AVAHO

Rapid advances in imaging technology have led to better spatial resolution with lower radiation doses to patients. These advances have helped to increase the use of diagnostic chest imaging, particularly in emergency departments and oncology centers, and in screening for coronary artery disease. As a result, there has been an explosion of incidental findings on chest imaging—including indeterminate lung nodules.^1,2

Lung nodules are rounded and well-circumscribed lung opacities (≤ 3 cm in diameter) that may present as solitary or multiple lesions in usually asymptomatic patients. Most lung nodules are benign, the result of an infectious or inflammatory process. Nodules that are ≤ 8 mm in diameter, unless they show increase in size over time, often can be safely followed with imaging surveillance. In contrast, lung nodules > 8 mm could represent an early-stage lung cancer, especially among patients with high-risk for developing lung cancer (ie, those with advanced age, heavy tobacco abuse, or emphysema) and should be further assessed with close imaging surveillance, either chest computed tomography (CT) alone or positron-emission tomography (PET)/CT, or tissue biopsy, based on the underlying likelihood of malignancy.

Patients who receive an early-stage lung cancer diagnosis can be offered curative treatments leading to improved 5-year survival rates.^3,4 Consequently, health care systems need to be able to identify these nodules accurately, in order to categorize and manage them accordingly to the Fleischner radiographic and American College of Chest Physicians clinical guidelines.^5,6 Unfortunately, many hospitals struggle to identify patients with incidental lung nodules found during diagnostic chest and abdominal imaging, due in part to poor adherence to Fleischner guidelines among radiologists for categorizing pulmonary nodules.^7,8

The Veterans Health Administration (VHA) system is interested in effectively detecting patients with incidental lung nodules. Veterans have a higher risk of developing lung cancer when compared with the entire US population, mainly due to a higher incidence of tobacco use.⁶ The prevalence of lung nodules among veterans with significant risk factors for lung cancer is about 60% nationwide, and up to 85% in the Midwest, due to the high prevalence of histoplasmosis.⁷ However, only a small percentage of these nodules represent an early stage primary lung cancer.

Several Veterans Integrated Service Networks (VISNs) in the VHA use a radiology diagnostic code to systematically identify imaging studies with presence of lung nodules. In VISN 23, which includes Minnesota, North Dakota, South Dakota, Iowa, and portions of neighboring states, the code used to identify these radiology studies is 44. However, there is high variability in the reporting and coding of imaging studies among radiologists, which could lead to misclassifying patients with lung nodules.⁸

Some studies suggest that using an automated text search algorithm within radiology reports can be a highly effective strategy to identify patients with lung nodules.^9,10 In this study, we compared the diagnostic performance of a newly developed text search algorithm applied to radiology reports with the current standard practice of using a radiology diagnostic code for identifying patients with lung nodules at the Iowa City US Department of Veterans Affairs (VA) Health Care System (ICVAHCS) hospital in Iowa.

Methods

Since 2014, The ICVAHCS has used a radiology diagnostic code to identify any imaging studies with lung nodules. The radiologist enters “44” at the end of the reading process using the Nuance Powerscribe 360 radiation reporting system. The code is uploaded into the VHA Corporate Data Warehouse (CDW), and it is located within the radiology exam domain. This strategy was created and implemented by the Minneapolis VA Health Care System in Minnesota for all the VA hospitals in VISN 23. A lung nodule registry nurse was provided with a list of radiology studies flagged with this radiology diagnostic code every 2 weeks. A chart review was then performed for all these studies to determine the presence of a lung nodule. When detected, the ordering health care provider was alerted and given recommendations for managing the nodule.

We initially searched for the radiology studies with a presumptive lung nodule using the radiology code 44 within the CDW. Separately, we applied the text search strategy only to radiology reports from chest and abdomen studies (ie, X-rays, CT, magnetic resonance imaging [MRI], and PET) that contained any of the keyword phrases. The text search strategy was modeled based on a natural language processing (NLP) algorithm developed by the Puget Sound VA Healthcare System in Seattle, Washington to identify lung nodules on radiology reports.⁹ Our algorithm included a series of text searches using Microsoft SQL. After several simulations using a random group of radiology reports, we chose the keywords: “lung AND nodul”; “pulm AND nodul”; “pulm AND mass”; “lung AND mass”; and “ground glass”. We selected only chest and abdomen studies because on several simulations using a random group of radiology reports, the vast majority of lung nodules were identified on chest and abdomen imaging studies. Also, it would not have been feasible to chart review the approximately 30,000 total radiology reports that were generated during the study period.

From January 1, 2016 through November 30, 2016, we applied both search strategies independently: radiology diagnostic code for lung nodules to all imaging studies, and text search to all radiology reports of chest and abdomen imaging studies in the CDW (Figure). We also collected demographic (eg, age, sex, race, rurality) and clinical (eg, medical comorbidities, tobacco use) information that were uploaded to the database automatically from CDW using International Statistical Classification of Diseases, Tenth Edition and demographic codes. The VHA uses the Rural-Urban Commuting Areas (RUCA) system to define rurality, which takes into account population density and how closely a community is linked socioeconomically to larger urban centers.¹¹ The protocol was reviewed and approved by the institutional review board of ICVAHCS and the University of Iowa.

Results

We identified 12,983 radiology studies that required manual review during the study period. We confirmed that 8,516 imaging studies had lung nodules, representing 2,912 patients. Subjects with lung nodules were predominantly male (96%), aged between 60 and 79 years (71%), and lived in a rural area (72%). More than 50% of these patients had COPD and over a third were current smokers (Table 1). The text search algorithm identified all of the patients identified by the radiology diagnostic code (n = 1,251). It also identified an additional 1,661 patients with lung nodules that otherwise would have been missed by the radiology code. Compared with those identified only by the text search, those identified by both the radiology coding and text search were older, had lower Charlson comorbidity scores, and were more likely to be a current smoker.

The text search algorithm identified more than twice as many patients with potential lung nodules compared with the radiology diagnostic code (4,071 vs 1,363) (Table 2). However, the text search algorithm was associated with a much higher number of false positives than was the diagnostic code (1,159 vs 112) and a lower PPV (72% [95% CI, 70.6-73.4] vs 92% [95% CI, 90.6-93.4], respectively). The text search algorithm identified 130 patients with lung nodules of moderate to high risk for malignancy (> 8 mm diameter) that were not identified by the radiology code. When the PPV of each search strategy was calculated based on imaging studies with nodules (most patients had > 1 imaging study), the results remained similar (98% for radiology code and 66% for text search). A larger proportion of the lung nodules detected by code 44 vs the text search algorithm were from CT chest studies.

Discussion

In a population of predominantly older male veterans with significant risk factors for lung cancer and high incidence of incidental lung nodules, applying a text search algorithm on radiology reports identified a substantial number of patients with lung nodules, including some with nodules > 8 mm, that were missed by the radiologist-generated code.^9,10 Improving the yield of detection for lung nodules in a population with high risk for lung cancer would increase the likelihood of detecting patients with potentially curable early-stage lung cancers, decreasing lung cancer mortality.

The reasons for the high number of patients with lung nodules missed by the radiology code are unclear. Potential explanations may include the lack of standardization of imaging reports by the radiologists (ie, only 21% of chest CTs used a standardized template describing a lung nodule in our study), a problem well recognized both within and outside VHA.^8,12

The text search algorithm identified more patients with lung nodules but had a higher rate of false positives when compared with the diagnostic code. The high rate of false positives resulted in more charts to review and an increased workload for the lung nodule registry team. The challenges presented by an increased workload should be balanced against the potential harms of missing nodules that develop into advanced cancer.

Text Search Adjustments

Refining the text search criteria algorithm and the chart review process may decrease the rate of false positives significantly without affecting detection of lung nodules. In subsequent simulations, we found that by adding an exclusion criteria to text search algorithm to remove reports with specific keywords we could substantially reduce the number of false positive reports without affecting the detection rate of the lung nodules. These exclusion criteria would exclude any reports that: (1) contain “nodul” within the next 8 words after mentioning “no”; (2) contain “clear” within the next 8 words after mentioning “lung” in the text (eg, “lungs appear to be clear”); (3) contain “clear” within the next 4 words after mentioning “otherwise” in the text (eg, “otherwise appear to be clear”). Based on our study results, we further refined the text search strategy by limiting the search to only chest imaging studies. When we applied the revised algorithm to a random sample of imaging reports, we found all the code 44 radiology reports were still captured, but we were able to reduce the number of radiology reports needing review by about 80%.

Although classification approaches are being refined to improve radiology performance in multiple categories of nodules, this study suggests that alternative approaches based on text algorithms can improve the capture of pulmonary nodules that require surveillance. These algorithms also can be used to augment radiologist reporting systems. This represents an investment in resources to build a team that should include a bioinformatics specialist, lung nodule registry personnel (review charts of the detected imaging studies with lung nodules, populating the lung nodule database, and determining and tracking the need of imaging follow up), a lung nodule clinic nurse coordinator, and a dedicated lung nodule clinic pulmonologist.

Radiology departments could employ this text search approach to identify missed nodules and use an audit and feedback system to train radiologists to code lung nodules consistently at the time of the initial reading to avoid delays in identifying patients with nodules. Alternatively, the more widespread use of a standardized CT chest radiology reports using Fleischner or the American College of Radiology Lung Imaging Reporting and Data System (Lung RADS) templates might improve the detection of patients with lung nodules.^5,13,14

Limitations

This study was performed in a single VHA hospital and the findings may not be generalizable to other settings of care. Second, our study design is susceptible to work-up bias because the results of a diagnostic test (eg, chest or abdomen imaging) affected whether the chart review was used to verify the test result. It was not feasible to review the patient records of all radiology studies done at the facility during the study period, consequently complete 2 × 2 tables could not be created to calculate sensitivity, specificity, and negative predictive value.

Conclusion

A text search algorithm of radiology reports increased the detection of patients with lung nodules when compared with radiology diagnostic coding alone. However, the improved detection was associated with a higher rate of false positives, which requires manually reviewing a larger number of patient’s chart reports. Future research and quality improvement should focus on standardizing the radiology reporting process and improving the efficiency and reliability of follow up and tracking of incidental lung nodules.

Acknowledgments

The work reported here was supported by a grant from the Office of Rural Health (N32-FY16Q1-S1-P01577), US Department of Veterans Affairs, Veterans Health Administration. We also had the support from the Veterans Rural Health Resource Center-Iowa City, and the Health Services Research and Development (HSR&D) Service through the Comprehensive Access and Delivery Research and Evaluation (CADRE) Center (REA 09-220).

Rapid advances in imaging technology have led to better spatial resolution with lower radiation doses to patients. These advances have helped to increase the use of diagnostic chest imaging, particularly in emergency departments and oncology centers, and in screening for coronary artery disease. As a result, there has been an explosion of incidental findings on chest imaging—including indeterminate lung nodules.^1,2

Lung nodules are rounded and well-circumscribed lung opacities (≤ 3 cm in diameter) that may present as solitary or multiple lesions in usually asymptomatic patients. Most lung nodules are benign, the result of an infectious or inflammatory process. Nodules that are ≤ 8 mm in diameter, unless they show increase in size over time, often can be safely followed with imaging surveillance. In contrast, lung nodules > 8 mm could represent an early-stage lung cancer, especially among patients with high-risk for developing lung cancer (ie, those with advanced age, heavy tobacco abuse, or emphysema) and should be further assessed with close imaging surveillance, either chest computed tomography (CT) alone or positron-emission tomography (PET)/CT, or tissue biopsy, based on the underlying likelihood of malignancy.

Patients who receive an early-stage lung cancer diagnosis can be offered curative treatments leading to improved 5-year survival rates.^3,4 Consequently, health care systems need to be able to identify these nodules accurately, in order to categorize and manage them accordingly to the Fleischner radiographic and American College of Chest Physicians clinical guidelines.^5,6 Unfortunately, many hospitals struggle to identify patients with incidental lung nodules found during diagnostic chest and abdominal imaging, due in part to poor adherence to Fleischner guidelines among radiologists for categorizing pulmonary nodules.^7,8

The Veterans Health Administration (VHA) system is interested in effectively detecting patients with incidental lung nodules. Veterans have a higher risk of developing lung cancer when compared with the entire US population, mainly due to a higher incidence of tobacco use.⁶ The prevalence of lung nodules among veterans with significant risk factors for lung cancer is about 60% nationwide, and up to 85% in the Midwest, due to the high prevalence of histoplasmosis.⁷ However, only a small percentage of these nodules represent an early stage primary lung cancer.

Several Veterans Integrated Service Networks (VISNs) in the VHA use a radiology diagnostic code to systematically identify imaging studies with presence of lung nodules. In VISN 23, which includes Minnesota, North Dakota, South Dakota, Iowa, and portions of neighboring states, the code used to identify these radiology studies is 44. However, there is high variability in the reporting and coding of imaging studies among radiologists, which could lead to misclassifying patients with lung nodules.⁸

Some studies suggest that using an automated text search algorithm within radiology reports can be a highly effective strategy to identify patients with lung nodules.^9,10 In this study, we compared the diagnostic performance of a newly developed text search algorithm applied to radiology reports with the current standard practice of using a radiology diagnostic code for identifying patients with lung nodules at the Iowa City US Department of Veterans Affairs (VA) Health Care System (ICVAHCS) hospital in Iowa.

Methods

Since 2014, The ICVAHCS has used a radiology diagnostic code to identify any imaging studies with lung nodules. The radiologist enters “44” at the end of the reading process using the Nuance Powerscribe 360 radiation reporting system. The code is uploaded into the VHA Corporate Data Warehouse (CDW), and it is located within the radiology exam domain. This strategy was created and implemented by the Minneapolis VA Health Care System in Minnesota for all the VA hospitals in VISN 23. A lung nodule registry nurse was provided with a list of radiology studies flagged with this radiology diagnostic code every 2 weeks. A chart review was then performed for all these studies to determine the presence of a lung nodule. When detected, the ordering health care provider was alerted and given recommendations for managing the nodule.

We initially searched for the radiology studies with a presumptive lung nodule using the radiology code 44 within the CDW. Separately, we applied the text search strategy only to radiology reports from chest and abdomen studies (ie, X-rays, CT, magnetic resonance imaging [MRI], and PET) that contained any of the keyword phrases. The text search strategy was modeled based on a natural language processing (NLP) algorithm developed by the Puget Sound VA Healthcare System in Seattle, Washington to identify lung nodules on radiology reports.⁹ Our algorithm included a series of text searches using Microsoft SQL. After several simulations using a random group of radiology reports, we chose the keywords: “lung AND nodul”; “pulm AND nodul”; “pulm AND mass”; “lung AND mass”; and “ground glass”. We selected only chest and abdomen studies because on several simulations using a random group of radiology reports, the vast majority of lung nodules were identified on chest and abdomen imaging studies. Also, it would not have been feasible to chart review the approximately 30,000 total radiology reports that were generated during the study period.

From January 1, 2016 through November 30, 2016, we applied both search strategies independently: radiology diagnostic code for lung nodules to all imaging studies, and text search to all radiology reports of chest and abdomen imaging studies in the CDW (Figure). We also collected demographic (eg, age, sex, race, rurality) and clinical (eg, medical comorbidities, tobacco use) information that were uploaded to the database automatically from CDW using International Statistical Classification of Diseases, Tenth Edition and demographic codes. The VHA uses the Rural-Urban Commuting Areas (RUCA) system to define rurality, which takes into account population density and how closely a community is linked socioeconomically to larger urban centers.¹¹ The protocol was reviewed and approved by the institutional review board of ICVAHCS and the University of Iowa.

Results

We identified 12,983 radiology studies that required manual review during the study period. We confirmed that 8,516 imaging studies had lung nodules, representing 2,912 patients. Subjects with lung nodules were predominantly male (96%), aged between 60 and 79 years (71%), and lived in a rural area (72%). More than 50% of these patients had COPD and over a third were current smokers (Table 1). The text search algorithm identified all of the patients identified by the radiology diagnostic code (n = 1,251). It also identified an additional 1,661 patients with lung nodules that otherwise would have been missed by the radiology code. Compared with those identified only by the text search, those identified by both the radiology coding and text search were older, had lower Charlson comorbidity scores, and were more likely to be a current smoker.

The text search algorithm identified more than twice as many patients with potential lung nodules compared with the radiology diagnostic code (4,071 vs 1,363) (Table 2). However, the text search algorithm was associated with a much higher number of false positives than was the diagnostic code (1,159 vs 112) and a lower PPV (72% [95% CI, 70.6-73.4] vs 92% [95% CI, 90.6-93.4], respectively). The text search algorithm identified 130 patients with lung nodules of moderate to high risk for malignancy (> 8 mm diameter) that were not identified by the radiology code. When the PPV of each search strategy was calculated based on imaging studies with nodules (most patients had > 1 imaging study), the results remained similar (98% for radiology code and 66% for text search). A larger proportion of the lung nodules detected by code 44 vs the text search algorithm were from CT chest studies.

Discussion

In a population of predominantly older male veterans with significant risk factors for lung cancer and high incidence of incidental lung nodules, applying a text search algorithm on radiology reports identified a substantial number of patients with lung nodules, including some with nodules > 8 mm, that were missed by the radiologist-generated code.^9,10 Improving the yield of detection for lung nodules in a population with high risk for lung cancer would increase the likelihood of detecting patients with potentially curable early-stage lung cancers, decreasing lung cancer mortality.

The reasons for the high number of patients with lung nodules missed by the radiology code are unclear. Potential explanations may include the lack of standardization of imaging reports by the radiologists (ie, only 21% of chest CTs used a standardized template describing a lung nodule in our study), a problem well recognized both within and outside VHA.^8,12

The text search algorithm identified more patients with lung nodules but had a higher rate of false positives when compared with the diagnostic code. The high rate of false positives resulted in more charts to review and an increased workload for the lung nodule registry team. The challenges presented by an increased workload should be balanced against the potential harms of missing nodules that develop into advanced cancer.

Text Search Adjustments

Refining the text search criteria algorithm and the chart review process may decrease the rate of false positives significantly without affecting detection of lung nodules. In subsequent simulations, we found that by adding an exclusion criteria to text search algorithm to remove reports with specific keywords we could substantially reduce the number of false positive reports without affecting the detection rate of the lung nodules. These exclusion criteria would exclude any reports that: (1) contain “nodul” within the next 8 words after mentioning “no”; (2) contain “clear” within the next 8 words after mentioning “lung” in the text (eg, “lungs appear to be clear”); (3) contain “clear” within the next 4 words after mentioning “otherwise” in the text (eg, “otherwise appear to be clear”). Based on our study results, we further refined the text search strategy by limiting the search to only chest imaging studies. When we applied the revised algorithm to a random sample of imaging reports, we found all the code 44 radiology reports were still captured, but we were able to reduce the number of radiology reports needing review by about 80%.

Although classification approaches are being refined to improve radiology performance in multiple categories of nodules, this study suggests that alternative approaches based on text algorithms can improve the capture of pulmonary nodules that require surveillance. These algorithms also can be used to augment radiologist reporting systems. This represents an investment in resources to build a team that should include a bioinformatics specialist, lung nodule registry personnel (review charts of the detected imaging studies with lung nodules, populating the lung nodule database, and determining and tracking the need of imaging follow up), a lung nodule clinic nurse coordinator, and a dedicated lung nodule clinic pulmonologist.

Radiology departments could employ this text search approach to identify missed nodules and use an audit and feedback system to train radiologists to code lung nodules consistently at the time of the initial reading to avoid delays in identifying patients with nodules. Alternatively, the more widespread use of a standardized CT chest radiology reports using Fleischner or the American College of Radiology Lung Imaging Reporting and Data System (Lung RADS) templates might improve the detection of patients with lung nodules.^5,13,14

Limitations

This study was performed in a single VHA hospital and the findings may not be generalizable to other settings of care. Second, our study design is susceptible to work-up bias because the results of a diagnostic test (eg, chest or abdomen imaging) affected whether the chart review was used to verify the test result. It was not feasible to review the patient records of all radiology studies done at the facility during the study period, consequently complete 2 × 2 tables could not be created to calculate sensitivity, specificity, and negative predictive value.

Conclusion

A text search algorithm of radiology reports increased the detection of patients with lung nodules when compared with radiology diagnostic coding alone. However, the improved detection was associated with a higher rate of false positives, which requires manually reviewing a larger number of patient’s chart reports. Future research and quality improvement should focus on standardizing the radiology reporting process and improving the efficiency and reliability of follow up and tracking of incidental lung nodules.

Acknowledgments

The work reported here was supported by a grant from the Office of Rural Health (N32-FY16Q1-S1-P01577), US Department of Veterans Affairs, Veterans Health Administration. We also had the support from the Veterans Rural Health Resource Center-Iowa City, and the Health Services Research and Development (HSR&D) Service through the Comprehensive Access and Delivery Research and Evaluation (CADRE) Center (REA 09-220).

Rapid advances in imaging technology have led to better spatial resolution with lower radiation doses to patients. These advances have helped to increase the use of diagnostic chest imaging, particularly in emergency departments and oncology centers, and in screening for coronary artery disease. As a result, there has been an explosion of incidental findings on chest imaging—including indeterminate lung nodules.^1,2

Lung nodules are rounded and well-circumscribed lung opacities (≤ 3 cm in diameter) that may present as solitary or multiple lesions in usually asymptomatic patients. Most lung nodules are benign, the result of an infectious or inflammatory process. Nodules that are ≤ 8 mm in diameter, unless they show increase in size over time, often can be safely followed with imaging surveillance. In contrast, lung nodules > 8 mm could represent an early-stage lung cancer, especially among patients with high-risk for developing lung cancer (ie, those with advanced age, heavy tobacco abuse, or emphysema) and should be further assessed with close imaging surveillance, either chest computed tomography (CT) alone or positron-emission tomography (PET)/CT, or tissue biopsy, based on the underlying likelihood of malignancy.

Patients who receive an early-stage lung cancer diagnosis can be offered curative treatments leading to improved 5-year survival rates.^3,4 Consequently, health care systems need to be able to identify these nodules accurately, in order to categorize and manage them accordingly to the Fleischner radiographic and American College of Chest Physicians clinical guidelines.^5,6 Unfortunately, many hospitals struggle to identify patients with incidental lung nodules found during diagnostic chest and abdominal imaging, due in part to poor adherence to Fleischner guidelines among radiologists for categorizing pulmonary nodules.^7,8

The Veterans Health Administration (VHA) system is interested in effectively detecting patients with incidental lung nodules. Veterans have a higher risk of developing lung cancer when compared with the entire US population, mainly due to a higher incidence of tobacco use.⁶ The prevalence of lung nodules among veterans with significant risk factors for lung cancer is about 60% nationwide, and up to 85% in the Midwest, due to the high prevalence of histoplasmosis.⁷ However, only a small percentage of these nodules represent an early stage primary lung cancer.

Several Veterans Integrated Service Networks (VISNs) in the VHA use a radiology diagnostic code to systematically identify imaging studies with presence of lung nodules. In VISN 23, which includes Minnesota, North Dakota, South Dakota, Iowa, and portions of neighboring states, the code used to identify these radiology studies is 44. However, there is high variability in the reporting and coding of imaging studies among radiologists, which could lead to misclassifying patients with lung nodules.⁸

Some studies suggest that using an automated text search algorithm within radiology reports can be a highly effective strategy to identify patients with lung nodules.^9,10 In this study, we compared the diagnostic performance of a newly developed text search algorithm applied to radiology reports with the current standard practice of using a radiology diagnostic code for identifying patients with lung nodules at the Iowa City US Department of Veterans Affairs (VA) Health Care System (ICVAHCS) hospital in Iowa.

Methods

Since 2014, The ICVAHCS has used a radiology diagnostic code to identify any imaging studies with lung nodules. The radiologist enters “44” at the end of the reading process using the Nuance Powerscribe 360 radiation reporting system. The code is uploaded into the VHA Corporate Data Warehouse (CDW), and it is located within the radiology exam domain. This strategy was created and implemented by the Minneapolis VA Health Care System in Minnesota for all the VA hospitals in VISN 23. A lung nodule registry nurse was provided with a list of radiology studies flagged with this radiology diagnostic code every 2 weeks. A chart review was then performed for all these studies to determine the presence of a lung nodule. When detected, the ordering health care provider was alerted and given recommendations for managing the nodule.

We initially searched for the radiology studies with a presumptive lung nodule using the radiology code 44 within the CDW. Separately, we applied the text search strategy only to radiology reports from chest and abdomen studies (ie, X-rays, CT, magnetic resonance imaging [MRI], and PET) that contained any of the keyword phrases. The text search strategy was modeled based on a natural language processing (NLP) algorithm developed by the Puget Sound VA Healthcare System in Seattle, Washington to identify lung nodules on radiology reports.⁹ Our algorithm included a series of text searches using Microsoft SQL. After several simulations using a random group of radiology reports, we chose the keywords: “lung AND nodul”; “pulm AND nodul”; “pulm AND mass”; “lung AND mass”; and “ground glass”. We selected only chest and abdomen studies because on several simulations using a random group of radiology reports, the vast majority of lung nodules were identified on chest and abdomen imaging studies. Also, it would not have been feasible to chart review the approximately 30,000 total radiology reports that were generated during the study period.

From January 1, 2016 through November 30, 2016, we applied both search strategies independently: radiology diagnostic code for lung nodules to all imaging studies, and text search to all radiology reports of chest and abdomen imaging studies in the CDW (Figure). We also collected demographic (eg, age, sex, race, rurality) and clinical (eg, medical comorbidities, tobacco use) information that were uploaded to the database automatically from CDW using International Statistical Classification of Diseases, Tenth Edition and demographic codes. The VHA uses the Rural-Urban Commuting Areas (RUCA) system to define rurality, which takes into account population density and how closely a community is linked socioeconomically to larger urban centers.¹¹ The protocol was reviewed and approved by the institutional review board of ICVAHCS and the University of Iowa.

Results

We identified 12,983 radiology studies that required manual review during the study period. We confirmed that 8,516 imaging studies had lung nodules, representing 2,912 patients. Subjects with lung nodules were predominantly male (96%), aged between 60 and 79 years (71%), and lived in a rural area (72%). More than 50% of these patients had COPD and over a third were current smokers (Table 1). The text search algorithm identified all of the patients identified by the radiology diagnostic code (n = 1,251). It also identified an additional 1,661 patients with lung nodules that otherwise would have been missed by the radiology code. Compared with those identified only by the text search, those identified by both the radiology coding and text search were older, had lower Charlson comorbidity scores, and were more likely to be a current smoker.

