AVAHO

Febrile neutropenia (FN) is a life-threatening oncologic emergency requiring timely evaluation and treatment. Chemotherapy-induced neutropenia is a major risk for life-threatening infection, and fever may be the only sign.^1,2 Unrecognized fever can progress to sepsis and may result in increased morbidity and mortality. FN is defined as the presence of fever with a single temperature of  ≥ 38.3 °C or a sustained temperature > 38 °C sustained over 1 hour with an absolute neutrophil count (ANC) of < 500 cells/mm³ or < 1000 cells/mm³ and expected to decrease to < 500 within 48 hours.^2,3 It is critical to quickly identify these patients on presentation to the emergency department (ED) and take appropriate steps to initiate treatment as soon as possible. To streamline care, the American Society of Clinical Oncology (ASCO) recommends that laboratory assessments be initiated within 15 minutes of triage and empiric antibiotic therapy be administered within 1 hour.²

In alignment with the Infectious Disease Society of America (IDSA) guidelines, the National Comprehensive Cancer Network (NCCN) highlights the importance of the initial assessment of fever and neutropenia and presents available treatment options for both inpatient and outpatient management of FN.¹ Once patients are identified, the appropriate laboratory tests and physical assessments should be initiated immediately. These tests include a complete blood count with differential, complete metabolic panel (CMP), and blood cultures from 2 separate IV sites.^1-3 The guidelines offer additional suggestions for cultures and radiographic assessments that may be completed based on clinical presentation.

Several available studies provide insight into methods of protocol creation and possible barriers to timely management. Previous research showed that an FN protocol for pediatric oncology patients aimed at antibiotic administration within 1 hour showed significant improvement from 35.0% to 55.4% of patients being treated on time.^3,4 Prescribers became more comfortable in using the protocol, and timing improved as the study progressed. Barriers noted were inconsistent ED triage, rotating ED staff, and limited understanding of the protocol.³ Yoshida and colleagues worked with the same population. Over the course of 1 year, 60% of patients were receiving antibiotics within 1 hour. The mean time decreased from 83 to 65 minutes, which the study investigators noted would continue to decrease with increased protocol comfort and use.⁵ Mattison and colleagues used nursing staff to identify patients with FN and begin antibiotic treatment. On triage, nurses took note of a temperature of > 38 °C or a sepsislike clinical picture that initiated their antibiotic proforma.^4,6 This resulted in 48.1% of patients receiving antibiotics within 15 minutes and 63.3% overall within 30 minutes of arrival.⁵ Other barriers to consider are ED crowding and the admission of higher acuity patients, which may delay the treatment of patients with FN.

The US Department of Veterans Affairs (VA) Richard L. Roudebush VA Medical Center (RLRVAMC) in Indianapolis, Indiana is a level 1A facility serving about 62,000 veterans annually and more than 13,000 unique veterans visiting the ED. RLRVAMC ED staff rotate often so the creation of a process will facilitate appropriate treatment as quickly as possible. The purpose of this protocol was to improve the mean time from triage to administration of antibiotics for patients with FN presenting to the ED.

Implementation

To quantify the perceived delay in antibiotic prescribing, a pre- and postprotocol retrospective chart review of patients who presented with FN to the RLRVAMC ED was conducted. Patients were identified through the electronic health record (EHR) based on 3 criteria: recorded/reported fever as defined above, ANC < 1000 cells/mm³, and administration of cancer treatment (IV and oral) within 4 weeks. The data collected in the postimplementation phase were identical to the pre-implementation phase. This included timing of blood cultures, choice/appropriateness of antibiotics based on guidelines, and length of admission. The pre-implementation period started on August 1, 2018, and ended on August 1, 2019, to allow for an adequate pre-implementation sample size. The protocol was then implemented on October 1, 2019, and data collection for the postimplementation phase began on October 1,2019, and ended on October 1, 2020.

The protocol was accompanied by EHR order sets initiated by both nurses and health care practitioners (HCPs), including physicians, nurse practitioners, and physician assistants. The nursing order set consisted of vitals and appropriate laboratory monitoring, and the practitioner order set housed medication orders and additional clinical monitoring for more patient-specific scenarios. On identification of at-risk patients, the nursing staff could initiate the neutropenic fever protocol without consulting an HCP. The patient was then assigned a higher acuity rank, and the HCP was tasked with seeing the patient immediately. In conjunction with a complete physical assessment, the HCP ordered appropriate antibiotics through the designated order set to streamline antibiotic selection. Antibiotic options included cefepime or piperacillin-tazobactam, and vancomycin when clinically indicated. Alternatives for patients allergic to penicillin also were available. The protocol intended to streamline workup and antibiotic selection but was not designed as a substitute for solid clinical decision making and complete assessment on behalf of the HCP; therefore, additional workup may have been necessary and documented in the EHR.

Findings

This patient population comprised 17 patients pre-implementation and 12 patients postimplementation, most of whom had solid tumor malignancies (88.2% and 83.3%, respectively) receiving platinum, taxane, or antimetabolite-based chemotherapy. In the pre-implementation group, most patients (70.5%) coming through the ED were treated with palliative intent. Only 25% of these received any prophylactic granulocyte-colony stimulating factor (G-CSF) based on risk for FN. The mean time from triage to the first dose of antibiotics decreased from 3.3 hours before protocol implementation to 2.3 hours after. Only 6% in the pre-implementation group compared with 17% in the postimplementation group received the first dose of antibiotics within the recommended 1-hour interval from triage. The most common antibiotics administered were cefepime and vancomycin. Eleven patients in each group (65% and 92%, respectively) were admitted to the inpatient service for further care, with 10 and 8 patients, respectively, experiencing a hospitalization > 72 hours. Of note, 41% of patients died pre-implementation vs 17% postimplementation.

Interpretation

The goal of this protocol was to optimize ED care of patients presenting with FN to better align with guideline-recommended time lines and antibiotics. The mean time from triage to administration of antibiotics decreased by 1.0 hour from the pre- to postimplementation phase, similar to the study by Mattison and colleagues.³ When removing an outlier from the postimplementation group, the mean time from triage to first dose further decreased to 1.8 hours. The percentage of patients receiving antibiotics within 1 hour of triage nearly tripled from 6% to 17%. Additionally, the percentage of patients empirically treated with appropriate antibiotics consistent with NCCN/ASCO/IDSA guidelines increased from 65% to 83%. Although goals for the optimization of care have not yet been reached, this protocol is the first step in the right direction.

Limitations

Several limitations and concerns arise when implementing a new protocol or workflow process. Overall, these limitations may contribute to delays, such as the willingness of team members to use an unfamiliar protocol or issues locating a new protocol. The nursing staff is challenged to triage patients quickly, which may add to an already busy environment. Frequent physician turnover may require more frequent education sessions. Also, a lag time between implementation and using the protocol may result in decreased protocol use during the designated postimplementation data collection phase.

On review, ED staff were excited to find a protocol that streamlined decision making and increased awareness for patients at risk. The COVID-19 pandemic may have been a confounder for the postimplementation phase. Data may have been skewed as some patients might have elected to stay at home to avoid potential COVID-19 exposure in the ED. Additionally, increased ED use by patients with COVID-19 may have resulted in longer wait times for an available bed, thereby minimizing the impact of the protocol on time from triage to administration of antibiotics. COVID-19 may also have contributed to postimplementation mortality. Of note, barcode medication administration (BCMA) was implemented in the ED in May 2019, which may account for undocumented delays in antibiotic administration as staff may have been unfamiliar with BCMA workflow.

Due to the retrospective nature of a chart review, the data rely on the timely input and accuracy of documented information. Data after the patient’s ED encounter (except inpatient hospitalization and deaths during the implementation period) were not collected due to the scope of the program being limited to the ED only. Last, this protocol was implemented at a single site, and the generalizability to implement the same protocol at other VA medical centers may be limited. After reaching out to other VA sites and several non-VA facilities, we were unable to find a site with a similar protocol or program emphasizing the importance of timely care, although there may have been established laboratory test and medication order sets within the EHR.

Future Direction

The newly established FN order sets will continue to streamline clinical decision making and antibiotic selection in this population. In our study, we learned that most patients coming through the ED were being treated with palliative intent. As a result, these patients also may have a higher risk for complications like FN. We hope to further analyze the impact on this group and consider the role of empiric dose reduction or increased G-CSF support to minimize FN.

More than half of the patients who were admitted to the inpatient service, remained in extended care for > 72 hours. Inpatient recovery time may cause delays in future cancer treatment cycles, dose reductions, and contribute to an overall decline in performance status. Six patients in the pre-implementation phase and 1 in the postimplementation phase were eligible for outpatient management per independent Multinational Association of Supportive Care in Cancer assessment. To increase comfort, a future goal would be to create an outpatient treatment order set on discharge from the ED to help identify and outline treatment options for low-risk patients. In addition to the ED, training staff in clinics with a similar protocol may enhance the identification of patients with FN. This may require a tailored protocol for this location using health technicians in taking vital signs before the HCP visit.

This protocol helped establish “code sepsis.” Code sepsis alerts are broadcast to alert pertinent members of the health care team to provide immediate medical attention to the veteran. Pharmacy can expedite the compounding of antibiotics and record review while radiology prioritizes the portable X-ray for quick and efficient imaging. The nursing team comes ready to administer antibiotics once cultures are drawn. The HCP's attention is focused on the physical examination to determine any additional steps/care that need to be accomplished. At our site, we plan to continue HCP, nursing, and other team member education on this oncologic emergency and the availability of a streamlined protocol. We would like to re-assess the data with a long team study now that the protocol has been in place for 3 years. We hope to continue to provide strong patient care with enhanced adherence to guidelines for patients with FN presenting to RLRVAMC.

Conclusions

Early identification and timely empiric antibiotic therapy are critical to improving outcomes for patients presenting to the ED with FN. The neutropenic fever protocol reduced time to antibiotics by about 1 hour with a higher percentage of patients receiving them in < 1 hour. Additional optimization of the order sets along with increased protocol comfort and staff education will help further reduce the time to antibiotic administration in alignment with guideline recommendations.

Febrile neutropenia (FN) is a life-threatening oncologic emergency requiring timely evaluation and treatment. Chemotherapy-induced neutropenia is a major risk for life-threatening infection, and fever may be the only sign.^1,2 Unrecognized fever can progress to sepsis and may result in increased morbidity and mortality. FN is defined as the presence of fever with a single temperature of  ≥ 38.3 °C or a sustained temperature > 38 °C sustained over 1 hour with an absolute neutrophil count (ANC) of < 500 cells/mm³ or < 1000 cells/mm³ and expected to decrease to < 500 within 48 hours.^2,3 It is critical to quickly identify these patients on presentation to the emergency department (ED) and take appropriate steps to initiate treatment as soon as possible. To streamline care, the American Society of Clinical Oncology (ASCO) recommends that laboratory assessments be initiated within 15 minutes of triage and empiric antibiotic therapy be administered within 1 hour.²

In alignment with the Infectious Disease Society of America (IDSA) guidelines, the National Comprehensive Cancer Network (NCCN) highlights the importance of the initial assessment of fever and neutropenia and presents available treatment options for both inpatient and outpatient management of FN.¹ Once patients are identified, the appropriate laboratory tests and physical assessments should be initiated immediately. These tests include a complete blood count with differential, complete metabolic panel (CMP), and blood cultures from 2 separate IV sites.^1-3 The guidelines offer additional suggestions for cultures and radiographic assessments that may be completed based on clinical presentation.

Several available studies provide insight into methods of protocol creation and possible barriers to timely management. Previous research showed that an FN protocol for pediatric oncology patients aimed at antibiotic administration within 1 hour showed significant improvement from 35.0% to 55.4% of patients being treated on time.^3,4 Prescribers became more comfortable in using the protocol, and timing improved as the study progressed. Barriers noted were inconsistent ED triage, rotating ED staff, and limited understanding of the protocol.³ Yoshida and colleagues worked with the same population. Over the course of 1 year, 60% of patients were receiving antibiotics within 1 hour. The mean time decreased from 83 to 65 minutes, which the study investigators noted would continue to decrease with increased protocol comfort and use.⁵ Mattison and colleagues used nursing staff to identify patients with FN and begin antibiotic treatment. On triage, nurses took note of a temperature of > 38 °C or a sepsislike clinical picture that initiated their antibiotic proforma.^4,6 This resulted in 48.1% of patients receiving antibiotics within 15 minutes and 63.3% overall within 30 minutes of arrival.⁵ Other barriers to consider are ED crowding and the admission of higher acuity patients, which may delay the treatment of patients with FN.

The US Department of Veterans Affairs (VA) Richard L. Roudebush VA Medical Center (RLRVAMC) in Indianapolis, Indiana is a level 1A facility serving about 62,000 veterans annually and more than 13,000 unique veterans visiting the ED. RLRVAMC ED staff rotate often so the creation of a process will facilitate appropriate treatment as quickly as possible. The purpose of this protocol was to improve the mean time from triage to administration of antibiotics for patients with FN presenting to the ED.

Implementation

To quantify the perceived delay in antibiotic prescribing, a pre- and postprotocol retrospective chart review of patients who presented with FN to the RLRVAMC ED was conducted. Patients were identified through the electronic health record (EHR) based on 3 criteria: recorded/reported fever as defined above, ANC < 1000 cells/mm³, and administration of cancer treatment (IV and oral) within 4 weeks. The data collected in the postimplementation phase were identical to the pre-implementation phase. This included timing of blood cultures, choice/appropriateness of antibiotics based on guidelines, and length of admission. The pre-implementation period started on August 1, 2018, and ended on August 1, 2019, to allow for an adequate pre-implementation sample size. The protocol was then implemented on October 1, 2019, and data collection for the postimplementation phase began on October 1,2019, and ended on October 1, 2020.

The protocol was accompanied by EHR order sets initiated by both nurses and health care practitioners (HCPs), including physicians, nurse practitioners, and physician assistants. The nursing order set consisted of vitals and appropriate laboratory monitoring, and the practitioner order set housed medication orders and additional clinical monitoring for more patient-specific scenarios. On identification of at-risk patients, the nursing staff could initiate the neutropenic fever protocol without consulting an HCP. The patient was then assigned a higher acuity rank, and the HCP was tasked with seeing the patient immediately. In conjunction with a complete physical assessment, the HCP ordered appropriate antibiotics through the designated order set to streamline antibiotic selection. Antibiotic options included cefepime or piperacillin-tazobactam, and vancomycin when clinically indicated. Alternatives for patients allergic to penicillin also were available. The protocol intended to streamline workup and antibiotic selection but was not designed as a substitute for solid clinical decision making and complete assessment on behalf of the HCP; therefore, additional workup may have been necessary and documented in the EHR.

Findings

This patient population comprised 17 patients pre-implementation and 12 patients postimplementation, most of whom had solid tumor malignancies (88.2% and 83.3%, respectively) receiving platinum, taxane, or antimetabolite-based chemotherapy. In the pre-implementation group, most patients (70.5%) coming through the ED were treated with palliative intent. Only 25% of these received any prophylactic granulocyte-colony stimulating factor (G-CSF) based on risk for FN. The mean time from triage to the first dose of antibiotics decreased from 3.3 hours before protocol implementation to 2.3 hours after. Only 6% in the pre-implementation group compared with 17% in the postimplementation group received the first dose of antibiotics within the recommended 1-hour interval from triage. The most common antibiotics administered were cefepime and vancomycin. Eleven patients in each group (65% and 92%, respectively) were admitted to the inpatient service for further care, with 10 and 8 patients, respectively, experiencing a hospitalization > 72 hours. Of note, 41% of patients died pre-implementation vs 17% postimplementation.

Interpretation

The goal of this protocol was to optimize ED care of patients presenting with FN to better align with guideline-recommended time lines and antibiotics. The mean time from triage to administration of antibiotics decreased by 1.0 hour from the pre- to postimplementation phase, similar to the study by Mattison and colleagues.³ When removing an outlier from the postimplementation group, the mean time from triage to first dose further decreased to 1.8 hours. The percentage of patients receiving antibiotics within 1 hour of triage nearly tripled from 6% to 17%. Additionally, the percentage of patients empirically treated with appropriate antibiotics consistent with NCCN/ASCO/IDSA guidelines increased from 65% to 83%. Although goals for the optimization of care have not yet been reached, this protocol is the first step in the right direction.

Limitations

Several limitations and concerns arise when implementing a new protocol or workflow process. Overall, these limitations may contribute to delays, such as the willingness of team members to use an unfamiliar protocol or issues locating a new protocol. The nursing staff is challenged to triage patients quickly, which may add to an already busy environment. Frequent physician turnover may require more frequent education sessions. Also, a lag time between implementation and using the protocol may result in decreased protocol use during the designated postimplementation data collection phase.

On review, ED staff were excited to find a protocol that streamlined decision making and increased awareness for patients at risk. The COVID-19 pandemic may have been a confounder for the postimplementation phase. Data may have been skewed as some patients might have elected to stay at home to avoid potential COVID-19 exposure in the ED. Additionally, increased ED use by patients with COVID-19 may have resulted in longer wait times for an available bed, thereby minimizing the impact of the protocol on time from triage to administration of antibiotics. COVID-19 may also have contributed to postimplementation mortality. Of note, barcode medication administration (BCMA) was implemented in the ED in May 2019, which may account for undocumented delays in antibiotic administration as staff may have been unfamiliar with BCMA workflow.

Due to the retrospective nature of a chart review, the data rely on the timely input and accuracy of documented information. Data after the patient’s ED encounter (except inpatient hospitalization and deaths during the implementation period) were not collected due to the scope of the program being limited to the ED only. Last, this protocol was implemented at a single site, and the generalizability to implement the same protocol at other VA medical centers may be limited. After reaching out to other VA sites and several non-VA facilities, we were unable to find a site with a similar protocol or program emphasizing the importance of timely care, although there may have been established laboratory test and medication order sets within the EHR.

Future Direction

The newly established FN order sets will continue to streamline clinical decision making and antibiotic selection in this population. In our study, we learned that most patients coming through the ED were being treated with palliative intent. As a result, these patients also may have a higher risk for complications like FN. We hope to further analyze the impact on this group and consider the role of empiric dose reduction or increased G-CSF support to minimize FN.

More than half of the patients who were admitted to the inpatient service, remained in extended care for > 72 hours. Inpatient recovery time may cause delays in future cancer treatment cycles, dose reductions, and contribute to an overall decline in performance status. Six patients in the pre-implementation phase and 1 in the postimplementation phase were eligible for outpatient management per independent Multinational Association of Supportive Care in Cancer assessment. To increase comfort, a future goal would be to create an outpatient treatment order set on discharge from the ED to help identify and outline treatment options for low-risk patients. In addition to the ED, training staff in clinics with a similar protocol may enhance the identification of patients with FN. This may require a tailored protocol for this location using health technicians in taking vital signs before the HCP visit.

