMO guidelines promote has never been more critical than during the pandemic, nor more aptly applied than to patients with lung cancer.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest. Dr. Duma disclosed relationships with AstraZeneca and Inivata.
The European Society for Medical Oncology (ESMO) has issued guidelines that provide a practical road map for managing lung cancer patients during the COVID-19 pandemic, but the guidelines don’t address some issues that may affect U.S. physicians.
ESMO’s lung cancer guidelines provide specific details on when to prioritize and when to delay care. However, the guidelines don’t provide recommendations for managing patients who cannot participate in telemedicine or patients who have seen their clinical trial halted because of the pandemic, two situations that may be familiar to U.S. physicians.
Prioritization
As with ESMO’s other disease-focused COVID-19 guidelines, the lung cancer guidelines are organized into three priority levels – high, medium, and low – which are applied to several domains of diagnosis and treatment.
High-priority recommendations apply to patients whose condition is either clinically unstable or whose cancer burden is immediately life-threatening. Medium-priority recommendations apply to patients in noncritical situations for whom delaying care beyond 6 weeks would likely lower the chance of a significant benefit from the intervention. Low-priority recommendations apply to patients whose condition is stable enough that services can be delayed for the duration of the COVID-19 pandemic.
ESMO applied the high-, medium-, and low-prioritization schema to clinically distinct domains of lung cancer management, including outpatient visits; imaging; surgical treatment and diagnostic intervention; radiation therapy; and medical oncology treatment of early, locally advanced, or metastatic lung cancer.
As an example, a high-priority outpatient visit would be a visit for a patient with a new diagnosis of lung cancer and disease-related symptoms, suspicion of advanced disease or small cell cancer, or a visit for treatment administration. Low-priority visits would be survivorship visits, follow-up for a patient with low or intermediate relapse risk, or a visit for psychological support alone. For each diagnostic and therapeutic domain, there are similarly explicit examples.
Strengths of the guidelines
Because of small cell lung cancer’s usually aggressive behavior, ESMO’s recommendations appropriately give high priority to the diagnosis and treatment of small cell lung cancer.
Regarding imaging of pulmonary nodules, ESMO’s guidelines are fairly faithful to the Fleischner Society’s 2017 recommendations (Radiographics. 2018 Sep-Oct;38[5]:1337-50).
Most importantly, ESMO urges oncologists to adjust their routines by amplifying telemedicine services, reducing clinic visits, delaying adjuvant radiation therapy, switching to oral therapies when possible, and taking minor liberties with the schedule and duration of immune-targeted therapy.
The guidelines contain advice on supportive therapies, particularly regarding more liberal use of myeloid growth factors for patients on cytotoxic chemotherapy and postponement of antiresorptive therapy when it is not needed urgently.
Unaddressed issues
ESMO’s guidelines do not suggest more liberal use of immune-targeted therapy alone for specific patient profiles, nor do the guidelines provide tips for enhancing mental and physical health of patients during this stressful time.
The guidelines put primacy on “patient safety.” However, Narjust Duma, MD, of the University of Wisconsin–Madison, noted that there may be other equally important considerations. The patient’s comfort level about management recommendations and the safety of family members are vital, especially those who are older or immunocompromised.
Dr. Duma also noted that access to care is an issue specific to the United States that is not specifically addressed in the ESMO guidelines.
Dr. Duma estimated that as many as 30%-40% of patients with lung cancer may have no access to the Internet, a smartphone, or the ability to set up a telemedicine encounter. A patient’s lack of health insurance, transportation, and shelter will also have a direct impact on a provider’s ability to implement the ESMO guidance.
In addition, ESMO’s lung cancer guidelines do not specifically address accrual of patients to research studies during the pandemic. In the United States, many institutions have decided to suspend recruitment of patients to clinical trials, and many developing studies have been put on hold.
Lung cancer management today
The COVID-19 pandemic poses unique challenges to cancer patient care, since cancer patients are at high risk of COVID-19-related mortality, but they also have a high risk of cancer progression and its associated morbidity and mortality. In an analysis of 355 Italian patients who died from COVID-19, 20% had active cancer (JAMA. 2020 Mar 23. doi: 10.1001/jama.2020.4683).
Patients with lung cancer may be particularly vulnerable to death from coronavirus infection caused by older age, comorbid conditions, and the frequent requirement for multiple modalities of treatment, including cytotoxic therapy. In China, among 18 patients with cancer and coronavirus infection, 28% had lung cancer, and those patients had a high risk of requiring ICU-level care (Lancet Oncol. 2020 Mar;21[3]:335-7).
Bearing these data in mind, even the most mundane aspects of lung cancer diagnosis, treatment, and follow-up require careful risk-benefit analysis before application to individual patients.
There are always gray areas, particularly in quantifying the risk of relapse or infection for individual patients. However, the articulation of the ESMO guidelines into the chosen domains should make them easy to apply in routine practice for many patients.
The holistic approach the ESMO guidelines promote has never been more critical than during the pandemic, nor more aptly applied than to patients with lung cancer.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest. Dr. Duma disclosed relationships with AstraZeneca and Inivata.
The European Society for Medical Oncology (ESMO) has issued guidelines that provide a practical road map for managing lung cancer patients during the COVID-19 pandemic, but the guidelines don’t address some issues that may affect U.S. physicians.
ESMO’s lung cancer guidelines provide specific details on when to prioritize and when to delay care. However, the guidelines don’t provide recommendations for managing patients who cannot participate in telemedicine or patients who have seen their clinical trial halted because of the pandemic, two situations that may be familiar to U.S. physicians.