The text search algorithm identified more than twice as many patients with potential lung nodules compared with the radiology diagnostic code (4,071 vs 1,363) (Table 2). However, the text search algorithm was associated with a much higher number of false positives than was the diagnostic code (1,159 vs 112) and a lower PPV (72% [95% CI, 70.6-73.4] vs 92% [95% CI, 90.6-93.4], respectively). The text search algorithm identified 130 patients with lung nodules of moderate to high risk for malignancy (> 8 mm diameter) that were not identified by the radiology code. When the PPV of each search strategy was calculated based on imaging studies with nodules (most patients had > 1 imaging study), the results remained similar (98% for radiology code and 66% for text search). A larger proportion of the lung nodules detected by code 44 vs the text search algorithm were from CT chest studies.

Discussion

In a population of predominantly older male veterans with significant risk factors for lung cancer and high incidence of incidental lung nodules, applying a text search algorithm on radiology reports identified a substantial number of patients with lung nodules, including some with nodules > 8 mm, that were missed by the radiologist-generated code.^9,10 Improving the yield of detection for lung nodules in a population with high risk for lung cancer would increase the likelihood of detecting patients with potentially curable early-stage lung cancers, decreasing lung cancer mortality.

The reasons for the high number of patients with lung nodules missed by the radiology code are unclear. Potential explanations may include the lack of standardization of imaging reports by the radiologists (ie, only 21% of chest CTs used a standardized template describing a lung nodule in our study), a problem well recognized both within and outside VHA.^8,12

The text search algorithm identified more patients with lung nodules but had a higher rate of false positives when compared with the diagnostic code. The high rate of false positives resulted in more charts to review and an increased workload for the lung nodule registry team. The challenges presented by an increased workload should be balanced against the potential harms of missing nodules that develop into advanced cancer.

Text Search Adjustments

Refining the text search criteria algorithm and the chart review process may decrease the rate of false positives significantly without affecting detection of lung nodules. In subsequent simulations, we found that by adding an exclusion criteria to text search algorithm to remove reports with specific keywords we could substantially reduce the number of false positive reports without affecting the detection rate of the lung nodules. These exclusion criteria would exclude any reports that: (1) contain “nodul” within the next 8 words after mentioning “no”; (2) contain “clear” within the next 8 words after mentioning “lung” in the text (eg, “lungs appear to be clear”); (3) contain “clear” within the next 4 words after mentioning “otherwise” in the text (eg, “otherwise appear to be clear”). Based on our study results, we further refined the text search strategy by limiting the search to only chest imaging studies. When we applied the revised algorithm to a random sample of imaging reports, we found all the code 44 radiology reports were still captured, but we were able to reduce the number of radiology reports needing review by about 80%.

Although classification approaches are being refined to improve radiology performance in multiple categories of nodules, this study suggests that alternative approaches based on text algorithms can improve the capture of pulmonary nodules that require surveillance. These algorithms also can be used to augment radiologist reporting systems. This represents an investment in resources to build a team that should include a bioinformatics specialist, lung nodule registry personnel (review charts of the detected imaging studies with lung nodules, populating the lung nodule database, and determining and tracking the need of imaging follow up), a lung nodule clinic nurse coordinator, and a dedicated lung nodule clinic pulmonologist.

Radiology departments could employ this text search approach to identify missed nodules and use an audit and feedback system to train radiologists to code lung nodules consistently at the time of the initial reading to avoid delays in identifying patients with nodules. Alternatively, the more widespread use of a standardized CT chest radiology reports using Fleischner or the American College of Radiology Lung Imaging Reporting and Data System (Lung RADS) templates might improve the detection of patients with lung nodules.^5,13,14

Limitations

This study was performed in a single VHA hospital and the findings may not be generalizable to other settings of care. Second, our study design is susceptible to work-up bias because the results of a diagnostic test (eg, chest or abdomen imaging) affected whether the chart review was used to verify the test result. It was not feasible to review the patient records of all radiology studies done at the facility during the study period, consequently complete 2 × 2 tables could not be created to calculate sensitivity, specificity, and negative predictive value.

Conclusion

A text search algorithm of radiology reports increased the detection of patients with lung nodules when compared with radiology diagnostic coding alone. However, the improved detection was associated with a higher rate of false positives, which requires manually reviewing a larger number of patient’s chart reports. Future research and quality improvement should focus on standardizing the radiology reporting process and improving the efficiency and reliability of follow up and tracking of incidental lung nodules.

Acknowledgments

The work reported here was supported by a grant from the Office of Rural Health (N32-FY16Q1-S1-P01577), US Department of Veterans Affairs, Veterans Health Administration. We also had the support from the Veterans Rural Health Resource Center-Iowa City, and the Health Services Research and Development (HSR&D) Service through the Comprehensive Access and Delivery Research and Evaluation (CADRE) Center (REA 09-220).

Single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) is a well-established technique for the evaluation of coronary artery disease (CAD).¹ To improve image quality, low-resolution computed tomography (CT) is used commonly for anatomical correct and artifact attenuation during SPECT MPI.² The low resolution, unenhanced CT images are considered low quality and are, therefore, labeled by the manufacturer as nondiagnostic. The CT portion of the MPI in many centers is used only for image fusion and attenuation correction, and these images are not routinely reviewed or reported by cardiologists.

Incidental findings by these low-resolution CT were frequent. However, clinically significant findings, including lung cancer, although relatively infrequent, were serious enough for major clinical management.^3-5 Currently, there are no consensus recommendations for reviewing low-resolution CT images or the interpretation of such incidental findings during cardiac MPI.⁶ Clinically, low-dose CT were used for early detection and screening of lung cancer and were associated with reduced lung-cancer and any cause mortality in National Lung Screening Trial (NLST).^7,8 Therefore, low-dose CT is recommended for lung cancer screening of high-risk patients by the US Preventive Service Task Force (USPSTF).⁹ In the veteran population, current and past smoking history are more common when compared with the general population; therefore, veterans are potentially at increased risk of lung cancer.¹⁰ In this study, we did not intend to use low-resolution CT for lung cancer screening or detection but rather to identify and report incidental findings of pulmonary/hilar malignancy detected during cardiac MPI.

Methods

The Siemens’ (Munich, Germany) Symbia Intevo Excel SPECT/CT MPI cameras with dedicated cardiac collimators were used at both the Dwight D. Eisenhower VA Medical Center (VAMC) in Leavenworth, Kansas and Colmery-O'Neil VAMC in Topeka, Kansas. The integrated CT scanner (x-ray tube current 30 to 240 mA; voltage 110 Kv with a 40 kW power generator) has the capability to image up to a 2-slice/rotation, each of 5.0 mm per slice with a scan time of about 30 seconds. The SPECT/CT gamma camera has a low energy (140 KeV), high resolution, parallel hole collimator with IQ SPECT capabilities.

The radiation dose received by the patients were expressed in dose length product (DLP), which reflects the total energy absorbed by the patient and represents integrated dose in terms of the total scan length. Additionally, each patients received 2 injections of Technetium Tc 99m sestamibi (1-day Protocol: 10 mCi rest injection, 30 mCi stress injection: 2-day Protocol for patients weighing > 350 pounds: 30 mCi at rest injection and 30 mCi at stress injection) for myocardial perfusion imaging.

All CT images and cardiac MPI findings were reviewed and reported contemporaneously by 1 of 2 experienced, board-certified radiologists who were blinded to patients’ clinical information except the indication for the cardiac stress testing. When suspicious pulmonary/hilar nodules or masses were detected, these findings and recommendations for further evaluation were conveyed to primary care provider or ordering physician via the electronic health record system.

All CT images were reviewed with cardiac MPI from September 1, 2017 to August 31, 2018. When pulmonary/hilar malignancies were identified, the health records were reviewed. Patients with known history of prior pulmonary malignancy were excluded from the study.

Results

A total of 1,098 patients underwent cardiac MPI during the study period. When the CT imaging and cardiac MPI were reviewed, incidental findings led to the diagnosis of lung cancer in 5 patients and hilar mantle cell lymphoma in 1 patient. Their clinical characteristics, CT findings, and types of malignancies for these 6 patients are summarized in the Table and Figure. Only 0.55% (6 of 1,098) patients were found to have incidental pulmonary/hilar malignancy with the cardiac evaluation low-resolution CT. Four patients with prior, known history of lung cancer were excluded from the study.

For the 6 patients found to have cancer, the average CT radiation dose during the cardiac MPI was 100 mGy-cm (range, 77 -133 mCy-cm). The subsequent chest CT with or without contrast delivered a radiation dose of 726.4 mGy-cm (range, 279.4 - 1,075 mGy-cm).

Discussion

Although incidental findings on low-resolution CT during cardiac MPI are frequent, clinically significant findings are less common. However, some incidental findings may be of important clinical significance.^3-5 A multicenter analysis by Coward and colleagues reported that 2.4% findings on low-resolution CT were significant enough to warrant follow-up tests, but only 0.2% were deemed potentially detrimental to patient outcomes (ie, pathology confirmed malignancies).¹² Thus, the authors suggested that routine reporting of incidental findings on low-dose CT images was not beneficial.^12,13

Currently, the majority of cardiac MPIs are reviewed and interpreted by nuclear cardiologists, the use of hybrid SPECT/CT for attenuation correction give rise of issue of reviewing and interpreting these CT images during cardiac MPI. Since low-dose, low-resolution CT are considered nondiagnostic, these images are not routinely and readily reviewed by cardiologists who are not trained or skilled in CT interpretations.

Studies of high-resolution cardiac CT (including multidetector CT with contrast) suggest that incidental extracardiac findings should always be reported as there was a 0.7% incidence of previously unknown malignancies, while others have argued against “performing large field reconstructionsfor the explicit purpose of screening as it will lead to additional cost, liability and anxiety without proven benefits.”^14-16 A review of incidental findings of cardiac CT by Earls suggested that all cardiac CT should be reconstructed in the maximal field of view available and images should be adequately reviewed to detect pathological findings.¹⁷ This led to an interesting discussion by Douglas and colleagues regarding the role of cardiologists and radiologists in this issue.¹⁸ Currently there is no uniform or consensus recommendations regarding incidental findings during cardiac CT imaging. Guidances range from no recommendations to optional reporting or mandatory reporting.^19-23

Risk Factors for Veterans

Lung cancer is the second most common cancer and the leading cause of cancer-related death in the US.²⁴ Smoking is the most important risk factor for lung cancer and CAD.²⁵ Current or past smoking are more common among the veterans.¹⁰ According to a report for the US Centers for Disease Control and Prevention report, about 29.2% US veterans use tobacco products between 2010-2015, which is similar to the rate reported in 1997.²⁶

When low-dose CT was used for lung cancer screening, it was associated with a 20.0% reduction in lung cancer mortality and a 6.7% reduction in any cause mortality.⁷ Currently, the US Preventive Services Task Force (USPSTF) recommends annual low-dose CT screening for lung cancer in high-risk adults that includes patients aged 55 to 80 years who have a 30-pack-year smoking history and currently smoke or have quit within the past 15 years.⁸

It is likely that the cardiac patients in this study might have pulmonary malignancy mortality similar to those reported in the NLST. While other studies have shown a low incidence (0.2%) of detection of malignancy by low-resolution CT during cardiac MPI,^12,13 in this study we found pulmonary or hilar malignancy in 0.55% of patients.The higher incidence of malignancy in our study might be due in part to differences in the patient population studied (ie, our veterans patients have a higher proportion of current or past smoking history).¹⁰

The CT used in this study is part of the cardiac imaging process. Therefore, there was no additional radiation exposure besides that of the cardiac MPI for patients. Despite the limitations of low-resolution CT, which may miss small lesions, this study showed 0.55% incidence of incidental detection of pulmonary/hilar malignancy. This is comparable with 0.65%/year of diagnosing lung cancer using low-dose CT for lung cancer screening in NLST.⁸

Two of the 5 study patients who were found to have lung cancer, had quit smoking > 15 years previously and thus would not be considered as high-risk for lung cancer screening according to USPSTF guideline. These patients would not have been candidates for annual low-dose CT lung cancer screening. This study suggests that it is appropriate and necessary to review the low-resolution CT images for incidental findings during cardiac MPI.

Limitations

The study was retrospective in nature and limited by its small number of patients. The CT modality used in the study also has limitations, including low resolution, respiratory motion artifacts, and scans that did not include the entire chest area. Therefore, small and apical lesions may have been missed. However, both sets of CT at rest and after stress were reviewed to reduce or minimize the effects of respiratory motion artifacts. The true prevalence or incidence of pulmonary/hilar malignancies may have been higher than reported here. Our study population of veterans may not be representative of the general population with regards to gender (as most of our veteran patient population are of male gender, vs general population), smoking history, or lung cancer risk, thus the results should be interpreted with caution.

Conclusion

Low-resolution CTs used for attenuation correction during cardiac MPI should be routinely reviewed and interpreted by a physician or radiologist skilled in CT interpretation in order to identify incidental findings of pulmonary/hilar malignancy. This would require close collaboration between cardiologists and radiologists in the field to ensure unfragmented and high-quality patient care.

Acknowledgements

We want to thank all the staffs in cardiology and radiology department on both campuses for their dedication for our patients. Special thanks to Laura Knox, Radiation Safety Officer, Nuclear Medicine Supervisor for her technical assistance.

Single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) is a well-established technique for the evaluation of coronary artery disease (CAD).¹ To improve image quality, low-resolution computed tomography (CT) is used commonly for anatomical correct and artifact attenuation during SPECT MPI.² The low resolution, unenhanced CT images are considered low quality and are, therefore, labeled by the manufacturer as nondiagnostic. The CT portion of the MPI in many centers is used only for image fusion and attenuation correction, and these images are not routinely reviewed or reported by cardiologists.

Incidental findings by these low-resolution CT were frequent. However, clinically significant findings, including lung cancer, although relatively infrequent, were serious enough for major clinical management.^3-5 Currently, there are no consensus recommendations for reviewing low-resolution CT images or the interpretation of such incidental findings during cardiac MPI.⁶ Clinically, low-dose CT were used for early detection and screening of lung cancer and were associated with reduced lung-cancer and any cause mortality in National Lung Screening Trial (NLST).^7,8 Therefore, low-dose CT is recommended for lung cancer screening of high-risk patients by the US Preventive Service Task Force (USPSTF).⁹ In the veteran population, current and past smoking history are more common when compared with the general population; therefore, veterans are potentially at increased risk of lung cancer.¹⁰ In this study, we did not intend to use low-resolution CT for lung cancer screening or detection but rather to identify and report incidental findings of pulmonary/hilar malignancy detected during cardiac MPI.

Methods

The Siemens’ (Munich, Germany) Symbia Intevo Excel SPECT/CT MPI cameras with dedicated cardiac collimators were used at both the Dwight D. Eisenhower VA Medical Center (VAMC) in Leavenworth, Kansas and Colmery-O'Neil VAMC in Topeka, Kansas. The integrated CT scanner (x-ray tube current 30 to 240 mA; voltage 110 Kv with a 40 kW power generator) has the capability to image up to a 2-slice/rotation, each of 5.0 mm per slice with a scan time of about 30 seconds. The SPECT/CT gamma camera has a low energy (140 KeV), high resolution, parallel hole collimator with IQ SPECT capabilities.

The radiation dose received by the patients were expressed in dose length product (DLP), which reflects the total energy absorbed by the patient and represents integrated dose in terms of the total scan length. Additionally, each patients received 2 injections of Technetium Tc 99m sestamibi (1-day Protocol: 10 mCi rest injection, 30 mCi stress injection: 2-day Protocol for patients weighing > 350 pounds: 30 mCi at rest injection and 30 mCi at stress injection) for myocardial perfusion imaging.

All CT images and cardiac MPI findings were reviewed and reported contemporaneously by 1 of 2 experienced, board-certified radiologists who were blinded to patients’ clinical information except the indication for the cardiac stress testing. When suspicious pulmonary/hilar nodules or masses were detected, these findings and recommendations for further evaluation were conveyed to primary care provider or ordering physician via the electronic health record system.

All CT images were reviewed with cardiac MPI from September 1, 2017 to August 31, 2018. When pulmonary/hilar malignancies were identified, the health records were reviewed. Patients with known history of prior pulmonary malignancy were excluded from the study.

Results

A total of 1,098 patients underwent cardiac MPI during the study period. When the CT imaging and cardiac MPI were reviewed, incidental findings led to the diagnosis of lung cancer in 5 patients and hilar mantle cell lymphoma in 1 patient. Their clinical characteristics, CT findings, and types of malignancies for these 6 patients are summarized in the Table and Figure. Only 0.55% (6 of 1,098) patients were found to have incidental pulmonary/hilar malignancy with the cardiac evaluation low-resolution CT. Four patients with prior, known history of lung cancer were excluded from the study.

For the 6 patients found to have cancer, the average CT radiation dose during the cardiac MPI was 100 mGy-cm (range, 77 -133 mCy-cm). The subsequent chest CT with or without contrast delivered a radiation dose of 726.4 mGy-cm (range, 279.4 - 1,075 mGy-cm).

Discussion

Although incidental findings on low-resolution CT during cardiac MPI are frequent, clinically significant findings are less common. However, some incidental findings may be of important clinical significance.^3-5 A multicenter analysis by Coward and colleagues reported that 2.4% findings on low-resolution CT were significant enough to warrant follow-up tests, but only 0.2% were deemed potentially detrimental to patient outcomes (ie, pathology confirmed malignancies).¹² Thus, the authors suggested that routine reporting of incidental findings on low-dose CT images was not beneficial.^12,13

Currently, the majority of cardiac MPIs are reviewed and interpreted by nuclear cardiologists, the use of hybrid SPECT/CT for attenuation correction give rise of issue of reviewing and interpreting these CT images during cardiac MPI. Since low-dose, low-resolution CT are considered nondiagnostic, these images are not routinely and readily reviewed by cardiologists who are not trained or skilled in CT interpretations.

Studies of high-resolution cardiac CT (including multidetector CT with contrast) suggest that incidental extracardiac findings should always be reported as there was a 0.7% incidence of previously unknown malignancies, while others have argued against “performing large field reconstructionsfor the explicit purpose of screening as it will lead to additional cost, liability and anxiety without proven benefits.”^14-16 A review of incidental findings of cardiac CT by Earls suggested that all cardiac CT should be reconstructed in the maximal field of view available and images should be adequately reviewed to detect pathological findings.¹⁷ This led to an interesting discussion by Douglas and colleagues regarding the role of cardiologists and radiologists in this issue.¹⁸ Currently there is no uniform or consensus recommendations regarding incidental findings during cardiac CT imaging. Guidances range from no recommendations to optional reporting or mandatory reporting.^19-23

Risk Factors for Veterans

Lung cancer is the second most common cancer and the leading cause of cancer-related death in the US.²⁴ Smoking is the most important risk factor for lung cancer and CAD.²⁵ Current or past smoking are more common among the veterans.¹⁰ According to a report for the US Centers for Disease Control and Prevention report, about 29.2% US veterans use tobacco products between 2010-2015, which is similar to the rate reported in 1997.²⁶

When low-dose CT was used for lung cancer screening, it was associated with a 20.0% reduction in lung cancer mortality and a 6.7% reduction in any cause mortality.⁷ Currently, the US Preventive Services Task Force (USPSTF) recommends annual low-dose CT screening for lung cancer in high-risk adults that includes patients aged 55 to 80 years who have a 30-pack-year smoking history and currently smoke or have quit within the past 15 years.⁸

It is likely that the cardiac patients in this study might have pulmonary malignancy mortality similar to those reported in the NLST. While other studies have shown a low incidence (0.2%) of detection of malignancy by low-resolution CT during cardiac MPI,^12,13 in this study we found pulmonary or hilar malignancy in 0.55% of patients.The higher incidence of malignancy in our study might be due in part to differences in the patient population studied (ie, our veterans patients have a higher proportion of current or past smoking history).¹⁰

The CT used in this study is part of the cardiac imaging process. Therefore, there was no additional radiation exposure besides that of the cardiac MPI for patients. Despite the limitations of low-resolution CT, which may miss small lesions, this study showed 0.55% incidence of incidental detection of pulmonary/hilar malignancy. This is comparable with 0.65%/year of diagnosing lung cancer using low-dose CT for lung cancer screening in NLST.⁸

Two of the 5 study patients who were found to have lung cancer, had quit smoking > 15 years previously and thus would not be considered as high-risk for lung cancer screening according to USPSTF guideline. These patients would not have been candidates for annual low-dose CT lung cancer screening. This study suggests that it is appropriate and necessary to review the low-resolution CT images for incidental findings during cardiac MPI.

Limitations

The study was retrospective in nature and limited by its small number of patients. The CT modality used in the study also has limitations, including low resolution, respiratory motion artifacts, and scans that did not include the entire chest area. Therefore, small and apical lesions may have been missed. However, both sets of CT at rest and after stress were reviewed to reduce or minimize the effects of respiratory motion artifacts. The true prevalence or incidence of pulmonary/hilar malignancies may have been higher than reported here. Our study population of veterans may not be representative of the general population with regards to gender (as most of our veteran patient population are of male gender, vs general population), smoking history, or lung cancer risk, thus the results should be interpreted with caution.

Conclusion

Low-resolution CTs used for attenuation correction during cardiac MPI should be routinely reviewed and interpreted by a physician or radiologist skilled in CT interpretation in order to identify incidental findings of pulmonary/hilar malignancy. This would require close collaboration between cardiologists and radiologists in the field to ensure unfragmented and high-quality patient care.

Acknowledgements

We want to thank all the staffs in cardiology and radiology department on both campuses for their dedication for our patients. Special thanks to Laura Knox, Radiation Safety Officer, Nuclear Medicine Supervisor for her technical assistance.

Single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) is a well-established technique for the evaluation of coronary artery disease (CAD).¹ To improve image quality, low-resolution computed tomography (CT) is used commonly for anatomical correct and artifact attenuation during SPECT MPI.² The low resolution, unenhanced CT images are considered low quality and are, therefore, labeled by the manufacturer as nondiagnostic. The CT portion of the MPI in many centers is used only for image fusion and attenuation correction, and these images are not routinely reviewed or reported by cardiologists.

Incidental findings by these low-resolution CT were frequent. However, clinically significant findings, including lung cancer, although relatively infrequent, were serious enough for major clinical management.^3-5 Currently, there are no consensus recommendations for reviewing low-resolution CT images or the interpretation of such incidental findings during cardiac MPI.⁶ Clinically, low-dose CT were used for early detection and screening of lung cancer and were associated with reduced lung-cancer and any cause mortality in National Lung Screening Trial (NLST).^7,8 Therefore, low-dose CT is recommended for lung cancer screening of high-risk patients by the US Preventive Service Task Force (USPSTF).⁹ In the veteran population, current and past smoking history are more common when compared with the general population; therefore, veterans are potentially at increased risk of lung cancer.¹⁰ In this study, we did not intend to use low-resolution CT for lung cancer screening or detection but rather to identify and report incidental findings of pulmonary/hilar malignancy detected during cardiac MPI.

Methods

The Siemens’ (Munich, Germany) Symbia Intevo Excel SPECT/CT MPI cameras with dedicated cardiac collimators were used at both the Dwight D. Eisenhower VA Medical Center (VAMC) in Leavenworth, Kansas and Colmery-O'Neil VAMC in Topeka, Kansas. The integrated CT scanner (x-ray tube current 30 to 240 mA; voltage 110 Kv with a 40 kW power generator) has the capability to image up to a 2-slice/rotation, each of 5.0 mm per slice with a scan time of about 30 seconds. The SPECT/CT gamma camera has a low energy (140 KeV), high resolution, parallel hole collimator with IQ SPECT capabilities.

The radiation dose received by the patients were expressed in dose length product (DLP), which reflects the total energy absorbed by the patient and represents integrated dose in terms of the total scan length. Additionally, each patients received 2 injections of Technetium Tc 99m sestamibi (1-day Protocol: 10 mCi rest injection, 30 mCi stress injection: 2-day Protocol for patients weighing > 350 pounds: 30 mCi at rest injection and 30 mCi at stress injection) for myocardial perfusion imaging.

All CT images and cardiac MPI findings were reviewed and reported contemporaneously by 1 of 2 experienced, board-certified radiologists who were blinded to patients’ clinical information except the indication for the cardiac stress testing. When suspicious pulmonary/hilar nodules or masses were detected, these findings and recommendations for further evaluation were conveyed to primary care provider or ordering physician via the electronic health record system.

All CT images were reviewed with cardiac MPI from September 1, 2017 to August 31, 2018. When pulmonary/hilar malignancies were identified, the health records were reviewed. Patients with known history of prior pulmonary malignancy were excluded from the study.

Results

A total of 1,098 patients underwent cardiac MPI during the study period. When the CT imaging and cardiac MPI were reviewed, incidental findings led to the diagnosis of lung cancer in 5 patients and hilar mantle cell lymphoma in 1 patient. Their clinical characteristics, CT findings, and types of malignancies for these 6 patients are summarized in the Table and Figure. Only 0.55% (6 of 1,098) patients were found to have incidental pulmonary/hilar malignancy with the cardiac evaluation low-resolution CT. Four patients with prior, known history of lung cancer were excluded from the study.

For the 6 patients found to have cancer, the average CT radiation dose during the cardiac MPI was 100 mGy-cm (range, 77 -133 mCy-cm). The subsequent chest CT with or without contrast delivered a radiation dose of 726.4 mGy-cm (range, 279.4 - 1,075 mGy-cm).

Discussion

Although incidental findings on low-resolution CT during cardiac MPI are frequent, clinically significant findings are less common. However, some incidental findings may be of important clinical significance.^3-5 A multicenter analysis by Coward and colleagues reported that 2.4% findings on low-resolution CT were significant enough to warrant follow-up tests, but only 0.2% were deemed potentially detrimental to patient outcomes (ie, pathology confirmed malignancies).¹² Thus, the authors suggested that routine reporting of incidental findings on low-dose CT images was not beneficial.^12,13

Currently, the majority of cardiac MPIs are reviewed and interpreted by nuclear cardiologists, the use of hybrid SPECT/CT for attenuation correction give rise of issue of reviewing and interpreting these CT images during cardiac MPI. Since low-dose, low-resolution CT are considered nondiagnostic, these images are not routinely and readily reviewed by cardiologists who are not trained or skilled in CT interpretations.