This protocol helped establish “code sepsis.” Code sepsis alerts are broadcast to alert pertinent members of the health care team to provide immediate medical attention to the veteran. Pharmacy can expedite the compounding of antibiotics and record review while radiology prioritizes the portable X-ray for quick and efficient imaging. The nursing team comes ready to administer antibiotics once cultures are drawn. The HCP's attention is focused on the physical examination to determine any additional steps/care that need to be accomplished. At our site, we plan to continue HCP, nursing, and other team member education on this oncologic emergency and the availability of a streamlined protocol. We would like to re-assess the data with a long team study now that the protocol has been in place for 3 years. We hope to continue to provide strong patient care with enhanced adherence to guidelines for patients with FN presenting to RLRVAMC.

Conclusions

Early identification and timely empiric antibiotic therapy are critical to improving outcomes for patients presenting to the ED with FN. The neutropenic fever protocol reduced time to antibiotics by about 1 hour with a higher percentage of patients receiving them in < 1 hour. Additional optimization of the order sets along with increased protocol comfort and staff education will help further reduce the time to antibiotic administration in alignment with guideline recommendations.

Febrile neutropenia (FN) is a life-threatening oncologic emergency requiring timely evaluation and treatment. Chemotherapy-induced neutropenia is a major risk for life-threatening infection, and fever may be the only sign.^1,2 Unrecognized fever can progress to sepsis and may result in increased morbidity and mortality. FN is defined as the presence of fever with a single temperature of  ≥ 38.3 °C or a sustained temperature > 38 °C sustained over 1 hour with an absolute neutrophil count (ANC) of < 500 cells/mm³ or < 1000 cells/mm³ and expected to decrease to < 500 within 48 hours.^2,3 It is critical to quickly identify these patients on presentation to the emergency department (ED) and take appropriate steps to initiate treatment as soon as possible. To streamline care, the American Society of Clinical Oncology (ASCO) recommends that laboratory assessments be initiated within 15 minutes of triage and empiric antibiotic therapy be administered within 1 hour.²

In alignment with the Infectious Disease Society of America (IDSA) guidelines, the National Comprehensive Cancer Network (NCCN) highlights the importance of the initial assessment of fever and neutropenia and presents available treatment options for both inpatient and outpatient management of FN.¹ Once patients are identified, the appropriate laboratory tests and physical assessments should be initiated immediately. These tests include a complete blood count with differential, complete metabolic panel (CMP), and blood cultures from 2 separate IV sites.^1-3 The guidelines offer additional suggestions for cultures and radiographic assessments that may be completed based on clinical presentation.

Several available studies provide insight into methods of protocol creation and possible barriers to timely management. Previous research showed that an FN protocol for pediatric oncology patients aimed at antibiotic administration within 1 hour showed significant improvement from 35.0% to 55.4% of patients being treated on time.^3,4 Prescribers became more comfortable in using the protocol, and timing improved as the study progressed. Barriers noted were inconsistent ED triage, rotating ED staff, and limited understanding of the protocol.³ Yoshida and colleagues worked with the same population. Over the course of 1 year, 60% of patients were receiving antibiotics within 1 hour. The mean time decreased from 83 to 65 minutes, which the study investigators noted would continue to decrease with increased protocol comfort and use.⁵ Mattison and colleagues used nursing staff to identify patients with FN and begin antibiotic treatment. On triage, nurses took note of a temperature of > 38 °C or a sepsislike clinical picture that initiated their antibiotic proforma.^4,6 This resulted in 48.1% of patients receiving antibiotics within 15 minutes and 63.3% overall within 30 minutes of arrival.⁵ Other barriers to consider are ED crowding and the admission of higher acuity patients, which may delay the treatment of patients with FN.

The US Department of Veterans Affairs (VA) Richard L. Roudebush VA Medical Center (RLRVAMC) in Indianapolis, Indiana is a level 1A facility serving about 62,000 veterans annually and more than 13,000 unique veterans visiting the ED. RLRVAMC ED staff rotate often so the creation of a process will facilitate appropriate treatment as quickly as possible. The purpose of this protocol was to improve the mean time from triage to administration of antibiotics for patients with FN presenting to the ED.

Implementation

To quantify the perceived delay in antibiotic prescribing, a pre- and postprotocol retrospective chart review of patients who presented with FN to the RLRVAMC ED was conducted. Patients were identified through the electronic health record (EHR) based on 3 criteria: recorded/reported fever as defined above, ANC < 1000 cells/mm³, and administration of cancer treatment (IV and oral) within 4 weeks. The data collected in the postimplementation phase were identical to the pre-implementation phase. This included timing of blood cultures, choice/appropriateness of antibiotics based on guidelines, and length of admission. The pre-implementation period started on August 1, 2018, and ended on August 1, 2019, to allow for an adequate pre-implementation sample size. The protocol was then implemented on October 1, 2019, and data collection for the postimplementation phase began on October 1,2019, and ended on October 1, 2020.

The protocol was accompanied by EHR order sets initiated by both nurses and health care practitioners (HCPs), including physicians, nurse practitioners, and physician assistants. The nursing order set consisted of vitals and appropriate laboratory monitoring, and the practitioner order set housed medication orders and additional clinical monitoring for more patient-specific scenarios. On identification of at-risk patients, the nursing staff could initiate the neutropenic fever protocol without consulting an HCP. The patient was then assigned a higher acuity rank, and the HCP was tasked with seeing the patient immediately. In conjunction with a complete physical assessment, the HCP ordered appropriate antibiotics through the designated order set to streamline antibiotic selection. Antibiotic options included cefepime or piperacillin-tazobactam, and vancomycin when clinically indicated. Alternatives for patients allergic to penicillin also were available. The protocol intended to streamline workup and antibiotic selection but was not designed as a substitute for solid clinical decision making and complete assessment on behalf of the HCP; therefore, additional workup may have been necessary and documented in the EHR.

Findings

This patient population comprised 17 patients pre-implementation and 12 patients postimplementation, most of whom had solid tumor malignancies (88.2% and 83.3%, respectively) receiving platinum, taxane, or antimetabolite-based chemotherapy. In the pre-implementation group, most patients (70.5%) coming through the ED were treated with palliative intent. Only 25% of these received any prophylactic granulocyte-colony stimulating factor (G-CSF) based on risk for FN. The mean time from triage to the first dose of antibiotics decreased from 3.3 hours before protocol implementation to 2.3 hours after. Only 6% in the pre-implementation group compared with 17% in the postimplementation group received the first dose of antibiotics within the recommended 1-hour interval from triage. The most common antibiotics administered were cefepime and vancomycin. Eleven patients in each group (65% and 92%, respectively) were admitted to the inpatient service for further care, with 10 and 8 patients, respectively, experiencing a hospitalization > 72 hours. Of note, 41% of patients died pre-implementation vs 17% postimplementation.

Interpretation

The goal of this protocol was to optimize ED care of patients presenting with FN to better align with guideline-recommended time lines and antibiotics. The mean time from triage to administration of antibiotics decreased by 1.0 hour from the pre- to postimplementation phase, similar to the study by Mattison and colleagues.³ When removing an outlier from the postimplementation group, the mean time from triage to first dose further decreased to 1.8 hours. The percentage of patients receiving antibiotics within 1 hour of triage nearly tripled from 6% to 17%. Additionally, the percentage of patients empirically treated with appropriate antibiotics consistent with NCCN/ASCO/IDSA guidelines increased from 65% to 83%. Although goals for the optimization of care have not yet been reached, this protocol is the first step in the right direction.

Limitations

Several limitations and concerns arise when implementing a new protocol or workflow process. Overall, these limitations may contribute to delays, such as the willingness of team members to use an unfamiliar protocol or issues locating a new protocol. The nursing staff is challenged to triage patients quickly, which may add to an already busy environment. Frequent physician turnover may require more frequent education sessions. Also, a lag time between implementation and using the protocol may result in decreased protocol use during the designated postimplementation data collection phase.

On review, ED staff were excited to find a protocol that streamlined decision making and increased awareness for patients at risk. The COVID-19 pandemic may have been a confounder for the postimplementation phase. Data may have been skewed as some patients might have elected to stay at home to avoid potential COVID-19 exposure in the ED. Additionally, increased ED use by patients with COVID-19 may have resulted in longer wait times for an available bed, thereby minimizing the impact of the protocol on time from triage to administration of antibiotics. COVID-19 may also have contributed to postimplementation mortality. Of note, barcode medication administration (BCMA) was implemented in the ED in May 2019, which may account for undocumented delays in antibiotic administration as staff may have been unfamiliar with BCMA workflow.

Due to the retrospective nature of a chart review, the data rely on the timely input and accuracy of documented information. Data after the patient’s ED encounter (except inpatient hospitalization and deaths during the implementation period) were not collected due to the scope of the program being limited to the ED only. Last, this protocol was implemented at a single site, and the generalizability to implement the same protocol at other VA medical centers may be limited. After reaching out to other VA sites and several non-VA facilities, we were unable to find a site with a similar protocol or program emphasizing the importance of timely care, although there may have been established laboratory test and medication order sets within the EHR.

Future Direction

The newly established FN order sets will continue to streamline clinical decision making and antibiotic selection in this population. In our study, we learned that most patients coming through the ED were being treated with palliative intent. As a result, these patients also may have a higher risk for complications like FN. We hope to further analyze the impact on this group and consider the role of empiric dose reduction or increased G-CSF support to minimize FN.

More than half of the patients who were admitted to the inpatient service, remained in extended care for > 72 hours. Inpatient recovery time may cause delays in future cancer treatment cycles, dose reductions, and contribute to an overall decline in performance status. Six patients in the pre-implementation phase and 1 in the postimplementation phase were eligible for outpatient management per independent Multinational Association of Supportive Care in Cancer assessment. To increase comfort, a future goal would be to create an outpatient treatment order set on discharge from the ED to help identify and outline treatment options for low-risk patients. In addition to the ED, training staff in clinics with a similar protocol may enhance the identification of patients with FN. This may require a tailored protocol for this location using health technicians in taking vital signs before the HCP visit.

This protocol helped establish “code sepsis.” Code sepsis alerts are broadcast to alert pertinent members of the health care team to provide immediate medical attention to the veteran. Pharmacy can expedite the compounding of antibiotics and record review while radiology prioritizes the portable X-ray for quick and efficient imaging. The nursing team comes ready to administer antibiotics once cultures are drawn. The HCP's attention is focused on the physical examination to determine any additional steps/care that need to be accomplished. At our site, we plan to continue HCP, nursing, and other team member education on this oncologic emergency and the availability of a streamlined protocol. We would like to re-assess the data with a long team study now that the protocol has been in place for 3 years. We hope to continue to provide strong patient care with enhanced adherence to guidelines for patients with FN presenting to RLRVAMC.

Conclusions

Early identification and timely empiric antibiotic therapy are critical to improving outcomes for patients presenting to the ED with FN. The neutropenic fever protocol reduced time to antibiotics by about 1 hour with a higher percentage of patients receiving them in < 1 hour. Additional optimization of the order sets along with increased protocol comfort and staff education will help further reduce the time to antibiotic administration in alignment with guideline recommendations.

A new study confirms that a plant-based diet with exercise can lower the risk of prostate cancer progressing or recurring.

The findings, which were reported at the 2023 ASCO Genitourinary Cancers Symposium in February, are based on a study of 2,038 men (median age, 64 years) with prostate cancer at stage T1, T2, or T3a.

“Consuming a whole foods plant-based diet may be an option to decrease risk for recurrence and improve overall survivorship,” said Vivian N. Liu, a clinical research coordinator at the University of California, San Francisco, who presented the findings.

The patients were interviewed about their diets at about 31.5 months after diagnosis. The study group was broken down into four groups based on how much of their diet consisted of a plant-based diet. Men in the highest quintile group who consumed at least 2.4 servings daily of fruit, 4.2 servings of vegetables, 2.6 servings of dairy, and 1.2 servings of meat (not seafood), had a 52% lower risk of progression (hazard ratio, 0.48; 95% confidence interval, 0.36-0.65; P-trend < 0.001) and a 53% lower risk of recurrence (HR, 0.47; 95% CI, 0.32-0.68; P-trend < 0.001), which was statistically significant. This compares with men in the lowest quintile who consumed 0.8 servings a day of fruit, 2.1 servings of vegetables, 3.1 servings of dairy, and 1.4 servings of meat. The findings were adjusted for total caloric intake, race, and smoking status.

For men over 65 years old, researchers found that a plant-based diet was associated with lower risk of recurrence (HR, 0.41; 95% CI, 0.24-0.7; P-trend = 0.03). And for those who exercised daily – in this case walking at a fast pace more than 3 times a week – a plant-based diet had a 56% (HR, 0.33; 95% CI, 0.26-0.73) lower risk of progression in the highest quintile group and a 59% decrease in recurrence (HR, 0.41; 95% CI, 0.25-0.68).

A new analysis like this, Ms. Liu said, “could guide people to make better, more healthful choices across their whole diet rather than adding or removing select foods.”

The primary endpoint was progression including recurrence, secondary treatment, bone metastases, and death due to prostate cancer, and the secondary endpoint was recurrence (PSA > 0.2ng/mL at 2 consecutive follow-up visits or during secondary treatment). At 7.4 years follow-up, there were 204 cases of progression.

“Fruits and vegetables contain antioxidants and anti-inflammatory components as well as dietary fiber that improve glucose control and reduce inflammation,” Ms. Liu said. In contrast, she said, animal-based foods may increase insulin resistance and insulin levels and boost levels of insulin-like growth factor 1, which is associated with prostate cancer risk. More studies, especially randomized controlled trials, are needed to provide evidence whether healthful plant-based foods and prostate cancer progression are connected.

NYU Langone Health urologist Natasha Gupta, MD, published a systematic review in 2022 on the impact of a plant-based diet on prostate cancer.* The review, which included 5 interventional studies and 11 observational studies, found that consuming a plant-based diet was associated with improvements in general health for men with prostate cancer. The observational studies found either a lower risk of prostate cancer or no significant difference.

“Patients often ask if there is anything that they can do to reduce the risk of recurrence, and it is great to be able to tell patients that a healthy lifestyle including plant-based foods and physical activity is helpful,” Dr. Gupta said.

The review’s coauthor, Stacy Loeb, MD, also of NYU Langone Health, said the new study was “a well-done observational study by experts in nutritional epidemiology from UCSF. It adds to a large body of evidence showing that plant-based diets improve health outcomes.”

“In the short-term, purchasing plant-based protein sources, such as beans and lentils, is less expensive than buying meat. Plant-based diets also reduce the risk of obesity, diabetes, and cardiovascular disease, which are associated with hundreds of thousands of dollars over a lifetime,” she said.

Limitations of the new study included the small number of non-White participants and self-reporting of diet. The study doesn’t examine the cost of various diets or the availability of plant-based foods like fresh produce, which can be limited in some neighborhoods.

Ms. Liu and colleagues plan to conduct a study that examines postdiagnostic plant-based diets in relation to prostate cancer–specific mortality. She and her team will also examine the plant-based dietary indices in relation to prostate cancer–specific quality of life at 2, 5, and 10 years from baseline.

The study authors, Dr. Loeb, and Dr. Gupta report no disclosures.

Correction, 3/17/23: An earlier version of this article misstated the name of NYU Langone Health.

A new study confirms that a plant-based diet with exercise can lower the risk of prostate cancer progressing or recurring.

The findings, which were reported at the 2023 ASCO Genitourinary Cancers Symposium in February, are based on a study of 2,038 men (median age, 64 years) with prostate cancer at stage T1, T2, or T3a.

“Consuming a whole foods plant-based diet may be an option to decrease risk for recurrence and improve overall survivorship,” said Vivian N. Liu, a clinical research coordinator at the University of California, San Francisco, who presented the findings.

The patients were interviewed about their diets at about 31.5 months after diagnosis. The study group was broken down into four groups based on how much of their diet consisted of a plant-based diet. Men in the highest quintile group who consumed at least 2.4 servings daily of fruit, 4.2 servings of vegetables, 2.6 servings of dairy, and 1.2 servings of meat (not seafood), had a 52% lower risk of progression (hazard ratio, 0.48; 95% confidence interval, 0.36-0.65; P-trend < 0.001) and a 53% lower risk of recurrence (HR, 0.47; 95% CI, 0.32-0.68; P-trend < 0.001), which was statistically significant. This compares with men in the lowest quintile who consumed 0.8 servings a day of fruit, 2.1 servings of vegetables, 3.1 servings of dairy, and 1.4 servings of meat. The findings were adjusted for total caloric intake, race, and smoking status.

For men over 65 years old, researchers found that a plant-based diet was associated with lower risk of recurrence (HR, 0.41; 95% CI, 0.24-0.7; P-trend = 0.03). And for those who exercised daily – in this case walking at a fast pace more than 3 times a week – a plant-based diet had a 56% (HR, 0.33; 95% CI, 0.26-0.73) lower risk of progression in the highest quintile group and a 59% decrease in recurrence (HR, 0.41; 95% CI, 0.25-0.68).

A new analysis like this, Ms. Liu said, “could guide people to make better, more healthful choices across their whole diet rather than adding or removing select foods.”

The primary endpoint was progression including recurrence, secondary treatment, bone metastases, and death due to prostate cancer, and the secondary endpoint was recurrence (PSA > 0.2ng/mL at 2 consecutive follow-up visits or during secondary treatment). At 7.4 years follow-up, there were 204 cases of progression.

“Fruits and vegetables contain antioxidants and anti-inflammatory components as well as dietary fiber that improve glucose control and reduce inflammation,” Ms. Liu said. In contrast, she said, animal-based foods may increase insulin resistance and insulin levels and boost levels of insulin-like growth factor 1, which is associated with prostate cancer risk. More studies, especially randomized controlled trials, are needed to provide evidence whether healthful plant-based foods and prostate cancer progression are connected.

NYU Langone Health urologist Natasha Gupta, MD, published a systematic review in 2022 on the impact of a plant-based diet on prostate cancer.* The review, which included 5 interventional studies and 11 observational studies, found that consuming a plant-based diet was associated with improvements in general health for men with prostate cancer. The observational studies found either a lower risk of prostate cancer or no significant difference.

“Patients often ask if there is anything that they can do to reduce the risk of recurrence, and it is great to be able to tell patients that a healthy lifestyle including plant-based foods and physical activity is helpful,” Dr. Gupta said.

The review’s coauthor, Stacy Loeb, MD, also of NYU Langone Health, said the new study was “a well-done observational study by experts in nutritional epidemiology from UCSF. It adds to a large body of evidence showing that plant-based diets improve health outcomes.”

