AVAHO

Hemophagocytic lymphohistiocytosis (HLH) is a rare and deadly disease in which unregulated proliferation of histiocytes and T-cell infiltration takes place. It is known as a pediatric disease in which gene defects result in impaired cytotoxic NK- and T-cell function. It has been associated with autosomal recessive inheritance pattern. Without therapy, survival for these patients with active familial HLH is approximately 2 months.

Recognition of the disease has increased over the years, and as a result the diagnosis of HLH in adults also has increased. An acquired form can be triggered by viruses like Epstein-Barr virus, influenza, HIV, lymphoid malignancies, rheumatologic disorders, or immunodeficiency disorders. Survival rates for untreated HLH have been reported at < 5%.¹ Despite early recognition and adequate treatment, HLH carries an overall mortality of 50% in the initial presentation, 90% die in the first 8 weeks of treatment due to uncontrolled disease.²

Case Presentation

A 56-year-old man with no active medical issues except for a remote history of non-Hodgkin lymphoma treated with chemotherapy and splenectomy in 1990 presented to the Veterans Affairs Caribbean Healthcare System in San Juan, Puerto Rico. He was admitted to the medicine ward due to community acquired pneumonia. Three days into admission his clinical status deteriorated, and the patient was transferred to the intensive care unit (ICU) due to acute respiratory failure and sepsis secondary to worsening pneumonia. Chest imaging demonstrated rapidly progressing diffuse bilateral infiltrates. Due to the severity of the chest imaging, a diagnostic bronchoscopy was performed.

The patient’s antibiotics regimen was empirically escalated to vancomycin 1500 mg IV every 12 hours and meropenem 2 g IV every 8 hours. Despite optimization of therapy, the patient did not show clinical signs of improvement. Febrile episodes persisted, pulmonary infiltrates and hypoxemia worsened, and the patient required a neuromuscular blockade. Since the bronchoscopy was nondiagnostic and deterioration persistent, the differential diagnosis was broadened. This led to the ordering of inflammatory markers. Laboratory testing showed ferritin levels > 16,000 ng/mL, pointing to HLH as a possible diagnosis. Further workup was remarkable for triglycerides of 1234 mg/dL and a fibrinogen of 0.77 g/L. In the setting of bicytopenia and persistent fever, HLH-94 regimen was started with dexamethasone 40 mg daily and etoposide 100 mg/m². CD25 levels of 154,701 pg/mL were demonstrated as well as a decreased immunoglobulin (Ig) G levels with absent IgM and IgA. Bone marrow biopsy was consistent with hemophagocytosis. The patient eventually was extubated and sent to the oncology ward to continue chemotherapy.

Discussion

A high clinical suspicion is warranted for rapid diagnosis and treatment as HLH evolves in most cases to multiorgan failure and death. The diagnostic criteria for HLH was developed by the Histiocyte Society in 1991 and then restructured in 2004.^3,4 In the first diagnostic tool developed in 1991, diagnosis was based on 5 criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). Three additional laboratory findings were also described as part of HLH diagnosis since 2004: low or absent NK-cell-activity, hyperferritinemia of > 500 ng/dL, and high-soluble interleukin-2-receptor levels (CD25) > 2400 U/mL. Overall, 5 of 8 criteria are needed for the HLH diagnosis.

Despite the common use of these diagnostic criteria, they were developed for the pediatric population but have not been validated for adult patients.⁵ For adult patients, the HScore was developed in 2014. It has 9 variables: 3 are based on clinical findings (known underlying immunosuppression, high temperature, and organomegaly; 5 are based on laboratory values (ferritin, serum glutamic oxaloacetic transaminase, cytopenia, triglycerides, and fibrinogen levels); the last variable uses cytologic findings in the bone marrow. In the initial study, probability of having HLH ranged from < 1% with an HScore of ≤ 90% to > 99% with an HScore of ≥ 250 in noncritically ill adults.⁵ A recently published retrospective study demonstrated the diagnostic reliability of both the HLH-2004 criteria and HScore in critically ill adult patients. This study concluded that the best prediction accuracy of HLH diagnosis for a cutoff of 4 fulfilled HLH-2004 criteria had a 95.0% sensitivity and 93.6% specificity and HScore cutoff of 168 reached a 100% sensitivity and 94.1% specificity.⁶

Conclusions

HLH is a rare and deadly disease increasingly more present in adults. Our patient who initially presented with a sepsis diagnosis was suspected of having a hematologic etiology for his clinical findings due to markedly elevated ferritin levels. In our patient, the HLH-94 treatment protocol was used, yielding favorable results. Given the lack of specific scientific data backing updated protocols such as HLH-2004 and a comparatively favorable safety profile, current guidelines still recommend using the HLH-94 treatment protocol. Decreasing ferritin levels may be used in conjunction with clinical improvement to demonstrate therapeutic response. Persistence of disease despite standard treatment may warrant novel therapies, such as emapalumab or HCT. Physicians need to be wary of an HLH diagnosis as early identification and treatment may improve its otherwise grim prognosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and deadly disease in which unregulated proliferation of histiocytes and T-cell infiltration takes place. It is known as a pediatric disease in which gene defects result in impaired cytotoxic NK- and T-cell function. It has been associated with autosomal recessive inheritance pattern. Without therapy, survival for these patients with active familial HLH is approximately 2 months.

Recognition of the disease has increased over the years, and as a result the diagnosis of HLH in adults also has increased. An acquired form can be triggered by viruses like Epstein-Barr virus, influenza, HIV, lymphoid malignancies, rheumatologic disorders, or immunodeficiency disorders. Survival rates for untreated HLH have been reported at < 5%.¹ Despite early recognition and adequate treatment, HLH carries an overall mortality of 50% in the initial presentation, 90% die in the first 8 weeks of treatment due to uncontrolled disease.²

Case Presentation

A 56-year-old man with no active medical issues except for a remote history of non-Hodgkin lymphoma treated with chemotherapy and splenectomy in 1990 presented to the Veterans Affairs Caribbean Healthcare System in San Juan, Puerto Rico. He was admitted to the medicine ward due to community acquired pneumonia. Three days into admission his clinical status deteriorated, and the patient was transferred to the intensive care unit (ICU) due to acute respiratory failure and sepsis secondary to worsening pneumonia. Chest imaging demonstrated rapidly progressing diffuse bilateral infiltrates. Due to the severity of the chest imaging, a diagnostic bronchoscopy was performed.

The patient’s antibiotics regimen was empirically escalated to vancomycin 1500 mg IV every 12 hours and meropenem 2 g IV every 8 hours. Despite optimization of therapy, the patient did not show clinical signs of improvement. Febrile episodes persisted, pulmonary infiltrates and hypoxemia worsened, and the patient required a neuromuscular blockade. Since the bronchoscopy was nondiagnostic and deterioration persistent, the differential diagnosis was broadened. This led to the ordering of inflammatory markers. Laboratory testing showed ferritin levels > 16,000 ng/mL, pointing to HLH as a possible diagnosis. Further workup was remarkable for triglycerides of 1234 mg/dL and a fibrinogen of 0.77 g/L. In the setting of bicytopenia and persistent fever, HLH-94 regimen was started with dexamethasone 40 mg daily and etoposide 100 mg/m². CD25 levels of 154,701 pg/mL were demonstrated as well as a decreased immunoglobulin (Ig) G levels with absent IgM and IgA. Bone marrow biopsy was consistent with hemophagocytosis. The patient eventually was extubated and sent to the oncology ward to continue chemotherapy.

Discussion

A high clinical suspicion is warranted for rapid diagnosis and treatment as HLH evolves in most cases to multiorgan failure and death. The diagnostic criteria for HLH was developed by the Histiocyte Society in 1991 and then restructured in 2004.^3,4 In the first diagnostic tool developed in 1991, diagnosis was based on 5 criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). Three additional laboratory findings were also described as part of HLH diagnosis since 2004: low or absent NK-cell-activity, hyperferritinemia of > 500 ng/dL, and high-soluble interleukin-2-receptor levels (CD25) > 2400 U/mL. Overall, 5 of 8 criteria are needed for the HLH diagnosis.

Despite the common use of these diagnostic criteria, they were developed for the pediatric population but have not been validated for adult patients.⁵ For adult patients, the HScore was developed in 2014. It has 9 variables: 3 are based on clinical findings (known underlying immunosuppression, high temperature, and organomegaly; 5 are based on laboratory values (ferritin, serum glutamic oxaloacetic transaminase, cytopenia, triglycerides, and fibrinogen levels); the last variable uses cytologic findings in the bone marrow. In the initial study, probability of having HLH ranged from < 1% with an HScore of ≤ 90% to > 99% with an HScore of ≥ 250 in noncritically ill adults.⁵ A recently published retrospective study demonstrated the diagnostic reliability of both the HLH-2004 criteria and HScore in critically ill adult patients. This study concluded that the best prediction accuracy of HLH diagnosis for a cutoff of 4 fulfilled HLH-2004 criteria had a 95.0% sensitivity and 93.6% specificity and HScore cutoff of 168 reached a 100% sensitivity and 94.1% specificity.⁶

Conclusions

HLH is a rare and deadly disease increasingly more present in adults. Our patient who initially presented with a sepsis diagnosis was suspected of having a hematologic etiology for his clinical findings due to markedly elevated ferritin levels. In our patient, the HLH-94 treatment protocol was used, yielding favorable results. Given the lack of specific scientific data backing updated protocols such as HLH-2004 and a comparatively favorable safety profile, current guidelines still recommend using the HLH-94 treatment protocol. Decreasing ferritin levels may be used in conjunction with clinical improvement to demonstrate therapeutic response. Persistence of disease despite standard treatment may warrant novel therapies, such as emapalumab or HCT. Physicians need to be wary of an HLH diagnosis as early identification and treatment may improve its otherwise grim prognosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and deadly disease in which unregulated proliferation of histiocytes and T-cell infiltration takes place. It is known as a pediatric disease in which gene defects result in impaired cytotoxic NK- and T-cell function. It has been associated with autosomal recessive inheritance pattern. Without therapy, survival for these patients with active familial HLH is approximately 2 months.

Recognition of the disease has increased over the years, and as a result the diagnosis of HLH in adults also has increased. An acquired form can be triggered by viruses like Epstein-Barr virus, influenza, HIV, lymphoid malignancies, rheumatologic disorders, or immunodeficiency disorders. Survival rates for untreated HLH have been reported at < 5%.¹ Despite early recognition and adequate treatment, HLH carries an overall mortality of 50% in the initial presentation, 90% die in the first 8 weeks of treatment due to uncontrolled disease.²

Case Presentation

A 56-year-old man with no active medical issues except for a remote history of non-Hodgkin lymphoma treated with chemotherapy and splenectomy in 1990 presented to the Veterans Affairs Caribbean Healthcare System in San Juan, Puerto Rico. He was admitted to the medicine ward due to community acquired pneumonia. Three days into admission his clinical status deteriorated, and the patient was transferred to the intensive care unit (ICU) due to acute respiratory failure and sepsis secondary to worsening pneumonia. Chest imaging demonstrated rapidly progressing diffuse bilateral infiltrates. Due to the severity of the chest imaging, a diagnostic bronchoscopy was performed.

The patient’s antibiotics regimen was empirically escalated to vancomycin 1500 mg IV every 12 hours and meropenem 2 g IV every 8 hours. Despite optimization of therapy, the patient did not show clinical signs of improvement. Febrile episodes persisted, pulmonary infiltrates and hypoxemia worsened, and the patient required a neuromuscular blockade. Since the bronchoscopy was nondiagnostic and deterioration persistent, the differential diagnosis was broadened. This led to the ordering of inflammatory markers. Laboratory testing showed ferritin levels > 16,000 ng/mL, pointing to HLH as a possible diagnosis. Further workup was remarkable for triglycerides of 1234 mg/dL and a fibrinogen of 0.77 g/L. In the setting of bicytopenia and persistent fever, HLH-94 regimen was started with dexamethasone 40 mg daily and etoposide 100 mg/m². CD25 levels of 154,701 pg/mL were demonstrated as well as a decreased immunoglobulin (Ig) G levels with absent IgM and IgA. Bone marrow biopsy was consistent with hemophagocytosis. The patient eventually was extubated and sent to the oncology ward to continue chemotherapy.

Discussion

A high clinical suspicion is warranted for rapid diagnosis and treatment as HLH evolves in most cases to multiorgan failure and death. The diagnostic criteria for HLH was developed by the Histiocyte Society in 1991 and then restructured in 2004.^3,4 In the first diagnostic tool developed in 1991, diagnosis was based on 5 criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). Three additional laboratory findings were also described as part of HLH diagnosis since 2004: low or absent NK-cell-activity, hyperferritinemia of > 500 ng/dL, and high-soluble interleukin-2-receptor levels (CD25) > 2400 U/mL. Overall, 5 of 8 criteria are needed for the HLH diagnosis.

Despite the common use of these diagnostic criteria, they were developed for the pediatric population but have not been validated for adult patients.⁵ For adult patients, the HScore was developed in 2014. It has 9 variables: 3 are based on clinical findings (known underlying immunosuppression, high temperature, and organomegaly; 5 are based on laboratory values (ferritin, serum glutamic oxaloacetic transaminase, cytopenia, triglycerides, and fibrinogen levels); the last variable uses cytologic findings in the bone marrow. In the initial study, probability of having HLH ranged from < 1% with an HScore of ≤ 90% to > 99% with an HScore of ≥ 250 in noncritically ill adults.⁵ A recently published retrospective study demonstrated the diagnostic reliability of both the HLH-2004 criteria and HScore in critically ill adult patients. This study concluded that the best prediction accuracy of HLH diagnosis for a cutoff of 4 fulfilled HLH-2004 criteria had a 95.0% sensitivity and 93.6% specificity and HScore cutoff of 168 reached a 100% sensitivity and 94.1% specificity.⁶

Conclusions

HLH is a rare and deadly disease increasingly more present in adults. Our patient who initially presented with a sepsis diagnosis was suspected of having a hematologic etiology for his clinical findings due to markedly elevated ferritin levels. In our patient, the HLH-94 treatment protocol was used, yielding favorable results. Given the lack of specific scientific data backing updated protocols such as HLH-2004 and a comparatively favorable safety profile, current guidelines still recommend using the HLH-94 treatment protocol. Decreasing ferritin levels may be used in conjunction with clinical improvement to demonstrate therapeutic response. Persistence of disease despite standard treatment may warrant novel therapies, such as emapalumab or HCT. Physicians need to be wary of an HLH diagnosis as early identification and treatment may improve its otherwise grim prognosis.

Introduction

SMARCA4-deficient thoracic sarcomas are a rare entity, first described in 2015 in a study of 19 patients with a median age of 41 years who presented with large compressive masses with frequent infiltration into surrounding tissues [1]. This malignancy is more frequent in younger males (median 41-59 years) with an extensive smoking history and has an aggressive course with a median overall survival of 4-7 months [1-3]. There is currently no established treatment, but case reports show promise for immunotherapy and immuno- chemotherapy [4-8].