Studies of high-resolution cardiac CT (including multidetector CT with contrast) suggest that incidental extracardiac findings should always be reported as there was a 0.7% incidence of previously unknown malignancies, while others have argued against “performing large field reconstructionsfor the explicit purpose of screening as it will lead to additional cost, liability and anxiety without proven benefits.”^14-16 A review of incidental findings of cardiac CT by Earls suggested that all cardiac CT should be reconstructed in the maximal field of view available and images should be adequately reviewed to detect pathological findings.¹⁷ This led to an interesting discussion by Douglas and colleagues regarding the role of cardiologists and radiologists in this issue.¹⁸ Currently there is no uniform or consensus recommendations regarding incidental findings during cardiac CT imaging. Guidances range from no recommendations to optional reporting or mandatory reporting.^19-23

Risk Factors for Veterans

Lung cancer is the second most common cancer and the leading cause of cancer-related death in the US.²⁴ Smoking is the most important risk factor for lung cancer and CAD.²⁵ Current or past smoking are more common among the veterans.¹⁰ According to a report for the US Centers for Disease Control and Prevention report, about 29.2% US veterans use tobacco products between 2010-2015, which is similar to the rate reported in 1997.²⁶

When low-dose CT was used for lung cancer screening, it was associated with a 20.0% reduction in lung cancer mortality and a 6.7% reduction in any cause mortality.⁷ Currently, the US Preventive Services Task Force (USPSTF) recommends annual low-dose CT screening for lung cancer in high-risk adults that includes patients aged 55 to 80 years who have a 30-pack-year smoking history and currently smoke or have quit within the past 15 years.⁸

It is likely that the cardiac patients in this study might have pulmonary malignancy mortality similar to those reported in the NLST. While other studies have shown a low incidence (0.2%) of detection of malignancy by low-resolution CT during cardiac MPI,^12,13 in this study we found pulmonary or hilar malignancy in 0.55% of patients.The higher incidence of malignancy in our study might be due in part to differences in the patient population studied (ie, our veterans patients have a higher proportion of current or past smoking history).¹⁰

The CT used in this study is part of the cardiac imaging process. Therefore, there was no additional radiation exposure besides that of the cardiac MPI for patients. Despite the limitations of low-resolution CT, which may miss small lesions, this study showed 0.55% incidence of incidental detection of pulmonary/hilar malignancy. This is comparable with 0.65%/year of diagnosing lung cancer using low-dose CT for lung cancer screening in NLST.⁸

Two of the 5 study patients who were found to have lung cancer, had quit smoking > 15 years previously and thus would not be considered as high-risk for lung cancer screening according to USPSTF guideline. These patients would not have been candidates for annual low-dose CT lung cancer screening. This study suggests that it is appropriate and necessary to review the low-resolution CT images for incidental findings during cardiac MPI.

Limitations

The study was retrospective in nature and limited by its small number of patients. The CT modality used in the study also has limitations, including low resolution, respiratory motion artifacts, and scans that did not include the entire chest area. Therefore, small and apical lesions may have been missed. However, both sets of CT at rest and after stress were reviewed to reduce or minimize the effects of respiratory motion artifacts. The true prevalence or incidence of pulmonary/hilar malignancies may have been higher than reported here. Our study population of veterans may not be representative of the general population with regards to gender (as most of our veteran patient population are of male gender, vs general population), smoking history, or lung cancer risk, thus the results should be interpreted with caution.

Conclusion

Low-resolution CTs used for attenuation correction during cardiac MPI should be routinely reviewed and interpreted by a physician or radiologist skilled in CT interpretation in order to identify incidental findings of pulmonary/hilar malignancy. This would require close collaboration between cardiologists and radiologists in the field to ensure unfragmented and high-quality patient care.

Acknowledgements

We want to thank all the staffs in cardiology and radiology department on both campuses for their dedication for our patients. Special thanks to Laura Knox, Radiation Safety Officer, Nuclear Medicine Supervisor for her technical assistance.

It was estimated that physicians would diagnose a form of invasive cancer > 1.7 million times in 2019. As the second most common cause of death in the US, > 600,000 people were projected to die from cancer in 2019.¹ Many individuals with cancer endure distress, which the National Comprehensive Cancer Network (NCCN) defines as a “multifactorial unpleasant experience of a psychological (ie, cognitive, behavioral, emotional), social, spiritual, and/or physical nature that may interfere with the ability to cope effectively with cancer, its physical symptoms, and its treatment.”^2,3 Distress in people living with cancer has been attributed to various psychosocial concerns, such as family problems, whichinclude dealing with partners and children; emotional problems, such as depression and anxiety; and physical symptoms, such as pain and fatigue.^4-9 Certain factors associated with distress may increase a patient’s risk for suicide.⁴

Veterans are at particularly high risk for suicide.¹⁰ In 2014, veterans accounted for 18% of completed suicides in the US but only were 8.5% of the total population that same year.¹⁰ Yet, little research has been done on the relationship between distress and suicide in veterans living with cancer. Aboumrad and colleagues found that 45% of veterans with cancer who completed suicide reported family issues and 41% endorsed chronic pain.¹¹ This study recommended continued efforts to assess and treat distress to lessen risk of suicide in veterans living with cancer; however, to date, only 1 study has specifically evaluated distress and problems endorsed among veterans living with cancer.⁷

Suicide prevention is of the highest priority to the US Department of Veterans Affairs (VA).¹² Consistent with the VA mission to end veteran suicide, the current study aimed to better understand the relationship between distress and suicide within a sample of veterans living with cancer. Findings would additionally be used to tailor clinical assessments and interventions for veterans living with cancer.

This study had 3 primary goals. First, we sought to understand demographic and clinical factors associated with low, moderate, and severe levels of distress in veterans living with cancer who were referred for psychology services. Second, the study investigated the most commonly endorsed problems by veterans living with cancer. Finally, we examined which problems were related to suicidal ideation (SI). It was hypothesized that veterans who reported severe distress would be significantly more likely to endorse SI when compared with veterans who reported mild or moderate distress. Based on existing literature, it was further hypothesized that family, emotional, and physical problems would be significantly associated with SI.^7,11

Methods

The current study was conducted at James A. Haley Veterans’ Hospital (JAHVH) in Tampa, Florida. Inclusion criteria included veterans who were diagnosed with cancer, attended an outpatient psychology-oncology evaluation, and completed mental health screening measures provided during their evaluation. Exclusion criteria included veterans who: were seen in response to an inpatient consult, were seen solely for a stem cell transplant evaluation, or did not complete the screening measures.

Measures

A veteran’s demographic (eg, age, sex, ethnicity) and clinical (eg, cancer type, stage of disease, recurrence, cancer treatments received) information was abstracted from their VA medical records. Marital status was assessed during a clinical interview and documented as part of the standardized suicide risk assessment.

The Distress Thermometer (DT) is a subjective measure developed by the NCCN.² The DT provides a visual representation of a thermometer and asks patients to rate their level of distress over the past week with 0 indicating no distress and 10 indicating extreme distress. A distress rating of 4 or higher is clinically significant.^4,6 Distress may be categorized into 3 levels of severity: mild distress (< 4), moderate distress (4-7), or severe distress (8-10). The DT has been found to have good face validity, sensitivity and specificity, and is user-friendly.^2,6,7,13

The measurement additionally lists 39 problems nested within 5 domains: practical, family, emotional, spiritual/religious, and physical. Patients may endorse listed items under each problem domain by indicating yes or no. Endorsement of various items are intended to provide more detailed information about sources of distress. Due to the predominantly male and mostly older population included in this study the ability to have children measure was removed from the family problem domain.

SI was assessed in 2 ways. First, by patients’ self-report through item-9 of the Patient Health Questionnaire-9 (PHQ-9).¹⁴ Item-9 asks “over the last 2 weeks, how often have you been bothered by thoughts that you would be better off dead or of hurting yourself in some way?” Responses range from 0 (not at all) to 3 (nearly every day).¹⁴ Responses > 0 were considered a positive screen for SI. The process of administering the PHQ-9 item-9 is part of a national VA directive for standardizing assessment of suicide risk (Steve Young, personal communication, May 23, 2018). The PHQ-9 has been found to have good construct validity when used with both medical samples and the general population along with good internal and test-retest reliability.^14,15 Second, all veterans also were asked directly about SI during clinical interview, the results of which were documented in health records using a standardized format for risk assessment.

Procedure

Participants were a sample of veterans who were referred for psychology-oncology services. The NCCN DT and Problems List were administered prior to the start of clinical interviews, which followed a checklist and included standardized assessments of SI and history of a suicide attempt(s). A licensed clinical psychologist or a postdoctoral resident conducted these assessments under the supervision of a licensed psychologist. Data gathered during the clinical interview and from the DT and problems list were documented in health records, which were retrospectively reviewed for relevant information (eg, cancer diagnosis, SI). Therefore, informed consent was waived. This study was approved by the JAHVH Institutional Review Board.

Analysis

Data were analyzed using SPSS Version 25. Data analysis proceeded in 3 steps. First, descriptive statistics included the demographic and clinical factors present in the current sample. Difference between those with and without suicidal ideation were compared using F-statistic for continuous variables and χ² analyses for categorical variables. Second, to examine relationships between each DT problem domain and SI, χ² analyses were conducted. Third, DT problem domains that had a significant relationship with SI were entered in a logistic regression. This analysis determined which items, if any, from a DT problem domain predicted SI. In the logistic regression model, history of suicide attempts was entered into the first block, as history of suicide attempts is a well-established risk factor for subsequent suicidal ideation. In the second block, other variables that were significantly related to suicidal ideation in the second step of analyses were included. Before interpreting the results of the logistic regression, model fit was tested using the Hosmer-Lemeshow test. Significance of each individual predictor variable in the model is reported using the Wald χ² statistic; each Wald statistic is compared with a χ² distribution with 1 degree of freedom (df). Results of logistic regression models also provide information about the effect of each predictor variable in the regression equation (beta weight), odds a veteran who endorsed each predictor variable in the model would also endorse SI (as indicated by the odds ratio), and an estimate of the amount of variance accounted for by each predictor variable (using Nagelkerke’s pseudo R², which ranges in value from 0 to 1 with higher values indicating more variance explained). For all analyses, P value of .05 (2-tailed) was used for statistical significance.

Results

The sample consisted of 174 veterans (Table 1). The majority (77.6%) were male with a mean age of nearly 62 years (range, 29-87). Most identified as white (74.1%) with half reporting they were either married or living with a partner.

Prostate cancer (19.0%) was the most common type of cancer among study participants followed by head and neck (18.4%), lymphoma/leukemia (11.5%), lung (11.5%), and breast (10.9%); 31.6% had metastatic disease and 14.9% had recurrent disease. Chemotherapy (42.5%) was the most common treatment modality, followed by surgery (38.5%) and radiation (31.6%). The sample was distributed among the 3 distress DT categories: mild (18.4%), moderate (42.5%), and severe (39.1%).

Problems Endorsed

Treatment decisions (44.3%) and insurance/financial concerns (35.1%) were the most frequently endorsed practical problems (Figure 1). Family health issues (33.9%) and dealing with partner (23.0%) were the most frequently endorsed family problems (Figure 2). Worry (73.0%) and depression (69.5%) were the most frequent emotional problems; of note, all emotional problems were endorsed by at least 50% of veterans (Figure 3). Fatigue (71.3%), sleep (70.7%), and pain (69%), were the most frequently endorsed physical problems (Figure 4). Spiritual/religious problems were endorsed by 15% of veterans.

Suicidal Ideation

Overall, 25.3% of veterans endorsed SI. About 20% of veterans reported a history of ≥ 1 suicide attempts in their lifetime. A significant relationship among distress categories and SI was found (χ² = 18.36, P < .001). Veterans with severe distress were more likely to endorse SI (42.7%) when compared with veterans with mild (9.4%) or moderate (16.2%) distress.

Similarly, a significant relationship among distress categories and a history of a suicide attempt(s) was found (χ² = 6.08, P = .048). Veterans with severe distress were more likely to have attempted suicide (29.4%) when compared with veterans with mild (12.5%) or moderate (14.9%) distress.

Discussion

This study aimed to understand factors associated with low, moderate, and severe levels of distress in veterans living with cancer who were referred for psychology services. As hypothesized, veterans who endorsed severe distress were significantly more likely to endorse SI. They also were more likely to have a history of a suicide attempt(s) when compared with those with mild or moderate distress.

A second aim of this study was to understand the most commonly endorsed problems. Consistent with prior literature, treatment decisions were the most commonly endorsed practical problem; worry and depression were the most common emotional problems; and fatigue, sleep, and pain were the most common physical problems.⁷

A finding unique to the current study is that family health issues and dealing with partner were specified as the most common family problems. However, a study by Smith and colleagues did not provide information about the rank of most frequently reported problems within this domain.⁷

The third aim was to understand which problems were related to SI. It was hypothesized that family, emotional, and physical problems would be related to SI. However, results indicated that only family problems (specifically, problems dealing with a partner) were significantly associated with SI among veterans living with cancer.

Contrary to expectations, emotional and physical problems were not found to have a significant relationship with SI. This is likely because veterans endorsed items nested within these problem domains with similar frequency. The lack of significant findings does not suggest that emotional and physical problems are not significant predictors of SI for veterans living with cancer, but that no specific emotional or physical symptom stood out as a predictor of suicidal ideation above the others.

The finding of a significant relationship between family problems (specifically, problems dealing with a partner) and SI in this study is consistent with findings of Aboumrad and colleagues in a study that examined root-cause analyses of completed suicides by veterans living with cancer.¹¹ They found that nearly half the sample endorsed family problems prior to their death, and a small but notable percentage of veterans who completed suicide reported divorce as a stressor prior to their death.

This finding may be explained by Thomas Joiner's interpersonal-psychological theory of suicidal behavior (IPT), which suggests that completed suicide may result from a thwarted sense of belonging, perceived burdensomeness, and acquired capability for suicide.¹⁶ Problems dealing with a partner may impact a veteran’s sense of belonging or social connectedness. Problems dealing with a partner also may be attributed to perceived burdens due to limitations imposed by living with cancer and/or undergoing treatment. In both circumstances, the veteran’s social support system may be negatively impacted, and perceived social support is a well-established protective factor against suicide.¹⁷

Partner distress is a second consideration. It is likely that veterans’ partners experienced their own distress in response to the veteran’s cancer diagnosis and/or treatment. The partner’s cause, severity, and expression of distress may contribute to problems for the couple.

Finally, the latter point of the IPT refers to acquired capability, or the ability to inflict deadly harm to oneself.¹⁸ A military sample was found to have more acquired capability for suicide when compared with a college undergraduate sample.¹⁹ A history of a suicide attempt(s) and male gender have been found to significantly predict acquired capability to complete suicide.¹⁸ Furthermore, because veterans living with cancer often are in pain, fear of pain associated with suicide may be reduced and, therefore, acquired capability increased. This suggests that male veterans living with cancer who are in pain, have a history of a suicide attempt(s), and current problems with their partner may be an extremely vulnerable population at-risk for suicide. Results from the current study emphasize the importance of veterans having access to mental health and crisis resources for problems dealing with their partner. Partner problems may foreshadow a potentially lethal type of distress.

Strengths

This study’s aims are consistent with the VA’s mission to end veteran suicide and contributes to literature in several important ways.¹² First, veterans living with cancer are an understudied population. The current study addresses a gap in existing literature by researching veterans living with cancer and aims to better understand the relationship between cancer-related distress and SI. Second, to the best of the authors’ knowledge, this study is the first to find that problems dealing with a partner significantly increases a veteran’s risk for SI above a history of a suicide attempt(s). Risk assessments now may be more comprehensive through inclusion of this distress factor.

It is recommended that future research use IPT to further investigate the relationship between problems dealing with a partner and SI.¹⁶ Future research may do so by including specific measures to assess for the tenants of the theory, including measurements of burdensomeness and belongingness. An expanded knowledge base about what makes problems dealing with a partner a significant suicide risk factor (eg, increased conflict, lack of support, etc.) would better enable clinicians to intervene effectively. Effective intervention may lessen suicidal behaviors or deaths from suicides within the Veteran population.

Limitations

One limitation is the focus on patients who accepted a mental health referral. This study design may limit the generalizability of results to veterans who would not accept mental health treatment. The homogenous sample of veterans is a second limitation. Most participants were male, white, and had a mean age of 62 years. These demographics are representative of the veterans that most typically utilize VA services; however, more research is needed on veterans living with cancer who are female and of diverse racial and ethnic backgrounds. There are likely differences in problems endorsed and factors associated with SI based on age, race, sex, and other socioeconomic factors. A third limitation is the cross-sectional, retrospective nature of this study. Future studies are advised to assess for distress at multiple time points. This is consistent with NCCN Standards of Care for Distress Management.² Longitudinal data would enable more findings about distress and SI throughout the course of cancer diagnosis and treatment, therefore enhancing clinical implications and informing future research.

Conclusion

This is among the first of studies to investigate distress and factors associated with SI in veterans living with cancer who were referred for psychology services. The prevalence of distress caused by psychosocial factors (including treatment decisions, worry, and depression) highlights the importance of including mental health services as part of comprehensive cancer treatment.

Distress due to treatment decisions may be attributed to a litany of factors such as a veteran’s consideration of adverse effects, effectiveness of treatments, changes to quality of life or functioning, and inclusion of alternative or complimentary treatments. These types of decisions often are reported to be difficult conversations to have with family members or loved ones, who are likely experiencing distress of their own. The role of a mental health provider to assist veterans in exploring their treatment decisions and the implications of such decisions appears important to lessening distress.

Early intervention for emotional symptoms would likely benefit veterans’ management of distress and may lessen suicide risk as depression is known to place veterans at-risk for SI.²⁰ This underscores the importance of timely distress assessment to prevent mild emotional distress from progressing to potentially severe or life-threatening emotional distress. For veterans with a psychiatric history, timely assessment and intervention is essential because psychiatric history is an established suicide risk factor that may be exacerbated by cancer-related distress.¹²

Furthermore, management of intolerable physical symptoms may lessen risk for suicide.⁴ Under medical guidance, fatigue may be improved using exercise.²¹ Behavioral intervention is commonly used as first-line treatment for sleep problems.²² While pain may be lessened through medication or nonpharmacological interventions.²³

Considering the numerous ways that distress may present itself (eg, practical, emotional, or physical) and increase risk for SI, it is essential that all veterans living with cancer are assessed for distress and SI, regardless of their presentation. Although veterans may not outwardly express distress, this does not indicate the absence of either distress or risk for suicide. For example, a veteran may be distressed due to financial concerns, transportation issues, and the health of his/her partner or spouse. This veteran may not exhibit visible symptoms of distress, as would be expected when the source of distress is emotional (eg, depression, anxiety). However, this veteran is equally vulnerable to impairing distress and SI as someone who exhibits emotional distress. Distress assessments should be further developed to capture both the visible and less apparent sources of distress, while also serving the imperative function of screening for suicide. Other researchers also have noted the necessity of this development.²⁴ Currently, the NCCN DT and Problems List does not include any assessment of SI or behavior.

Finally, this study identified a potentially critical factor to include in distress assessment: problems dealing with a partner. Problems dealing with a partner have been noted as a source of distress in existing literature, but this is the first study to find problems dealing with a partner to be a predictor of SI in veterans living with cancer.^4-6

Because partners often attend appointments with veterans, it is not surprising that problems dealing with their partner are not disclosed more readily. It is recommended that clinicians ask veterans about potential problems with their partner when they are alone. Directly gathering information about such problems while assessing for distress may assist health care workers in providing the most effective, accurate type of intervention in a timely manner, and potentially mitigate risk for suicide.

As recommended by the NCCN and numerous researchers, findings from the current study underscore the importance of accurate, timely assessment of distress.^2,4,8 This study makes several important recommendations about how distress assessment may be strengthened and further developed, specifically for the veteran population. This study also expands the current knowledge base of what is known about veterans living with cancer, and has begun to fill a gap in the existing literature. Consistent with the VA mission to end veteran suicide, results suggest that veterans living with cancer should be regularly screened for distress, asked about distress related to their partner, and assessed for SI. Continued efforts to enhance assessment of and response to distress may lessen suicide risk in veterans with cancer.¹¹

Acknowledgements

This study is the result of work supported with resources and the use of facilities at the James A. Haley Veterans’ Hospital.

It was estimated that physicians would diagnose a form of invasive cancer > 1.7 million times in 2019. As the second most common cause of death in the US, > 600,000 people were projected to die from cancer in 2019.¹ Many individuals with cancer endure distress, which the National Comprehensive Cancer Network (NCCN) defines as a “multifactorial unpleasant experience of a psychological (ie, cognitive, behavioral, emotional), social, spiritual, and/or physical nature that may interfere with the ability to cope effectively with cancer, its physical symptoms, and its treatment.”^2,3 Distress in people living with cancer has been attributed to various psychosocial concerns, such as family problems, whichinclude dealing with partners and children; emotional problems, such as depression and anxiety; and physical symptoms, such as pain and fatigue.^4-9 Certain factors associated with distress may increase a patient’s risk for suicide.⁴

Veterans are at particularly high risk for suicide.¹⁰ In 2014, veterans accounted for 18% of completed suicides in the US but only were 8.5% of the total population that same year.¹⁰ Yet, little research has been done on the relationship between distress and suicide in veterans living with cancer. Aboumrad and colleagues found that 45% of veterans with cancer who completed suicide reported family issues and 41% endorsed chronic pain.¹¹ This study recommended continued efforts to assess and treat distress to lessen risk of suicide in veterans living with cancer; however, to date, only 1 study has specifically evaluated distress and problems endorsed among veterans living with cancer.⁷

Suicide prevention is of the highest priority to the US Department of Veterans Affairs (VA).¹² Consistent with the VA mission to end veteran suicide, the current study aimed to better understand the relationship between distress and suicide within a sample of veterans living with cancer. Findings would additionally be used to tailor clinical assessments and interventions for veterans living with cancer.

This study had 3 primary goals. First, we sought to understand demographic and clinical factors associated with low, moderate, and severe levels of distress in veterans living with cancer who were referred for psychology services. Second, the study investigated the most commonly endorsed problems by veterans living with cancer. Finally, we examined which problems were related to suicidal ideation (SI). It was hypothesized that veterans who reported severe distress would be significantly more likely to endorse SI when compared with veterans who reported mild or moderate distress. Based on existing literature, it was further hypothesized that family, emotional, and physical problems would be significantly associated with SI.^7,11

Methods

The current study was conducted at James A. Haley Veterans’ Hospital (JAHVH) in Tampa, Florida. Inclusion criteria included veterans who were diagnosed with cancer, attended an outpatient psychology-oncology evaluation, and completed mental health screening measures provided during their evaluation. Exclusion criteria included veterans who: were seen in response to an inpatient consult, were seen solely for a stem cell transplant evaluation, or did not complete the screening measures.

Measures

A veteran’s demographic (eg, age, sex, ethnicity) and clinical (eg, cancer type, stage of disease, recurrence, cancer treatments received) information was abstracted from their VA medical records. Marital status was assessed during a clinical interview and documented as part of the standardized suicide risk assessment.

The Distress Thermometer (DT) is a subjective measure developed by the NCCN.² The DT provides a visual representation of a thermometer and asks patients to rate their level of distress over the past week with 0 indicating no distress and 10 indicating extreme distress. A distress rating of 4 or higher is clinically significant.^4,6 Distress may be categorized into 3 levels of severity: mild distress (< 4), moderate distress (4-7), or severe distress (8-10). The DT has been found to have good face validity, sensitivity and specificity, and is user-friendly.^2,6,7,13

The measurement additionally lists 39 problems nested within 5 domains: practical, family, emotional, spiritual/religious, and physical. Patients may endorse listed items under each problem domain by indicating yes or no. Endorsement of various items are intended to provide more detailed information about sources of distress. Due to the predominantly male and mostly older population included in this study the ability to have children measure was removed from the family problem domain.

SI was assessed in 2 ways. First, by patients’ self-report through item-9 of the Patient Health Questionnaire-9 (PHQ-9).¹⁴ Item-9 asks “over the last 2 weeks, how often have you been bothered by thoughts that you would be better off dead or of hurting yourself in some way?” Responses range from 0 (not at all) to 3 (nearly every day).¹⁴ Responses > 0 were considered a positive screen for SI. The process of administering the PHQ-9 item-9 is part of a national VA directive for standardizing assessment of suicide risk (Steve Young, personal communication, May 23, 2018). The PHQ-9 has been found to have good construct validity when used with both medical samples and the general population along with good internal and test-retest reliability.^14,15 Second, all veterans also were asked directly about SI during clinical interview, the results of which were documented in health records using a standardized format for risk assessment.

Procedure

Participants were a sample of veterans who were referred for psychology-oncology services. The NCCN DT and Problems List were administered prior to the start of clinical interviews, which followed a checklist and included standardized assessments of SI and history of a suicide attempt(s). A licensed clinical psychologist or a postdoctoral resident conducted these assessments under the supervision of a licensed psychologist. Data gathered during the clinical interview and from the DT and problems list were documented in health records, which were retrospectively reviewed for relevant information (eg, cancer diagnosis, SI). Therefore, informed consent was waived. This study was approved by the JAHVH Institutional Review Board.

Analysis

Data were analyzed using SPSS Version 25. Data analysis proceeded in 3 steps. First, descriptive statistics included the demographic and clinical factors present in the current sample. Difference between those with and without suicidal ideation were compared using F-statistic for continuous variables and χ² analyses for categorical variables. Second, to examine relationships between each DT problem domain and SI, χ² analyses were conducted. Third, DT problem domains that had a significant relationship with SI were entered in a logistic regression. This analysis determined which items, if any, from a DT problem domain predicted SI. In the logistic regression model, history of suicide attempts was entered into the first block, as history of suicide attempts is a well-established risk factor for subsequent suicidal ideation. In the second block, other variables that were significantly related to suicidal ideation in the second step of analyses were included. Before interpreting the results of the logistic regression, model fit was tested using the Hosmer-Lemeshow test. Significance of each individual predictor variable in the model is reported using the Wald χ² statistic; each Wald statistic is compared with a χ² distribution with 1 degree of freedom (df). Results of logistic regression models also provide information about the effect of each predictor variable in the regression equation (beta weight), odds a veteran who endorsed each predictor variable in the model would also endorse SI (as indicated by the odds ratio), and an estimate of the amount of variance accounted for by each predictor variable (using Nagelkerke’s pseudo R², which ranges in value from 0 to 1 with higher values indicating more variance explained). For all analyses, P value of .05 (2-tailed) was used for statistical significance.