Prioritization
As with ESMO’s other disease-focused COVID-19 guidelines, the lung cancer guidelines are organized into three priority levels – high, medium, and low – which are applied to several domains of diagnosis and treatment.
High-priority recommendations apply to patients whose condition is either clinically unstable or whose cancer burden is immediately life-threatening. Medium-priority recommendations apply to patients in noncritical situations for whom delaying care beyond 6 weeks would likely lower the chance of a significant benefit from the intervention. Low-priority recommendations apply to patients whose condition is stable enough that services can be delayed for the duration of the COVID-19 pandemic.
ESMO applied the high-, medium-, and low-prioritization schema to clinically distinct domains of lung cancer management, including outpatient visits; imaging; surgical treatment and diagnostic intervention; radiation therapy; and medical oncology treatment of early, locally advanced, or metastatic lung cancer.
As an example, a high-priority outpatient visit would be a visit for a patient with a new diagnosis of lung cancer and disease-related symptoms, suspicion of advanced disease or small cell cancer, or a visit for treatment administration. Low-priority visits would be survivorship visits, follow-up for a patient with low or intermediate relapse risk, or a visit for psychological support alone. For each diagnostic and therapeutic domain, there are similarly explicit examples.
Strengths of the guidelines
Because of small cell lung cancer’s usually aggressive behavior, ESMO’s recommendations appropriately give high priority to the diagnosis and treatment of small cell lung cancer.
Regarding imaging of pulmonary nodules, ESMO’s guidelines are fairly faithful to the Fleischner Society’s 2017 recommendations (Radiographics. 2018 Sep-Oct;38[5]:1337-50).
Most importantly, ESMO urges oncologists to adjust their routines by amplifying telemedicine services, reducing clinic visits, delaying adjuvant radiation therapy, switching to oral therapies when possible, and taking minor liberties with the schedule and duration of immune-targeted therapy.
The guidelines contain advice on supportive therapies, particularly regarding more liberal use of myeloid growth factors for patients on cytotoxic chemotherapy and postponement of antiresorptive therapy when it is not needed urgently.
Unaddressed issues
ESMO’s guidelines do not suggest more liberal use of immune-targeted therapy alone for specific patient profiles, nor do the guidelines provide tips for enhancing mental and physical health of patients during this stressful time.
The guidelines put primacy on “patient safety.” However, Narjust Duma, MD, of the University of Wisconsin–Madison, noted that there may be other equally important considerations. The patient’s comfort level about management recommendations and the safety of family members are vital, especially those who are older or immunocompromised.
Dr. Duma also noted that access to care is an issue specific to the United States that is not specifically addressed in the ESMO guidelines.
Dr. Duma estimated that as many as 30%-40% of patients with lung cancer may have no access to the Internet, a smartphone, or the ability to set up a telemedicine encounter. A patient’s lack of health insurance, transportation, and shelter will also have a direct impact on a provider’s ability to implement the ESMO guidance.
In addition, ESMO’s lung cancer guidelines do not specifically address accrual of patients to research studies during the pandemic. In the United States, many institutions have decided to suspend recruitment of patients to clinical trials, and many developing studies have been put on hold.
Lung cancer management today
The COVID-19 pandemic poses unique challenges to cancer patient care, since cancer patients are at high risk of COVID-19-related mortality, but they also have a high risk of cancer progression and its associated morbidity and mortality. In an analysis of 355 Italian patients who died from COVID-19, 20% had active cancer (JAMA. 2020 Mar 23. doi: 10.1001/jama.2020.4683).
Patients with lung cancer may be particularly vulnerable to death from coronavirus infection caused by older age, comorbid conditions, and the frequent requirement for multiple modalities of treatment, including cytotoxic therapy. In China, among 18 patients with cancer and coronavirus infection, 28% had lung cancer, and those patients had a high risk of requiring ICU-level care (Lancet Oncol. 2020 Mar;21[3]:335-7).
Bearing these data in mind, even the most mundane aspects of lung cancer diagnosis, treatment, and follow-up require careful risk-benefit analysis before application to individual patients.
There are always gray areas, particularly in quantifying the risk of relapse or infection for individual patients. However, the articulation of the ESMO guidelines into the chosen domains should make them easy to apply in routine practice for many patients.
The holistic approach the ESMO guidelines promote has never been more critical than during the pandemic, nor more aptly applied than to patients with lung cancer.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest. Dr. Duma disclosed relationships with AstraZeneca and Inivata.
Advice from the front lines: How cancer centers can cope with COVID-19
according to the medical director of a cancer care alliance in the first U.S. epicenter of the coronavirus outbreak.
Jennie R. Crews, MD, the medical director of the Seattle Cancer Care Alliance (SCCA), discussed the SCCA experience and offered advice for other cancer centers in a webinar hosted by the Association of Community Cancer Centers.
Dr. Crews highlighted the SCCA’s use of algorithms to predict which patients can be managed via telehealth and which require face-to-face visits, human resource issues that arose at SCCA, screening and testing procedures, and the importance of communication with patients, caregivers, and staff.
Communication
Dr. Crews stressed the value of clear, regular, and internally consistent staff communication in a variety of formats. SCCA sends daily email blasts to their personnel regarding policies and procedures, which are archived on the SCCA intranet site.
SCCA also holds weekly town hall meetings at which leaders respond to staff questions regarding practical matters they have encountered and future plans. Providers’ up-to-the-minute familiarity with policies and procedures enables all team members to uniformly and clearly communicate to patients and caregivers.