Case Report

We present the case of a 62 year old male with a 44 pack year smoking history who first presented to the emergency department (ED) with left shoulder pain in December 2020. He was initially treated with muscle relaxers but returned to the ED ten days later with hemoptysis and rapid weight loss. X-ray showed a 14.2 X 11.7 cm mass with rightward deviation of the trachea. PET scan showed extensive central necrosis with a surrounding pleural effusion and local pleural and nodal metastasis but no distant disease. He underwent thoracentesis which was negative for malignant cells. He underwent CT-guided biopsy in 1/2021, which showed predominantly discohesive small blue cells with pleomorphic cell contour and slightly plasmacytoid features. Extensive pathology review led to a diagnosis of SMARCA4 deficient thoracic sarcoma. On presentation to oncology clinic in 2/2021 his functional status had markedly deteriorated. He was started on ipilimumab/ nivolumab (ipi/nivo) and 1 week after his first cycle was admitted for severe left arm swelling and pain. Imaging showed significant progression of disease and new adrenal metastasis. He received cycle two of ipi/ nivo and was able to be discharged home on oxygen. By his follow-up appointment for cycle three of ipi/nivo in 3/2021, the patient was wheelchair bound with severe dyspnea. X-ray showed the mass now occupied the majority of the left hemi-thorax with worsening tracheal deviation. After discussion, the patient went home on hospice and died 8 days later. As demonstrated by this case, SMARCA4-deficient sarcoma requires high clinical suspicion with prompt diagnosis and treatment given its remarkably rapid progression and poor outcomes.

Introduction

SMARCA4-deficient thoracic sarcomas are a rare entity, first described in 2015 in a study of 19 patients with a median age of 41 years who presented with large compressive masses with frequent infiltration into surrounding tissues [1]. This malignancy is more frequent in younger males (median 41-59 years) with an extensive smoking history and has an aggressive course with a median overall survival of 4-7 months [1-3]. There is currently no established treatment, but case reports show promise for immunotherapy and immuno- chemotherapy [4-8].

Case Report

We present the case of a 62 year old male with a 44 pack year smoking history who first presented to the emergency department (ED) with left shoulder pain in December 2020. He was initially treated with muscle relaxers but returned to the ED ten days later with hemoptysis and rapid weight loss. X-ray showed a 14.2 X 11.7 cm mass with rightward deviation of the trachea. PET scan showed extensive central necrosis with a surrounding pleural effusion and local pleural and nodal metastasis but no distant disease. He underwent thoracentesis which was negative for malignant cells. He underwent CT-guided biopsy in 1/2021, which showed predominantly discohesive small blue cells with pleomorphic cell contour and slightly plasmacytoid features. Extensive pathology review led to a diagnosis of SMARCA4 deficient thoracic sarcoma. On presentation to oncology clinic in 2/2021 his functional status had markedly deteriorated. He was started on ipilimumab/ nivolumab (ipi/nivo) and 1 week after his first cycle was admitted for severe left arm swelling and pain. Imaging showed significant progression of disease and new adrenal metastasis. He received cycle two of ipi/ nivo and was able to be discharged home on oxygen. By his follow-up appointment for cycle three of ipi/nivo in 3/2021, the patient was wheelchair bound with severe dyspnea. X-ray showed the mass now occupied the majority of the left hemi-thorax with worsening tracheal deviation. After discussion, the patient went home on hospice and died 8 days later. As demonstrated by this case, SMARCA4-deficient sarcoma requires high clinical suspicion with prompt diagnosis and treatment given its remarkably rapid progression and poor outcomes.

Introduction

SMARCA4-deficient thoracic sarcomas are a rare entity, first described in 2015 in a study of 19 patients with a median age of 41 years who presented with large compressive masses with frequent infiltration into surrounding tissues [1]. This malignancy is more frequent in younger males (median 41-59 years) with an extensive smoking history and has an aggressive course with a median overall survival of 4-7 months [1-3]. There is currently no established treatment, but case reports show promise for immunotherapy and immuno- chemotherapy [4-8].

Case Report

We present the case of a 62 year old male with a 44 pack year smoking history who first presented to the emergency department (ED) with left shoulder pain in December 2020. He was initially treated with muscle relaxers but returned to the ED ten days later with hemoptysis and rapid weight loss. X-ray showed a 14.2 X 11.7 cm mass with rightward deviation of the trachea. PET scan showed extensive central necrosis with a surrounding pleural effusion and local pleural and nodal metastasis but no distant disease. He underwent thoracentesis which was negative for malignant cells. He underwent CT-guided biopsy in 1/2021, which showed predominantly discohesive small blue cells with pleomorphic cell contour and slightly plasmacytoid features. Extensive pathology review led to a diagnosis of SMARCA4 deficient thoracic sarcoma. On presentation to oncology clinic in 2/2021 his functional status had markedly deteriorated. He was started on ipilimumab/ nivolumab (ipi/nivo) and 1 week after his first cycle was admitted for severe left arm swelling and pain. Imaging showed significant progression of disease and new adrenal metastasis. He received cycle two of ipi/ nivo and was able to be discharged home on oxygen. By his follow-up appointment for cycle three of ipi/nivo in 3/2021, the patient was wheelchair bound with severe dyspnea. X-ray showed the mass now occupied the majority of the left hemi-thorax with worsening tracheal deviation. After discussion, the patient went home on hospice and died 8 days later. As demonstrated by this case, SMARCA4-deficient sarcoma requires high clinical suspicion with prompt diagnosis and treatment given its remarkably rapid progression and poor outcomes.

Nearly 80% of men with metastatic prostate cancer died from their malignancy, according to a retrospective cohort study involving 26,000-plus American men diagnosed with advanced disease in roughly the last 20 years.

The findings fill an information gap because, remarkably, “data are lacking” on causes of death among men whose prostate cancer has spread to other sites, say lead author Ahmed Elmehrath, MD, of Cairo University, Egypt, and colleagues.

“It was an important realization by our team that prostate cancer was the cause of death in 78% of patients,” said senior author Omar Alhalabi, MD, of University of Texas MD Anderson Cancer Center, Houston, in an email.

“Most patients with metastatic prostate cancer die from it, rather than other possible causes of death,” confirm Samuel Merriel, MSc, Tanimola Martins, PhD, and Sarah Bailey, PhD, University of Exeter, United Kingdom, in an accompanying editorial. The study was published last month in JAMA Network Open.

The findings represent the near opposite of a commonly held – and comforting – belief about early-stage disease: “You die with prostate cancer, not from it.”

That old saying is articulated in various ways, such as this from the Prostate Cancer Foundation: “We can confirm that there are those prostate cancers a man may die with and not of, while others are very aggressive.” The American Cancer Society says this: “Prostate cancer can be a serious disease, but most men diagnosed with prostate cancer do not die from it.”

However, these commonplace comments do not cover metastatic disease, which is what the authors of the new study decided to focus on.  

The team used data from the Surveillance, Epidemiology, and End Results Program (SEER) database to gather a sample of 26,168 U.S. men who received a diagnosis of metastatic prostate cancer from January 2000 to December 2016. They then analyzed the data in 2020 and found that 16,732 men (64%) had died during the follow-up period.

The majority of these deaths (77.8%) were from prostate cancer, 5.5% were from other cancers, and 16.7% were from noncancer causes, including cardiovascular diseases, chronic obstructive pulmonary disease, and cerebrovascular diseases.

Senior author Dr. Alhalabi acknowledged a limitation in these findings – that the SEER database relies on causes of death extracted from death certificates. “Death certificates have limited granularity in terms of the details they can contain about the cause of death and also have reporting bias,” he said.

Most of the prostate cancer deaths (59%) occurred within 2 years. The 5-year overall survival rate in the study group was 26%.

The deadliness of metastatic disease “reinforces the need for innovations to promote early-stage diagnosis,” comment the editorialists. Striking a hopeful note, they also say that “new tests for prostate cancer detection may reduce the proportion of patients who receive a diagnosis at a late stage.”
 

Death from other causes

The mean age at metastatic prostate cancer diagnosis in the study was roughly 71 years. Most of the cohort was White (74.5%) and had a diagnosis of stage M1b metastatic prostate cancer (72.7%), which means the cancer had spread to the bones.

Among men in the cohort, the rates of death from septicemia, suicide, accidents, COPD, and cerebrovascular diseases were significantly increased compared with the general U.S. male population, the team observes.

Thus, the study authors were concerned with not only with death from metastatic prostate cancer but death from other causes.

That concern is rooted in the established fact that there is now improved survival among patients with prostate cancer in the U.S., including among men with advanced disease. “Patients tend to live long enough after a prostate cancer diagnosis for non–cancer-related comorbidities to be associated with their overall survival,” they write.

The editorialists agree: Prostate cancer “has a high long-term survival rate compared with almost all other cancer types and signals the need for greater holistic care for patients.”

As noted above, cardiovascular diseases were the most common cause of nonprostate cancer–related deaths in the new study.

As in the management of other cancers, there is concern among clinicians and researchers about the cardiotoxic effects of prostate cancer treatments.

The study authors point to a 2017 analysis that showed that men with prostate cancer and no prior cardiac disease had greater risk of heart failure after taking androgen deprivation therapy (ADT), a common treatment used when the disease recurs after definitive treatment. Another study suggested an association between cardiotoxic effects of ADT and myocardial infarction regardless of medical history in general.

The authors of the current study say that such findings highlight “the importance of multidisciplinary care for such patients and the role of primary care physicians in optimizing cardiovascular risk prevention and providing early referrals to cardiologists.”

Further, the team says that tailoring “ADT to each patient’s needs may be associated with improved survival, especially for patients with factors associated with cardiovascular disease.”

Who should lead the way in multidisciplinary care? “The answer probably is case-by-case,” said Dr. Alhalabi, adding that it might depend on the presence of underlying morbidities such as cardiovascular disease and COPD.

“It is also important for the oncologist (‘the gatekeeper’) to try to mitigate the potential metabolic effects of hormonal deprivation therapy such as weight gain, decreased muscle mass, hyperlipidemia, etc.,” he added.

The study had no specific funding. The study authors and editorialists have disclosed no relevant financial relationships.

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

Nearly 80% of men with metastatic prostate cancer died from their malignancy, according to a retrospective cohort study involving 26,000-plus American men diagnosed with advanced disease in roughly the last 20 years.

The findings fill an information gap because, remarkably, “data are lacking” on causes of death among men whose prostate cancer has spread to other sites, say lead author Ahmed Elmehrath, MD, of Cairo University, Egypt, and colleagues.

“It was an important realization by our team that prostate cancer was the cause of death in 78% of patients,” said senior author Omar Alhalabi, MD, of University of Texas MD Anderson Cancer Center, Houston, in an email.

“Most patients with metastatic prostate cancer die from it, rather than other possible causes of death,” confirm Samuel Merriel, MSc, Tanimola Martins, PhD, and Sarah Bailey, PhD, University of Exeter, United Kingdom, in an accompanying editorial. The study was published last month in JAMA Network Open.

The findings represent the near opposite of a commonly held – and comforting – belief about early-stage disease: “You die with prostate cancer, not from it.”

That old saying is articulated in various ways, such as this from the Prostate Cancer Foundation: “We can confirm that there are those prostate cancers a man may die with and not of, while others are very aggressive.” The American Cancer Society says this: “Prostate cancer can be a serious disease, but most men diagnosed with prostate cancer do not die from it.”

However, these commonplace comments do not cover metastatic disease, which is what the authors of the new study decided to focus on.  

The team used data from the Surveillance, Epidemiology, and End Results Program (SEER) database to gather a sample of 26,168 U.S. men who received a diagnosis of metastatic prostate cancer from January 2000 to December 2016. They then analyzed the data in 2020 and found that 16,732 men (64%) had died during the follow-up period.

The majority of these deaths (77.8%) were from prostate cancer, 5.5% were from other cancers, and 16.7% were from noncancer causes, including cardiovascular diseases, chronic obstructive pulmonary disease, and cerebrovascular diseases.

Senior author Dr. Alhalabi acknowledged a limitation in these findings – that the SEER database relies on causes of death extracted from death certificates. “Death certificates have limited granularity in terms of the details they can contain about the cause of death and also have reporting bias,” he said.

Most of the prostate cancer deaths (59%) occurred within 2 years. The 5-year overall survival rate in the study group was 26%.

The deadliness of metastatic disease “reinforces the need for innovations to promote early-stage diagnosis,” comment the editorialists. Striking a hopeful note, they also say that “new tests for prostate cancer detection may reduce the proportion of patients who receive a diagnosis at a late stage.”
 

Death from other causes

The mean age at metastatic prostate cancer diagnosis in the study was roughly 71 years. Most of the cohort was White (74.5%) and had a diagnosis of stage M1b metastatic prostate cancer (72.7%), which means the cancer had spread to the bones.

Among men in the cohort, the rates of death from septicemia, suicide, accidents, COPD, and cerebrovascular diseases were significantly increased compared with the general U.S. male population, the team observes.

Thus, the study authors were concerned with not only with death from metastatic prostate cancer but death from other causes.

That concern is rooted in the established fact that there is now improved survival among patients with prostate cancer in the U.S., including among men with advanced disease. “Patients tend to live long enough after a prostate cancer diagnosis for non–cancer-related comorbidities to be associated with their overall survival,” they write.

The editorialists agree: Prostate cancer “has a high long-term survival rate compared with almost all other cancer types and signals the need for greater holistic care for patients.”

As noted above, cardiovascular diseases were the most common cause of nonprostate cancer–related deaths in the new study.

As in the management of other cancers, there is concern among clinicians and researchers about the cardiotoxic effects of prostate cancer treatments.

The study authors point to a 2017 analysis that showed that men with prostate cancer and no prior cardiac disease had greater risk of heart failure after taking androgen deprivation therapy (ADT), a common treatment used when the disease recurs after definitive treatment. Another study suggested an association between cardiotoxic effects of ADT and myocardial infarction regardless of medical history in general.

The authors of the current study say that such findings highlight “the importance of multidisciplinary care for such patients and the role of primary care physicians in optimizing cardiovascular risk prevention and providing early referrals to cardiologists.”

Further, the team says that tailoring “ADT to each patient’s needs may be associated with improved survival, especially for patients with factors associated with cardiovascular disease.”

Who should lead the way in multidisciplinary care? “The answer probably is case-by-case,” said Dr. Alhalabi, adding that it might depend on the presence of underlying morbidities such as cardiovascular disease and COPD.

“It is also important for the oncologist (‘the gatekeeper’) to try to mitigate the potential metabolic effects of hormonal deprivation therapy such as weight gain, decreased muscle mass, hyperlipidemia, etc.,” he added.

The study had no specific funding. The study authors and editorialists have disclosed no relevant financial relationships.

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

Nearly 80% of men with metastatic prostate cancer died from their malignancy, according to a retrospective cohort study involving 26,000-plus American men diagnosed with advanced disease in roughly the last 20 years.

The findings fill an information gap because, remarkably, “data are lacking” on causes of death among men whose prostate cancer has spread to other sites, say lead author Ahmed Elmehrath, MD, of Cairo University, Egypt, and colleagues.

“It was an important realization by our team that prostate cancer was the cause of death in 78% of patients,” said senior author Omar Alhalabi, MD, of University of Texas MD Anderson Cancer Center, Houston, in an email.

“Most patients with metastatic prostate cancer die from it, rather than other possible causes of death,” confirm Samuel Merriel, MSc, Tanimola Martins, PhD, and Sarah Bailey, PhD, University of Exeter, United Kingdom, in an accompanying editorial. The study was published last month in JAMA Network Open.

The findings represent the near opposite of a commonly held – and comforting – belief about early-stage disease: “You die with prostate cancer, not from it.”

That old saying is articulated in various ways, such as this from the Prostate Cancer Foundation: “We can confirm that there are those prostate cancers a man may die with and not of, while others are very aggressive.” The American Cancer Society says this: “Prostate cancer can be a serious disease, but most men diagnosed with prostate cancer do not die from it.”

However, these commonplace comments do not cover metastatic disease, which is what the authors of the new study decided to focus on.  

The team used data from the Surveillance, Epidemiology, and End Results Program (SEER) database to gather a sample of 26,168 U.S. men who received a diagnosis of metastatic prostate cancer from January 2000 to December 2016. They then analyzed the data in 2020 and found that 16,732 men (64%) had died during the follow-up period.