Results

The sample consisted of 174 veterans (Table 1). The majority (77.6%) were male with a mean age of nearly 62 years (range, 29-87). Most identified as white (74.1%) with half reporting they were either married or living with a partner.

Prostate cancer (19.0%) was the most common type of cancer among study participants followed by head and neck (18.4%), lymphoma/leukemia (11.5%), lung (11.5%), and breast (10.9%); 31.6% had metastatic disease and 14.9% had recurrent disease. Chemotherapy (42.5%) was the most common treatment modality, followed by surgery (38.5%) and radiation (31.6%). The sample was distributed among the 3 distress DT categories: mild (18.4%), moderate (42.5%), and severe (39.1%).

Problems Endorsed

Treatment decisions (44.3%) and insurance/financial concerns (35.1%) were the most frequently endorsed practical problems (Figure 1). Family health issues (33.9%) and dealing with partner (23.0%) were the most frequently endorsed family problems (Figure 2). Worry (73.0%) and depression (69.5%) were the most frequent emotional problems; of note, all emotional problems were endorsed by at least 50% of veterans (Figure 3). Fatigue (71.3%), sleep (70.7%), and pain (69%), were the most frequently endorsed physical problems (Figure 4). Spiritual/religious problems were endorsed by 15% of veterans.

Suicidal Ideation

Overall, 25.3% of veterans endorsed SI. About 20% of veterans reported a history of ≥ 1 suicide attempts in their lifetime. A significant relationship among distress categories and SI was found (χ² = 18.36, P < .001). Veterans with severe distress were more likely to endorse SI (42.7%) when compared with veterans with mild (9.4%) or moderate (16.2%) distress.

Similarly, a significant relationship among distress categories and a history of a suicide attempt(s) was found (χ² = 6.08, P = .048). Veterans with severe distress were more likely to have attempted suicide (29.4%) when compared with veterans with mild (12.5%) or moderate (14.9%) distress.

Discussion

This study aimed to understand factors associated with low, moderate, and severe levels of distress in veterans living with cancer who were referred for psychology services. As hypothesized, veterans who endorsed severe distress were significantly more likely to endorse SI. They also were more likely to have a history of a suicide attempt(s) when compared with those with mild or moderate distress.

A second aim of this study was to understand the most commonly endorsed problems. Consistent with prior literature, treatment decisions were the most commonly endorsed practical problem; worry and depression were the most common emotional problems; and fatigue, sleep, and pain were the most common physical problems.⁷

A finding unique to the current study is that family health issues and dealing with partner were specified as the most common family problems. However, a study by Smith and colleagues did not provide information about the rank of most frequently reported problems within this domain.⁷

The third aim was to understand which problems were related to SI. It was hypothesized that family, emotional, and physical problems would be related to SI. However, results indicated that only family problems (specifically, problems dealing with a partner) were significantly associated with SI among veterans living with cancer.

Contrary to expectations, emotional and physical problems were not found to have a significant relationship with SI. This is likely because veterans endorsed items nested within these problem domains with similar frequency. The lack of significant findings does not suggest that emotional and physical problems are not significant predictors of SI for veterans living with cancer, but that no specific emotional or physical symptom stood out as a predictor of suicidal ideation above the others.

The finding of a significant relationship between family problems (specifically, problems dealing with a partner) and SI in this study is consistent with findings of Aboumrad and colleagues in a study that examined root-cause analyses of completed suicides by veterans living with cancer.¹¹ They found that nearly half the sample endorsed family problems prior to their death, and a small but notable percentage of veterans who completed suicide reported divorce as a stressor prior to their death.

This finding may be explained by Thomas Joiner's interpersonal-psychological theory of suicidal behavior (IPT), which suggests that completed suicide may result from a thwarted sense of belonging, perceived burdensomeness, and acquired capability for suicide.¹⁶ Problems dealing with a partner may impact a veteran’s sense of belonging or social connectedness. Problems dealing with a partner also may be attributed to perceived burdens due to limitations imposed by living with cancer and/or undergoing treatment. In both circumstances, the veteran’s social support system may be negatively impacted, and perceived social support is a well-established protective factor against suicide.¹⁷

Partner distress is a second consideration. It is likely that veterans’ partners experienced their own distress in response to the veteran’s cancer diagnosis and/or treatment. The partner’s cause, severity, and expression of distress may contribute to problems for the couple.

Finally, the latter point of the IPT refers to acquired capability, or the ability to inflict deadly harm to oneself.¹⁸ A military sample was found to have more acquired capability for suicide when compared with a college undergraduate sample.¹⁹ A history of a suicide attempt(s) and male gender have been found to significantly predict acquired capability to complete suicide.¹⁸ Furthermore, because veterans living with cancer often are in pain, fear of pain associated with suicide may be reduced and, therefore, acquired capability increased. This suggests that male veterans living with cancer who are in pain, have a history of a suicide attempt(s), and current problems with their partner may be an extremely vulnerable population at-risk for suicide. Results from the current study emphasize the importance of veterans having access to mental health and crisis resources for problems dealing with their partner. Partner problems may foreshadow a potentially lethal type of distress.

Strengths

This study’s aims are consistent with the VA’s mission to end veteran suicide and contributes to literature in several important ways.¹² First, veterans living with cancer are an understudied population. The current study addresses a gap in existing literature by researching veterans living with cancer and aims to better understand the relationship between cancer-related distress and SI. Second, to the best of the authors’ knowledge, this study is the first to find that problems dealing with a partner significantly increases a veteran’s risk for SI above a history of a suicide attempt(s). Risk assessments now may be more comprehensive through inclusion of this distress factor.

It is recommended that future research use IPT to further investigate the relationship between problems dealing with a partner and SI.¹⁶ Future research may do so by including specific measures to assess for the tenants of the theory, including measurements of burdensomeness and belongingness. An expanded knowledge base about what makes problems dealing with a partner a significant suicide risk factor (eg, increased conflict, lack of support, etc.) would better enable clinicians to intervene effectively. Effective intervention may lessen suicidal behaviors or deaths from suicides within the Veteran population.

Limitations

One limitation is the focus on patients who accepted a mental health referral. This study design may limit the generalizability of results to veterans who would not accept mental health treatment. The homogenous sample of veterans is a second limitation. Most participants were male, white, and had a mean age of 62 years. These demographics are representative of the veterans that most typically utilize VA services; however, more research is needed on veterans living with cancer who are female and of diverse racial and ethnic backgrounds. There are likely differences in problems endorsed and factors associated with SI based on age, race, sex, and other socioeconomic factors. A third limitation is the cross-sectional, retrospective nature of this study. Future studies are advised to assess for distress at multiple time points. This is consistent with NCCN Standards of Care for Distress Management.² Longitudinal data would enable more findings about distress and SI throughout the course of cancer diagnosis and treatment, therefore enhancing clinical implications and informing future research.

Conclusion

This is among the first of studies to investigate distress and factors associated with SI in veterans living with cancer who were referred for psychology services. The prevalence of distress caused by psychosocial factors (including treatment decisions, worry, and depression) highlights the importance of including mental health services as part of comprehensive cancer treatment.

Distress due to treatment decisions may be attributed to a litany of factors such as a veteran’s consideration of adverse effects, effectiveness of treatments, changes to quality of life or functioning, and inclusion of alternative or complimentary treatments. These types of decisions often are reported to be difficult conversations to have with family members or loved ones, who are likely experiencing distress of their own. The role of a mental health provider to assist veterans in exploring their treatment decisions and the implications of such decisions appears important to lessening distress.

Early intervention for emotional symptoms would likely benefit veterans’ management of distress and may lessen suicide risk as depression is known to place veterans at-risk for SI.²⁰ This underscores the importance of timely distress assessment to prevent mild emotional distress from progressing to potentially severe or life-threatening emotional distress. For veterans with a psychiatric history, timely assessment and intervention is essential because psychiatric history is an established suicide risk factor that may be exacerbated by cancer-related distress.¹²

Furthermore, management of intolerable physical symptoms may lessen risk for suicide.⁴ Under medical guidance, fatigue may be improved using exercise.²¹ Behavioral intervention is commonly used as first-line treatment for sleep problems.²² While pain may be lessened through medication or nonpharmacological interventions.²³

Considering the numerous ways that distress may present itself (eg, practical, emotional, or physical) and increase risk for SI, it is essential that all veterans living with cancer are assessed for distress and SI, regardless of their presentation. Although veterans may not outwardly express distress, this does not indicate the absence of either distress or risk for suicide. For example, a veteran may be distressed due to financial concerns, transportation issues, and the health of his/her partner or spouse. This veteran may not exhibit visible symptoms of distress, as would be expected when the source of distress is emotional (eg, depression, anxiety). However, this veteran is equally vulnerable to impairing distress and SI as someone who exhibits emotional distress. Distress assessments should be further developed to capture both the visible and less apparent sources of distress, while also serving the imperative function of screening for suicide. Other researchers also have noted the necessity of this development.²⁴ Currently, the NCCN DT and Problems List does not include any assessment of SI or behavior.

Finally, this study identified a potentially critical factor to include in distress assessment: problems dealing with a partner. Problems dealing with a partner have been noted as a source of distress in existing literature, but this is the first study to find problems dealing with a partner to be a predictor of SI in veterans living with cancer.^4-6

Because partners often attend appointments with veterans, it is not surprising that problems dealing with their partner are not disclosed more readily. It is recommended that clinicians ask veterans about potential problems with their partner when they are alone. Directly gathering information about such problems while assessing for distress may assist health care workers in providing the most effective, accurate type of intervention in a timely manner, and potentially mitigate risk for suicide.

As recommended by the NCCN and numerous researchers, findings from the current study underscore the importance of accurate, timely assessment of distress.^2,4,8 This study makes several important recommendations about how distress assessment may be strengthened and further developed, specifically for the veteran population. This study also expands the current knowledge base of what is known about veterans living with cancer, and has begun to fill a gap in the existing literature. Consistent with the VA mission to end veteran suicide, results suggest that veterans living with cancer should be regularly screened for distress, asked about distress related to their partner, and assessed for SI. Continued efforts to enhance assessment of and response to distress may lessen suicide risk in veterans with cancer.¹¹

Acknowledgements

This study is the result of work supported with resources and the use of facilities at the James A. Haley Veterans’ Hospital.

It was estimated that physicians would diagnose a form of invasive cancer > 1.7 million times in 2019. As the second most common cause of death in the US, > 600,000 people were projected to die from cancer in 2019.¹ Many individuals with cancer endure distress, which the National Comprehensive Cancer Network (NCCN) defines as a “multifactorial unpleasant experience of a psychological (ie, cognitive, behavioral, emotional), social, spiritual, and/or physical nature that may interfere with the ability to cope effectively with cancer, its physical symptoms, and its treatment.”^2,3 Distress in people living with cancer has been attributed to various psychosocial concerns, such as family problems, whichinclude dealing with partners and children; emotional problems, such as depression and anxiety; and physical symptoms, such as pain and fatigue.^4-9 Certain factors associated with distress may increase a patient’s risk for suicide.⁴

Veterans are at particularly high risk for suicide.¹⁰ In 2014, veterans accounted for 18% of completed suicides in the US but only were 8.5% of the total population that same year.¹⁰ Yet, little research has been done on the relationship between distress and suicide in veterans living with cancer. Aboumrad and colleagues found that 45% of veterans with cancer who completed suicide reported family issues and 41% endorsed chronic pain.¹¹ This study recommended continued efforts to assess and treat distress to lessen risk of suicide in veterans living with cancer; however, to date, only 1 study has specifically evaluated distress and problems endorsed among veterans living with cancer.⁷

Suicide prevention is of the highest priority to the US Department of Veterans Affairs (VA).¹² Consistent with the VA mission to end veteran suicide, the current study aimed to better understand the relationship between distress and suicide within a sample of veterans living with cancer. Findings would additionally be used to tailor clinical assessments and interventions for veterans living with cancer.

This study had 3 primary goals. First, we sought to understand demographic and clinical factors associated with low, moderate, and severe levels of distress in veterans living with cancer who were referred for psychology services. Second, the study investigated the most commonly endorsed problems by veterans living with cancer. Finally, we examined which problems were related to suicidal ideation (SI). It was hypothesized that veterans who reported severe distress would be significantly more likely to endorse SI when compared with veterans who reported mild or moderate distress. Based on existing literature, it was further hypothesized that family, emotional, and physical problems would be significantly associated with SI.^7,11

Methods

The current study was conducted at James A. Haley Veterans’ Hospital (JAHVH) in Tampa, Florida. Inclusion criteria included veterans who were diagnosed with cancer, attended an outpatient psychology-oncology evaluation, and completed mental health screening measures provided during their evaluation. Exclusion criteria included veterans who: were seen in response to an inpatient consult, were seen solely for a stem cell transplant evaluation, or did not complete the screening measures.

Measures

A veteran’s demographic (eg, age, sex, ethnicity) and clinical (eg, cancer type, stage of disease, recurrence, cancer treatments received) information was abstracted from their VA medical records. Marital status was assessed during a clinical interview and documented as part of the standardized suicide risk assessment.

The Distress Thermometer (DT) is a subjective measure developed by the NCCN.² The DT provides a visual representation of a thermometer and asks patients to rate their level of distress over the past week with 0 indicating no distress and 10 indicating extreme distress. A distress rating of 4 or higher is clinically significant.^4,6 Distress may be categorized into 3 levels of severity: mild distress (< 4), moderate distress (4-7), or severe distress (8-10). The DT has been found to have good face validity, sensitivity and specificity, and is user-friendly.^2,6,7,13

The measurement additionally lists 39 problems nested within 5 domains: practical, family, emotional, spiritual/religious, and physical. Patients may endorse listed items under each problem domain by indicating yes or no. Endorsement of various items are intended to provide more detailed information about sources of distress. Due to the predominantly male and mostly older population included in this study the ability to have children measure was removed from the family problem domain.

SI was assessed in 2 ways. First, by patients’ self-report through item-9 of the Patient Health Questionnaire-9 (PHQ-9).¹⁴ Item-9 asks “over the last 2 weeks, how often have you been bothered by thoughts that you would be better off dead or of hurting yourself in some way?” Responses range from 0 (not at all) to 3 (nearly every day).¹⁴ Responses > 0 were considered a positive screen for SI. The process of administering the PHQ-9 item-9 is part of a national VA directive for standardizing assessment of suicide risk (Steve Young, personal communication, May 23, 2018). The PHQ-9 has been found to have good construct validity when used with both medical samples and the general population along with good internal and test-retest reliability.^14,15 Second, all veterans also were asked directly about SI during clinical interview, the results of which were documented in health records using a standardized format for risk assessment.

Procedure

Participants were a sample of veterans who were referred for psychology-oncology services. The NCCN DT and Problems List were administered prior to the start of clinical interviews, which followed a checklist and included standardized assessments of SI and history of a suicide attempt(s). A licensed clinical psychologist or a postdoctoral resident conducted these assessments under the supervision of a licensed psychologist. Data gathered during the clinical interview and from the DT and problems list were documented in health records, which were retrospectively reviewed for relevant information (eg, cancer diagnosis, SI). Therefore, informed consent was waived. This study was approved by the JAHVH Institutional Review Board.

Analysis

Data were analyzed using SPSS Version 25. Data analysis proceeded in 3 steps. First, descriptive statistics included the demographic and clinical factors present in the current sample. Difference between those with and without suicidal ideation were compared using F-statistic for continuous variables and χ² analyses for categorical variables. Second, to examine relationships between each DT problem domain and SI, χ² analyses were conducted. Third, DT problem domains that had a significant relationship with SI were entered in a logistic regression. This analysis determined which items, if any, from a DT problem domain predicted SI. In the logistic regression model, history of suicide attempts was entered into the first block, as history of suicide attempts is a well-established risk factor for subsequent suicidal ideation. In the second block, other variables that were significantly related to suicidal ideation in the second step of analyses were included. Before interpreting the results of the logistic regression, model fit was tested using the Hosmer-Lemeshow test. Significance of each individual predictor variable in the model is reported using the Wald χ² statistic; each Wald statistic is compared with a χ² distribution with 1 degree of freedom (df). Results of logistic regression models also provide information about the effect of each predictor variable in the regression equation (beta weight), odds a veteran who endorsed each predictor variable in the model would also endorse SI (as indicated by the odds ratio), and an estimate of the amount of variance accounted for by each predictor variable (using Nagelkerke’s pseudo R², which ranges in value from 0 to 1 with higher values indicating more variance explained). For all analyses, P value of .05 (2-tailed) was used for statistical significance.

Results

The sample consisted of 174 veterans (Table 1). The majority (77.6%) were male with a mean age of nearly 62 years (range, 29-87). Most identified as white (74.1%) with half reporting they were either married or living with a partner.

Prostate cancer (19.0%) was the most common type of cancer among study participants followed by head and neck (18.4%), lymphoma/leukemia (11.5%), lung (11.5%), and breast (10.9%); 31.6% had metastatic disease and 14.9% had recurrent disease. Chemotherapy (42.5%) was the most common treatment modality, followed by surgery (38.5%) and radiation (31.6%). The sample was distributed among the 3 distress DT categories: mild (18.4%), moderate (42.5%), and severe (39.1%).

Problems Endorsed

Treatment decisions (44.3%) and insurance/financial concerns (35.1%) were the most frequently endorsed practical problems (Figure 1). Family health issues (33.9%) and dealing with partner (23.0%) were the most frequently endorsed family problems (Figure 2). Worry (73.0%) and depression (69.5%) were the most frequent emotional problems; of note, all emotional problems were endorsed by at least 50% of veterans (Figure 3). Fatigue (71.3%), sleep (70.7%), and pain (69%), were the most frequently endorsed physical problems (Figure 4). Spiritual/religious problems were endorsed by 15% of veterans.

Suicidal Ideation

Overall, 25.3% of veterans endorsed SI. About 20% of veterans reported a history of ≥ 1 suicide attempts in their lifetime. A significant relationship among distress categories and SI was found (χ² = 18.36, P < .001). Veterans with severe distress were more likely to endorse SI (42.7%) when compared with veterans with mild (9.4%) or moderate (16.2%) distress.

Similarly, a significant relationship among distress categories and a history of a suicide attempt(s) was found (χ² = 6.08, P = .048). Veterans with severe distress were more likely to have attempted suicide (29.4%) when compared with veterans with mild (12.5%) or moderate (14.9%) distress.

Discussion

This study aimed to understand factors associated with low, moderate, and severe levels of distress in veterans living with cancer who were referred for psychology services. As hypothesized, veterans who endorsed severe distress were significantly more likely to endorse SI. They also were more likely to have a history of a suicide attempt(s) when compared with those with mild or moderate distress.

A second aim of this study was to understand the most commonly endorsed problems. Consistent with prior literature, treatment decisions were the most commonly endorsed practical problem; worry and depression were the most common emotional problems; and fatigue, sleep, and pain were the most common physical problems.⁷

A finding unique to the current study is that family health issues and dealing with partner were specified as the most common family problems. However, a study by Smith and colleagues did not provide information about the rank of most frequently reported problems within this domain.⁷

The third aim was to understand which problems were related to SI. It was hypothesized that family, emotional, and physical problems would be related to SI. However, results indicated that only family problems (specifically, problems dealing with a partner) were significantly associated with SI among veterans living with cancer.

Contrary to expectations, emotional and physical problems were not found to have a significant relationship with SI. This is likely because veterans endorsed items nested within these problem domains with similar frequency. The lack of significant findings does not suggest that emotional and physical problems are not significant predictors of SI for veterans living with cancer, but that no specific emotional or physical symptom stood out as a predictor of suicidal ideation above the others.

The finding of a significant relationship between family problems (specifically, problems dealing with a partner) and SI in this study is consistent with findings of Aboumrad and colleagues in a study that examined root-cause analyses of completed suicides by veterans living with cancer.¹¹ They found that nearly half the sample endorsed family problems prior to their death, and a small but notable percentage of veterans who completed suicide reported divorce as a stressor prior to their death.

This finding may be explained by Thomas Joiner's interpersonal-psychological theory of suicidal behavior (IPT), which suggests that completed suicide may result from a thwarted sense of belonging, perceived burdensomeness, and acquired capability for suicide.¹⁶ Problems dealing with a partner may impact a veteran’s sense of belonging or social connectedness. Problems dealing with a partner also may be attributed to perceived burdens due to limitations imposed by living with cancer and/or undergoing treatment. In both circumstances, the veteran’s social support system may be negatively impacted, and perceived social support is a well-established protective factor against suicide.¹⁷

Partner distress is a second consideration. It is likely that veterans’ partners experienced their own distress in response to the veteran’s cancer diagnosis and/or treatment. The partner’s cause, severity, and expression of distress may contribute to problems for the couple.

Finally, the latter point of the IPT refers to acquired capability, or the ability to inflict deadly harm to oneself.¹⁸ A military sample was found to have more acquired capability for suicide when compared with a college undergraduate sample.¹⁹ A history of a suicide attempt(s) and male gender have been found to significantly predict acquired capability to complete suicide.¹⁸ Furthermore, because veterans living with cancer often are in pain, fear of pain associated with suicide may be reduced and, therefore, acquired capability increased. This suggests that male veterans living with cancer who are in pain, have a history of a suicide attempt(s), and current problems with their partner may be an extremely vulnerable population at-risk for suicide. Results from the current study emphasize the importance of veterans having access to mental health and crisis resources for problems dealing with their partner. Partner problems may foreshadow a potentially lethal type of distress.

Strengths

This study’s aims are consistent with the VA’s mission to end veteran suicide and contributes to literature in several important ways.¹² First, veterans living with cancer are an understudied population. The current study addresses a gap in existing literature by researching veterans living with cancer and aims to better understand the relationship between cancer-related distress and SI. Second, to the best of the authors’ knowledge, this study is the first to find that problems dealing with a partner significantly increases a veteran’s risk for SI above a history of a suicide attempt(s). Risk assessments now may be more comprehensive through inclusion of this distress factor.

It is recommended that future research use IPT to further investigate the relationship between problems dealing with a partner and SI.¹⁶ Future research may do so by including specific measures to assess for the tenants of the theory, including measurements of burdensomeness and belongingness. An expanded knowledge base about what makes problems dealing with a partner a significant suicide risk factor (eg, increased conflict, lack of support, etc.) would better enable clinicians to intervene effectively. Effective intervention may lessen suicidal behaviors or deaths from suicides within the Veteran population.

Limitations

One limitation is the focus on patients who accepted a mental health referral. This study design may limit the generalizability of results to veterans who would not accept mental health treatment. The homogenous sample of veterans is a second limitation. Most participants were male, white, and had a mean age of 62 years. These demographics are representative of the veterans that most typically utilize VA services; however, more research is needed on veterans living with cancer who are female and of diverse racial and ethnic backgrounds. There are likely differences in problems endorsed and factors associated with SI based on age, race, sex, and other socioeconomic factors. A third limitation is the cross-sectional, retrospective nature of this study. Future studies are advised to assess for distress at multiple time points. This is consistent with NCCN Standards of Care for Distress Management.² Longitudinal data would enable more findings about distress and SI throughout the course of cancer diagnosis and treatment, therefore enhancing clinical implications and informing future research.

Conclusion

This is among the first of studies to investigate distress and factors associated with SI in veterans living with cancer who were referred for psychology services. The prevalence of distress caused by psychosocial factors (including treatment decisions, worry, and depression) highlights the importance of including mental health services as part of comprehensive cancer treatment.

Distress due to treatment decisions may be attributed to a litany of factors such as a veteran’s consideration of adverse effects, effectiveness of treatments, changes to quality of life or functioning, and inclusion of alternative or complimentary treatments. These types of decisions often are reported to be difficult conversations to have with family members or loved ones, who are likely experiencing distress of their own. The role of a mental health provider to assist veterans in exploring their treatment decisions and the implications of such decisions appears important to lessening distress.

Early intervention for emotional symptoms would likely benefit veterans’ management of distress and may lessen suicide risk as depression is known to place veterans at-risk for SI.²⁰ This underscores the importance of timely distress assessment to prevent mild emotional distress from progressing to potentially severe or life-threatening emotional distress. For veterans with a psychiatric history, timely assessment and intervention is essential because psychiatric history is an established suicide risk factor that may be exacerbated by cancer-related distress.¹²

Furthermore, management of intolerable physical symptoms may lessen risk for suicide.⁴ Under medical guidance, fatigue may be improved using exercise.²¹ Behavioral intervention is commonly used as first-line treatment for sleep problems.²² While pain may be lessened through medication or nonpharmacological interventions.²³

Considering the numerous ways that distress may present itself (eg, practical, emotional, or physical) and increase risk for SI, it is essential that all veterans living with cancer are assessed for distress and SI, regardless of their presentation. Although veterans may not outwardly express distress, this does not indicate the absence of either distress or risk for suicide. For example, a veteran may be distressed due to financial concerns, transportation issues, and the health of his/her partner or spouse. This veteran may not exhibit visible symptoms of distress, as would be expected when the source of distress is emotional (eg, depression, anxiety). However, this veteran is equally vulnerable to impairing distress and SI as someone who exhibits emotional distress. Distress assessments should be further developed to capture both the visible and less apparent sources of distress, while also serving the imperative function of screening for suicide. Other researchers also have noted the necessity of this development.²⁴ Currently, the NCCN DT and Problems List does not include any assessment of SI or behavior.

Finally, this study identified a potentially critical factor to include in distress assessment: problems dealing with a partner. Problems dealing with a partner have been noted as a source of distress in existing literature, but this is the first study to find problems dealing with a partner to be a predictor of SI in veterans living with cancer.^4-6

Because partners often attend appointments with veterans, it is not surprising that problems dealing with their partner are not disclosed more readily. It is recommended that clinicians ask veterans about potential problems with their partner when they are alone. Directly gathering information about such problems while assessing for distress may assist health care workers in providing the most effective, accurate type of intervention in a timely manner, and potentially mitigate risk for suicide.