“In the short-term, purchasing plant-based protein sources, such as beans and lentils, is less expensive than buying meat. Plant-based diets also reduce the risk of obesity, diabetes, and cardiovascular disease, which are associated with hundreds of thousands of dollars over a lifetime,” she said.

Limitations of the new study included the small number of non-White participants and self-reporting of diet. The study doesn’t examine the cost of various diets or the availability of plant-based foods like fresh produce, which can be limited in some neighborhoods.

Ms. Liu and colleagues plan to conduct a study that examines postdiagnostic plant-based diets in relation to prostate cancer–specific mortality. She and her team will also examine the plant-based dietary indices in relation to prostate cancer–specific quality of life at 2, 5, and 10 years from baseline.

The study authors, Dr. Loeb, and Dr. Gupta report no disclosures.

Correction, 3/17/23: An earlier version of this article misstated the name of NYU Langone Health.

A new study confirms that a plant-based diet with exercise can lower the risk of prostate cancer progressing or recurring.

The findings, which were reported at the 2023 ASCO Genitourinary Cancers Symposium in February, are based on a study of 2,038 men (median age, 64 years) with prostate cancer at stage T1, T2, or T3a.

“Consuming a whole foods plant-based diet may be an option to decrease risk for recurrence and improve overall survivorship,” said Vivian N. Liu, a clinical research coordinator at the University of California, San Francisco, who presented the findings.

The patients were interviewed about their diets at about 31.5 months after diagnosis. The study group was broken down into four groups based on how much of their diet consisted of a plant-based diet. Men in the highest quintile group who consumed at least 2.4 servings daily of fruit, 4.2 servings of vegetables, 2.6 servings of dairy, and 1.2 servings of meat (not seafood), had a 52% lower risk of progression (hazard ratio, 0.48; 95% confidence interval, 0.36-0.65; P-trend < 0.001) and a 53% lower risk of recurrence (HR, 0.47; 95% CI, 0.32-0.68; P-trend < 0.001), which was statistically significant. This compares with men in the lowest quintile who consumed 0.8 servings a day of fruit, 2.1 servings of vegetables, 3.1 servings of dairy, and 1.4 servings of meat. The findings were adjusted for total caloric intake, race, and smoking status.

For men over 65 years old, researchers found that a plant-based diet was associated with lower risk of recurrence (HR, 0.41; 95% CI, 0.24-0.7; P-trend = 0.03). And for those who exercised daily – in this case walking at a fast pace more than 3 times a week – a plant-based diet had a 56% (HR, 0.33; 95% CI, 0.26-0.73) lower risk of progression in the highest quintile group and a 59% decrease in recurrence (HR, 0.41; 95% CI, 0.25-0.68).

A new analysis like this, Ms. Liu said, “could guide people to make better, more healthful choices across their whole diet rather than adding or removing select foods.”

The primary endpoint was progression including recurrence, secondary treatment, bone metastases, and death due to prostate cancer, and the secondary endpoint was recurrence (PSA > 0.2ng/mL at 2 consecutive follow-up visits or during secondary treatment). At 7.4 years follow-up, there were 204 cases of progression.

“Fruits and vegetables contain antioxidants and anti-inflammatory components as well as dietary fiber that improve glucose control and reduce inflammation,” Ms. Liu said. In contrast, she said, animal-based foods may increase insulin resistance and insulin levels and boost levels of insulin-like growth factor 1, which is associated with prostate cancer risk. More studies, especially randomized controlled trials, are needed to provide evidence whether healthful plant-based foods and prostate cancer progression are connected.

NYU Langone Health urologist Natasha Gupta, MD, published a systematic review in 2022 on the impact of a plant-based diet on prostate cancer.* The review, which included 5 interventional studies and 11 observational studies, found that consuming a plant-based diet was associated with improvements in general health for men with prostate cancer. The observational studies found either a lower risk of prostate cancer or no significant difference.

“Patients often ask if there is anything that they can do to reduce the risk of recurrence, and it is great to be able to tell patients that a healthy lifestyle including plant-based foods and physical activity is helpful,” Dr. Gupta said.

The review’s coauthor, Stacy Loeb, MD, also of NYU Langone Health, said the new study was “a well-done observational study by experts in nutritional epidemiology from UCSF. It adds to a large body of evidence showing that plant-based diets improve health outcomes.”

“In the short-term, purchasing plant-based protein sources, such as beans and lentils, is less expensive than buying meat. Plant-based diets also reduce the risk of obesity, diabetes, and cardiovascular disease, which are associated with hundreds of thousands of dollars over a lifetime,” she said.

Limitations of the new study included the small number of non-White participants and self-reporting of diet. The study doesn’t examine the cost of various diets or the availability of plant-based foods like fresh produce, which can be limited in some neighborhoods.

Ms. Liu and colleagues plan to conduct a study that examines postdiagnostic plant-based diets in relation to prostate cancer–specific mortality. She and her team will also examine the plant-based dietary indices in relation to prostate cancer–specific quality of life at 2, 5, and 10 years from baseline.

The study authors, Dr. Loeb, and Dr. Gupta report no disclosures.

Correction, 3/17/23: An earlier version of this article misstated the name of NYU Langone Health.

With #Ozempic and #ozempicweightloss continuing to trend on social media, along with the mainstream media focusing on celebrities who rely on Ozempic (semaglutide) for weight loss, the daily requests for this new medication have been increasing.

Accompanying these requests are concerns and questions about potential risks, including this most recent message from one of my patients: “Dr. P – I saw the warnings. Is this medication going to make me get thyroid cancer? Please let me know!”

Let’s look at what we know to date, including recent studies, and how to advise our patients on this very hot topic.
 

Using GLP-1 receptor agonists for obesity

We have extensive prior experience with glucagon-like peptide 1 (GLP-1) receptor agonists, such as semaglutide, for treating type 2 diabetes and now recently as agents for weight loss.

Large clinical trials have documented the benefits of this medication class not only for weight reduction but also for cardiovascular and renal benefits in patients with diabetes. The subcutaneously injectable medications work by promoting insulin secretion, slowing gastric emptying, and suppressing glucagon secretion, with a low risk for hypoglycemia.

The Food and Drug Administration approved daily-injection GLP-1 agonist liraglutide for weight loss in 2014, and weekly-injection semaglutide for chronic weight management in 2021, in patients with a body mass index ≥ 27 with at least one weight-related condition or a BMI ≥ 30.

The brand name for semaglutide approved for weight loss is Wegovy, and the dose is slightly higher (maximum 2.4 mg/wk) than that of Ozempic (maximum 2.0 mg/wk), which is semaglutide approved for type 2 diabetes.

In trials for weight loss, data showed a mean change in body weight of almost 15% in the semaglutide group at week 68 compared with placebo, which is very impressive, particularly compared with other FDA-approved oral long-term weight loss medications.

The newest synthetic dual-acting agent is tirzepatide, which targets GLP-1 but is also a glucose-dependent insulinotropic polypeptide (GIP) agonist. The weekly subcutaneous injection was approved in May 2022 as Mounjaro for treating type 2 diabetes and produced even greater weight loss than semaglutide in clinical trials. Tirzepatide is now in trials for obesity and is under expedited review by the FDA for weight loss.
 

Why the concern about thyroid cancer?

Early on with the FDA approvals of GLP-1 agonists, a warning accompanied the products’ labels to not use this class of medications in patients with medullary thyroid cancer, a family history of medullary thyroid cancer, or multiple endocrine neoplasia syndrome type 2. This warning was based on data from animal studies.

Human pancreatic cells aren’t the only cells that express GLP-1 receptors. These receptors are also expressed by parafollicular cells (C cells) of the thyroid, which secrete calcitonin and are the cells involved in medullary thyroid cancer. A dose-related and duration-dependent increase in thyroid C-cell tumor incidence was noted in rodents. The same relationship was not demonstrated in monkeys. Humans have far fewer C cells than rats, and human C cells have very low expression of the GLP-1 receptor.

Over a decade ago, a study examining the FDA’s database of reported adverse events found an increased risk for thyroid cancer in patients treated with exenatide, another GLP-1 agonist. The reporting system wasn’t designed to distinguish thyroid cancer subtypes.

Numerous subsequent studies didn’t confirm this relationship. The LEADER trial looked at liraglutide in patients with type 2 diabetes and showed no effect of GLP-1 receptor activation on human serum calcitonin levels, C-cell proliferation, or C-cell malignancy. Similarly, a large meta-analysis in patients with type 2 diabetes didn’t find a statistically increased risk for thyroid cancer with liraglutide, and no thyroid malignancies were reported with exenatide.

Two U.S. administrative databases from commercial health plans (a retrospective cohort study and a nested case-control study) compared type 2 diabetes patients who were taking exenatide vs. other antidiabetic drugs and found that exenatide was not significantly associated with an increased risk for thyroid cancer.

And a recent meta-analysis of 45 trials showed no significant effects on the occurrence of thyroid cancer with GLP-1 receptor agonists. Of note, it did find an increased risk for overall thyroid disorders, although there was no clear statistically significant finding pointing to a specific thyroid disorder.

Differing from prior studies, a recent nationwide French health care system study provided newer data suggesting a moderate increased risk for thyroid cancer in a cohort of patients with type 2 diabetes who were taking GLP-1 agonists. The increase in relative risk was noted for all types of thyroid cancer in patients using GLP-1 receptor agonists for 1-3 years.

An accompanying commentary by Caroline A. Thompson, PhD, and Til Stürmer, MD, provides perspective on this study’s potential limitations. These include detection bias, as the study results focused only on the statistically significant data. Also discussed were limitations to the case-control design, issues with claims-based tumor type classification (unavailability of surgical pathology), and an inability to adjust for family history and obesity, which is a risk factor alone for thyroid cancer. There was also no adjustment for exposure to head/neck radiation.

While this study has important findings to consider, it deserves further investigation, with future studies linking data to tumor registry data before a change is made in clinical practice.

No clear relationship has been drawn between GLP-1 receptor agonists and thyroid cancer in humans. Numerous confounding factors limit the data. Studies generally don’t specify the type of thyroid cancer, and they lump medullary thyroid cancer, the rarest form, with papillary thyroid cancer.

Is a detection bias present where weight loss makes nodules more visible on the neck among those treated with GLP-1 agonists? And/or are patients treated with GLP-1 agonists being screened more stringently for thyroid nodules and/or cancer?
 

How to advise our patients and respond to the EMR messages

The TikTok videos may continue, the celebrity chatter may increase, and we, as physicians, will continue to look to real-world data with randomized controlled trials to tailor our decision-making and guide our patients.

It’s prudent to advise patients that if they have a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2, in particular, they should avoid using this class of medication. Thyroid cancer remains a rare outcome, and GLP-1 receptor agonists remain a very important and beneficial treatment option for the right patient.

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

With #Ozempic and #ozempicweightloss continuing to trend on social media, along with the mainstream media focusing on celebrities who rely on Ozempic (semaglutide) for weight loss, the daily requests for this new medication have been increasing.

Accompanying these requests are concerns and questions about potential risks, including this most recent message from one of my patients: “Dr. P – I saw the warnings. Is this medication going to make me get thyroid cancer? Please let me know!”

Let’s look at what we know to date, including recent studies, and how to advise our patients on this very hot topic.
 

Using GLP-1 receptor agonists for obesity

We have extensive prior experience with glucagon-like peptide 1 (GLP-1) receptor agonists, such as semaglutide, for treating type 2 diabetes and now recently as agents for weight loss.

Large clinical trials have documented the benefits of this medication class not only for weight reduction but also for cardiovascular and renal benefits in patients with diabetes. The subcutaneously injectable medications work by promoting insulin secretion, slowing gastric emptying, and suppressing glucagon secretion, with a low risk for hypoglycemia.

The Food and Drug Administration approved daily-injection GLP-1 agonist liraglutide for weight loss in 2014, and weekly-injection semaglutide for chronic weight management in 2021, in patients with a body mass index ≥ 27 with at least one weight-related condition or a BMI ≥ 30.

The brand name for semaglutide approved for weight loss is Wegovy, and the dose is slightly higher (maximum 2.4 mg/wk) than that of Ozempic (maximum 2.0 mg/wk), which is semaglutide approved for type 2 diabetes.

In trials for weight loss, data showed a mean change in body weight of almost 15% in the semaglutide group at week 68 compared with placebo, which is very impressive, particularly compared with other FDA-approved oral long-term weight loss medications.

The newest synthetic dual-acting agent is tirzepatide, which targets GLP-1 but is also a glucose-dependent insulinotropic polypeptide (GIP) agonist. The weekly subcutaneous injection was approved in May 2022 as Mounjaro for treating type 2 diabetes and produced even greater weight loss than semaglutide in clinical trials. Tirzepatide is now in trials for obesity and is under expedited review by the FDA for weight loss.
 

Why the concern about thyroid cancer?

Early on with the FDA approvals of GLP-1 agonists, a warning accompanied the products’ labels to not use this class of medications in patients with medullary thyroid cancer, a family history of medullary thyroid cancer, or multiple endocrine neoplasia syndrome type 2. This warning was based on data from animal studies.

Human pancreatic cells aren’t the only cells that express GLP-1 receptors. These receptors are also expressed by parafollicular cells (C cells) of the thyroid, which secrete calcitonin and are the cells involved in medullary thyroid cancer. A dose-related and duration-dependent increase in thyroid C-cell tumor incidence was noted in rodents. The same relationship was not demonstrated in monkeys. Humans have far fewer C cells than rats, and human C cells have very low expression of the GLP-1 receptor.

Over a decade ago, a study examining the FDA’s database of reported adverse events found an increased risk for thyroid cancer in patients treated with exenatide, another GLP-1 agonist. The reporting system wasn’t designed to distinguish thyroid cancer subtypes.

Numerous subsequent studies didn’t confirm this relationship. The LEADER trial looked at liraglutide in patients with type 2 diabetes and showed no effect of GLP-1 receptor activation on human serum calcitonin levels, C-cell proliferation, or C-cell malignancy. Similarly, a large meta-analysis in patients with type 2 diabetes didn’t find a statistically increased risk for thyroid cancer with liraglutide, and no thyroid malignancies were reported with exenatide.

Two U.S. administrative databases from commercial health plans (a retrospective cohort study and a nested case-control study) compared type 2 diabetes patients who were taking exenatide vs. other antidiabetic drugs and found that exenatide was not significantly associated with an increased risk for thyroid cancer.

And a recent meta-analysis of 45 trials showed no significant effects on the occurrence of thyroid cancer with GLP-1 receptor agonists. Of note, it did find an increased risk for overall thyroid disorders, although there was no clear statistically significant finding pointing to a specific thyroid disorder.

Differing from prior studies, a recent nationwide French health care system study provided newer data suggesting a moderate increased risk for thyroid cancer in a cohort of patients with type 2 diabetes who were taking GLP-1 agonists. The increase in relative risk was noted for all types of thyroid cancer in patients using GLP-1 receptor agonists for 1-3 years.

An accompanying commentary by Caroline A. Thompson, PhD, and Til Stürmer, MD, provides perspective on this study’s potential limitations. These include detection bias, as the study results focused only on the statistically significant data. Also discussed were limitations to the case-control design, issues with claims-based tumor type classification (unavailability of surgical pathology), and an inability to adjust for family history and obesity, which is a risk factor alone for thyroid cancer. There was also no adjustment for exposure to head/neck radiation.

While this study has important findings to consider, it deserves further investigation, with future studies linking data to tumor registry data before a change is made in clinical practice.

No clear relationship has been drawn between GLP-1 receptor agonists and thyroid cancer in humans. Numerous confounding factors limit the data. Studies generally don’t specify the type of thyroid cancer, and they lump medullary thyroid cancer, the rarest form, with papillary thyroid cancer.

Is a detection bias present where weight loss makes nodules more visible on the neck among those treated with GLP-1 agonists? And/or are patients treated with GLP-1 agonists being screened more stringently for thyroid nodules and/or cancer?
 

How to advise our patients and respond to the EMR messages

The TikTok videos may continue, the celebrity chatter may increase, and we, as physicians, will continue to look to real-world data with randomized controlled trials to tailor our decision-making and guide our patients.

It’s prudent to advise patients that if they have a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2, in particular, they should avoid using this class of medication. Thyroid cancer remains a rare outcome, and GLP-1 receptor agonists remain a very important and beneficial treatment option for the right patient.

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

With #Ozempic and #ozempicweightloss continuing to trend on social media, along with the mainstream media focusing on celebrities who rely on Ozempic (semaglutide) for weight loss, the daily requests for this new medication have been increasing.

Accompanying these requests are concerns and questions about potential risks, including this most recent message from one of my patients: “Dr. P – I saw the warnings. Is this medication going to make me get thyroid cancer? Please let me know!”

Let’s look at what we know to date, including recent studies, and how to advise our patients on this very hot topic.
 

Using GLP-1 receptor agonists for obesity

We have extensive prior experience with glucagon-like peptide 1 (GLP-1) receptor agonists, such as semaglutide, for treating type 2 diabetes and now recently as agents for weight loss.

Large clinical trials have documented the benefits of this medication class not only for weight reduction but also for cardiovascular and renal benefits in patients with diabetes. The subcutaneously injectable medications work by promoting insulin secretion, slowing gastric emptying, and suppressing glucagon secretion, with a low risk for hypoglycemia.

The Food and Drug Administration approved daily-injection GLP-1 agonist liraglutide for weight loss in 2014, and weekly-injection semaglutide for chronic weight management in 2021, in patients with a body mass index ≥ 27 with at least one weight-related condition or a BMI ≥ 30.

The brand name for semaglutide approved for weight loss is Wegovy, and the dose is slightly higher (maximum 2.4 mg/wk) than that of Ozempic (maximum 2.0 mg/wk), which is semaglutide approved for type 2 diabetes.

In trials for weight loss, data showed a mean change in body weight of almost 15% in the semaglutide group at week 68 compared with placebo, which is very impressive, particularly compared with other FDA-approved oral long-term weight loss medications.

The newest synthetic dual-acting agent is tirzepatide, which targets GLP-1 but is also a glucose-dependent insulinotropic polypeptide (GIP) agonist. The weekly subcutaneous injection was approved in May 2022 as Mounjaro for treating type 2 diabetes and produced even greater weight loss than semaglutide in clinical trials. Tirzepatide is now in trials for obesity and is under expedited review by the FDA for weight loss.
 

Why the concern about thyroid cancer?

Early on with the FDA approvals of GLP-1 agonists, a warning accompanied the products’ labels to not use this class of medications in patients with medullary thyroid cancer, a family history of medullary thyroid cancer, or multiple endocrine neoplasia syndrome type 2. This warning was based on data from animal studies.