Dr. Crews emphasized the value of consistency and “over-communication” in projecting confidence and preparedness to patients and caregivers during an unsettling time. SCCA has developed fact sheets, posted current information on the SCCA website, and provided education during doorway screenings.
Screening and testing
All SCCA staff members are screened daily at the practice entrance so they have personal experience with the process utilized for patients. Because symptoms associated with coronavirus infection may overlap with cancer treatment–related complaints, SCCA clinicians have expanded the typical coronavirus screening questionnaire for patients on cancer treatment.
Patients with ambiguous symptoms are masked, taken to a physically separate area of the SCCA clinics, and screened further by an advanced practice provider. The patients are then triaged to either the clinic for treatment or to the emergency department for further triage and care.
Although testing processes and procedures have been modified, Dr. Crews advised codifying those policies and procedures, including notification of results and follow-up for both patients and staff. Dr. Crews also stressed the importance of clearly articulated return-to-work policies for staff who have potential exposure and/or positive test results.
At the University of Washington’s virology laboratory, they have a test turnaround time of less than 12 hours.
Planning ahead
Dr. Crews highlighted the importance of community-based surge planning, utilizing predictive models to assess inpatient capacity requirements and potential repurposing of providers.
The SCCA is prepared to close selected community sites and shift personnel to other locations if personnel needs cannot be met because of illness or quarantine. Contingency plans include specialized pharmacy services for patients requiring chemotherapy.
The SCCA has not yet experienced shortages of personal protective equipment (PPE). However, Dr. Crews said staff require detailed education regarding the use of PPE in order to safeguard the supply while providing maximal staff protection.
Helping the helpers
During the pandemic, SCCA has dealt with a variety of challenging human resource issues, including:
- Extending sick time beyond what was previously “stored” in staff members’ earned time off.
- Childcare during an extended hiatus in school and daycare schedules.
- Programs to maintain and/or restore employee wellness (including staff-centered support services, spiritual care, mindfulness exercises, and town halls).
Dr. Crews also discussed recruitment of community resources to provide meals for staff from local restaurants with restricted hours and transportation resources for staff and patients, as visitors are restricted (currently one per patient).
Managing care
Dr. Crews noted that the University of Washington had a foundational structure for a telehealth program prior to the pandemic. Their telehealth committee enabled SCCA to scale up the service quickly with their academic partners, including training modules for and certification of providers, outfitting off-site personnel with dedicated lines and hardware, and provision of personal Zoom accounts.
SCCA also devised algorithms for determining when face-to-face visits, remote management, or deferred visits are appropriate in various scenarios. The algorithms were developed by disease-specialized teams.
As a general rule, routine chemotherapy and radiation are administered on schedule. On-treatment and follow-up office visits are conducted via telehealth if possible. In some cases, initiation of chemotherapy and radiation has been delayed, and screening services have been suspended.
In response to questions about palliative care during the pandemic, Dr. Crews said SCCA has encouraged their patients to complete, review, or update their advance directives. The SCCA has not had the need to resuscitate a coronavirus-infected outpatient but has instituted policies for utilizing full PPE on any patient requiring resuscitation.
In her closing remarks, Dr. Crews stressed that the response to COVID-19 in Washington state has required an intense collaboration among colleagues, the community, and government leaders, as the actions required extended far beyond medical decision makers alone.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
according to the medical director of a cancer care alliance in the first U.S. epicenter of the coronavirus outbreak.
Jennie R. Crews, MD, the medical director of the Seattle Cancer Care Alliance (SCCA), discussed the SCCA experience and offered advice for other cancer centers in a webinar hosted by the Association of Community Cancer Centers.
Dr. Crews highlighted the SCCA’s use of algorithms to predict which patients can be managed via telehealth and which require face-to-face visits, human resource issues that arose at SCCA, screening and testing procedures, and the importance of communication with patients, caregivers, and staff.
Communication
Dr. Crews stressed the value of clear, regular, and internally consistent staff communication in a variety of formats. SCCA sends daily email blasts to their personnel regarding policies and procedures, which are archived on the SCCA intranet site.
SCCA also holds weekly town hall meetings at which leaders respond to staff questions regarding practical matters they have encountered and future plans. Providers’ up-to-the-minute familiarity with policies and procedures enables all team members to uniformly and clearly communicate to patients and caregivers.
Dr. Crews emphasized the value of consistency and “over-communication” in projecting confidence and preparedness to patients and caregivers during an unsettling time. SCCA has developed fact sheets, posted current information on the SCCA website, and provided education during doorway screenings.
Screening and testing
All SCCA staff members are screened daily at the practice entrance so they have personal experience with the process utilized for patients. Because symptoms associated with coronavirus infection may overlap with cancer treatment–related complaints, SCCA clinicians have expanded the typical coronavirus screening questionnaire for patients on cancer treatment.
Patients with ambiguous symptoms are masked, taken to a physically separate area of the SCCA clinics, and screened further by an advanced practice provider. The patients are then triaged to either the clinic for treatment or to the emergency department for further triage and care.
Although testing processes and procedures have been modified, Dr. Crews advised codifying those policies and procedures, including notification of results and follow-up for both patients and staff. Dr. Crews also stressed the importance of clearly articulated return-to-work policies for staff who have potential exposure and/or positive test results.
At the University of Washington’s virology laboratory, they have a test turnaround time of less than 12 hours.
Planning ahead
Dr. Crews highlighted the importance of community-based surge planning, utilizing predictive models to assess inpatient capacity requirements and potential repurposing of providers.