As recommended by the NCCN and numerous researchers, findings from the current study underscore the importance of accurate, timely assessment of distress.^2,4,8 This study makes several important recommendations about how distress assessment may be strengthened and further developed, specifically for the veteran population. This study also expands the current knowledge base of what is known about veterans living with cancer, and has begun to fill a gap in the existing literature. Consistent with the VA mission to end veteran suicide, results suggest that veterans living with cancer should be regularly screened for distress, asked about distress related to their partner, and assessed for SI. Continued efforts to enhance assessment of and response to distress may lessen suicide risk in veterans with cancer.¹¹

Acknowledgements

This study is the result of work supported with resources and the use of facilities at the James A. Haley Veterans’ Hospital.

Chronic lymphocytic leukemia (CLL) is the most common leukemia diagnosed in developed countries, with an estimated 21,040 new diagnoses of CLL expected in the US in 2020. ^1-3 CLL is an indolent cancer characterized by the accumulation of B-lymphocytes in the blood, marrow, and lymphoid tissues. ⁴ It has a heterogeneous clinical course; the majority of patients are observed or receive delayed treatment following diagnosis, while a minority of patients require immediate treatment. After first-line treatment, some patients experience prolonged remissions while others require retreatment within 1 or 2 years. Fortunately, advances in cancer biology and therapeutics in the last decade have increased the number of treatment options available for patients with CLL.

Until recently, most CLL treatments relied on a chemotherapy or a chemoimmunotherapy backbone; however, the last few years have seen novel therapies introduced, such as small molecule inhibitors to target molecular pathways that promote the normal development, expansion, and survival of B-cells.⁵ One such therapy is ibrutinib, a targeted Bruton tyrosine kinase inhibitor that received accelerated approval by the US Food and Drug Administration (FDA) in February 2014 for patients with CLL who received at least 1 prior therapy. The FDA later expanded this approval to include use of ibrutinib in patients with CLL with relapsed or refractory disease, with or without chromosome 17p deletion. In 2016, based on data from the RESONATE-17 study, the FDA approved ibrutinib for first-line therapy in patients with CLL.⁶

Ibrutinib’s efficacy, ease of administration and dosing (all doses are oral and fixed, rather than based on weight or body surface area), and relatively favorable safety profile have resulted in a rapid growth in its adoption.⁷ Since its adverse event (AE) profile is generally more tolerable than that of a typical chemoimmunotherapy, its use in older patients with CLL and patients with significant comorbidities is particularly appealing.⁸

However, the results of some clinical trials suggest an association between treatment with ibrutinib and an increased risk of bleeding-related events of any grade (44%) and major bleeding events (4%).^7,8 The incidence of major bleeding events was reported to be higher (9%) in one clinical trial and at 5-year follow-up, although this trial did not exclude patients receiving concomitant oral anticoagulation with warfarin.^6,9

Heterogeneity in clinical trials’ definitions of major bleeding confounded the ability to calculate bleeding risk in patients treated with ibrutinib in a systematic review and meta-analysis that called for more data.¹⁰ Additionally, patients with factors that might increase the risk of major bleeding with ibrutinib treatment were likely underrepresented in clinical trials, given the carefully selected nature of clinical trial subjects. These factors include renal or hepatic disease, gastrointestinal disease, and use of a number of concomitant medications such as antiplatelets or anticoagulant medications. Accounting for use of the latter is particularly important because patients who develop atrial fibrillation (Afib), one of the recognized AEs of treatment with ibrutinib, often are treated with anticoagulant medications in order to decrease the risk of stroke or other thromboembolic complications.

Methods

The VHA maintains the centralized US Department of Veterans Affairs Cancer Registry System (VACRS), with electronic medical record data and other sources captured in its Corporate Data Warehouse (CDW). The VHA CDW is a national repository comprising data from several VHA clinical and administrative systems. The CDW includes patient identifiers; demographics; vital status; lab information; administrative information (such as diagnostic International Statistical Classification of Diseases and Related Health Problems [ICD-9] codes); medication dispensation tables (such as outpatient fill); IV package information; and notes from radiology, pathology, outpatient and inpatient admission, discharge, and daily progress.

Registrars abstract all cancer cases within the VHA system (or diagnosed outside the VHA, if patients subsequently receive treatment in the VHA). It is estimated that VACRS captures 3% of cancer cases in the US.¹² Like most registries, VACRS captures data such as diagnosis, age, gender, race, and vital status.

Study Definitions

Prevalence of comorbidities that could increase bleeding risk was determined using administrative ICD-9-CM codes. Liver disease was identified by presence of cirrhosis, hepatitis C virus, or alcoholic liver disease using administrative codes validated by Kramer and colleagues, who reported positive and negative predictive values of 90% and 87% for cirrhosis, 93% and 92% for hepatitis C virus, and 71% and 98% for alcoholic liver disease.¹³ Similarly, end-stage liver disease was identified using a validated coding algorithm developed by Goldberg and colleagues, with a positive predictive value of 89.3%.¹⁴ The presence of controlled or uncontrolled diabetes mellitus (DM) was identified using the procedure described by Guzman and colleagues.¹⁵ Quan’s algorithm was used to calculate Charlson Comorbidity Index (CCI) based on ICD-9-CM codes for inpatient and outpatient visits within a 6-month lookback period prior to treatment initiation.¹⁶

A major bleeding event was defined as a hospitalization with an ICD-9-CM code suggestive of major bleeding as the primary reason, as defined by Lane and colleagues in their study of major bleeding related to warfarin in a cohort of patients treated within the VHA.¹⁷ Incidence rates of major bleeding events were identified during the first 6 months of treatment. Incidence of Afib—defined as an inpatient or outpatient encounter with the 427.31 ICD-9-CM code—also was examined within the first 6 months after starting treatment. The period of 6 months was chosen because bendamustine must be discontinued after 6 months.

Study Analysis

Descriptive statistics were used to examine patient demographics, disease characteristics, and treatment history from initial CLL diagnosis through end of study observation period. Categorical variables were summarized using frequencies and accompanying proportions, while a mean and standard deviation were used to summarize continuous variables. For the means of continuous variables and of categorical data, 95% CIs were used. Proportions and accompanying 95% CIs characterized treatment patterns, including line of therapy, comorbidities, and bleeding events. Treatment duration was described using mean and accompanying 95% CI. Statistical tests were not conducted for comparisons among treatment groups. Patients were censored at the end of follow-up, defined as the earliest of the following scenarios: (1) end of study observation period (December 31, 2016); (2) development of a secondary cancer; or (3) last day of contact given absence of care within the VHA for ≥ 18 months (with care defined as oncology and/or oncology/hematology visit with an associated note). Analysis was performed using R 3.4.0.

Results

Between 2010 and 2014, 2,796 patients were diagnosed and received care for CLL within the VHA. Overall, all 172 patients who were treated with ibrutinib during our inclusion period were selected. These patients were treated between January 1, 2014 and December 31, 2016, following ibrutinib’s approval in early 2014. An additional 291 patients were selected who received BR (Table). Reflecting the predominantly male population of the VHA, 282 (97%) BR patients and 167 (97%) ibrutinib patients were male. The median age at diagnosis was 67 years for BR patients and 69 years for ibrutinib patients. About 76% of patients who received ibrutinib and 82% of patients who received BR were non-Hispanic white; 17% and 14% were African American, respectively.

Less than 10% of patients receiving either ibrutinib or BR had liver disease per criteria used by Kramer and colleagues, or end-stage liver disease using criteria developed by Goldberg and colleagues.^12,13 About 5% of patients had a history of previous bleeding in the 6-month period prior to initiating either therapy. Mean CCI (excluding malignancy) score was 1.5 (range, 0-11) for the ibrutinib group, and 2.1 (range, 0-9) for the BR group. About 16% of the ibrutinib group had controlled DM and fewer than 10% had uncontrolled DM, while 4% of patients in the BR group met the criteria for controlled DM and another 4% met the criteria for uncontrolled DM.

There was very low utilization of anticoagulant or antiplatelet medication prior to initiation of ibrutinib (2.9% and 2.3%, respectively) or BR (< 1% each). In the first 6 months after treatment initiation, about 8% of patients in both ibrutinib and BR cohorts received anticoagulant medication while antiplatelet utilization was < 5% in either group.

In the BR group, 8 patients (2.7%) experienced a major bleeding event, while 14 patients (8.1%) in the ibrutinib group experienced a bleeding event (P = .008). While these numbers were too low to perform a formal statistical analysis of the association between clinical covariates and bleeding in either group, there did not seem to be an association between bleeding and liver disease or DM. Of patients who experienced a bleeding event, about 1 in 4 patients had had a prior bleeding event in both the ibrutinib and the BR groups. Interestingly, while none of the patients who experienced a bleeding event while receiving BR were taking concomitant anticoagulant medication, 3 of the 14 patients who experienced a bleeding event in the ibrutinib group showed evidence of anticoagulant utilization. Finally, the incidence of Afib (defined as patients with no evidence of Afib in the 6 months prior to treatment but with evidence of Afib in the 6 months following treatment initiation) was 4% in the BR group, and about 8% in the ibrutinib group (P = .003).

Discussion

To the authors’ knowledge, this study is the first to examine the real-world incidence of bleeding and Afib in veterans who received ibrutinib for CLL in the first year of its availability. The study found minimal use of anticoagulants and/or antiplatelet agents prior to receiving first-line ibrutinib or BR, and very low use of these agents in the first 6 months following the initiation of first-line treatment. This finding suggests a high awareness among VA providers of potential adverse effects (AEs) of ibrutinib and chemotherapy, and a careful selection of patients that lack risk factors for AEs.

In patients treated with first-line ibrutinib when compared with patients treated with first-line BR, moderate increases in bleeding (2.7% vs 8.1%, P = .008) and Afib (10.5% vs 3%, P = .003) also were observed. These results are concordant with previous findings examining the use of ibrutinib in patients with CLL.^18-20

Limitations

The results of this study should be interpreted with caution, as some limitations must be considered. The study was conducted in the early days of ibrutinib adoption. Since then, more patients have been treated with ibrutinib and for longer durations. As clinicians gain more familiarity and with ibrutinib, and as additional novel therapeutics emerge, it is possible that the initial awareness about risks for possible AEs may diminish; patients with high comorbidity burdens and concomitant medications would be especially vulnerable in cases of reduced physician vigilance.

Another limitation of this study stems from the potential for dual system use among patients treated in the VHA. Concurrent or alternating use of multiple health care systems (use of VHA and private-sector facilities) may present gaps in the reconstruction of patient histories, resulting in missing data as patients transition between commercial, the Centers for Medicare and Medicaid Services, and VHA care. As a result, the results presented here do not reflect instances where a patient experienced a bleeding event treated outside the VA.

Problems with missing data also may occur due to incomplete extraction from the electronic health record; these issues were addressed by leveraging an understanding of the multiple data marts within the CDW environment to harmonize missing and/or erroneous information through use of other data marts when possible. Lastly, this research represents a population-level study of the VHA, thus all findings are directly relevant to the VHA. The generalizability of the findings outside the VHA would depend on the characteristics of the external population.

Conclusion

Real-world evidence from a nationwide cohort of veteran patients with CLL treated with ibrutinib suggest that, while there is an association of increased bleeding-related events and Afib, the risk is comparable to those reported in previous studies.^18-20 These findings suggest that patients in real-world clinical care settings with higher levels of comorbidities may be at a slight increased risk for bleeding events and Afib.

Chronic lymphocytic leukemia (CLL) is the most common leukemia diagnosed in developed countries, with an estimated 21,040 new diagnoses of CLL expected in the US in 2020. ^1-3 CLL is an indolent cancer characterized by the accumulation of B-lymphocytes in the blood, marrow, and lymphoid tissues. ⁴ It has a heterogeneous clinical course; the majority of patients are observed or receive delayed treatment following diagnosis, while a minority of patients require immediate treatment. After first-line treatment, some patients experience prolonged remissions while others require retreatment within 1 or 2 years. Fortunately, advances in cancer biology and therapeutics in the last decade have increased the number of treatment options available for patients with CLL.

Until recently, most CLL treatments relied on a chemotherapy or a chemoimmunotherapy backbone; however, the last few years have seen novel therapies introduced, such as small molecule inhibitors to target molecular pathways that promote the normal development, expansion, and survival of B-cells.⁵ One such therapy is ibrutinib, a targeted Bruton tyrosine kinase inhibitor that received accelerated approval by the US Food and Drug Administration (FDA) in February 2014 for patients with CLL who received at least 1 prior therapy. The FDA later expanded this approval to include use of ibrutinib in patients with CLL with relapsed or refractory disease, with or without chromosome 17p deletion. In 2016, based on data from the RESONATE-17 study, the FDA approved ibrutinib for first-line therapy in patients with CLL.⁶

Ibrutinib’s efficacy, ease of administration and dosing (all doses are oral and fixed, rather than based on weight or body surface area), and relatively favorable safety profile have resulted in a rapid growth in its adoption.⁷ Since its adverse event (AE) profile is generally more tolerable than that of a typical chemoimmunotherapy, its use in older patients with CLL and patients with significant comorbidities is particularly appealing.⁸

However, the results of some clinical trials suggest an association between treatment with ibrutinib and an increased risk of bleeding-related events of any grade (44%) and major bleeding events (4%).^7,8 The incidence of major bleeding events was reported to be higher (9%) in one clinical trial and at 5-year follow-up, although this trial did not exclude patients receiving concomitant oral anticoagulation with warfarin.^6,9

Heterogeneity in clinical trials’ definitions of major bleeding confounded the ability to calculate bleeding risk in patients treated with ibrutinib in a systematic review and meta-analysis that called for more data.¹⁰ Additionally, patients with factors that might increase the risk of major bleeding with ibrutinib treatment were likely underrepresented in clinical trials, given the carefully selected nature of clinical trial subjects. These factors include renal or hepatic disease, gastrointestinal disease, and use of a number of concomitant medications such as antiplatelets or anticoagulant medications. Accounting for use of the latter is particularly important because patients who develop atrial fibrillation (Afib), one of the recognized AEs of treatment with ibrutinib, often are treated with anticoagulant medications in order to decrease the risk of stroke or other thromboembolic complications.

Methods

The VHA maintains the centralized US Department of Veterans Affairs Cancer Registry System (VACRS), with electronic medical record data and other sources captured in its Corporate Data Warehouse (CDW). The VHA CDW is a national repository comprising data from several VHA clinical and administrative systems. The CDW includes patient identifiers; demographics; vital status; lab information; administrative information (such as diagnostic International Statistical Classification of Diseases and Related Health Problems [ICD-9] codes); medication dispensation tables (such as outpatient fill); IV package information; and notes from radiology, pathology, outpatient and inpatient admission, discharge, and daily progress.

Registrars abstract all cancer cases within the VHA system (or diagnosed outside the VHA, if patients subsequently receive treatment in the VHA). It is estimated that VACRS captures 3% of cancer cases in the US.¹² Like most registries, VACRS captures data such as diagnosis, age, gender, race, and vital status.

Study Definitions

Prevalence of comorbidities that could increase bleeding risk was determined using administrative ICD-9-CM codes. Liver disease was identified by presence of cirrhosis, hepatitis C virus, or alcoholic liver disease using administrative codes validated by Kramer and colleagues, who reported positive and negative predictive values of 90% and 87% for cirrhosis, 93% and 92% for hepatitis C virus, and 71% and 98% for alcoholic liver disease.¹³ Similarly, end-stage liver disease was identified using a validated coding algorithm developed by Goldberg and colleagues, with a positive predictive value of 89.3%.¹⁴ The presence of controlled or uncontrolled diabetes mellitus (DM) was identified using the procedure described by Guzman and colleagues.¹⁵ Quan’s algorithm was used to calculate Charlson Comorbidity Index (CCI) based on ICD-9-CM codes for inpatient and outpatient visits within a 6-month lookback period prior to treatment initiation.¹⁶

A major bleeding event was defined as a hospitalization with an ICD-9-CM code suggestive of major bleeding as the primary reason, as defined by Lane and colleagues in their study of major bleeding related to warfarin in a cohort of patients treated within the VHA.¹⁷ Incidence rates of major bleeding events were identified during the first 6 months of treatment. Incidence of Afib—defined as an inpatient or outpatient encounter with the 427.31 ICD-9-CM code—also was examined within the first 6 months after starting treatment. The period of 6 months was chosen because bendamustine must be discontinued after 6 months.

Study Analysis

Descriptive statistics were used to examine patient demographics, disease characteristics, and treatment history from initial CLL diagnosis through end of study observation period. Categorical variables were summarized using frequencies and accompanying proportions, while a mean and standard deviation were used to summarize continuous variables. For the means of continuous variables and of categorical data, 95% CIs were used. Proportions and accompanying 95% CIs characterized treatment patterns, including line of therapy, comorbidities, and bleeding events. Treatment duration was described using mean and accompanying 95% CI. Statistical tests were not conducted for comparisons among treatment groups. Patients were censored at the end of follow-up, defined as the earliest of the following scenarios: (1) end of study observation period (December 31, 2016); (2) development of a secondary cancer; or (3) last day of contact given absence of care within the VHA for ≥ 18 months (with care defined as oncology and/or oncology/hematology visit with an associated note). Analysis was performed using R 3.4.0.

Results

Between 2010 and 2014, 2,796 patients were diagnosed and received care for CLL within the VHA. Overall, all 172 patients who were treated with ibrutinib during our inclusion period were selected. These patients were treated between January 1, 2014 and December 31, 2016, following ibrutinib’s approval in early 2014. An additional 291 patients were selected who received BR (Table). Reflecting the predominantly male population of the VHA, 282 (97%) BR patients and 167 (97%) ibrutinib patients were male. The median age at diagnosis was 67 years for BR patients and 69 years for ibrutinib patients. About 76% of patients who received ibrutinib and 82% of patients who received BR were non-Hispanic white; 17% and 14% were African American, respectively.

Less than 10% of patients receiving either ibrutinib or BR had liver disease per criteria used by Kramer and colleagues, or end-stage liver disease using criteria developed by Goldberg and colleagues.^12,13 About 5% of patients had a history of previous bleeding in the 6-month period prior to initiating either therapy. Mean CCI (excluding malignancy) score was 1.5 (range, 0-11) for the ibrutinib group, and 2.1 (range, 0-9) for the BR group. About 16% of the ibrutinib group had controlled DM and fewer than 10% had uncontrolled DM, while 4% of patients in the BR group met the criteria for controlled DM and another 4% met the criteria for uncontrolled DM.

There was very low utilization of anticoagulant or antiplatelet medication prior to initiation of ibrutinib (2.9% and 2.3%, respectively) or BR (< 1% each). In the first 6 months after treatment initiation, about 8% of patients in both ibrutinib and BR cohorts received anticoagulant medication while antiplatelet utilization was < 5% in either group.

In the BR group, 8 patients (2.7%) experienced a major bleeding event, while 14 patients (8.1%) in the ibrutinib group experienced a bleeding event (P = .008). While these numbers were too low to perform a formal statistical analysis of the association between clinical covariates and bleeding in either group, there did not seem to be an association between bleeding and liver disease or DM. Of patients who experienced a bleeding event, about 1 in 4 patients had had a prior bleeding event in both the ibrutinib and the BR groups. Interestingly, while none of the patients who experienced a bleeding event while receiving BR were taking concomitant anticoagulant medication, 3 of the 14 patients who experienced a bleeding event in the ibrutinib group showed evidence of anticoagulant utilization. Finally, the incidence of Afib (defined as patients with no evidence of Afib in the 6 months prior to treatment but with evidence of Afib in the 6 months following treatment initiation) was 4% in the BR group, and about 8% in the ibrutinib group (P = .003).

Discussion

To the authors’ knowledge, this study is the first to examine the real-world incidence of bleeding and Afib in veterans who received ibrutinib for CLL in the first year of its availability. The study found minimal use of anticoagulants and/or antiplatelet agents prior to receiving first-line ibrutinib or BR, and very low use of these agents in the first 6 months following the initiation of first-line treatment. This finding suggests a high awareness among VA providers of potential adverse effects (AEs) of ibrutinib and chemotherapy, and a careful selection of patients that lack risk factors for AEs.

In patients treated with first-line ibrutinib when compared with patients treated with first-line BR, moderate increases in bleeding (2.7% vs 8.1%, P = .008) and Afib (10.5% vs 3%, P = .003) also were observed. These results are concordant with previous findings examining the use of ibrutinib in patients with CLL.^18-20

Limitations

The results of this study should be interpreted with caution, as some limitations must be considered. The study was conducted in the early days of ibrutinib adoption. Since then, more patients have been treated with ibrutinib and for longer durations. As clinicians gain more familiarity and with ibrutinib, and as additional novel therapeutics emerge, it is possible that the initial awareness about risks for possible AEs may diminish; patients with high comorbidity burdens and concomitant medications would be especially vulnerable in cases of reduced physician vigilance.

Another limitation of this study stems from the potential for dual system use among patients treated in the VHA. Concurrent or alternating use of multiple health care systems (use of VHA and private-sector facilities) may present gaps in the reconstruction of patient histories, resulting in missing data as patients transition between commercial, the Centers for Medicare and Medicaid Services, and VHA care. As a result, the results presented here do not reflect instances where a patient experienced a bleeding event treated outside the VA.

Problems with missing data also may occur due to incomplete extraction from the electronic health record; these issues were addressed by leveraging an understanding of the multiple data marts within the CDW environment to harmonize missing and/or erroneous information through use of other data marts when possible. Lastly, this research represents a population-level study of the VHA, thus all findings are directly relevant to the VHA. The generalizability of the findings outside the VHA would depend on the characteristics of the external population.

Conclusion

Real-world evidence from a nationwide cohort of veteran patients with CLL treated with ibrutinib suggest that, while there is an association of increased bleeding-related events and Afib, the risk is comparable to those reported in previous studies.^18-20 These findings suggest that patients in real-world clinical care settings with higher levels of comorbidities may be at a slight increased risk for bleeding events and Afib.

Chronic lymphocytic leukemia (CLL) is the most common leukemia diagnosed in developed countries, with an estimated 21,040 new diagnoses of CLL expected in the US in 2020. ^1-3 CLL is an indolent cancer characterized by the accumulation of B-lymphocytes in the blood, marrow, and lymphoid tissues. ⁴ It has a heterogeneous clinical course; the majority of patients are observed or receive delayed treatment following diagnosis, while a minority of patients require immediate treatment. After first-line treatment, some patients experience prolonged remissions while others require retreatment within 1 or 2 years. Fortunately, advances in cancer biology and therapeutics in the last decade have increased the number of treatment options available for patients with CLL.

Until recently, most CLL treatments relied on a chemotherapy or a chemoimmunotherapy backbone; however, the last few years have seen novel therapies introduced, such as small molecule inhibitors to target molecular pathways that promote the normal development, expansion, and survival of B-cells.⁵ One such therapy is ibrutinib, a targeted Bruton tyrosine kinase inhibitor that received accelerated approval by the US Food and Drug Administration (FDA) in February 2014 for patients with CLL who received at least 1 prior therapy. The FDA later expanded this approval to include use of ibrutinib in patients with CLL with relapsed or refractory disease, with or without chromosome 17p deletion. In 2016, based on data from the RESONATE-17 study, the FDA approved ibrutinib for first-line therapy in patients with CLL.⁶

Ibrutinib’s efficacy, ease of administration and dosing (all doses are oral and fixed, rather than based on weight or body surface area), and relatively favorable safety profile have resulted in a rapid growth in its adoption.⁷ Since its adverse event (AE) profile is generally more tolerable than that of a typical chemoimmunotherapy, its use in older patients with CLL and patients with significant comorbidities is particularly appealing.⁸

However, the results of some clinical trials suggest an association between treatment with ibrutinib and an increased risk of bleeding-related events of any grade (44%) and major bleeding events (4%).^7,8 The incidence of major bleeding events was reported to be higher (9%) in one clinical trial and at 5-year follow-up, although this trial did not exclude patients receiving concomitant oral anticoagulation with warfarin.^6,9

Heterogeneity in clinical trials’ definitions of major bleeding confounded the ability to calculate bleeding risk in patients treated with ibrutinib in a systematic review and meta-analysis that called for more data.¹⁰ Additionally, patients with factors that might increase the risk of major bleeding with ibrutinib treatment were likely underrepresented in clinical trials, given the carefully selected nature of clinical trial subjects. These factors include renal or hepatic disease, gastrointestinal disease, and use of a number of concomitant medications such as antiplatelets or anticoagulant medications. Accounting for use of the latter is particularly important because patients who develop atrial fibrillation (Afib), one of the recognized AEs of treatment with ibrutinib, often are treated with anticoagulant medications in order to decrease the risk of stroke or other thromboembolic complications.

Methods

The VHA maintains the centralized US Department of Veterans Affairs Cancer Registry System (VACRS), with electronic medical record data and other sources captured in its Corporate Data Warehouse (CDW). The VHA CDW is a national repository comprising data from several VHA clinical and administrative systems. The CDW includes patient identifiers; demographics; vital status; lab information; administrative information (such as diagnostic International Statistical Classification of Diseases and Related Health Problems [ICD-9] codes); medication dispensation tables (such as outpatient fill); IV package information; and notes from radiology, pathology, outpatient and inpatient admission, discharge, and daily progress.

Registrars abstract all cancer cases within the VHA system (or diagnosed outside the VHA, if patients subsequently receive treatment in the VHA). It is estimated that VACRS captures 3% of cancer cases in the US.¹² Like most registries, VACRS captures data such as diagnosis, age, gender, race, and vital status.

Study Definitions

Prevalence of comorbidities that could increase bleeding risk was determined using administrative ICD-9-CM codes. Liver disease was identified by presence of cirrhosis, hepatitis C virus, or alcoholic liver disease using administrative codes validated by Kramer and colleagues, who reported positive and negative predictive values of 90% and 87% for cirrhosis, 93% and 92% for hepatitis C virus, and 71% and 98% for alcoholic liver disease.¹³ Similarly, end-stage liver disease was identified using a validated coding algorithm developed by Goldberg and colleagues, with a positive predictive value of 89.3%.¹⁴ The presence of controlled or uncontrolled diabetes mellitus (DM) was identified using the procedure described by Guzman and colleagues.¹⁵ Quan’s algorithm was used to calculate Charlson Comorbidity Index (CCI) based on ICD-9-CM codes for inpatient and outpatient visits within a 6-month lookback period prior to treatment initiation.¹⁶

A major bleeding event was defined as a hospitalization with an ICD-9-CM code suggestive of major bleeding as the primary reason, as defined by Lane and colleagues in their study of major bleeding related to warfarin in a cohort of patients treated within the VHA.¹⁷ Incidence rates of major bleeding events were identified during the first 6 months of treatment. Incidence of Afib—defined as an inpatient or outpatient encounter with the 427.31 ICD-9-CM code—also was examined within the first 6 months after starting treatment. The period of 6 months was chosen because bendamustine must be discontinued after 6 months.