Human pancreatic cells aren’t the only cells that express GLP-1 receptors. These receptors are also expressed by parafollicular cells (C cells) of the thyroid, which secrete calcitonin and are the cells involved in medullary thyroid cancer. A dose-related and duration-dependent increase in thyroid C-cell tumor incidence was noted in rodents. The same relationship was not demonstrated in monkeys. Humans have far fewer C cells than rats, and human C cells have very low expression of the GLP-1 receptor.

Over a decade ago, a study examining the FDA’s database of reported adverse events found an increased risk for thyroid cancer in patients treated with exenatide, another GLP-1 agonist. The reporting system wasn’t designed to distinguish thyroid cancer subtypes.

Numerous subsequent studies didn’t confirm this relationship. The LEADER trial looked at liraglutide in patients with type 2 diabetes and showed no effect of GLP-1 receptor activation on human serum calcitonin levels, C-cell proliferation, or C-cell malignancy. Similarly, a large meta-analysis in patients with type 2 diabetes didn’t find a statistically increased risk for thyroid cancer with liraglutide, and no thyroid malignancies were reported with exenatide.

Two U.S. administrative databases from commercial health plans (a retrospective cohort study and a nested case-control study) compared type 2 diabetes patients who were taking exenatide vs. other antidiabetic drugs and found that exenatide was not significantly associated with an increased risk for thyroid cancer.

And a recent meta-analysis of 45 trials showed no significant effects on the occurrence of thyroid cancer with GLP-1 receptor agonists. Of note, it did find an increased risk for overall thyroid disorders, although there was no clear statistically significant finding pointing to a specific thyroid disorder.

Differing from prior studies, a recent nationwide French health care system study provided newer data suggesting a moderate increased risk for thyroid cancer in a cohort of patients with type 2 diabetes who were taking GLP-1 agonists. The increase in relative risk was noted for all types of thyroid cancer in patients using GLP-1 receptor agonists for 1-3 years.

An accompanying commentary by Caroline A. Thompson, PhD, and Til Stürmer, MD, provides perspective on this study’s potential limitations. These include detection bias, as the study results focused only on the statistically significant data. Also discussed were limitations to the case-control design, issues with claims-based tumor type classification (unavailability of surgical pathology), and an inability to adjust for family history and obesity, which is a risk factor alone for thyroid cancer. There was also no adjustment for exposure to head/neck radiation.

While this study has important findings to consider, it deserves further investigation, with future studies linking data to tumor registry data before a change is made in clinical practice.

No clear relationship has been drawn between GLP-1 receptor agonists and thyroid cancer in humans. Numerous confounding factors limit the data. Studies generally don’t specify the type of thyroid cancer, and they lump medullary thyroid cancer, the rarest form, with papillary thyroid cancer.

Is a detection bias present where weight loss makes nodules more visible on the neck among those treated with GLP-1 agonists? And/or are patients treated with GLP-1 agonists being screened more stringently for thyroid nodules and/or cancer?
 

How to advise our patients and respond to the EMR messages

The TikTok videos may continue, the celebrity chatter may increase, and we, as physicians, will continue to look to real-world data with randomized controlled trials to tailor our decision-making and guide our patients.

It’s prudent to advise patients that if they have a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2, in particular, they should avoid using this class of medication. Thyroid cancer remains a rare outcome, and GLP-1 receptor agonists remain a very important and beneficial treatment option for the right patient.

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

A qualitative study of breast cancer screening–age women finds that few women identified breast density as a risk factor for breast cancer.

Most women did not feel confident they knew what actions could mitigate breast cancer risk, leading researchers to the conclusion that comprehensive education about breast cancer risks and prevention strategies is needed.

The study was published earlier this year in JAMA Network Open.

“Forty [percent] to 50% of women who undergo mammography fall into the two highest breast density categories,” said the study’s lead author Christine Gunn, PhD, of the Dartmouth Institute for Health Policy and Clinical Practice, N.H. “Breast cancer risk increases from 1.2-4.0 times depending on the level of breast density. By comparison, a first-degree family history of breast cancer, particularly in premenopausal women, confers a two-fold higher breast cancer risk.”

Dr. Gunn’s study is based on a survey of 2,306 women (between 40 and 76 years old) that was conducted between 2019 and 2020. The goal was to determine how well women understood cancer risks associated with dense breast tissue. The final analysis included 1,858 women (9% Asian, 27% Black, 14% Hispanic, 43% White, and 7% other race or ethnicity).

Breast density was thought to be a greater risk than not having children, drinking daily, and having had a prior breast biopsy, according to 52%, 53%, and 48% of respondents, respectively. Breast density was believed to be a lesser breast cancer risk than having a first-degree relative with breast cancer by 93% of women, and 65% of women felt it was a lesser risk than being overweight or obese.

Of the 61 women who completed follow-up interviews, 6 described breast density as a contributing factor to breast cancer risk. And, 17 women did not know whether it was possible to reduce their breast cancer risk.
 

Doctors must notify patients in writing

Breast tissue falls under one of four categories: fatty tissue, scattered areas of dense fibroglandular tissue, many areas of glandular and connective tissue, or extremely dense tissue. The tissue is considered dense if it falls under heterogeneously dense or extremely dense, and in those cases, follow-up testing with ultrasound or MRI may be necessary. This is important, Dr. Gunn said, because dense tissue can make “it harder to find cancers because connective tissue appears white on the mammogram, potentially masking tumors.”

Prior studies have found that many clinicians are uncomfortable counseling patients on the implications of breast density and cancer risk, the authors wrote.

However, under the Mammography Quality Standards Act, which was updated on March 10, the Food and Drug Administration requires that patients be provided with a mammography report summary that “identifies whether the patient has dense or nondense breast tissue.” The report, which should be written in lay language, should also specify the “significance” of the dense tissue.

While some states mandate notification regardless of the density level, most only notify women if heterogeneously dense or extremely dense tissue has been identified, Dr. Gunn said. But the rules are inconsistent, she said. In some facilities in Massachusetts, for example, women may receive a mammography report letter and a separate breast density letter. “For some, it has been really confusing. They received a letter saying that their mammography was normal and then another one saying that they have dense breasts – resulting in a lot of uncertainty and anxiety. We don’t want to overly alarm people. We want them to understand their risk,” she said.

Breast density can be considered among other risk factors, including alcohol use, obesity, diet, parity, prior breast biopsy, and inherited unfavorable genetic mutations. “If the total lifetime risk is above 20%, that opens up further screening options, such as a breast MRI, which will catch more cancers than a breast mammogram by itself,” Dr. Gunn said.

“The challenges for physicians and patients around collecting and understanding breast density information in the context of other risk factors can potentially lead to disparities in who gets to know their risk and who doesn’t,” Dr. Gunn said. It would be possible, she speculated, to create or use existing risk calculators integrated into medical records and populated with information gathered in premammography visit questionnaires. Ideally, a radiologist could hand the patient results in real time at the end of the mammography visit, integrating risk estimates with mammography findings to make recommendations.

This study was supported by grant RSG-133017-CPHPS from the American Cancer Society.
 

A qualitative study of breast cancer screening–age women finds that few women identified breast density as a risk factor for breast cancer.

Most women did not feel confident they knew what actions could mitigate breast cancer risk, leading researchers to the conclusion that comprehensive education about breast cancer risks and prevention strategies is needed.

The study was published earlier this year in JAMA Network Open.

“Forty [percent] to 50% of women who undergo mammography fall into the two highest breast density categories,” said the study’s lead author Christine Gunn, PhD, of the Dartmouth Institute for Health Policy and Clinical Practice, N.H. “Breast cancer risk increases from 1.2-4.0 times depending on the level of breast density. By comparison, a first-degree family history of breast cancer, particularly in premenopausal women, confers a two-fold higher breast cancer risk.”

Dr. Gunn’s study is based on a survey of 2,306 women (between 40 and 76 years old) that was conducted between 2019 and 2020. The goal was to determine how well women understood cancer risks associated with dense breast tissue. The final analysis included 1,858 women (9% Asian, 27% Black, 14% Hispanic, 43% White, and 7% other race or ethnicity).

Breast density was thought to be a greater risk than not having children, drinking daily, and having had a prior breast biopsy, according to 52%, 53%, and 48% of respondents, respectively. Breast density was believed to be a lesser breast cancer risk than having a first-degree relative with breast cancer by 93% of women, and 65% of women felt it was a lesser risk than being overweight or obese.

Of the 61 women who completed follow-up interviews, 6 described breast density as a contributing factor to breast cancer risk. And, 17 women did not know whether it was possible to reduce their breast cancer risk.
 

Doctors must notify patients in writing

Breast tissue falls under one of four categories: fatty tissue, scattered areas of dense fibroglandular tissue, many areas of glandular and connective tissue, or extremely dense tissue. The tissue is considered dense if it falls under heterogeneously dense or extremely dense, and in those cases, follow-up testing with ultrasound or MRI may be necessary. This is important, Dr. Gunn said, because dense tissue can make “it harder to find cancers because connective tissue appears white on the mammogram, potentially masking tumors.”

Prior studies have found that many clinicians are uncomfortable counseling patients on the implications of breast density and cancer risk, the authors wrote.

However, under the Mammography Quality Standards Act, which was updated on March 10, the Food and Drug Administration requires that patients be provided with a mammography report summary that “identifies whether the patient has dense or nondense breast tissue.” The report, which should be written in lay language, should also specify the “significance” of the dense tissue.

While some states mandate notification regardless of the density level, most only notify women if heterogeneously dense or extremely dense tissue has been identified, Dr. Gunn said. But the rules are inconsistent, she said. In some facilities in Massachusetts, for example, women may receive a mammography report letter and a separate breast density letter. “For some, it has been really confusing. They received a letter saying that their mammography was normal and then another one saying that they have dense breasts – resulting in a lot of uncertainty and anxiety. We don’t want to overly alarm people. We want them to understand their risk,” she said.

Breast density can be considered among other risk factors, including alcohol use, obesity, diet, parity, prior breast biopsy, and inherited unfavorable genetic mutations. “If the total lifetime risk is above 20%, that opens up further screening options, such as a breast MRI, which will catch more cancers than a breast mammogram by itself,” Dr. Gunn said.

“The challenges for physicians and patients around collecting and understanding breast density information in the context of other risk factors can potentially lead to disparities in who gets to know their risk and who doesn’t,” Dr. Gunn said. It would be possible, she speculated, to create or use existing risk calculators integrated into medical records and populated with information gathered in premammography visit questionnaires. Ideally, a radiologist could hand the patient results in real time at the end of the mammography visit, integrating risk estimates with mammography findings to make recommendations.

This study was supported by grant RSG-133017-CPHPS from the American Cancer Society.
 

A qualitative study of breast cancer screening–age women finds that few women identified breast density as a risk factor for breast cancer.

Most women did not feel confident they knew what actions could mitigate breast cancer risk, leading researchers to the conclusion that comprehensive education about breast cancer risks and prevention strategies is needed.

The study was published earlier this year in JAMA Network Open.

“Forty [percent] to 50% of women who undergo mammography fall into the two highest breast density categories,” said the study’s lead author Christine Gunn, PhD, of the Dartmouth Institute for Health Policy and Clinical Practice, N.H. “Breast cancer risk increases from 1.2-4.0 times depending on the level of breast density. By comparison, a first-degree family history of breast cancer, particularly in premenopausal women, confers a two-fold higher breast cancer risk.”

Dr. Gunn’s study is based on a survey of 2,306 women (between 40 and 76 years old) that was conducted between 2019 and 2020. The goal was to determine how well women understood cancer risks associated with dense breast tissue. The final analysis included 1,858 women (9% Asian, 27% Black, 14% Hispanic, 43% White, and 7% other race or ethnicity).

Breast density was thought to be a greater risk than not having children, drinking daily, and having had a prior breast biopsy, according to 52%, 53%, and 48% of respondents, respectively. Breast density was believed to be a lesser breast cancer risk than having a first-degree relative with breast cancer by 93% of women, and 65% of women felt it was a lesser risk than being overweight or obese.

Of the 61 women who completed follow-up interviews, 6 described breast density as a contributing factor to breast cancer risk. And, 17 women did not know whether it was possible to reduce their breast cancer risk.
 

Doctors must notify patients in writing

Breast tissue falls under one of four categories: fatty tissue, scattered areas of dense fibroglandular tissue, many areas of glandular and connective tissue, or extremely dense tissue. The tissue is considered dense if it falls under heterogeneously dense or extremely dense, and in those cases, follow-up testing with ultrasound or MRI may be necessary. This is important, Dr. Gunn said, because dense tissue can make “it harder to find cancers because connective tissue appears white on the mammogram, potentially masking tumors.”

Prior studies have found that many clinicians are uncomfortable counseling patients on the implications of breast density and cancer risk, the authors wrote.

However, under the Mammography Quality Standards Act, which was updated on March 10, the Food and Drug Administration requires that patients be provided with a mammography report summary that “identifies whether the patient has dense or nondense breast tissue.” The report, which should be written in lay language, should also specify the “significance” of the dense tissue.

While some states mandate notification regardless of the density level, most only notify women if heterogeneously dense or extremely dense tissue has been identified, Dr. Gunn said. But the rules are inconsistent, she said. In some facilities in Massachusetts, for example, women may receive a mammography report letter and a separate breast density letter. “For some, it has been really confusing. They received a letter saying that their mammography was normal and then another one saying that they have dense breasts – resulting in a lot of uncertainty and anxiety. We don’t want to overly alarm people. We want them to understand their risk,” she said.

Breast density can be considered among other risk factors, including alcohol use, obesity, diet, parity, prior breast biopsy, and inherited unfavorable genetic mutations. “If the total lifetime risk is above 20%, that opens up further screening options, such as a breast MRI, which will catch more cancers than a breast mammogram by itself,” Dr. Gunn said.

“The challenges for physicians and patients around collecting and understanding breast density information in the context of other risk factors can potentially lead to disparities in who gets to know their risk and who doesn’t,” Dr. Gunn said. It would be possible, she speculated, to create or use existing risk calculators integrated into medical records and populated with information gathered in premammography visit questionnaires. Ideally, a radiologist could hand the patient results in real time at the end of the mammography visit, integrating risk estimates with mammography findings to make recommendations.

This study was supported by grant RSG-133017-CPHPS from the American Cancer Society.
 

In Western diets, dairy and beef are ubiquitous: Milk goes with coffee, melted cheese with pizza, and chili with rice. But what if dairy products and beef contained a new kind of pathogen that could infect you as a child and trigger cancer or multiple sclerosis (MS) 40-70 years later?

Researchers from the German Cancer Research Center (DKFZ) suspect that such zoonoses are possibly widespread and are therefore recommending that infants not be given dairy products until they are at least age 1 year. However, in two joint statements, the German Federal Institute for Risk Assessment (BfR) and the Max Rubner Institute (MRI) have rejected such theories.

In 2008, Harald zur Hausen, MD, DSc, received the Nobel Prize in Medicine for his discovery that human papillomaviruses cause cervical cancer. His starting point was the observation that sexually abstinent women, such as nuns, rarely develop this cancer. So it was possible to draw the conclusion that pathogens are transmitted during sexual intercourse, explain Dr. zur Hausen and his wife Ethel-Michele de Villiers, PhD, both of DKFZ Heidelberg.

Papillomaviruses, as well as human herpes and Epstein-Barr viruses (EBV), polyomaviruses, and retroviruses, cause cancer in a direct way: by inserting their genes into the DNA of human cells. With a latency of a few years to a few decades, the proteins formed through expression stimulate malignant growth by altering the regulating host gene.
 

Acid radicals

However, viruses – just like bacteria and parasites – can also indirectly trigger cancer. One mechanism for this triggering is the disruption of immune defenses, as shown by the sometimes drastically increased tumor incidence with AIDS or with immunosuppressants after transplants. Chronic inflammation is a second mechanism that generates acid radicals and thereby causes random mutations in replicating cells. Examples include stomach cancer caused by Helicobacter pylori and liver cancer caused by Schistosoma, liver fluke, and hepatitis B and C viruses.

According to Dr. de Villiers and Dr. zur Hausen, there are good reasons to believe that other pathogens could cause chronic inflammation and thereby lead to cancer. Epidemiologic data suggest that dairy and meat products from European cows (Bos taurus) are a potential source. This is because colon cancer and breast cancer commonly occur in places where these foods are heavily consumed (that is, in North America, Argentina, Europe, and Australia). In contrast, the rate is low in India, where cows are revered as holy animals. Also noteworthy is that women with a lactose intolerance rarely develop breast cancer.
 

Viral progeny

In fact, the researchers found single-stranded DNA rings that originated in viruses, which they named bovine meat and milk factors (BMMF), in the intestines of patients with colon cancer. They reported, “This new class of pathogen deserves, in our opinion at least, to become the focus of cancer development and further chronic diseases.” They also detected elevated levels of acid radicals in these areas (that is, oxidative stress), which is typical for chronic inflammation.

The researchers assume that infants, whose immune system is not yet fully matured, ingest the BMMF as soon as they have dairy. Therefore, there is no need for adults to avoid dairy or beef because everyone is infected anyway, said Dr. zur Hausen.
 

‘Breast milk is healthy’

Dr. De Villiers and Dr. zur Hausen outlined more evidence of cancer-triggering pathogens. Mothers who have breastfed are less likely, especially after multiple pregnancies, to develop tumors in various organs or to have MS and type 2 diabetes. The authors attribute the protective effect to oligosaccharides in breast milk, which begin to be formed midway through the pregnancy. They bind to lectin receptors and, in so doing, mask the terminal molecule onto which the viruses need to dock. As a result, their port of entry into the cells is blocked.

The oligosaccharides also protect the baby against life-threatening infections by blocking access by rotaviruses and noroviruses. In this way, especially if breastfeeding lasts a long time – around 1 year – the period of incomplete immunocompetence is bridged.
 

Colon cancer

To date, it has been assumed that around 20% of all cancerous diseases globally are caused by infections, said the researchers. But if the suspected BMMF cases are included, this figure rises to 50%, even to around 80%, for colon cancer. If the suspicion is confirmed, the consequences for prevention and therapy would be significant.

The voice of a Nobel prize winner undoubtedly carries weight, but at the time, Dr. zur Hausen still had to convince a host of skeptics with his discovery that a viral infection is a major cause of cervical cancer. Nonetheless, some indicators suggest that he and his wife have found a dead end this time.
 

Institutional skepticism

When his working group made the results public in February 2019, the DKFZ felt the need to give an all-clear signal in response to alarmed press reports. There is no reason to see dairy and meat consumption as something negative. Similarly, in their first joint statement, the BfR and the MRI judged the data to be insufficient and called for further studies. Multiple research teams began to focus on BMMF as a result. In what foods can they be found? Are they more common in patients with cancer than in healthy people? Are they infectious? Do they cause inflammation and cancer?