The SCCA is prepared to close selected community sites and shift personnel to other locations if personnel needs cannot be met because of illness or quarantine. Contingency plans include specialized pharmacy services for patients requiring chemotherapy.
The SCCA has not yet experienced shortages of personal protective equipment (PPE). However, Dr. Crews said staff require detailed education regarding the use of PPE in order to safeguard the supply while providing maximal staff protection.
Helping the helpers
During the pandemic, SCCA has dealt with a variety of challenging human resource issues, including:
- Extending sick time beyond what was previously “stored” in staff members’ earned time off.
- Childcare during an extended hiatus in school and daycare schedules.
- Programs to maintain and/or restore employee wellness (including staff-centered support services, spiritual care, mindfulness exercises, and town halls).
Dr. Crews also discussed recruitment of community resources to provide meals for staff from local restaurants with restricted hours and transportation resources for staff and patients, as visitors are restricted (currently one per patient).
Managing care
Dr. Crews noted that the University of Washington had a foundational structure for a telehealth program prior to the pandemic. Their telehealth committee enabled SCCA to scale up the service quickly with their academic partners, including training modules for and certification of providers, outfitting off-site personnel with dedicated lines and hardware, and provision of personal Zoom accounts.
SCCA also devised algorithms for determining when face-to-face visits, remote management, or deferred visits are appropriate in various scenarios. The algorithms were developed by disease-specialized teams.
As a general rule, routine chemotherapy and radiation are administered on schedule. On-treatment and follow-up office visits are conducted via telehealth if possible. In some cases, initiation of chemotherapy and radiation has been delayed, and screening services have been suspended.
In response to questions about palliative care during the pandemic, Dr. Crews said SCCA has encouraged their patients to complete, review, or update their advance directives. The SCCA has not had the need to resuscitate a coronavirus-infected outpatient but has instituted policies for utilizing full PPE on any patient requiring resuscitation.
In her closing remarks, Dr. Crews stressed that the response to COVID-19 in Washington state has required an intense collaboration among colleagues, the community, and government leaders, as the actions required extended far beyond medical decision makers alone.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
according to the medical director of a cancer care alliance in the first U.S. epicenter of the coronavirus outbreak.
Jennie R. Crews, MD, the medical director of the Seattle Cancer Care Alliance (SCCA), discussed the SCCA experience and offered advice for other cancer centers in a webinar hosted by the Association of Community Cancer Centers.
Dr. Crews highlighted the SCCA’s use of algorithms to predict which patients can be managed via telehealth and which require face-to-face visits, human resource issues that arose at SCCA, screening and testing procedures, and the importance of communication with patients, caregivers, and staff.
Communication
Dr. Crews stressed the value of clear, regular, and internally consistent staff communication in a variety of formats. SCCA sends daily email blasts to their personnel regarding policies and procedures, which are archived on the SCCA intranet site.
SCCA also holds weekly town hall meetings at which leaders respond to staff questions regarding practical matters they have encountered and future plans. Providers’ up-to-the-minute familiarity with policies and procedures enables all team members to uniformly and clearly communicate to patients and caregivers.
Dr. Crews emphasized the value of consistency and “over-communication” in projecting confidence and preparedness to patients and caregivers during an unsettling time. SCCA has developed fact sheets, posted current information on the SCCA website, and provided education during doorway screenings.
Screening and testing
All SCCA staff members are screened daily at the practice entrance so they have personal experience with the process utilized for patients. Because symptoms associated with coronavirus infection may overlap with cancer treatment–related complaints, SCCA clinicians have expanded the typical coronavirus screening questionnaire for patients on cancer treatment.
Patients with ambiguous symptoms are masked, taken to a physically separate area of the SCCA clinics, and screened further by an advanced practice provider. The patients are then triaged to either the clinic for treatment or to the emergency department for further triage and care.
Although testing processes and procedures have been modified, Dr. Crews advised codifying those policies and procedures, including notification of results and follow-up for both patients and staff. Dr. Crews also stressed the importance of clearly articulated return-to-work policies for staff who have potential exposure and/or positive test results.
At the University of Washington’s virology laboratory, they have a test turnaround time of less than 12 hours.
Planning ahead
Dr. Crews highlighted the importance of community-based surge planning, utilizing predictive models to assess inpatient capacity requirements and potential repurposing of providers.
The SCCA is prepared to close selected community sites and shift personnel to other locations if personnel needs cannot be met because of illness or quarantine. Contingency plans include specialized pharmacy services for patients requiring chemotherapy.
The SCCA has not yet experienced shortages of personal protective equipment (PPE). However, Dr. Crews said staff require detailed education regarding the use of PPE in order to safeguard the supply while providing maximal staff protection.
Helping the helpers
During the pandemic, SCCA has dealt with a variety of challenging human resource issues, including:
- Extending sick time beyond what was previously “stored” in staff members’ earned time off.
- Childcare during an extended hiatus in school and daycare schedules.
- Programs to maintain and/or restore employee wellness (including staff-centered support services, spiritual care, mindfulness exercises, and town halls).
Dr. Crews also discussed recruitment of community resources to provide meals for staff from local restaurants with restricted hours and transportation resources for staff and patients, as visitors are restricted (currently one per patient).
Managing care
Dr. Crews noted that the University of Washington had a foundational structure for a telehealth program prior to the pandemic. Their telehealth committee enabled SCCA to scale up the service quickly with their academic partners, including training modules for and certification of providers, outfitting off-site personnel with dedicated lines and hardware, and provision of personal Zoom accounts.