Study Analysis

Descriptive statistics were used to examine patient demographics, disease characteristics, and treatment history from initial CLL diagnosis through end of study observation period. Categorical variables were summarized using frequencies and accompanying proportions, while a mean and standard deviation were used to summarize continuous variables. For the means of continuous variables and of categorical data, 95% CIs were used. Proportions and accompanying 95% CIs characterized treatment patterns, including line of therapy, comorbidities, and bleeding events. Treatment duration was described using mean and accompanying 95% CI. Statistical tests were not conducted for comparisons among treatment groups. Patients were censored at the end of follow-up, defined as the earliest of the following scenarios: (1) end of study observation period (December 31, 2016); (2) development of a secondary cancer; or (3) last day of contact given absence of care within the VHA for ≥ 18 months (with care defined as oncology and/or oncology/hematology visit with an associated note). Analysis was performed using R 3.4.0.

Results

Between 2010 and 2014, 2,796 patients were diagnosed and received care for CLL within the VHA. Overall, all 172 patients who were treated with ibrutinib during our inclusion period were selected. These patients were treated between January 1, 2014 and December 31, 2016, following ibrutinib’s approval in early 2014. An additional 291 patients were selected who received BR (Table). Reflecting the predominantly male population of the VHA, 282 (97%) BR patients and 167 (97%) ibrutinib patients were male. The median age at diagnosis was 67 years for BR patients and 69 years for ibrutinib patients. About 76% of patients who received ibrutinib and 82% of patients who received BR were non-Hispanic white; 17% and 14% were African American, respectively.

Less than 10% of patients receiving either ibrutinib or BR had liver disease per criteria used by Kramer and colleagues, or end-stage liver disease using criteria developed by Goldberg and colleagues.^12,13 About 5% of patients had a history of previous bleeding in the 6-month period prior to initiating either therapy. Mean CCI (excluding malignancy) score was 1.5 (range, 0-11) for the ibrutinib group, and 2.1 (range, 0-9) for the BR group. About 16% of the ibrutinib group had controlled DM and fewer than 10% had uncontrolled DM, while 4% of patients in the BR group met the criteria for controlled DM and another 4% met the criteria for uncontrolled DM.

There was very low utilization of anticoagulant or antiplatelet medication prior to initiation of ibrutinib (2.9% and 2.3%, respectively) or BR (< 1% each). In the first 6 months after treatment initiation, about 8% of patients in both ibrutinib and BR cohorts received anticoagulant medication while antiplatelet utilization was < 5% in either group.

In the BR group, 8 patients (2.7%) experienced a major bleeding event, while 14 patients (8.1%) in the ibrutinib group experienced a bleeding event (P = .008). While these numbers were too low to perform a formal statistical analysis of the association between clinical covariates and bleeding in either group, there did not seem to be an association between bleeding and liver disease or DM. Of patients who experienced a bleeding event, about 1 in 4 patients had had a prior bleeding event in both the ibrutinib and the BR groups. Interestingly, while none of the patients who experienced a bleeding event while receiving BR were taking concomitant anticoagulant medication, 3 of the 14 patients who experienced a bleeding event in the ibrutinib group showed evidence of anticoagulant utilization. Finally, the incidence of Afib (defined as patients with no evidence of Afib in the 6 months prior to treatment but with evidence of Afib in the 6 months following treatment initiation) was 4% in the BR group, and about 8% in the ibrutinib group (P = .003).

Discussion

To the authors’ knowledge, this study is the first to examine the real-world incidence of bleeding and Afib in veterans who received ibrutinib for CLL in the first year of its availability. The study found minimal use of anticoagulants and/or antiplatelet agents prior to receiving first-line ibrutinib or BR, and very low use of these agents in the first 6 months following the initiation of first-line treatment. This finding suggests a high awareness among VA providers of potential adverse effects (AEs) of ibrutinib and chemotherapy, and a careful selection of patients that lack risk factors for AEs.

In patients treated with first-line ibrutinib when compared with patients treated with first-line BR, moderate increases in bleeding (2.7% vs 8.1%, P = .008) and Afib (10.5% vs 3%, P = .003) also were observed. These results are concordant with previous findings examining the use of ibrutinib in patients with CLL.^18-20

Limitations

The results of this study should be interpreted with caution, as some limitations must be considered. The study was conducted in the early days of ibrutinib adoption. Since then, more patients have been treated with ibrutinib and for longer durations. As clinicians gain more familiarity and with ibrutinib, and as additional novel therapeutics emerge, it is possible that the initial awareness about risks for possible AEs may diminish; patients with high comorbidity burdens and concomitant medications would be especially vulnerable in cases of reduced physician vigilance.

Another limitation of this study stems from the potential for dual system use among patients treated in the VHA. Concurrent or alternating use of multiple health care systems (use of VHA and private-sector facilities) may present gaps in the reconstruction of patient histories, resulting in missing data as patients transition between commercial, the Centers for Medicare and Medicaid Services, and VHA care. As a result, the results presented here do not reflect instances where a patient experienced a bleeding event treated outside the VA.

Problems with missing data also may occur due to incomplete extraction from the electronic health record; these issues were addressed by leveraging an understanding of the multiple data marts within the CDW environment to harmonize missing and/or erroneous information through use of other data marts when possible. Lastly, this research represents a population-level study of the VHA, thus all findings are directly relevant to the VHA. The generalizability of the findings outside the VHA would depend on the characteristics of the external population.

Conclusion

Real-world evidence from a nationwide cohort of veteran patients with CLL treated with ibrutinib suggest that, while there is an association of increased bleeding-related events and Afib, the risk is comparable to those reported in previous studies.^18-20 These findings suggest that patients in real-world clinical care settings with higher levels of comorbidities may be at a slight increased risk for bleeding events and Afib.

Lung cancer is the leading cause of cancer mortality both in the US and worldwide.¹ Many patients diagnosed with lung cancer present with advanced disease with thoracic symptoms such as cough, hemoptysis, dyspnea, and chest pain.^2-4 Palliative radiotherapy is routinely used in patients with locally advanced and metastatic lung cancer with the goal of relieving these symptoms and improving quality of life. Guidelines published by the American Society for Radiation Oncology (ASTRO) in 2011, and updated in 2018, provide recommendations on palliation of lung cancer with external beam radiotherapy (EBRT) and clarify the roles of concurrent chemotherapy and endobronchial brachytherapy (EBB) for palliation.^5,6

After prostate cancer, lung cancer is the second most frequently diagnosed cancer in the Veterans Health Administration (VHA).⁷ The VHA consists of 172 medical centers and is the largest integrated health care system in the US. At the time of this study, 40 of these centers had onsite radiation facilities. The VHA Palliative Radiation Taskforce has conducted a series of surveys to evaluate use of palliative radiotherapy in the VHA, determine VHA practice concordance with ASTRO and American College of Radiology (ACR) guidelines, and direct educational efforts towards addressing gaps in knowledge. These efforts are directed at ensuring best practices throughout this large and heterogeneous healthcare system. In 2016 a survey was conducted to evaluate concordance of VHA radiation oncologist (RO) practice with the 2011 ASTRO guidelines on palliative thoracic radiotherapy for non-small cell lung cancer (NSCLC).

Methods

A survey instrument was generated by VHA National Palliative Radiotherapy Taskforce members. It was reviewed and approved for use by the VHA Patient Care Services office. In May of 2016, the online survey was sent to the 88 VHA ROs practicing at the 40 sites with onsite radiation facilities. The survey aimed to determine patterns of practice for palliation of thoracic symptoms secondary to lung cancer.

Demographic information obtained included years in practice, employment status, academic appointment, board certification, and familiarity with ASTRO lung cancer guidelines. Two clinical scenarios were presented to glean opinions on dose/fractionation schemes preferred, use of concurrent chemotherapy, and use of EBB and/or yttrium aluminum garnet (YAG) laser technology. Survey questions also assessed use of EBRT for palliation of hemoptysis, chest wall pain, and/or stridor as well as use of stereotactic body radiotherapy (SBRT) for palliation.

Survey results were assessed for concordance with published ASTRO guidelines. χ² tests were run to test for associations between demographic factors such as academic appointment, years of practice, full time vs part time employment, and familiarity with ASTRO palliative lung cancer guidelines, with use of EBRT for palliation, dose and fractionation preference, use of concurrent chemotherapy, and strategy for management of endobronchial lesions.

Results

Of the 88 physicians surveyed, 54 responded for a response rate of 61%. Respondents represented 37 of the 40 (93%) VHA radiation oncology departments (Table 1). Among respondents, most were board certified (96%), held academic appointments (91%), and were full-time employees (85%). Forty-four percent of respondents were in practice for > 20 years, 19% for 11 to 20 years, 20% for 6 to 10 years, and 17% for < 6 years. A majority reported familiarity with the ASTRO guidelines (64%), while just 11% reported no familiarity with the guidelines.

When asked about use of SBRT for palliation of hemoptysis, stridor, and/or chest pain, the majority (87%) preferred conventional EBRT. Of the 13% who reported use of SBRT, most (11%) performed it onsite, with 2% of respondents referring offsite to non-VHA centers for the service. When asked about use of EBB for palliation, only 2% reported use of that procedure at their facilities, while 26% reported referral to non-VHA facilities for EBB. The remaining 72% of respondents favor use of conventional EBRT.

Respondents were presented with a case of a male patient aged 70 years who smoked and had widely metastatic NSCLC, a life expectancy of about 3 months, and 10/10 chest wall pain from direct tumor invasion. All respondents recommended palliative radiotherapy. The preferred fractionation was 20 Gray (Gy) in 5 fractions, which was recommended by 69% of respondents. The remainder recommended 30 Gy in 10 fractions (22%) or a single fraction of 10 Gy (9%). No respondent recommended the longer fractionation options of 60 Gy in 30 fractions, 45 Gy in 15 fractions, or 40 Gy in 20 fractions. The majority (98%) did not recommend concurrent chemotherapy.

When the above case was modified for an endobronchial lesion requiring palliation with associated lung collapse, rather than chest wall invasion, 20 respondents (38%) reported they would refer for EBB, and 20 respondents reported they would refer for YAG laser. As > 1 answer could be selected for this question, there were 12 respondents who selected both EBB and YAG laser; 8 selected only EBB, and 8 selected only YAG laser. Many respondents added comments about treating with EBRT, which had not been presented as an answer choice. Nearly half of respondents (49%) were amenable to referral for the use of EBB or YAG laser for lung reexpansion prior to radiotherapy. Three respondents mentioned referral for an endobronchial stent prior to palliative radiotherapy to address this question.

Discussion

This survey was conducted to evaluate concordance of management of metastatic lung cancer in the VHA with ASTRO guidelines. The relationship between respondents’ familiarity with the guidelines and responses also was evaluated to determine the impact such guidelines have on decision-making. The ASTRO guidelines for palliative thoracic radiation make recommendations regarding 3 issues: (1) radiation doses and fractionations for palliation; (2) the role of EBB; and (3) the use of concurrent chemotherapy.^5,6

Radiation Dose and Fractionation for Palliation

A variety of dose/fractionation schemes are considered appropriate in the ASTRO guideline statement, including more prolonged courses such as 30 Gy/10 fractions as well as more hypofractionated regimens (ie, 20 Gy/5 fractions, 17 Gy/2 fractions, and a single fraction of 10 Gy). Higher dose regimens, such as 30 Gy/10 fractions, have been associated with prolonged survival, as well as increased toxicities such as radiation esophagitis.⁸ Therefore, the guidelines support use of 30 Gy/10 fractions for patients with good performance status while encouraging use of more hypofractionated regimens for patients with poor performance status. In considering more hypofractionated regimens, one must consider the possibility of adverse effects that can be associated with higher dose per fraction. For instance, 17 Gy/2 fractions has been associated with myelopathy; therefore it should be used with caution and careful treatment planning.⁹

For the survey case example (a male aged 70 years with a 3-month life expectancy who required palliation for chest wall pain), all respondents selected hypofractionated regimens; with no respondent selected the more prolonged fractionations of 60 Gy/30 fractions, 45 Gy/15 fractions, or 40 Gy/20 fractions. These more prolonged fractionations are not endorsed by the guidelines in general, and particularly not for a patient with poor life expectancy. All responses for this case selected by survey respondents are considered appropriate per the consensus guideline statement.

Role of Concurrent Chemotherapy

The ASTRO guidelines do not support use of concurrent chemotherapy for palliation of stage IV NSCLC.^5,6 The 2018 updated guidelines established a role for concurrent chemotherapy for patients with stage III NSCLC with good performance status and life expectancy of > 3 months. This updated recommendation is based on data from 2 randomized trials demonstrating improvement in overall survival with the addition of chemotherapy for patients with stage III NSCLC undergoing palliative radiotherapy.^10-12

These newer studies are in contrast to an older randomized study by Ball and colleagues that demonstrated greater toxicity from concurrent chemotherapy, with no improvement in outcomes such as palliation of symptoms, overall survival, or progression free survival.¹³ In contrast to the newer studies that included only patients with stage III NSCLC, about half of the patients in the Ball and colleagues study had known metastatic disease.^10-13 Of note, staging for metastatic disease was not carried out routinely, so it is possible that a greater proportion of patients had metastatic disease that would have been seen on imaging. In concordance with the guidelines, 98% of the survey respondents did not recommend concurrent chemotherapy for palliation of intrathoracic symptom; only 1 respondent recommended use of chemotherapy for palliation.

Role of Endobronchial Brachytherapy

EBB involves implantation of radioactive sources for treatment of endobronchial lesions causing obstructive symptoms.¹⁴ Given the lack of randomized data that demonstrate a benefit of EBB over EBRT, the ASTRO guidelines do not endorse routine use of EBB for initial palliative management.^15,16 The ASTRO guidelines reference a Cochrane Review of 13 trials that concluded that EBRT alone is superior to EBB alone for initial palliation of symptoms from endobronchial NSCLC.¹⁷

Of respondents surveyed, only 1 facility offered onsite EBB. The majority of respondents (72%) preferred the use of conventional EBRT techniques, while 26% refer to non-VHA centers for EBB. Lack of incorporation of EBB into routine VHA practice likely is a reflection of the unclear role of this technology based on the available literature and ASTRO guidelines. In the setting of a right lower lung collapse, more respondents (49%) would consider use of EBB or YAG laser technology for lung reexpansion prior to EBRT.

The ASTRO guidelines recommend that initial EBB in conjunction with EBRT be considered based on randomized data demonstrating significant improvement in lung reexpansion and in patient reported dyspnea with addition of EBB to EBRT over EBRT alone.¹⁸ However, the guidelines do not mandate the use of EBB in this situation. It is possible that targeted education regarding the role of EBB would improve knowledge of the potential benefit in the setting of lung collapse and increase the percentage of VHA ROs who would recommend this procedure.

Limitations

The study is limited by lack of generalizability of these findings to all ROs in the country. It is also possible that physician responses do not represent practice patterns with complete accuracy. The use of EBB varied among practitioners. Further study of this technology is necessary to clarify its role in the management of endobronchial obstructive symptoms and to determine whether efforts should be made to increase access to EBB within the VHA.

Conclusions

Most of the ROs who responded to our survey were cognizant and compliant with current ASTRO guidelines on management of lung cancer. Furthermore, familiarity with ASTRO guidelines and management choices were not associated with the respondents’ years in practice, academic appointment, full-time vs part-time status, or familiarity with ASTRO guidelines. This study is a nationwide survey of ROs in the VHA system that reflects the radiation-related care received by veterans with metastatic lung cancer. Responses were obtained from 93% of the 40 radiation oncology centers, so it is likely that the survey accurately represents the decision-making process at the majority of centers. It is possible that those who did not respond to the survey do not treat thoracic cases.

Lung cancer is the leading cause of cancer mortality both in the US and worldwide.¹ Many patients diagnosed with lung cancer present with advanced disease with thoracic symptoms such as cough, hemoptysis, dyspnea, and chest pain.^2-4 Palliative radiotherapy is routinely used in patients with locally advanced and metastatic lung cancer with the goal of relieving these symptoms and improving quality of life. Guidelines published by the American Society for Radiation Oncology (ASTRO) in 2011, and updated in 2018, provide recommendations on palliation of lung cancer with external beam radiotherapy (EBRT) and clarify the roles of concurrent chemotherapy and endobronchial brachytherapy (EBB) for palliation.^5,6

After prostate cancer, lung cancer is the second most frequently diagnosed cancer in the Veterans Health Administration (VHA).⁷ The VHA consists of 172 medical centers and is the largest integrated health care system in the US. At the time of this study, 40 of these centers had onsite radiation facilities. The VHA Palliative Radiation Taskforce has conducted a series of surveys to evaluate use of palliative radiotherapy in the VHA, determine VHA practice concordance with ASTRO and American College of Radiology (ACR) guidelines, and direct educational efforts towards addressing gaps in knowledge. These efforts are directed at ensuring best practices throughout this large and heterogeneous healthcare system. In 2016 a survey was conducted to evaluate concordance of VHA radiation oncologist (RO) practice with the 2011 ASTRO guidelines on palliative thoracic radiotherapy for non-small cell lung cancer (NSCLC).

Methods

A survey instrument was generated by VHA National Palliative Radiotherapy Taskforce members. It was reviewed and approved for use by the VHA Patient Care Services office. In May of 2016, the online survey was sent to the 88 VHA ROs practicing at the 40 sites with onsite radiation facilities. The survey aimed to determine patterns of practice for palliation of thoracic symptoms secondary to lung cancer.

Demographic information obtained included years in practice, employment status, academic appointment, board certification, and familiarity with ASTRO lung cancer guidelines. Two clinical scenarios were presented to glean opinions on dose/fractionation schemes preferred, use of concurrent chemotherapy, and use of EBB and/or yttrium aluminum garnet (YAG) laser technology. Survey questions also assessed use of EBRT for palliation of hemoptysis, chest wall pain, and/or stridor as well as use of stereotactic body radiotherapy (SBRT) for palliation.

Survey results were assessed for concordance with published ASTRO guidelines. χ² tests were run to test for associations between demographic factors such as academic appointment, years of practice, full time vs part time employment, and familiarity with ASTRO palliative lung cancer guidelines, with use of EBRT for palliation, dose and fractionation preference, use of concurrent chemotherapy, and strategy for management of endobronchial lesions.

Results

Of the 88 physicians surveyed, 54 responded for a response rate of 61%. Respondents represented 37 of the 40 (93%) VHA radiation oncology departments (Table 1). Among respondents, most were board certified (96%), held academic appointments (91%), and were full-time employees (85%). Forty-four percent of respondents were in practice for > 20 years, 19% for 11 to 20 years, 20% for 6 to 10 years, and 17% for < 6 years. A majority reported familiarity with the ASTRO guidelines (64%), while just 11% reported no familiarity with the guidelines.

When asked about use of SBRT for palliation of hemoptysis, stridor, and/or chest pain, the majority (87%) preferred conventional EBRT. Of the 13% who reported use of SBRT, most (11%) performed it onsite, with 2% of respondents referring offsite to non-VHA centers for the service. When asked about use of EBB for palliation, only 2% reported use of that procedure at their facilities, while 26% reported referral to non-VHA facilities for EBB. The remaining 72% of respondents favor use of conventional EBRT.

Respondents were presented with a case of a male patient aged 70 years who smoked and had widely metastatic NSCLC, a life expectancy of about 3 months, and 10/10 chest wall pain from direct tumor invasion. All respondents recommended palliative radiotherapy. The preferred fractionation was 20 Gray (Gy) in 5 fractions, which was recommended by 69% of respondents. The remainder recommended 30 Gy in 10 fractions (22%) or a single fraction of 10 Gy (9%). No respondent recommended the longer fractionation options of 60 Gy in 30 fractions, 45 Gy in 15 fractions, or 40 Gy in 20 fractions. The majority (98%) did not recommend concurrent chemotherapy.

When the above case was modified for an endobronchial lesion requiring palliation with associated lung collapse, rather than chest wall invasion, 20 respondents (38%) reported they would refer for EBB, and 20 respondents reported they would refer for YAG laser. As > 1 answer could be selected for this question, there were 12 respondents who selected both EBB and YAG laser; 8 selected only EBB, and 8 selected only YAG laser. Many respondents added comments about treating with EBRT, which had not been presented as an answer choice. Nearly half of respondents (49%) were amenable to referral for the use of EBB or YAG laser for lung reexpansion prior to radiotherapy. Three respondents mentioned referral for an endobronchial stent prior to palliative radiotherapy to address this question.

Discussion

This survey was conducted to evaluate concordance of management of metastatic lung cancer in the VHA with ASTRO guidelines. The relationship between respondents’ familiarity with the guidelines and responses also was evaluated to determine the impact such guidelines have on decision-making. The ASTRO guidelines for palliative thoracic radiation make recommendations regarding 3 issues: (1) radiation doses and fractionations for palliation; (2) the role of EBB; and (3) the use of concurrent chemotherapy.^5,6

Radiation Dose and Fractionation for Palliation

A variety of dose/fractionation schemes are considered appropriate in the ASTRO guideline statement, including more prolonged courses such as 30 Gy/10 fractions as well as more hypofractionated regimens (ie, 20 Gy/5 fractions, 17 Gy/2 fractions, and a single fraction of 10 Gy). Higher dose regimens, such as 30 Gy/10 fractions, have been associated with prolonged survival, as well as increased toxicities such as radiation esophagitis.⁸ Therefore, the guidelines support use of 30 Gy/10 fractions for patients with good performance status while encouraging use of more hypofractionated regimens for patients with poor performance status. In considering more hypofractionated regimens, one must consider the possibility of adverse effects that can be associated with higher dose per fraction. For instance, 17 Gy/2 fractions has been associated with myelopathy; therefore it should be used with caution and careful treatment planning.⁹

For the survey case example (a male aged 70 years with a 3-month life expectancy who required palliation for chest wall pain), all respondents selected hypofractionated regimens; with no respondent selected the more prolonged fractionations of 60 Gy/30 fractions, 45 Gy/15 fractions, or 40 Gy/20 fractions. These more prolonged fractionations are not endorsed by the guidelines in general, and particularly not for a patient with poor life expectancy. All responses for this case selected by survey respondents are considered appropriate per the consensus guideline statement.

Role of Concurrent Chemotherapy

The ASTRO guidelines do not support use of concurrent chemotherapy for palliation of stage IV NSCLC.^5,6 The 2018 updated guidelines established a role for concurrent chemotherapy for patients with stage III NSCLC with good performance status and life expectancy of > 3 months. This updated recommendation is based on data from 2 randomized trials demonstrating improvement in overall survival with the addition of chemotherapy for patients with stage III NSCLC undergoing palliative radiotherapy.^10-12

These newer studies are in contrast to an older randomized study by Ball and colleagues that demonstrated greater toxicity from concurrent chemotherapy, with no improvement in outcomes such as palliation of symptoms, overall survival, or progression free survival.¹³ In contrast to the newer studies that included only patients with stage III NSCLC, about half of the patients in the Ball and colleagues study had known metastatic disease.^10-13 Of note, staging for metastatic disease was not carried out routinely, so it is possible that a greater proportion of patients had metastatic disease that would have been seen on imaging. In concordance with the guidelines, 98% of the survey respondents did not recommend concurrent chemotherapy for palliation of intrathoracic symptom; only 1 respondent recommended use of chemotherapy for palliation.

Role of Endobronchial Brachytherapy

EBB involves implantation of radioactive sources for treatment of endobronchial lesions causing obstructive symptoms.¹⁴ Given the lack of randomized data that demonstrate a benefit of EBB over EBRT, the ASTRO guidelines do not endorse routine use of EBB for initial palliative management.^15,16 The ASTRO guidelines reference a Cochrane Review of 13 trials that concluded that EBRT alone is superior to EBB alone for initial palliation of symptoms from endobronchial NSCLC.¹⁷

Of respondents surveyed, only 1 facility offered onsite EBB. The majority of respondents (72%) preferred the use of conventional EBRT techniques, while 26% refer to non-VHA centers for EBB. Lack of incorporation of EBB into routine VHA practice likely is a reflection of the unclear role of this technology based on the available literature and ASTRO guidelines. In the setting of a right lower lung collapse, more respondents (49%) would consider use of EBB or YAG laser technology for lung reexpansion prior to EBRT.

The ASTRO guidelines recommend that initial EBB in conjunction with EBRT be considered based on randomized data demonstrating significant improvement in lung reexpansion and in patient reported dyspnea with addition of EBB to EBRT over EBRT alone.¹⁸ However, the guidelines do not mandate the use of EBB in this situation. It is possible that targeted education regarding the role of EBB would improve knowledge of the potential benefit in the setting of lung collapse and increase the percentage of VHA ROs who would recommend this procedure.

Limitations

The study is limited by lack of generalizability of these findings to all ROs in the country. It is also possible that physician responses do not represent practice patterns with complete accuracy. The use of EBB varied among practitioners. Further study of this technology is necessary to clarify its role in the management of endobronchial obstructive symptoms and to determine whether efforts should be made to increase access to EBB within the VHA.

Conclusions

Most of the ROs who responded to our survey were cognizant and compliant with current ASTRO guidelines on management of lung cancer. Furthermore, familiarity with ASTRO guidelines and management choices were not associated with the respondents’ years in practice, academic appointment, full-time vs part-time status, or familiarity with ASTRO guidelines. This study is a nationwide survey of ROs in the VHA system that reflects the radiation-related care received by veterans with metastatic lung cancer. Responses were obtained from 93% of the 40 radiation oncology centers, so it is likely that the survey accurately represents the decision-making process at the majority of centers. It is possible that those who did not respond to the survey do not treat thoracic cases.