The majority of these deaths (77.8%) were from prostate cancer, 5.5% were from other cancers, and 16.7% were from noncancer causes, including cardiovascular diseases, chronic obstructive pulmonary disease, and cerebrovascular diseases.

Senior author Dr. Alhalabi acknowledged a limitation in these findings – that the SEER database relies on causes of death extracted from death certificates. “Death certificates have limited granularity in terms of the details they can contain about the cause of death and also have reporting bias,” he said.

Most of the prostate cancer deaths (59%) occurred within 2 years. The 5-year overall survival rate in the study group was 26%.

The deadliness of metastatic disease “reinforces the need for innovations to promote early-stage diagnosis,” comment the editorialists. Striking a hopeful note, they also say that “new tests for prostate cancer detection may reduce the proportion of patients who receive a diagnosis at a late stage.”
 

Death from other causes

The mean age at metastatic prostate cancer diagnosis in the study was roughly 71 years. Most of the cohort was White (74.5%) and had a diagnosis of stage M1b metastatic prostate cancer (72.7%), which means the cancer had spread to the bones.

Among men in the cohort, the rates of death from septicemia, suicide, accidents, COPD, and cerebrovascular diseases were significantly increased compared with the general U.S. male population, the team observes.

Thus, the study authors were concerned with not only with death from metastatic prostate cancer but death from other causes.

That concern is rooted in the established fact that there is now improved survival among patients with prostate cancer in the U.S., including among men with advanced disease. “Patients tend to live long enough after a prostate cancer diagnosis for non–cancer-related comorbidities to be associated with their overall survival,” they write.

The editorialists agree: Prostate cancer “has a high long-term survival rate compared with almost all other cancer types and signals the need for greater holistic care for patients.”

As noted above, cardiovascular diseases were the most common cause of nonprostate cancer–related deaths in the new study.

As in the management of other cancers, there is concern among clinicians and researchers about the cardiotoxic effects of prostate cancer treatments.

The study authors point to a 2017 analysis that showed that men with prostate cancer and no prior cardiac disease had greater risk of heart failure after taking androgen deprivation therapy (ADT), a common treatment used when the disease recurs after definitive treatment. Another study suggested an association between cardiotoxic effects of ADT and myocardial infarction regardless of medical history in general.

The authors of the current study say that such findings highlight “the importance of multidisciplinary care for such patients and the role of primary care physicians in optimizing cardiovascular risk prevention and providing early referrals to cardiologists.”

Further, the team says that tailoring “ADT to each patient’s needs may be associated with improved survival, especially for patients with factors associated with cardiovascular disease.”

Who should lead the way in multidisciplinary care? “The answer probably is case-by-case,” said Dr. Alhalabi, adding that it might depend on the presence of underlying morbidities such as cardiovascular disease and COPD.

“It is also important for the oncologist (‘the gatekeeper’) to try to mitigate the potential metabolic effects of hormonal deprivation therapy such as weight gain, decreased muscle mass, hyperlipidemia, etc.,” he added.

The study had no specific funding. The study authors and editorialists have disclosed no relevant financial relationships.

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

The decades-long search for a safe, effective adjuvant therapy for patients with resected kidney cancer at high risk of recurrence appears to have taken a big step in the right direction, according to expert opinion.

The high hopes have been generated by results from the randomized, phase 3 KEYNOTE-564 trial, showing that monotherapy with pembrolizumab (Keytruda, Merck) was associated with significantly longer disease-free survival (DFS) after nephrectomy than placebo (77.3% vs. 68.1%, respectively). Median follow-up was 24 months.

The results come from the trial’s first interim analysis of data from 994 patients with clear-cell renal cell carcinoma (RCC) at high risk of recurrence.

For the pembrolizumab group, the estimated percentage alive at 24 months was 96.6%, compared with 93.5% in the placebo group (hazard ratio for death, 0.54), said Toni Choueiri, MD, of the Dana-Farber Cancer Institute, Boston, and colleagues.

However, grade 3 or higher adverse events (any cause) occurred at almost twice the rate in the pembrolizumab versus the placebo group (32.4% vs. 17.7%). The new study was published online Aug. 18, 2021, in the New England Journal of Medicine.

The study results were first presented at the 2021 American Society of Clinical Oncology annual meeting and described as likely to be practice changing in this setting, as reported by this news organization.

Currently, this patient population has “no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence,” observed the authors.

That’s about to change, as the trial results “herald the dawn of a new era in the treatment of renal cell carcinoma,” Rana McKay, MD, University of California San Diego Health, wrote in an accompanying editorial.

Multiple studies have investigated potential adjuvant therapies in RCC since the 1980s, she observed.

“For the first time, we now have an effective adjuvant immunotherapy option for patients with resected renal cell carcinoma at high risk of recurrence,” Dr. McKay said in an interview.

To date, the lack of clinically beneficial adjuvant therapy options in RCC has been “humbling,” Dr. Choueiri said in an interview. “We hope we can push the envelope further and get more patients with RCC some good options that make them live longer and better.”

Although the standard of care for patients diagnosed with locoregional RCC is partial or total nephrectomy, nearly half of patients eventually experience disease recurrence following surgery, Dr. Choueiri noted.

“No standard, globally approved adjuvant therapy options are currently available for this population,” he said. Clinical guidelines recommend patients at high risk of disease recurrence after surgery be entered into a clinical trial or undergo active surveillance.

Researchers will continue to follow the results for overall survival, a secondary endpoint. “The very early look suggests encouraging results [in overall survival] with an HR of 0.54,” Dr. Choueiri noted.

In the meantime, the prolongation of DFS represents a clear clinical benefit, said Dr. McKay, “given the magnitude of the increase” and “the limited incidence of toxic effects.”

KEYNOTE-564 will alter the adjuvant treatment landscape for RCC as a positive phase 3 trial of adjuvant immunotherapy for the disease, she added.

A number of earlier studies have investigated the use of adjuvant vascular endothelial growth factor–targeting agents in RCC. Only the 2016 Sunitinib Treatment of Renal Adjuvant Cancer (S-TRAC) trial showed improved DFS with sunitinib, compared with placebo (6.8 vs. 5.6 years). Subsequently, sunitinib was approved for adjuvant use in the United States. However, the S-TRAC trial also showed that sunitinib therapy was associated with an increased incidence of toxic effects and lower quality of life scores, and researchers did not observe any benefit in overall survival.

“Despite regulatory approval in the U.S., sunitinib is not approved for adjuvant use by the European Medicines Agency and has limited utilization in clinical practice given the low benefit-risk ratio,” Dr. McKay pointed out.
 

Study details

KEYNOTE-564 involved 996 patients with clear-cell RCC at high risk for recurrence after nephrectomy, with or without metastasectomy. They were randomly assigned in a 1:1 ratio to receive a 200-mg dose of adjuvant pembrolizumab or placebo given intravenously once every 3 weeks for up to 17 cycles for approximately 1 year.

The vast majority of patients enrolled in the study had localized disease with no evidence of metastases (M0) and intermediate to high or high risk of disease recurrence after partial or complete nephrectomy. However, 5.8% of patients in both the pembrolizumab and placebo groups had M1 NED (metastatic stage 1, no evidence of disease) status after nephrectomy and resection of metastatic lesions. These patients were also at intermediate to high or high risk of recurrence.

The benefit of pembrolizumab, compared with placebo, was maintained in this subgroup, said the investigators. “At this point, we continue to look at the data, but we know that there was a benefit for DFS in the population we included,” said Dr. Choueiri. “When we looked at several subgroups such as PD-L1 status, geography, gender, performance status, M0/M1, all HRs were less than 1 suggesting benefit from pembrolizumab over placebo.”

“Subset analyses by stage are going to be important to determine which group of patients will derive the most benefit,” asserted Dr. McKay. “While those with M1 NED appear to derive benefit with HR for DFS of 0.29, those with M1 NED comprise a small percentage of patient enrolled in the trial.”

Studies exploring tissue- and blood-based biomarkers, including circulating tumor DNA, will be key to identify patients at highest risk for recurrence or adjuvant treatment, Dr. McKay emphasized. “The adoption of adjuvant immune checkpoint inhibitors brings along new questions regarding patient selection, therapeutic use in patients with non–clear-cell renal cell carcinoma, and systemic treatment after recurrence during or after the receipt of adjuvant therapy.”

KEYNOTE-564 was funded by Merck. Multiple study authors including Dr. Choueiri have financial ties to the pharmaceutical industry, including Merck.

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

The decades-long search for a safe, effective adjuvant therapy for patients with resected kidney cancer at high risk of recurrence appears to have taken a big step in the right direction, according to expert opinion.

The high hopes have been generated by results from the randomized, phase 3 KEYNOTE-564 trial, showing that monotherapy with pembrolizumab (Keytruda, Merck) was associated with significantly longer disease-free survival (DFS) after nephrectomy than placebo (77.3% vs. 68.1%, respectively). Median follow-up was 24 months.

The results come from the trial’s first interim analysis of data from 994 patients with clear-cell renal cell carcinoma (RCC) at high risk of recurrence.

For the pembrolizumab group, the estimated percentage alive at 24 months was 96.6%, compared with 93.5% in the placebo group (hazard ratio for death, 0.54), said Toni Choueiri, MD, of the Dana-Farber Cancer Institute, Boston, and colleagues.

However, grade 3 or higher adverse events (any cause) occurred at almost twice the rate in the pembrolizumab versus the placebo group (32.4% vs. 17.7%). The new study was published online Aug. 18, 2021, in the New England Journal of Medicine.

The study results were first presented at the 2021 American Society of Clinical Oncology annual meeting and described as likely to be practice changing in this setting, as reported by this news organization.

Currently, this patient population has “no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence,” observed the authors.

That’s about to change, as the trial results “herald the dawn of a new era in the treatment of renal cell carcinoma,” Rana McKay, MD, University of California San Diego Health, wrote in an accompanying editorial.

Multiple studies have investigated potential adjuvant therapies in RCC since the 1980s, she observed.

“For the first time, we now have an effective adjuvant immunotherapy option for patients with resected renal cell carcinoma at high risk of recurrence,” Dr. McKay said in an interview.

To date, the lack of clinically beneficial adjuvant therapy options in RCC has been “humbling,” Dr. Choueiri said in an interview. “We hope we can push the envelope further and get more patients with RCC some good options that make them live longer and better.”

Although the standard of care for patients diagnosed with locoregional RCC is partial or total nephrectomy, nearly half of patients eventually experience disease recurrence following surgery, Dr. Choueiri noted.

“No standard, globally approved adjuvant therapy options are currently available for this population,” he said. Clinical guidelines recommend patients at high risk of disease recurrence after surgery be entered into a clinical trial or undergo active surveillance.

Researchers will continue to follow the results for overall survival, a secondary endpoint. “The very early look suggests encouraging results [in overall survival] with an HR of 0.54,” Dr. Choueiri noted.

In the meantime, the prolongation of DFS represents a clear clinical benefit, said Dr. McKay, “given the magnitude of the increase” and “the limited incidence of toxic effects.”

KEYNOTE-564 will alter the adjuvant treatment landscape for RCC as a positive phase 3 trial of adjuvant immunotherapy for the disease, she added.

A number of earlier studies have investigated the use of adjuvant vascular endothelial growth factor–targeting agents in RCC. Only the 2016 Sunitinib Treatment of Renal Adjuvant Cancer (S-TRAC) trial showed improved DFS with sunitinib, compared with placebo (6.8 vs. 5.6 years). Subsequently, sunitinib was approved for adjuvant use in the United States. However, the S-TRAC trial also showed that sunitinib therapy was associated with an increased incidence of toxic effects and lower quality of life scores, and researchers did not observe any benefit in overall survival.

“Despite regulatory approval in the U.S., sunitinib is not approved for adjuvant use by the European Medicines Agency and has limited utilization in clinical practice given the low benefit-risk ratio,” Dr. McKay pointed out.
 

Study details

KEYNOTE-564 involved 996 patients with clear-cell RCC at high risk for recurrence after nephrectomy, with or without metastasectomy. They were randomly assigned in a 1:1 ratio to receive a 200-mg dose of adjuvant pembrolizumab or placebo given intravenously once every 3 weeks for up to 17 cycles for approximately 1 year.

The vast majority of patients enrolled in the study had localized disease with no evidence of metastases (M0) and intermediate to high or high risk of disease recurrence after partial or complete nephrectomy. However, 5.8% of patients in both the pembrolizumab and placebo groups had M1 NED (metastatic stage 1, no evidence of disease) status after nephrectomy and resection of metastatic lesions. These patients were also at intermediate to high or high risk of recurrence.

The benefit of pembrolizumab, compared with placebo, was maintained in this subgroup, said the investigators. “At this point, we continue to look at the data, but we know that there was a benefit for DFS in the population we included,” said Dr. Choueiri. “When we looked at several subgroups such as PD-L1 status, geography, gender, performance status, M0/M1, all HRs were less than 1 suggesting benefit from pembrolizumab over placebo.”

“Subset analyses by stage are going to be important to determine which group of patients will derive the most benefit,” asserted Dr. McKay. “While those with M1 NED appear to derive benefit with HR for DFS of 0.29, those with M1 NED comprise a small percentage of patient enrolled in the trial.”

Studies exploring tissue- and blood-based biomarkers, including circulating tumor DNA, will be key to identify patients at highest risk for recurrence or adjuvant treatment, Dr. McKay emphasized. “The adoption of adjuvant immune checkpoint inhibitors brings along new questions regarding patient selection, therapeutic use in patients with non–clear-cell renal cell carcinoma, and systemic treatment after recurrence during or after the receipt of adjuvant therapy.”

KEYNOTE-564 was funded by Merck. Multiple study authors including Dr. Choueiri have financial ties to the pharmaceutical industry, including Merck.

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

The decades-long search for a safe, effective adjuvant therapy for patients with resected kidney cancer at high risk of recurrence appears to have taken a big step in the right direction, according to expert opinion.

The high hopes have been generated by results from the randomized, phase 3 KEYNOTE-564 trial, showing that monotherapy with pembrolizumab (Keytruda, Merck) was associated with significantly longer disease-free survival (DFS) after nephrectomy than placebo (77.3% vs. 68.1%, respectively). Median follow-up was 24 months.

The results come from the trial’s first interim analysis of data from 994 patients with clear-cell renal cell carcinoma (RCC) at high risk of recurrence.

For the pembrolizumab group, the estimated percentage alive at 24 months was 96.6%, compared with 93.5% in the placebo group (hazard ratio for death, 0.54), said Toni Choueiri, MD, of the Dana-Farber Cancer Institute, Boston, and colleagues.

However, grade 3 or higher adverse events (any cause) occurred at almost twice the rate in the pembrolizumab versus the placebo group (32.4% vs. 17.7%). The new study was published online Aug. 18, 2021, in the New England Journal of Medicine.

The study results were first presented at the 2021 American Society of Clinical Oncology annual meeting and described as likely to be practice changing in this setting, as reported by this news organization.

Currently, this patient population has “no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence,” observed the authors.

That’s about to change, as the trial results “herald the dawn of a new era in the treatment of renal cell carcinoma,” Rana McKay, MD, University of California San Diego Health, wrote in an accompanying editorial.

Multiple studies have investigated potential adjuvant therapies in RCC since the 1980s, she observed.

“For the first time, we now have an effective adjuvant immunotherapy option for patients with resected renal cell carcinoma at high risk of recurrence,” Dr. McKay said in an interview.

To date, the lack of clinically beneficial adjuvant therapy options in RCC has been “humbling,” Dr. Choueiri said in an interview. “We hope we can push the envelope further and get more patients with RCC some good options that make them live longer and better.”