The findings presented in a second statement by the BfR and MRI at the end of November 2022 contradicted the claims made by the DKFZ scientists across the board. In no way do BMMF represent new pathogens. They are variants of already known DNA sequences. In addition, they are present in numerous animal-based and plant-based foods, including pork, fish, fruit, vegetables, and nuts.

BMMF do not possess the ability to infect human cells, the institutes said. The proof that they are damaging to one’s health was also absent. It is true that the incidence of intestinal tumors correlates positively with the consumption of red and processed meat – which in no way signifies causality – but dairy products are linked to a reduced risk. On the other hand, breast cancer cannot be associated with the consumption of beef or dairy.

Therefore, both institutes recommend continuing to use these products as supplementary diet for infants because of their micronutrients. They further stated that the products are safe for people of all ages.
 

Association with MS?

Unperturbed, Dr. de Villiers and Dr. zur Hausen went one step further in their current article. They posited that MS is also associated with the consumption of dairy products and beef. Here too geographic distribution prompted the idea to look for BMMF in the brain lesions of patients with MS. The researchers isolated ring-shaped DNA molecules that proved to be closely related to BMMF from dairy and cattle blood. “The result was electrifying for us.”

However, there are several other factors to consider, such as vitamin D3 deficiency. This is because the incidence of MS decreases the further you travel from the poles toward the equator (that is, as solar radiation increases). Also, EBV clearly plays a role because patients with MS display increased titers of EBV antibodies. One study also showed that people in Antarctica excreted reactivated EBV in their saliva during winter and that vitamin D3 stopped the viral secretion.

Under these conditions, the researchers hypothesized that MS is caused by a double infection of brain cells by EBV and BMMF. EBV is reactivated by a lack of vitamin D3, and the BMMF multiply and are eventually converted into proteins. A focal immunoreaction causes the Schwann cells and oligodendrocytes to malfunction, which leads to the destruction of the myelin sheaths around the nerve fibers.

This article was translated from the Medscape German Edition. A version appeared on Medscape.com.

In Western diets, dairy and beef are ubiquitous: Milk goes with coffee, melted cheese with pizza, and chili with rice. But what if dairy products and beef contained a new kind of pathogen that could infect you as a child and trigger cancer or multiple sclerosis (MS) 40-70 years later?

Researchers from the German Cancer Research Center (DKFZ) suspect that such zoonoses are possibly widespread and are therefore recommending that infants not be given dairy products until they are at least age 1 year. However, in two joint statements, the German Federal Institute for Risk Assessment (BfR) and the Max Rubner Institute (MRI) have rejected such theories.

In 2008, Harald zur Hausen, MD, DSc, received the Nobel Prize in Medicine for his discovery that human papillomaviruses cause cervical cancer. His starting point was the observation that sexually abstinent women, such as nuns, rarely develop this cancer. So it was possible to draw the conclusion that pathogens are transmitted during sexual intercourse, explain Dr. zur Hausen and his wife Ethel-Michele de Villiers, PhD, both of DKFZ Heidelberg.

Papillomaviruses, as well as human herpes and Epstein-Barr viruses (EBV), polyomaviruses, and retroviruses, cause cancer in a direct way: by inserting their genes into the DNA of human cells. With a latency of a few years to a few decades, the proteins formed through expression stimulate malignant growth by altering the regulating host gene.
 

Acid radicals

However, viruses – just like bacteria and parasites – can also indirectly trigger cancer. One mechanism for this triggering is the disruption of immune defenses, as shown by the sometimes drastically increased tumor incidence with AIDS or with immunosuppressants after transplants. Chronic inflammation is a second mechanism that generates acid radicals and thereby causes random mutations in replicating cells. Examples include stomach cancer caused by Helicobacter pylori and liver cancer caused by Schistosoma, liver fluke, and hepatitis B and C viruses.

According to Dr. de Villiers and Dr. zur Hausen, there are good reasons to believe that other pathogens could cause chronic inflammation and thereby lead to cancer. Epidemiologic data suggest that dairy and meat products from European cows (Bos taurus) are a potential source. This is because colon cancer and breast cancer commonly occur in places where these foods are heavily consumed (that is, in North America, Argentina, Europe, and Australia). In contrast, the rate is low in India, where cows are revered as holy animals. Also noteworthy is that women with a lactose intolerance rarely develop breast cancer.
 

Viral progeny

In fact, the researchers found single-stranded DNA rings that originated in viruses, which they named bovine meat and milk factors (BMMF), in the intestines of patients with colon cancer. They reported, “This new class of pathogen deserves, in our opinion at least, to become the focus of cancer development and further chronic diseases.” They also detected elevated levels of acid radicals in these areas (that is, oxidative stress), which is typical for chronic inflammation.

The researchers assume that infants, whose immune system is not yet fully matured, ingest the BMMF as soon as they have dairy. Therefore, there is no need for adults to avoid dairy or beef because everyone is infected anyway, said Dr. zur Hausen.
 

‘Breast milk is healthy’

Dr. De Villiers and Dr. zur Hausen outlined more evidence of cancer-triggering pathogens. Mothers who have breastfed are less likely, especially after multiple pregnancies, to develop tumors in various organs or to have MS and type 2 diabetes. The authors attribute the protective effect to oligosaccharides in breast milk, which begin to be formed midway through the pregnancy. They bind to lectin receptors and, in so doing, mask the terminal molecule onto which the viruses need to dock. As a result, their port of entry into the cells is blocked.

The oligosaccharides also protect the baby against life-threatening infections by blocking access by rotaviruses and noroviruses. In this way, especially if breastfeeding lasts a long time – around 1 year – the period of incomplete immunocompetence is bridged.
 

Colon cancer

To date, it has been assumed that around 20% of all cancerous diseases globally are caused by infections, said the researchers. But if the suspected BMMF cases are included, this figure rises to 50%, even to around 80%, for colon cancer. If the suspicion is confirmed, the consequences for prevention and therapy would be significant.

The voice of a Nobel prize winner undoubtedly carries weight, but at the time, Dr. zur Hausen still had to convince a host of skeptics with his discovery that a viral infection is a major cause of cervical cancer. Nonetheless, some indicators suggest that he and his wife have found a dead end this time.
 

Institutional skepticism

When his working group made the results public in February 2019, the DKFZ felt the need to give an all-clear signal in response to alarmed press reports. There is no reason to see dairy and meat consumption as something negative. Similarly, in their first joint statement, the BfR and the MRI judged the data to be insufficient and called for further studies. Multiple research teams began to focus on BMMF as a result. In what foods can they be found? Are they more common in patients with cancer than in healthy people? Are they infectious? Do they cause inflammation and cancer?

The findings presented in a second statement by the BfR and MRI at the end of November 2022 contradicted the claims made by the DKFZ scientists across the board. In no way do BMMF represent new pathogens. They are variants of already known DNA sequences. In addition, they are present in numerous animal-based and plant-based foods, including pork, fish, fruit, vegetables, and nuts.

BMMF do not possess the ability to infect human cells, the institutes said. The proof that they are damaging to one’s health was also absent. It is true that the incidence of intestinal tumors correlates positively with the consumption of red and processed meat – which in no way signifies causality – but dairy products are linked to a reduced risk. On the other hand, breast cancer cannot be associated with the consumption of beef or dairy.

Therefore, both institutes recommend continuing to use these products as supplementary diet for infants because of their micronutrients. They further stated that the products are safe for people of all ages.
 

Association with MS?

Unperturbed, Dr. de Villiers and Dr. zur Hausen went one step further in their current article. They posited that MS is also associated with the consumption of dairy products and beef. Here too geographic distribution prompted the idea to look for BMMF in the brain lesions of patients with MS. The researchers isolated ring-shaped DNA molecules that proved to be closely related to BMMF from dairy and cattle blood. “The result was electrifying for us.”

However, there are several other factors to consider, such as vitamin D3 deficiency. This is because the incidence of MS decreases the further you travel from the poles toward the equator (that is, as solar radiation increases). Also, EBV clearly plays a role because patients with MS display increased titers of EBV antibodies. One study also showed that people in Antarctica excreted reactivated EBV in their saliva during winter and that vitamin D3 stopped the viral secretion.

Under these conditions, the researchers hypothesized that MS is caused by a double infection of brain cells by EBV and BMMF. EBV is reactivated by a lack of vitamin D3, and the BMMF multiply and are eventually converted into proteins. A focal immunoreaction causes the Schwann cells and oligodendrocytes to malfunction, which leads to the destruction of the myelin sheaths around the nerve fibers.

This article was translated from the Medscape German Edition. A version appeared on Medscape.com.

In Western diets, dairy and beef are ubiquitous: Milk goes with coffee, melted cheese with pizza, and chili with rice. But what if dairy products and beef contained a new kind of pathogen that could infect you as a child and trigger cancer or multiple sclerosis (MS) 40-70 years later?

Researchers from the German Cancer Research Center (DKFZ) suspect that such zoonoses are possibly widespread and are therefore recommending that infants not be given dairy products until they are at least age 1 year. However, in two joint statements, the German Federal Institute for Risk Assessment (BfR) and the Max Rubner Institute (MRI) have rejected such theories.

In 2008, Harald zur Hausen, MD, DSc, received the Nobel Prize in Medicine for his discovery that human papillomaviruses cause cervical cancer. His starting point was the observation that sexually abstinent women, such as nuns, rarely develop this cancer. So it was possible to draw the conclusion that pathogens are transmitted during sexual intercourse, explain Dr. zur Hausen and his wife Ethel-Michele de Villiers, PhD, both of DKFZ Heidelberg.

Papillomaviruses, as well as human herpes and Epstein-Barr viruses (EBV), polyomaviruses, and retroviruses, cause cancer in a direct way: by inserting their genes into the DNA of human cells. With a latency of a few years to a few decades, the proteins formed through expression stimulate malignant growth by altering the regulating host gene.
 

Acid radicals

However, viruses – just like bacteria and parasites – can also indirectly trigger cancer. One mechanism for this triggering is the disruption of immune defenses, as shown by the sometimes drastically increased tumor incidence with AIDS or with immunosuppressants after transplants. Chronic inflammation is a second mechanism that generates acid radicals and thereby causes random mutations in replicating cells. Examples include stomach cancer caused by Helicobacter pylori and liver cancer caused by Schistosoma, liver fluke, and hepatitis B and C viruses.

According to Dr. de Villiers and Dr. zur Hausen, there are good reasons to believe that other pathogens could cause chronic inflammation and thereby lead to cancer. Epidemiologic data suggest that dairy and meat products from European cows (Bos taurus) are a potential source. This is because colon cancer and breast cancer commonly occur in places where these foods are heavily consumed (that is, in North America, Argentina, Europe, and Australia). In contrast, the rate is low in India, where cows are revered as holy animals. Also noteworthy is that women with a lactose intolerance rarely develop breast cancer.
 

Viral progeny

In fact, the researchers found single-stranded DNA rings that originated in viruses, which they named bovine meat and milk factors (BMMF), in the intestines of patients with colon cancer. They reported, “This new class of pathogen deserves, in our opinion at least, to become the focus of cancer development and further chronic diseases.” They also detected elevated levels of acid radicals in these areas (that is, oxidative stress), which is typical for chronic inflammation.

The researchers assume that infants, whose immune system is not yet fully matured, ingest the BMMF as soon as they have dairy. Therefore, there is no need for adults to avoid dairy or beef because everyone is infected anyway, said Dr. zur Hausen.
 

‘Breast milk is healthy’

Dr. De Villiers and Dr. zur Hausen outlined more evidence of cancer-triggering pathogens. Mothers who have breastfed are less likely, especially after multiple pregnancies, to develop tumors in various organs or to have MS and type 2 diabetes. The authors attribute the protective effect to oligosaccharides in breast milk, which begin to be formed midway through the pregnancy. They bind to lectin receptors and, in so doing, mask the terminal molecule onto which the viruses need to dock. As a result, their port of entry into the cells is blocked.

The oligosaccharides also protect the baby against life-threatening infections by blocking access by rotaviruses and noroviruses. In this way, especially if breastfeeding lasts a long time – around 1 year – the period of incomplete immunocompetence is bridged.
 

Colon cancer

To date, it has been assumed that around 20% of all cancerous diseases globally are caused by infections, said the researchers. But if the suspected BMMF cases are included, this figure rises to 50%, even to around 80%, for colon cancer. If the suspicion is confirmed, the consequences for prevention and therapy would be significant.

The voice of a Nobel prize winner undoubtedly carries weight, but at the time, Dr. zur Hausen still had to convince a host of skeptics with his discovery that a viral infection is a major cause of cervical cancer. Nonetheless, some indicators suggest that he and his wife have found a dead end this time.
 

Institutional skepticism

When his working group made the results public in February 2019, the DKFZ felt the need to give an all-clear signal in response to alarmed press reports. There is no reason to see dairy and meat consumption as something negative. Similarly, in their first joint statement, the BfR and the MRI judged the data to be insufficient and called for further studies. Multiple research teams began to focus on BMMF as a result. In what foods can they be found? Are they more common in patients with cancer than in healthy people? Are they infectious? Do they cause inflammation and cancer?

The findings presented in a second statement by the BfR and MRI at the end of November 2022 contradicted the claims made by the DKFZ scientists across the board. In no way do BMMF represent new pathogens. They are variants of already known DNA sequences. In addition, they are present in numerous animal-based and plant-based foods, including pork, fish, fruit, vegetables, and nuts.

BMMF do not possess the ability to infect human cells, the institutes said. The proof that they are damaging to one’s health was also absent. It is true that the incidence of intestinal tumors correlates positively with the consumption of red and processed meat – which in no way signifies causality – but dairy products are linked to a reduced risk. On the other hand, breast cancer cannot be associated with the consumption of beef or dairy.

Therefore, both institutes recommend continuing to use these products as supplementary diet for infants because of their micronutrients. They further stated that the products are safe for people of all ages.
 

Association with MS?

Unperturbed, Dr. de Villiers and Dr. zur Hausen went one step further in their current article. They posited that MS is also associated with the consumption of dairy products and beef. Here too geographic distribution prompted the idea to look for BMMF in the brain lesions of patients with MS. The researchers isolated ring-shaped DNA molecules that proved to be closely related to BMMF from dairy and cattle blood. “The result was electrifying for us.”

However, there are several other factors to consider, such as vitamin D3 deficiency. This is because the incidence of MS decreases the further you travel from the poles toward the equator (that is, as solar radiation increases). Also, EBV clearly plays a role because patients with MS display increased titers of EBV antibodies. One study also showed that people in Antarctica excreted reactivated EBV in their saliva during winter and that vitamin D3 stopped the viral secretion.

Under these conditions, the researchers hypothesized that MS is caused by a double infection of brain cells by EBV and BMMF. EBV is reactivated by a lack of vitamin D3, and the BMMF multiply and are eventually converted into proteins. A focal immunoreaction causes the Schwann cells and oligodendrocytes to malfunction, which leads to the destruction of the myelin sheaths around the nerve fibers.

This article was translated from the Medscape German Edition. A version appeared on Medscape.com.

Digital rectal examination (DRE) is neither helpful nor useful as a solitary prostate cancer screening tool in middle-aged men, say investigators reporting the PROBASE study.

The study compared risk-adapted screening measures in men who had prostate-specific antigen (PSA) measured at age 45 with those who had PSA measurements plus DRE at age 50.

The results show that as a solitary screening tool, 99% of DREs did not raise suspicion for prostate cancer, and among the 57 cases where DRE did raise suspicion, only three men were found to have cancer, all of which were low-grade, reported Agne Krilaviciute, PhD, from the German Cancer Research Center in Heidelberg, and colleagues.

“We also see that the cancer detection rate by PSA is four times higher compared to the DRE detection. Around 18% of the tumors are located in the part of the prostate where DRE cannot detect them,” she said in an oral presentation at the European Association of Urology Congress.

The investigators found that the majority of prostate cancers that occurred in this relatively young population were International Society of Urological Pathology grade 1 (Gleason score 3 + 3 = 6) or grade 2 (Gleason 3 + 4 = 7). DRE yields positive results in only about 12% of cases of ISUP grade 1 or 2, they noted.

“We conclude that DRE as a solitary screening test does not lead to a significant PCa [prostate cancer] detection rate in young men,” Dr. Krilaviciute said.
 

Falling by the wayside

The study adds to the growing body of evidence that DRE may not be especially helpful as either a screening tool or when used in active surveillance of men with prostate cancer.

An international consensus panel found that DRE could be safely skipped for active surveillance when MRI and other more accurate and objective measures, such as biomarkers, are available.

A prostate cancer expert who was not involved in the PROBASE study told this news organization that when he was in medical school, it would have been considered a serious lapse of practice not to perform a DRE, but that things have changed considerably over the past several years.

“We have PSA now, we have technology with MRI, and the yield of digital rectal examination is very low,” commented Julio Pow-Sang, MD, chief of the genitourinary oncology program at Moffitt Cancer Center in Tampa, Fla.

“Empirically, it’s very rare to find positive cancer through rectal exam in this day and age of PSA,” he said, adding that the examination itself is highly subjective, with varying results depending on the skills of the particular examiner.

“I think that in time, with good studies like this, digital rectal exam specifically for prostate cancer is going to slowly fade away,” Dr. Pow-Sang said.
 

PROBASE results

PROBASE was a randomized screening study enrolling men at age 45 to test a risk-adapted screening strategy using a baseline PSA value with the additional offer of DRE in a large subcohort of participants.

The study was conducted in Germany, and the authors note that the “German statutory early detection program recommends DRE as a stand-alone screening test starting annually at age 45.”

The PROBASE investigators enrolled 46,495 men from February 2014 through December 2019.

Among the first 23,194 men enrolled, 6,537 underwent DRE at enrollment without a study PSA test.

In this group, 6,480 DREs (99%) were not suspicious for cancer, and 57 (1%) were. Of those with suspected prostate cancer, 37 underwent biopsy and 20 did not. Of those biopsied, only two were found to have prostate cancer. This translated into a cancer detection rate of 0.03% for DRE.

After a median of 6.6 years of follow-up, only one additional case of ISUP grade 2 prostate cancer was detected among the 6,357 men who had DREs at enrollment, translating into a prostate cancer detection rate of .05%.

The investigators also looked at men who suspicious DRE findings at baseline. They assumed that a DRE-detectable tumor at age 45 would still be manifest 5 years later and should be detectable with PSA at age 50. Of the 57 men with initially suspicious findings, 11 returned for PSA screening but refused biopsy, and of this group only one had an elevated PSA level. He then underwent biopsy, but the findings were negative.

Of those who underwent biopsy on the basis of DRE, 16 had prostatitis, 14 had benign prostatic hyperplasia, 1 had high-grade prostatic intraepithelial neoplasia, 1 had atypical small acinar proliferation, and 3 had equivocal findings.

In total, the investigators found 24 tumors among men screened with DRE. Of these, 3 occurred in men with results deemed suspicious and 21 were in men with unsuspicious digital exams. All of the tumors were ISUP grade 1, 2, or 3 tumors.

Among 245 men who had biopsies for a PSA level equal to or higher than 3 ng/mL, primarily Prostate Imaging Reporting and Data System (PI-RADS) 3-5 tumors, DRE findings at the time of biopsy were unsuspicious in about 82% of cases, Dr. Krilaviciute said.

“We also used MRI data to determine what proportion of tumors would be potentially detectable by DRE. We estimated that around 18% of tumors are located in the upper part of the prostate, which is not detectable by DRE,” she said. “Even excluding those tumors, still the DRE detection rate is low in palpable tumors.”

Although DRE performed better in higher-grade tumors, 80% of the tumors in the PROBASE participants were ISUP grade 1 or 2 and were likely to be undetected by DRE, she added.

“In Germany, the recommendations for the screening still include 45-year-olds to go with annual DRE. The PROBASE trial allowed us to evaluate for the first time what was the diagnostic performance for DRE at such a young age, and we see that 99% of men undergoing DRE have no suspicious findings, and among the 1% of suspicious findings having cancers extremely unlikely,” she said.

The study was supported by Deutsche Krebshilfe (German Cancer Aid). Dr. Krilaviciute and Dr. Pow-Sang reported having no relevant conflicts of interest.

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

Digital rectal examination (DRE) is neither helpful nor useful as a solitary prostate cancer screening tool in middle-aged men, say investigators reporting the PROBASE study.

The study compared risk-adapted screening measures in men who had prostate-specific antigen (PSA) measured at age 45 with those who had PSA measurements plus DRE at age 50.

The results show that as a solitary screening tool, 99% of DREs did not raise suspicion for prostate cancer, and among the 57 cases where DRE did raise suspicion, only three men were found to have cancer, all of which were low-grade, reported Agne Krilaviciute, PhD, from the German Cancer Research Center in Heidelberg, and colleagues.

“We also see that the cancer detection rate by PSA is four times higher compared to the DRE detection. Around 18% of the tumors are located in the part of the prostate where DRE cannot detect them,” she said in an oral presentation at the European Association of Urology Congress.

The investigators found that the majority of prostate cancers that occurred in this relatively young population were International Society of Urological Pathology grade 1 (Gleason score 3 + 3 = 6) or grade 2 (Gleason 3 + 4 = 7). DRE yields positive results in only about 12% of cases of ISUP grade 1 or 2, they noted.

“We conclude that DRE as a solitary screening test does not lead to a significant PCa [prostate cancer] detection rate in young men,” Dr. Krilaviciute said.
 

Falling by the wayside

The study adds to the growing body of evidence that DRE may not be especially helpful as either a screening tool or when used in active surveillance of men with prostate cancer.

An international consensus panel found that DRE could be safely skipped for active surveillance when MRI and other more accurate and objective measures, such as biomarkers, are available.

A prostate cancer expert who was not involved in the PROBASE study told this news organization that when he was in medical school, it would have been considered a serious lapse of practice not to perform a DRE, but that things have changed considerably over the past several years.

“We have PSA now, we have technology with MRI, and the yield of digital rectal examination is very low,” commented Julio Pow-Sang, MD, chief of the genitourinary oncology program at Moffitt Cancer Center in Tampa, Fla.

“Empirically, it’s very rare to find positive cancer through rectal exam in this day and age of PSA,” he said, adding that the examination itself is highly subjective, with varying results depending on the skills of the particular examiner.

“I think that in time, with good studies like this, digital rectal exam specifically for prostate cancer is going to slowly fade away,” Dr. Pow-Sang said.
 

PROBASE results

PROBASE was a randomized screening study enrolling men at age 45 to test a risk-adapted screening strategy using a baseline PSA value with the additional offer of DRE in a large subcohort of participants.

The study was conducted in Germany, and the authors note that the “German statutory early detection program recommends DRE as a stand-alone screening test starting annually at age 45.”

The PROBASE investigators enrolled 46,495 men from February 2014 through December 2019.

Among the first 23,194 men enrolled, 6,537 underwent DRE at enrollment without a study PSA test.

In this group, 6,480 DREs (99%) were not suspicious for cancer, and 57 (1%) were. Of those with suspected prostate cancer, 37 underwent biopsy and 20 did not. Of those biopsied, only two were found to have prostate cancer. This translated into a cancer detection rate of 0.03% for DRE.

After a median of 6.6 years of follow-up, only one additional case of ISUP grade 2 prostate cancer was detected among the 6,357 men who had DREs at enrollment, translating into a prostate cancer detection rate of .05%.

The investigators also looked at men who suspicious DRE findings at baseline. They assumed that a DRE-detectable tumor at age 45 would still be manifest 5 years later and should be detectable with PSA at age 50. Of the 57 men with initially suspicious findings, 11 returned for PSA screening but refused biopsy, and of this group only one had an elevated PSA level. He then underwent biopsy, but the findings were negative.

Of those who underwent biopsy on the basis of DRE, 16 had prostatitis, 14 had benign prostatic hyperplasia, 1 had high-grade prostatic intraepithelial neoplasia, 1 had atypical small acinar proliferation, and 3 had equivocal findings.

In total, the investigators found 24 tumors among men screened with DRE. Of these, 3 occurred in men with results deemed suspicious and 21 were in men with unsuspicious digital exams. All of the tumors were ISUP grade 1, 2, or 3 tumors.

Among 245 men who had biopsies for a PSA level equal to or higher than 3 ng/mL, primarily Prostate Imaging Reporting and Data System (PI-RADS) 3-5 tumors, DRE findings at the time of biopsy were unsuspicious in about 82% of cases, Dr. Krilaviciute said.

“We also used MRI data to determine what proportion of tumors would be potentially detectable by DRE. We estimated that around 18% of tumors are located in the upper part of the prostate, which is not detectable by DRE,” she said. “Even excluding those tumors, still the DRE detection rate is low in palpable tumors.”

Although DRE performed better in higher-grade tumors, 80% of the tumors in the PROBASE participants were ISUP grade 1 or 2 and were likely to be undetected by DRE, she added.

“In Germany, the recommendations for the screening still include 45-year-olds to go with annual DRE. The PROBASE trial allowed us to evaluate for the first time what was the diagnostic performance for DRE at such a young age, and we see that 99% of men undergoing DRE have no suspicious findings, and among the 1% of suspicious findings having cancers extremely unlikely,” she said.

The study was supported by Deutsche Krebshilfe (German Cancer Aid). Dr. Krilaviciute and Dr. Pow-Sang reported having no relevant conflicts of interest.

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

Digital rectal examination (DRE) is neither helpful nor useful as a solitary prostate cancer screening tool in middle-aged men, say investigators reporting the PROBASE study.

The study compared risk-adapted screening measures in men who had prostate-specific antigen (PSA) measured at age 45 with those who had PSA measurements plus DRE at age 50.

The results show that as a solitary screening tool, 99% of DREs did not raise suspicion for prostate cancer, and among the 57 cases where DRE did raise suspicion, only three men were found to have cancer, all of which were low-grade, reported Agne Krilaviciute, PhD, from the German Cancer Research Center in Heidelberg, and colleagues.

“We also see that the cancer detection rate by PSA is four times higher compared to the DRE detection. Around 18% of the tumors are located in the part of the prostate where DRE cannot detect them,” she said in an oral presentation at the European Association of Urology Congress.

The investigators found that the majority of prostate cancers that occurred in this relatively young population were International Society of Urological Pathology grade 1 (Gleason score 3 + 3 = 6) or grade 2 (Gleason 3 + 4 = 7). DRE yields positive results in only about 12% of cases of ISUP grade 1 or 2, they noted.

“We conclude that DRE as a solitary screening test does not lead to a significant PCa [prostate cancer] detection rate in young men,” Dr. Krilaviciute said.
 

Falling by the wayside

The study adds to the growing body of evidence that DRE may not be especially helpful as either a screening tool or when used in active surveillance of men with prostate cancer.

An international consensus panel found that DRE could be safely skipped for active surveillance when MRI and other more accurate and objective measures, such as biomarkers, are available.

A prostate cancer expert who was not involved in the PROBASE study told this news organization that when he was in medical school, it would have been considered a serious lapse of practice not to perform a DRE, but that things have changed considerably over the past several years.

“We have PSA now, we have technology with MRI, and the yield of digital rectal examination is very low,” commented Julio Pow-Sang, MD, chief of the genitourinary oncology program at Moffitt Cancer Center in Tampa, Fla.

“Empirically, it’s very rare to find positive cancer through rectal exam in this day and age of PSA,” he said, adding that the examination itself is highly subjective, with varying results depending on the skills of the particular examiner.

“I think that in time, with good studies like this, digital rectal exam specifically for prostate cancer is going to slowly fade away,” Dr. Pow-Sang said.
 

PROBASE results

PROBASE was a randomized screening study enrolling men at age 45 to test a risk-adapted screening strategy using a baseline PSA value with the additional offer of DRE in a large subcohort of participants.

The study was conducted in Germany, and the authors note that the “German statutory early detection program recommends DRE as a stand-alone screening test starting annually at age 45.”

The PROBASE investigators enrolled 46,495 men from February 2014 through December 2019.

Among the first 23,194 men enrolled, 6,537 underwent DRE at enrollment without a study PSA test.

In this group, 6,480 DREs (99%) were not suspicious for cancer, and 57 (1%) were. Of those with suspected prostate cancer, 37 underwent biopsy and 20 did not. Of those biopsied, only two were found to have prostate cancer. This translated into a cancer detection rate of 0.03% for DRE.

After a median of 6.6 years of follow-up, only one additional case of ISUP grade 2 prostate cancer was detected among the 6,357 men who had DREs at enrollment, translating into a prostate cancer detection rate of .05%.

The investigators also looked at men who suspicious DRE findings at baseline. They assumed that a DRE-detectable tumor at age 45 would still be manifest 5 years later and should be detectable with PSA at age 50. Of the 57 men with initially suspicious findings, 11 returned for PSA screening but refused biopsy, and of this group only one had an elevated PSA level. He then underwent biopsy, but the findings were negative.

Of those who underwent biopsy on the basis of DRE, 16 had prostatitis, 14 had benign prostatic hyperplasia, 1 had high-grade prostatic intraepithelial neoplasia, 1 had atypical small acinar proliferation, and 3 had equivocal findings.

In total, the investigators found 24 tumors among men screened with DRE. Of these, 3 occurred in men with results deemed suspicious and 21 were in men with unsuspicious digital exams. All of the tumors were ISUP grade 1, 2, or 3 tumors.

Among 245 men who had biopsies for a PSA level equal to or higher than 3 ng/mL, primarily Prostate Imaging Reporting and Data System (PI-RADS) 3-5 tumors, DRE findings at the time of biopsy were unsuspicious in about 82% of cases, Dr. Krilaviciute said.

“We also used MRI data to determine what proportion of tumors would be potentially detectable by DRE. We estimated that around 18% of tumors are located in the upper part of the prostate, which is not detectable by DRE,” she said. “Even excluding those tumors, still the DRE detection rate is low in palpable tumors.”

Although DRE performed better in higher-grade tumors, 80% of the tumors in the PROBASE participants were ISUP grade 1 or 2 and were likely to be undetected by DRE, she added.

“In Germany, the recommendations for the screening still include 45-year-olds to go with annual DRE. The PROBASE trial allowed us to evaluate for the first time what was the diagnostic performance for DRE at such a young age, and we see that 99% of men undergoing DRE have no suspicious findings, and among the 1% of suspicious findings having cancers extremely unlikely,” she said.

The study was supported by Deutsche Krebshilfe (German Cancer Aid). Dr. Krilaviciute and Dr. Pow-Sang reported having no relevant conflicts of interest.

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

A simple urine test for genetic mutations in urine-derived DNA can predict urothelial cancer up to 12 years before patients develop symptoms, an international team of researchers claims.

The test, if validated in further studies, has the potential to serve as a cancer screening tool for individuals at elevated risk for bladder cancer due to genetics, smoking, or from environmental exposures to known carcinogens, and it could help to reduce the frequency of unnecessary cystoscopies, say urologists who were not involved in the research.

The test involved was performed using a next-generation sequencing assay (UroAmp, Convergent Genomics, based in San Francisco) that identifies mutations in 60 genes associated with bladder cancer. New research reported at the annual congress of the European Association of Urology described the screening model that focused on 10 key genes covered in the assay.

In training and validation cohorts, the urinary comprehensive genomic profiling test accurately predicted future bladder cancer in 66% of patient urine samples, including some that had been collected more than a decade prior to being tested, reported Florence Le Calvez-Kelm, PhD, MSc, from the International Agency for Research on Cancer, Lyon, France.

“Our results provide first evidence from a population-based cohort study of preclinical urothelial cancer detection with urinary comprehensive genomic profiling,” she told the meeting.

The results were consistent both in individuals with known risk factors for bladder cancer who were undergoing cystoscopy and in those with no evidence of disease, she said.

“Research of this nature is very encouraging, as it shows that our ability to identify molecular alterations in liquid biopsies such as urine that might indicate cancer is constantly improving,” commented Joost Boormans, MD, PhD, a urologist at the Erasmus University Medical Center, Rotterdam, Netherlands, and a member of the EAU Scientific Congress Office.

“While we do need to develop more accurate diagnostics, it’s unlikely that we’ll have a mass screening program for bladder cancer in the near future,” he continued. “Where a urine test for genetic mutations could show its value is in reducing cystoscopies and scans in bladder cancer patients who are being monitored for recurrence, as well as those referred for blood in their urine. A simple urine test would be far easier for patients to undergo than invasive procedures or scans, as well as being less costly for health services.”

Dr. Le Calvez-Kelm and colleagues had previously shown that promoter mutations in the gene encoding for the enzyme telomerase reverse transcriptase (TERT) identified in urine were “promising noninvasive biomarkers” for early detection of bladder cancer.

They found that TERT mutations in urine could predict which patients were likely to develop urothelial cancer with 48% sensitivity and 100% specificity.

In the study presented at EAU23, they hypothesized that uCGP of DNA in urine could offer enhanced sensitivity for early detection of urothelial cancer.

They first used the 60-gene assay to create a training set using urine samples from 46 patients with de novo urothelial cancer, 40 with recurrent cancer, and 140 healthy controls.

They then tested the model in two validation cohorts. The first validation cohort consisted of samples from 22 patients with de novo cancer, 48 with recurrent urothelial cancer, and 96 controls from a case-control study conducted at Massachusetts General Hospital, Boston, and Ohio State University, Columbus.

The second validation cohort included 29 patients from the prospective Golestan Cohort Study who subsequently developed urothelial cancer, with 98 controls.

In all, 10 genes were identified as optimal for inclusion in a screening model, which was trained to an overall sensitivity of 88% and a 97% sensitivity for high-grade tumors, with a specificity of 94%.

In the MGH/OSU validation cohort the sensitivity of the models was 71%, and the specificity was 94%. In the Golestan cohort, the sensitivity was 66%, with a specificity of 94%. This compared favorably with the performance of the TERT-only screening model, which, as noted before, had a sensitivity of 48%, albeit with 100% specificity.

“Interestingly, when we broke down the analysis according to the lag time between urine collection and diagnosis, sensitivity increased as the time to diagnosis decreased, so the closer we got to the diagnosis, the higher was the sensitivity,” Dr. Le Calvez-Kelm said.

When the analysis was limited to urothelial cancers diagnosed within 7 years of sample collection, the sensitivity for detecting preclinical cancer improved to 86%, compared with 57% for a test of TERT promoter mutations alone. 

Among the patients in the Golestan cohort, uCGP-predicted positive results were associated with a more than eightfold higher risk for worse cancer-free survival, compared with uCGP-predicted negatives (hazard ratio 8.5, P < .0001).

“Of course, further studies are needed to validate this finding and to assess the clinical utility in other longitudinal cohorts,” Dr. Le Calvez-Kelm concluded.

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

A simple urine test for genetic mutations in urine-derived DNA can predict urothelial cancer up to 12 years before patients develop symptoms, an international team of researchers claims.

The test, if validated in further studies, has the potential to serve as a cancer screening tool for individuals at elevated risk for bladder cancer due to genetics, smoking, or from environmental exposures to known carcinogens, and it could help to reduce the frequency of unnecessary cystoscopies, say urologists who were not involved in the research.

The test involved was performed using a next-generation sequencing assay (UroAmp, Convergent Genomics, based in San Francisco) that identifies mutations in 60 genes associated with bladder cancer. New research reported at the annual congress of the European Association of Urology described the screening model that focused on 10 key genes covered in the assay.

In training and validation cohorts, the urinary comprehensive genomic profiling test accurately predicted future bladder cancer in 66% of patient urine samples, including some that had been collected more than a decade prior to being tested, reported Florence Le Calvez-Kelm, PhD, MSc, from the International Agency for Research on Cancer, Lyon, France.

“Our results provide first evidence from a population-based cohort study of preclinical urothelial cancer detection with urinary comprehensive genomic profiling,” she told the meeting.

The results were consistent both in individuals with known risk factors for bladder cancer who were undergoing cystoscopy and in those with no evidence of disease, she said.

“Research of this nature is very encouraging, as it shows that our ability to identify molecular alterations in liquid biopsies such as urine that might indicate cancer is constantly improving,” commented Joost Boormans, MD, PhD, a urologist at the Erasmus University Medical Center, Rotterdam, Netherlands, and a member of the EAU Scientific Congress Office.

“While we do need to develop more accurate diagnostics, it’s unlikely that we’ll have a mass screening program for bladder cancer in the near future,” he continued. “Where a urine test for genetic mutations could show its value is in reducing cystoscopies and scans in bladder cancer patients who are being monitored for recurrence, as well as those referred for blood in their urine. A simple urine test would be far easier for patients to undergo than invasive procedures or scans, as well as being less costly for health services.”

Dr. Le Calvez-Kelm and colleagues had previously shown that promoter mutations in the gene encoding for the enzyme telomerase reverse transcriptase (TERT) identified in urine were “promising noninvasive biomarkers” for early detection of bladder cancer.

They found that TERT mutations in urine could predict which patients were likely to develop urothelial cancer with 48% sensitivity and 100% specificity.

In the study presented at EAU23, they hypothesized that uCGP of DNA in urine could offer enhanced sensitivity for early detection of urothelial cancer.

They first used the 60-gene assay to create a training set using urine samples from 46 patients with de novo urothelial cancer, 40 with recurrent cancer, and 140 healthy controls.

They then tested the model in two validation cohorts. The first validation cohort consisted of samples from 22 patients with de novo cancer, 48 with recurrent urothelial cancer, and 96 controls from a case-control study conducted at Massachusetts General Hospital, Boston, and Ohio State University, Columbus.

The second validation cohort included 29 patients from the prospective Golestan Cohort Study who subsequently developed urothelial cancer, with 98 controls.

In all, 10 genes were identified as optimal for inclusion in a screening model, which was trained to an overall sensitivity of 88% and a 97% sensitivity for high-grade tumors, with a specificity of 94%.

In the MGH/OSU validation cohort the sensitivity of the models was 71%, and the specificity was 94%. In the Golestan cohort, the sensitivity was 66%, with a specificity of 94%. This compared favorably with the performance of the TERT-only screening model, which, as noted before, had a sensitivity of 48%, albeit with 100% specificity.

“Interestingly, when we broke down the analysis according to the lag time between urine collection and diagnosis, sensitivity increased as the time to diagnosis decreased, so the closer we got to the diagnosis, the higher was the sensitivity,” Dr. Le Calvez-Kelm said.

When the analysis was limited to urothelial cancers diagnosed within 7 years of sample collection, the sensitivity for detecting preclinical cancer improved to 86%, compared with 57% for a test of TERT promoter mutations alone. 

Among the patients in the Golestan cohort, uCGP-predicted positive results were associated with a more than eightfold higher risk for worse cancer-free survival, compared with uCGP-predicted negatives (hazard ratio 8.5, P < .0001).

“Of course, further studies are needed to validate this finding and to assess the clinical utility in other longitudinal cohorts,” Dr. Le Calvez-Kelm concluded.

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

A simple urine test for genetic mutations in urine-derived DNA can predict urothelial cancer up to 12 years before patients develop symptoms, an international team of researchers claims.

The test, if validated in further studies, has the potential to serve as a cancer screening tool for individuals at elevated risk for bladder cancer due to genetics, smoking, or from environmental exposures to known carcinogens, and it could help to reduce the frequency of unnecessary cystoscopies, say urologists who were not involved in the research.

The test involved was performed using a next-generation sequencing assay (UroAmp, Convergent Genomics, based in San Francisco) that identifies mutations in 60 genes associated with bladder cancer. New research reported at the annual congress of the European Association of Urology described the screening model that focused on 10 key genes covered in the assay.

In training and validation cohorts, the urinary comprehensive genomic profiling test accurately predicted future bladder cancer in 66% of patient urine samples, including some that had been collected more than a decade prior to being tested, reported Florence Le Calvez-Kelm, PhD, MSc, from the International Agency for Research on Cancer, Lyon, France.

“Our results provide first evidence from a population-based cohort study of preclinical urothelial cancer detection with urinary comprehensive genomic profiling,” she told the meeting.

The results were consistent both in individuals with known risk factors for bladder cancer who were undergoing cystoscopy and in those with no evidence of disease, she said.

“Research of this nature is very encouraging, as it shows that our ability to identify molecular alterations in liquid biopsies such as urine that might indicate cancer is constantly improving,” commented Joost Boormans, MD, PhD, a urologist at the Erasmus University Medical Center, Rotterdam, Netherlands, and a member of the EAU Scientific Congress Office.

“While we do need to develop more accurate diagnostics, it’s unlikely that we’ll have a mass screening program for bladder cancer in the near future,” he continued. “Where a urine test for genetic mutations could show its value is in reducing cystoscopies and scans in bladder cancer patients who are being monitored for recurrence, as well as those referred for blood in their urine. A simple urine test would be far easier for patients to undergo than invasive procedures or scans, as well as being less costly for health services.”

Dr. Le Calvez-Kelm and colleagues had previously shown that promoter mutations in the gene encoding for the enzyme telomerase reverse transcriptase (TERT) identified in urine were “promising noninvasive biomarkers” for early detection of bladder cancer.

They found that TERT mutations in urine could predict which patients were likely to develop urothelial cancer with 48% sensitivity and 100% specificity.

In the study presented at EAU23, they hypothesized that uCGP of DNA in urine could offer enhanced sensitivity for early detection of urothelial cancer.

They first used the 60-gene assay to create a training set using urine samples from 46 patients with de novo urothelial cancer, 40 with recurrent cancer, and 140 healthy controls.

They then tested the model in two validation cohorts. The first validation cohort consisted of samples from 22 patients with de novo cancer, 48 with recurrent urothelial cancer, and 96 controls from a case-control study conducted at Massachusetts General Hospital, Boston, and Ohio State University, Columbus.

The second validation cohort included 29 patients from the prospective Golestan Cohort Study who subsequently developed urothelial cancer, with 98 controls.

In all, 10 genes were identified as optimal for inclusion in a screening model, which was trained to an overall sensitivity of 88% and a 97% sensitivity for high-grade tumors, with a specificity of 94%.

In the MGH/OSU validation cohort the sensitivity of the models was 71%, and the specificity was 94%. In the Golestan cohort, the sensitivity was 66%, with a specificity of 94%. This compared favorably with the performance of the TERT-only screening model, which, as noted before, had a sensitivity of 48%, albeit with 100% specificity.

“Interestingly, when we broke down the analysis according to the lag time between urine collection and diagnosis, sensitivity increased as the time to diagnosis decreased, so the closer we got to the diagnosis, the higher was the sensitivity,” Dr. Le Calvez-Kelm said.

When the analysis was limited to urothelial cancers diagnosed within 7 years of sample collection, the sensitivity for detecting preclinical cancer improved to 86%, compared with 57% for a test of TERT promoter mutations alone. 

Among the patients in the Golestan cohort, uCGP-predicted positive results were associated with a more than eightfold higher risk for worse cancer-free survival, compared with uCGP-predicted negatives (hazard ratio 8.5, P < .0001).

“Of course, further studies are needed to validate this finding and to assess the clinical utility in other longitudinal cohorts,” Dr. Le Calvez-Kelm concluded.

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

A growing body of evidence shows that deeper and larger tumors can be safely removed with endoscopy instead of surgery when individual patient risk is taken into account, according to a review by Eva P.D. Verheij, a doctoral candidate at Amsterdam University Medical Center, and colleagues.

“Management of patients with superficial esophageal adenocarcinoma (EAC) is becoming less invasive and more patient-tailored,” the researchers wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “In the future, watchful waiting may be a valid alternative to surgery in selected cases.”

Courtesy Eva P. D. Verheij

The investigators examined new advances that have been made in the management of superficial esophageal adenocarcinomas by endoscopy, and they address how guidelines may be falling short in light of newly published evidence.

Surgery is usually the first choice for the management of advanced esophageal adenocarcinoma. “Endoscopic treatment has become the cornerstone for early cancer confined to the mucosa,” the authors wrote.

“For low-risk submucosal EAC, which only invades the superficial submucosa (sm1, i.e. less than 500 mcm) without any other risk factors, endoscopic treatment as an alternative to surgery is gaining acceptance because multiple studies have demonstrated a very low risk of lymph node metastases (less than 2% for these lesions),” the investigators wrote. Although surgical resection with lymphadenectomy is currently the recommended treatment for cases with deep submucosal invasion, poor differentiation, or lymphovascular invasion, the investigators suggested that even these tumors may be within an endoscopist’s reach.

While the rate of lymph node metastasis for such patients has been reported to be as high as 46%, more recent endoscopic studies show a metastasis rate range of up to 20% after 23-63 months of follow-up.

“One possible explanation for the discrepancy in lymph node metastases rates between surgical and endoscopic studies could be the different preparation of slides for histopathological assessment,” the investigators wrote. “In general, the cuts in surgical specimen are made with wider intervals (±5 mm) than the cuts in endoscopic resection specimens (2-3 mm), with additional cuts in case of submucosal invasion. The hypothesis is that this wider interval may result in missing the area with the deepest tumor infiltration. This could result in an underdiagnosis of the actual invasion depth, and therefore an overestimation of the associated lymph node metastases risk.” A study published in August 2022 in Gastrointestinal Endoscopy found an annual metastases risk of 6.9% in patients with high-risk T1a EAC.

“Given its invasiveness and associated morbidity and mortality, esophagectomy may be overtreatment in those patients who will not develop lymph node metastases,” the investigators wrote. “Given the technical advances in endoscopy that enable us to radically remove large EACs, and to perform more meticulous follow-up, it might be time to swing the pendulum and only send those patients for surgery who have an indisputable indication for surgery, instead of performing esophagectomy as a prophylactic treatment.”

To truly find the limits of endoscopic resection for EAC, however, more research is needed.

“Ongoing studies are necessary to evaluate the lymph node metastases risk on an individual basis, using presence of histological risk factors. By predicting the risk of lymph node metastases, and considering patients’ wishes and condition, one might decide to perform esophagectomy or watchful waiting with strict endoscopic follow-up. In high-risk cases, we may use sentinel node navigated surgery in the future as an extra safety check before deciding on optimal management,” the authors wrote.

The investigators disclosed relationships Medtronic, C2 Therapeutics/Pentax Medical, MicroTech, and Aqua Medical.

A growing body of evidence shows that deeper and larger tumors can be safely removed with endoscopy instead of surgery when individual patient risk is taken into account, according to a review by Eva P.D. Verheij, a doctoral candidate at Amsterdam University Medical Center, and colleagues.

“Management of patients with superficial esophageal adenocarcinoma (EAC) is becoming less invasive and more patient-tailored,” the researchers wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “In the future, watchful waiting may be a valid alternative to surgery in selected cases.”

Courtesy Eva P. D. Verheij

The investigators examined new advances that have been made in the management of superficial esophageal adenocarcinomas by endoscopy, and they address how guidelines may be falling short in light of newly published evidence.

Surgery is usually the first choice for the management of advanced esophageal adenocarcinoma. “Endoscopic treatment has become the cornerstone for early cancer confined to the mucosa,” the authors wrote.

“For low-risk submucosal EAC, which only invades the superficial submucosa (sm1, i.e. less than 500 mcm) without any other risk factors, endoscopic treatment as an alternative to surgery is gaining acceptance because multiple studies have demonstrated a very low risk of lymph node metastases (less than 2% for these lesions),” the investigators wrote. Although surgical resection with lymphadenectomy is currently the recommended treatment for cases with deep submucosal invasion, poor differentiation, or lymphovascular invasion, the investigators suggested that even these tumors may be within an endoscopist’s reach.

While the rate of lymph node metastasis for such patients has been reported to be as high as 46%, more recent endoscopic studies show a metastasis rate range of up to 20% after 23-63 months of follow-up.

“One possible explanation for the discrepancy in lymph node metastases rates between surgical and endoscopic studies could be the different preparation of slides for histopathological assessment,” the investigators wrote. “In general, the cuts in surgical specimen are made with wider intervals (±5 mm) than the cuts in endoscopic resection specimens (2-3 mm), with additional cuts in case of submucosal invasion. The hypothesis is that this wider interval may result in missing the area with the deepest tumor infiltration. This could result in an underdiagnosis of the actual invasion depth, and therefore an overestimation of the associated lymph node metastases risk.” A study published in August 2022 in Gastrointestinal Endoscopy found an annual metastases risk of 6.9% in patients with high-risk T1a EAC.

“Given its invasiveness and associated morbidity and mortality, esophagectomy may be overtreatment in those patients who will not develop lymph node metastases,” the investigators wrote. “Given the technical advances in endoscopy that enable us to radically remove large EACs, and to perform more meticulous follow-up, it might be time to swing the pendulum and only send those patients for surgery who have an indisputable indication for surgery, instead of performing esophagectomy as a prophylactic treatment.”

To truly find the limits of endoscopic resection for EAC, however, more research is needed.

“Ongoing studies are necessary to evaluate the lymph node metastases risk on an individual basis, using presence of histological risk factors. By predicting the risk of lymph node metastases, and considering patients’ wishes and condition, one might decide to perform esophagectomy or watchful waiting with strict endoscopic follow-up. In high-risk cases, we may use sentinel node navigated surgery in the future as an extra safety check before deciding on optimal management,” the authors wrote.

The investigators disclosed relationships Medtronic, C2 Therapeutics/Pentax Medical, MicroTech, and Aqua Medical.

A growing body of evidence shows that deeper and larger tumors can be safely removed with endoscopy instead of surgery when individual patient risk is taken into account, according to a review by Eva P.D. Verheij, a doctoral candidate at Amsterdam University Medical Center, and colleagues.

“Management of patients with superficial esophageal adenocarcinoma (EAC) is becoming less invasive and more patient-tailored,” the researchers wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “In the future, watchful waiting may be a valid alternative to surgery in selected cases.”

Courtesy Eva P. D. Verheij

The investigators examined new advances that have been made in the management of superficial esophageal adenocarcinomas by endoscopy, and they address how guidelines may be falling short in light of newly published evidence.

Surgery is usually the first choice for the management of advanced esophageal adenocarcinoma. “Endoscopic treatment has become the cornerstone for early cancer confined to the mucosa,” the authors wrote.

“For low-risk submucosal EAC, which only invades the superficial submucosa (sm1, i.e. less than 500 mcm) without any other risk factors, endoscopic treatment as an alternative to surgery is gaining acceptance because multiple studies have demonstrated a very low risk of lymph node metastases (less than 2% for these lesions),” the investigators wrote. Although surgical resection with lymphadenectomy is currently the recommended treatment for cases with deep submucosal invasion, poor differentiation, or lymphovascular invasion, the investigators suggested that even these tumors may be within an endoscopist’s reach.

While the rate of lymph node metastasis for such patients has been reported to be as high as 46%, more recent endoscopic studies show a metastasis rate range of up to 20% after 23-63 months of follow-up.

“One possible explanation for the discrepancy in lymph node metastases rates between surgical and endoscopic studies could be the different preparation of slides for histopathological assessment,” the investigators wrote. “In general, the cuts in surgical specimen are made with wider intervals (±5 mm) than the cuts in endoscopic resection specimens (2-3 mm), with additional cuts in case of submucosal invasion. The hypothesis is that this wider interval may result in missing the area with the deepest tumor infiltration. This could result in an underdiagnosis of the actual invasion depth, and therefore an overestimation of the associated lymph node metastases risk.” A study published in August 2022 in Gastrointestinal Endoscopy found an annual metastases risk of 6.9% in patients with high-risk T1a EAC.

“Given its invasiveness and associated morbidity and mortality, esophagectomy may be overtreatment in those patients who will not develop lymph node metastases,” the investigators wrote. “Given the technical advances in endoscopy that enable us to radically remove large EACs, and to perform more meticulous follow-up, it might be time to swing the pendulum and only send those patients for surgery who have an indisputable indication for surgery, instead of performing esophagectomy as a prophylactic treatment.”

To truly find the limits of endoscopic resection for EAC, however, more research is needed.

“Ongoing studies are necessary to evaluate the lymph node metastases risk on an individual basis, using presence of histological risk factors. By predicting the risk of lymph node metastases, and considering patients’ wishes and condition, one might decide to perform esophagectomy or watchful waiting with strict endoscopic follow-up. In high-risk cases, we may use sentinel node navigated surgery in the future as an extra safety check before deciding on optimal management,” the authors wrote.

The investigators disclosed relationships Medtronic, C2 Therapeutics/Pentax Medical, MicroTech, and Aqua Medical.

Radiation dermatitis is one of the most common side effects of radiotherapy for women with breast cancer. Results from a phase 3 trial add to previous evidence from smaller trials that show that a silicone-based film can protect skin from this side effect. 

But it is not being used much in clinical practice. Instead, radiation dermatitis is usually treated after the fact, most often with aqueous creams.

The product is Mepitel film, from Swedish medical device company Mölnlycke Health Care.

It should be used for women who are at high risk for developing radiation dermatitis, said Edward Chow, MBBS, PhD, of the department of radiation oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, who was the senior author of the phase 3 study published recently in the Journal of Clinical Oncology.

“Other doctors think that because radiation dermatitis isn’t life-threatening it isn’t as important, but the condition does affect the quality of life for patients,” Dr. Chow said. “If we can lessen the pain and discomfort, why wouldn’t we as physicians?”

Dr. Chow’s open-label, multicenter trial was conducted in 376 women with large breasts (bra cup size C or larger) who were undergoing radiotherapy after lumpectomy or mastectomy. The primary endpoint was grade 2 or 3 radiation dermatitis using the Common Terminology Criteria for Adverse Events. (Grade 2 is described as moderate, whereas grade 3 is severe.) 

The film significantly reduced the incidence of grade 2 or 3 radiation dermatitis, down to  15.5% compared with 45.6% in patients receiving standard care (odds ratio, 0.20, 95% confidence interval, 0.12-0.34, P < .0001). 

There was also a significant reduction in grade 3 radiation dermatitis (2.8% vs. 13.6%; OR, 0.19; P < .0002) and moist desquamation (8% vs. 19.2%; OR, 0.36; P = .002).

“The film was remarkably effective and helped protect patients from potentially debilitating side effects,” commented Corey Speers, MD, PhD, a radiation oncologist with University Hospitals, Cleveland, who saw the study data presented during a plenary session at the annual meeting of the American Society of Clinical Oncology.

He believes that preventing radiation dermatitis before it develops is the best way to care for patients. 

“[Radiation dermatitis] is usually associated with pain and discomfort and can lead to more serious issues like infection or delayed wound healing, and unfortunately, there aren’t effective treatments for it once it’s developed, so preventing it is our most effective strategy,” Dr. Speers said. 

One reason for the film not being used much could be that it takes time apply the film, suggested Patries Herst, PhD, department of radiation therapy, University of Otago, Wellington, New Zealand. She was the lead author of a study published in 2014 that also analyzed the effectiveness of the film in preventing radiation dermatitis.

In their trial, a research radiation therapist applied the film to women when they were starting their radiotherapy. The film is applied to a portion of the breast or chest wall, and Dr. Herst emphasized the importance of applying the film correctly, making sure the film is not stretched during application and not overlapping other pieces of the film, while also making sure that it conforms to the breast shape. The film was replaced when it would curl too much around the sides, approximately every 1 or 2 weeks. 

“Radiation therapy itself is very short. And so you have about 10 minutes for every patient,” she explained.

“But applying the film adds 20-30 minutes and it’s really awkward to apply properly,” Dr. Herst said. “You have to tap it in and then have to maybe cut it so that it fits better. And hospitals say, ‘We don’t have the time’ and that is still the biggest issue that we’re seeing right now.”

In Dr. Chow’s study, the average time spent applying the film on lumpectomy patients was 55 minutes and was slightly shorter at 45 minutes for mastectomy patients. He acknowledged that it does take time that staff at most hospitals and clinics simply don’t have.

Dr. Chow suggested that perhaps a family member or other caregiver could apply the film, and he referenced an educational video from the manufacturer that provides in-depth instructions on the correct way to apply the film for radiotherapy patients. However, this could lead to errors and a waste of product if not the film was not applied properly. 

The cost of Mepitel film may also be a deterrent. Dr. Chow’s study noted that, during the entire course of radiotherapy, the cost for the film was about $80-$100 per patient. However, he believes the benefits outweigh the cost. 

In addition, there have been issues with supplies, and it has been difficult for people to get their hands on the actual product.

Currently, the Mayo Clinic is also conducting a study testing Mepitel Film for radiation dermatitis in breast cancer patients following mastectomy. Mayo Clinic principal investigator Kimberly Corbin, MD, could not go into great detail about the ongoing trial, but she said it has been difficult to get the product. 

“We have been using the film at Mayo for a number of years,” Dr. Corbin said, but we “have found that it is challenging to get supplies.”

“While we have generally been able to have some supply established through our store here, we know that is not typical and it is difficult for patients to access,” she said. In addition, “there are not a ton of centers with experience in application.”

A representative with Mölnlycke Health Care, Allyson Bower-Willner, could not comment on the distribution of Mepitel film in the United States or if the company plans to increase the amount of product shipped. The film is available “to a limited set of customers,” she said.

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

Radiation dermatitis is one of the most common side effects of radiotherapy for women with breast cancer. Results from a phase 3 trial add to previous evidence from smaller trials that show that a silicone-based film can protect skin from this side effect. 

But it is not being used much in clinical practice. Instead, radiation dermatitis is usually treated after the fact, most often with aqueous creams.

The product is Mepitel film, from Swedish medical device company Mölnlycke Health Care.

It should be used for women who are at high risk for developing radiation dermatitis, said Edward Chow, MBBS, PhD, of the department of radiation oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, who was the senior author of the phase 3 study published recently in the Journal of Clinical Oncology.

“Other doctors think that because radiation dermatitis isn’t life-threatening it isn’t as important, but the condition does affect the quality of life for patients,” Dr. Chow said. “If we can lessen the pain and discomfort, why wouldn’t we as physicians?”

Dr. Chow’s open-label, multicenter trial was conducted in 376 women with large breasts (bra cup size C or larger) who were undergoing radiotherapy after lumpectomy or mastectomy. The primary endpoint was grade 2 or 3 radiation dermatitis using the Common Terminology Criteria for Adverse Events. (Grade 2 is described as moderate, whereas grade 3 is severe.) 

The film significantly reduced the incidence of grade 2 or 3 radiation dermatitis, down to  15.5% compared with 45.6% in patients receiving standard care (odds ratio, 0.20, 95% confidence interval, 0.12-0.34, P < .0001). 

There was also a significant reduction in grade 3 radiation dermatitis (2.8% vs. 13.6%; OR, 0.19; P < .0002) and moist desquamation (8% vs. 19.2%; OR, 0.36; P = .002).

“The film was remarkably effective and helped protect patients from potentially debilitating side effects,” commented Corey Speers, MD, PhD, a radiation oncologist with University Hospitals, Cleveland, who saw the study data presented during a plenary session at the annual meeting of the American Society of Clinical Oncology.

He believes that preventing radiation dermatitis before it develops is the best way to care for patients. 

“[Radiation dermatitis] is usually associated with pain and discomfort and can lead to more serious issues like infection or delayed wound healing, and unfortunately, there aren’t effective treatments for it once it’s developed, so preventing it is our most effective strategy,” Dr. Speers said. 

One reason for the film not being used much could be that it takes time apply the film, suggested Patries Herst, PhD, department of radiation therapy, University of Otago, Wellington, New Zealand. She was the lead author of a study published in 2014 that also analyzed the effectiveness of the film in preventing radiation dermatitis.

In their trial, a research radiation therapist applied the film to women when they were starting their radiotherapy. The film is applied to a portion of the breast or chest wall, and Dr. Herst emphasized the importance of applying the film correctly, making sure the film is not stretched during application and not overlapping other pieces of the film, while also making sure that it conforms to the breast shape. The film was replaced when it would curl too much around the sides, approximately every 1 or 2 weeks. 

“Radiation therapy itself is very short. And so you have about 10 minutes for every patient,” she explained.

“But applying the film adds 20-30 minutes and it’s really awkward to apply properly,” Dr. Herst said. “You have to tap it in and then have to maybe cut it so that it fits better. And hospitals say, ‘We don’t have the time’ and that is still the biggest issue that we’re seeing right now.”

In Dr. Chow’s study, the average time spent applying the film on lumpectomy patients was 55 minutes and was slightly shorter at 45 minutes for mastectomy patients. He acknowledged that it does take time that staff at most hospitals and clinics simply don’t have.

Dr. Chow suggested that perhaps a family member or other caregiver could apply the film, and he referenced an educational video from the manufacturer that provides in-depth instructions on the correct way to apply the film for radiotherapy patients. However, this could lead to errors and a waste of product if not the film was not applied properly. 

The cost of Mepitel film may also be a deterrent. Dr. Chow’s study noted that, during the entire course of radiotherapy, the cost for the film was about $80-$100 per patient. However, he believes the benefits outweigh the cost. 

In addition, there have been issues with supplies, and it has been difficult for people to get their hands on the actual product.

Currently, the Mayo Clinic is also conducting a study testing Mepitel Film for radiation dermatitis in breast cancer patients following mastectomy. Mayo Clinic principal investigator Kimberly Corbin, MD, could not go into great detail about the ongoing trial, but she said it has been difficult to get the product. 

“We have been using the film at Mayo for a number of years,” Dr. Corbin said, but we “have found that it is challenging to get supplies.”

“While we have generally been able to have some supply established through our store here, we know that is not typical and it is difficult for patients to access,” she said. In addition, “there are not a ton of centers with experience in application.”

A representative with Mölnlycke Health Care, Allyson Bower-Willner, could not comment on the distribution of Mepitel film in the United States or if the company plans to increase the amount of product shipped. The film is available “to a limited set of customers,” she said.

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

Radiation dermatitis is one of the most common side effects of radiotherapy for women with breast cancer. Results from a phase 3 trial add to previous evidence from smaller trials that show that a silicone-based film can protect skin from this side effect. 

But it is not being used much in clinical practice. Instead, radiation dermatitis is usually treated after the fact, most often with aqueous creams.

The product is Mepitel film, from Swedish medical device company Mölnlycke Health Care.

It should be used for women who are at high risk for developing radiation dermatitis, said Edward Chow, MBBS, PhD, of the department of radiation oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, who was the senior author of the phase 3 study published recently in the Journal of Clinical Oncology.

“Other doctors think that because radiation dermatitis isn’t life-threatening it isn’t as important, but the condition does affect the quality of life for patients,” Dr. Chow said. “If we can lessen the pain and discomfort, why wouldn’t we as physicians?”

Dr. Chow’s open-label, multicenter trial was conducted in 376 women with large breasts (bra cup size C or larger) who were undergoing radiotherapy after lumpectomy or mastectomy. The primary endpoint was grade 2 or 3 radiation dermatitis using the Common Terminology Criteria for Adverse Events. (Grade 2 is described as moderate, whereas grade 3 is severe.) 

The film significantly reduced the incidence of grade 2 or 3 radiation dermatitis, down to  15.5% compared with 45.6% in patients receiving standard care (odds ratio, 0.20, 95% confidence interval, 0.12-0.34, P < .0001). 

There was also a significant reduction in grade 3 radiation dermatitis (2.8% vs. 13.6%; OR, 0.19; P < .0002) and moist desquamation (8% vs. 19.2%; OR, 0.36; P = .002).

“The film was remarkably effective and helped protect patients from potentially debilitating side effects,” commented Corey Speers, MD, PhD, a radiation oncologist with University Hospitals, Cleveland, who saw the study data presented during a plenary session at the annual meeting of the American Society of Clinical Oncology.

He believes that preventing radiation dermatitis before it develops is the best way to care for patients. 

“[Radiation dermatitis] is usually associated with pain and discomfort and can lead to more serious issues like infection or delayed wound healing, and unfortunately, there aren’t effective treatments for it once it’s developed, so preventing it is our most effective strategy,” Dr. Speers said. 

One reason for the film not being used much could be that it takes time apply the film, suggested Patries Herst, PhD, department of radiation therapy, University of Otago, Wellington, New Zealand. She was the lead author of a study published in 2014 that also analyzed the effectiveness of the film in preventing radiation dermatitis.

In their trial, a research radiation therapist applied the film to women when they were starting their radiotherapy. The film is applied to a portion of the breast or chest wall, and Dr. Herst emphasized the importance of applying the film correctly, making sure the film is not stretched during application and not overlapping other pieces of the film, while also making sure that it conforms to the breast shape. The film was replaced when it would curl too much around the sides, approximately every 1 or 2 weeks. 

“Radiation therapy itself is very short. And so you have about 10 minutes for every patient,” she explained.

“But applying the film adds 20-30 minutes and it’s really awkward to apply properly,” Dr. Herst said. “You have to tap it in and then have to maybe cut it so that it fits better. And hospitals say, ‘We don’t have the time’ and that is still the biggest issue that we’re seeing right now.”

In Dr. Chow’s study, the average time spent applying the film on lumpectomy patients was 55 minutes and was slightly shorter at 45 minutes for mastectomy patients. He acknowledged that it does take time that staff at most hospitals and clinics simply don’t have.

Dr. Chow suggested that perhaps a family member or other caregiver could apply the film, and he referenced an educational video from the manufacturer that provides in-depth instructions on the correct way to apply the film for radiotherapy patients. However, this could lead to errors and a waste of product if not the film was not applied properly. 

The cost of Mepitel film may also be a deterrent. Dr. Chow’s study noted that, during the entire course of radiotherapy, the cost for the film was about $80-$100 per patient. However, he believes the benefits outweigh the cost. 

In addition, there have been issues with supplies, and it has been difficult for people to get their hands on the actual product.

Currently, the Mayo Clinic is also conducting a study testing Mepitel Film for radiation dermatitis in breast cancer patients following mastectomy. Mayo Clinic principal investigator Kimberly Corbin, MD, could not go into great detail about the ongoing trial, but she said it has been difficult to get the product. 

“We have been using the film at Mayo for a number of years,” Dr. Corbin said, but we “have found that it is challenging to get supplies.”

“While we have generally been able to have some supply established through our store here, we know that is not typical and it is difficult for patients to access,” she said. In addition, “there are not a ton of centers with experience in application.”

A representative with Mölnlycke Health Care, Allyson Bower-Willner, could not comment on the distribution of Mepitel film in the United States or if the company plans to increase the amount of product shipped. The film is available “to a limited set of customers,” she said.

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

Researchers are calling for the extent of skin erythema to be considered as an outcome measure in patients who develop chronic cutaneous graft-versus-host disease (ccGVHD) after allogeneic stem cell transplants for various blood cancers.

“There is value in collecting erythema serially over time as a continuous variable on a scale of 0%-100%” to identify high-risk patients for prophylactic and preemptive treatment, say investigators led by dermatologist Emily Baumrin, MD, director of the GVHD clinic at the University of Pennsylvania, Philadelphia.

They report a study of more than 300 patients with ccGVHD, which found that the extent of skin erythema strongly predicted the risk for death from GVHD.

Of the 267 patients with cutaneous GVHD at baseline, 103 patients died, the majority without a relapse of their blood cancer.

With additional research, erythema body surface area (BSA) should be “introduced as an outcome measure in clinical practice and trials,” they conclude.

At the moment, the NIH Skin Score is commonly used for risk assessment in cutaneous GVHD, but the researchers found that erythema BSA out-predicts this score.

The investigators explain that the NIH Skin Score does incorporate erythema surface area, but it does so as a categorical variable, not a continuous variable. Among other additional factors, it also includes assessments of skin sclerosis, which the investigators found was not associated with GVHD mortality.

Overall, the composite score waters down the weight given to erythema BSA because the score is “driven by stable sclerotic features, and erythema changes are missed,” they explain.

The study was published online in JAMA Dermatology.
 

Study details

The study included 469 patients with chronic GVHD (cGVHD), of whom 267 (57%) had cutaneous cGVHD at enrollment and 89 (19%) developed skin involvement subsequently.

All of the patients were on systemic immunosuppression for GVHD after allogeneic stem cell transplants for various blood cancers.

They were enrolled from 2007 through 2012 at nine U.S. medical centers – all members of the Chronic Graft Versus Host Disease Consortium – and they were followed until 2018.

Erythema BSA and NIH Skin Score were assessed at baseline and then every 3-6 months. Erythema was the first manifestation of skin involvement in the majority of patients, with a median surface area involvement of 11% at baseline.

The study team found that the extent of erythema at first follow-up visit was associated with both nonrelapse mortality (hazard ratio, 1.33 per 10% BSA increase; P < .001) and overall survival (HR, 1.28 per 10% BSA increase; P < .001), whereas extent of sclerotic skin involvement was not associated with either.

Participants in the study were predominantly White. The investigators note that “BSA assessments of erythema may be less reliable in patients with darker skin.”

The work was funded by the Department of Veterans Affairs and the National Institutes of Health. Dr. Baumrin had no disclosures; one coauthor is an employee of CorEvitas, and two others reported grants/adviser fees from several companies, including Janssen, Mallinckrodt, and Pfizer.

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

Researchers are calling for the extent of skin erythema to be considered as an outcome measure in patients who develop chronic cutaneous graft-versus-host disease (ccGVHD) after allogeneic stem cell transplants for various blood cancers.

“There is value in collecting erythema serially over time as a continuous variable on a scale of 0%-100%” to identify high-risk patients for prophylactic and preemptive treatment, say investigators led by dermatologist Emily Baumrin, MD, director of the GVHD clinic at the University of Pennsylvania, Philadelphia.

They report a study of more than 300 patients with ccGVHD, which found that the extent of skin erythema strongly predicted the risk for death from GVHD.

Of the 267 patients with cutaneous GVHD at baseline, 103 patients died, the majority without a relapse of their blood cancer.

With additional research, erythema body surface area (BSA) should be “introduced as an outcome measure in clinical practice and trials,” they conclude.

At the moment, the NIH Skin Score is commonly used for risk assessment in cutaneous GVHD, but the researchers found that erythema BSA out-predicts this score.

The investigators explain that the NIH Skin Score does incorporate erythema surface area, but it does so as a categorical variable, not a continuous variable. Among other additional factors, it also includes assessments of skin sclerosis, which the investigators found was not associated with GVHD mortality.

Overall, the composite score waters down the weight given to erythema BSA because the score is “driven by stable sclerotic features, and erythema changes are missed,” they explain.

The study was published online in JAMA Dermatology.
 

Study details

The study included 469 patients with chronic GVHD (cGVHD), of whom 267 (57%) had cutaneous cGVHD at enrollment and 89 (19%) developed skin involvement subsequently.

All of the patients were on systemic immunosuppression for GVHD after allogeneic stem cell transplants for various blood cancers.

They were enrolled from 2007 through 2012 at nine U.S. medical centers – all members of the Chronic Graft Versus Host Disease Consortium – and they were followed until 2018.

Erythema BSA and NIH Skin Score were assessed at baseline and then every 3-6 months. Erythema was the first manifestation of skin involvement in the majority of patients, with a median surface area involvement of 11% at baseline.

The study team found that the extent of erythema at first follow-up visit was associated with both nonrelapse mortality (hazard ratio, 1.33 per 10% BSA increase; P < .001) and overall survival (HR, 1.28 per 10% BSA increase; P < .001), whereas extent of sclerotic skin involvement was not associated with either.

Participants in the study were predominantly White. The investigators note that “BSA assessments of erythema may be less reliable in patients with darker skin.”

The work was funded by the Department of Veterans Affairs and the National Institutes of Health. Dr. Baumrin had no disclosures; one coauthor is an employee of CorEvitas, and two others reported grants/adviser fees from several companies, including Janssen, Mallinckrodt, and Pfizer.

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

Researchers are calling for the extent of skin erythema to be considered as an outcome measure in patients who develop chronic cutaneous graft-versus-host disease (ccGVHD) after allogeneic stem cell transplants for various blood cancers.

“There is value in collecting erythema serially over time as a continuous variable on a scale of 0%-100%” to identify high-risk patients for prophylactic and preemptive treatment, say investigators led by dermatologist Emily Baumrin, MD, director of the GVHD clinic at the University of Pennsylvania, Philadelphia.

They report a study of more than 300 patients with ccGVHD, which found that the extent of skin erythema strongly predicted the risk for death from GVHD.

Of the 267 patients with cutaneous GVHD at baseline, 103 patients died, the majority without a relapse of their blood cancer.

With additional research, erythema body surface area (BSA) should be “introduced as an outcome measure in clinical practice and trials,” they conclude.

At the moment, the NIH Skin Score is commonly used for risk assessment in cutaneous GVHD, but the researchers found that erythema BSA out-predicts this score.

The investigators explain that the NIH Skin Score does incorporate erythema surface area, but it does so as a categorical variable, not a continuous variable. Among other additional factors, it also includes assessments of skin sclerosis, which the investigators found was not associated with GVHD mortality.

Overall, the composite score waters down the weight given to erythema BSA because the score is “driven by stable sclerotic features, and erythema changes are missed,” they explain.

The study was published online in JAMA Dermatology.
 

Study details

The study included 469 patients with chronic GVHD (cGVHD), of whom 267 (57%) had cutaneous cGVHD at enrollment and 89 (19%) developed skin involvement subsequently.

All of the patients were on systemic immunosuppression for GVHD after allogeneic stem cell transplants for various blood cancers.

They were enrolled from 2007 through 2012 at nine U.S. medical centers – all members of the Chronic Graft Versus Host Disease Consortium – and they were followed until 2018.

Erythema BSA and NIH Skin Score were assessed at baseline and then every 3-6 months. Erythema was the first manifestation of skin involvement in the majority of patients, with a median surface area involvement of 11% at baseline.

The study team found that the extent of erythema at first follow-up visit was associated with both nonrelapse mortality (hazard ratio, 1.33 per 10% BSA increase; P < .001) and overall survival (HR, 1.28 per 10% BSA increase; P < .001), whereas extent of sclerotic skin involvement was not associated with either.

Participants in the study were predominantly White. The investigators note that “BSA assessments of erythema may be less reliable in patients with darker skin.”

The work was funded by the Department of Veterans Affairs and the National Institutes of Health. Dr. Baumrin had no disclosures; one coauthor is an employee of CorEvitas, and two others reported grants/adviser fees from several companies, including Janssen, Mallinckrodt, and Pfizer.

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