SCCA also devised algorithms for determining when face-to-face visits, remote management, or deferred visits are appropriate in various scenarios. The algorithms were developed by disease-specialized teams.
As a general rule, routine chemotherapy and radiation are administered on schedule. On-treatment and follow-up office visits are conducted via telehealth if possible. In some cases, initiation of chemotherapy and radiation has been delayed, and screening services have been suspended.
In response to questions about palliative care during the pandemic, Dr. Crews said SCCA has encouraged their patients to complete, review, or update their advance directives. The SCCA has not had the need to resuscitate a coronavirus-infected outpatient but has instituted policies for utilizing full PPE on any patient requiring resuscitation.
In her closing remarks, Dr. Crews stressed that the response to COVID-19 in Washington state has required an intense collaboration among colleagues, the community, and government leaders, as the actions required extended far beyond medical decision makers alone.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
‘Impressive’ SOLO3 results should influence practice
In this edition of “Applying research to practice,” I highlight a study suggesting olaparib is helpful in patients BRCA mutations experiencing multiple relapses of ovarian cancer.
SOLO3 was the first phase 3 trial comparing the oral PARP inhibitor olaparib (OLA; 300 mg twice daily) with physician’s choice of intravenous single-agent chemotherapy (TPC) in relapsed high-grade serous or endometroid ovarian, fallopian tube, or primary peritoneal cancer (J Clin Oncol. 2020 Feb 19. doi: 10.1200/JCO.19.02745).
The trial involved 266 BRCA-mutated patients who had received two (approximately 50%) or more lines of platinum-based TPC. All patients were required to be completely platinum sensitive (progression beyond 12 months from last platinum exposure) or partially platinum sensitive (progression within 6-12 months).
Women were randomized to receive either OLA or nonplatinum TPC (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan). After an amendment to the study in 2017, the primary endpoint was objective response rate, determined by blinded independent central review, with a variety of secondary endpoints.
Among 223 patients with measurable disease, the objective response rate was 72.2% with OLA and 51.4% with TPC (odds ratio, 2.53; P = .002). Across all patients, the median progression-free survival was significantly better with OLA (13.4 months) than with TPC (9.2 months; P = .013). Overall survival data were immature.
The superiority of OLA for the primary endpoint was maintained in multiple subgroups of patients, including those who had received only two prior lines of therapy (OR, 3.44) and those who had three or more prior lines (OR, 2.21). Time to first subsequent therapy (HR, 0.48) and time to treatment discontinuation or death (HR, 0.17) were significantly longer for OLA than for TPC.
Adverse events were consistent with the established safety profiles of OLA and chemotherapy. The most common grade 3 or higher adverse events were anemia (21.3%) with OLA and neutropenia (15.8%) and hand-foot syndrome (11.8%) with TPC.
However, median treatment durations were substantially and consistently longer for OLA than for TPC, and there were fewer treatment discontinuations because of toxicity for OLA than for TPC. At the time of data cutoff, 43 patients in the OLA group and 1 patient in the TPC cohort remained on treatment.
How these results influence practice
The results of the SOLO3 trial are clear: Treatment with OLA is a reasonable alternative to nonplatinum-containing chemotherapy for women with BRCA mutations and platinum-sensitive ovarian cancer. OLA is a “chemotherapy-free” option for these patients in the second- and later-line settings.
Less clear are the following:
- How many patients with BRCA mutations will not have already received a PARP inhibitor in the frontline maintenance setting in the future? SOLO3 required modification in the accrual target and endpoint because of challenges in patient recruitment from the entry of PARP inhibitors into routine clinical practice.
- Would OLA be superior to a carboplatin doublet rather than a nonplatinum single agent in patients with two prior relapses of platinum-sensitive ovarian cancer? Standard practice would be for patients in the second-line setting to receive a platinum doublet.
- Is extending the platinum-free interval a worthwhile objective, or would some patients prefer a finite interval of a platinum doublet over an indefinite period of treatment with OLA?
All phase 3 clinical trials have limitations since they require years to complete and the applicability of the results are challenged by intercurrent advances in treatment options and diagnostic tests.
However, overall, the results of SOLO3 are impressive and should influence clinical practice for the subset of relapsed ovarian cancer patients who would have qualified to participate in it. OLA represents an important treatment advance for a group of patients who are trying to string together remission after remission, with limited negative impact on quality of life.
Dr. Lyss was an oncologist and researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
In this edition of “Applying research to practice,” I highlight a study suggesting olaparib is helpful in patients BRCA mutations experiencing multiple relapses of ovarian cancer.
SOLO3 was the first phase 3 trial comparing the oral PARP inhibitor olaparib (OLA; 300 mg twice daily) with physician’s choice of intravenous single-agent chemotherapy (TPC) in relapsed high-grade serous or endometroid ovarian, fallopian tube, or primary peritoneal cancer (J Clin Oncol. 2020 Feb 19. doi: 10.1200/JCO.19.02745).
The trial involved 266 BRCA-mutated patients who had received two (approximately 50%) or more lines of platinum-based TPC. All patients were required to be completely platinum sensitive (progression beyond 12 months from last platinum exposure) or partially platinum sensitive (progression within 6-12 months).
Women were randomized to receive either OLA or nonplatinum TPC (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan). After an amendment to the study in 2017, the primary endpoint was objective response rate, determined by blinded independent central review, with a variety of secondary endpoints.
Among 223 patients with measurable disease, the objective response rate was 72.2% with OLA and 51.4% with TPC (odds ratio, 2.53; P = .002). Across all patients, the median progression-free survival was significantly better with OLA (13.4 months) than with TPC (9.2 months; P = .013). Overall survival data were immature.