Although the standard of care for patients diagnosed with locoregional RCC is partial or total nephrectomy, nearly half of patients eventually experience disease recurrence following surgery, Dr. Choueiri noted.

“No standard, globally approved adjuvant therapy options are currently available for this population,” he said. Clinical guidelines recommend patients at high risk of disease recurrence after surgery be entered into a clinical trial or undergo active surveillance.

Researchers will continue to follow the results for overall survival, a secondary endpoint. “The very early look suggests encouraging results [in overall survival] with an HR of 0.54,” Dr. Choueiri noted.

In the meantime, the prolongation of DFS represents a clear clinical benefit, said Dr. McKay, “given the magnitude of the increase” and “the limited incidence of toxic effects.”

KEYNOTE-564 will alter the adjuvant treatment landscape for RCC as a positive phase 3 trial of adjuvant immunotherapy for the disease, she added.

A number of earlier studies have investigated the use of adjuvant vascular endothelial growth factor–targeting agents in RCC. Only the 2016 Sunitinib Treatment of Renal Adjuvant Cancer (S-TRAC) trial showed improved DFS with sunitinib, compared with placebo (6.8 vs. 5.6 years). Subsequently, sunitinib was approved for adjuvant use in the United States. However, the S-TRAC trial also showed that sunitinib therapy was associated with an increased incidence of toxic effects and lower quality of life scores, and researchers did not observe any benefit in overall survival.

“Despite regulatory approval in the U.S., sunitinib is not approved for adjuvant use by the European Medicines Agency and has limited utilization in clinical practice given the low benefit-risk ratio,” Dr. McKay pointed out.
 

Study details

KEYNOTE-564 involved 996 patients with clear-cell RCC at high risk for recurrence after nephrectomy, with or without metastasectomy. They were randomly assigned in a 1:1 ratio to receive a 200-mg dose of adjuvant pembrolizumab or placebo given intravenously once every 3 weeks for up to 17 cycles for approximately 1 year.

The vast majority of patients enrolled in the study had localized disease with no evidence of metastases (M0) and intermediate to high or high risk of disease recurrence after partial or complete nephrectomy. However, 5.8% of patients in both the pembrolizumab and placebo groups had M1 NED (metastatic stage 1, no evidence of disease) status after nephrectomy and resection of metastatic lesions. These patients were also at intermediate to high or high risk of recurrence.

The benefit of pembrolizumab, compared with placebo, was maintained in this subgroup, said the investigators. “At this point, we continue to look at the data, but we know that there was a benefit for DFS in the population we included,” said Dr. Choueiri. “When we looked at several subgroups such as PD-L1 status, geography, gender, performance status, M0/M1, all HRs were less than 1 suggesting benefit from pembrolizumab over placebo.”

“Subset analyses by stage are going to be important to determine which group of patients will derive the most benefit,” asserted Dr. McKay. “While those with M1 NED appear to derive benefit with HR for DFS of 0.29, those with M1 NED comprise a small percentage of patient enrolled in the trial.”

Studies exploring tissue- and blood-based biomarkers, including circulating tumor DNA, will be key to identify patients at highest risk for recurrence or adjuvant treatment, Dr. McKay emphasized. “The adoption of adjuvant immune checkpoint inhibitors brings along new questions regarding patient selection, therapeutic use in patients with non–clear-cell renal cell carcinoma, and systemic treatment after recurrence during or after the receipt of adjuvant therapy.”

KEYNOTE-564 was funded by Merck. Multiple study authors including Dr. Choueiri have financial ties to the pharmaceutical industry, including Merck.

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

Experts at the National Comprehensive Cancer Network have now issued an updated recommendation for COVID-19 vaccination in people with cancer. The panel calls for these patients to be among the highest-priority group to be vaccinated against COVID-19 and to receive the newly approved third dose of vaccine.

The NCCN has recommended in February that all patients receiving active cancer treatment should receive a COVID-19 vaccine and should be prioritized for vaccination. In August, the FDA authorized a third dose of either the Pfizer or Moderna COVID-19 vaccines for people with compromised immune systems. Those eligible for a third dose include solid organ transplant recipients, those undergoing cancer treatments, and people with autoimmune diseases that suppress their immune systems

The new NCCN recommendations state that the following groups should be considered eligible for a third dose of the mRNA COVID-19 vaccine immediately, based on the latest decisions from the Food and Drug Administration and the Centers for Disease Control and Prevention:

• Patients with solid tumors (either new or recurring) receiving treatment within 1 year of their initial vaccine dose, regardless of their type of cancer therapy.
• Patients with active hematologic malignancies regardless of whether they are currently receiving cancer therapy.
• Anyone who received a stem cell transplant (SCT) or engineered cellular therapy (for example, chimeric antigen receptor T cells), especially within the past 2 years.
• Any recipients of allogeneic SCT on immunosuppressive therapy or with a history of graft-versus-host disease regardless of the time of transplant.
• Anyone with an additional immunosuppressive condition (for example, HIV) or being treated with immunosuppressive agents unrelated to their cancer therapy.

Cancer patients at high risk of complications

As previously reported by this news organization, infection with COVID-19 in people with cancer can severely impact survival. One study published in 2020 found that patients with both COVID-19 infection and progressing cancer had a fivefold increase in the risk of 30-day mortality, compared with COVID-19–positive cancer patients who were in remission or had no evidence of cancer.

Another study found that cancer type, stage, and recent treatment could affect outcomes of COVID-19 in patients with cancer. Patients with hematologic malignancies and metastatic cancers had higher risks of developing severe or critical COVID-19 symptoms, being admitted to the ICU, requiring ventilation, and dying. Conversely, those with nonmetastatic disease had outcomes that were comparable with persons without cancer and a COVID-19 infection. This study also found that having undergone recent surgery or receiving immunotherapy also put patients at a higher risk of poor outcomes, although patients with cancer who were treated with radiotherapy had outcomes similar to those of noncancer COVID-19 patients.

“COVID-19 can be very dangerous, especially for people living with cancer, which is why we’re so grateful for safe and effective vaccines that are saving lives,” Robert W. Carlson, MD, CEO of NCCN, said in a statement.
 

Right timing and location

The current NCCN update also recommends that individuals wait at least 4 weeks between the second and third doses, and those who are infected with COVID-19 after being vaccinated should wait until they have documented clearance of the virus before receiving a third dose.

It also recommends that people who live in the same household with immunocompromised individuals should also get a third dose once it becomes available, and that it is best to have a third dose of the same type of vaccine as the first two doses. However, a different mRNA vaccine is also acceptable.

Immunocompromised individuals should try to receive their third dose in a health care delivery setting, as opposed to a pharmacy or public vaccination clinic if possible, as it would limit their risk of exposure to the general population.

Steve Pergam, MD, MPH, associate professor, vaccine and infectious disease division, Fred Hutchinson Cancer Research Center, Seattle, commented that it is still necessary to take precautions, even after getting the booster dose.

“That means, even after a third dose of vaccine, we still recommend immunocompromised people, such as those undergoing cancer treatment, continue to be cautious, wear masks, and avoid large group gatherings, particularly around those who are unvaccinated,” said Dr. Pergam, who is also coleader of the NCCN COVID-19 Vaccination Advisory Committee. “All of us should do our part to reduce the spread of COVID-19 and get vaccinated to protect those around us from preventable suffering.”

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

Experts at the National Comprehensive Cancer Network have now issued an updated recommendation for COVID-19 vaccination in people with cancer. The panel calls for these patients to be among the highest-priority group to be vaccinated against COVID-19 and to receive the newly approved third dose of vaccine.

The NCCN has recommended in February that all patients receiving active cancer treatment should receive a COVID-19 vaccine and should be prioritized for vaccination. In August, the FDA authorized a third dose of either the Pfizer or Moderna COVID-19 vaccines for people with compromised immune systems. Those eligible for a third dose include solid organ transplant recipients, those undergoing cancer treatments, and people with autoimmune diseases that suppress their immune systems

The new NCCN recommendations state that the following groups should be considered eligible for a third dose of the mRNA COVID-19 vaccine immediately, based on the latest decisions from the Food and Drug Administration and the Centers for Disease Control and Prevention:

• Patients with solid tumors (either new or recurring) receiving treatment within 1 year of their initial vaccine dose, regardless of their type of cancer therapy.
• Patients with active hematologic malignancies regardless of whether they are currently receiving cancer therapy.
• Anyone who received a stem cell transplant (SCT) or engineered cellular therapy (for example, chimeric antigen receptor T cells), especially within the past 2 years.
• Any recipients of allogeneic SCT on immunosuppressive therapy or with a history of graft-versus-host disease regardless of the time of transplant.
• Anyone with an additional immunosuppressive condition (for example, HIV) or being treated with immunosuppressive agents unrelated to their cancer therapy.

Cancer patients at high risk of complications

As previously reported by this news organization, infection with COVID-19 in people with cancer can severely impact survival. One study published in 2020 found that patients with both COVID-19 infection and progressing cancer had a fivefold increase in the risk of 30-day mortality, compared with COVID-19–positive cancer patients who were in remission or had no evidence of cancer.

Another study found that cancer type, stage, and recent treatment could affect outcomes of COVID-19 in patients with cancer. Patients with hematologic malignancies and metastatic cancers had higher risks of developing severe or critical COVID-19 symptoms, being admitted to the ICU, requiring ventilation, and dying. Conversely, those with nonmetastatic disease had outcomes that were comparable with persons without cancer and a COVID-19 infection. This study also found that having undergone recent surgery or receiving immunotherapy also put patients at a higher risk of poor outcomes, although patients with cancer who were treated with radiotherapy had outcomes similar to those of noncancer COVID-19 patients.

“COVID-19 can be very dangerous, especially for people living with cancer, which is why we’re so grateful for safe and effective vaccines that are saving lives,” Robert W. Carlson, MD, CEO of NCCN, said in a statement.
 

Right timing and location

The current NCCN update also recommends that individuals wait at least 4 weeks between the second and third doses, and those who are infected with COVID-19 after being vaccinated should wait until they have documented clearance of the virus before receiving a third dose.

It also recommends that people who live in the same household with immunocompromised individuals should also get a third dose once it becomes available, and that it is best to have a third dose of the same type of vaccine as the first two doses. However, a different mRNA vaccine is also acceptable.

Immunocompromised individuals should try to receive their third dose in a health care delivery setting, as opposed to a pharmacy or public vaccination clinic if possible, as it would limit their risk of exposure to the general population.

Steve Pergam, MD, MPH, associate professor, vaccine and infectious disease division, Fred Hutchinson Cancer Research Center, Seattle, commented that it is still necessary to take precautions, even after getting the booster dose.

“That means, even after a third dose of vaccine, we still recommend immunocompromised people, such as those undergoing cancer treatment, continue to be cautious, wear masks, and avoid large group gatherings, particularly around those who are unvaccinated,” said Dr. Pergam, who is also coleader of the NCCN COVID-19 Vaccination Advisory Committee. “All of us should do our part to reduce the spread of COVID-19 and get vaccinated to protect those around us from preventable suffering.”

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

Experts at the National Comprehensive Cancer Network have now issued an updated recommendation for COVID-19 vaccination in people with cancer. The panel calls for these patients to be among the highest-priority group to be vaccinated against COVID-19 and to receive the newly approved third dose of vaccine.

The NCCN has recommended in February that all patients receiving active cancer treatment should receive a COVID-19 vaccine and should be prioritized for vaccination. In August, the FDA authorized a third dose of either the Pfizer or Moderna COVID-19 vaccines for people with compromised immune systems. Those eligible for a third dose include solid organ transplant recipients, those undergoing cancer treatments, and people with autoimmune diseases that suppress their immune systems

The new NCCN recommendations state that the following groups should be considered eligible for a third dose of the mRNA COVID-19 vaccine immediately, based on the latest decisions from the Food and Drug Administration and the Centers for Disease Control and Prevention:

• Patients with solid tumors (either new or recurring) receiving treatment within 1 year of their initial vaccine dose, regardless of their type of cancer therapy.
• Patients with active hematologic malignancies regardless of whether they are currently receiving cancer therapy.
• Anyone who received a stem cell transplant (SCT) or engineered cellular therapy (for example, chimeric antigen receptor T cells), especially within the past 2 years.
• Any recipients of allogeneic SCT on immunosuppressive therapy or with a history of graft-versus-host disease regardless of the time of transplant.
• Anyone with an additional immunosuppressive condition (for example, HIV) or being treated with immunosuppressive agents unrelated to their cancer therapy.

Cancer patients at high risk of complications

As previously reported by this news organization, infection with COVID-19 in people with cancer can severely impact survival. One study published in 2020 found that patients with both COVID-19 infection and progressing cancer had a fivefold increase in the risk of 30-day mortality, compared with COVID-19–positive cancer patients who were in remission or had no evidence of cancer.

Another study found that cancer type, stage, and recent treatment could affect outcomes of COVID-19 in patients with cancer. Patients with hematologic malignancies and metastatic cancers had higher risks of developing severe or critical COVID-19 symptoms, being admitted to the ICU, requiring ventilation, and dying. Conversely, those with nonmetastatic disease had outcomes that were comparable with persons without cancer and a COVID-19 infection. This study also found that having undergone recent surgery or receiving immunotherapy also put patients at a higher risk of poor outcomes, although patients with cancer who were treated with radiotherapy had outcomes similar to those of noncancer COVID-19 patients.

“COVID-19 can be very dangerous, especially for people living with cancer, which is why we’re so grateful for safe and effective vaccines that are saving lives,” Robert W. Carlson, MD, CEO of NCCN, said in a statement.
 

Right timing and location

The current NCCN update also recommends that individuals wait at least 4 weeks between the second and third doses, and those who are infected with COVID-19 after being vaccinated should wait until they have documented clearance of the virus before receiving a third dose.

It also recommends that people who live in the same household with immunocompromised individuals should also get a third dose once it becomes available, and that it is best to have a third dose of the same type of vaccine as the first two doses. However, a different mRNA vaccine is also acceptable.

Immunocompromised individuals should try to receive their third dose in a health care delivery setting, as opposed to a pharmacy or public vaccination clinic if possible, as it would limit their risk of exposure to the general population.

Steve Pergam, MD, MPH, associate professor, vaccine and infectious disease division, Fred Hutchinson Cancer Research Center, Seattle, commented that it is still necessary to take precautions, even after getting the booster dose.

“That means, even after a third dose of vaccine, we still recommend immunocompromised people, such as those undergoing cancer treatment, continue to be cautious, wear masks, and avoid large group gatherings, particularly around those who are unvaccinated,” said Dr. Pergam, who is also coleader of the NCCN COVID-19 Vaccination Advisory Committee. “All of us should do our part to reduce the spread of COVID-19 and get vaccinated to protect those around us from preventable suffering.”