Lung cancer is the leading cause of cancer mortality both in the US and worldwide.¹ Many patients diagnosed with lung cancer present with advanced disease with thoracic symptoms such as cough, hemoptysis, dyspnea, and chest pain.^2-4 Palliative radiotherapy is routinely used in patients with locally advanced and metastatic lung cancer with the goal of relieving these symptoms and improving quality of life. Guidelines published by the American Society for Radiation Oncology (ASTRO) in 2011, and updated in 2018, provide recommendations on palliation of lung cancer with external beam radiotherapy (EBRT) and clarify the roles of concurrent chemotherapy and endobronchial brachytherapy (EBB) for palliation.^5,6

After prostate cancer, lung cancer is the second most frequently diagnosed cancer in the Veterans Health Administration (VHA).⁷ The VHA consists of 172 medical centers and is the largest integrated health care system in the US. At the time of this study, 40 of these centers had onsite radiation facilities. The VHA Palliative Radiation Taskforce has conducted a series of surveys to evaluate use of palliative radiotherapy in the VHA, determine VHA practice concordance with ASTRO and American College of Radiology (ACR) guidelines, and direct educational efforts towards addressing gaps in knowledge. These efforts are directed at ensuring best practices throughout this large and heterogeneous healthcare system. In 2016 a survey was conducted to evaluate concordance of VHA radiation oncologist (RO) practice with the 2011 ASTRO guidelines on palliative thoracic radiotherapy for non-small cell lung cancer (NSCLC).

Methods

A survey instrument was generated by VHA National Palliative Radiotherapy Taskforce members. It was reviewed and approved for use by the VHA Patient Care Services office. In May of 2016, the online survey was sent to the 88 VHA ROs practicing at the 40 sites with onsite radiation facilities. The survey aimed to determine patterns of practice for palliation of thoracic symptoms secondary to lung cancer.

Demographic information obtained included years in practice, employment status, academic appointment, board certification, and familiarity with ASTRO lung cancer guidelines. Two clinical scenarios were presented to glean opinions on dose/fractionation schemes preferred, use of concurrent chemotherapy, and use of EBB and/or yttrium aluminum garnet (YAG) laser technology. Survey questions also assessed use of EBRT for palliation of hemoptysis, chest wall pain, and/or stridor as well as use of stereotactic body radiotherapy (SBRT) for palliation.

Survey results were assessed for concordance with published ASTRO guidelines. χ² tests were run to test for associations between demographic factors such as academic appointment, years of practice, full time vs part time employment, and familiarity with ASTRO palliative lung cancer guidelines, with use of EBRT for palliation, dose and fractionation preference, use of concurrent chemotherapy, and strategy for management of endobronchial lesions.

Results

Of the 88 physicians surveyed, 54 responded for a response rate of 61%. Respondents represented 37 of the 40 (93%) VHA radiation oncology departments (Table 1). Among respondents, most were board certified (96%), held academic appointments (91%), and were full-time employees (85%). Forty-four percent of respondents were in practice for > 20 years, 19% for 11 to 20 years, 20% for 6 to 10 years, and 17% for < 6 years. A majority reported familiarity with the ASTRO guidelines (64%), while just 11% reported no familiarity with the guidelines.

When asked about use of SBRT for palliation of hemoptysis, stridor, and/or chest pain, the majority (87%) preferred conventional EBRT. Of the 13% who reported use of SBRT, most (11%) performed it onsite, with 2% of respondents referring offsite to non-VHA centers for the service. When asked about use of EBB for palliation, only 2% reported use of that procedure at their facilities, while 26% reported referral to non-VHA facilities for EBB. The remaining 72% of respondents favor use of conventional EBRT.

Respondents were presented with a case of a male patient aged 70 years who smoked and had widely metastatic NSCLC, a life expectancy of about 3 months, and 10/10 chest wall pain from direct tumor invasion. All respondents recommended palliative radiotherapy. The preferred fractionation was 20 Gray (Gy) in 5 fractions, which was recommended by 69% of respondents. The remainder recommended 30 Gy in 10 fractions (22%) or a single fraction of 10 Gy (9%). No respondent recommended the longer fractionation options of 60 Gy in 30 fractions, 45 Gy in 15 fractions, or 40 Gy in 20 fractions. The majority (98%) did not recommend concurrent chemotherapy.

When the above case was modified for an endobronchial lesion requiring palliation with associated lung collapse, rather than chest wall invasion, 20 respondents (38%) reported they would refer for EBB, and 20 respondents reported they would refer for YAG laser. As > 1 answer could be selected for this question, there were 12 respondents who selected both EBB and YAG laser; 8 selected only EBB, and 8 selected only YAG laser. Many respondents added comments about treating with EBRT, which had not been presented as an answer choice. Nearly half of respondents (49%) were amenable to referral for the use of EBB or YAG laser for lung reexpansion prior to radiotherapy. Three respondents mentioned referral for an endobronchial stent prior to palliative radiotherapy to address this question.

Discussion

This survey was conducted to evaluate concordance of management of metastatic lung cancer in the VHA with ASTRO guidelines. The relationship between respondents’ familiarity with the guidelines and responses also was evaluated to determine the impact such guidelines have on decision-making. The ASTRO guidelines for palliative thoracic radiation make recommendations regarding 3 issues: (1) radiation doses and fractionations for palliation; (2) the role of EBB; and (3) the use of concurrent chemotherapy.^5,6

Radiation Dose and Fractionation for Palliation

A variety of dose/fractionation schemes are considered appropriate in the ASTRO guideline statement, including more prolonged courses such as 30 Gy/10 fractions as well as more hypofractionated regimens (ie, 20 Gy/5 fractions, 17 Gy/2 fractions, and a single fraction of 10 Gy). Higher dose regimens, such as 30 Gy/10 fractions, have been associated with prolonged survival, as well as increased toxicities such as radiation esophagitis.⁸ Therefore, the guidelines support use of 30 Gy/10 fractions for patients with good performance status while encouraging use of more hypofractionated regimens for patients with poor performance status. In considering more hypofractionated regimens, one must consider the possibility of adverse effects that can be associated with higher dose per fraction. For instance, 17 Gy/2 fractions has been associated with myelopathy; therefore it should be used with caution and careful treatment planning.⁹

For the survey case example (a male aged 70 years with a 3-month life expectancy who required palliation for chest wall pain), all respondents selected hypofractionated regimens; with no respondent selected the more prolonged fractionations of 60 Gy/30 fractions, 45 Gy/15 fractions, or 40 Gy/20 fractions. These more prolonged fractionations are not endorsed by the guidelines in general, and particularly not for a patient with poor life expectancy. All responses for this case selected by survey respondents are considered appropriate per the consensus guideline statement.

Role of Concurrent Chemotherapy

The ASTRO guidelines do not support use of concurrent chemotherapy for palliation of stage IV NSCLC.^5,6 The 2018 updated guidelines established a role for concurrent chemotherapy for patients with stage III NSCLC with good performance status and life expectancy of > 3 months. This updated recommendation is based on data from 2 randomized trials demonstrating improvement in overall survival with the addition of chemotherapy for patients with stage III NSCLC undergoing palliative radiotherapy.^10-12

These newer studies are in contrast to an older randomized study by Ball and colleagues that demonstrated greater toxicity from concurrent chemotherapy, with no improvement in outcomes such as palliation of symptoms, overall survival, or progression free survival.¹³ In contrast to the newer studies that included only patients with stage III NSCLC, about half of the patients in the Ball and colleagues study had known metastatic disease.^10-13 Of note, staging for metastatic disease was not carried out routinely, so it is possible that a greater proportion of patients had metastatic disease that would have been seen on imaging. In concordance with the guidelines, 98% of the survey respondents did not recommend concurrent chemotherapy for palliation of intrathoracic symptom; only 1 respondent recommended use of chemotherapy for palliation.

Role of Endobronchial Brachytherapy

EBB involves implantation of radioactive sources for treatment of endobronchial lesions causing obstructive symptoms.¹⁴ Given the lack of randomized data that demonstrate a benefit of EBB over EBRT, the ASTRO guidelines do not endorse routine use of EBB for initial palliative management.^15,16 The ASTRO guidelines reference a Cochrane Review of 13 trials that concluded that EBRT alone is superior to EBB alone for initial palliation of symptoms from endobronchial NSCLC.¹⁷

Of respondents surveyed, only 1 facility offered onsite EBB. The majority of respondents (72%) preferred the use of conventional EBRT techniques, while 26% refer to non-VHA centers for EBB. Lack of incorporation of EBB into routine VHA practice likely is a reflection of the unclear role of this technology based on the available literature and ASTRO guidelines. In the setting of a right lower lung collapse, more respondents (49%) would consider use of EBB or YAG laser technology for lung reexpansion prior to EBRT.

The ASTRO guidelines recommend that initial EBB in conjunction with EBRT be considered based on randomized data demonstrating significant improvement in lung reexpansion and in patient reported dyspnea with addition of EBB to EBRT over EBRT alone.¹⁸ However, the guidelines do not mandate the use of EBB in this situation. It is possible that targeted education regarding the role of EBB would improve knowledge of the potential benefit in the setting of lung collapse and increase the percentage of VHA ROs who would recommend this procedure.

Limitations

The study is limited by lack of generalizability of these findings to all ROs in the country. It is also possible that physician responses do not represent practice patterns with complete accuracy. The use of EBB varied among practitioners. Further study of this technology is necessary to clarify its role in the management of endobronchial obstructive symptoms and to determine whether efforts should be made to increase access to EBB within the VHA.

Conclusions

Most of the ROs who responded to our survey were cognizant and compliant with current ASTRO guidelines on management of lung cancer. Furthermore, familiarity with ASTRO guidelines and management choices were not associated with the respondents’ years in practice, academic appointment, full-time vs part-time status, or familiarity with ASTRO guidelines. This study is a nationwide survey of ROs in the VHA system that reflects the radiation-related care received by veterans with metastatic lung cancer. Responses were obtained from 93% of the 40 radiation oncology centers, so it is likely that the survey accurately represents the decision-making process at the majority of centers. It is possible that those who did not respond to the survey do not treat thoracic cases.

Few ever see this side of cancer care. Our cameras go behind the scenes as a surgical oncologist faces a crucial moment in the OR in this first episode of a new video series, The Oncologists.

Medscape Oncology © 2021 WebMD, LLC

Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.

Cite this: A Pivotal Moment in Cancer Surgery, Captured on Film - Medscape - Feb 18, 2021.

Few ever see this side of cancer care. Our cameras go behind the scenes as a surgical oncologist faces a crucial moment in the OR in this first episode of a new video series, The Oncologists.

Medscape Oncology © 2021 WebMD, LLC

Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.

Cite this: A Pivotal Moment in Cancer Surgery, Captured on Film - Medscape - Feb 18, 2021.

Few ever see this side of cancer care. Our cameras go behind the scenes as a surgical oncologist faces a crucial moment in the OR in this first episode of a new video series, The Oncologists.

Medscape Oncology © 2021 WebMD, LLC

Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.

Cite this: A Pivotal Moment in Cancer Surgery, Captured on Film - Medscape - Feb 18, 2021.

Second-line treatment with sintilimab improved survival, when compared with docetaxel, in patients with advanced/metastatic squamous non–small cell lung cancer (sqNSCLC) in a phase 3 trial.

Sintilimab improved both overall survival (OS) and progression-free survival (PFS), according to Yuankai Shi, MD, of the Chinese Academy of Medical Sciences & Peking Union Medical College in Beijing.

Dr. Shi presented these findings, from the ORIENT-3 study, at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT041).

ORIENT-3 enrolled and randomized 290 patients with stage IIIB/IIIC or IV sqNSCLC and disease progression during or after first-line platimum-based chemotherapy. They were randomized 1:1 to receive sintilimab at 200 mg or docetaxel at 75 mg/m²intravenously every 3 weeks until disease progression or intolerable toxicity.

The median age was 60 years in the sintilimab arm and 61 years in the docetaxel arm. A majority of patients were men (94% in the sintilimab arm and 90% in the docetaxel arm), most were current or former smokers (90% and 80%, respectively), and more than three-quarters had an ECOG performance status of 1 (76% and 77%, respectively). More than half of patients had a PD-L1 tumor proportion score (TPS) of 1% or greater (57% and 47%, respectively), and 81% of patients in both arms had stage IV disease.

Results: Survival and safety

Patients in the sintilimab arm received a median of 8.0 cycles of therapy (range, 1-45), and those in the docetaxel arm received a median of 2.0 cycles of therapy (range, 1-15).

At a median follow-up of 23.56 months, the median OS was significantly longer in the sintilimab arm than in the docetaxel arm – 11.79 months and 8.25 months, respectively (hazard ratio, 0.74; P = .02489). OS benefits were generally consistent across subgroups.

The secondary endpoints of PFS and objective response rate also favored sintilimab, Dr. Shi reported.

The median PFS was 4.30 months in the sintilimab arm and 2.79 months in the docetaxel arm (HR, 0.52; P < .00001). Confirmed objective response rates were 25.5% and 2.2%, respectively; the median duration of response was 12.45 months and 4.14 months, respectively; and disease control rates were 65.5% and 37.8%, respectively.

“Sintilimab had a favorable safety profile over docetaxel, with a lower frequency of grade 3 or higher treatment-related adverse events, with no new safety signals observed,” Dr. Shi said.

Treatment-related adverse events (TRAEs) occurred in 84.7% of patients receiving sintilimab and 83.1% of those receiving docetaxel. Hypothyroidism was the most common TRAE in the sintilimab arm (18.1%), and alopecia was the most common TRAE in the docetaxel arm (34.6%).

Grade 3 or higher TRAEs were less frequent in the sintilimab arm than in the docetaxel arm (18.1% vs. 36.2%). Rates of discontinuation because of TRAEs were 12.5% and 5.4% in the sintilimab and docetaxel arms, respectively. TRAEs leading to death occurred in five patients in the sintilimab arm and one in the docetaxel arm.

Use in the real world

Noting sintilimab’s significant OS and PFS benefits as well as superior response rate and duration of response, Dr. Shi concluded, “Sintilimab might provide an alternative second-line treatment option for advanced and metastatic sqNSCLC.”

AACR moderator Marina Garassino, MD, of the University of Chicago, commented on the potential utility of sintilimab and tislelizumab, another checkpoint inhibitor that was evaluated in NSCLC in the RATIONALE 303 trial (AACR 2021, Abstract CT039). Dr. Garassino observed that both drugs have demonstrated superiority to docetaxel as second-line therapy in NSCLC.

Although there have been no head-to-head trials, sintilimab and tislelizumab appear to be very similar to the already approved immune checkpoint inhibitors, which are currently being used as first-line treatment.

“That similarity would make them inappropriate for second-line treatment, except in countries where immune checkpoint inhibitors are not yet approved for first-line therapy,” Dr. Garassino noted.

When asked to comment on the higher treatment-related death rate observed with sintilimab, Dr. Garassino said, “We need to remember that these drugs were developed in China with a population that may have a side effect profile differing from that of a Western population. Also, we are very familiar with this class of drugs and know how to treat their side effects. Similar drugs but different populations and different trials, so it’s very hard to judge.”

Dr. Garassino speculated that with the “super expensive” price tags on the new checkpoint inhibitors, having additional agents that could provide choice and drive prices down would be welcome.

ORIENT-3 was funded by Innovent Biologics and Eli Lilly. Dr. Shi disclosed consultancy for Innovent Biologics. Dr. Garassino disclosed relationships with Eli Lilly, AstraZeneca, Novartis, and several other companies, not including Innovent Biologics.

Second-line treatment with sintilimab improved survival, when compared with docetaxel, in patients with advanced/metastatic squamous non–small cell lung cancer (sqNSCLC) in a phase 3 trial.

Sintilimab improved both overall survival (OS) and progression-free survival (PFS), according to Yuankai Shi, MD, of the Chinese Academy of Medical Sciences & Peking Union Medical College in Beijing.

Dr. Shi presented these findings, from the ORIENT-3 study, at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT041).

ORIENT-3 enrolled and randomized 290 patients with stage IIIB/IIIC or IV sqNSCLC and disease progression during or after first-line platimum-based chemotherapy. They were randomized 1:1 to receive sintilimab at 200 mg or docetaxel at 75 mg/m²intravenously every 3 weeks until disease progression or intolerable toxicity.

The median age was 60 years in the sintilimab arm and 61 years in the docetaxel arm. A majority of patients were men (94% in the sintilimab arm and 90% in the docetaxel arm), most were current or former smokers (90% and 80%, respectively), and more than three-quarters had an ECOG performance status of 1 (76% and 77%, respectively). More than half of patients had a PD-L1 tumor proportion score (TPS) of 1% or greater (57% and 47%, respectively), and 81% of patients in both arms had stage IV disease.

Results: Survival and safety

Patients in the sintilimab arm received a median of 8.0 cycles of therapy (range, 1-45), and those in the docetaxel arm received a median of 2.0 cycles of therapy (range, 1-15).

At a median follow-up of 23.56 months, the median OS was significantly longer in the sintilimab arm than in the docetaxel arm – 11.79 months and 8.25 months, respectively (hazard ratio, 0.74; P = .02489). OS benefits were generally consistent across subgroups.

The secondary endpoints of PFS and objective response rate also favored sintilimab, Dr. Shi reported.

The median PFS was 4.30 months in the sintilimab arm and 2.79 months in the docetaxel arm (HR, 0.52; P < .00001). Confirmed objective response rates were 25.5% and 2.2%, respectively; the median duration of response was 12.45 months and 4.14 months, respectively; and disease control rates were 65.5% and 37.8%, respectively.

“Sintilimab had a favorable safety profile over docetaxel, with a lower frequency of grade 3 or higher treatment-related adverse events, with no new safety signals observed,” Dr. Shi said.

Treatment-related adverse events (TRAEs) occurred in 84.7% of patients receiving sintilimab and 83.1% of those receiving docetaxel. Hypothyroidism was the most common TRAE in the sintilimab arm (18.1%), and alopecia was the most common TRAE in the docetaxel arm (34.6%).

Grade 3 or higher TRAEs were less frequent in the sintilimab arm than in the docetaxel arm (18.1% vs. 36.2%). Rates of discontinuation because of TRAEs were 12.5% and 5.4% in the sintilimab and docetaxel arms, respectively. TRAEs leading to death occurred in five patients in the sintilimab arm and one in the docetaxel arm.

Use in the real world

Noting sintilimab’s significant OS and PFS benefits as well as superior response rate and duration of response, Dr. Shi concluded, “Sintilimab might provide an alternative second-line treatment option for advanced and metastatic sqNSCLC.”

AACR moderator Marina Garassino, MD, of the University of Chicago, commented on the potential utility of sintilimab and tislelizumab, another checkpoint inhibitor that was evaluated in NSCLC in the RATIONALE 303 trial (AACR 2021, Abstract CT039). Dr. Garassino observed that both drugs have demonstrated superiority to docetaxel as second-line therapy in NSCLC.

Although there have been no head-to-head trials, sintilimab and tislelizumab appear to be very similar to the already approved immune checkpoint inhibitors, which are currently being used as first-line treatment.

“That similarity would make them inappropriate for second-line treatment, except in countries where immune checkpoint inhibitors are not yet approved for first-line therapy,” Dr. Garassino noted.

When asked to comment on the higher treatment-related death rate observed with sintilimab, Dr. Garassino said, “We need to remember that these drugs were developed in China with a population that may have a side effect profile differing from that of a Western population. Also, we are very familiar with this class of drugs and know how to treat their side effects. Similar drugs but different populations and different trials, so it’s very hard to judge.”

Dr. Garassino speculated that with the “super expensive” price tags on the new checkpoint inhibitors, having additional agents that could provide choice and drive prices down would be welcome.

ORIENT-3 was funded by Innovent Biologics and Eli Lilly. Dr. Shi disclosed consultancy for Innovent Biologics. Dr. Garassino disclosed relationships with Eli Lilly, AstraZeneca, Novartis, and several other companies, not including Innovent Biologics.

Second-line treatment with sintilimab improved survival, when compared with docetaxel, in patients with advanced/metastatic squamous non–small cell lung cancer (sqNSCLC) in a phase 3 trial.

Sintilimab improved both overall survival (OS) and progression-free survival (PFS), according to Yuankai Shi, MD, of the Chinese Academy of Medical Sciences & Peking Union Medical College in Beijing.

Dr. Shi presented these findings, from the ORIENT-3 study, at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT041).

ORIENT-3 enrolled and randomized 290 patients with stage IIIB/IIIC or IV sqNSCLC and disease progression during or after first-line platimum-based chemotherapy. They were randomized 1:1 to receive sintilimab at 200 mg or docetaxel at 75 mg/m²intravenously every 3 weeks until disease progression or intolerable toxicity.

The median age was 60 years in the sintilimab arm and 61 years in the docetaxel arm. A majority of patients were men (94% in the sintilimab arm and 90% in the docetaxel arm), most were current or former smokers (90% and 80%, respectively), and more than three-quarters had an ECOG performance status of 1 (76% and 77%, respectively). More than half of patients had a PD-L1 tumor proportion score (TPS) of 1% or greater (57% and 47%, respectively), and 81% of patients in both arms had stage IV disease.

Results: Survival and safety

Patients in the sintilimab arm received a median of 8.0 cycles of therapy (range, 1-45), and those in the docetaxel arm received a median of 2.0 cycles of therapy (range, 1-15).

At a median follow-up of 23.56 months, the median OS was significantly longer in the sintilimab arm than in the docetaxel arm – 11.79 months and 8.25 months, respectively (hazard ratio, 0.74; P = .02489). OS benefits were generally consistent across subgroups.

The secondary endpoints of PFS and objective response rate also favored sintilimab, Dr. Shi reported.

The median PFS was 4.30 months in the sintilimab arm and 2.79 months in the docetaxel arm (HR, 0.52; P < .00001). Confirmed objective response rates were 25.5% and 2.2%, respectively; the median duration of response was 12.45 months and 4.14 months, respectively; and disease control rates were 65.5% and 37.8%, respectively.

“Sintilimab had a favorable safety profile over docetaxel, with a lower frequency of grade 3 or higher treatment-related adverse events, with no new safety signals observed,” Dr. Shi said.

Treatment-related adverse events (TRAEs) occurred in 84.7% of patients receiving sintilimab and 83.1% of those receiving docetaxel. Hypothyroidism was the most common TRAE in the sintilimab arm (18.1%), and alopecia was the most common TRAE in the docetaxel arm (34.6%).

Grade 3 or higher TRAEs were less frequent in the sintilimab arm than in the docetaxel arm (18.1% vs. 36.2%). Rates of discontinuation because of TRAEs were 12.5% and 5.4% in the sintilimab and docetaxel arms, respectively. TRAEs leading to death occurred in five patients in the sintilimab arm and one in the docetaxel arm.

Use in the real world

Noting sintilimab’s significant OS and PFS benefits as well as superior response rate and duration of response, Dr. Shi concluded, “Sintilimab might provide an alternative second-line treatment option for advanced and metastatic sqNSCLC.”

AACR moderator Marina Garassino, MD, of the University of Chicago, commented on the potential utility of sintilimab and tislelizumab, another checkpoint inhibitor that was evaluated in NSCLC in the RATIONALE 303 trial (AACR 2021, Abstract CT039). Dr. Garassino observed that both drugs have demonstrated superiority to docetaxel as second-line therapy in NSCLC.

Although there have been no head-to-head trials, sintilimab and tislelizumab appear to be very similar to the already approved immune checkpoint inhibitors, which are currently being used as first-line treatment.

“That similarity would make them inappropriate for second-line treatment, except in countries where immune checkpoint inhibitors are not yet approved for first-line therapy,” Dr. Garassino noted.

When asked to comment on the higher treatment-related death rate observed with sintilimab, Dr. Garassino said, “We need to remember that these drugs were developed in China with a population that may have a side effect profile differing from that of a Western population. Also, we are very familiar with this class of drugs and know how to treat their side effects. Similar drugs but different populations and different trials, so it’s very hard to judge.”

Dr. Garassino speculated that with the “super expensive” price tags on the new checkpoint inhibitors, having additional agents that could provide choice and drive prices down would be welcome.

ORIENT-3 was funded by Innovent Biologics and Eli Lilly. Dr. Shi disclosed consultancy for Innovent Biologics. Dr. Garassino disclosed relationships with Eli Lilly, AstraZeneca, Novartis, and several other companies, not including Innovent Biologics.

Two more cancer indications that had been granted accelerated approval by the Food and Drug Administration are going to stay in place, at least for now. This was the verdict after the second day of a historic 3-day meeting (April 27-29) and follows a similar verdict from day 1.

Federal advisers so far have supported the idea of maintaining conditional approvals of some cancer indications for a number of immune checkpoint inhibitors, despite poor results in studies that were meant to confirm the benefit of these medicines for certain patients.

On the second day (April 28) of the FDA meeting, the Oncologic Drugs Advisory Committee (ODAC) supported the views of pharmaceutical companies in two more cases of what top agency staff call “dangling accelerated approvals.”

ODAC voted 10-1 in favor of maintaining the indication for atezolizumab (Tecentriq) for the first-line treatment of cisplatin-ineligible patients with advanced/metastatic urothelial carcinoma, pending final overall survival results from the IMvigor130 trial.

ODAC also voted 5-3 that day in favor of maintaining accelerated approval for pembrolizumab (Keytruda) for first-line cisplatin- and carboplatin-ineligible patients with advanced/metastatic urothelial carcinoma.

The FDA often follows the advice of its panels, but it is not bound to do so. If the FDA were to decide to strip the indications in question from these PD-1 medicines, such decisions would not remove these drugs from the market. The three drugs have already been approved for a number of other cancer indications.

Off-label prescribing is not uncommon in oncology, but a loss of an approved indication would affect reimbursement for these medicines, Scot Ebbinghaus, MD, vice president of oncology clinical research at Merck (the manufacturer of pembrolizumab), told ODAC members during a discussion of the possible consequences of removing the indications in question.

“Access to those treatments may end up being substantially limited, and really the best way to ensure that there’s access is to maintain FDA approval,” Dr. Ebbinghaus said.

Another participant at the meeting asked the panel and the FDA to consider the burden on patients in paying for medicines that have not yet proved to be beneficial.

Diana Zuckerman, PhD, of the nonprofit National Center for Health Research, noted that the ODAC panel included physicians who see cancer patients.

“You’re used to trying different types of treatments in hopes that something will work,” she said. “Shouldn’t cancer patients be eligible for free treatment in clinical trials instead of paying for treatment that isn’t proven to work?”

Rapid development of PD-1 drugs

Top officials at the FDA framed the challenges with accelerated approvals for immunotherapy drugs in an April 21 article in The New England Journal of Medicine. Over the course of about 6 years, the FDA approved six of these PD-1 or PD-L1 drugs for more than 75 indications in oncology, wrote Richard Pazdur, MD, and Julia A. Beaver, MD, of the FDA.

“Development of drugs in this class occurred more rapidly than that in any other therapeutic area in history,” they wrote.