The superiority of OLA for the primary endpoint was maintained in multiple subgroups of patients, including those who had received only two prior lines of therapy (OR, 3.44) and those who had three or more prior lines (OR, 2.21). Time to first subsequent therapy (HR, 0.48) and time to treatment discontinuation or death (HR, 0.17) were significantly longer for OLA than for TPC.
Adverse events were consistent with the established safety profiles of OLA and chemotherapy. The most common grade 3 or higher adverse events were anemia (21.3%) with OLA and neutropenia (15.8%) and hand-foot syndrome (11.8%) with TPC.
However, median treatment durations were substantially and consistently longer for OLA than for TPC, and there were fewer treatment discontinuations because of toxicity for OLA than for TPC. At the time of data cutoff, 43 patients in the OLA group and 1 patient in the TPC cohort remained on treatment.
How these results influence practice
The results of the SOLO3 trial are clear: Treatment with OLA is a reasonable alternative to nonplatinum-containing chemotherapy for women with BRCA mutations and platinum-sensitive ovarian cancer. OLA is a “chemotherapy-free” option for these patients in the second- and later-line settings.
Less clear are the following:
- How many patients with BRCA mutations will not have already received a PARP inhibitor in the frontline maintenance setting in the future? SOLO3 required modification in the accrual target and endpoint because of challenges in patient recruitment from the entry of PARP inhibitors into routine clinical practice.
- Would OLA be superior to a carboplatin doublet rather than a nonplatinum single agent in patients with two prior relapses of platinum-sensitive ovarian cancer? Standard practice would be for patients in the second-line setting to receive a platinum doublet.
- Is extending the platinum-free interval a worthwhile objective, or would some patients prefer a finite interval of a platinum doublet over an indefinite period of treatment with OLA?
All phase 3 clinical trials have limitations since they require years to complete and the applicability of the results are challenged by intercurrent advances in treatment options and diagnostic tests.
However, overall, the results of SOLO3 are impressive and should influence clinical practice for the subset of relapsed ovarian cancer patients who would have qualified to participate in it. OLA represents an important treatment advance for a group of patients who are trying to string together remission after remission, with limited negative impact on quality of life.
Dr. Lyss was an oncologist and researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
In this edition of “Applying research to practice,” I highlight a study suggesting olaparib is helpful in patients BRCA mutations experiencing multiple relapses of ovarian cancer.
SOLO3 was the first phase 3 trial comparing the oral PARP inhibitor olaparib (OLA; 300 mg twice daily) with physician’s choice of intravenous single-agent chemotherapy (TPC) in relapsed high-grade serous or endometroid ovarian, fallopian tube, or primary peritoneal cancer (J Clin Oncol. 2020 Feb 19. doi: 10.1200/JCO.19.02745).
The trial involved 266 BRCA-mutated patients who had received two (approximately 50%) or more lines of platinum-based TPC. All patients were required to be completely platinum sensitive (progression beyond 12 months from last platinum exposure) or partially platinum sensitive (progression within 6-12 months).
Women were randomized to receive either OLA or nonplatinum TPC (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan). After an amendment to the study in 2017, the primary endpoint was objective response rate, determined by blinded independent central review, with a variety of secondary endpoints.
Among 223 patients with measurable disease, the objective response rate was 72.2% with OLA and 51.4% with TPC (odds ratio, 2.53; P = .002). Across all patients, the median progression-free survival was significantly better with OLA (13.4 months) than with TPC (9.2 months; P = .013). Overall survival data were immature.
The superiority of OLA for the primary endpoint was maintained in multiple subgroups of patients, including those who had received only two prior lines of therapy (OR, 3.44) and those who had three or more prior lines (OR, 2.21). Time to first subsequent therapy (HR, 0.48) and time to treatment discontinuation or death (HR, 0.17) were significantly longer for OLA than for TPC.
Adverse events were consistent with the established safety profiles of OLA and chemotherapy. The most common grade 3 or higher adverse events were anemia (21.3%) with OLA and neutropenia (15.8%) and hand-foot syndrome (11.8%) with TPC.
However, median treatment durations were substantially and consistently longer for OLA than for TPC, and there were fewer treatment discontinuations because of toxicity for OLA than for TPC. At the time of data cutoff, 43 patients in the OLA group and 1 patient in the TPC cohort remained on treatment.
How these results influence practice
The results of the SOLO3 trial are clear: Treatment with OLA is a reasonable alternative to nonplatinum-containing chemotherapy for women with BRCA mutations and platinum-sensitive ovarian cancer. OLA is a “chemotherapy-free” option for these patients in the second- and later-line settings.
Less clear are the following:
- How many patients with BRCA mutations will not have already received a PARP inhibitor in the frontline maintenance setting in the future? SOLO3 required modification in the accrual target and endpoint because of challenges in patient recruitment from the entry of PARP inhibitors into routine clinical practice.
- Would OLA be superior to a carboplatin doublet rather than a nonplatinum single agent in patients with two prior relapses of platinum-sensitive ovarian cancer? Standard practice would be for patients in the second-line setting to receive a platinum doublet.
- Is extending the platinum-free interval a worthwhile objective, or would some patients prefer a finite interval of a platinum doublet over an indefinite period of treatment with OLA?
All phase 3 clinical trials have limitations since they require years to complete and the applicability of the results are challenged by intercurrent advances in treatment options and diagnostic tests.