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

Advances in Hematology and Oncology

• Integrated Care for Cancer-Related Distress
• Solid Tumor Checkpoint Inhibitor Dosing Models and Toxicity
• Evidence-Based Algorithm for Prostate Cancer Bone Health
• QOL and Toxicity After High-Dose Brachytherapy for Prostate Cancer
• An Interdisciplinary Approach to Comorbid Pancreatic Cancer and Substance Use Disorder
• Three Primary Cancers in a Veteran With Toxic Exposures

Advances in Hematology and Oncology

• Integrated Care for Cancer-Related Distress
• Solid Tumor Checkpoint Inhibitor Dosing Models and Toxicity
• Evidence-Based Algorithm for Prostate Cancer Bone Health
• QOL and Toxicity After High-Dose Brachytherapy for Prostate Cancer
• An Interdisciplinary Approach to Comorbid Pancreatic Cancer and Substance Use Disorder
• Three Primary Cancers in a Veteran With Toxic Exposures

Advances in Hematology and Oncology

• Integrated Care for Cancer-Related Distress
• Solid Tumor Checkpoint Inhibitor Dosing Models and Toxicity
• Evidence-Based Algorithm for Prostate Cancer Bone Health
• QOL and Toxicity After High-Dose Brachytherapy for Prostate Cancer
• An Interdisciplinary Approach to Comorbid Pancreatic Cancer and Substance Use Disorder
• Three Primary Cancers in a Veteran With Toxic Exposures

Hepatocellular cancer (HCC) is the most common type of hepatic cancers, accounting for 65% of all hepatic cancers.¹ Among all cancers, HCC is one of the fastest growing causes of death in the United States, and the rate of new HCC cases are on the rise over several decades.² There are many risk factors leading to HCC, including alcohol use, obesity, and smoking. Infection with hepatitis C virus (HCV) poses a significant risk.¹

The pathogenesis of HCV-induced carcinogenesis is mediated by a unique host-induced immunologic response. Viral replication induces production of inflammatory factors, such as tumor necrosis factor (TNF-α), interferon (IFN), and oxidative stress on hepatocytes, resulting in cell injury, death, and regeneration. Repetitive cycles of cellular death and regeneration induce fibrosis, which may lead to cirrhosis.³ Hence, early treatment of HCV infection and achieving sustained virologic response (SVR) may lead to decreased incidence and mortality associated with HCC.

Treatment of HCV infection has become more effective with the development of direct-acting antivirals (DAAs) leading to SVR in > 90% of patients compared with 40 to 50% with IFN-based treatment.^4,5 DAAs have been proved safe and highly effective in eradicating HCV infection even in patients with advanced liver disease with decompensated cirrhosis.⁶ Although achieving SVR indicates a complete cure from chronic HCV infection, several studies have shown subsequent risk of developing HCC persists even after successful HCV treatment.^7-9 Some studies show that using DAAs to achieve SVR in patients with HCV infection leads to a decreased relative risk of HCC development compared with patients who do not receive treatment.^10-12 But data on HCC risk following DAA-induced SVR vs IFN-induced SVR are somewhat conflicting.

Much of the information regarding the association between SVR and HCC has been gleaned from large data banks without accounting for individual patient characteristics that can be obtained through full chart review. Due to small sample sizes in many chart review studies, the impact that SVR from DAA therapy has on the progression and severity of HCC is not entirely clear. The aim of our study is to evaluate the effect of HCV treatment and SVR status on overall survival (OS) in patients with HCC. Second, we aim to compare survival benefits, if any exist, among the 2 major HCV treatment modalities (IFN vs DAA).

Methods

We performed a retrospective review of patients at Memphis Veterans Affairs Medical Center (VAMC) in Tennessee to determine whether treatment for HCV infection in general, and achieving SVR in particular, makes a difference in progression, recurrence, or OS among patients with HCV infection who develop HCC. We identified 111 patients with a diagnosis of both HCV and new or recurrent HCC lesions from November 2008 to March 2019 (Table 1). We divided these patients based on their HCV treatment status, SVR status, and treatment types (IFN vs DAA).

The inclusion criteria were patients aged > 18 years treated at the Memphis VAMC who have HCV infection and developed HCC. Exclusion criteria were patients who developed HCC from other causes such as alcoholic steatohepatitis, hepatitis B virus infection, hemochromatosis, patients without HCV infection, and patients who were not established at the Memphis VAMC. This protocol was approved by the Memphis VAMC Institutional Review Board.

Statistical Analysis

OS was measured from the date of HCC diagnosis to the date of death or last follow-up. Progression-free survival (PFS) was defined from the date of HCC treatment initiation to the date of first HCC recurrence. We compared survival data for the SVR and non-SVR subgroups, the HCV treatment vs non-HCV treatment subgroups, and the IFN therapy vs DAA therapy subgroups, using the Kaplan-Meier method. The differences between subgroups were assessed using a log-rank test. Multivariate analysis using Cox proportional hazards regression model was used to identify factors that had significant impact on OS. Those factors included age; race; alcohol, tobacco, and illicit drug use; SVR status; HCV treatment status; IFN-based regimen vs DAA; MELD, and Child-Pugh scores. The results were expressed as hazard ratios (HRs) and 95% CI. Calculations were made using Statistical Analysis SAS and IBM SPSS software.

Results

The study included 111 patients. The mean age was 65.7 years; all were male and half of were Black patients. The gender imbalance was due to the predominantly male patient population at Memphis VAMC. Among 111 patients with HCV infection and HCC, 68 patients were treated for HCV infection and had significantly improved OS and PFS compared with the nontreatment group. The median 5-year OS was 44.6 months (95% CI, 966-3202) in the treated HCV infection group compared with 15.1 months in the untreated HCV infection group with a Wilcoxon P = .0005 (Figure 1). Similarly, patients treated for HCV infection had a significantly better 5-year PFS of 15.3 months (95% CI, 294-726) compared with the nontreatment group 9.5 months (95% CI, 205-405) with a Wilcoxon P = .04 (Figure 2).

Among 68 patients treated for HCV infection, 51 achieved SVR, and 34 achieved SVR after the diagnosis of HCC. Patients who achieved SVR had an improved 5-year OS when compared with patients who did not achieve SVR (median 65.8 months [95% CI, 1222-NA] vs 15.7 months [95% CI, 242-853], Wilcoxon P < .001) (Figure 3). Similarly, patients with SVR had improved 5-year PFS when compared with the non-SVR group (median 20.5 months [95% CI, 431-914] vs 8.9 months [95% CI, 191-340], Wilcoxon P = .007 (Figure 4). Achievement of SVR after HCC diagnosis suggests a significantly improved OS (HR 0.37) compared with achievement prior to HCC diagnosis (HR, 0.65; 95% CI, 0.23-1.82, P = .41)

Discussion

The survival benefit of HCV eradication and achieving SVR status has been well established in patients with HCC.¹³ In a retrospective cohort study of 250 patients with HCV infection who had received curative treatment for HCC, multivariate analysis demonstrated that achieving SVR is an independent predictor of OS.¹⁴ The 3-year and 5-year OS rates were 97% and 94% for the SVR group, and 91% and 60% for the non‐SVR group, respectively (P < .001). Similarly, according to Sou and colleagues, of 122 patients with HCV-related HCC, patients with SVR had longer OS than patients with no SVR (P = .04).¹⁵ One of the hypotheses that could explain the survival benefit in patients who achieved SVR is the effect of achieving SVR in reducing persistent liver inflammation and associated liver mortality, and therefore lowering risks of complication in patients with HCC.¹⁶ In our study, multivariate analysis shows that achieving SVR is associated with significant improved OS (HR, 0.33). In contrast, patients with HCC who have not achieved SVR are associated with worse survival (HR, 3.24). This finding supports early treatment of HCV to obtain SVR in HCV-related patients with HCC, even after development of HCC.

Among 68 patients treated for HCV infection, 45 patients were treated after HCC diagnosis, and 34 patients achieved SVR after HCC diagnosis. The average time between HCV infection treatment after HCC diagnosis was 6 months. Our data suggested that achievement of SVR after HCC diagnosis suggests an improved OS (HR, 0.37) compared with achievement prior to HCC diagnosis (HR, 0.65; 95% CI,0.23-1.82; P = .41). This lack of statistical significance is likely due to small sample size of patients achieving SVR prior to HCC diagnosis. Our results are consistent with the findings regarding the efficacy and timing of DAA treatment in patients with active HCC. According to Singal and colleagues, achieving SVR after DAA therapy may result in improved liver function and facilitate additional HCC-directed therapy, which potentially improves survival.^17-19

Nagaoki and colleagues found that there was no significant difference in OS in patients with HCC between the DAA and IFN groups. According to the study, the 3-year and 5-year OS rates were 96% and 96% for DAA patients and 93% and 73% for IFN patients, respectively (P = .16).¹⁴ This finding is consistent with the results of our study. HCV treatment type (IFN vs DAA) was not found to be associated with either OS or PFS time, regardless of time period.

Limitations

Our findings were limited in that our study population is too small to conduct further subset analysis that would allow statistical significance of those subsets, such as the suggested benefit of SVR in patients who presented with HCC after antiviral therapy. Another limitation is the all-male population, likely a result of the older veteran population at the Memphis VAMC. The mean age at diagnosis was 65 years, which is slightly higher than the general population. Compared to the SEER database, HCC is most frequently diagnosed among people aged 55 to 64 years.²³ The age difference was likely due to our aging veteran population.

Further studies are needed to determine the significance of SVR on HCC recurrence and treatment. Immunotherapy is now first-line treatment for patients with local advanced HCC. All the immunotherapy studies excluded patients with active HCV infection. Hence, we need more data on HCV treatment timing among patients scheduled to start treatment with immunotherapy.

Conclusions

In a population of older veterans, treatment of HCV infection leads to OS benefit among patients with HCC. In addition, patients with HCV infection who achieve SVR have an OS benefit over patients unable to achieve SVR. The type of treatment, DAA vs IFN-based regimen, did not show significant survival benefit.

Hepatocellular cancer (HCC) is the most common type of hepatic cancers, accounting for 65% of all hepatic cancers.¹ Among all cancers, HCC is one of the fastest growing causes of death in the United States, and the rate of new HCC cases are on the rise over several decades.² There are many risk factors leading to HCC, including alcohol use, obesity, and smoking. Infection with hepatitis C virus (HCV) poses a significant risk.¹

The pathogenesis of HCV-induced carcinogenesis is mediated by a unique host-induced immunologic response. Viral replication induces production of inflammatory factors, such as tumor necrosis factor (TNF-α), interferon (IFN), and oxidative stress on hepatocytes, resulting in cell injury, death, and regeneration. Repetitive cycles of cellular death and regeneration induce fibrosis, which may lead to cirrhosis.³ Hence, early treatment of HCV infection and achieving sustained virologic response (SVR) may lead to decreased incidence and mortality associated with HCC.

Treatment of HCV infection has become more effective with the development of direct-acting antivirals (DAAs) leading to SVR in > 90% of patients compared with 40 to 50% with IFN-based treatment.^4,5 DAAs have been proved safe and highly effective in eradicating HCV infection even in patients with advanced liver disease with decompensated cirrhosis.⁶ Although achieving SVR indicates a complete cure from chronic HCV infection, several studies have shown subsequent risk of developing HCC persists even after successful HCV treatment.^7-9 Some studies show that using DAAs to achieve SVR in patients with HCV infection leads to a decreased relative risk of HCC development compared with patients who do not receive treatment.^10-12 But data on HCC risk following DAA-induced SVR vs IFN-induced SVR are somewhat conflicting.

Much of the information regarding the association between SVR and HCC has been gleaned from large data banks without accounting for individual patient characteristics that can be obtained through full chart review. Due to small sample sizes in many chart review studies, the impact that SVR from DAA therapy has on the progression and severity of HCC is not entirely clear. The aim of our study is to evaluate the effect of HCV treatment and SVR status on overall survival (OS) in patients with HCC. Second, we aim to compare survival benefits, if any exist, among the 2 major HCV treatment modalities (IFN vs DAA).

Methods

We performed a retrospective review of patients at Memphis Veterans Affairs Medical Center (VAMC) in Tennessee to determine whether treatment for HCV infection in general, and achieving SVR in particular, makes a difference in progression, recurrence, or OS among patients with HCV infection who develop HCC. We identified 111 patients with a diagnosis of both HCV and new or recurrent HCC lesions from November 2008 to March 2019 (Table 1). We divided these patients based on their HCV treatment status, SVR status, and treatment types (IFN vs DAA).

The inclusion criteria were patients aged > 18 years treated at the Memphis VAMC who have HCV infection and developed HCC. Exclusion criteria were patients who developed HCC from other causes such as alcoholic steatohepatitis, hepatitis B virus infection, hemochromatosis, patients without HCV infection, and patients who were not established at the Memphis VAMC. This protocol was approved by the Memphis VAMC Institutional Review Board.

Statistical Analysis

OS was measured from the date of HCC diagnosis to the date of death or last follow-up. Progression-free survival (PFS) was defined from the date of HCC treatment initiation to the date of first HCC recurrence. We compared survival data for the SVR and non-SVR subgroups, the HCV treatment vs non-HCV treatment subgroups, and the IFN therapy vs DAA therapy subgroups, using the Kaplan-Meier method. The differences between subgroups were assessed using a log-rank test. Multivariate analysis using Cox proportional hazards regression model was used to identify factors that had significant impact on OS. Those factors included age; race; alcohol, tobacco, and illicit drug use; SVR status; HCV treatment status; IFN-based regimen vs DAA; MELD, and Child-Pugh scores. The results were expressed as hazard ratios (HRs) and 95% CI. Calculations were made using Statistical Analysis SAS and IBM SPSS software.

Results

The study included 111 patients. The mean age was 65.7 years; all were male and half of were Black patients. The gender imbalance was due to the predominantly male patient population at Memphis VAMC. Among 111 patients with HCV infection and HCC, 68 patients were treated for HCV infection and had significantly improved OS and PFS compared with the nontreatment group. The median 5-year OS was 44.6 months (95% CI, 966-3202) in the treated HCV infection group compared with 15.1 months in the untreated HCV infection group with a Wilcoxon P = .0005 (Figure 1). Similarly, patients treated for HCV infection had a significantly better 5-year PFS of 15.3 months (95% CI, 294-726) compared with the nontreatment group 9.5 months (95% CI, 205-405) with a Wilcoxon P = .04 (Figure 2).

Among 68 patients treated for HCV infection, 51 achieved SVR, and 34 achieved SVR after the diagnosis of HCC. Patients who achieved SVR had an improved 5-year OS when compared with patients who did not achieve SVR (median 65.8 months [95% CI, 1222-NA] vs 15.7 months [95% CI, 242-853], Wilcoxon P < .001) (Figure 3). Similarly, patients with SVR had improved 5-year PFS when compared with the non-SVR group (median 20.5 months [95% CI, 431-914] vs 8.9 months [95% CI, 191-340], Wilcoxon P = .007 (Figure 4). Achievement of SVR after HCC diagnosis suggests a significantly improved OS (HR 0.37) compared with achievement prior to HCC diagnosis (HR, 0.65; 95% CI, 0.23-1.82, P = .41)

Discussion

The survival benefit of HCV eradication and achieving SVR status has been well established in patients with HCC.¹³ In a retrospective cohort study of 250 patients with HCV infection who had received curative treatment for HCC, multivariate analysis demonstrated that achieving SVR is an independent predictor of OS.¹⁴ The 3-year and 5-year OS rates were 97% and 94% for the SVR group, and 91% and 60% for the non‐SVR group, respectively (P < .001). Similarly, according to Sou and colleagues, of 122 patients with HCV-related HCC, patients with SVR had longer OS than patients with no SVR (P = .04).¹⁵ One of the hypotheses that could explain the survival benefit in patients who achieved SVR is the effect of achieving SVR in reducing persistent liver inflammation and associated liver mortality, and therefore lowering risks of complication in patients with HCC.¹⁶ In our study, multivariate analysis shows that achieving SVR is associated with significant improved OS (HR, 0.33). In contrast, patients with HCC who have not achieved SVR are associated with worse survival (HR, 3.24). This finding supports early treatment of HCV to obtain SVR in HCV-related patients with HCC, even after development of HCC.

Among 68 patients treated for HCV infection, 45 patients were treated after HCC diagnosis, and 34 patients achieved SVR after HCC diagnosis. The average time between HCV infection treatment after HCC diagnosis was 6 months. Our data suggested that achievement of SVR after HCC diagnosis suggests an improved OS (HR, 0.37) compared with achievement prior to HCC diagnosis (HR, 0.65; 95% CI,0.23-1.82; P = .41). This lack of statistical significance is likely due to small sample size of patients achieving SVR prior to HCC diagnosis. Our results are consistent with the findings regarding the efficacy and timing of DAA treatment in patients with active HCC. According to Singal and colleagues, achieving SVR after DAA therapy may result in improved liver function and facilitate additional HCC-directed therapy, which potentially improves survival.^17-19

Nagaoki and colleagues found that there was no significant difference in OS in patients with HCC between the DAA and IFN groups. According to the study, the 3-year and 5-year OS rates were 96% and 96% for DAA patients and 93% and 73% for IFN patients, respectively (P = .16).¹⁴ This finding is consistent with the results of our study. HCV treatment type (IFN vs DAA) was not found to be associated with either OS or PFS time, regardless of time period.

Limitations

Our findings were limited in that our study population is too small to conduct further subset analysis that would allow statistical significance of those subsets, such as the suggested benefit of SVR in patients who presented with HCC after antiviral therapy. Another limitation is the all-male population, likely a result of the older veteran population at the Memphis VAMC. The mean age at diagnosis was 65 years, which is slightly higher than the general population. Compared to the SEER database, HCC is most frequently diagnosed among people aged 55 to 64 years.²³ The age difference was likely due to our aging veteran population.

Further studies are needed to determine the significance of SVR on HCC recurrence and treatment. Immunotherapy is now first-line treatment for patients with local advanced HCC. All the immunotherapy studies excluded patients with active HCV infection. Hence, we need more data on HCV treatment timing among patients scheduled to start treatment with immunotherapy.

Conclusions

In a population of older veterans, treatment of HCV infection leads to OS benefit among patients with HCC. In addition, patients with HCV infection who achieve SVR have an OS benefit over patients unable to achieve SVR. The type of treatment, DAA vs IFN-based regimen, did not show significant survival benefit.

Hepatocellular cancer (HCC) is the most common type of hepatic cancers, accounting for 65% of all hepatic cancers.¹ Among all cancers, HCC is one of the fastest growing causes of death in the United States, and the rate of new HCC cases are on the rise over several decades.² There are many risk factors leading to HCC, including alcohol use, obesity, and smoking. Infection with hepatitis C virus (HCV) poses a significant risk.¹

The pathogenesis of HCV-induced carcinogenesis is mediated by a unique host-induced immunologic response. Viral replication induces production of inflammatory factors, such as tumor necrosis factor (TNF-α), interferon (IFN), and oxidative stress on hepatocytes, resulting in cell injury, death, and regeneration. Repetitive cycles of cellular death and regeneration induce fibrosis, which may lead to cirrhosis.³ Hence, early treatment of HCV infection and achieving sustained virologic response (SVR) may lead to decreased incidence and mortality associated with HCC.

Treatment of HCV infection has become more effective with the development of direct-acting antivirals (DAAs) leading to SVR in > 90% of patients compared with 40 to 50% with IFN-based treatment.^4,5 DAAs have been proved safe and highly effective in eradicating HCV infection even in patients with advanced liver disease with decompensated cirrhosis.⁶ Although achieving SVR indicates a complete cure from chronic HCV infection, several studies have shown subsequent risk of developing HCC persists even after successful HCV treatment.^7-9 Some studies show that using DAAs to achieve SVR in patients with HCV infection leads to a decreased relative risk of HCC development compared with patients who do not receive treatment.^10-12 But data on HCC risk following DAA-induced SVR vs IFN-induced SVR are somewhat conflicting.

Much of the information regarding the association between SVR and HCC has been gleaned from large data banks without accounting for individual patient characteristics that can be obtained through full chart review. Due to small sample sizes in many chart review studies, the impact that SVR from DAA therapy has on the progression and severity of HCC is not entirely clear. The aim of our study is to evaluate the effect of HCV treatment and SVR status on overall survival (OS) in patients with HCC. Second, we aim to compare survival benefits, if any exist, among the 2 major HCV treatment modalities (IFN vs DAA).

Methods

We performed a retrospective review of patients at Memphis Veterans Affairs Medical Center (VAMC) in Tennessee to determine whether treatment for HCV infection in general, and achieving SVR in particular, makes a difference in progression, recurrence, or OS among patients with HCV infection who develop HCC. We identified 111 patients with a diagnosis of both HCV and new or recurrent HCC lesions from November 2008 to March 2019 (Table 1). We divided these patients based on their HCV treatment status, SVR status, and treatment types (IFN vs DAA).

The inclusion criteria were patients aged > 18 years treated at the Memphis VAMC who have HCV infection and developed HCC. Exclusion criteria were patients who developed HCC from other causes such as alcoholic steatohepatitis, hepatitis B virus infection, hemochromatosis, patients without HCV infection, and patients who were not established at the Memphis VAMC. This protocol was approved by the Memphis VAMC Institutional Review Board.

Statistical Analysis

OS was measured from the date of HCC diagnosis to the date of death or last follow-up. Progression-free survival (PFS) was defined from the date of HCC treatment initiation to the date of first HCC recurrence. We compared survival data for the SVR and non-SVR subgroups, the HCV treatment vs non-HCV treatment subgroups, and the IFN therapy vs DAA therapy subgroups, using the Kaplan-Meier method. The differences between subgroups were assessed using a log-rank test. Multivariate analysis using Cox proportional hazards regression model was used to identify factors that had significant impact on OS. Those factors included age; race; alcohol, tobacco, and illicit drug use; SVR status; HCV treatment status; IFN-based regimen vs DAA; MELD, and Child-Pugh scores. The results were expressed as hazard ratios (HRs) and 95% CI. Calculations were made using Statistical Analysis SAS and IBM SPSS software.

Results

The study included 111 patients. The mean age was 65.7 years; all were male and half of were Black patients. The gender imbalance was due to the predominantly male patient population at Memphis VAMC. Among 111 patients with HCV infection and HCC, 68 patients were treated for HCV infection and had significantly improved OS and PFS compared with the nontreatment group. The median 5-year OS was 44.6 months (95% CI, 966-3202) in the treated HCV infection group compared with 15.1 months in the untreated HCV infection group with a Wilcoxon P = .0005 (Figure 1). Similarly, patients treated for HCV infection had a significantly better 5-year PFS of 15.3 months (95% CI, 294-726) compared with the nontreatment group 9.5 months (95% CI, 205-405) with a Wilcoxon P = .04 (Figure 2).

Among 68 patients treated for HCV infection, 51 achieved SVR, and 34 achieved SVR after the diagnosis of HCC. Patients who achieved SVR had an improved 5-year OS when compared with patients who did not achieve SVR (median 65.8 months [95% CI, 1222-NA] vs 15.7 months [95% CI, 242-853], Wilcoxon P < .001) (Figure 3). Similarly, patients with SVR had improved 5-year PFS when compared with the non-SVR group (median 20.5 months [95% CI, 431-914] vs 8.9 months [95% CI, 191-340], Wilcoxon P = .007 (Figure 4). Achievement of SVR after HCC diagnosis suggests a significantly improved OS (HR 0.37) compared with achievement prior to HCC diagnosis (HR, 0.65; 95% CI, 0.23-1.82, P = .41)

Discussion

The survival benefit of HCV eradication and achieving SVR status has been well established in patients with HCC.¹³ In a retrospective cohort study of 250 patients with HCV infection who had received curative treatment for HCC, multivariate analysis demonstrated that achieving SVR is an independent predictor of OS.¹⁴ The 3-year and 5-year OS rates were 97% and 94% for the SVR group, and 91% and 60% for the non‐SVR group, respectively (P < .001). Similarly, according to Sou and colleagues, of 122 patients with HCV-related HCC, patients with SVR had longer OS than patients with no SVR (P = .04).¹⁵ One of the hypotheses that could explain the survival benefit in patients who achieved SVR is the effect of achieving SVR in reducing persistent liver inflammation and associated liver mortality, and therefore lowering risks of complication in patients with HCC.¹⁶ In our study, multivariate analysis shows that achieving SVR is associated with significant improved OS (HR, 0.33). In contrast, patients with HCC who have not achieved SVR are associated with worse survival (HR, 3.24). This finding supports early treatment of HCV to obtain SVR in HCV-related patients with HCC, even after development of HCC.

Among 68 patients treated for HCV infection, 45 patients were treated after HCC diagnosis, and 34 patients achieved SVR after HCC diagnosis. The average time between HCV infection treatment after HCC diagnosis was 6 months. Our data suggested that achievement of SVR after HCC diagnosis suggests an improved OS (HR, 0.37) compared with achievement prior to HCC diagnosis (HR, 0.65; 95% CI,0.23-1.82; P = .41). This lack of statistical significance is likely due to small sample size of patients achieving SVR prior to HCC diagnosis. Our results are consistent with the findings regarding the efficacy and timing of DAA treatment in patients with active HCC. According to Singal and colleagues, achieving SVR after DAA therapy may result in improved liver function and facilitate additional HCC-directed therapy, which potentially improves survival.^17-19

Nagaoki and colleagues found that there was no significant difference in OS in patients with HCC between the DAA and IFN groups. According to the study, the 3-year and 5-year OS rates were 96% and 96% for DAA patients and 93% and 73% for IFN patients, respectively (P = .16).¹⁴ This finding is consistent with the results of our study. HCV treatment type (IFN vs DAA) was not found to be associated with either OS or PFS time, regardless of time period.

Limitations

Our findings were limited in that our study population is too small to conduct further subset analysis that would allow statistical significance of those subsets, such as the suggested benefit of SVR in patients who presented with HCC after antiviral therapy. Another limitation is the all-male population, likely a result of the older veteran population at the Memphis VAMC. The mean age at diagnosis was 65 years, which is slightly higher than the general population. Compared to the SEER database, HCC is most frequently diagnosed among people aged 55 to 64 years.²³ The age difference was likely due to our aging veteran population.

Further studies are needed to determine the significance of SVR on HCC recurrence and treatment. Immunotherapy is now first-line treatment for patients with local advanced HCC. All the immunotherapy studies excluded patients with active HCV infection. Hence, we need more data on HCV treatment timing among patients scheduled to start treatment with immunotherapy.

Conclusions

In a population of older veterans, treatment of HCV infection leads to OS benefit among patients with HCC. In addition, patients with HCV infection who achieve SVR have an OS benefit over patients unable to achieve SVR. The type of treatment, DAA vs IFN-based regimen, did not show significant survival benefit.

The first global trial to compare the cardiovascular (CV) safety of two therapies for prostate cancer proved inconclusive because of inadequate enrollment and events, but the study is a harbinger of growth in the emerging specialty of cardio-oncology, according to experts.

European Society of Cardiology

“Many new cancer agents have extended patient survival, yet some of these agents have significant potential cardiovascular toxicity,” said Renato D. Lopes, MD, in presenting a study at the annual congress of the European Society of Cardiology.

In the context of improving survival in patients with or at risk for both cancer and cardiovascular disease, he suggested that the prostate cancer study he led could be “a model for interdisciplinary collaboration” needed to address the relative and sometimes competing risks of these disease states.

This point was seconded by several pioneers in cardio-oncology who participated in the discussion of the results of the trial, called PRONOUNCE.

“We know many drugs in oncology increase cardiovascular risk, so these are the types of trials we need,” according Thomas M. Suter, MD, who leads the cardio-oncology service at the University Hospital, Berne, Switzerland. He was the ESC-invited discussant for PRONOUNCE.
 

More than 100 centers in 12 countries involved

In PRONOUNCE, 545 patients with prostate cancer and established atherosclerotic cardiovascular disease were randomized to degarelix, a gonadotropin-releasing hormone antagonist, or leuprolide, a GnRH agonist. The patients were enrolled at 113 participating centers in 12 countries. All of the patients had an indication for an androgen-deprivation therapy (ADT).

In numerous previous studies, “ADT has been associated with higher CV morbidity and mortality, particularly in men with preexisting CV disease,” explained Dr. Lopes, but the relative cardiovascular safety of GnRH agonists relative to GnRH antagonists has been “controversial.”

The PRONOUNCE study was designed to resolve this issue, but the study was terminated early because of slow enrollment (not related to the COVID-19 pandemic). The planned enrollment was 900 patients.

In addition, the rate of major adverse cardiovascular events (MACE), defined as myocardial infarction, stroke, or death, was lower over the course of follow-up than anticipated in the study design.
 

No significant difference on primary endpoint

At the end of 12 months, MACE occurred in 11 (4.1%) of patients randomized to leuprolide and 15 (5.5%) of those randomized to degarelix. The greater hazard ratio for MACE in the degarelix group did not approach statistical significance (hazard ratio, 1.28; P = .53).

As a result, the question of the relative CV safety of these drugs “remains unresolved,” according to Dr. Lopes, professor of medicine at Duke University Medical Center, Durham, N.C.

This does not diminish the need to answer this question. In the addition to the fact that cancer is a malignancy primarily of advancing age when CV disease is prevalent – the mean age in this study was 73 years and 44% were over age 75 – it is often an indolent disease with long periods of survival, according to Dr. Lopes. About half of prostate cancer patients have concomitant CV disease, and about half will receive ADT at some point in their treatment.

In patients receiving ADT, leuprolide is far more commonly used than GnRH antagonists, which are offered in only about 4% of patients, according to data cited by Dr. Lopes. The underlying hypothesis of this study was that leuprolide is associated with greater CV risk, which might have been relevant to a risk-benefit calculation, if the hypothesis had been confirmed.
 

Cancer drugs can increase CV risk

Based on experimental data, “there is concern the leuprolide is involved in plaque destabilization,” said Dr. Lopes, but he noted that ADTs in general are associated with adverse metabolic changes, including increases in LDL cholesterol, insulin resistance, and body fat, all of which could be relevant to CV risk.

It is the improving rates of survival for prostate cancer as well for other types of cancer that have increased attention to the potential for cancer drugs to increase CV risk, another major cause of early mortality. For these competing risks, objective data are needed to evaluate a relative risk-to-benefit ratio for treatment choices.

This dilemma led the ESC to recently establish its Council on Cardio-Oncology, and many centers around the world are also creating interdisciplinary groups to guide treatment choices for patients with both diseases.

“You will certainly get a lot of referrals,” said Rudolf de Boer, MD, professor of translational cardiology, University Medical Center, Groningen, Netherlands. Basing his remark on his own experience starting a cardio-oncology clinic at his institution, he called this work challenging and agreed that the need for objective data is urgent.

“We need data to provide common ground on which to judge relative risks,” Dr. de Boer said. He also praised the PRONOUNCE investigators for their efforts even if the data failed to answer the question posed.

The PRONOUNCE results were published online in Circulation at the time of Dr. Lopes’s presentation.

The study received funding from Ferring Pharmaceuticals. Dr. Lopes reports financial relationships with Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi. Dr. Suter reports financial relationships with Boehringer Ingelheim, GlaxoSmithKline, and Roche. Dr. de Boer reports financial relationships with AstraZeneca, Abbott, Bristol-Myers Squibb, Novartis, Novo Nordisk, and Roche.

The first global trial to compare the cardiovascular (CV) safety of two therapies for prostate cancer proved inconclusive because of inadequate enrollment and events, but the study is a harbinger of growth in the emerging specialty of cardio-oncology, according to experts.

European Society of Cardiology

“Many new cancer agents have extended patient survival, yet some of these agents have significant potential cardiovascular toxicity,” said Renato D. Lopes, MD, in presenting a study at the annual congress of the European Society of Cardiology.

In the context of improving survival in patients with or at risk for both cancer and cardiovascular disease, he suggested that the prostate cancer study he led could be “a model for interdisciplinary collaboration” needed to address the relative and sometimes competing risks of these disease states.

This point was seconded by several pioneers in cardio-oncology who participated in the discussion of the results of the trial, called PRONOUNCE.

“We know many drugs in oncology increase cardiovascular risk, so these are the types of trials we need,” according Thomas M. Suter, MD, who leads the cardio-oncology service at the University Hospital, Berne, Switzerland. He was the ESC-invited discussant for PRONOUNCE.
 

More than 100 centers in 12 countries involved

In PRONOUNCE, 545 patients with prostate cancer and established atherosclerotic cardiovascular disease were randomized to degarelix, a gonadotropin-releasing hormone antagonist, or leuprolide, a GnRH agonist. The patients were enrolled at 113 participating centers in 12 countries. All of the patients had an indication for an androgen-deprivation therapy (ADT).

In numerous previous studies, “ADT has been associated with higher CV morbidity and mortality, particularly in men with preexisting CV disease,” explained Dr. Lopes, but the relative cardiovascular safety of GnRH agonists relative to GnRH antagonists has been “controversial.”

The PRONOUNCE study was designed to resolve this issue, but the study was terminated early because of slow enrollment (not related to the COVID-19 pandemic). The planned enrollment was 900 patients.

In addition, the rate of major adverse cardiovascular events (MACE), defined as myocardial infarction, stroke, or death, was lower over the course of follow-up than anticipated in the study design.
 

No significant difference on primary endpoint

At the end of 12 months, MACE occurred in 11 (4.1%) of patients randomized to leuprolide and 15 (5.5%) of those randomized to degarelix. The greater hazard ratio for MACE in the degarelix group did not approach statistical significance (hazard ratio, 1.28; P = .53).

As a result, the question of the relative CV safety of these drugs “remains unresolved,” according to Dr. Lopes, professor of medicine at Duke University Medical Center, Durham, N.C.

This does not diminish the need to answer this question. In the addition to the fact that cancer is a malignancy primarily of advancing age when CV disease is prevalent – the mean age in this study was 73 years and 44% were over age 75 – it is often an indolent disease with long periods of survival, according to Dr. Lopes. About half of prostate cancer patients have concomitant CV disease, and about half will receive ADT at some point in their treatment.

In patients receiving ADT, leuprolide is far more commonly used than GnRH antagonists, which are offered in only about 4% of patients, according to data cited by Dr. Lopes. The underlying hypothesis of this study was that leuprolide is associated with greater CV risk, which might have been relevant to a risk-benefit calculation, if the hypothesis had been confirmed.
 

Cancer drugs can increase CV risk

Based on experimental data, “there is concern the leuprolide is involved in plaque destabilization,” said Dr. Lopes, but he noted that ADTs in general are associated with adverse metabolic changes, including increases in LDL cholesterol, insulin resistance, and body fat, all of which could be relevant to CV risk.

It is the improving rates of survival for prostate cancer as well for other types of cancer that have increased attention to the potential for cancer drugs to increase CV risk, another major cause of early mortality. For these competing risks, objective data are needed to evaluate a relative risk-to-benefit ratio for treatment choices.

This dilemma led the ESC to recently establish its Council on Cardio-Oncology, and many centers around the world are also creating interdisciplinary groups to guide treatment choices for patients with both diseases.

“You will certainly get a lot of referrals,” said Rudolf de Boer, MD, professor of translational cardiology, University Medical Center, Groningen, Netherlands. Basing his remark on his own experience starting a cardio-oncology clinic at his institution, he called this work challenging and agreed that the need for objective data is urgent.

“We need data to provide common ground on which to judge relative risks,” Dr. de Boer said. He also praised the PRONOUNCE investigators for their efforts even if the data failed to answer the question posed.

The PRONOUNCE results were published online in Circulation at the time of Dr. Lopes’s presentation.

The study received funding from Ferring Pharmaceuticals. Dr. Lopes reports financial relationships with Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi. Dr. Suter reports financial relationships with Boehringer Ingelheim, GlaxoSmithKline, and Roche. Dr. de Boer reports financial relationships with AstraZeneca, Abbott, Bristol-Myers Squibb, Novartis, Novo Nordisk, and Roche.

The first global trial to compare the cardiovascular (CV) safety of two therapies for prostate cancer proved inconclusive because of inadequate enrollment and events, but the study is a harbinger of growth in the emerging specialty of cardio-oncology, according to experts.

European Society of Cardiology

“Many new cancer agents have extended patient survival, yet some of these agents have significant potential cardiovascular toxicity,” said Renato D. Lopes, MD, in presenting a study at the annual congress of the European Society of Cardiology.

In the context of improving survival in patients with or at risk for both cancer and cardiovascular disease, he suggested that the prostate cancer study he led could be “a model for interdisciplinary collaboration” needed to address the relative and sometimes competing risks of these disease states.

This point was seconded by several pioneers in cardio-oncology who participated in the discussion of the results of the trial, called PRONOUNCE.

“We know many drugs in oncology increase cardiovascular risk, so these are the types of trials we need,” according Thomas M. Suter, MD, who leads the cardio-oncology service at the University Hospital, Berne, Switzerland. He was the ESC-invited discussant for PRONOUNCE.
 

More than 100 centers in 12 countries involved

In PRONOUNCE, 545 patients with prostate cancer and established atherosclerotic cardiovascular disease were randomized to degarelix, a gonadotropin-releasing hormone antagonist, or leuprolide, a GnRH agonist. The patients were enrolled at 113 participating centers in 12 countries. All of the patients had an indication for an androgen-deprivation therapy (ADT).

In numerous previous studies, “ADT has been associated with higher CV morbidity and mortality, particularly in men with preexisting CV disease,” explained Dr. Lopes, but the relative cardiovascular safety of GnRH agonists relative to GnRH antagonists has been “controversial.”

The PRONOUNCE study was designed to resolve this issue, but the study was terminated early because of slow enrollment (not related to the COVID-19 pandemic). The planned enrollment was 900 patients.

In addition, the rate of major adverse cardiovascular events (MACE), defined as myocardial infarction, stroke, or death, was lower over the course of follow-up than anticipated in the study design.
 

No significant difference on primary endpoint

At the end of 12 months, MACE occurred in 11 (4.1%) of patients randomized to leuprolide and 15 (5.5%) of those randomized to degarelix. The greater hazard ratio for MACE in the degarelix group did not approach statistical significance (hazard ratio, 1.28; P = .53).

As a result, the question of the relative CV safety of these drugs “remains unresolved,” according to Dr. Lopes, professor of medicine at Duke University Medical Center, Durham, N.C.

This does not diminish the need to answer this question. In the addition to the fact that cancer is a malignancy primarily of advancing age when CV disease is prevalent – the mean age in this study was 73 years and 44% were over age 75 – it is often an indolent disease with long periods of survival, according to Dr. Lopes. About half of prostate cancer patients have concomitant CV disease, and about half will receive ADT at some point in their treatment.

In patients receiving ADT, leuprolide is far more commonly used than GnRH antagonists, which are offered in only about 4% of patients, according to data cited by Dr. Lopes. The underlying hypothesis of this study was that leuprolide is associated with greater CV risk, which might have been relevant to a risk-benefit calculation, if the hypothesis had been confirmed.
 

Cancer drugs can increase CV risk

Based on experimental data, “there is concern the leuprolide is involved in plaque destabilization,” said Dr. Lopes, but he noted that ADTs in general are associated with adverse metabolic changes, including increases in LDL cholesterol, insulin resistance, and body fat, all of which could be relevant to CV risk.

It is the improving rates of survival for prostate cancer as well for other types of cancer that have increased attention to the potential for cancer drugs to increase CV risk, another major cause of early mortality. For these competing risks, objective data are needed to evaluate a relative risk-to-benefit ratio for treatment choices.

This dilemma led the ESC to recently establish its Council on Cardio-Oncology, and many centers around the world are also creating interdisciplinary groups to guide treatment choices for patients with both diseases.

“You will certainly get a lot of referrals,” said Rudolf de Boer, MD, professor of translational cardiology, University Medical Center, Groningen, Netherlands. Basing his remark on his own experience starting a cardio-oncology clinic at his institution, he called this work challenging and agreed that the need for objective data is urgent.

“We need data to provide common ground on which to judge relative risks,” Dr. de Boer said. He also praised the PRONOUNCE investigators for their efforts even if the data failed to answer the question posed.

The PRONOUNCE results were published online in Circulation at the time of Dr. Lopes’s presentation.

The study received funding from Ferring Pharmaceuticals. Dr. Lopes reports financial relationships with Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi. Dr. Suter reports financial relationships with Boehringer Ingelheim, GlaxoSmithKline, and Roche. Dr. de Boer reports financial relationships with AstraZeneca, Abbott, Bristol-Myers Squibb, Novartis, Novo Nordisk, and Roche.

Breast cancer screening rates at community health centers (CHCs) in the United States declined during the pandemic, particularly among Black and uninsured individuals, based on a retrospective look at 32 sites.

Still, drops in screening were less dramatic than national declines previously reported, possibly because of the American Cancer Society–directed CHANGE program, which was simultaneously underway at the CHCs involved, reported lead author Stacey A. Fedewa, PhD, senior principal scientist at the ACS in Atlanta, and colleagues.

“This is one of the first studies to examine breast cancer screening rates during the pandemic specifically among clinics providing care to communities of color and lower income populations, a group with lower utilization of and greater barriers to [breast cancer] screening,” the investigators wrote in Cancer. “This is important because these populations have longstanding barriers to accessing care, lower breast screening rates, higher breast cancer mortality rates, and are especially vulnerable to health care disruptions.”

According to a previous analysis of electronic health records by Mast and Munoz del Rio, breast cancer screening rates in the United States dropped 94% in March/April 2020, when the COVID-19 pandemic was declared a national emergency. Although a recent follow-up report showed a rebound in breast cancer screening, the estimated rate remains 13% below average.

The present study evaluated data from 32 out of 1,385 CHCs in the United States. All centers were involved in the ACS-run CHANGE grant program, which funded the clinics for 2 years, during which time they implemented at least three evidence-based provider and client interventions, such as patient navigation or electronic medical record enhancements. The clinics reported breast cancer screening rates on a routine basis throughout the 2-year period, beginning August 2018.

Breast cancer screening rate was defined as the percentage of women aged 50-74 years who had a screening mammogram within the past 27 months, out of a total pool of women who had a medical visit within the past year. For 2018, 2019, and 2020, respectively, 142,207; 142,003; and 150,630 women had a medical visit. Screening rates were compared across years in either June or July. Findings were further characterized by demographic characteristics, urban/rural status, and clinic region.

From 2018 to 2019 breast cancer screening rates rose 18%, from 45.8% to 53.9%. This increase was followed by an 8% decline during the 2019-2020 period, from 53.9% to 49.6%.

The investigators estimated the number of missed mammograms and breast cancer diagnoses for two comparative, hypothetical scenarios: first, if the rising trend from 2018 to 2019 had continued through 2020, and second, if the rate had plateaued at 53.9%.

The rising trend model suggested that 47,517 fewer mammograms than normal were conducted during 2019-2020, resulting in 242 missed breast cancer diagnoses, of which 166 were invasive and 76 were ductal carcinoma in situ. The plateau model suggested that 6,477 fewer mammograms were conducted, leading to 33 missed diagnoses.

Compared with the 8% decline in screening overall, the rate among Black patients dropped 12%, while rates at clinics with a lower proportion of uninsured patients dropped an average of 15%. In contrast, clinics in the South did not have a significant reduction in screening, “possibly reflecting lower baseline rates or impact of stay-at-home orders,” the investigators wrote.

Dr. Fedewa and colleagues also noted that their findings were less dramatic than those reported by Mast and Munoz del Rio. They suggested that the CHANGE program may have softened the blow dealt by the pandemic.

“The CHANGE program–funded interventions – that were established before and continued through 2020 – may have mitigated the pandemic’s effects on breast cancer screening services among the 32 CHCs that were studied,” they wrote. “Further investigation of breast cancer screening rates among additional CHCs will further inform where targeted interventions (e.g., client reminders, education on return to screening) are most needed.”

According to Madeline Sutton, MD, assistant professor of obstetrics and gynecology at Morehouse School of Medicine, Atlanta, “Progress seen with the CHANGE program should be duplicated in other clinical venues based on improvements seen in numbers of mammograms and breast cancers detected.”

Still, Dr. Sutton noted that the racial/ethnic disparities remain cause for concern.

“This study has implications for persons served at CHCs, especially if breast cancer racial/ethnic disparities are unintentionally widened during this pandemic,” Dr. Sutton said in a written comment. “Policy-level changes that decrease BCSR [breast cancer screen rate] gaps for women are warranted.”

Ana Velázquez Mañana, MD, a medical oncology fellow at the University of California, San Francisco, suggested that the effects of the pandemic may have been even more pronounced among medically underserved patients in whom interventions to increase screening were not being conducted, as they were through the CHANGE program.

“One must wonder to what degree these interventions reduced the decline in screening mammography rates observed during the pandemic and to what degree could disparities in screening be magnified in community health centers with less resources,” Dr. Velázquez said in a written comment. “Therefore, understanding barriers to breast cancer screening among our specific health care systems is key to guide resource allocation and the development of evidence-based multilevel interventions that can address these barriers, and ultimately increase screening rates.”

Dr. Velázquez also noted that the study by Dr. Fedewa and colleagues may have missed drops in screening among vulnerable populations that occurred later in the pandemic and in geographic hotspots. In a recent JAMA Network Open study, Dr. Velázquez reported a 41% drop in breast cancer screening at a safety-net hospital in San Francisco during the first stay-at-home order, which lasted from Feb. 1, 2020 to May 31, 2020.

The Breast Health Equity CHANGE grant was funded by the National Football League in partnership with the American Cancer Society. The investigators reported employment by the American Cancer Society. Dr. Wehling and Dr. Wysocki disclosed grants from Pfizer unrelated to this research. Dr. Sutton and Dr. Velázquez disclosed no conflicts of interest.

Breast cancer screening rates at community health centers (CHCs) in the United States declined during the pandemic, particularly among Black and uninsured individuals, based on a retrospective look at 32 sites.

Still, drops in screening were less dramatic than national declines previously reported, possibly because of the American Cancer Society–directed CHANGE program, which was simultaneously underway at the CHCs involved, reported lead author Stacey A. Fedewa, PhD, senior principal scientist at the ACS in Atlanta, and colleagues.

“This is one of the first studies to examine breast cancer screening rates during the pandemic specifically among clinics providing care to communities of color and lower income populations, a group with lower utilization of and greater barriers to [breast cancer] screening,” the investigators wrote in Cancer. “This is important because these populations have longstanding barriers to accessing care, lower breast screening rates, higher breast cancer mortality rates, and are especially vulnerable to health care disruptions.”

According to a previous analysis of electronic health records by Mast and Munoz del Rio, breast cancer screening rates in the United States dropped 94% in March/April 2020, when the COVID-19 pandemic was declared a national emergency. Although a recent follow-up report showed a rebound in breast cancer screening, the estimated rate remains 13% below average.

The present study evaluated data from 32 out of 1,385 CHCs in the United States. All centers were involved in the ACS-run CHANGE grant program, which funded the clinics for 2 years, during which time they implemented at least three evidence-based provider and client interventions, such as patient navigation or electronic medical record enhancements. The clinics reported breast cancer screening rates on a routine basis throughout the 2-year period, beginning August 2018.

Breast cancer screening rate was defined as the percentage of women aged 50-74 years who had a screening mammogram within the past 27 months, out of a total pool of women who had a medical visit within the past year. For 2018, 2019, and 2020, respectively, 142,207; 142,003; and 150,630 women had a medical visit. Screening rates were compared across years in either June or July. Findings were further characterized by demographic characteristics, urban/rural status, and clinic region.

From 2018 to 2019 breast cancer screening rates rose 18%, from 45.8% to 53.9%. This increase was followed by an 8% decline during the 2019-2020 period, from 53.9% to 49.6%.

The investigators estimated the number of missed mammograms and breast cancer diagnoses for two comparative, hypothetical scenarios: first, if the rising trend from 2018 to 2019 had continued through 2020, and second, if the rate had plateaued at 53.9%.

The rising trend model suggested that 47,517 fewer mammograms than normal were conducted during 2019-2020, resulting in 242 missed breast cancer diagnoses, of which 166 were invasive and 76 were ductal carcinoma in situ. The plateau model suggested that 6,477 fewer mammograms were conducted, leading to 33 missed diagnoses.

Compared with the 8% decline in screening overall, the rate among Black patients dropped 12%, while rates at clinics with a lower proportion of uninsured patients dropped an average of 15%. In contrast, clinics in the South did not have a significant reduction in screening, “possibly reflecting lower baseline rates or impact of stay-at-home orders,” the investigators wrote.

Dr. Fedewa and colleagues also noted that their findings were less dramatic than those reported by Mast and Munoz del Rio. They suggested that the CHANGE program may have softened the blow dealt by the pandemic.

“The CHANGE program–funded interventions – that were established before and continued through 2020 – may have mitigated the pandemic’s effects on breast cancer screening services among the 32 CHCs that were studied,” they wrote. “Further investigation of breast cancer screening rates among additional CHCs will further inform where targeted interventions (e.g., client reminders, education on return to screening) are most needed.”

According to Madeline Sutton, MD, assistant professor of obstetrics and gynecology at Morehouse School of Medicine, Atlanta, “Progress seen with the CHANGE program should be duplicated in other clinical venues based on improvements seen in numbers of mammograms and breast cancers detected.”

Still, Dr. Sutton noted that the racial/ethnic disparities remain cause for concern.

“This study has implications for persons served at CHCs, especially if breast cancer racial/ethnic disparities are unintentionally widened during this pandemic,” Dr. Sutton said in a written comment. “Policy-level changes that decrease BCSR [breast cancer screen rate] gaps for women are warranted.”

Ana Velázquez Mañana, MD, a medical oncology fellow at the University of California, San Francisco, suggested that the effects of the pandemic may have been even more pronounced among medically underserved patients in whom interventions to increase screening were not being conducted, as they were through the CHANGE program.

“One must wonder to what degree these interventions reduced the decline in screening mammography rates observed during the pandemic and to what degree could disparities in screening be magnified in community health centers with less resources,” Dr. Velázquez said in a written comment. “Therefore, understanding barriers to breast cancer screening among our specific health care systems is key to guide resource allocation and the development of evidence-based multilevel interventions that can address these barriers, and ultimately increase screening rates.”

Dr. Velázquez also noted that the study by Dr. Fedewa and colleagues may have missed drops in screening among vulnerable populations that occurred later in the pandemic and in geographic hotspots. In a recent JAMA Network Open study, Dr. Velázquez reported a 41% drop in breast cancer screening at a safety-net hospital in San Francisco during the first stay-at-home order, which lasted from Feb. 1, 2020 to May 31, 2020.

The Breast Health Equity CHANGE grant was funded by the National Football League in partnership with the American Cancer Society. The investigators reported employment by the American Cancer Society. Dr. Wehling and Dr. Wysocki disclosed grants from Pfizer unrelated to this research. Dr. Sutton and Dr. Velázquez disclosed no conflicts of interest.

Breast cancer screening rates at community health centers (CHCs) in the United States declined during the pandemic, particularly among Black and uninsured individuals, based on a retrospective look at 32 sites.

Still, drops in screening were less dramatic than national declines previously reported, possibly because of the American Cancer Society–directed CHANGE program, which was simultaneously underway at the CHCs involved, reported lead author Stacey A. Fedewa, PhD, senior principal scientist at the ACS in Atlanta, and colleagues.

“This is one of the first studies to examine breast cancer screening rates during the pandemic specifically among clinics providing care to communities of color and lower income populations, a group with lower utilization of and greater barriers to [breast cancer] screening,” the investigators wrote in Cancer. “This is important because these populations have longstanding barriers to accessing care, lower breast screening rates, higher breast cancer mortality rates, and are especially vulnerable to health care disruptions.”

According to a previous analysis of electronic health records by Mast and Munoz del Rio, breast cancer screening rates in the United States dropped 94% in March/April 2020, when the COVID-19 pandemic was declared a national emergency. Although a recent follow-up report showed a rebound in breast cancer screening, the estimated rate remains 13% below average.

The present study evaluated data from 32 out of 1,385 CHCs in the United States. All centers were involved in the ACS-run CHANGE grant program, which funded the clinics for 2 years, during which time they implemented at least three evidence-based provider and client interventions, such as patient navigation or electronic medical record enhancements. The clinics reported breast cancer screening rates on a routine basis throughout the 2-year period, beginning August 2018.

Breast cancer screening rate was defined as the percentage of women aged 50-74 years who had a screening mammogram within the past 27 months, out of a total pool of women who had a medical visit within the past year. For 2018, 2019, and 2020, respectively, 142,207; 142,003; and 150,630 women had a medical visit. Screening rates were compared across years in either June or July. Findings were further characterized by demographic characteristics, urban/rural status, and clinic region.

From 2018 to 2019 breast cancer screening rates rose 18%, from 45.8% to 53.9%. This increase was followed by an 8% decline during the 2019-2020 period, from 53.9% to 49.6%.

The investigators estimated the number of missed mammograms and breast cancer diagnoses for two comparative, hypothetical scenarios: first, if the rising trend from 2018 to 2019 had continued through 2020, and second, if the rate had plateaued at 53.9%.

The rising trend model suggested that 47,517 fewer mammograms than normal were conducted during 2019-2020, resulting in 242 missed breast cancer diagnoses, of which 166 were invasive and 76 were ductal carcinoma in situ. The plateau model suggested that 6,477 fewer mammograms were conducted, leading to 33 missed diagnoses.

Compared with the 8% decline in screening overall, the rate among Black patients dropped 12%, while rates at clinics with a lower proportion of uninsured patients dropped an average of 15%. In contrast, clinics in the South did not have a significant reduction in screening, “possibly reflecting lower baseline rates or impact of stay-at-home orders,” the investigators wrote.

Dr. Fedewa and colleagues also noted that their findings were less dramatic than those reported by Mast and Munoz del Rio. They suggested that the CHANGE program may have softened the blow dealt by the pandemic.

“The CHANGE program–funded interventions – that were established before and continued through 2020 – may have mitigated the pandemic’s effects on breast cancer screening services among the 32 CHCs that were studied,” they wrote. “Further investigation of breast cancer screening rates among additional CHCs will further inform where targeted interventions (e.g., client reminders, education on return to screening) are most needed.”

According to Madeline Sutton, MD, assistant professor of obstetrics and gynecology at Morehouse School of Medicine, Atlanta, “Progress seen with the CHANGE program should be duplicated in other clinical venues based on improvements seen in numbers of mammograms and breast cancers detected.”

Still, Dr. Sutton noted that the racial/ethnic disparities remain cause for concern.

“This study has implications for persons served at CHCs, especially if breast cancer racial/ethnic disparities are unintentionally widened during this pandemic,” Dr. Sutton said in a written comment. “Policy-level changes that decrease BCSR [breast cancer screen rate] gaps for women are warranted.”

Ana Velázquez Mañana, MD, a medical oncology fellow at the University of California, San Francisco, suggested that the effects of the pandemic may have been even more pronounced among medically underserved patients in whom interventions to increase screening were not being conducted, as they were through the CHANGE program.

“One must wonder to what degree these interventions reduced the decline in screening mammography rates observed during the pandemic and to what degree could disparities in screening be magnified in community health centers with less resources,” Dr. Velázquez said in a written comment. “Therefore, understanding barriers to breast cancer screening among our specific health care systems is key to guide resource allocation and the development of evidence-based multilevel interventions that can address these barriers, and ultimately increase screening rates.”

Dr. Velázquez also noted that the study by Dr. Fedewa and colleagues may have missed drops in screening among vulnerable populations that occurred later in the pandemic and in geographic hotspots. In a recent JAMA Network Open study, Dr. Velázquez reported a 41% drop in breast cancer screening at a safety-net hospital in San Francisco during the first stay-at-home order, which lasted from Feb. 1, 2020 to May 31, 2020.

The Breast Health Equity CHANGE grant was funded by the National Football League in partnership with the American Cancer Society. The investigators reported employment by the American Cancer Society. Dr. Wehling and Dr. Wysocki disclosed grants from Pfizer unrelated to this research. Dr. Sutton and Dr. Velázquez disclosed no conflicts of interest.

The Food and Drug Administration is urging health care providers to immediately stop use of and discard all Eco-Med ultrasound gels and lotions because of risk for bacterial contamination with Burkholderia cepacia complex (Bcc). Earlier this month, the Centers for Disease Control and Prevention and the FDA announced an outbreak of at least 15 Bcc infections associated with contaminated ultrasound gel, and, according to the FDA, Eco-Med ultrasound gels have now been linked to at least 59 infections, 48 of which were blood infections.

On Aug. 4, the Canadian pharmaceutical company, based in Etobicoke, Ont., initiated a voluntary recall of certain lots of EcoGel 200 Ultrasound gel because of contamination with Bcc, but now the FDA warns that all Eco-Med’s ultrasound gels and lotions are at risk.

“The FDA’s determination is based on concerns that the company did not complete its investigation of the issues, the root cause and extent of bacterial contamination was not identified, and multiple products could be affected by manufacturing issues associated with the company’s ultrasound gel (such as inappropriate testing of finished product, inadequate testing of raw materials, and a lack of environmental controls),” the FDA said in a letter to health care providers published Aug. 18.

The letter lists 25 products manufactured by Eco-Med that are sold by distributors in 10 different countries, including the United States and Canada. The list may not be completely comprehensive, the organization notes.

Eco-Med has ceased all operations and is no longer manufacturing or distributing products, according to the FDA statement. Both phone numbers listed for the company were not in operation at the time of reporting.

Beyond stopping use of and discarding Eco-Med products, the FDA recommends that health care providers and facilities stop purchases of Eco-Med products, contact distributors with product disposal questions, and follow professional society guidelines and CDC guidelines for ultrasound use and cleaning products. Providers are encouraged to report adverse events related to Eco-Med ultrasound gels or lotions through MedWatch: The FDA Safety Information and Adverse Event Reporting program.

Though Eco-Med is listed as one of the “prominent players in the ultrasound gel market,” according to a June 2020 report by Grand View Research, the announcement will likely not cause many issues, Lauren Golding, MD, chair of the American College of Radiology Commission on Ultrasound, said in an interview.

“Fortunately, several companies produce ultrasound gel. Barring unforeseen circumstances, we do not expect this FDA action to have a widespread impact on patients’ access to ultrasound exams in the United States,” she said.

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

The Food and Drug Administration is urging health care providers to immediately stop use of and discard all Eco-Med ultrasound gels and lotions because of risk for bacterial contamination with Burkholderia cepacia complex (Bcc). Earlier this month, the Centers for Disease Control and Prevention and the FDA announced an outbreak of at least 15 Bcc infections associated with contaminated ultrasound gel, and, according to the FDA, Eco-Med ultrasound gels have now been linked to at least 59 infections, 48 of which were blood infections.

On Aug. 4, the Canadian pharmaceutical company, based in Etobicoke, Ont., initiated a voluntary recall of certain lots of EcoGel 200 Ultrasound gel because of contamination with Bcc, but now the FDA warns that all Eco-Med’s ultrasound gels and lotions are at risk.

“The FDA’s determination is based on concerns that the company did not complete its investigation of the issues, the root cause and extent of bacterial contamination was not identified, and multiple products could be affected by manufacturing issues associated with the company’s ultrasound gel (such as inappropriate testing of finished product, inadequate testing of raw materials, and a lack of environmental controls),” the FDA said in a letter to health care providers published Aug. 18.

The letter lists 25 products manufactured by Eco-Med that are sold by distributors in 10 different countries, including the United States and Canada. The list may not be completely comprehensive, the organization notes.

Eco-Med has ceased all operations and is no longer manufacturing or distributing products, according to the FDA statement. Both phone numbers listed for the company were not in operation at the time of reporting.

Beyond stopping use of and discarding Eco-Med products, the FDA recommends that health care providers and facilities stop purchases of Eco-Med products, contact distributors with product disposal questions, and follow professional society guidelines and CDC guidelines for ultrasound use and cleaning products. Providers are encouraged to report adverse events related to Eco-Med ultrasound gels or lotions through MedWatch: The FDA Safety Information and Adverse Event Reporting program.

Though Eco-Med is listed as one of the “prominent players in the ultrasound gel market,” according to a June 2020 report by Grand View Research, the announcement will likely not cause many issues, Lauren Golding, MD, chair of the American College of Radiology Commission on Ultrasound, said in an interview.

“Fortunately, several companies produce ultrasound gel. Barring unforeseen circumstances, we do not expect this FDA action to have a widespread impact on patients’ access to ultrasound exams in the United States,” she said.

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

The Food and Drug Administration is urging health care providers to immediately stop use of and discard all Eco-Med ultrasound gels and lotions because of risk for bacterial contamination with Burkholderia cepacia complex (Bcc). Earlier this month, the Centers for Disease Control and Prevention and the FDA announced an outbreak of at least 15 Bcc infections associated with contaminated ultrasound gel, and, according to the FDA, Eco-Med ultrasound gels have now been linked to at least 59 infections, 48 of which were blood infections.

On Aug. 4, the Canadian pharmaceutical company, based in Etobicoke, Ont., initiated a voluntary recall of certain lots of EcoGel 200 Ultrasound gel because of contamination with Bcc, but now the FDA warns that all Eco-Med’s ultrasound gels and lotions are at risk.

“The FDA’s determination is based on concerns that the company did not complete its investigation of the issues, the root cause and extent of bacterial contamination was not identified, and multiple products could be affected by manufacturing issues associated with the company’s ultrasound gel (such as inappropriate testing of finished product, inadequate testing of raw materials, and a lack of environmental controls),” the FDA said in a letter to health care providers published Aug. 18.

The letter lists 25 products manufactured by Eco-Med that are sold by distributors in 10 different countries, including the United States and Canada. The list may not be completely comprehensive, the organization notes.

Eco-Med has ceased all operations and is no longer manufacturing or distributing products, according to the FDA statement. Both phone numbers listed for the company were not in operation at the time of reporting.

Beyond stopping use of and discarding Eco-Med products, the FDA recommends that health care providers and facilities stop purchases of Eco-Med products, contact distributors with product disposal questions, and follow professional society guidelines and CDC guidelines for ultrasound use and cleaning products. Providers are encouraged to report adverse events related to Eco-Med ultrasound gels or lotions through MedWatch: The FDA Safety Information and Adverse Event Reporting program.

Though Eco-Med is listed as one of the “prominent players in the ultrasound gel market,” according to a June 2020 report by Grand View Research, the announcement will likely not cause many issues, Lauren Golding, MD, chair of the American College of Radiology Commission on Ultrasound, said in an interview.

“Fortunately, several companies produce ultrasound gel. Barring unforeseen circumstances, we do not expect this FDA action to have a widespread impact on patients’ access to ultrasound exams in the United States,” she said.

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