In 10 cases, the required follow-up trials did not confirm the expected benefit, and yet marketing authorization for these drugs continued, leading Dr. Pazdur and Dr. Beaver to dub these “dangling” accelerated approvals. Four of these indications were voluntarily withdrawn. For the other six indications, the FDA sought feedback from ODAC during the 3-day meeting. Over the first 2 days of the meeting, ODAC recommended that three of these cancer indications remain. Three more will be considered on the last day of the meeting.

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

Two more cancer indications that had been granted accelerated approval by the Food and Drug Administration are going to stay in place, at least for now. This was the verdict after the second day of a historic 3-day meeting (April 27-29) and follows a similar verdict from day 1.

Federal advisers so far have supported the idea of maintaining conditional approvals of some cancer indications for a number of immune checkpoint inhibitors, despite poor results in studies that were meant to confirm the benefit of these medicines for certain patients.

On the second day (April 28) of the FDA meeting, the Oncologic Drugs Advisory Committee (ODAC) supported the views of pharmaceutical companies in two more cases of what top agency staff call “dangling accelerated approvals.”

ODAC voted 10-1 in favor of maintaining the indication for atezolizumab (Tecentriq) for the first-line treatment of cisplatin-ineligible patients with advanced/metastatic urothelial carcinoma, pending final overall survival results from the IMvigor130 trial.

ODAC also voted 5-3 that day in favor of maintaining accelerated approval for pembrolizumab (Keytruda) for first-line cisplatin- and carboplatin-ineligible patients with advanced/metastatic urothelial carcinoma.

The FDA often follows the advice of its panels, but it is not bound to do so. If the FDA were to decide to strip the indications in question from these PD-1 medicines, such decisions would not remove these drugs from the market. The three drugs have already been approved for a number of other cancer indications.

Off-label prescribing is not uncommon in oncology, but a loss of an approved indication would affect reimbursement for these medicines, Scot Ebbinghaus, MD, vice president of oncology clinical research at Merck (the manufacturer of pembrolizumab), told ODAC members during a discussion of the possible consequences of removing the indications in question.

“Access to those treatments may end up being substantially limited, and really the best way to ensure that there’s access is to maintain FDA approval,” Dr. Ebbinghaus said.

Another participant at the meeting asked the panel and the FDA to consider the burden on patients in paying for medicines that have not yet proved to be beneficial.

Diana Zuckerman, PhD, of the nonprofit National Center for Health Research, noted that the ODAC panel included physicians who see cancer patients.

“You’re used to trying different types of treatments in hopes that something will work,” she said. “Shouldn’t cancer patients be eligible for free treatment in clinical trials instead of paying for treatment that isn’t proven to work?”

Rapid development of PD-1 drugs

Top officials at the FDA framed the challenges with accelerated approvals for immunotherapy drugs in an April 21 article in The New England Journal of Medicine. Over the course of about 6 years, the FDA approved six of these PD-1 or PD-L1 drugs for more than 75 indications in oncology, wrote Richard Pazdur, MD, and Julia A. Beaver, MD, of the FDA.

“Development of drugs in this class occurred more rapidly than that in any other therapeutic area in history,” they wrote.

In 10 cases, the required follow-up trials did not confirm the expected benefit, and yet marketing authorization for these drugs continued, leading Dr. Pazdur and Dr. Beaver to dub these “dangling” accelerated approvals. Four of these indications were voluntarily withdrawn. For the other six indications, the FDA sought feedback from ODAC during the 3-day meeting. Over the first 2 days of the meeting, ODAC recommended that three of these cancer indications remain. Three more will be considered on the last day of the meeting.

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

Two more cancer indications that had been granted accelerated approval by the Food and Drug Administration are going to stay in place, at least for now. This was the verdict after the second day of a historic 3-day meeting (April 27-29) and follows a similar verdict from day 1.

Federal advisers so far have supported the idea of maintaining conditional approvals of some cancer indications for a number of immune checkpoint inhibitors, despite poor results in studies that were meant to confirm the benefit of these medicines for certain patients.

On the second day (April 28) of the FDA meeting, the Oncologic Drugs Advisory Committee (ODAC) supported the views of pharmaceutical companies in two more cases of what top agency staff call “dangling accelerated approvals.”

ODAC voted 10-1 in favor of maintaining the indication for atezolizumab (Tecentriq) for the first-line treatment of cisplatin-ineligible patients with advanced/metastatic urothelial carcinoma, pending final overall survival results from the IMvigor130 trial.

ODAC also voted 5-3 that day in favor of maintaining accelerated approval for pembrolizumab (Keytruda) for first-line cisplatin- and carboplatin-ineligible patients with advanced/metastatic urothelial carcinoma.

The FDA often follows the advice of its panels, but it is not bound to do so. If the FDA were to decide to strip the indications in question from these PD-1 medicines, such decisions would not remove these drugs from the market. The three drugs have already been approved for a number of other cancer indications.

Off-label prescribing is not uncommon in oncology, but a loss of an approved indication would affect reimbursement for these medicines, Scot Ebbinghaus, MD, vice president of oncology clinical research at Merck (the manufacturer of pembrolizumab), told ODAC members during a discussion of the possible consequences of removing the indications in question.

“Access to those treatments may end up being substantially limited, and really the best way to ensure that there’s access is to maintain FDA approval,” Dr. Ebbinghaus said.

Another participant at the meeting asked the panel and the FDA to consider the burden on patients in paying for medicines that have not yet proved to be beneficial.

Diana Zuckerman, PhD, of the nonprofit National Center for Health Research, noted that the ODAC panel included physicians who see cancer patients.

“You’re used to trying different types of treatments in hopes that something will work,” she said. “Shouldn’t cancer patients be eligible for free treatment in clinical trials instead of paying for treatment that isn’t proven to work?”

Rapid development of PD-1 drugs

Top officials at the FDA framed the challenges with accelerated approvals for immunotherapy drugs in an April 21 article in The New England Journal of Medicine. Over the course of about 6 years, the FDA approved six of these PD-1 or PD-L1 drugs for more than 75 indications in oncology, wrote Richard Pazdur, MD, and Julia A. Beaver, MD, of the FDA.

“Development of drugs in this class occurred more rapidly than that in any other therapeutic area in history,” they wrote.

In 10 cases, the required follow-up trials did not confirm the expected benefit, and yet marketing authorization for these drugs continued, leading Dr. Pazdur and Dr. Beaver to dub these “dangling” accelerated approvals. Four of these indications were voluntarily withdrawn. For the other six indications, the FDA sought feedback from ODAC during the 3-day meeting. Over the first 2 days of the meeting, ODAC recommended that three of these cancer indications remain. Three more will be considered on the last day of the meeting.

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

Universal multigene panel testing of colorectal cancer patients can detect heritable mutations that would not have been discovered with guideline-based testing, according to new research.

A prospective study of universal genetic testing suggested that one in six colorectal cancer patients have an inherited genetic predisposition to the cancer. More than half of the patients with genetic mutations identified in this study would have been missed if the patients had undergone genetic testing based on current practice. In 11% of patients, the genetic findings led to a change in treatment, including the type of surgery or targeted cancer therapy.

These results were presented at the American College of Medical Genetics and Genomics annual meeting and published in Clinical Gastroenterology and Hepatology.

“This study shows the limitations of relying on current clinical practice guidelines for genetic evaluation, which prioritize age of cancer diagnosis and family cancer history,” said investigator Niloy Jewel Samadder, MD, of the Mayo Clinic in Phoenix.

“We were surprised that more than 50% of the patients with a genetic mutation would not have been identified had we relied on national practice guidelines or only used a small colon cancer-specific gene panel, as is commonly employed in clinical practice. The fact that more than 10% of patients actually had changes in the type of surgery or chemo/immunotherapy they received gives the strongest indicator of how genetics can revolutionize and individualize cancer care,” Dr. Samadder said.

He added that identifying a germline predisposition has multiple values, including understanding the reason patients and their family members develop specific cancers, preventing the development of new cancers in patients and family members by providing targeted prevention and screening for those at genetic risk, and improving survival in patients with a genetic driver of cancer via targeted therapy.
 

Study details

The researchers used a next-generation sequencing platform with more than 80 genes in colorectal cancer patients (not selected for age or family history) receiving care at Mayo Clinic Cancer Centers between April 1, 2018, and March 31, 2020.

The study included 361 patients with a median age of 57 years. Pathogenic germline variants were identified in 56 patients (15.5%), including 44 patients with moderate and high penetrance cancer susceptibility genes.

Younger age (under 50 years old) was associated with having a germline mutation, but “more importantly, gender, family cancer history, and stage of cancer were not,” Dr. Samadder said.

“The current clinical guidelines rely heavily on these characteristics to determine who should and should not be referred for genetic testing,” he continued. “Our study suggests that even older patients with colorectal cancer have a high rate of having pathogenic germline mutations [12%], so restricting genetic testing to only those under age 50 will miss a substantial portion of patients who might benefit from this test.”
 

Genetic testing for all

“Our findings support the broad use of genetic testing in all colorectal cancer patients, regardless of age, gender, ethnicity, family cancer history, or stage of cancer,” Dr. Samadder said.

“This study adds to a growing body of literature that provides evidence that cancer susceptibility due to variants in single genes is more common than previously appreciated,” said Marc S. Williams, MD, president of the American College of Medical Genetics and Genomics. “Current testing guidelines seem to be relatively insensitive and miss opportunities for testing of patients.”

Dr. Williams noted that 11% of patients in this study had a change in disease management related to a genetic testing result, which is “a relatively modest impact.”

“Another potential advantage of [universal] testing was the opportunity to test at-risk relatives,” Dr. Williams added. “However, only 16% of eligible individuals pursued testing. This is consistent with other studies and represents an opportunity for testing new ways to improve uptake of cascade screening.”

Dr. Williams said rigorous prospective studies enrolling large numbers of patients from diverse backgrounds are needed to inform the development and updating of genetic testing guidelines.

He disclosed no conflicts of interest. Dr. Samadder disclosed relationships with Janssen Research and Development, Recursion Pharmaceuticals, and Cancer Prevention Pharmaceuticals. The research was funded by the Mayo Clinic, Desert Mountain Members’ CARE Foundation, David and Twila Woods Foundation, and the Gerstner Foundation.

Universal multigene panel testing of colorectal cancer patients can detect heritable mutations that would not have been discovered with guideline-based testing, according to new research.

A prospective study of universal genetic testing suggested that one in six colorectal cancer patients have an inherited genetic predisposition to the cancer. More than half of the patients with genetic mutations identified in this study would have been missed if the patients had undergone genetic testing based on current practice. In 11% of patients, the genetic findings led to a change in treatment, including the type of surgery or targeted cancer therapy.

These results were presented at the American College of Medical Genetics and Genomics annual meeting and published in Clinical Gastroenterology and Hepatology.

“This study shows the limitations of relying on current clinical practice guidelines for genetic evaluation, which prioritize age of cancer diagnosis and family cancer history,” said investigator Niloy Jewel Samadder, MD, of the Mayo Clinic in Phoenix.

“We were surprised that more than 50% of the patients with a genetic mutation would not have been identified had we relied on national practice guidelines or only used a small colon cancer-specific gene panel, as is commonly employed in clinical practice. The fact that more than 10% of patients actually had changes in the type of surgery or chemo/immunotherapy they received gives the strongest indicator of how genetics can revolutionize and individualize cancer care,” Dr. Samadder said.

He added that identifying a germline predisposition has multiple values, including understanding the reason patients and their family members develop specific cancers, preventing the development of new cancers in patients and family members by providing targeted prevention and screening for those at genetic risk, and improving survival in patients with a genetic driver of cancer via targeted therapy.
 

Study details

The researchers used a next-generation sequencing platform with more than 80 genes in colorectal cancer patients (not selected for age or family history) receiving care at Mayo Clinic Cancer Centers between April 1, 2018, and March 31, 2020.

The study included 361 patients with a median age of 57 years. Pathogenic germline variants were identified in 56 patients (15.5%), including 44 patients with moderate and high penetrance cancer susceptibility genes.

Younger age (under 50 years old) was associated with having a germline mutation, but “more importantly, gender, family cancer history, and stage of cancer were not,” Dr. Samadder said.

“The current clinical guidelines rely heavily on these characteristics to determine who should and should not be referred for genetic testing,” he continued. “Our study suggests that even older patients with colorectal cancer have a high rate of having pathogenic germline mutations [12%], so restricting genetic testing to only those under age 50 will miss a substantial portion of patients who might benefit from this test.”
 

Genetic testing for all

“Our findings support the broad use of genetic testing in all colorectal cancer patients, regardless of age, gender, ethnicity, family cancer history, or stage of cancer,” Dr. Samadder said.

“This study adds to a growing body of literature that provides evidence that cancer susceptibility due to variants in single genes is more common than previously appreciated,” said Marc S. Williams, MD, president of the American College of Medical Genetics and Genomics. “Current testing guidelines seem to be relatively insensitive and miss opportunities for testing of patients.”

Dr. Williams noted that 11% of patients in this study had a change in disease management related to a genetic testing result, which is “a relatively modest impact.”

“Another potential advantage of [universal] testing was the opportunity to test at-risk relatives,” Dr. Williams added. “However, only 16% of eligible individuals pursued testing. This is consistent with other studies and represents an opportunity for testing new ways to improve uptake of cascade screening.”

Dr. Williams said rigorous prospective studies enrolling large numbers of patients from diverse backgrounds are needed to inform the development and updating of genetic testing guidelines.

He disclosed no conflicts of interest. Dr. Samadder disclosed relationships with Janssen Research and Development, Recursion Pharmaceuticals, and Cancer Prevention Pharmaceuticals. The research was funded by the Mayo Clinic, Desert Mountain Members’ CARE Foundation, David and Twila Woods Foundation, and the Gerstner Foundation.

Universal multigene panel testing of colorectal cancer patients can detect heritable mutations that would not have been discovered with guideline-based testing, according to new research.

A prospective study of universal genetic testing suggested that one in six colorectal cancer patients have an inherited genetic predisposition to the cancer. More than half of the patients with genetic mutations identified in this study would have been missed if the patients had undergone genetic testing based on current practice. In 11% of patients, the genetic findings led to a change in treatment, including the type of surgery or targeted cancer therapy.

These results were presented at the American College of Medical Genetics and Genomics annual meeting and published in Clinical Gastroenterology and Hepatology.

“This study shows the limitations of relying on current clinical practice guidelines for genetic evaluation, which prioritize age of cancer diagnosis and family cancer history,” said investigator Niloy Jewel Samadder, MD, of the Mayo Clinic in Phoenix.

“We were surprised that more than 50% of the patients with a genetic mutation would not have been identified had we relied on national practice guidelines or only used a small colon cancer-specific gene panel, as is commonly employed in clinical practice. The fact that more than 10% of patients actually had changes in the type of surgery or chemo/immunotherapy they received gives the strongest indicator of how genetics can revolutionize and individualize cancer care,” Dr. Samadder said.

He added that identifying a germline predisposition has multiple values, including understanding the reason patients and their family members develop specific cancers, preventing the development of new cancers in patients and family members by providing targeted prevention and screening for those at genetic risk, and improving survival in patients with a genetic driver of cancer via targeted therapy.
 

Study details

The researchers used a next-generation sequencing platform with more than 80 genes in colorectal cancer patients (not selected for age or family history) receiving care at Mayo Clinic Cancer Centers between April 1, 2018, and March 31, 2020.

The study included 361 patients with a median age of 57 years. Pathogenic germline variants were identified in 56 patients (15.5%), including 44 patients with moderate and high penetrance cancer susceptibility genes.

Younger age (under 50 years old) was associated with having a germline mutation, but “more importantly, gender, family cancer history, and stage of cancer were not,” Dr. Samadder said.

“The current clinical guidelines rely heavily on these characteristics to determine who should and should not be referred for genetic testing,” he continued. “Our study suggests that even older patients with colorectal cancer have a high rate of having pathogenic germline mutations [12%], so restricting genetic testing to only those under age 50 will miss a substantial portion of patients who might benefit from this test.”
 

Genetic testing for all

“Our findings support the broad use of genetic testing in all colorectal cancer patients, regardless of age, gender, ethnicity, family cancer history, or stage of cancer,” Dr. Samadder said.

“This study adds to a growing body of literature that provides evidence that cancer susceptibility due to variants in single genes is more common than previously appreciated,” said Marc S. Williams, MD, president of the American College of Medical Genetics and Genomics. “Current testing guidelines seem to be relatively insensitive and miss opportunities for testing of patients.”

Dr. Williams noted that 11% of patients in this study had a change in disease management related to a genetic testing result, which is “a relatively modest impact.”

“Another potential advantage of [universal] testing was the opportunity to test at-risk relatives,” Dr. Williams added. “However, only 16% of eligible individuals pursued testing. This is consistent with other studies and represents an opportunity for testing new ways to improve uptake of cascade screening.”

Dr. Williams said rigorous prospective studies enrolling large numbers of patients from diverse backgrounds are needed to inform the development and updating of genetic testing guidelines.

He disclosed no conflicts of interest. Dr. Samadder disclosed relationships with Janssen Research and Development, Recursion Pharmaceuticals, and Cancer Prevention Pharmaceuticals. The research was funded by the Mayo Clinic, Desert Mountain Members’ CARE Foundation, David and Twila Woods Foundation, and the Gerstner Foundation.

Nivolumab continues to demonstrate a substantial survival benefit over docetaxel at 5 years in advanced non-small cell lung cancer (NSCLC) patients who progressed on platinum-based therapies, according to a pooled analysis of two phase 3 trials published in the Journal of Clinical Oncology.

Across the two studies – CheckMate 017 and 057 – 854 patients were randomized 1:1 following progression on platinum therapy to either nivolumab at 3 mg/kg once every 2 weeks or docetaxel at 75 mg/m² once every 3 weeks until further progression or unacceptable toxicity. Previously reported overall survival (OS) outcomes favored nivolumab.

At a minimum follow-up of 5.4 years, 50 nivolumab-treated patients and 9 docetaxel-treated patients were still alive.

The 5-year OS rates were 13.4% in the nivolumab arm and 2.6% in the docetaxel arm. The 5-year progression-free survival (PFS) rates were 8% and 0%, respectively.

There were no new safety signals with nivolumab, and there was no evidence of select late-onset grade 3-4 adverse events.

According to the study authors, this analysis is the longest phase 3 follow-up to date of a PD-1 inhibitor in previously treated, advanced NSCLC, and it suggests that “long-term survival beyond 5 years may ... be possible in NSCLC.”

“The results indicate that some patients with NSCLC can have long-lasting benefit from checkpoint inhibitors. We have seen similar results in terms of long-term OS with pembrolizumab,” said investigator Hossein Borghaei, DO, chief of thoracic medical oncology at the Fox Chase Cancer Center in Philadelphia.

Dr. Borghaei said the question now is “how to identify the population that really benefits from these treatments. We think PD-L1–high [patients] have a better chance, [as do patients with] tumors that have a higher percentage of tumor-infiltrating lymphocytes, but there’s nothing concrete beyond that.”

No baseline clinical or tumor factors emerged to distinguish between long-and short-term survivors, but the 5-year OS rate was 18.3% among nivolumab-treated patients with PD-L1 expression at or above 1% versus 8% among patients with expression below 1%.

The optimal duration of nivolumab treatment beyond 1 year is also uncertain.

The median duration of therapy was 36.9 months in the 5-year survivors treated with nivolumab, and 36% of patients (18/50) were still on nivolumab at the 5-year mark.

The median duration of time off treatment was 41.9 months among patients who discontinued nivolumab. Five patients (10%) were off treatment with no subsequent therapy and had not progressed at 5 years, “suggesting benefit even for patients who stopped nivolumab treatment,” the researchers wrote.

They also found that nivolumab-treated patients who remained alive at 3 years appeared to stabilize and plateau thereafter, with early response suggesting better long-term outcomes. The majority of patients without disease progression at 2, 3, and 4 years, for instance, remained progression free at 5 years. Nearly one-third of patients who achieved an objective response with nivolumab – but none of the patients who responded to docetaxel – had ongoing responses at 5 years.

Similarly, nivolumab-treated patients without disease progression at 2 years and 3 years had an 82% and 93% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression free at 5 years.

This research was funded by Bristol-Myers Squibb. Dr. Borghaei and coauthors disclosed numerous ties to the company, including employment.

[email protected]

Nivolumab continues to demonstrate a substantial survival benefit over docetaxel at 5 years in advanced non-small cell lung cancer (NSCLC) patients who progressed on platinum-based therapies, according to a pooled analysis of two phase 3 trials published in the Journal of Clinical Oncology.

Across the two studies – CheckMate 017 and 057 – 854 patients were randomized 1:1 following progression on platinum therapy to either nivolumab at 3 mg/kg once every 2 weeks or docetaxel at 75 mg/m² once every 3 weeks until further progression or unacceptable toxicity. Previously reported overall survival (OS) outcomes favored nivolumab.

At a minimum follow-up of 5.4 years, 50 nivolumab-treated patients and 9 docetaxel-treated patients were still alive.

The 5-year OS rates were 13.4% in the nivolumab arm and 2.6% in the docetaxel arm. The 5-year progression-free survival (PFS) rates were 8% and 0%, respectively.

There were no new safety signals with nivolumab, and there was no evidence of select late-onset grade 3-4 adverse events.

According to the study authors, this analysis is the longest phase 3 follow-up to date of a PD-1 inhibitor in previously treated, advanced NSCLC, and it suggests that “long-term survival beyond 5 years may ... be possible in NSCLC.”

“The results indicate that some patients with NSCLC can have long-lasting benefit from checkpoint inhibitors. We have seen similar results in terms of long-term OS with pembrolizumab,” said investigator Hossein Borghaei, DO, chief of thoracic medical oncology at the Fox Chase Cancer Center in Philadelphia.

Dr. Borghaei said the question now is “how to identify the population that really benefits from these treatments. We think PD-L1–high [patients] have a better chance, [as do patients with] tumors that have a higher percentage of tumor-infiltrating lymphocytes, but there’s nothing concrete beyond that.”

No baseline clinical or tumor factors emerged to distinguish between long-and short-term survivors, but the 5-year OS rate was 18.3% among nivolumab-treated patients with PD-L1 expression at or above 1% versus 8% among patients with expression below 1%.

The optimal duration of nivolumab treatment beyond 1 year is also uncertain.

The median duration of therapy was 36.9 months in the 5-year survivors treated with nivolumab, and 36% of patients (18/50) were still on nivolumab at the 5-year mark.

The median duration of time off treatment was 41.9 months among patients who discontinued nivolumab. Five patients (10%) were off treatment with no subsequent therapy and had not progressed at 5 years, “suggesting benefit even for patients who stopped nivolumab treatment,” the researchers wrote.

They also found that nivolumab-treated patients who remained alive at 3 years appeared to stabilize and plateau thereafter, with early response suggesting better long-term outcomes. The majority of patients without disease progression at 2, 3, and 4 years, for instance, remained progression free at 5 years. Nearly one-third of patients who achieved an objective response with nivolumab – but none of the patients who responded to docetaxel – had ongoing responses at 5 years.

Similarly, nivolumab-treated patients without disease progression at 2 years and 3 years had an 82% and 93% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression free at 5 years.

This research was funded by Bristol-Myers Squibb. Dr. Borghaei and coauthors disclosed numerous ties to the company, including employment.

[email protected]

Nivolumab continues to demonstrate a substantial survival benefit over docetaxel at 5 years in advanced non-small cell lung cancer (NSCLC) patients who progressed on platinum-based therapies, according to a pooled analysis of two phase 3 trials published in the Journal of Clinical Oncology.

Across the two studies – CheckMate 017 and 057 – 854 patients were randomized 1:1 following progression on platinum therapy to either nivolumab at 3 mg/kg once every 2 weeks or docetaxel at 75 mg/m² once every 3 weeks until further progression or unacceptable toxicity. Previously reported overall survival (OS) outcomes favored nivolumab.

At a minimum follow-up of 5.4 years, 50 nivolumab-treated patients and 9 docetaxel-treated patients were still alive.

The 5-year OS rates were 13.4% in the nivolumab arm and 2.6% in the docetaxel arm. The 5-year progression-free survival (PFS) rates were 8% and 0%, respectively.

There were no new safety signals with nivolumab, and there was no evidence of select late-onset grade 3-4 adverse events.

According to the study authors, this analysis is the longest phase 3 follow-up to date of a PD-1 inhibitor in previously treated, advanced NSCLC, and it suggests that “long-term survival beyond 5 years may ... be possible in NSCLC.”

“The results indicate that some patients with NSCLC can have long-lasting benefit from checkpoint inhibitors. We have seen similar results in terms of long-term OS with pembrolizumab,” said investigator Hossein Borghaei, DO, chief of thoracic medical oncology at the Fox Chase Cancer Center in Philadelphia.

Dr. Borghaei said the question now is “how to identify the population that really benefits from these treatments. We think PD-L1–high [patients] have a better chance, [as do patients with] tumors that have a higher percentage of tumor-infiltrating lymphocytes, but there’s nothing concrete beyond that.”

No baseline clinical or tumor factors emerged to distinguish between long-and short-term survivors, but the 5-year OS rate was 18.3% among nivolumab-treated patients with PD-L1 expression at or above 1% versus 8% among patients with expression below 1%.

The optimal duration of nivolumab treatment beyond 1 year is also uncertain.

The median duration of therapy was 36.9 months in the 5-year survivors treated with nivolumab, and 36% of patients (18/50) were still on nivolumab at the 5-year mark.

The median duration of time off treatment was 41.9 months among patients who discontinued nivolumab. Five patients (10%) were off treatment with no subsequent therapy and had not progressed at 5 years, “suggesting benefit even for patients who stopped nivolumab treatment,” the researchers wrote.

They also found that nivolumab-treated patients who remained alive at 3 years appeared to stabilize and plateau thereafter, with early response suggesting better long-term outcomes. The majority of patients without disease progression at 2, 3, and 4 years, for instance, remained progression free at 5 years. Nearly one-third of patients who achieved an objective response with nivolumab – but none of the patients who responded to docetaxel – had ongoing responses at 5 years.

Similarly, nivolumab-treated patients without disease progression at 2 years and 3 years had an 82% and 93% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression free at 5 years.

This research was funded by Bristol-Myers Squibb. Dr. Borghaei and coauthors disclosed numerous ties to the company, including employment.

[email protected]