However, overall, the results of SOLO3 are impressive and should influence clinical practice for the subset of relapsed ovarian cancer patients who would have qualified to participate in it. OLA represents an important treatment advance for a group of patients who are trying to string together remission after remission, with limited negative impact on quality of life.
Dr. Lyss was an oncologist and researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
Responsible use of breast cancer screening
In this edition of “Applying research to practice,” I examine a study suggesting that annual screening mammography does not reduce the risk of death from breast cancer in women aged 75 years and older. I also highlight a related editorial noting that we should optimize treatment as well as screening for breast cancer.
Regular screening mammography in women aged 50-69 years prevents 21.3 breast cancer deaths among 10,000 women over a 10-year time period (Ann Intern Med. 2016 Feb 16;164[4]:244-55). However, in the published screening trials, few participants were older than 70 years of age.
More than half of women above age 74 receive annual mammograms (Health, United States, 2018. www.cdc.gov/nchs/data/hus/hus18.pdf). And more than a third of breast cancer deaths occur in women aged 70 years or older (CA Cancer J Clin. 2016 Mar-Apr;66[2]:96-114).
Do older women benefit from annual mammography to the same extent as younger women? Is there a point at which benefit ends?
To answer these questions, Xabier García-Albéniz, MD, PhD, of Harvard Medical School in Boston, and colleagues studied 1,058,013 women enrolled in Medicare during 2000-2008 (Ann Intern Med. 2020 Feb 25. doi: 10.7326/M18-1199).
The researchers examined data on patients aged 70-84 years who had a life expectancy of at least 10 years, at least one recent mammogram, and no history of breast cancer. The team emulated a prospective trial by examining deaths over an 8-year period for women aged 70 years and older who either continued or stopped screening mammography. The researchers conducted separate analyses for women aged 70-74 years and those aged 75-84 years.
Diagnoses of breast cancer were, not surprisingly, higher in the continued-screening group, but there were no major reductions in breast cancer–related deaths.
Among women aged 70-74 years, the estimated 8-year risk for breast cancer death was reduced for women who continued screening versus those who stopped it by one death per 1,000 women (hazard ratio, 0.78). Among women aged 75-84 years, the 8-year risk reduction was 0.07 deaths per 1,000 women (HR, 1.00).
The authors concluded that continuing mammographic screening past age 75 years resulted in no material difference in cancer-specific mortality over an 8-year time period, in comparison with stopping regular screening examinations.
Considering treatment as well as screening
For a variety of reasons (ethical, economic, methodologic), it is unreasonable to expect a randomized, clinical trial examining the value of mammography in older women. An informative alternative would be a well-designed, large-scale, population-based, observational study that takes into consideration potentially confounding variables of the binary strategies of continuing screening versus stopping it.
Although the 8-year risk of breast cancer in older women is not low among screened women – 5.5% in women aged 70-74 years and 5.8% in women aged 75-84 years – and mammography remains an effective screening tool, the effect of screening on breast cancer mortality appears to decline as women age.
In the editorial that accompanies the study by Dr. García-Albéniz and colleagues, Otis Brawley, MD, of Johns Hopkins University, Baltimore, highlighted the role of inadequate, ineffective, inconvenient, or poorly tolerated treatment in older women (Ann Intern Med. 2020 Feb 25. doi: 10.7326/M20-0429).
Dr. Brawley illustrated that focusing too much on screening diverts attention from the major driver of cancer mortality in older women: suboptimal treatment. That certainly has been the case for the dramatic impact of improved lung cancer treatment on mortality, despite a statistically significant impact of screening on lung cancer mortality as well.
As with lung cancer screening, Dr. Brawley describes the goal of defining “personalized screening recommendations” in breast cancer, or screening that is targeted to the highest-risk women and those who stand a high chance of benefiting from treatment if they are diagnosed with breast cancer.
As our population ages and health care expenditures continue to rise, there can be little disagreement that responsible use of cancer diagnostics will be as vital as judicious application of treatment.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations.
In this edition of “Applying research to practice,” I examine a study suggesting that annual screening mammography does not reduce the risk of death from breast cancer in women aged 75 years and older. I also highlight a related editorial noting that we should optimize treatment as well as screening for breast cancer.
Regular screening mammography in women aged 50-69 years prevents 21.3 breast cancer deaths among 10,000 women over a 10-year time period (Ann Intern Med. 2016 Feb 16;164[4]:244-55). However, in the published screening trials, few participants were older than 70 years of age.
More than half of women above age 74 receive annual mammograms (Health, United States, 2018. www.cdc.gov/nchs/data/hus/hus18.pdf). And more than a third of breast cancer deaths occur in women aged 70 years or older (CA Cancer J Clin. 2016 Mar-Apr;66[2]:96-114).
Do older women benefit from annual mammography to the same extent as younger women? Is there a point at which benefit ends?
To answer these questions, Xabier García-Albéniz, MD, PhD, of Harvard Medical School in Boston, and colleagues studied 1,058,013 women enrolled in Medicare during 2000-2008 (Ann Intern Med. 2020 Feb 25. doi: 10.7326/M18-1199).
The researchers examined data on patients aged 70-84 years who had a life expectancy of at least 10 years, at least one recent mammogram, and no history of breast cancer. The team emulated a prospective trial by examining deaths over an 8-year period for women aged 70 years and older who either continued or stopped screening mammography. The researchers conducted separate analyses for women aged 70-74 years and those aged 75-84 years.
Diagnoses of breast cancer were, not surprisingly, higher in the continued-screening group, but there were no major reductions in breast cancer–related deaths.
Among women aged 70-74 years, the estimated 8-year risk for breast cancer death was reduced for women who continued screening versus those who stopped it by one death per 1,000 women (hazard ratio, 0.78). Among women aged 75-84 years, the 8-year risk reduction was 0.07 deaths per 1,000 women (HR, 1.00).
The authors concluded that continuing mammographic screening past age 75 years resulted in no material difference in cancer-specific mortality over an 8-year time period, in comparison with stopping regular screening examinations.
Considering treatment as well as screening
For a variety of reasons (ethical, economic, methodologic), it is unreasonable to expect a randomized, clinical trial examining the value of mammography in older women. An informative alternative would be a well-designed, large-scale, population-based, observational study that takes into consideration potentially confounding variables of the binary strategies of continuing screening versus stopping it.
Although the 8-year risk of breast cancer in older women is not low among screened women – 5.5% in women aged 70-74 years and 5.8% in women aged 75-84 years – and mammography remains an effective screening tool, the effect of screening on breast cancer mortality appears to decline as women age.
In the editorial that accompanies the study by Dr. García-Albéniz and colleagues, Otis Brawley, MD, of Johns Hopkins University, Baltimore, highlighted the role of inadequate, ineffective, inconvenient, or poorly tolerated treatment in older women (Ann Intern Med. 2020 Feb 25. doi: 10.7326/M20-0429).
Dr. Brawley illustrated that focusing too much on screening diverts attention from the major driver of cancer mortality in older women: suboptimal treatment. That certainly has been the case for the dramatic impact of improved lung cancer treatment on mortality, despite a statistically significant impact of screening on lung cancer mortality as well.
As with lung cancer screening, Dr. Brawley describes the goal of defining “personalized screening recommendations” in breast cancer, or screening that is targeted to the highest-risk women and those who stand a high chance of benefiting from treatment if they are diagnosed with breast cancer.
As our population ages and health care expenditures continue to rise, there can be little disagreement that responsible use of cancer diagnostics will be as vital as judicious application of treatment.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations.
In this edition of “Applying research to practice,” I examine a study suggesting that annual screening mammography does not reduce the risk of death from breast cancer in women aged 75 years and older. I also highlight a related editorial noting that we should optimize treatment as well as screening for breast cancer.
Regular screening mammography in women aged 50-69 years prevents 21.3 breast cancer deaths among 10,000 women over a 10-year time period (Ann Intern Med. 2016 Feb 16;164[4]:244-55). However, in the published screening trials, few participants were older than 70 years of age.
More than half of women above age 74 receive annual mammograms (Health, United States, 2018. www.cdc.gov/nchs/data/hus/hus18.pdf). And more than a third of breast cancer deaths occur in women aged 70 years or older (CA Cancer J Clin. 2016 Mar-Apr;66[2]:96-114).
Do older women benefit from annual mammography to the same extent as younger women? Is there a point at which benefit ends?
To answer these questions, Xabier García-Albéniz, MD, PhD, of Harvard Medical School in Boston, and colleagues studied 1,058,013 women enrolled in Medicare during 2000-2008 (Ann Intern Med. 2020 Feb 25. doi: 10.7326/M18-1199).
The researchers examined data on patients aged 70-84 years who had a life expectancy of at least 10 years, at least one recent mammogram, and no history of breast cancer. The team emulated a prospective trial by examining deaths over an 8-year period for women aged 70 years and older who either continued or stopped screening mammography. The researchers conducted separate analyses for women aged 70-74 years and those aged 75-84 years.
Diagnoses of breast cancer were, not surprisingly, higher in the continued-screening group, but there were no major reductions in breast cancer–related deaths.
Among women aged 70-74 years, the estimated 8-year risk for breast cancer death was reduced for women who continued screening versus those who stopped it by one death per 1,000 women (hazard ratio, 0.78). Among women aged 75-84 years, the 8-year risk reduction was 0.07 deaths per 1,000 women (HR, 1.00).
The authors concluded that continuing mammographic screening past age 75 years resulted in no material difference in cancer-specific mortality over an 8-year time period, in comparison with stopping regular screening examinations.
Considering treatment as well as screening
For a variety of reasons (ethical, economic, methodologic), it is unreasonable to expect a randomized, clinical trial examining the value of mammography in older women. An informative alternative would be a well-designed, large-scale, population-based, observational study that takes into consideration potentially confounding variables of the binary strategies of continuing screening versus stopping it.
Although the 8-year risk of breast cancer in older women is not low among screened women – 5.5% in women aged 70-74 years and 5.8% in women aged 75-84 years – and mammography remains an effective screening tool, the effect of screening on breast cancer mortality appears to decline as women age.
In the editorial that accompanies the study by Dr. García-Albéniz and colleagues, Otis Brawley, MD, of Johns Hopkins University, Baltimore, highlighted the role of inadequate, ineffective, inconvenient, or poorly tolerated treatment in older women (Ann Intern Med. 2020 Feb 25. doi: 10.7326/M20-0429).
Dr. Brawley illustrated that focusing too much on screening diverts attention from the major driver of cancer mortality in older women: suboptimal treatment. That certainly has been the case for the dramatic impact of improved lung cancer treatment on mortality, despite a statistically significant impact of screening on lung cancer mortality as well.
As with lung cancer screening, Dr. Brawley describes the goal of defining “personalized screening recommendations” in breast cancer, or screening that is targeted to the highest-risk women and those who stand a high chance of benefiting from treatment if they are diagnosed with breast cancer.
As our population ages and health care expenditures continue to rise, there can be little disagreement that responsible use of cancer diagnostics will be as vital as judicious application of treatment.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations.