SAN FRANCISCO – Posttraumatic stress disorder symptoms triggered by a life-threatening medical illness differ from the more common PTSD, the source of which is an external trauma such as an assault or natural disaster, according to Renee El-Gabalawy, PhD.

“This suggests implications for diagnostic classification. Maybe, in future editions of the DSM, we should think of this as a subtype of PTSD or potentially as a new diagnostic category, although it’s far too early to make any conclusions about that,” Dr. El-Gabalawy said at the annual conference of the Anxiety and Depression Association of America.

[email protected]

SAN FRANCISCO – Posttraumatic stress disorder symptoms triggered by a life-threatening medical illness differ from the more common PTSD, the source of which is an external trauma such as an assault or natural disaster, according to Renee El-Gabalawy, PhD.

“This suggests implications for diagnostic classification. Maybe, in future editions of the DSM, we should think of this as a subtype of PTSD or potentially as a new diagnostic category, although it’s far too early to make any conclusions about that,” Dr. El-Gabalawy said at the annual conference of the Anxiety and Depression Association of America.

[email protected]

SAN FRANCISCO – Posttraumatic stress disorder symptoms triggered by a life-threatening medical illness differ from the more common PTSD, the source of which is an external trauma such as an assault or natural disaster, according to Renee El-Gabalawy, PhD.

“This suggests implications for diagnostic classification. Maybe, in future editions of the DSM, we should think of this as a subtype of PTSD or potentially as a new diagnostic category, although it’s far too early to make any conclusions about that,” Dr. El-Gabalawy said at the annual conference of the Anxiety and Depression Association of America.

[email protected]

In 2017 there will be nearly 1.7 million new cancer cases diagnosed, and over 600,000 cancer deaths in the Unites States.¹ A 2013 Institute of Medicine report highlighted problems with the current quality of cancer care, including high costs and fragmentation of care.² Other national reports have called for improvements in the overall quality of care and for reducing costly and possibly avoidable use of health services such as emergency department (ED) visits.^3-6 Reduction of avoidable ED visits is often cited as a pathway to reduce costs by avoiding unnecessary tests and treatments that occur in the ED and subsequent hospital admissions.^7,8

ED crowding, long waits, and unpredictable treatment environments can also make an ED visit an unpleasant experience for the patient. ED visits during cancer treatment can be particularly troubling and present health concerns for patients who are immunocompromised. In particular, cancer patients in the ED have been found to experience delays in the administration of analgesics, antiemetics, or antibiotics.⁹

Few studies have examined ED use or its associated predictors among cancer patients. Reports to date that have described ED use have focused on different cancers, which makes comparisons across studies difficult.¹⁰ Moreover, the time frames of interest and the type of event after which ED use is evaluated (ie, diagnosis or treatment) are inconsistent in the existing literature.¹⁰ Some studies quantifying ED use excluded patients admitted to the hospital after an ED visit.^11,12 Taken together, these studies do not provide a clear overview of the extent of ED use by cancer patients or the amount of cancer-related care provided by EDs.

Patterns of ED use among cancer patients derived from large and generalizable samples may help inform providers about true risk factors for ED use. In addition, prioritizing new interventions and focusing future research on groups of patients who are at higher risk for preventable ED use could also improve overall care. To address these issues, accurate estimates of ED use among cancer patients are required.

To our knowledge, this is the first study to describe ED use across a range of cancers in a large population-based sample and to consider the timing of ED visits in relation to initial diagnosis. The findings could provide benchmark comparison data to inform future efforts to identify the subset of possibly preventable ED visits and to design interventions to address preventable ED use.

Material and methods

Data source

California’s Office of Statewide Health Planning and Development (OSHPD) manages the patient discharge dataset (PDD) and the emergency department use (EDU) dataset, providing a high-quality source of information on inpatient and ED use in the state.¹³ A principal diagnosis and up to 24 secondary diagnoses are recorded in OSHPD datasets. The EDU dataset was used to identify treat-and-release ED visits, and the PDD was used to identify hospitalizations initiated in the ED. The California Cancer Registry (CCR) obtains demographic and diagnosis information for every new invasive cancer diagnosed in California, and data collected by the registry are considered to be complete.¹⁴ CCR-OSPHD-linked data provide high-quality health care use information for cancer patients in California.^15,16 Using an encrypted version of the social security number called the record linkage number (RLN), we linked the CCR records to the corresponding OSHPD files from 2009-2010.

Institutional review board approval for this study was obtained from the University of California, Davis, Human Subjects Committee and the State of California Committee for the Protection of Human Subjects.

Analysis

ED visits. Visits were included if they occurred on or up to 365 days after the date of cancer diagnosis recorded in the CCR. The visits were coded in mutually exclusive groups as occurring within 30, 31-180, and 181-365 days of diagnosis. Subsequently, we flagged each person as having any ED visit (Yes/No) within 180 days and within 365 days of diagnosis, and we tallied the total number of visits occurring within these time frames for each person.

Cancer type. We used relevant site and histology codes to classify cancer type into 24 mutually exclusive categories using the Surveillance Epidemiology and End Result‘s International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3) Recode Definitions^17-19 (Suppl Figure 1).

Individual-level variables. Sociodemographic information for each person was collected from the CCR including gender, age, race/ethnicity, marital status, health insurance status, rural residence, survival time in months, neighborhood socio-economic (SES) status based on the Yang index, and the American Joint Committee on Cancer (AJCC) stage.^20,21

Data analysis

Demographic information was analyzed for the cohort using descriptive statistics (frequencies, proportions, means, standard deviations, and ranges) and evaluated for correlations. Fewer than 20 observations had missing data and we removed those observations from our analyses on an item-specific basis.

We tabulated ED visits by cancer type and time from diagnosis and then collapsed visit-level data by RLN to determine the number of ED visits for each person in the sample. The number of days from diagnosis to first ED visit was also tabulated. The cohort was stratified by cancer type and cumulative rates of ED visits were tabulated for individuals with ED visits within 0-180 and 0-365 days from diagnosis. To test the robustness of the findings adjusting for confounding factors known to impact ED use, we used logistic regression to model any ED use (Yes/No) as a function of age, gender, race/ethnicity, cancer stage, insurance status, marital status, urban residence, and Yang SES. After model estimation, we used the method of recycled predictions controlling for the confounding variables to compute the marginal probabilities of ED use by cancer type.²² To adjust for the possible impact of survival on ED use, we performed sensitivity analyses and estimated predicted probabilities adjusting for survival. Separate analyses were performed first adjusting for whether the patient died during the course of each month after diagnosis and then adjusting for whether or not the patient died within 180 days of diagnosis. All analyses were conducted using Stata 13.1.²³

Results

The CCR identified 222,087 adults with a new primary cancer diagnosis in 2009-2010. After excluding those with Stage 0 cancer (n = 21,154) and nonmelanoma skin cancer (n = 1,031), for whom data are inconsistently collected by CCR, a total of 199,872 individuals were included in the analytic sample. Of those patients (Table 1), most were white non-Hispanic (62%), women (51%), holders of private insurance (53%), married (56%), and urban residents (86%). Most were older than 50 years and had either Stage I or Stage II cancer. The most common cancer types were breast (17%), prostate (16%), lung (11%), and colon (9%; results not shown). In unadjusted comparisons, the incidence of ED use was significantly higher among those who were older, of non-Hispanic black race/ethnicity, uninsured, in the lowest SES group, widowed, or diagnosed with Stage IV cancer (Table 1).

ED visits

Within 365 days after initial cancer diagnosis, 87,025 cancer patients made a total of 197,886 ED visits (not shown in tables). Of those visits, 68% (n = 134,556) occurred within 180 days of diagnosis, with 22% (n = 43,535) occurring within the first 30 days and 46% (n = 91,027) occurring within 31-180 days after diagnosis (Figure). Given that most of the visits occurred within 180 days of diagnosis, we used that time frame in subsequent analyses. Among all ED visits within 180 days of diagnosis (Table 2), the largest proportions of visits were made by those with lung cancer (16%), breast cancer (11%), and colon cancer (10%).

About 51% of visits resulted in admission to the hospital and 45% in discharge (Table 2). For some cancers (lung, colon, non-Hodgkin lymphoma, pancreatic, digestive, liver, stomach, leukemia, and myeloma) most of the visits resulted in admission to the hospital (Table 2). Among visits resulting in admission, the top three principal diagnoses were: septicemia (8%), cardiovascular problems (7%), and complications from surgery (5%) (not shown in tables). Among visits resulting in a discharge home, the three top principal diagnoses were abdominal pain (7%), cardiovascular problems (6%), and urinary, kidney, and bladder complaints other than a urinary tract infection (5%) (results not shown).

Individuals

The cumulative incidence of at least one ED visit was 35% (n = 70,813) within 180 days after diagnosis (Table 3). Visit rates varied by cancer type: individuals with pancreatic (62%), brain (60%), and lung (55%) cancers had the highest cumulative incidences of ED use within 180 days of diagnosis (Table 3). Those with melanoma (14%), prostate (17%), and eye (18%) cancers had the lowest cumulative incidences of ED visits (Table 3).

For patients with certain cancers (eg, lung, pancreas, leukemia) the proportion of individuals with an initial ED visit was highest in the first 30 days after diagnosis (Table 3). For individuals with other cancers (eg, breast, prostate, melanoma) the proportion of individuals with an initial ED visit increased by more than 5% during the 31-181–day time period. Those with the remaining cancers had less than 5% change in cumulative ED use between the two time periods.

The number of visits per person ranged from 0-44 during the first 180 days after diagnosis (results not shown in tables). Of all patients diagnosed with cancer, 20% (n = 39,429) had one ED visit, 8% (n = 16,238) had two visits, and 7% (n = 14,760) had three or more visits. Of those patients having at least one ED visit within 180 days of diagnosis, 44% (n = 31,080) had two or more visits and 21% (n = 14,760) had 3 or more visits.

Discussion

This study extends previous research by describing ED use for more than 20 cancer types by time from diagnosis in a large, heterogeneous and population-based sample of recently diagnosed adults in California. We found that 16% of newly diagnosed individuals with cancer used the ED within 30 days of diagnosis, 35% within 6 months of diagnosis, and 44% within 1 year of diagnosis. These findings suggest that ED use by cancer patients is more than double that of the US general population and is higher than previously estimated for cancer patients.^10,24 In 2010, about 21% of the US population visited the ED, compared with 44% of cancer patients in the same time period.²⁴ Although persons with greater medical need, such as those with cancer, inevitably require more health services, new approaches are needed to explore the extent to which some of these visits by cancer patients could be prevented by providing care in other settings.

Few studies have examined ED use by cancer patients, but previous findings suggest that 1%-12% of cancer patients use the ED within 30 days of diagnosis, and 15%-25% use the ED within a year of diagnosis.^10,25,26 One study did report higher rates of ED use by cancer patients, but attributed the increased use to changes in Medicaid copayments.²⁷ The finding that ED use is higher among cancer patients than previously considered is important for several reasons. First, high rates of ED use may reflect excessive fragmentation in cancer care, or patients’ inability to access providers when acute concerns arise. Furthermore, providers and policymakers may be particularly interested in populations with high ED use because reducing potentially preventable ED use is often cited as one of the goals of care coordination and alternative health care model programs.^2,28,29

The number of newly diagnosed cancer patients with multiple ED visits is also substantial. We found 15% of recently diagnosed cancer patients had two or more ED visits within 180 days of diagnosis, compared with 8% of the general US population having two or more ED visits in all of 2010.²⁴ Among cancer patients with at least one ED visit, 44% visited more than once. Repeat visits may represent worsening health status, continued unmet health needs, or new complications that might have been prevented or treated in other health care settings. In addition, there may be opportunities to identify cancer patients at risk for multiple visits at their initial ED visit. A better understanding of the reasons for ED visits and the factors driving unmet need – such as inadequate patient education, limited access to specialty services, or failure to admit a patient to resolve a problem appropriately (eg, pain, infection) – may help to identify which visits are potentially preventable. Ultimately, failure to adequately describe the number of cancer patients that visit the ED and the number of times they visit may result in a lost opportunity for improvement in care, the patient experience and cost reduction in cancer care.

The distinction between cancer types that account for the most ED visits and cancer types with the highest cumulative incidences of ED use is informative. For instance, lung cancer patients accounted for the largest number of ED visits and over half of those with lung cancer visited the ED within 180 days of diagnosis. However, although more than 60% of individuals with pancreatic cancer visited an ED within 180 days of diagnosis; they accounted for only 5% of all ED visits by cancer patients during the same time period. This in part reflects the relative frequency of these cancers. However, prostate cancer, which has a high incidence rate, represents about 8% of all ED visits by cancer patients, yet only 17% of all prostate cancer patients visit the ED within 180 days of diagnosis.

One approach to reduce the absolute number of ED visits by cancer patients would be to target the most frequent users of the ED such as lung, breast, prostate, and colon cancer patients. These cancers are the most common in the general population, so proportionate reduction in ED visits in these groups would have a large overall impact on ED use. Alternatively, patients with cancers that have high rates of ED use could be targeted with interventions to better address their needs. Additional studies of ED use among cancer patients, including understudied cancers, are needed to determine whether care provided in the ED could be provided in alternate clinical settings. Such research can also support training of emergency department staff to manage the full range of cancer-related conditions presenting to the ED.

Another approach to identifying potentially avoidable ED visits is to explore visits that result in admission to the hospital compared with those that result in discharge from the ED. In some circumstances, visits that result in discharge home may not have been true medical emergencies, and therefore might have been preventable. It is also true that even an acute problem requiring admission may have been preventable with timely outpatient management. While we found that 45% of visits ended in discharge home, over half of cancer patients who visit the ED are admitted to the hospital. This is higher than admission rates from the ED for the U.S. population overall (11%-15%),^30-32and even higher than the estimated rate of individuals with chronic conditions, such as diabetes (42%), who visit the ED and then are subsequently admitted to the hospital.³³

Relatively high rates of admissions may indicate that cancer patients seeking care in the ED require increased medical attention; however, it is possible that other explanations exist. For instance, ED physicians may be uncomfortable with complex cancer cases and may admit patients to be evaluated by a specialist. As such, it is possible that some of these admissions could have been appropriate for outpatient follow up. It is also possible that patients are referred to the ED for admission to the hospital. In these situations the ED visit may be entirely preventable through a direct admission process, although such processes are not available at all institutions and may vary by the admitting provider. For instance, if a hospitalist is overseeing the hospital stay, they may prefer the admission to occur through the ED, whereas a primary care provider or oncologist may be more likely to facilitate a direct admission. Future research could address the extent to which admissions from the ED may be avoidable by examining reasons for and length of admission following an ED visit. While this study found top reasons for admission (principal diagnosis) to be septicemia, cardiovascular complaints and complications from surgery, cumulatively these diagnosis accounted for less than 20% of admissions from the ED. Examining frequent diagnoses by cancer type will also provide insight into potentially avoidable ED use, which may vary by disease course and treatment regimen.

The distribution of days from diagnosis to the first ED visit also varied by cancer type. This variation is likely attributable, at least in part, to differences in condition-specific treatment regimens, severity of illness, and stage at diagnosis. For example, patients with ED visits within 30 days of diagnosis may be those with advanced stage cancers who are at higher risk of complications, or they may be visiting the ED for post-surgical problems. Likewise, individuals who incur visits during later time periods may be undergoing longer treatment regimens. Further research is warranted to explore site-specific predictors of ED use and high-risk periods, accounting for cancer treatment and the timing of treatments.

In summary, ED use among cancer patients is substantial and higher than previously reported. Most ED visits occur within the first 180 days after diagnosis, suggesting focus on the first 30 days after hospital discharge may be misguided. Time frames for ED measurement in future research should be selected with careful attention to cancer-specific periods within which most ED use occurs and the outcomes of interest. Furthermore, better models identifying cancer-specific predictors of ED use, which account for treatment and comorbidities, will facilitate the development of interventions focused on high-risk segments of this population. Research is needed to explore cancer-specific reasons for ED visits and which ED admission diagnoses may be potentially preventable.

Limitations

The limitations of this study include those common to use of administrative and registry data and the CCR and OSHPD data in particular. While CCR data are known to be complete with respect to demographic and cancer information, treatment data is less robust and specific treatment dates are not available.^14,34 As a result, we were unable to analyze ED use in relation to receipt of outpatient treatment. As we included all ED visits on or up to a year after the day of diagnosis, it is possible that our analysis includes diagnoses that occurred in conjunction with an ED visits. However, it is unlikely a reporting hospital would report a cancer diagnosis to the CCR without a corresponding hospital admission. Therefore, we assume such cases to be rare.

Lastly, California had lower prevalence of health insurance coverage and higher market penetration by health maintenance organizations, relative to the national average, which may limit the generalizability of the results to other states.³⁵ At the same time, CCR-OSHPD linked data offer the advantage of providing complete data to enumerate ED visits among patients whether they were discharged home or subsequently admitted to hospital.

In 2017 there will be nearly 1.7 million new cancer cases diagnosed, and over 600,000 cancer deaths in the Unites States.¹ A 2013 Institute of Medicine report highlighted problems with the current quality of cancer care, including high costs and fragmentation of care.² Other national reports have called for improvements in the overall quality of care and for reducing costly and possibly avoidable use of health services such as emergency department (ED) visits.^3-6 Reduction of avoidable ED visits is often cited as a pathway to reduce costs by avoiding unnecessary tests and treatments that occur in the ED and subsequent hospital admissions.^7,8

ED crowding, long waits, and unpredictable treatment environments can also make an ED visit an unpleasant experience for the patient. ED visits during cancer treatment can be particularly troubling and present health concerns for patients who are immunocompromised. In particular, cancer patients in the ED have been found to experience delays in the administration of analgesics, antiemetics, or antibiotics.⁹

Few studies have examined ED use or its associated predictors among cancer patients. Reports to date that have described ED use have focused on different cancers, which makes comparisons across studies difficult.¹⁰ Moreover, the time frames of interest and the type of event after which ED use is evaluated (ie, diagnosis or treatment) are inconsistent in the existing literature.¹⁰ Some studies quantifying ED use excluded patients admitted to the hospital after an ED visit.^11,12 Taken together, these studies do not provide a clear overview of the extent of ED use by cancer patients or the amount of cancer-related care provided by EDs.

Patterns of ED use among cancer patients derived from large and generalizable samples may help inform providers about true risk factors for ED use. In addition, prioritizing new interventions and focusing future research on groups of patients who are at higher risk for preventable ED use could also improve overall care. To address these issues, accurate estimates of ED use among cancer patients are required.

To our knowledge, this is the first study to describe ED use across a range of cancers in a large population-based sample and to consider the timing of ED visits in relation to initial diagnosis. The findings could provide benchmark comparison data to inform future efforts to identify the subset of possibly preventable ED visits and to design interventions to address preventable ED use.

Material and methods

Data source

California’s Office of Statewide Health Planning and Development (OSHPD) manages the patient discharge dataset (PDD) and the emergency department use (EDU) dataset, providing a high-quality source of information on inpatient and ED use in the state.¹³ A principal diagnosis and up to 24 secondary diagnoses are recorded in OSHPD datasets. The EDU dataset was used to identify treat-and-release ED visits, and the PDD was used to identify hospitalizations initiated in the ED. The California Cancer Registry (CCR) obtains demographic and diagnosis information for every new invasive cancer diagnosed in California, and data collected by the registry are considered to be complete.¹⁴ CCR-OSPHD-linked data provide high-quality health care use information for cancer patients in California.^15,16 Using an encrypted version of the social security number called the record linkage number (RLN), we linked the CCR records to the corresponding OSHPD files from 2009-2010.

Institutional review board approval for this study was obtained from the University of California, Davis, Human Subjects Committee and the State of California Committee for the Protection of Human Subjects.

Analysis

ED visits. Visits were included if they occurred on or up to 365 days after the date of cancer diagnosis recorded in the CCR. The visits were coded in mutually exclusive groups as occurring within 30, 31-180, and 181-365 days of diagnosis. Subsequently, we flagged each person as having any ED visit (Yes/No) within 180 days and within 365 days of diagnosis, and we tallied the total number of visits occurring within these time frames for each person.

Cancer type. We used relevant site and histology codes to classify cancer type into 24 mutually exclusive categories using the Surveillance Epidemiology and End Result‘s International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3) Recode Definitions^17-19 (Suppl Figure 1).

Individual-level variables. Sociodemographic information for each person was collected from the CCR including gender, age, race/ethnicity, marital status, health insurance status, rural residence, survival time in months, neighborhood socio-economic (SES) status based on the Yang index, and the American Joint Committee on Cancer (AJCC) stage.^20,21

Data analysis

Demographic information was analyzed for the cohort using descriptive statistics (frequencies, proportions, means, standard deviations, and ranges) and evaluated for correlations. Fewer than 20 observations had missing data and we removed those observations from our analyses on an item-specific basis.

We tabulated ED visits by cancer type and time from diagnosis and then collapsed visit-level data by RLN to determine the number of ED visits for each person in the sample. The number of days from diagnosis to first ED visit was also tabulated. The cohort was stratified by cancer type and cumulative rates of ED visits were tabulated for individuals with ED visits within 0-180 and 0-365 days from diagnosis. To test the robustness of the findings adjusting for confounding factors known to impact ED use, we used logistic regression to model any ED use (Yes/No) as a function of age, gender, race/ethnicity, cancer stage, insurance status, marital status, urban residence, and Yang SES. After model estimation, we used the method of recycled predictions controlling for the confounding variables to compute the marginal probabilities of ED use by cancer type.²² To adjust for the possible impact of survival on ED use, we performed sensitivity analyses and estimated predicted probabilities adjusting for survival. Separate analyses were performed first adjusting for whether the patient died during the course of each month after diagnosis and then adjusting for whether or not the patient died within 180 days of diagnosis. All analyses were conducted using Stata 13.1.²³

Results

The CCR identified 222,087 adults with a new primary cancer diagnosis in 2009-2010. After excluding those with Stage 0 cancer (n = 21,154) and nonmelanoma skin cancer (n = 1,031), for whom data are inconsistently collected by CCR, a total of 199,872 individuals were included in the analytic sample. Of those patients (Table 1), most were white non-Hispanic (62%), women (51%), holders of private insurance (53%), married (56%), and urban residents (86%). Most were older than 50 years and had either Stage I or Stage II cancer. The most common cancer types were breast (17%), prostate (16%), lung (11%), and colon (9%; results not shown). In unadjusted comparisons, the incidence of ED use was significantly higher among those who were older, of non-Hispanic black race/ethnicity, uninsured, in the lowest SES group, widowed, or diagnosed with Stage IV cancer (Table 1).

ED visits

Within 365 days after initial cancer diagnosis, 87,025 cancer patients made a total of 197,886 ED visits (not shown in tables). Of those visits, 68% (n = 134,556) occurred within 180 days of diagnosis, with 22% (n = 43,535) occurring within the first 30 days and 46% (n = 91,027) occurring within 31-180 days after diagnosis (Figure). Given that most of the visits occurred within 180 days of diagnosis, we used that time frame in subsequent analyses. Among all ED visits within 180 days of diagnosis (Table 2), the largest proportions of visits were made by those with lung cancer (16%), breast cancer (11%), and colon cancer (10%).

About 51% of visits resulted in admission to the hospital and 45% in discharge (Table 2). For some cancers (lung, colon, non-Hodgkin lymphoma, pancreatic, digestive, liver, stomach, leukemia, and myeloma) most of the visits resulted in admission to the hospital (Table 2). Among visits resulting in admission, the top three principal diagnoses were: septicemia (8%), cardiovascular problems (7%), and complications from surgery (5%) (not shown in tables). Among visits resulting in a discharge home, the three top principal diagnoses were abdominal pain (7%), cardiovascular problems (6%), and urinary, kidney, and bladder complaints other than a urinary tract infection (5%) (results not shown).

Individuals

The cumulative incidence of at least one ED visit was 35% (n = 70,813) within 180 days after diagnosis (Table 3). Visit rates varied by cancer type: individuals with pancreatic (62%), brain (60%), and lung (55%) cancers had the highest cumulative incidences of ED use within 180 days of diagnosis (Table 3). Those with melanoma (14%), prostate (17%), and eye (18%) cancers had the lowest cumulative incidences of ED visits (Table 3).

For patients with certain cancers (eg, lung, pancreas, leukemia) the proportion of individuals with an initial ED visit was highest in the first 30 days after diagnosis (Table 3). For individuals with other cancers (eg, breast, prostate, melanoma) the proportion of individuals with an initial ED visit increased by more than 5% during the 31-181–day time period. Those with the remaining cancers had less than 5% change in cumulative ED use between the two time periods.

The number of visits per person ranged from 0-44 during the first 180 days after diagnosis (results not shown in tables). Of all patients diagnosed with cancer, 20% (n = 39,429) had one ED visit, 8% (n = 16,238) had two visits, and 7% (n = 14,760) had three or more visits. Of those patients having at least one ED visit within 180 days of diagnosis, 44% (n = 31,080) had two or more visits and 21% (n = 14,760) had 3 or more visits.

Discussion

This study extends previous research by describing ED use for more than 20 cancer types by time from diagnosis in a large, heterogeneous and population-based sample of recently diagnosed adults in California. We found that 16% of newly diagnosed individuals with cancer used the ED within 30 days of diagnosis, 35% within 6 months of diagnosis, and 44% within 1 year of diagnosis. These findings suggest that ED use by cancer patients is more than double that of the US general population and is higher than previously estimated for cancer patients.^10,24 In 2010, about 21% of the US population visited the ED, compared with 44% of cancer patients in the same time period.²⁴ Although persons with greater medical need, such as those with cancer, inevitably require more health services, new approaches are needed to explore the extent to which some of these visits by cancer patients could be prevented by providing care in other settings.

Few studies have examined ED use by cancer patients, but previous findings suggest that 1%-12% of cancer patients use the ED within 30 days of diagnosis, and 15%-25% use the ED within a year of diagnosis.^10,25,26 One study did report higher rates of ED use by cancer patients, but attributed the increased use to changes in Medicaid copayments.²⁷ The finding that ED use is higher among cancer patients than previously considered is important for several reasons. First, high rates of ED use may reflect excessive fragmentation in cancer care, or patients’ inability to access providers when acute concerns arise. Furthermore, providers and policymakers may be particularly interested in populations with high ED use because reducing potentially preventable ED use is often cited as one of the goals of care coordination and alternative health care model programs.^2,28,29

The number of newly diagnosed cancer patients with multiple ED visits is also substantial. We found 15% of recently diagnosed cancer patients had two or more ED visits within 180 days of diagnosis, compared with 8% of the general US population having two or more ED visits in all of 2010.²⁴ Among cancer patients with at least one ED visit, 44% visited more than once. Repeat visits may represent worsening health status, continued unmet health needs, or new complications that might have been prevented or treated in other health care settings. In addition, there may be opportunities to identify cancer patients at risk for multiple visits at their initial ED visit. A better understanding of the reasons for ED visits and the factors driving unmet need – such as inadequate patient education, limited access to specialty services, or failure to admit a patient to resolve a problem appropriately (eg, pain, infection) – may help to identify which visits are potentially preventable. Ultimately, failure to adequately describe the number of cancer patients that visit the ED and the number of times they visit may result in a lost opportunity for improvement in care, the patient experience and cost reduction in cancer care.

The distinction between cancer types that account for the most ED visits and cancer types with the highest cumulative incidences of ED use is informative. For instance, lung cancer patients accounted for the largest number of ED visits and over half of those with lung cancer visited the ED within 180 days of diagnosis. However, although more than 60% of individuals with pancreatic cancer visited an ED within 180 days of diagnosis; they accounted for only 5% of all ED visits by cancer patients during the same time period. This in part reflects the relative frequency of these cancers. However, prostate cancer, which has a high incidence rate, represents about 8% of all ED visits by cancer patients, yet only 17% of all prostate cancer patients visit the ED within 180 days of diagnosis.

One approach to reduce the absolute number of ED visits by cancer patients would be to target the most frequent users of the ED such as lung, breast, prostate, and colon cancer patients. These cancers are the most common in the general population, so proportionate reduction in ED visits in these groups would have a large overall impact on ED use. Alternatively, patients with cancers that have high rates of ED use could be targeted with interventions to better address their needs. Additional studies of ED use among cancer patients, including understudied cancers, are needed to determine whether care provided in the ED could be provided in alternate clinical settings. Such research can also support training of emergency department staff to manage the full range of cancer-related conditions presenting to the ED.

Another approach to identifying potentially avoidable ED visits is to explore visits that result in admission to the hospital compared with those that result in discharge from the ED. In some circumstances, visits that result in discharge home may not have been true medical emergencies, and therefore might have been preventable. It is also true that even an acute problem requiring admission may have been preventable with timely outpatient management. While we found that 45% of visits ended in discharge home, over half of cancer patients who visit the ED are admitted to the hospital. This is higher than admission rates from the ED for the U.S. population overall (11%-15%),^30-32and even higher than the estimated rate of individuals with chronic conditions, such as diabetes (42%), who visit the ED and then are subsequently admitted to the hospital.³³

Relatively high rates of admissions may indicate that cancer patients seeking care in the ED require increased medical attention; however, it is possible that other explanations exist. For instance, ED physicians may be uncomfortable with complex cancer cases and may admit patients to be evaluated by a specialist. As such, it is possible that some of these admissions could have been appropriate for outpatient follow up. It is also possible that patients are referred to the ED for admission to the hospital. In these situations the ED visit may be entirely preventable through a direct admission process, although such processes are not available at all institutions and may vary by the admitting provider. For instance, if a hospitalist is overseeing the hospital stay, they may prefer the admission to occur through the ED, whereas a primary care provider or oncologist may be more likely to facilitate a direct admission. Future research could address the extent to which admissions from the ED may be avoidable by examining reasons for and length of admission following an ED visit. While this study found top reasons for admission (principal diagnosis) to be septicemia, cardiovascular complaints and complications from surgery, cumulatively these diagnosis accounted for less than 20% of admissions from the ED. Examining frequent diagnoses by cancer type will also provide insight into potentially avoidable ED use, which may vary by disease course and treatment regimen.

The distribution of days from diagnosis to the first ED visit also varied by cancer type. This variation is likely attributable, at least in part, to differences in condition-specific treatment regimens, severity of illness, and stage at diagnosis. For example, patients with ED visits within 30 days of diagnosis may be those with advanced stage cancers who are at higher risk of complications, or they may be visiting the ED for post-surgical problems. Likewise, individuals who incur visits during later time periods may be undergoing longer treatment regimens. Further research is warranted to explore site-specific predictors of ED use and high-risk periods, accounting for cancer treatment and the timing of treatments.

In summary, ED use among cancer patients is substantial and higher than previously reported. Most ED visits occur within the first 180 days after diagnosis, suggesting focus on the first 30 days after hospital discharge may be misguided. Time frames for ED measurement in future research should be selected with careful attention to cancer-specific periods within which most ED use occurs and the outcomes of interest. Furthermore, better models identifying cancer-specific predictors of ED use, which account for treatment and comorbidities, will facilitate the development of interventions focused on high-risk segments of this population. Research is needed to explore cancer-specific reasons for ED visits and which ED admission diagnoses may be potentially preventable.

Limitations

The limitations of this study include those common to use of administrative and registry data and the CCR and OSHPD data in particular. While CCR data are known to be complete with respect to demographic and cancer information, treatment data is less robust and specific treatment dates are not available.^14,34 As a result, we were unable to analyze ED use in relation to receipt of outpatient treatment. As we included all ED visits on or up to a year after the day of diagnosis, it is possible that our analysis includes diagnoses that occurred in conjunction with an ED visits. However, it is unlikely a reporting hospital would report a cancer diagnosis to the CCR without a corresponding hospital admission. Therefore, we assume such cases to be rare.

Lastly, California had lower prevalence of health insurance coverage and higher market penetration by health maintenance organizations, relative to the national average, which may limit the generalizability of the results to other states.³⁵ At the same time, CCR-OSHPD linked data offer the advantage of providing complete data to enumerate ED visits among patients whether they were discharged home or subsequently admitted to hospital.

In 2017 there will be nearly 1.7 million new cancer cases diagnosed, and over 600,000 cancer deaths in the Unites States.¹ A 2013 Institute of Medicine report highlighted problems with the current quality of cancer care, including high costs and fragmentation of care.² Other national reports have called for improvements in the overall quality of care and for reducing costly and possibly avoidable use of health services such as emergency department (ED) visits.^3-6 Reduction of avoidable ED visits is often cited as a pathway to reduce costs by avoiding unnecessary tests and treatments that occur in the ED and subsequent hospital admissions.^7,8

ED crowding, long waits, and unpredictable treatment environments can also make an ED visit an unpleasant experience for the patient. ED visits during cancer treatment can be particularly troubling and present health concerns for patients who are immunocompromised. In particular, cancer patients in the ED have been found to experience delays in the administration of analgesics, antiemetics, or antibiotics.⁹

Few studies have examined ED use or its associated predictors among cancer patients. Reports to date that have described ED use have focused on different cancers, which makes comparisons across studies difficult.¹⁰ Moreover, the time frames of interest and the type of event after which ED use is evaluated (ie, diagnosis or treatment) are inconsistent in the existing literature.¹⁰ Some studies quantifying ED use excluded patients admitted to the hospital after an ED visit.^11,12 Taken together, these studies do not provide a clear overview of the extent of ED use by cancer patients or the amount of cancer-related care provided by EDs.

Patterns of ED use among cancer patients derived from large and generalizable samples may help inform providers about true risk factors for ED use. In addition, prioritizing new interventions and focusing future research on groups of patients who are at higher risk for preventable ED use could also improve overall care. To address these issues, accurate estimates of ED use among cancer patients are required.

To our knowledge, this is the first study to describe ED use across a range of cancers in a large population-based sample and to consider the timing of ED visits in relation to initial diagnosis. The findings could provide benchmark comparison data to inform future efforts to identify the subset of possibly preventable ED visits and to design interventions to address preventable ED use.

Material and methods

Data source

California’s Office of Statewide Health Planning and Development (OSHPD) manages the patient discharge dataset (PDD) and the emergency department use (EDU) dataset, providing a high-quality source of information on inpatient and ED use in the state.¹³ A principal diagnosis and up to 24 secondary diagnoses are recorded in OSHPD datasets. The EDU dataset was used to identify treat-and-release ED visits, and the PDD was used to identify hospitalizations initiated in the ED. The California Cancer Registry (CCR) obtains demographic and diagnosis information for every new invasive cancer diagnosed in California, and data collected by the registry are considered to be complete.¹⁴ CCR-OSPHD-linked data provide high-quality health care use information for cancer patients in California.^15,16 Using an encrypted version of the social security number called the record linkage number (RLN), we linked the CCR records to the corresponding OSHPD files from 2009-2010.

Institutional review board approval for this study was obtained from the University of California, Davis, Human Subjects Committee and the State of California Committee for the Protection of Human Subjects.

Analysis

ED visits. Visits were included if they occurred on or up to 365 days after the date of cancer diagnosis recorded in the CCR. The visits were coded in mutually exclusive groups as occurring within 30, 31-180, and 181-365 days of diagnosis. Subsequently, we flagged each person as having any ED visit (Yes/No) within 180 days and within 365 days of diagnosis, and we tallied the total number of visits occurring within these time frames for each person.

Cancer type. We used relevant site and histology codes to classify cancer type into 24 mutually exclusive categories using the Surveillance Epidemiology and End Result‘s International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3) Recode Definitions^17-19 (Suppl Figure 1).

Individual-level variables. Sociodemographic information for each person was collected from the CCR including gender, age, race/ethnicity, marital status, health insurance status, rural residence, survival time in months, neighborhood socio-economic (SES) status based on the Yang index, and the American Joint Committee on Cancer (AJCC) stage.^20,21

Data analysis

Demographic information was analyzed for the cohort using descriptive statistics (frequencies, proportions, means, standard deviations, and ranges) and evaluated for correlations. Fewer than 20 observations had missing data and we removed those observations from our analyses on an item-specific basis.

We tabulated ED visits by cancer type and time from diagnosis and then collapsed visit-level data by RLN to determine the number of ED visits for each person in the sample. The number of days from diagnosis to first ED visit was also tabulated. The cohort was stratified by cancer type and cumulative rates of ED visits were tabulated for individuals with ED visits within 0-180 and 0-365 days from diagnosis. To test the robustness of the findings adjusting for confounding factors known to impact ED use, we used logistic regression to model any ED use (Yes/No) as a function of age, gender, race/ethnicity, cancer stage, insurance status, marital status, urban residence, and Yang SES. After model estimation, we used the method of recycled predictions controlling for the confounding variables to compute the marginal probabilities of ED use by cancer type.²² To adjust for the possible impact of survival on ED use, we performed sensitivity analyses and estimated predicted probabilities adjusting for survival. Separate analyses were performed first adjusting for whether the patient died during the course of each month after diagnosis and then adjusting for whether or not the patient died within 180 days of diagnosis. All analyses were conducted using Stata 13.1.²³

Results

The CCR identified 222,087 adults with a new primary cancer diagnosis in 2009-2010. After excluding those with Stage 0 cancer (n = 21,154) and nonmelanoma skin cancer (n = 1,031), for whom data are inconsistently collected by CCR, a total of 199,872 individuals were included in the analytic sample. Of those patients (Table 1), most were white non-Hispanic (62%), women (51%), holders of private insurance (53%), married (56%), and urban residents (86%). Most were older than 50 years and had either Stage I or Stage II cancer. The most common cancer types were breast (17%), prostate (16%), lung (11%), and colon (9%; results not shown). In unadjusted comparisons, the incidence of ED use was significantly higher among those who were older, of non-Hispanic black race/ethnicity, uninsured, in the lowest SES group, widowed, or diagnosed with Stage IV cancer (Table 1).

ED visits

Within 365 days after initial cancer diagnosis, 87,025 cancer patients made a total of 197,886 ED visits (not shown in tables). Of those visits, 68% (n = 134,556) occurred within 180 days of diagnosis, with 22% (n = 43,535) occurring within the first 30 days and 46% (n = 91,027) occurring within 31-180 days after diagnosis (Figure). Given that most of the visits occurred within 180 days of diagnosis, we used that time frame in subsequent analyses. Among all ED visits within 180 days of diagnosis (Table 2), the largest proportions of visits were made by those with lung cancer (16%), breast cancer (11%), and colon cancer (10%).

About 51% of visits resulted in admission to the hospital and 45% in discharge (Table 2). For some cancers (lung, colon, non-Hodgkin lymphoma, pancreatic, digestive, liver, stomach, leukemia, and myeloma) most of the visits resulted in admission to the hospital (Table 2). Among visits resulting in admission, the top three principal diagnoses were: septicemia (8%), cardiovascular problems (7%), and complications from surgery (5%) (not shown in tables). Among visits resulting in a discharge home, the three top principal diagnoses were abdominal pain (7%), cardiovascular problems (6%), and urinary, kidney, and bladder complaints other than a urinary tract infection (5%) (results not shown).

Individuals

The cumulative incidence of at least one ED visit was 35% (n = 70,813) within 180 days after diagnosis (Table 3). Visit rates varied by cancer type: individuals with pancreatic (62%), brain (60%), and lung (55%) cancers had the highest cumulative incidences of ED use within 180 days of diagnosis (Table 3). Those with melanoma (14%), prostate (17%), and eye (18%) cancers had the lowest cumulative incidences of ED visits (Table 3).

For patients with certain cancers (eg, lung, pancreas, leukemia) the proportion of individuals with an initial ED visit was highest in the first 30 days after diagnosis (Table 3). For individuals with other cancers (eg, breast, prostate, melanoma) the proportion of individuals with an initial ED visit increased by more than 5% during the 31-181–day time period. Those with the remaining cancers had less than 5% change in cumulative ED use between the two time periods.

The number of visits per person ranged from 0-44 during the first 180 days after diagnosis (results not shown in tables). Of all patients diagnosed with cancer, 20% (n = 39,429) had one ED visit, 8% (n = 16,238) had two visits, and 7% (n = 14,760) had three or more visits. Of those patients having at least one ED visit within 180 days of diagnosis, 44% (n = 31,080) had two or more visits and 21% (n = 14,760) had 3 or more visits.

Discussion

This study extends previous research by describing ED use for more than 20 cancer types by time from diagnosis in a large, heterogeneous and population-based sample of recently diagnosed adults in California. We found that 16% of newly diagnosed individuals with cancer used the ED within 30 days of diagnosis, 35% within 6 months of diagnosis, and 44% within 1 year of diagnosis. These findings suggest that ED use by cancer patients is more than double that of the US general population and is higher than previously estimated for cancer patients.^10,24 In 2010, about 21% of the US population visited the ED, compared with 44% of cancer patients in the same time period.²⁴ Although persons with greater medical need, such as those with cancer, inevitably require more health services, new approaches are needed to explore the extent to which some of these visits by cancer patients could be prevented by providing care in other settings.

Few studies have examined ED use by cancer patients, but previous findings suggest that 1%-12% of cancer patients use the ED within 30 days of diagnosis, and 15%-25% use the ED within a year of diagnosis.^10,25,26 One study did report higher rates of ED use by cancer patients, but attributed the increased use to changes in Medicaid copayments.²⁷ The finding that ED use is higher among cancer patients than previously considered is important for several reasons. First, high rates of ED use may reflect excessive fragmentation in cancer care, or patients’ inability to access providers when acute concerns arise. Furthermore, providers and policymakers may be particularly interested in populations with high ED use because reducing potentially preventable ED use is often cited as one of the goals of care coordination and alternative health care model programs.^2,28,29

The number of newly diagnosed cancer patients with multiple ED visits is also substantial. We found 15% of recently diagnosed cancer patients had two or more ED visits within 180 days of diagnosis, compared with 8% of the general US population having two or more ED visits in all of 2010.²⁴ Among cancer patients with at least one ED visit, 44% visited more than once. Repeat visits may represent worsening health status, continued unmet health needs, or new complications that might have been prevented or treated in other health care settings. In addition, there may be opportunities to identify cancer patients at risk for multiple visits at their initial ED visit. A better understanding of the reasons for ED visits and the factors driving unmet need – such as inadequate patient education, limited access to specialty services, or failure to admit a patient to resolve a problem appropriately (eg, pain, infection) – may help to identify which visits are potentially preventable. Ultimately, failure to adequately describe the number of cancer patients that visit the ED and the number of times they visit may result in a lost opportunity for improvement in care, the patient experience and cost reduction in cancer care.

The distinction between cancer types that account for the most ED visits and cancer types with the highest cumulative incidences of ED use is informative. For instance, lung cancer patients accounted for the largest number of ED visits and over half of those with lung cancer visited the ED within 180 days of diagnosis. However, although more than 60% of individuals with pancreatic cancer visited an ED within 180 days of diagnosis; they accounted for only 5% of all ED visits by cancer patients during the same time period. This in part reflects the relative frequency of these cancers. However, prostate cancer, which has a high incidence rate, represents about 8% of all ED visits by cancer patients, yet only 17% of all prostate cancer patients visit the ED within 180 days of diagnosis.

One approach to reduce the absolute number of ED visits by cancer patients would be to target the most frequent users of the ED such as lung, breast, prostate, and colon cancer patients. These cancers are the most common in the general population, so proportionate reduction in ED visits in these groups would have a large overall impact on ED use. Alternatively, patients with cancers that have high rates of ED use could be targeted with interventions to better address their needs. Additional studies of ED use among cancer patients, including understudied cancers, are needed to determine whether care provided in the ED could be provided in alternate clinical settings. Such research can also support training of emergency department staff to manage the full range of cancer-related conditions presenting to the ED.

Another approach to identifying potentially avoidable ED visits is to explore visits that result in admission to the hospital compared with those that result in discharge from the ED. In some circumstances, visits that result in discharge home may not have been true medical emergencies, and therefore might have been preventable. It is also true that even an acute problem requiring admission may have been preventable with timely outpatient management. While we found that 45% of visits ended in discharge home, over half of cancer patients who visit the ED are admitted to the hospital. This is higher than admission rates from the ED for the U.S. population overall (11%-15%),^30-32and even higher than the estimated rate of individuals with chronic conditions, such as diabetes (42%), who visit the ED and then are subsequently admitted to the hospital.³³

Relatively high rates of admissions may indicate that cancer patients seeking care in the ED require increased medical attention; however, it is possible that other explanations exist. For instance, ED physicians may be uncomfortable with complex cancer cases and may admit patients to be evaluated by a specialist. As such, it is possible that some of these admissions could have been appropriate for outpatient follow up. It is also possible that patients are referred to the ED for admission to the hospital. In these situations the ED visit may be entirely preventable through a direct admission process, although such processes are not available at all institutions and may vary by the admitting provider. For instance, if a hospitalist is overseeing the hospital stay, they may prefer the admission to occur through the ED, whereas a primary care provider or oncologist may be more likely to facilitate a direct admission. Future research could address the extent to which admissions from the ED may be avoidable by examining reasons for and length of admission following an ED visit. While this study found top reasons for admission (principal diagnosis) to be septicemia, cardiovascular complaints and complications from surgery, cumulatively these diagnosis accounted for less than 20% of admissions from the ED. Examining frequent diagnoses by cancer type will also provide insight into potentially avoidable ED use, which may vary by disease course and treatment regimen.

The distribution of days from diagnosis to the first ED visit also varied by cancer type. This variation is likely attributable, at least in part, to differences in condition-specific treatment regimens, severity of illness, and stage at diagnosis. For example, patients with ED visits within 30 days of diagnosis may be those with advanced stage cancers who are at higher risk of complications, or they may be visiting the ED for post-surgical problems. Likewise, individuals who incur visits during later time periods may be undergoing longer treatment regimens. Further research is warranted to explore site-specific predictors of ED use and high-risk periods, accounting for cancer treatment and the timing of treatments.

In summary, ED use among cancer patients is substantial and higher than previously reported. Most ED visits occur within the first 180 days after diagnosis, suggesting focus on the first 30 days after hospital discharge may be misguided. Time frames for ED measurement in future research should be selected with careful attention to cancer-specific periods within which most ED use occurs and the outcomes of interest. Furthermore, better models identifying cancer-specific predictors of ED use, which account for treatment and comorbidities, will facilitate the development of interventions focused on high-risk segments of this population. Research is needed to explore cancer-specific reasons for ED visits and which ED admission diagnoses may be potentially preventable.

Limitations

The limitations of this study include those common to use of administrative and registry data and the CCR and OSHPD data in particular. While CCR data are known to be complete with respect to demographic and cancer information, treatment data is less robust and specific treatment dates are not available.^14,34 As a result, we were unable to analyze ED use in relation to receipt of outpatient treatment. As we included all ED visits on or up to a year after the day of diagnosis, it is possible that our analysis includes diagnoses that occurred in conjunction with an ED visits. However, it is unlikely a reporting hospital would report a cancer diagnosis to the CCR without a corresponding hospital admission. Therefore, we assume such cases to be rare.

Lastly, California had lower prevalence of health insurance coverage and higher market penetration by health maintenance organizations, relative to the national average, which may limit the generalizability of the results to other states.³⁵ At the same time, CCR-OSHPD linked data offer the advantage of providing complete data to enumerate ED visits among patients whether they were discharged home or subsequently admitted to hospital.

Mammalian target of rapamycin (mTOR), a serine–threonine protein kinase, operates in the phosphoinositide 3-kinase (PI3K)–protein kinase B (AKT)–mTOR signal transduction pathway regulating both normal and cancer cellular processes, including cell growth, proliferation, motility, survival, and protein and lipid synthesis.¹ Genetic alterations affecting this pathway, including mutations in receptor tyrosine kinases PI3K and AKT, occur frequently in human cancers,² supporting the rationale to develop drugs that target pathway components, such as mTOR inhibitors.

Two mTOR inhibitors are currently approved by the US Food and Drug Administration for cancer treatment: temsirolimus, for advanced renal cell carcinoma (RCC; approved 2007)³ and everolimus, for advanced RCC (approved 2009), advanced pancreatic neuroendocrine tumors (pNET; approved 2011), and hormone receptor-positive (HR-positive), human epidermal growth factor receptor-2 (HER2)-negative advanced breast cancer (approved 2012).⁴ Another mTOR inhibitor, sirolimus, is approved for use as an immunosuppressive agent and prophylactic against organ rejection after kidney transplant.⁵

Stomatitis, inflammation of the oral mucosa with contributing factors of genetic predisposition, nutritional deficiencies, infections, and immunological or hematologic dysfunction,⁶ occurs frequently as a side effect associated with mTOR inhibitor treatment.^7-9 Left untreated or managed unsatisfactorily, mTOR inhibitor-associated stomatitis (mIAS) may cause patients discomfort and trouble with maintaining adequate nutritional intake and proper oral hygiene, as well as strict adherence to cancer treatment. It is therefore important for health care providers of cancer patients receiving mTOR inhibitor treatment to be knowledgeable about this side effect. The purpose of the present systematic review of published literature is to provide a better understanding of the differential diagnosis of mIAS, the pathophysiology of mIAS, preventive strategies for patients initiating mTOR inhibitor treatment, and treatment options available to manage mIAS.

Method

The PubMed database was searched with the terms mTOR inhibitor and stomatitis (no date restriction); 79 articles were retrieved, and all abstracts were reviewed to select those relevant to the aims of this review article. To understand future directions for management and prevention of mIAS, a search of clinicaltrials.gov was performed with the terms temsirolimus everolimus stomatitis yielding 12 clinical trials, of which 4 were excluded: 1 trial was terminated due to slow accrual, the status of 1 trial had not been verified in >2 years, and 2 studies focused on efficacy outcomes. A search of the American Society of Clinical Oncology (ASCO) meeting abstracts database was performed to assess the availability of clinical trial data; the search was limited to 2011-2016 and terms were stomatitis in the title and mTOR in the abstract or title. Seven abstracts were retrieved; 2 discussed stomatitis prevention (1 as a “trial-in-progress” and 1 presented results of the trial); the other 5 abstracts presented meta-analyses or reviews of previous clinical studies to assess the risk, incidence, management, and resolution of mIAS.

Review findings

Incidence of mIAS in patients treated for cancer

Two recent meta-analyses quantified the rate of mIAS in patients receiving mTOR inhibitors. Shameem and colleagues¹⁰ identified 9 randomized studies of everolimus (8 phase 3, 1 phase 2) and 2 of temsirolimus (1 each phase 2 and 3) involving a total of 4752 patients with a variety of tumor types including angiomyolipoma, breast, gastric, giant cell astrocytoma, pNET, and RCC. Patients received everolimus monotherapy (n = 1,075) or in combination with exemestane (n = 485), tamoxifen (n = 54), letrozole (n = 137), or octreotide (n = 216). Temsirolimus was administered as monotherapy (n = 208) or in combination with interferon
(n = 210) or letrozole (n = 550). The incidence of all-grade stomatitis in the 11 studies ranged from 11%-63%, and the overall incidence of any grade stomatitis was 33.5% (95% confidence interval [CI], 21.9%-47.6%). The concurrent use of a second agent may have confounded these findings because, for example, stomatitis has been reported in pooled analyses and in postmarketing experience with letrozole.¹¹

Rugo and colleagues¹² evaluated the incidence of stomatitis in 1455 patients participating in 5 phase 3 randomized clinical trials of everolimus in breast cancer, carcinoid tumor, pNET, and RCC. Patients received everolimus monotherapy
(n = 478) or in combination with exemestane (n = 482), trastuzumab plus vinorelbine (n = 280), or octreotide
(n = 215). The incidence of stomatitis in patients receiving everolimus was 59%-71%, compared with 19%-29% in 1,071 patients of the comparator arms (placebo, and placebo–trastuzumab–vinorelbine). The overall incidence of any grade stomatitis was 67%; most events were mild (grade 1/2); 9% of stomatitis events were moderate to severe (grade 3/4).

Differential clinical presentation of mIAS and severity

Oral mucositis is a common significant adverse event (AE) that occurs in patients with cancer who receive standard chemotherapy regimens and/or radiation therapy,¹³ so it is important to recognize that the clinical presentation of mIAS differs from that of oral mucositis (Table 1, Figure ^14,15).¹⁶ mIAS shares some similarities with aphthous ulcers (also referred to as canker sores), a common oral condition with varied causes related to systemic disorders, gastrointestinal disorders, and infections, among others .¹⁷ In general, mIAS ulcers develop with a median onset of 10 days (range, 4-25 days) after initiation of mTOR inhibitor treatment and resolve in about 1-3 weeks after dose interruption/reduction of everolimus.^16,18,19 mIAS ulcers appear as distinct, oval lesions with a central gray area surrounded by peripheral erythema. They are usually localized to the movable mucosa of the mouth and oropharynx. Although mIAS lesions are usually small, they are quite painful and may cluster.

Differential diagnosis of mIAS should be made based on physical examination and medical history, with consideration given to appearance of lesions (number, size, and location), current infection status, and current medications. Specific diagnostic testing should be conducted to confirm a coexisting or alternative cause of oral lesions.¹⁷

Although there are many different scales for grading mIAS severity, the most commonly used are the National Cancer Institute Common Terminology Criteria for Adverse Events (based on patient function, symptoms, and intervention needs) and the World Health Organization oral mucositis scales (based on symptoms, clinical presentation, and interference with patient function).^20-22 These scales distinguish between mild lesions (grade 1/2) and moderate to severe lesions (grade 3/4) that cause significant pain or interfere with oral intake.

Pathophysiology of mIAS

The pathophysiology mIAS is incompletely understood. The ubiquitous role of the PI3K-AKT-mTOR pathway in regulating broad cellular functions suggests that mTOR inhibition is likely to have wide-ranging effects on many biological processes. It is not known whether disruption of one or more processes – or upsetting the balance of mTOR activities – underlies the formation of mIAS.

Differences between mIAS and oral mucositis, including clinical presentation and concomitant toxicities,^16,23 suggest that the two types of oral lesions are fundamentally distinct. This distinction is supported by animal studies in which mTOR inhibition was found to almost completely prevent the appearance of oral mucositis in irradiated mice. The protective effect of mTOR inhibition is mediated through suppression of oxidative stress generated by radiation therapy.²⁴

Although mIAS and recurrent aphthous ulcers share some similarities, it is not clear whether they also share a common pathophysiology. Recent studies suggest that patients with recurrent aphthous ulcers have immune dysfunction that leads to excessive immune response to normally innocuous substrates in the oral mucosa.²⁵ mTOR inhibition can have proinflammatory activity by promoting autophagy, a process that stimulates antigen presentation and activation of T cells that produce proinflammatory cytokines.²⁶ It is interesting to note that the incidence of stomatitis in patients receiving sirolimus after kidney transplant is relatively low, 3%-20%.⁵ Sirolimus is administered in combination with other immunosuppressants, namely cyclosporine and corticosteroids, so it suggests that concomitant use of a steroid-based regimen may have a preventive or therapeutic effect. However, posttransplant sirolimus is typically administered at relatively low doses, which might account in part for the lower incidence of mIAS observed. Ongoing clinical studies of steroid-based mouthwashes in patients receiving everolimus should shed light on this.

Other study findings have shown that inhibition of the PI3K-AKT-mTOR signaling pathway affects skin wound healing,^27,28 which raises the possibility that mIAS may stem from a diminished capacity to repair physical injuries to the oral mucosa. More research is needed to elucidate the pathophysiology of mIAS.

Preventive measures for patients initiating mTOR inhibitor treatment

There are preventive measures for mIAS that have not yet been backed up with evidence-based findings, although several clinical studies that are underway aim to address this gap (Table 2). The hypotheses about the pathophysiology of mIAS suggest that certain preventive and therapeutic interventions might be effective against mIAS. For example, two studies are evaluating the use of steroid-based mouthwashes in patients receiving everolimus, based on the hypothesis that mIAS may arise from an inflammatory process; another study will evaluate a mucoadhesive oral wound rinse, based on the hypothesis that wound protection might prevent mIAS. Glutamine suspension is also under evaluation as it is understood to have wound-preventative and tissue-repair properties, and another study is focused on dentist-guided oral management. Recent results of one of these trials (SWISH),²⁹ reported that preventative care with a dexamethasone mouthwash 3-4 times a day significantly minimized or prevented the incidence of all grades of stomatitis in women receiving everolimus plus exemestane therapy for advanced/metastatic breast cancer compared with the incidence of stomatitis observed in a previously published phase 3 trial (BOLERO-2)^30,31 of everolimus plus exemestane in the same patient population. Results from several other studies are expected soon.

Current approaches to mIAS prevention are based largely on clinical experience with chemotherapy- or radiation-induced oral mucositis (Table 3).^13,32 Preventive measures use three main strategies: establish and maintain good routine oral care; modify diet to avoid potentially damaging foods; and improve patient education about mIAS. In regard to patient education, numerous studies have reported that establishing an institutional protocol for oral care helped reduce the incidence of chemotherapy- or radiation-induced oral mucositis.^33-40 An ongoing clinical study that will randomize patients to receive oral care education from oral surgeons or instruction on brushing only (NCT02376985) is investigating whether having an oral care protocol holds for patients with mIAS. The hypothesis is that focusing attention on oral care and educating patients to recognize the onset of mIAS facilitates early detection and promotes early intervention.

Therapeutic measures for patients with mIAS

Therapeutic measures for mIAS are based largely on experience with chemotherapy- or radiation-induced oral mucositis or recurrent aphthous ulcers (Table 3) and vary in part by the severity of lesions. Treatments for mild mIAS aim to ameliorate symptoms (eg, topical analgesics for pain), protect the oral mucosa (eg, mucoadhesive gels or viscous solutions that coat the oral cavity), prevent potential sequelae (eg, prophylactic antibiotics to avoid secondary infections), and reduce inflammation/immune response (eg, steroid-based mouth rinses, topical steroids, or topical anti-inflammatory agents). Treatments for mild mIAS are generally local rather than systemic.

Treatment options for moderate to severe mIAS include systemic approaches that generally carry increased risk of AEs and, therefore, should be reserved for patients with multiple lesions, uncontrolled or poorly controlled pain, or greatly diminished oral food intake (Table 3).⁴¹ When mIAS cannot be controlled with the interventions described, the dose of the mTOR inhibitor can be reduced with the recognition that dose modification of anticancer therapy may affect disease outcomes.²⁹ The experience of reduction or interruption of treatment with everolimus in the BOLERO-2 trial as a strategy for management of AEs is discussed in a recent review.²⁹ Prescribing information for both temsirolimus and everolimus specify that grade 3 AEs be treated with temporary dose interruption, and with resolution (temsirolimus: grade ≤2; everolimus: grade ≤1), treatment may be resumed at lower doses (temsirolimus: reduce by 5 mg/week; no lower than 15 mg/week; everolimus: reduce by half the previously administered dose).^3,4 Grade 4 events due to treatment with temsirolimus may also be treated with dose interruption/reduction; the everolimus prescribing information advises treatment discontinuation for grade 4 stomatitis.

Summary and discussion

mTOR inhibitors can be effective treatments for patients with advanced cancer, specifically for advanced RCC, advanced pNET, and HR+, HER2-negative advanced breast cancer. Although mIAS may occur in many patients, it is usually grade 1 or 2 in severity. mIAS has an early onset, usually within the first 2 weeks of treatment^16,19,42 and a relatively rapid resolution, usually within 3 weeks.^16,19 Thus, most cases of mIAS are self-limiting.

The relatively recent emergence of mIAS poses short-term challenges regarding diagnosis, assessment, prevention, and treatment. Several clinical studies are underway to evaluate a range of interventions for their preventive and therapeutic efficacy in mIAS. Furthermore, our growing understanding of the underlying pathophysiology of mIAS can guide how mIAS is managed and what interventions patients receive.

Although mIAS is believed to differ from chemotherapy- or radiation-induced oral mucositis and aphthous ulcers, much can be learned from the treatment of both of these. Several strategies have been proposed to limit the occurrence of mIAS (Table 3). First, establish an oral care protocol. Educate patients who are initiating treatment with an mTOR inhibitor on implementation of the oral care protocol and emphasize adherence. Second, educate patients on the symptoms and timing of mIAS. Patients may hesitate to report mild symptoms or assume they are innocuous, so be clear that reporting all symptoms is important to allow timely clinical evaluation. Early recognition of mIAS facilitates early intervention and can prevent dose modification and interruption. Third, implement the preventive and treatment measures described. Many of the preventive measures can be incorporated into an oral care protocol.

The advent of mTOR inhibitors has clinically benefited many patients with cancer. Although side effects, like mIAS, may develop during treatment, they should not be considered insurmountable. Through education, vigilance, and aggressive management, health care providers and patients can work together to help patients maintain their quality of life while continuing to optimally address their disease.
 

Acknowledgment

The authors thank Anna Lau, PhD, and Patricia Segarini, PhD, of Percolation Communications LLC, for their editorial assistance. Funding for manuscript development was provided by Novartis Pharmaceuticals Corp.

Mammalian target of rapamycin (mTOR), a serine–threonine protein kinase, operates in the phosphoinositide 3-kinase (PI3K)–protein kinase B (AKT)–mTOR signal transduction pathway regulating both normal and cancer cellular processes, including cell growth, proliferation, motility, survival, and protein and lipid synthesis.¹ Genetic alterations affecting this pathway, including mutations in receptor tyrosine kinases PI3K and AKT, occur frequently in human cancers,² supporting the rationale to develop drugs that target pathway components, such as mTOR inhibitors.

Two mTOR inhibitors are currently approved by the US Food and Drug Administration for cancer treatment: temsirolimus, for advanced renal cell carcinoma (RCC; approved 2007)³ and everolimus, for advanced RCC (approved 2009), advanced pancreatic neuroendocrine tumors (pNET; approved 2011), and hormone receptor-positive (HR-positive), human epidermal growth factor receptor-2 (HER2)-negative advanced breast cancer (approved 2012).⁴ Another mTOR inhibitor, sirolimus, is approved for use as an immunosuppressive agent and prophylactic against organ rejection after kidney transplant.⁵

Stomatitis, inflammation of the oral mucosa with contributing factors of genetic predisposition, nutritional deficiencies, infections, and immunological or hematologic dysfunction,⁶ occurs frequently as a side effect associated with mTOR inhibitor treatment.^7-9 Left untreated or managed unsatisfactorily, mTOR inhibitor-associated stomatitis (mIAS) may cause patients discomfort and trouble with maintaining adequate nutritional intake and proper oral hygiene, as well as strict adherence to cancer treatment. It is therefore important for health care providers of cancer patients receiving mTOR inhibitor treatment to be knowledgeable about this side effect. The purpose of the present systematic review of published literature is to provide a better understanding of the differential diagnosis of mIAS, the pathophysiology of mIAS, preventive strategies for patients initiating mTOR inhibitor treatment, and treatment options available to manage mIAS.

Method

The PubMed database was searched with the terms mTOR inhibitor and stomatitis (no date restriction); 79 articles were retrieved, and all abstracts were reviewed to select those relevant to the aims of this review article. To understand future directions for management and prevention of mIAS, a search of clinicaltrials.gov was performed with the terms temsirolimus everolimus stomatitis yielding 12 clinical trials, of which 4 were excluded: 1 trial was terminated due to slow accrual, the status of 1 trial had not been verified in >2 years, and 2 studies focused on efficacy outcomes. A search of the American Society of Clinical Oncology (ASCO) meeting abstracts database was performed to assess the availability of clinical trial data; the search was limited to 2011-2016 and terms were stomatitis in the title and mTOR in the abstract or title. Seven abstracts were retrieved; 2 discussed stomatitis prevention (1 as a “trial-in-progress” and 1 presented results of the trial); the other 5 abstracts presented meta-analyses or reviews of previous clinical studies to assess the risk, incidence, management, and resolution of mIAS.

Review findings

Incidence of mIAS in patients treated for cancer

Two recent meta-analyses quantified the rate of mIAS in patients receiving mTOR inhibitors. Shameem and colleagues¹⁰ identified 9 randomized studies of everolimus (8 phase 3, 1 phase 2) and 2 of temsirolimus (1 each phase 2 and 3) involving a total of 4752 patients with a variety of tumor types including angiomyolipoma, breast, gastric, giant cell astrocytoma, pNET, and RCC. Patients received everolimus monotherapy (n = 1,075) or in combination with exemestane (n = 485), tamoxifen (n = 54), letrozole (n = 137), or octreotide (n = 216). Temsirolimus was administered as monotherapy (n = 208) or in combination with interferon
(n = 210) or letrozole (n = 550). The incidence of all-grade stomatitis in the 11 studies ranged from 11%-63%, and the overall incidence of any grade stomatitis was 33.5% (95% confidence interval [CI], 21.9%-47.6%). The concurrent use of a second agent may have confounded these findings because, for example, stomatitis has been reported in pooled analyses and in postmarketing experience with letrozole.¹¹

Rugo and colleagues¹² evaluated the incidence of stomatitis in 1455 patients participating in 5 phase 3 randomized clinical trials of everolimus in breast cancer, carcinoid tumor, pNET, and RCC. Patients received everolimus monotherapy
(n = 478) or in combination with exemestane (n = 482), trastuzumab plus vinorelbine (n = 280), or octreotide
(n = 215). The incidence of stomatitis in patients receiving everolimus was 59%-71%, compared with 19%-29% in 1,071 patients of the comparator arms (placebo, and placebo–trastuzumab–vinorelbine). The overall incidence of any grade stomatitis was 67%; most events were mild (grade 1/2); 9% of stomatitis events were moderate to severe (grade 3/4).

Differential clinical presentation of mIAS and severity

Oral mucositis is a common significant adverse event (AE) that occurs in patients with cancer who receive standard chemotherapy regimens and/or radiation therapy,¹³ so it is important to recognize that the clinical presentation of mIAS differs from that of oral mucositis (Table 1, Figure ^14,15).¹⁶ mIAS shares some similarities with aphthous ulcers (also referred to as canker sores), a common oral condition with varied causes related to systemic disorders, gastrointestinal disorders, and infections, among others .¹⁷ In general, mIAS ulcers develop with a median onset of 10 days (range, 4-25 days) after initiation of mTOR inhibitor treatment and resolve in about 1-3 weeks after dose interruption/reduction of everolimus.^16,18,19 mIAS ulcers appear as distinct, oval lesions with a central gray area surrounded by peripheral erythema. They are usually localized to the movable mucosa of the mouth and oropharynx. Although mIAS lesions are usually small, they are quite painful and may cluster.

Differential diagnosis of mIAS should be made based on physical examination and medical history, with consideration given to appearance of lesions (number, size, and location), current infection status, and current medications. Specific diagnostic testing should be conducted to confirm a coexisting or alternative cause of oral lesions.¹⁷

Although there are many different scales for grading mIAS severity, the most commonly used are the National Cancer Institute Common Terminology Criteria for Adverse Events (based on patient function, symptoms, and intervention needs) and the World Health Organization oral mucositis scales (based on symptoms, clinical presentation, and interference with patient function).^20-22 These scales distinguish between mild lesions (grade 1/2) and moderate to severe lesions (grade 3/4) that cause significant pain or interfere with oral intake.

Pathophysiology of mIAS

The pathophysiology mIAS is incompletely understood. The ubiquitous role of the PI3K-AKT-mTOR pathway in regulating broad cellular functions suggests that mTOR inhibition is likely to have wide-ranging effects on many biological processes. It is not known whether disruption of one or more processes – or upsetting the balance of mTOR activities – underlies the formation of mIAS.

Differences between mIAS and oral mucositis, including clinical presentation and concomitant toxicities,^16,23 suggest that the two types of oral lesions are fundamentally distinct. This distinction is supported by animal studies in which mTOR inhibition was found to almost completely prevent the appearance of oral mucositis in irradiated mice. The protective effect of mTOR inhibition is mediated through suppression of oxidative stress generated by radiation therapy.²⁴

Although mIAS and recurrent aphthous ulcers share some similarities, it is not clear whether they also share a common pathophysiology. Recent studies suggest that patients with recurrent aphthous ulcers have immune dysfunction that leads to excessive immune response to normally innocuous substrates in the oral mucosa.²⁵ mTOR inhibition can have proinflammatory activity by promoting autophagy, a process that stimulates antigen presentation and activation of T cells that produce proinflammatory cytokines.²⁶ It is interesting to note that the incidence of stomatitis in patients receiving sirolimus after kidney transplant is relatively low, 3%-20%.⁵ Sirolimus is administered in combination with other immunosuppressants, namely cyclosporine and corticosteroids, so it suggests that concomitant use of a steroid-based regimen may have a preventive or therapeutic effect. However, posttransplant sirolimus is typically administered at relatively low doses, which might account in part for the lower incidence of mIAS observed. Ongoing clinical studies of steroid-based mouthwashes in patients receiving everolimus should shed light on this.

Other study findings have shown that inhibition of the PI3K-AKT-mTOR signaling pathway affects skin wound healing,^27,28 which raises the possibility that mIAS may stem from a diminished capacity to repair physical injuries to the oral mucosa. More research is needed to elucidate the pathophysiology of mIAS.

Preventive measures for patients initiating mTOR inhibitor treatment

There are preventive measures for mIAS that have not yet been backed up with evidence-based findings, although several clinical studies that are underway aim to address this gap (Table 2). The hypotheses about the pathophysiology of mIAS suggest that certain preventive and therapeutic interventions might be effective against mIAS. For example, two studies are evaluating the use of steroid-based mouthwashes in patients receiving everolimus, based on the hypothesis that mIAS may arise from an inflammatory process; another study will evaluate a mucoadhesive oral wound rinse, based on the hypothesis that wound protection might prevent mIAS. Glutamine suspension is also under evaluation as it is understood to have wound-preventative and tissue-repair properties, and another study is focused on dentist-guided oral management. Recent results of one of these trials (SWISH),²⁹ reported that preventative care with a dexamethasone mouthwash 3-4 times a day significantly minimized or prevented the incidence of all grades of stomatitis in women receiving everolimus plus exemestane therapy for advanced/metastatic breast cancer compared with the incidence of stomatitis observed in a previously published phase 3 trial (BOLERO-2)^30,31 of everolimus plus exemestane in the same patient population. Results from several other studies are expected soon.

Current approaches to mIAS prevention are based largely on clinical experience with chemotherapy- or radiation-induced oral mucositis (Table 3).^13,32 Preventive measures use three main strategies: establish and maintain good routine oral care; modify diet to avoid potentially damaging foods; and improve patient education about mIAS. In regard to patient education, numerous studies have reported that establishing an institutional protocol for oral care helped reduce the incidence of chemotherapy- or radiation-induced oral mucositis.^33-40 An ongoing clinical study that will randomize patients to receive oral care education from oral surgeons or instruction on brushing only (NCT02376985) is investigating whether having an oral care protocol holds for patients with mIAS. The hypothesis is that focusing attention on oral care and educating patients to recognize the onset of mIAS facilitates early detection and promotes early intervention.

Therapeutic measures for patients with mIAS

Therapeutic measures for mIAS are based largely on experience with chemotherapy- or radiation-induced oral mucositis or recurrent aphthous ulcers (Table 3) and vary in part by the severity of lesions. Treatments for mild mIAS aim to ameliorate symptoms (eg, topical analgesics for pain), protect the oral mucosa (eg, mucoadhesive gels or viscous solutions that coat the oral cavity), prevent potential sequelae (eg, prophylactic antibiotics to avoid secondary infections), and reduce inflammation/immune response (eg, steroid-based mouth rinses, topical steroids, or topical anti-inflammatory agents). Treatments for mild mIAS are generally local rather than systemic.

Treatment options for moderate to severe mIAS include systemic approaches that generally carry increased risk of AEs and, therefore, should be reserved for patients with multiple lesions, uncontrolled or poorly controlled pain, or greatly diminished oral food intake (Table 3).⁴¹ When mIAS cannot be controlled with the interventions described, the dose of the mTOR inhibitor can be reduced with the recognition that dose modification of anticancer therapy may affect disease outcomes.²⁹ The experience of reduction or interruption of treatment with everolimus in the BOLERO-2 trial as a strategy for management of AEs is discussed in a recent review.²⁹ Prescribing information for both temsirolimus and everolimus specify that grade 3 AEs be treated with temporary dose interruption, and with resolution (temsirolimus: grade ≤2; everolimus: grade ≤1), treatment may be resumed at lower doses (temsirolimus: reduce by 5 mg/week; no lower than 15 mg/week; everolimus: reduce by half the previously administered dose).^3,4 Grade 4 events due to treatment with temsirolimus may also be treated with dose interruption/reduction; the everolimus prescribing information advises treatment discontinuation for grade 4 stomatitis.

Summary and discussion

mTOR inhibitors can be effective treatments for patients with advanced cancer, specifically for advanced RCC, advanced pNET, and HR+, HER2-negative advanced breast cancer. Although mIAS may occur in many patients, it is usually grade 1 or 2 in severity. mIAS has an early onset, usually within the first 2 weeks of treatment^16,19,42 and a relatively rapid resolution, usually within 3 weeks.^16,19 Thus, most cases of mIAS are self-limiting.

The relatively recent emergence of mIAS poses short-term challenges regarding diagnosis, assessment, prevention, and treatment. Several clinical studies are underway to evaluate a range of interventions for their preventive and therapeutic efficacy in mIAS. Furthermore, our growing understanding of the underlying pathophysiology of mIAS can guide how mIAS is managed and what interventions patients receive.

Although mIAS is believed to differ from chemotherapy- or radiation-induced oral mucositis and aphthous ulcers, much can be learned from the treatment of both of these. Several strategies have been proposed to limit the occurrence of mIAS (Table 3). First, establish an oral care protocol. Educate patients who are initiating treatment with an mTOR inhibitor on implementation of the oral care protocol and emphasize adherence. Second, educate patients on the symptoms and timing of mIAS. Patients may hesitate to report mild symptoms or assume they are innocuous, so be clear that reporting all symptoms is important to allow timely clinical evaluation. Early recognition of mIAS facilitates early intervention and can prevent dose modification and interruption. Third, implement the preventive and treatment measures described. Many of the preventive measures can be incorporated into an oral care protocol.

The advent of mTOR inhibitors has clinically benefited many patients with cancer. Although side effects, like mIAS, may develop during treatment, they should not be considered insurmountable. Through education, vigilance, and aggressive management, health care providers and patients can work together to help patients maintain their quality of life while continuing to optimally address their disease.
 

Acknowledgment

The authors thank Anna Lau, PhD, and Patricia Segarini, PhD, of Percolation Communications LLC, for their editorial assistance. Funding for manuscript development was provided by Novartis Pharmaceuticals Corp.

Mammalian target of rapamycin (mTOR), a serine–threonine protein kinase, operates in the phosphoinositide 3-kinase (PI3K)–protein kinase B (AKT)–mTOR signal transduction pathway regulating both normal and cancer cellular processes, including cell growth, proliferation, motility, survival, and protein and lipid synthesis.¹ Genetic alterations affecting this pathway, including mutations in receptor tyrosine kinases PI3K and AKT, occur frequently in human cancers,² supporting the rationale to develop drugs that target pathway components, such as mTOR inhibitors.

Two mTOR inhibitors are currently approved by the US Food and Drug Administration for cancer treatment: temsirolimus, for advanced renal cell carcinoma (RCC; approved 2007)³ and everolimus, for advanced RCC (approved 2009), advanced pancreatic neuroendocrine tumors (pNET; approved 2011), and hormone receptor-positive (HR-positive), human epidermal growth factor receptor-2 (HER2)-negative advanced breast cancer (approved 2012).⁴ Another mTOR inhibitor, sirolimus, is approved for use as an immunosuppressive agent and prophylactic against organ rejection after kidney transplant.⁵

Stomatitis, inflammation of the oral mucosa with contributing factors of genetic predisposition, nutritional deficiencies, infections, and immunological or hematologic dysfunction,⁶ occurs frequently as a side effect associated with mTOR inhibitor treatment.^7-9 Left untreated or managed unsatisfactorily, mTOR inhibitor-associated stomatitis (mIAS) may cause patients discomfort and trouble with maintaining adequate nutritional intake and proper oral hygiene, as well as strict adherence to cancer treatment. It is therefore important for health care providers of cancer patients receiving mTOR inhibitor treatment to be knowledgeable about this side effect. The purpose of the present systematic review of published literature is to provide a better understanding of the differential diagnosis of mIAS, the pathophysiology of mIAS, preventive strategies for patients initiating mTOR inhibitor treatment, and treatment options available to manage mIAS.

Method

The PubMed database was searched with the terms mTOR inhibitor and stomatitis (no date restriction); 79 articles were retrieved, and all abstracts were reviewed to select those relevant to the aims of this review article. To understand future directions for management and prevention of mIAS, a search of clinicaltrials.gov was performed with the terms temsirolimus everolimus stomatitis yielding 12 clinical trials, of which 4 were excluded: 1 trial was terminated due to slow accrual, the status of 1 trial had not been verified in >2 years, and 2 studies focused on efficacy outcomes. A search of the American Society of Clinical Oncology (ASCO) meeting abstracts database was performed to assess the availability of clinical trial data; the search was limited to 2011-2016 and terms were stomatitis in the title and mTOR in the abstract or title. Seven abstracts were retrieved; 2 discussed stomatitis prevention (1 as a “trial-in-progress” and 1 presented results of the trial); the other 5 abstracts presented meta-analyses or reviews of previous clinical studies to assess the risk, incidence, management, and resolution of mIAS.

Review findings

Incidence of mIAS in patients treated for cancer

Two recent meta-analyses quantified the rate of mIAS in patients receiving mTOR inhibitors. Shameem and colleagues¹⁰ identified 9 randomized studies of everolimus (8 phase 3, 1 phase 2) and 2 of temsirolimus (1 each phase 2 and 3) involving a total of 4752 patients with a variety of tumor types including angiomyolipoma, breast, gastric, giant cell astrocytoma, pNET, and RCC. Patients received everolimus monotherapy (n = 1,075) or in combination with exemestane (n = 485), tamoxifen (n = 54), letrozole (n = 137), or octreotide (n = 216). Temsirolimus was administered as monotherapy (n = 208) or in combination with interferon
(n = 210) or letrozole (n = 550). The incidence of all-grade stomatitis in the 11 studies ranged from 11%-63%, and the overall incidence of any grade stomatitis was 33.5% (95% confidence interval [CI], 21.9%-47.6%). The concurrent use of a second agent may have confounded these findings because, for example, stomatitis has been reported in pooled analyses and in postmarketing experience with letrozole.¹¹

Rugo and colleagues¹² evaluated the incidence of stomatitis in 1455 patients participating in 5 phase 3 randomized clinical trials of everolimus in breast cancer, carcinoid tumor, pNET, and RCC. Patients received everolimus monotherapy
(n = 478) or in combination with exemestane (n = 482), trastuzumab plus vinorelbine (n = 280), or octreotide
(n = 215). The incidence of stomatitis in patients receiving everolimus was 59%-71%, compared with 19%-29% in 1,071 patients of the comparator arms (placebo, and placebo–trastuzumab–vinorelbine). The overall incidence of any grade stomatitis was 67%; most events were mild (grade 1/2); 9% of stomatitis events were moderate to severe (grade 3/4).

Differential clinical presentation of mIAS and severity

Oral mucositis is a common significant adverse event (AE) that occurs in patients with cancer who receive standard chemotherapy regimens and/or radiation therapy,¹³ so it is important to recognize that the clinical presentation of mIAS differs from that of oral mucositis (Table 1, Figure ^14,15).¹⁶ mIAS shares some similarities with aphthous ulcers (also referred to as canker sores), a common oral condition with varied causes related to systemic disorders, gastrointestinal disorders, and infections, among others .¹⁷ In general, mIAS ulcers develop with a median onset of 10 days (range, 4-25 days) after initiation of mTOR inhibitor treatment and resolve in about 1-3 weeks after dose interruption/reduction of everolimus.^16,18,19 mIAS ulcers appear as distinct, oval lesions with a central gray area surrounded by peripheral erythema. They are usually localized to the movable mucosa of the mouth and oropharynx. Although mIAS lesions are usually small, they are quite painful and may cluster.

Differential diagnosis of mIAS should be made based on physical examination and medical history, with consideration given to appearance of lesions (number, size, and location), current infection status, and current medications. Specific diagnostic testing should be conducted to confirm a coexisting or alternative cause of oral lesions.¹⁷

Although there are many different scales for grading mIAS severity, the most commonly used are the National Cancer Institute Common Terminology Criteria for Adverse Events (based on patient function, symptoms, and intervention needs) and the World Health Organization oral mucositis scales (based on symptoms, clinical presentation, and interference with patient function).^20-22 These scales distinguish between mild lesions (grade 1/2) and moderate to severe lesions (grade 3/4) that cause significant pain or interfere with oral intake.

Pathophysiology of mIAS

The pathophysiology mIAS is incompletely understood. The ubiquitous role of the PI3K-AKT-mTOR pathway in regulating broad cellular functions suggests that mTOR inhibition is likely to have wide-ranging effects on many biological processes. It is not known whether disruption of one or more processes – or upsetting the balance of mTOR activities – underlies the formation of mIAS.

Differences between mIAS and oral mucositis, including clinical presentation and concomitant toxicities,^16,23 suggest that the two types of oral lesions are fundamentally distinct. This distinction is supported by animal studies in which mTOR inhibition was found to almost completely prevent the appearance of oral mucositis in irradiated mice. The protective effect of mTOR inhibition is mediated through suppression of oxidative stress generated by radiation therapy.²⁴

Although mIAS and recurrent aphthous ulcers share some similarities, it is not clear whether they also share a common pathophysiology. Recent studies suggest that patients with recurrent aphthous ulcers have immune dysfunction that leads to excessive immune response to normally innocuous substrates in the oral mucosa.²⁵ mTOR inhibition can have proinflammatory activity by promoting autophagy, a process that stimulates antigen presentation and activation of T cells that produce proinflammatory cytokines.²⁶ It is interesting to note that the incidence of stomatitis in patients receiving sirolimus after kidney transplant is relatively low, 3%-20%.⁵ Sirolimus is administered in combination with other immunosuppressants, namely cyclosporine and corticosteroids, so it suggests that concomitant use of a steroid-based regimen may have a preventive or therapeutic effect. However, posttransplant sirolimus is typically administered at relatively low doses, which might account in part for the lower incidence of mIAS observed. Ongoing clinical studies of steroid-based mouthwashes in patients receiving everolimus should shed light on this.

Other study findings have shown that inhibition of the PI3K-AKT-mTOR signaling pathway affects skin wound healing,^27,28 which raises the possibility that mIAS may stem from a diminished capacity to repair physical injuries to the oral mucosa. More research is needed to elucidate the pathophysiology of mIAS.

Preventive measures for patients initiating mTOR inhibitor treatment

There are preventive measures for mIAS that have not yet been backed up with evidence-based findings, although several clinical studies that are underway aim to address this gap (Table 2). The hypotheses about the pathophysiology of mIAS suggest that certain preventive and therapeutic interventions might be effective against mIAS. For example, two studies are evaluating the use of steroid-based mouthwashes in patients receiving everolimus, based on the hypothesis that mIAS may arise from an inflammatory process; another study will evaluate a mucoadhesive oral wound rinse, based on the hypothesis that wound protection might prevent mIAS. Glutamine suspension is also under evaluation as it is understood to have wound-preventative and tissue-repair properties, and another study is focused on dentist-guided oral management. Recent results of one of these trials (SWISH),²⁹ reported that preventative care with a dexamethasone mouthwash 3-4 times a day significantly minimized or prevented the incidence of all grades of stomatitis in women receiving everolimus plus exemestane therapy for advanced/metastatic breast cancer compared with the incidence of stomatitis observed in a previously published phase 3 trial (BOLERO-2)^30,31 of everolimus plus exemestane in the same patient population. Results from several other studies are expected soon.

Current approaches to mIAS prevention are based largely on clinical experience with chemotherapy- or radiation-induced oral mucositis (Table 3).^13,32 Preventive measures use three main strategies: establish and maintain good routine oral care; modify diet to avoid potentially damaging foods; and improve patient education about mIAS. In regard to patient education, numerous studies have reported that establishing an institutional protocol for oral care helped reduce the incidence of chemotherapy- or radiation-induced oral mucositis.^33-40 An ongoing clinical study that will randomize patients to receive oral care education from oral surgeons or instruction on brushing only (NCT02376985) is investigating whether having an oral care protocol holds for patients with mIAS. The hypothesis is that focusing attention on oral care and educating patients to recognize the onset of mIAS facilitates early detection and promotes early intervention.

Therapeutic measures for patients with mIAS

Therapeutic measures for mIAS are based largely on experience with chemotherapy- or radiation-induced oral mucositis or recurrent aphthous ulcers (Table 3) and vary in part by the severity of lesions. Treatments for mild mIAS aim to ameliorate symptoms (eg, topical analgesics for pain), protect the oral mucosa (eg, mucoadhesive gels or viscous solutions that coat the oral cavity), prevent potential sequelae (eg, prophylactic antibiotics to avoid secondary infections), and reduce inflammation/immune response (eg, steroid-based mouth rinses, topical steroids, or topical anti-inflammatory agents). Treatments for mild mIAS are generally local rather than systemic.

Treatment options for moderate to severe mIAS include systemic approaches that generally carry increased risk of AEs and, therefore, should be reserved for patients with multiple lesions, uncontrolled or poorly controlled pain, or greatly diminished oral food intake (Table 3).⁴¹ When mIAS cannot be controlled with the interventions described, the dose of the mTOR inhibitor can be reduced with the recognition that dose modification of anticancer therapy may affect disease outcomes.²⁹ The experience of reduction or interruption of treatment with everolimus in the BOLERO-2 trial as a strategy for management of AEs is discussed in a recent review.²⁹ Prescribing information for both temsirolimus and everolimus specify that grade 3 AEs be treated with temporary dose interruption, and with resolution (temsirolimus: grade ≤2; everolimus: grade ≤1), treatment may be resumed at lower doses (temsirolimus: reduce by 5 mg/week; no lower than 15 mg/week; everolimus: reduce by half the previously administered dose).^3,4 Grade 4 events due to treatment with temsirolimus may also be treated with dose interruption/reduction; the everolimus prescribing information advises treatment discontinuation for grade 4 stomatitis.

Summary and discussion

mTOR inhibitors can be effective treatments for patients with advanced cancer, specifically for advanced RCC, advanced pNET, and HR+, HER2-negative advanced breast cancer. Although mIAS may occur in many patients, it is usually grade 1 or 2 in severity. mIAS has an early onset, usually within the first 2 weeks of treatment^16,19,42 and a relatively rapid resolution, usually within 3 weeks.^16,19 Thus, most cases of mIAS are self-limiting.

The relatively recent emergence of mIAS poses short-term challenges regarding diagnosis, assessment, prevention, and treatment. Several clinical studies are underway to evaluate a range of interventions for their preventive and therapeutic efficacy in mIAS. Furthermore, our growing understanding of the underlying pathophysiology of mIAS can guide how mIAS is managed and what interventions patients receive.

Although mIAS is believed to differ from chemotherapy- or radiation-induced oral mucositis and aphthous ulcers, much can be learned from the treatment of both of these. Several strategies have been proposed to limit the occurrence of mIAS (Table 3). First, establish an oral care protocol. Educate patients who are initiating treatment with an mTOR inhibitor on implementation of the oral care protocol and emphasize adherence. Second, educate patients on the symptoms and timing of mIAS. Patients may hesitate to report mild symptoms or assume they are innocuous, so be clear that reporting all symptoms is important to allow timely clinical evaluation. Early recognition of mIAS facilitates early intervention and can prevent dose modification and interruption. Third, implement the preventive and treatment measures described. Many of the preventive measures can be incorporated into an oral care protocol.

The advent of mTOR inhibitors has clinically benefited many patients with cancer. Although side effects, like mIAS, may develop during treatment, they should not be considered insurmountable. Through education, vigilance, and aggressive management, health care providers and patients can work together to help patients maintain their quality of life while continuing to optimally address their disease.
 

Acknowledgment

The authors thank Anna Lau, PhD, and Patricia Segarini, PhD, of Percolation Communications LLC, for their editorial assistance. Funding for manuscript development was provided by Novartis Pharmaceuticals Corp.

Despite available antiemetic therapies, chemotherapy-induced nausea and vomiting (CINV) following highly emetogenic chemotherapy (HEC), particularly in the delayed phase (>24-120 h after chemotherapy), continues to impair patient quality of life and chemotherapy compliance.¹ Cisplatin-based chemotherapy, classified as HEC at any dose,² is widely used to treat cancers such as non–small-cell and small-cell lung cancer, sarcomas, germ-cell tumors, lymphoma, and ovarian cancer. Cisplatin is associated with a biphasic pattern of CINV and may induce delayed-onset nausea and vomiting, reaching maximum intensity of 48-72 hours after administration and lasting 6-7 days.² CINV after cisplatin-based therapy may be severe enough to cause chemotherapy discontinuation or dose reductions.³ Being female is a known risk factor for CINV, and because cisplatin-based regimens are often used to treat women with gynecologic cancers, this patient population is at even higher risk for CINV.^4,5

5-hydroxytryptamine type 3 (5-HT₃) receptor antagonists (RAs; eg, granisetron, ondansetron, dolasetron, and palonosetron) have been the cornerstone of CINV therapy for decades and remain an integral part of contemporary antiemetic treatment regimens. Most current antiemetic guidelines for HEC recommend a 3-drug regimen, comprising a 5-HT₃ RA, a neurokinin 1 (NK-1) RA, and a corticosteroid (dexamethasone).^2,6,7 A regimen of olanzapine (antipsychotic), palonosetron (5-HT₃ RA), and dexamethasone (corticosteroid) has been recommended as an alternative option. Recently, the oral fixed-dose combination of netupitant and palonosetron (NEPA) was approved and has shown efficacy in the cisplatin setting.^8,9 However, the administration of oral medication to patients experiencing CINV and those with head and neck cancer may be difficult.¹⁰ Alternative antiemetic treatments that provide CINV control into the delayed phase and with a convenient route of administration, are needed.

APF530 is a novel extended-release granisetron formulation that provides sustained release of therapeutic concentrations for ≥5 days. The Biochronomer tri(ethylene glycol) poly(orthoester) (TEG-POE) vehicle releases granisetron slowly by polymer hydrolysis after it has been injected subcutaneously (SC) into the abdomen or upper arm.^11,12 In 2016, the US Food and Drug Administration approved APF530 in combination with other antiemetics for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC) or anthracycline plus cyclophosphamide (AC) combination chemotherapy regimens based on data from 2 pivotal phase 3 trials.¹³

A phase 3 trial demonstrated noninferiority of APF530 (500 mg, SC) to palonosetron (0.25 mg, intravenously [IV]), each with dexamethasone (corticosteroid), in the control of acute-phase CINV after MEC or HEC, and delayed-phase CINV after MEC (classified by Hesketh criteria).^14,15 Furthermore, APF530 provided sustained CINV control over multiple cycles of chemotherapy.¹⁶ Numerically higher complete response (CR: no emesis, no rescue medication use) rates were observed with APF530, compared with palonosetron, in the delayed phase after HEC (APF530 500 mg, 67.1%; palonosetron 0.25 mg, 64.3%).¹⁵

A reanalysis of study endpoints by newer emetogenicity classification guidelines from the American Society of Clinical Oncology (ASCO)⁷ maintained overall study conclusions.¹⁷ Notably, the numerically higher CR rates with APF530 in the delayed phase following HEC were enhanced (APF530 500 mg, 55.8%; palonosetron 0.25 mg, 50.5%), suggesting a need for further examination in this setting. The subsequent APF530 phase 3 MAGIC trial (Modified Absorption of Granisetron In the prevention of CINV; NCT02106494), compared APF530 (500 mg, SC) with ondansetron (0.15 mg/kg, IV), each with fosaprepitant (NK-1 RA) and dexamethasone in patients receiving HEC. The primary endpoint was met: the APF530 regimen demonstrated superior delayed-phase CR compared with the ondansetron regimen (64.7% vs 56.6%; 95% confidence interval [CI]:
1.7-14.4; P = .014; 8.0% absolute improvement).¹⁸

APF530 also demonstrated a significant benefit over ondansetron for other endpoints including nausea control, rescue medication use, and satisfaction with antiemetic therapy.¹⁸ APF530 is the first and only 5-HT₃ RA to demonstrate superiority over another in a phase 3 efficacy trial using a guideline-recommended 3-drug regimen for both arms.

A prespecified MAGIC trial analysis of the primary endpoint by intent to receive cisplatin (≥50 mg/m², Yes/No) demonstrated a pronounced treatment benefit in terms of delayed-phase CR rates with the APF530 regimen among patients in the cisplatin (≥50 mg/m², Yes) stratum (CR: 65.3% vs 54.7%; 95% CI: -1.4-22.7; 10.6% absolute improvement).¹⁸ These results are compelling, since cisplatin represents a particularly emetogenic class of chemotherapy; a more in-depth analysis of additional MAGIC trial endpoints for these patients would be of clinical interest, and is presented here. Efficacy endpoints in this analysis include CR in the overall and acute phases, complete control (CC) and total response (TR) rates, rescue medication use, nausea frequency, and safety.

Methods

Study design and patients

The MAGIC trial was a prospective, randomized, multicenter, placebo-controlled, double-blind, double-dummy phase 3 trial conducted at 77 centers across the United States. The study protocol was reviewed and approved by the institutional review board at each participating center, and conducted according to the Declaration of Helsinki. The study design, previously presented in detail,¹⁸ is reviewed briefly here.

Eligible men and women were 18-80 years of age with histologically or cytologically confirmed malignancy (cancer type information was not captured) and were entering the first cycle of their single-day HEC treatment (defined by ASCO 2011 emetogenicity criteria).⁷ Patients had Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 0 or 1, no history or presence of significant cardiac disease or QT interval prolongation, and adequate bone marrow, kidney, and liver function. All patients provided written informed consent.

Procedures

Patients were stratified by planned receipt of the cisplatin regimen ≥50 mg/m² (Yes/No), randomized 1:1 to receive APF530 500 mg SC (granisetron 10 mg) or ondansetron 0.15 mg/kg IV (up to a maximum of 16 mg as a single dose) on day 1 (Figure 1). The APF530 arm received the ondansetron saline placebo, and the ondansetron arm received the APF530 SC placebo containing the TEG-POE vehicle. All patients were scheduled to receive fosaprepitant 150 mg IV and dexamethasone 12 mg IV on day 1, then oral dexamethasone 8 mg once daily on day 2 and 8 mg twice daily on days 3 and 4. Rescue medication was allowed at the investigator’s discretion.

Outcomes

The primary objective of the trial was to demonstrate the superiority of APF530 500 mg SC compared with ondansetron 0.15 mg/kg IV, as part of the current guideline-recommended 3-drug regimen, in preventing delayed-phase CINV after HEC. The primary endpoint was delayed-phase (24-120 h) CR (no emetic episodes [vomit or retch] and no rescue medication use). In addition, a prespecified analysis of delayed-phase CR by randomization strata (planned use of cisplatin) was performed.

Secondary and other endpoints included overall-phase CR
(0-120 h); delayed-, overall-, and acute-phase complete control (CC: CR and no more than mild nausea); delayed-, overall-, and acute-phase total response (TR; CR and no nausea); and rescue medication use. A post hoc analysis of nausea severity was also conducted. Safety assessments included treatment-emergent adverse events (TEAEs), injection-site reactions (ISRs), laboratory parameters, and vital signs. TEAEs were assessed by type, duration, severity, and relationship to study drug. ISR timing and severity were captured in patient diaries.

Statistical analysis

All efficacy analyses were conducted using the modified intent-to-treat population (mITT; randomized patients who received study drug and a HEC regimen and had post-baseline efficacy data). Safety assessments were performed on the safety population (randomized patients who received study drug).

This analysis conducted on the subgroup of patients with intent to receive cisplatin (cisplatin randomization stratum, ≥50 mg/m², Yes) was exploratory and was not powered to detect treatment differences. Preplanned analyses compared CR, CC, and TR rates across treatment arms using 95% CIs.

Post hoc analyses of time to first rescue medication use, proportion of patients with rescue medication use, and less frequent nausea were performed. All P values were calculated using the Cochran-Mantel-Haenszel chi square test. Rescue medication use results were based on observed data, without imputation for missing results (ie, calculated from the number of patients with a response). Further analyses of efficacy endpoints CR, CC, and TR in the subset of female patients in the cisplatin randomization stratum were performed. Safety assessments were summarized descriptively.

Results

A total of 942 patients were randomized across 77 US centers during March 31, 2014 and May 15, 2015 (471 APF530, 471 ondansetron). Among those, 264 had intent to receive cisplatin and were included in the cisplatin randomization stratum (≥50 mg/m², Yes) (Figure 2). A total of 256 patients in the cisplatin stratum received study drug and were included in the safety population (126 APF530, 130 ondansetron); 252 patients were included in the mITT population (124 APF530, 128 ondansetron).

Baseline demographics were generally balanced between treatment arms (Table 1). The proportion of female patients was 41.1% (51/124) and 48.4% (62/128) in the APF530 and ondansetron arms, respectively. The majority of patients had an ECOG PS of 0 (57.3% [71/124] APF530; 60.2% [77/128] ondansetron). The most common cisplatin-based chemotherapy regimen in both treatment arms was cisplatin and gemcitabine (25.0% [31/124] APF530; 28.9% [37/128] ondansetron) (Suppl Table 1). Two patients in the APF530 arm and 3 patients in the ondansetron arm either received a lower cisplatin dose (<50 mg/m²) or did not go on to receive cisplatin as intended at randomization (Suppl Table 1). As previously reported, in the cisplatin stratum (Table 2), delayed-phase CR was numerically higher in the APF530 arm versus the ondansetron arm, with a corresponding treatment difference of 10.6% (65.3% [81/124] APF530; 54.7% [70/128] ondansetron; 95% CI [-1.4, 22.7]; P = .085). Although the CI contains 0, the result is consistent with the significant benefit observed in the overall study population (64.7% [291/450] APF530; 56.6% [256/452] ondansetron; 95% CI [1.7, 14.4];
P = .014).¹⁸ This more in-depth analysis found similar trends favoring the APF530 over the ondansetron regimen across overall- and acute-phase CR (Table 2).

A significantly greater proportion of patients in the APF530 arm, compared with the ondansetron arm, reported no rescue medication use during the delayed phase (74.4% [90/121] APF530; 62.6% [77/123] ondansetron; P = .048). Trends in favor of APF530 were observed in the overall phase (71.1% [86/121] APF530; 61.8% [76/123] ondansetron; P = .125) and acute phase (86.9% [106/122] APF530; 81.9% [104/127] ondansetron; P = .278). Time to first rescue medication use was consistently longer in the APF530 arm, compared with the ondansetron arm, although not statistically significantly (P = .150) (Figure 3).

The APF530 regimen was generally well tolerated in the cisplatin subgroup, and no new safety signals were identified (Table 3). Most patients experienced at least one TEAE. Excluding ISRs, TEAE incidences were 72.2% and 66.9% in the APF530 and ondansetron arms, respectively; most common were constipation, fatigue, nausea, diarrhea, dehydration, and headache. Excluding ISRs, the most common treatment-related TEAEs in the APF530 and ondansetron arms were constipation (2.4% and 2.3%, respectively and headache (3.2% and 4.6%).

Discussion

The MAGIC trial is the first phase 3 efficacy trial in the prevention of CINV in patients receiving HEC using the current guideline-recommended 3-drug antiemetic regimen in both treatment arms.¹⁸ Ondansetron was chosen as the appropriate 5-HT₃ RA comparator because no other 5-HT₃ RA has shown superiority to ondansetron in delayed-phase CINV following HEC. Furthermore, ondansetron is indicated for prevention of nausea and vomiting associated with initial and repeat courses of chemotherapy, including high-dose cisplatin.¹⁹ The MAGIC trial primary endpoint was met for the overall study population; in the context of a 3-drug regimen, APF530 demonstrated superior control of delayed-phase CINV following HEC compared with standard-of-care ondansetron.¹⁸ As reported previously, significant benefits were also observed with the APF530 regimen over the ondansetron regimen in terms of rescue medication use, patient satisfaction with antiemetic therapy, and nausea frequency in the overall study population.¹⁸

Cisplatin is generally regarded as one of the most emetogenic chemotherapeutic agents. For this reason, cisplatin is often evaluated separately in clinical trials, and was a stratification factor in the MAGIC trial. Consistent with the previously reported significant results,¹⁸ trends in the cisplatin stratum analysis favored the APF530 regimen, compared with the ondansetron regimen, in delayed- and overall-phase CR (treatment difference: 10.6%).¹⁸ Numerical trends presented here favoring the APF530 regimen over the ondansetron regimen were observed in CC and TR, two more stringent measures of CINV control that account for incidence of nausea. Furthermore, among women in the cisplatin stratum, a population at increased risk for CINV, the numerically higher CR, CC, and TR persisted in the APF530 arm, compared with the ondansetron arm.

The APF530 regimen was generally well tolerated in the cisplatin stratum, and no new safety signals were identified. The most common TEAEs were ISRs, mostly mild or moderate and resolving by study end. The double-dummy design resulted in ISRs in the ondansetron arm due to TEG-POE vehicle as the dummy APF530 injection. Transient ISRs have been observed with other agents administered SC, and are expected.^20,21 Excluding ISRs, TEAEs were generally consistent with those observed for the 5-HT₃ RA class.²²

This analysis of patients randomized to receive cisplatin-based HEC in the MAGIC trial is exploratory and was not sufficiently powered to detect between-arm differences. Five total patients did not go on to receive cisplatin ≥50 mg/m² as intended at randomization (2 APF530, 3 ondansetron); however, this is not uncommon in large clinical trials and represents less than 2% of patients in this analysis.

Recent phase 3 studies in patients receiving cisplatin-based HEC showed significant improvement in CINV prevention with the current guideline-recommended 3-drug regimen over the traditional 2-drug regimen (5-HT₃ RA + dexamethasone).^8,23 Results presented here, in a similar population receiving cisplatin-based HEC, suggest that in the context of a 3-drug antiemetic regimen in both treatment arms, APF530 provides additional benefit in CINV prevention compared with the standard of care, ondansetron. Furthermore, a recent phase 3 trial in patients receiving cisplatin or AC-based HEC demonstrated significant improvement in nausea when olanzapine was added to a traditional 3-drug regimen of a 5-HT₃ RA, NK-1 RA, and dexamethasone.²⁴ These compelling data support the addition of olanzapine as a fourth agent to the CINV treatment regimen to provide further control of nausea, which has been one of the more difficult components of CINV to control to date.

APF530 is the only 5-HT₃ RA to demonstrate superiority over another as part of the guideline-recommended regimen in a 3-drug versus 3-drug phase 3 efficacy trial examining antiemetic efficacy following HEC. Results from the MAGIC trial, this exploratory analysis, and previous studies in MEC and HEC provide clinically meaningful benefits in preventing both acute- and delayed-phase CINV following guideline-specified MEC or HEC regimens. Consequently, APF530 was approved for use in combination with other antiemetics for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of MEC or AC combination chemotherapy regimens.¹³ Both the superior control of delayed-phase CINV following HEC demonstrated by the MAGIC trial¹⁸ and the consistent trends in the cisplatin stratum indicate a particular benefit for high-risk patients receiving high doses of cisplatin.

Acknowledgments

Joanna K Sandilos Rega, PhD, of SciStrategy Communications provided medical writing assistance, supported by Heron Therapeutics Inc, the maker of the study drug.

Despite available antiemetic therapies, chemotherapy-induced nausea and vomiting (CINV) following highly emetogenic chemotherapy (HEC), particularly in the delayed phase (>24-120 h after chemotherapy), continues to impair patient quality of life and chemotherapy compliance.¹ Cisplatin-based chemotherapy, classified as HEC at any dose,² is widely used to treat cancers such as non–small-cell and small-cell lung cancer, sarcomas, germ-cell tumors, lymphoma, and ovarian cancer. Cisplatin is associated with a biphasic pattern of CINV and may induce delayed-onset nausea and vomiting, reaching maximum intensity of 48-72 hours after administration and lasting 6-7 days.² CINV after cisplatin-based therapy may be severe enough to cause chemotherapy discontinuation or dose reductions.³ Being female is a known risk factor for CINV, and because cisplatin-based regimens are often used to treat women with gynecologic cancers, this patient population is at even higher risk for CINV.^4,5

5-hydroxytryptamine type 3 (5-HT₃) receptor antagonists (RAs; eg, granisetron, ondansetron, dolasetron, and palonosetron) have been the cornerstone of CINV therapy for decades and remain an integral part of contemporary antiemetic treatment regimens. Most current antiemetic guidelines for HEC recommend a 3-drug regimen, comprising a 5-HT₃ RA, a neurokinin 1 (NK-1) RA, and a corticosteroid (dexamethasone).^2,6,7 A regimen of olanzapine (antipsychotic), palonosetron (5-HT₃ RA), and dexamethasone (corticosteroid) has been recommended as an alternative option. Recently, the oral fixed-dose combination of netupitant and palonosetron (NEPA) was approved and has shown efficacy in the cisplatin setting.^8,9 However, the administration of oral medication to patients experiencing CINV and those with head and neck cancer may be difficult.¹⁰ Alternative antiemetic treatments that provide CINV control into the delayed phase and with a convenient route of administration, are needed.

APF530 is a novel extended-release granisetron formulation that provides sustained release of therapeutic concentrations for ≥5 days. The Biochronomer tri(ethylene glycol) poly(orthoester) (TEG-POE) vehicle releases granisetron slowly by polymer hydrolysis after it has been injected subcutaneously (SC) into the abdomen or upper arm.^11,12 In 2016, the US Food and Drug Administration approved APF530 in combination with other antiemetics for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC) or anthracycline plus cyclophosphamide (AC) combination chemotherapy regimens based on data from 2 pivotal phase 3 trials.¹³

A phase 3 trial demonstrated noninferiority of APF530 (500 mg, SC) to palonosetron (0.25 mg, intravenously [IV]), each with dexamethasone (corticosteroid), in the control of acute-phase CINV after MEC or HEC, and delayed-phase CINV after MEC (classified by Hesketh criteria).^14,15 Furthermore, APF530 provided sustained CINV control over multiple cycles of chemotherapy.¹⁶ Numerically higher complete response (CR: no emesis, no rescue medication use) rates were observed with APF530, compared with palonosetron, in the delayed phase after HEC (APF530 500 mg, 67.1%; palonosetron 0.25 mg, 64.3%).¹⁵

A reanalysis of study endpoints by newer emetogenicity classification guidelines from the American Society of Clinical Oncology (ASCO)⁷ maintained overall study conclusions.¹⁷ Notably, the numerically higher CR rates with APF530 in the delayed phase following HEC were enhanced (APF530 500 mg, 55.8%; palonosetron 0.25 mg, 50.5%), suggesting a need for further examination in this setting. The subsequent APF530 phase 3 MAGIC trial (Modified Absorption of Granisetron In the prevention of CINV; NCT02106494), compared APF530 (500 mg, SC) with ondansetron (0.15 mg/kg, IV), each with fosaprepitant (NK-1 RA) and dexamethasone in patients receiving HEC. The primary endpoint was met: the APF530 regimen demonstrated superior delayed-phase CR compared with the ondansetron regimen (64.7% vs 56.6%; 95% confidence interval [CI]:
1.7-14.4; P = .014; 8.0% absolute improvement).¹⁸

APF530 also demonstrated a significant benefit over ondansetron for other endpoints including nausea control, rescue medication use, and satisfaction with antiemetic therapy.¹⁸ APF530 is the first and only 5-HT₃ RA to demonstrate superiority over another in a phase 3 efficacy trial using a guideline-recommended 3-drug regimen for both arms.

A prespecified MAGIC trial analysis of the primary endpoint by intent to receive cisplatin (≥50 mg/m², Yes/No) demonstrated a pronounced treatment benefit in terms of delayed-phase CR rates with the APF530 regimen among patients in the cisplatin (≥50 mg/m², Yes) stratum (CR: 65.3% vs 54.7%; 95% CI: -1.4-22.7; 10.6% absolute improvement).¹⁸ These results are compelling, since cisplatin represents a particularly emetogenic class of chemotherapy; a more in-depth analysis of additional MAGIC trial endpoints for these patients would be of clinical interest, and is presented here. Efficacy endpoints in this analysis include CR in the overall and acute phases, complete control (CC) and total response (TR) rates, rescue medication use, nausea frequency, and safety.

Methods

Study design and patients

The MAGIC trial was a prospective, randomized, multicenter, placebo-controlled, double-blind, double-dummy phase 3 trial conducted at 77 centers across the United States. The study protocol was reviewed and approved by the institutional review board at each participating center, and conducted according to the Declaration of Helsinki. The study design, previously presented in detail,¹⁸ is reviewed briefly here.

Eligible men and women were 18-80 years of age with histologically or cytologically confirmed malignancy (cancer type information was not captured) and were entering the first cycle of their single-day HEC treatment (defined by ASCO 2011 emetogenicity criteria).⁷ Patients had Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 0 or 1, no history or presence of significant cardiac disease or QT interval prolongation, and adequate bone marrow, kidney, and liver function. All patients provided written informed consent.

Procedures

Patients were stratified by planned receipt of the cisplatin regimen ≥50 mg/m² (Yes/No), randomized 1:1 to receive APF530 500 mg SC (granisetron 10 mg) or ondansetron 0.15 mg/kg IV (up to a maximum of 16 mg as a single dose) on day 1 (Figure 1). The APF530 arm received the ondansetron saline placebo, and the ondansetron arm received the APF530 SC placebo containing the TEG-POE vehicle. All patients were scheduled to receive fosaprepitant 150 mg IV and dexamethasone 12 mg IV on day 1, then oral dexamethasone 8 mg once daily on day 2 and 8 mg twice daily on days 3 and 4. Rescue medication was allowed at the investigator’s discretion.

Outcomes

The primary objective of the trial was to demonstrate the superiority of APF530 500 mg SC compared with ondansetron 0.15 mg/kg IV, as part of the current guideline-recommended 3-drug regimen, in preventing delayed-phase CINV after HEC. The primary endpoint was delayed-phase (24-120 h) CR (no emetic episodes [vomit or retch] and no rescue medication use). In addition, a prespecified analysis of delayed-phase CR by randomization strata (planned use of cisplatin) was performed.

Secondary and other endpoints included overall-phase CR
(0-120 h); delayed-, overall-, and acute-phase complete control (CC: CR and no more than mild nausea); delayed-, overall-, and acute-phase total response (TR; CR and no nausea); and rescue medication use. A post hoc analysis of nausea severity was also conducted. Safety assessments included treatment-emergent adverse events (TEAEs), injection-site reactions (ISRs), laboratory parameters, and vital signs. TEAEs were assessed by type, duration, severity, and relationship to study drug. ISR timing and severity were captured in patient diaries.

Statistical analysis

All efficacy analyses were conducted using the modified intent-to-treat population (mITT; randomized patients who received study drug and a HEC regimen and had post-baseline efficacy data). Safety assessments were performed on the safety population (randomized patients who received study drug).

This analysis conducted on the subgroup of patients with intent to receive cisplatin (cisplatin randomization stratum, ≥50 mg/m², Yes) was exploratory and was not powered to detect treatment differences. Preplanned analyses compared CR, CC, and TR rates across treatment arms using 95% CIs.

Post hoc analyses of time to first rescue medication use, proportion of patients with rescue medication use, and less frequent nausea were performed. All P values were calculated using the Cochran-Mantel-Haenszel chi square test. Rescue medication use results were based on observed data, without imputation for missing results (ie, calculated from the number of patients with a response). Further analyses of efficacy endpoints CR, CC, and TR in the subset of female patients in the cisplatin randomization stratum were performed. Safety assessments were summarized descriptively.

Results

A total of 942 patients were randomized across 77 US centers during March 31, 2014 and May 15, 2015 (471 APF530, 471 ondansetron). Among those, 264 had intent to receive cisplatin and were included in the cisplatin randomization stratum (≥50 mg/m², Yes) (Figure 2). A total of 256 patients in the cisplatin stratum received study drug and were included in the safety population (126 APF530, 130 ondansetron); 252 patients were included in the mITT population (124 APF530, 128 ondansetron).

Baseline demographics were generally balanced between treatment arms (Table 1). The proportion of female patients was 41.1% (51/124) and 48.4% (62/128) in the APF530 and ondansetron arms, respectively. The majority of patients had an ECOG PS of 0 (57.3% [71/124] APF530; 60.2% [77/128] ondansetron). The most common cisplatin-based chemotherapy regimen in both treatment arms was cisplatin and gemcitabine (25.0% [31/124] APF530; 28.9% [37/128] ondansetron) (Suppl Table 1). Two patients in the APF530 arm and 3 patients in the ondansetron arm either received a lower cisplatin dose (<50 mg/m²) or did not go on to receive cisplatin as intended at randomization (Suppl Table 1). As previously reported, in the cisplatin stratum (Table 2), delayed-phase CR was numerically higher in the APF530 arm versus the ondansetron arm, with a corresponding treatment difference of 10.6% (65.3% [81/124] APF530; 54.7% [70/128] ondansetron; 95% CI [-1.4, 22.7]; P = .085). Although the CI contains 0, the result is consistent with the significant benefit observed in the overall study population (64.7% [291/450] APF530; 56.6% [256/452] ondansetron; 95% CI [1.7, 14.4];
P = .014).¹⁸ This more in-depth analysis found similar trends favoring the APF530 over the ondansetron regimen across overall- and acute-phase CR (Table 2).

A significantly greater proportion of patients in the APF530 arm, compared with the ondansetron arm, reported no rescue medication use during the delayed phase (74.4% [90/121] APF530; 62.6% [77/123] ondansetron; P = .048). Trends in favor of APF530 were observed in the overall phase (71.1% [86/121] APF530; 61.8% [76/123] ondansetron; P = .125) and acute phase (86.9% [106/122] APF530; 81.9% [104/127] ondansetron; P = .278). Time to first rescue medication use was consistently longer in the APF530 arm, compared with the ondansetron arm, although not statistically significantly (P = .150) (Figure 3).

The APF530 regimen was generally well tolerated in the cisplatin subgroup, and no new safety signals were identified (Table 3). Most patients experienced at least one TEAE. Excluding ISRs, TEAE incidences were 72.2% and 66.9% in the APF530 and ondansetron arms, respectively; most common were constipation, fatigue, nausea, diarrhea, dehydration, and headache. Excluding ISRs, the most common treatment-related TEAEs in the APF530 and ondansetron arms were constipation (2.4% and 2.3%, respectively and headache (3.2% and 4.6%).

Discussion

The MAGIC trial is the first phase 3 efficacy trial in the prevention of CINV in patients receiving HEC using the current guideline-recommended 3-drug antiemetic regimen in both treatment arms.¹⁸ Ondansetron was chosen as the appropriate 5-HT₃ RA comparator because no other 5-HT₃ RA has shown superiority to ondansetron in delayed-phase CINV following HEC. Furthermore, ondansetron is indicated for prevention of nausea and vomiting associated with initial and repeat courses of chemotherapy, including high-dose cisplatin.¹⁹ The MAGIC trial primary endpoint was met for the overall study population; in the context of a 3-drug regimen, APF530 demonstrated superior control of delayed-phase CINV following HEC compared with standard-of-care ondansetron.¹⁸ As reported previously, significant benefits were also observed with the APF530 regimen over the ondansetron regimen in terms of rescue medication use, patient satisfaction with antiemetic therapy, and nausea frequency in the overall study population.¹⁸

Cisplatin is generally regarded as one of the most emetogenic chemotherapeutic agents. For this reason, cisplatin is often evaluated separately in clinical trials, and was a stratification factor in the MAGIC trial. Consistent with the previously reported significant results,¹⁸ trends in the cisplatin stratum analysis favored the APF530 regimen, compared with the ondansetron regimen, in delayed- and overall-phase CR (treatment difference: 10.6%).¹⁸ Numerical trends presented here favoring the APF530 regimen over the ondansetron regimen were observed in CC and TR, two more stringent measures of CINV control that account for incidence of nausea. Furthermore, among women in the cisplatin stratum, a population at increased risk for CINV, the numerically higher CR, CC, and TR persisted in the APF530 arm, compared with the ondansetron arm.

The APF530 regimen was generally well tolerated in the cisplatin stratum, and no new safety signals were identified. The most common TEAEs were ISRs, mostly mild or moderate and resolving by study end. The double-dummy design resulted in ISRs in the ondansetron arm due to TEG-POE vehicle as the dummy APF530 injection. Transient ISRs have been observed with other agents administered SC, and are expected.^20,21 Excluding ISRs, TEAEs were generally consistent with those observed for the 5-HT₃ RA class.²²

This analysis of patients randomized to receive cisplatin-based HEC in the MAGIC trial is exploratory and was not sufficiently powered to detect between-arm differences. Five total patients did not go on to receive cisplatin ≥50 mg/m² as intended at randomization (2 APF530, 3 ondansetron); however, this is not uncommon in large clinical trials and represents less than 2% of patients in this analysis.

Recent phase 3 studies in patients receiving cisplatin-based HEC showed significant improvement in CINV prevention with the current guideline-recommended 3-drug regimen over the traditional 2-drug regimen (5-HT₃ RA + dexamethasone).^8,23 Results presented here, in a similar population receiving cisplatin-based HEC, suggest that in the context of a 3-drug antiemetic regimen in both treatment arms, APF530 provides additional benefit in CINV prevention compared with the standard of care, ondansetron. Furthermore, a recent phase 3 trial in patients receiving cisplatin or AC-based HEC demonstrated significant improvement in nausea when olanzapine was added to a traditional 3-drug regimen of a 5-HT₃ RA, NK-1 RA, and dexamethasone.²⁴ These compelling data support the addition of olanzapine as a fourth agent to the CINV treatment regimen to provide further control of nausea, which has been one of the more difficult components of CINV to control to date.

APF530 is the only 5-HT₃ RA to demonstrate superiority over another as part of the guideline-recommended regimen in a 3-drug versus 3-drug phase 3 efficacy trial examining antiemetic efficacy following HEC. Results from the MAGIC trial, this exploratory analysis, and previous studies in MEC and HEC provide clinically meaningful benefits in preventing both acute- and delayed-phase CINV following guideline-specified MEC or HEC regimens. Consequently, APF530 was approved for use in combination with other antiemetics for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of MEC or AC combination chemotherapy regimens.¹³ Both the superior control of delayed-phase CINV following HEC demonstrated by the MAGIC trial¹⁸ and the consistent trends in the cisplatin stratum indicate a particular benefit for high-risk patients receiving high doses of cisplatin.

Acknowledgments

Joanna K Sandilos Rega, PhD, of SciStrategy Communications provided medical writing assistance, supported by Heron Therapeutics Inc, the maker of the study drug.

Despite available antiemetic therapies, chemotherapy-induced nausea and vomiting (CINV) following highly emetogenic chemotherapy (HEC), particularly in the delayed phase (>24-120 h after chemotherapy), continues to impair patient quality of life and chemotherapy compliance.¹ Cisplatin-based chemotherapy, classified as HEC at any dose,² is widely used to treat cancers such as non–small-cell and small-cell lung cancer, sarcomas, germ-cell tumors, lymphoma, and ovarian cancer. Cisplatin is associated with a biphasic pattern of CINV and may induce delayed-onset nausea and vomiting, reaching maximum intensity of 48-72 hours after administration and lasting 6-7 days.² CINV after cisplatin-based therapy may be severe enough to cause chemotherapy discontinuation or dose reductions.³ Being female is a known risk factor for CINV, and because cisplatin-based regimens are often used to treat women with gynecologic cancers, this patient population is at even higher risk for CINV.^4,5

5-hydroxytryptamine type 3 (5-HT₃) receptor antagonists (RAs; eg, granisetron, ondansetron, dolasetron, and palonosetron) have been the cornerstone of CINV therapy for decades and remain an integral part of contemporary antiemetic treatment regimens. Most current antiemetic guidelines for HEC recommend a 3-drug regimen, comprising a 5-HT₃ RA, a neurokinin 1 (NK-1) RA, and a corticosteroid (dexamethasone).^2,6,7 A regimen of olanzapine (antipsychotic), palonosetron (5-HT₃ RA), and dexamethasone (corticosteroid) has been recommended as an alternative option. Recently, the oral fixed-dose combination of netupitant and palonosetron (NEPA) was approved and has shown efficacy in the cisplatin setting.^8,9 However, the administration of oral medication to patients experiencing CINV and those with head and neck cancer may be difficult.¹⁰ Alternative antiemetic treatments that provide CINV control into the delayed phase and with a convenient route of administration, are needed.

APF530 is a novel extended-release granisetron formulation that provides sustained release of therapeutic concentrations for ≥5 days. The Biochronomer tri(ethylene glycol) poly(orthoester) (TEG-POE) vehicle releases granisetron slowly by polymer hydrolysis after it has been injected subcutaneously (SC) into the abdomen or upper arm.^11,12 In 2016, the US Food and Drug Administration approved APF530 in combination with other antiemetics for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC) or anthracycline plus cyclophosphamide (AC) combination chemotherapy regimens based on data from 2 pivotal phase 3 trials.¹³

A phase 3 trial demonstrated noninferiority of APF530 (500 mg, SC) to palonosetron (0.25 mg, intravenously [IV]), each with dexamethasone (corticosteroid), in the control of acute-phase CINV after MEC or HEC, and delayed-phase CINV after MEC (classified by Hesketh criteria).^14,15 Furthermore, APF530 provided sustained CINV control over multiple cycles of chemotherapy.¹⁶ Numerically higher complete response (CR: no emesis, no rescue medication use) rates were observed with APF530, compared with palonosetron, in the delayed phase after HEC (APF530 500 mg, 67.1%; palonosetron 0.25 mg, 64.3%).¹⁵

A reanalysis of study endpoints by newer emetogenicity classification guidelines from the American Society of Clinical Oncology (ASCO)⁷ maintained overall study conclusions.¹⁷ Notably, the numerically higher CR rates with APF530 in the delayed phase following HEC were enhanced (APF530 500 mg, 55.8%; palonosetron 0.25 mg, 50.5%), suggesting a need for further examination in this setting. The subsequent APF530 phase 3 MAGIC trial (Modified Absorption of Granisetron In the prevention of CINV; NCT02106494), compared APF530 (500 mg, SC) with ondansetron (0.15 mg/kg, IV), each with fosaprepitant (NK-1 RA) and dexamethasone in patients receiving HEC. The primary endpoint was met: the APF530 regimen demonstrated superior delayed-phase CR compared with the ondansetron regimen (64.7% vs 56.6%; 95% confidence interval [CI]:
1.7-14.4; P = .014; 8.0% absolute improvement).¹⁸

APF530 also demonstrated a significant benefit over ondansetron for other endpoints including nausea control, rescue medication use, and satisfaction with antiemetic therapy.¹⁸ APF530 is the first and only 5-HT₃ RA to demonstrate superiority over another in a phase 3 efficacy trial using a guideline-recommended 3-drug regimen for both arms.

A prespecified MAGIC trial analysis of the primary endpoint by intent to receive cisplatin (≥50 mg/m², Yes/No) demonstrated a pronounced treatment benefit in terms of delayed-phase CR rates with the APF530 regimen among patients in the cisplatin (≥50 mg/m², Yes) stratum (CR: 65.3% vs 54.7%; 95% CI: -1.4-22.7; 10.6% absolute improvement).¹⁸ These results are compelling, since cisplatin represents a particularly emetogenic class of chemotherapy; a more in-depth analysis of additional MAGIC trial endpoints for these patients would be of clinical interest, and is presented here. Efficacy endpoints in this analysis include CR in the overall and acute phases, complete control (CC) and total response (TR) rates, rescue medication use, nausea frequency, and safety.

Methods

Study design and patients

The MAGIC trial was a prospective, randomized, multicenter, placebo-controlled, double-blind, double-dummy phase 3 trial conducted at 77 centers across the United States. The study protocol was reviewed and approved by the institutional review board at each participating center, and conducted according to the Declaration of Helsinki. The study design, previously presented in detail,¹⁸ is reviewed briefly here.

Eligible men and women were 18-80 years of age with histologically or cytologically confirmed malignancy (cancer type information was not captured) and were entering the first cycle of their single-day HEC treatment (defined by ASCO 2011 emetogenicity criteria).⁷ Patients had Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 0 or 1, no history or presence of significant cardiac disease or QT interval prolongation, and adequate bone marrow, kidney, and liver function. All patients provided written informed consent.

Procedures

Patients were stratified by planned receipt of the cisplatin regimen ≥50 mg/m² (Yes/No), randomized 1:1 to receive APF530 500 mg SC (granisetron 10 mg) or ondansetron 0.15 mg/kg IV (up to a maximum of 16 mg as a single dose) on day 1 (Figure 1). The APF530 arm received the ondansetron saline placebo, and the ondansetron arm received the APF530 SC placebo containing the TEG-POE vehicle. All patients were scheduled to receive fosaprepitant 150 mg IV and dexamethasone 12 mg IV on day 1, then oral dexamethasone 8 mg once daily on day 2 and 8 mg twice daily on days 3 and 4. Rescue medication was allowed at the investigator’s discretion.

Outcomes

The primary objective of the trial was to demonstrate the superiority of APF530 500 mg SC compared with ondansetron 0.15 mg/kg IV, as part of the current guideline-recommended 3-drug regimen, in preventing delayed-phase CINV after HEC. The primary endpoint was delayed-phase (24-120 h) CR (no emetic episodes [vomit or retch] and no rescue medication use). In addition, a prespecified analysis of delayed-phase CR by randomization strata (planned use of cisplatin) was performed.

Secondary and other endpoints included overall-phase CR
(0-120 h); delayed-, overall-, and acute-phase complete control (CC: CR and no more than mild nausea); delayed-, overall-, and acute-phase total response (TR; CR and no nausea); and rescue medication use. A post hoc analysis of nausea severity was also conducted. Safety assessments included treatment-emergent adverse events (TEAEs), injection-site reactions (ISRs), laboratory parameters, and vital signs. TEAEs were assessed by type, duration, severity, and relationship to study drug. ISR timing and severity were captured in patient diaries.

Statistical analysis

All efficacy analyses were conducted using the modified intent-to-treat population (mITT; randomized patients who received study drug and a HEC regimen and had post-baseline efficacy data). Safety assessments were performed on the safety population (randomized patients who received study drug).

This analysis conducted on the subgroup of patients with intent to receive cisplatin (cisplatin randomization stratum, ≥50 mg/m², Yes) was exploratory and was not powered to detect treatment differences. Preplanned analyses compared CR, CC, and TR rates across treatment arms using 95% CIs.

Post hoc analyses of time to first rescue medication use, proportion of patients with rescue medication use, and less frequent nausea were performed. All P values were calculated using the Cochran-Mantel-Haenszel chi square test. Rescue medication use results were based on observed data, without imputation for missing results (ie, calculated from the number of patients with a response). Further analyses of efficacy endpoints CR, CC, and TR in the subset of female patients in the cisplatin randomization stratum were performed. Safety assessments were summarized descriptively.

Results

A total of 942 patients were randomized across 77 US centers during March 31, 2014 and May 15, 2015 (471 APF530, 471 ondansetron). Among those, 264 had intent to receive cisplatin and were included in the cisplatin randomization stratum (≥50 mg/m², Yes) (Figure 2). A total of 256 patients in the cisplatin stratum received study drug and were included in the safety population (126 APF530, 130 ondansetron); 252 patients were included in the mITT population (124 APF530, 128 ondansetron).

Baseline demographics were generally balanced between treatment arms (Table 1). The proportion of female patients was 41.1% (51/124) and 48.4% (62/128) in the APF530 and ondansetron arms, respectively. The majority of patients had an ECOG PS of 0 (57.3% [71/124] APF530; 60.2% [77/128] ondansetron). The most common cisplatin-based chemotherapy regimen in both treatment arms was cisplatin and gemcitabine (25.0% [31/124] APF530; 28.9% [37/128] ondansetron) (Suppl Table 1). Two patients in the APF530 arm and 3 patients in the ondansetron arm either received a lower cisplatin dose (<50 mg/m²) or did not go on to receive cisplatin as intended at randomization (Suppl Table 1). As previously reported, in the cisplatin stratum (Table 2), delayed-phase CR was numerically higher in the APF530 arm versus the ondansetron arm, with a corresponding treatment difference of 10.6% (65.3% [81/124] APF530; 54.7% [70/128] ondansetron; 95% CI [-1.4, 22.7]; P = .085). Although the CI contains 0, the result is consistent with the significant benefit observed in the overall study population (64.7% [291/450] APF530; 56.6% [256/452] ondansetron; 95% CI [1.7, 14.4];
P = .014).¹⁸ This more in-depth analysis found similar trends favoring the APF530 over the ondansetron regimen across overall- and acute-phase CR (Table 2).

A significantly greater proportion of patients in the APF530 arm, compared with the ondansetron arm, reported no rescue medication use during the delayed phase (74.4% [90/121] APF530; 62.6% [77/123] ondansetron; P = .048). Trends in favor of APF530 were observed in the overall phase (71.1% [86/121] APF530; 61.8% [76/123] ondansetron; P = .125) and acute phase (86.9% [106/122] APF530; 81.9% [104/127] ondansetron; P = .278). Time to first rescue medication use was consistently longer in the APF530 arm, compared with the ondansetron arm, although not statistically significantly (P = .150) (Figure 3).

The APF530 regimen was generally well tolerated in the cisplatin subgroup, and no new safety signals were identified (Table 3). Most patients experienced at least one TEAE. Excluding ISRs, TEAE incidences were 72.2% and 66.9% in the APF530 and ondansetron arms, respectively; most common were constipation, fatigue, nausea, diarrhea, dehydration, and headache. Excluding ISRs, the most common treatment-related TEAEs in the APF530 and ondansetron arms were constipation (2.4% and 2.3%, respectively and headache (3.2% and 4.6%).

Discussion

The MAGIC trial is the first phase 3 efficacy trial in the prevention of CINV in patients receiving HEC using the current guideline-recommended 3-drug antiemetic regimen in both treatment arms.¹⁸ Ondansetron was chosen as the appropriate 5-HT₃ RA comparator because no other 5-HT₃ RA has shown superiority to ondansetron in delayed-phase CINV following HEC. Furthermore, ondansetron is indicated for prevention of nausea and vomiting associated with initial and repeat courses of chemotherapy, including high-dose cisplatin.¹⁹ The MAGIC trial primary endpoint was met for the overall study population; in the context of a 3-drug regimen, APF530 demonstrated superior control of delayed-phase CINV following HEC compared with standard-of-care ondansetron.¹⁸ As reported previously, significant benefits were also observed with the APF530 regimen over the ondansetron regimen in terms of rescue medication use, patient satisfaction with antiemetic therapy, and nausea frequency in the overall study population.¹⁸

Cisplatin is generally regarded as one of the most emetogenic chemotherapeutic agents. For this reason, cisplatin is often evaluated separately in clinical trials, and was a stratification factor in the MAGIC trial. Consistent with the previously reported significant results,¹⁸ trends in the cisplatin stratum analysis favored the APF530 regimen, compared with the ondansetron regimen, in delayed- and overall-phase CR (treatment difference: 10.6%).¹⁸ Numerical trends presented here favoring the APF530 regimen over the ondansetron regimen were observed in CC and TR, two more stringent measures of CINV control that account for incidence of nausea. Furthermore, among women in the cisplatin stratum, a population at increased risk for CINV, the numerically higher CR, CC, and TR persisted in the APF530 arm, compared with the ondansetron arm.

The APF530 regimen was generally well tolerated in the cisplatin stratum, and no new safety signals were identified. The most common TEAEs were ISRs, mostly mild or moderate and resolving by study end. The double-dummy design resulted in ISRs in the ondansetron arm due to TEG-POE vehicle as the dummy APF530 injection. Transient ISRs have been observed with other agents administered SC, and are expected.^20,21 Excluding ISRs, TEAEs were generally consistent with those observed for the 5-HT₃ RA class.²²

This analysis of patients randomized to receive cisplatin-based HEC in the MAGIC trial is exploratory and was not sufficiently powered to detect between-arm differences. Five total patients did not go on to receive cisplatin ≥50 mg/m² as intended at randomization (2 APF530, 3 ondansetron); however, this is not uncommon in large clinical trials and represents less than 2% of patients in this analysis.

Recent phase 3 studies in patients receiving cisplatin-based HEC showed significant improvement in CINV prevention with the current guideline-recommended 3-drug regimen over the traditional 2-drug regimen (5-HT₃ RA + dexamethasone).^8,23 Results presented here, in a similar population receiving cisplatin-based HEC, suggest that in the context of a 3-drug antiemetic regimen in both treatment arms, APF530 provides additional benefit in CINV prevention compared with the standard of care, ondansetron. Furthermore, a recent phase 3 trial in patients receiving cisplatin or AC-based HEC demonstrated significant improvement in nausea when olanzapine was added to a traditional 3-drug regimen of a 5-HT₃ RA, NK-1 RA, and dexamethasone.²⁴ These compelling data support the addition of olanzapine as a fourth agent to the CINV treatment regimen to provide further control of nausea, which has been one of the more difficult components of CINV to control to date.

APF530 is the only 5-HT₃ RA to demonstrate superiority over another as part of the guideline-recommended regimen in a 3-drug versus 3-drug phase 3 efficacy trial examining antiemetic efficacy following HEC. Results from the MAGIC trial, this exploratory analysis, and previous studies in MEC and HEC provide clinically meaningful benefits in preventing both acute- and delayed-phase CINV following guideline-specified MEC or HEC regimens. Consequently, APF530 was approved for use in combination with other antiemetics for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of MEC or AC combination chemotherapy regimens.¹³ Both the superior control of delayed-phase CINV following HEC demonstrated by the MAGIC trial¹⁸ and the consistent trends in the cisplatin stratum indicate a particular benefit for high-risk patients receiving high doses of cisplatin.

Acknowledgments

Joanna K Sandilos Rega, PhD, of SciStrategy Communications provided medical writing assistance, supported by Heron Therapeutics Inc, the maker of the study drug.

Despite the recent advances in systemic therapy, metastatic spread to the brain continues to be the most common neurologic complication of many cancers. The clinical incidence of brain metastases varies with primary cancer diagnosis, with estimates ranging from 1.2%-19.8%.^1,2 Metastatic spread to the brain is even more prevalent at autopsy, with evidence of intracranial tumor being found in 26% of patients in some series.³ It is possible that the clinical incidence of metastatic disease to the brain will continue to increase as newer therapeutic agents improve survival and imaging techniques continue to improve.

The management of brain metastases has changed rapidly as technological improvements have made treatment increasingly safe and efficacious. Traditionally, treatment consisted of radiotherapy to the whole brain, with or without surgical resection.^4,5 More recently, stereotactic radiosurgery (SRS) has been adopted on the basis of evidence that it is safe and efficacious alone or in combination with radiotherapy to the whole brain.⁶ Further evidence is emerging that neurocognitive outcomes are improved when whole-brain radiotherapy (WBRT) is omitted, which possibly contributes to improved patient quality of life.⁷ Taking into account this and other data, the American Society for Radiation Oncology’s Choosing Wisely campaign now recommends not routinely adding WBRT to radiosurgery in patients with limited brain metastases.⁸

Despite this recommendation, many patients continue to benefit from WBRT, and it remains a common treatment in radiation oncology clinics across the US for several reasons. Many patients present with multiple brain metastases and are ineligible for radiosurgery. Even for technically eligible patients, WBRT has been shown to improve local control and decrease the rate of distant brain failure over radiosurgery alone.⁶ With higher rates of subsequent failures, patients receiving radiosurgery alone must adhere to more rigorous follow-up and imaging schedules, which can be difficult for many rural patients who have to travel long distances to centers. Furthermore, there is some suggestion that this decreased failure rate may result in improved survival in highly selected patients with excellent disease and performance status.⁹ Controversies exist, however, and strong institutional biases persist, contributing to significant differences in practice. We surveyed academic radiation oncologists and in an effort to identify and describe practice patterns in the delivery of WBRT at academic centers.

Methods

We conducted a thorough review of available literature on radiation for brain metastases and based on our findings, devised a survey 19 questions to ascertain practice patterns and treatment delivery among US academic physicians (Table 1). After obtaining institutional review board approval to do the study, we sent the survey to program coordinators at radiation oncology programs that are accredited by the Accreditation Council for Graduate Medical Education. We instructed coordinators to e-mail the survey to their practicing resident and attending physicians. The surveys were created using SurveyMonkey software. We obtained informed consent from the providers. A total of 3 follow-up e-mails were sent to each recipient of the survey to solicit responses, similar to the Dillman Total Design Survey Method.¹⁰

SPSS version 22.0 was used to analyze the data in an exploratory fashion. Statistical methods were used to assess the association of demographic data with SRS and WBRT delivery and treatment technique items when the analyses involved percentages that included the Pearson chi-square statistic and the chi-square test for linear trend. When the analysis focused on ranking data, the Kruskal-Wallis test, Mann-Whitney U test, the Jonckheere-Terpstra and the Kendall tau-b rank correlation were used as appropriate. If there were small sample sizes within some groups, then exact significant levels were assessed. Statistical significance was set by convention at P < .05.

Results

We received 95 responses of which 87 were considered complete for analysis. Forty-seven percent of the 87 respondents were not board-certified, and the remainder had passed their radiobiology and physics boards exams. A majority of respondents (70%, 61 of 87) were physicians who had been in practice for ≤5 years. Fifty-four percent of respondents were located in the Northeast US, 22% in the South, 14% in the West, and 10% in the Midwest and Hawaii (Table 2).

We used the chi-square test for linear trends to assess for a relationship between years of practice and whether respondents deviated from their typical method of WBRT therapy when treating more radioresistant tumors (melanoma, renal cell carcinoma). Respondents were classified by years in practice: 0-5, 6-10, 11-20, and >21 years. The results showed a linear association, with those in practice for longer periods more likely to use SRS alone, P = .027 (Figure 1).

Discussion

The incidence of brain metastases is increasing because of improvements in diagnostic imaging techniques and advancements in systemic therapy control of extracranial disease but not of intracranial disease or metastasis, because therapies do not cross the blood-brain barrier.^11,12 Brain metastases are the most common type of brain tumor. Given that most chemotherapeutic agents cannot cross the blood-brain barrier, radiotherapy is considered a means of treatment and of controlling brain metastases. Early data from the 1950s¹³ and 1960s¹⁴ have suggested clinical improvement with brain radiation, making radiotherapy the cornerstone for treatment of brain metastases.

The Radiation Therapy Oncology Group (RTOG) has evaluated several fractionation schedules, with 5 schemas evaluated by the RTOG 6901 and 7361 studies: 30 Gy in 10 fractions, 30 Gy in 15 fractions, 40 Gy in 15 fractions, 40 Gy in 20 fractions, and 20 Gy in 5 fractions. The combined results from these two trials showed that outcomes were similar for patients treated with a shorter regimen than for those treated with a more protracted schedule. In our study, respondents reported that they most frequently treated brain metastases to a total dose of 30 Gy in 10 fractions. Given the results of the aforementioned RTOG trials and practice patterns among academic physicians, we recommend all practitioners consider a shorter hypofractioned course when treating brain metastases with WBRT. This will also reduce delays for patients who are likely to benefit greatly from earlier enrollment into hospice care, because protracted radiation schedules typically are not covered while a patient is in hospice.

Pharmacologic management for patients with brain metastases is important for symptomatic improvement. Glucocorticoids are important for palliation of symptoms from edema and increased intracranial pressure.¹⁵ However, steroids have a multitude of side effects and their use in asymptomatic patients is unnecessary. Improvements in imaging and detection¹¹ have allowed us to find smaller and asymptomatic brain tumors. In our survey, it was promising to see a change in former practice patterns, with only 8% of academic practitioners regularly prescribing steroids to all of their patients receiving whole-brain radiation.

Diminished cognitive function and short-term memory loss are troublesome side effects of WBRT. As cancer patients live longer, such cognitive dysfunction will become more than just a nuisance. The RTOG has investigated the use of prophylactic memantine for patients receiving whole-brain radiation to determine if it would aid in the preservation of cognition. It found that patients who received memantine did better and had delayed time to cognitive decline and a reduced rate of memory decline, executive function, and processing speed.¹⁶ In our study, about a third of practitioners prescribed memantine and it was reserved for patients who had an otherwise favorable prognosis.

The RTOG has also investigated adjusting treatment technique for patients who receive WBRT. RTOG 0933 was a phase 2 trial that evaluated hippocampal avoidance during deliverance of WBRT with intensity-modulated radiation therapy (IMRT). Results showed that avoiding the hippocampus during WBRT was associated with improved memory preservation and patient quality of life.¹⁷ In a survey of practicing radiation oncologists in the US, most reported that they did not use memantine or IMRT for hippocampal sparing when delivering whole-brain radiation.¹⁸ Given the positive results of RTOG 0933 and 0614, the NRG Oncology research organization is conducting a phase 3 randomized trial that compares memantine use for patients receiving whole-brain radiation with or without hippocampal sparing to determine if patients will have reduced cognitive decline. All patients receiving WBRT should be considered for enrolment on this trial if they are eligible.

The delivery of brain radiation has continued to change, especially with the introduction of SRS. Recent publication of a meta-analysis of three phase 3 trials evaluating SRS with or without WBRT for 1-4 brain metastases showed that patients aged 50 years or younger experienced a survival benefit with SRS, and the omission of whole-brain radiation did not affect distant brain relapse rates. ¹⁹ The authors recommended that for this population, SRS alone is the preferred treatment. In our study, physicians who had been in practice for a longer time were more likely to treat using SRS alone. The results showed a linear association, with those in practice for a longer time being more likely to use SRS alone compared with those practicing for a shorter time (P = .027). Accordingly, 67% of respondents (8 of 12) who had been in practice for 11 or more years used SRS alone, whereas 24% (14 of 58) who had practiced for 0-5 years and 42% (5 of 12) who had practice from 6-10 years used SRS alone (Figure 1). When treating with SRS, younger practitioners placed more importance on the status of extracranial disease, whereas older practitioners placed more importance on tumor histopathology.

The use of repeat whole-brain reirradiation is more controversial among practitioners.^20-22 Son and colleagues evaluated patients who needed whole-brain reirradiation after intracranial disease progression.²² The authors noted that patients with stable extracranial disease benefited from reirradiation. In our study, we found that when considering whole-brain reirradiation, older practitioners placed more importance on tumor histology than other factors.

As far as we know, this is the first study evaluating the practices and patterns of care with regard to the delivery of brain radiation in academic centers in the US. We found that time in practice was the most significant predictor of treatment technique and delivery. We also found that older practitioners place more importance on tumor histopathology compared with younger practitioners. A limitation of this study is that we had contact information only for program coordinators at ACGME-accredited programs. As such, we were not able to assess practice patterns among community practitioners. In addition, it seemed that residents and junior faculty were more likely to respond to this survey, likely because of the dissemination pattern. Given the evolution and diversity of treatment regimens for brain metastases, we believe that patients with brain metastases should be managed individually using a multidisciplinary approach.

Despite the recent advances in systemic therapy, metastatic spread to the brain continues to be the most common neurologic complication of many cancers. The clinical incidence of brain metastases varies with primary cancer diagnosis, with estimates ranging from 1.2%-19.8%.^1,2 Metastatic spread to the brain is even more prevalent at autopsy, with evidence of intracranial tumor being found in 26% of patients in some series.³ It is possible that the clinical incidence of metastatic disease to the brain will continue to increase as newer therapeutic agents improve survival and imaging techniques continue to improve.

The management of brain metastases has changed rapidly as technological improvements have made treatment increasingly safe and efficacious. Traditionally, treatment consisted of radiotherapy to the whole brain, with or without surgical resection.^4,5 More recently, stereotactic radiosurgery (SRS) has been adopted on the basis of evidence that it is safe and efficacious alone or in combination with radiotherapy to the whole brain.⁶ Further evidence is emerging that neurocognitive outcomes are improved when whole-brain radiotherapy (WBRT) is omitted, which possibly contributes to improved patient quality of life.⁷ Taking into account this and other data, the American Society for Radiation Oncology’s Choosing Wisely campaign now recommends not routinely adding WBRT to radiosurgery in patients with limited brain metastases.⁸

Despite this recommendation, many patients continue to benefit from WBRT, and it remains a common treatment in radiation oncology clinics across the US for several reasons. Many patients present with multiple brain metastases and are ineligible for radiosurgery. Even for technically eligible patients, WBRT has been shown to improve local control and decrease the rate of distant brain failure over radiosurgery alone.⁶ With higher rates of subsequent failures, patients receiving radiosurgery alone must adhere to more rigorous follow-up and imaging schedules, which can be difficult for many rural patients who have to travel long distances to centers. Furthermore, there is some suggestion that this decreased failure rate may result in improved survival in highly selected patients with excellent disease and performance status.⁹ Controversies exist, however, and strong institutional biases persist, contributing to significant differences in practice. We surveyed academic radiation oncologists and in an effort to identify and describe practice patterns in the delivery of WBRT at academic centers.

Methods

We conducted a thorough review of available literature on radiation for brain metastases and based on our findings, devised a survey 19 questions to ascertain practice patterns and treatment delivery among US academic physicians (Table 1). After obtaining institutional review board approval to do the study, we sent the survey to program coordinators at radiation oncology programs that are accredited by the Accreditation Council for Graduate Medical Education. We instructed coordinators to e-mail the survey to their practicing resident and attending physicians. The surveys were created using SurveyMonkey software. We obtained informed consent from the providers. A total of 3 follow-up e-mails were sent to each recipient of the survey to solicit responses, similar to the Dillman Total Design Survey Method.¹⁰

SPSS version 22.0 was used to analyze the data in an exploratory fashion. Statistical methods were used to assess the association of demographic data with SRS and WBRT delivery and treatment technique items when the analyses involved percentages that included the Pearson chi-square statistic and the chi-square test for linear trend. When the analysis focused on ranking data, the Kruskal-Wallis test, Mann-Whitney U test, the Jonckheere-Terpstra and the Kendall tau-b rank correlation were used as appropriate. If there were small sample sizes within some groups, then exact significant levels were assessed. Statistical significance was set by convention at P < .05.

Results

We received 95 responses of which 87 were considered complete for analysis. Forty-seven percent of the 87 respondents were not board-certified, and the remainder had passed their radiobiology and physics boards exams. A majority of respondents (70%, 61 of 87) were physicians who had been in practice for ≤5 years. Fifty-four percent of respondents were located in the Northeast US, 22% in the South, 14% in the West, and 10% in the Midwest and Hawaii (Table 2).

We used the chi-square test for linear trends to assess for a relationship between years of practice and whether respondents deviated from their typical method of WBRT therapy when treating more radioresistant tumors (melanoma, renal cell carcinoma). Respondents were classified by years in practice: 0-5, 6-10, 11-20, and >21 years. The results showed a linear association, with those in practice for longer periods more likely to use SRS alone, P = .027 (Figure 1).

Discussion

The incidence of brain metastases is increasing because of improvements in diagnostic imaging techniques and advancements in systemic therapy control of extracranial disease but not of intracranial disease or metastasis, because therapies do not cross the blood-brain barrier.^11,12 Brain metastases are the most common type of brain tumor. Given that most chemotherapeutic agents cannot cross the blood-brain barrier, radiotherapy is considered a means of treatment and of controlling brain metastases. Early data from the 1950s¹³ and 1960s¹⁴ have suggested clinical improvement with brain radiation, making radiotherapy the cornerstone for treatment of brain metastases.

The Radiation Therapy Oncology Group (RTOG) has evaluated several fractionation schedules, with 5 schemas evaluated by the RTOG 6901 and 7361 studies: 30 Gy in 10 fractions, 30 Gy in 15 fractions, 40 Gy in 15 fractions, 40 Gy in 20 fractions, and 20 Gy in 5 fractions. The combined results from these two trials showed that outcomes were similar for patients treated with a shorter regimen than for those treated with a more protracted schedule. In our study, respondents reported that they most frequently treated brain metastases to a total dose of 30 Gy in 10 fractions. Given the results of the aforementioned RTOG trials and practice patterns among academic physicians, we recommend all practitioners consider a shorter hypofractioned course when treating brain metastases with WBRT. This will also reduce delays for patients who are likely to benefit greatly from earlier enrollment into hospice care, because protracted radiation schedules typically are not covered while a patient is in hospice.

Pharmacologic management for patients with brain metastases is important for symptomatic improvement. Glucocorticoids are important for palliation of symptoms from edema and increased intracranial pressure.¹⁵ However, steroids have a multitude of side effects and their use in asymptomatic patients is unnecessary. Improvements in imaging and detection¹¹ have allowed us to find smaller and asymptomatic brain tumors. In our survey, it was promising to see a change in former practice patterns, with only 8% of academic practitioners regularly prescribing steroids to all of their patients receiving whole-brain radiation.

Diminished cognitive function and short-term memory loss are troublesome side effects of WBRT. As cancer patients live longer, such cognitive dysfunction will become more than just a nuisance. The RTOG has investigated the use of prophylactic memantine for patients receiving whole-brain radiation to determine if it would aid in the preservation of cognition. It found that patients who received memantine did better and had delayed time to cognitive decline and a reduced rate of memory decline, executive function, and processing speed.¹⁶ In our study, about a third of practitioners prescribed memantine and it was reserved for patients who had an otherwise favorable prognosis.

The RTOG has also investigated adjusting treatment technique for patients who receive WBRT. RTOG 0933 was a phase 2 trial that evaluated hippocampal avoidance during deliverance of WBRT with intensity-modulated radiation therapy (IMRT). Results showed that avoiding the hippocampus during WBRT was associated with improved memory preservation and patient quality of life.¹⁷ In a survey of practicing radiation oncologists in the US, most reported that they did not use memantine or IMRT for hippocampal sparing when delivering whole-brain radiation.¹⁸ Given the positive results of RTOG 0933 and 0614, the NRG Oncology research organization is conducting a phase 3 randomized trial that compares memantine use for patients receiving whole-brain radiation with or without hippocampal sparing to determine if patients will have reduced cognitive decline. All patients receiving WBRT should be considered for enrolment on this trial if they are eligible.

The delivery of brain radiation has continued to change, especially with the introduction of SRS. Recent publication of a meta-analysis of three phase 3 trials evaluating SRS with or without WBRT for 1-4 brain metastases showed that patients aged 50 years or younger experienced a survival benefit with SRS, and the omission of whole-brain radiation did not affect distant brain relapse rates. ¹⁹ The authors recommended that for this population, SRS alone is the preferred treatment. In our study, physicians who had been in practice for a longer time were more likely to treat using SRS alone. The results showed a linear association, with those in practice for a longer time being more likely to use SRS alone compared with those practicing for a shorter time (P = .027). Accordingly, 67% of respondents (8 of 12) who had been in practice for 11 or more years used SRS alone, whereas 24% (14 of 58) who had practiced for 0-5 years and 42% (5 of 12) who had practice from 6-10 years used SRS alone (Figure 1). When treating with SRS, younger practitioners placed more importance on the status of extracranial disease, whereas older practitioners placed more importance on tumor histopathology.

The use of repeat whole-brain reirradiation is more controversial among practitioners.^20-22 Son and colleagues evaluated patients who needed whole-brain reirradiation after intracranial disease progression.²² The authors noted that patients with stable extracranial disease benefited from reirradiation. In our study, we found that when considering whole-brain reirradiation, older practitioners placed more importance on tumor histology than other factors.

As far as we know, this is the first study evaluating the practices and patterns of care with regard to the delivery of brain radiation in academic centers in the US. We found that time in practice was the most significant predictor of treatment technique and delivery. We also found that older practitioners place more importance on tumor histopathology compared with younger practitioners. A limitation of this study is that we had contact information only for program coordinators at ACGME-accredited programs. As such, we were not able to assess practice patterns among community practitioners. In addition, it seemed that residents and junior faculty were more likely to respond to this survey, likely because of the dissemination pattern. Given the evolution and diversity of treatment regimens for brain metastases, we believe that patients with brain metastases should be managed individually using a multidisciplinary approach.

Despite the recent advances in systemic therapy, metastatic spread to the brain continues to be the most common neurologic complication of many cancers. The clinical incidence of brain metastases varies with primary cancer diagnosis, with estimates ranging from 1.2%-19.8%.^1,2 Metastatic spread to the brain is even more prevalent at autopsy, with evidence of intracranial tumor being found in 26% of patients in some series.³ It is possible that the clinical incidence of metastatic disease to the brain will continue to increase as newer therapeutic agents improve survival and imaging techniques continue to improve.

The management of brain metastases has changed rapidly as technological improvements have made treatment increasingly safe and efficacious. Traditionally, treatment consisted of radiotherapy to the whole brain, with or without surgical resection.^4,5 More recently, stereotactic radiosurgery (SRS) has been adopted on the basis of evidence that it is safe and efficacious alone or in combination with radiotherapy to the whole brain.⁶ Further evidence is emerging that neurocognitive outcomes are improved when whole-brain radiotherapy (WBRT) is omitted, which possibly contributes to improved patient quality of life.⁷ Taking into account this and other data, the American Society for Radiation Oncology’s Choosing Wisely campaign now recommends not routinely adding WBRT to radiosurgery in patients with limited brain metastases.⁸

Despite this recommendation, many patients continue to benefit from WBRT, and it remains a common treatment in radiation oncology clinics across the US for several reasons. Many patients present with multiple brain metastases and are ineligible for radiosurgery. Even for technically eligible patients, WBRT has been shown to improve local control and decrease the rate of distant brain failure over radiosurgery alone.⁶ With higher rates of subsequent failures, patients receiving radiosurgery alone must adhere to more rigorous follow-up and imaging schedules, which can be difficult for many rural patients who have to travel long distances to centers. Furthermore, there is some suggestion that this decreased failure rate may result in improved survival in highly selected patients with excellent disease and performance status.⁹ Controversies exist, however, and strong institutional biases persist, contributing to significant differences in practice. We surveyed academic radiation oncologists and in an effort to identify and describe practice patterns in the delivery of WBRT at academic centers.

Methods

We conducted a thorough review of available literature on radiation for brain metastases and based on our findings, devised a survey 19 questions to ascertain practice patterns and treatment delivery among US academic physicians (Table 1). After obtaining institutional review board approval to do the study, we sent the survey to program coordinators at radiation oncology programs that are accredited by the Accreditation Council for Graduate Medical Education. We instructed coordinators to e-mail the survey to their practicing resident and attending physicians. The surveys were created using SurveyMonkey software. We obtained informed consent from the providers. A total of 3 follow-up e-mails were sent to each recipient of the survey to solicit responses, similar to the Dillman Total Design Survey Method.¹⁰

SPSS version 22.0 was used to analyze the data in an exploratory fashion. Statistical methods were used to assess the association of demographic data with SRS and WBRT delivery and treatment technique items when the analyses involved percentages that included the Pearson chi-square statistic and the chi-square test for linear trend. When the analysis focused on ranking data, the Kruskal-Wallis test, Mann-Whitney U test, the Jonckheere-Terpstra and the Kendall tau-b rank correlation were used as appropriate. If there were small sample sizes within some groups, then exact significant levels were assessed. Statistical significance was set by convention at P < .05.

Results

We received 95 responses of which 87 were considered complete for analysis. Forty-seven percent of the 87 respondents were not board-certified, and the remainder had passed their radiobiology and physics boards exams. A majority of respondents (70%, 61 of 87) were physicians who had been in practice for ≤5 years. Fifty-four percent of respondents were located in the Northeast US, 22% in the South, 14% in the West, and 10% in the Midwest and Hawaii (Table 2).

We used the chi-square test for linear trends to assess for a relationship between years of practice and whether respondents deviated from their typical method of WBRT therapy when treating more radioresistant tumors (melanoma, renal cell carcinoma). Respondents were classified by years in practice: 0-5, 6-10, 11-20, and >21 years. The results showed a linear association, with those in practice for longer periods more likely to use SRS alone, P = .027 (Figure 1).

Discussion

The incidence of brain metastases is increasing because of improvements in diagnostic imaging techniques and advancements in systemic therapy control of extracranial disease but not of intracranial disease or metastasis, because therapies do not cross the blood-brain barrier.^11,12 Brain metastases are the most common type of brain tumor. Given that most chemotherapeutic agents cannot cross the blood-brain barrier, radiotherapy is considered a means of treatment and of controlling brain metastases. Early data from the 1950s¹³ and 1960s¹⁴ have suggested clinical improvement with brain radiation, making radiotherapy the cornerstone for treatment of brain metastases.

The Radiation Therapy Oncology Group (RTOG) has evaluated several fractionation schedules, with 5 schemas evaluated by the RTOG 6901 and 7361 studies: 30 Gy in 10 fractions, 30 Gy in 15 fractions, 40 Gy in 15 fractions, 40 Gy in 20 fractions, and 20 Gy in 5 fractions. The combined results from these two trials showed that outcomes were similar for patients treated with a shorter regimen than for those treated with a more protracted schedule. In our study, respondents reported that they most frequently treated brain metastases to a total dose of 30 Gy in 10 fractions. Given the results of the aforementioned RTOG trials and practice patterns among academic physicians, we recommend all practitioners consider a shorter hypofractioned course when treating brain metastases with WBRT. This will also reduce delays for patients who are likely to benefit greatly from earlier enrollment into hospice care, because protracted radiation schedules typically are not covered while a patient is in hospice.

Pharmacologic management for patients with brain metastases is important for symptomatic improvement. Glucocorticoids are important for palliation of symptoms from edema and increased intracranial pressure.¹⁵ However, steroids have a multitude of side effects and their use in asymptomatic patients is unnecessary. Improvements in imaging and detection¹¹ have allowed us to find smaller and asymptomatic brain tumors. In our survey, it was promising to see a change in former practice patterns, with only 8% of academic practitioners regularly prescribing steroids to all of their patients receiving whole-brain radiation.

Diminished cognitive function and short-term memory loss are troublesome side effects of WBRT. As cancer patients live longer, such cognitive dysfunction will become more than just a nuisance. The RTOG has investigated the use of prophylactic memantine for patients receiving whole-brain radiation to determine if it would aid in the preservation of cognition. It found that patients who received memantine did better and had delayed time to cognitive decline and a reduced rate of memory decline, executive function, and processing speed.¹⁶ In our study, about a third of practitioners prescribed memantine and it was reserved for patients who had an otherwise favorable prognosis.

The RTOG has also investigated adjusting treatment technique for patients who receive WBRT. RTOG 0933 was a phase 2 trial that evaluated hippocampal avoidance during deliverance of WBRT with intensity-modulated radiation therapy (IMRT). Results showed that avoiding the hippocampus during WBRT was associated with improved memory preservation and patient quality of life.¹⁷ In a survey of practicing radiation oncologists in the US, most reported that they did not use memantine or IMRT for hippocampal sparing when delivering whole-brain radiation.¹⁸ Given the positive results of RTOG 0933 and 0614, the NRG Oncology research organization is conducting a phase 3 randomized trial that compares memantine use for patients receiving whole-brain radiation with or without hippocampal sparing to determine if patients will have reduced cognitive decline. All patients receiving WBRT should be considered for enrolment on this trial if they are eligible.

The delivery of brain radiation has continued to change, especially with the introduction of SRS. Recent publication of a meta-analysis of three phase 3 trials evaluating SRS with or without WBRT for 1-4 brain metastases showed that patients aged 50 years or younger experienced a survival benefit with SRS, and the omission of whole-brain radiation did not affect distant brain relapse rates. ¹⁹ The authors recommended that for this population, SRS alone is the preferred treatment. In our study, physicians who had been in practice for a longer time were more likely to treat using SRS alone. The results showed a linear association, with those in practice for a longer time being more likely to use SRS alone compared with those practicing for a shorter time (P = .027). Accordingly, 67% of respondents (8 of 12) who had been in practice for 11 or more years used SRS alone, whereas 24% (14 of 58) who had practiced for 0-5 years and 42% (5 of 12) who had practice from 6-10 years used SRS alone (Figure 1). When treating with SRS, younger practitioners placed more importance on the status of extracranial disease, whereas older practitioners placed more importance on tumor histopathology.

The use of repeat whole-brain reirradiation is more controversial among practitioners.^20-22 Son and colleagues evaluated patients who needed whole-brain reirradiation after intracranial disease progression.²² The authors noted that patients with stable extracranial disease benefited from reirradiation. In our study, we found that when considering whole-brain reirradiation, older practitioners placed more importance on tumor histology than other factors.

As far as we know, this is the first study evaluating the practices and patterns of care with regard to the delivery of brain radiation in academic centers in the US. We found that time in practice was the most significant predictor of treatment technique and delivery. We also found that older practitioners place more importance on tumor histopathology compared with younger practitioners. A limitation of this study is that we had contact information only for program coordinators at ACGME-accredited programs. As such, we were not able to assess practice patterns among community practitioners. In addition, it seemed that residents and junior faculty were more likely to respond to this survey, likely because of the dissemination pattern. Given the evolution and diversity of treatment regimens for brain metastases, we believe that patients with brain metastases should be managed individually using a multidisciplinary approach.

A comprehensive, patient-centered approach is required to accomplish cancer best standards of care.¹ This approach reflects the holistic conceptualization of health in which the physical, emotional, and social dimensions of the human being are considered when providing medical care. As a result, to look after all patient needs, interdisciplinary and well-coordinated interventions are recommended. Cancer patients should be provided not only with diagnostic, treatment, and follow-up clinical service, but also with the supportive assistance that may positively influence all aspects of their health.

To appraise physical, social, emotional and spiritual issues and to develop supportive interventional action plans, the National Comprehensive Cancer Network (NCCN) recommends screening all cancer patients for distress.² In particular, screening the emotional component of distress occupies a prominent place in this process because it is now recognized as the sixth vital sign in oncology.³ Even though the influence of emotional distress over cancer mortality rates and disease progression is still under scrutiny,⁴ its plausible implications over treatment compliance have been pointed out. Patients with higher levels of emotional distress show lower adherence to treatment and poorer health outcomes.⁵ Furthermore, prevalence rates of emotional distress in cancer patients from ambulatory settings⁶ and oncology surgical units have been studied and have provided justification for distress management.⁷ Studies have shown low ability among oncologists to identify patients in distress and oncologists’ tendency to judge distress higher than the patients themselves.⁸ As a consequence, to achieve systematic distress evaluations and appropriate referrals for care, guidelines for distress management should be implemented in clinical settings. It is recommended that tests are conducted to find brief screening instruments and procedures to assure accurate interventions according to patient specific needs.

This article presents the process of implementing a distress management program at HIMA-San Pablo Oncologic Hospital in Caguas, Puerto Rico, with particular emphasis on the management of emotional distress, which has been defined as the feeling of suffering that cancer patients may experience after diagnosis. In addition, we have included data from a pilot study that was completed for content validation of the Patient Health Questionnaire (PHQ-9) to estimate depression levels in Puerto Rican cancer patients.

Methods

HIMA-San Pablo operates a group of privately owned hospitals in Puerto Rico. It established a cancer center in Caguas in 2007, recruiting a multispecialty medical faculty to provide cancer care and bone marrow transplants for adult and pediatric patients. The cancer center, currently named HIMA-San Pablo Oncologic Hospital (HSPOH), is a hospital within a hospital licensed by the Puerto Rico Department of Health. In 2007, a cancer committee was established as the steering committee to ensure the delivery of cancer care according to best standards of care. The committee took responsibility for developing all activities needed to achieve the American College of Surgeons’ Commission on Cancer (CoC) accreditation under the category of Comprehensive Community Cancer Center. The committee established a psychosocial team to develop a protocol for the delivery of distress management for adult patients. (The psychosocial needs of pediatric patients are assessed through other procedures.)

To develop the protocol, principles of input-output model of research and quality analysis in health care were applied.⁹ The input-output model, with its origin in engineering, helped map systematic activities to transform empirical data on cancer psychosocial care into operational procedures. Focus was given to data gathering (input), information organization and analysis (throughput), and the schematization of emotional distress management care (output).

The input phase

In the input phase, elements of psychosocial care and operational definitions related to distress management in general were identified through literature review (Table 1). Basic parameters for distress management were clarified, resulting in a conceptual framework based in four remarks: First, according to NCCN, distress is a multifactorial unpleasant emotional experience of a psychological, social, and spiritual nature. It may interfere with the ability to cope effectively with cancer, its symptoms and its treatment. Its intensity may fluctuate from feelings of suffering and fear to incapacitating manifestations of anxiety and depression² and its severity may hamper patient quality of life and treatment compliance.

Second, distress management requires the intervention of an interdisciplinary team with both medical and allied health professionals. This may include mental health specialists and other professionals with training and experience in cancer-related issues, who work with reciprocal channels of communication for the exchange of patient information.

Third, NCCN recommends using the Distress Thermometer for patient initial distress screening.^10-12 It consists of a numeric scale ranging from 0 (no distress) to 10 (severe distress) in which patients classify their level of distress. The numeric scale is followed by a section in which patients identify areas of practical, familiar, emotional, spiritual/ religious, and physical concerns. Based on responses, interviews may follow to set distress management interventions.

Fourth, screening and assessment are different but sequential and complementary stages of distress management. Screening is viewed as a rapid strategy to identify cancer patients in distress. Assessment looks out for a broader appraisal and documentation of factors with repercussions over patient distress level and resiliency capability.¹³ In many instances, the patient’s emotional distress is better understood in the assessment phase.

The throughput phase

Within the throughput phase of information organization and analysis, an inventory of health professionals and other in-house consultants needed for distress management was completed. Roles and procedures for information sharing were determined, and we established collaborative agreements with professionals in the community who could contribute to distress management. Members of the psychosocial team held workshops to discuss elements of NCCN guidelines for distress management and to create an action plan for the implementation of the protocol. Data analyses were performed to create a demographic profile of the oncology population at the hospital and assess patient willingness to receive emotional support services,¹⁶ which led to the implementation of support group meetings at which additional substantive information was collected about issues affecting cancer patients’ emotions.

The NCCN Distress Thermometer for measuring distress was translated to Spanish. Its format was adapted, and it was identified as a distress screening tool (DST), which we named Distress Assessment Tool for Oncology Patients (Figure 1). The instrument helps for rapid screening of patient needs and proper determination of initial interventions. In addition, psychometric properties of several instruments were reviewed for instances when patient emotional distress could not be clearly determined. We decided to proceed with the validation of the 9-item Patient Health Questionnaire (PHQ-9) to estimate patient depression level. A proposal for content validation of the PHQ-9 was approved by the University of Puerto Rico institutional review board, and patients were recruited to participate in the pilot study.

The PHQ-9. The PHQ-9 is a self-report version of the PRIME-MD instrument developed to assess mental disorders in clinical settings. It is based on DSM-IV diagnostic criteria.¹⁷ The PHQ-9 is the depression module with nine depression symptoms to check off if they become the cause of emotional impairment. Respondents categorized depression symptoms in four frequency degrees representing numeric values: 0 (not at all), 1 (several days), 2 (more than half the days), 3 (nearly every day). Measures of depression severity are subsequently determined in a Likert-type scale according to numeric calculations of responses: 0-4 (none severe depression), 5-9 (mild), 10-14 (moderate), 15-19 (moderately severe), and 20-27 (severe-major depression).

The instrument is widely used because of its validity in small and large populations. It showed adequate reliability and validity in a small sample of head and neck cancer patients, with a Cronbach’s alpha of 0.80 and a correlation coefficient of 0.71.¹⁸ Similarly, it showed good performance in identifying major depression in 4264 cancer outpatients, with sensitivity of 93%, specificity of 81%, and a positive predictive value (PPV) of 25% and negative predictive value (NPV) of 99%.¹⁹ Even when administered on a touch screen computer, the instrument showed valid data of depression from patients in treatment.²⁰

The Beck Depression Inventory. We used the Beck Depression Inventory (BDI-II) Spanish version as the gold standard measure for the validation study. It is a 22-items inventory that measures attitudes and symptoms of depression.²¹ It can be administered in 10 minutes and has shown good psychometric measures when administered in Spain and Puerto Rico.^{22, 23}

The pilot study. In all, 44 cancer patients who were receiving outpatient treatment at the radiotherapy unit agreed to participate in the study. The participants signed a consent form after the confidentiality protection measures and the main objectives of the study had been explained to them. Patients were interviewed individually during November and December 2012, with the Spanish versions of the PHQ-9 and BDI-II administered by one of two interviewers. At the beginning of each interview, the patient was asked 10 questions so that we could gather demographic data and confirm participant eligibility: aged 21 years or older, born and raised in Puerto Rico, being a Spanish speaker, and having a primary cancer diagnosis with no previous disease. Three patients were excluded from the sample because they either had cancer previously or had a recurrence or metastasis. The final sample consisted of 41 outpatients (N = 41).

Data analysis for demographics was completed with STATA v.12 software. Measures of central tendency and dispersion as well as PHQ-9 internal consistency analysis were made through Cronbach alpha with SPSS.

From a total of 41 patients surveyed, 22 (54%) were men and 19 (46%) were women, with an overall median age of 61 years. Among the men, 15 (68%) had a prostate cancer diagnosis and among women, 9 (47.4%) had a breast cancer diagnosis. In regard to health insurance, 19 (46%) had Medicare or Veterans/federal insurance coverage, and 13 (32%) had Reforma, the Puerto Rican government health insurance program partially funded by Medicaid funds. In addition, 8 participants (20%) were unemployed or disabled. As previously stated, all of the patients were in ambulatory care. Only 3 (7%) were participating in support groups.

Of all the respondents, 16 (39%) reported some level of depression. In particular, 2 (5%) showed severe-major depression, 4 (10%) moderately severe depression, and 10 (24%) moderate depression. Of those with depression, 8 (50%) were women, 8 (50%) were men. All 6 of the patients with head and neck cancer showed moderate or moderately severe depression (Table 2).

When respondent PHQ-9 scoring reflected moderate to severe depression (>10), a letter was sent to the patient’s radio-oncologist for referral to counseling and clinical psychological evaluation. All participants had access to the support group program, to a radiotherapy education program meeting weekly, and written information about their cancer diagnosis and treatment. They also were interviewed by the psychosocial coordinator or patient navigator for further assessment.

The output phase

In the output phase, a graphic representing the process of emotional assessment at the institution was created and then modified. PHQ-9 was added to the process when it was found suitable to assess level of depression contributing to the identification of patients requiring psychological and psychiatric assistance which by other means would be missed. PHQ-9 was useful in the busy clinical setting as it was completed, scored and interpreted in minutes. It showed the potential for routine evaluations when looking to identify improvement or deterioration in depression levels thus helping to monitor responses to treatment and providing insights for follow up interventions. As stated by NCCN guidelines, distress should be monitored, documented and managed at all stages of the cancer continuum.

Results and discussion

The protocol for distress management at HSPOH is based on the 2013 NCCN guidelines. Cancer patients are screened for levels of distress in all settings (inpatients and outpatients). Screening is held with the DST Spanish translation at the moment of diagnosis or as soon as possible after a diagnosis is made. Screening for distress is also done before or after surgery, in recurrence or progression, and when clinically indicated. Patients are informed that distress management is an essential part of their care and are encouraged to provide information so that we can make a proper need assessment.

Patients are screened by the psychosocial coordinator or patient navigator who administers the DST followed by in-depth interviews for additional appraisal. An action plan is designed based on patient needs, which include their intervention and the intervention of other members of the psychosocial team from the institution and/or from the community. Additional in-house health professionals contributing in distress management include, but are not limited to: physicians; clinical psychologists; health educators; social workers; dietitians; chaplains; and physical, respiratory, speech, and/or swallow therapists. Follow-up and rescreening sessions are scheduled to assure coordination of services between those health professionals as well as to secure continuity of distress management during all stages of the cancer continuum.

The results of the DST are filed in patient medical records. Members of the psychosocial team also document their interventions in the patient medical record, which helps in the exchange of information among the cancer care team. The psychosocial team meets once a month – or as required for extraordinary cases – to review and discuss the cases, determine the best options for distress management, and identify areas for psychosocial care improvement. Those findings and the results of distress management in patient level of satisfaction are then reported and discussed quarterly by the psychosocial coordinator and the cancer committee.

Figure 2 shows in what phase of emotional distress assessment the PHQ-9 was included. Patients reporting four or more of the six areas of concern related to emotional distress in the DST (Figure 1) are automatically referred to a mental health specialist. But when patients report three areas of concern with no clear data on their specific level of depression, PHQ-9 is administered to differentiate those who need a mental health specialist from those who could be adequately supported by health education and support group interventions. In this way detrimental outcomes such as duplicity and over or underuse of services and resources are reduced. In addition, it is recognized that using an interview after the administration of the DST to determine distress management actions does not always provide enough information about a patient’s emotional circumstances and previous comorbidities. Patient responses during interviews may be influenced by the patient’s level of literacy, verbal comprehension, and communication style,²⁴ so emotional distress can go unrecognized during interviews, resulting in delays for treatment and supportive care.

National guidelines in oncology consider such socio-ecological models emphasizing the delivery of patient-centered, interdisciplinary, and evidence-based care. That does not mean that institutions should apply protocols of psychosocial care as previously developed, but that they should test, review, adapt, and improve them during the implementation of the care. In fact, NCCN encourages conducting trials to examine protocols, screening instruments, and models of intervention to determine applicability to particular settings.²

Findings from a study by NCCN member institutions to evaluate progress of implementing distress management guidelines found that 53% (n = 8) of respondent institutions conducted routine distress screening. Of those, 37.5% (3) relied only on interviews. That finding is of concern because if interviews are not standardized and have not been systematically evaluated, then their sensitivity and specificity in identifying distressed patients is unknown.²⁶ Accordingly, the process described in this article and the PHQ-9 validation was an effort to standardize emotional distress management, and was underlined as an achievement during the CoC accreditation visit to the cancer center in December 2013. The hospital was accredited as a comprehensive community cancer center with gold commendations, becoming the first privately owned hospital in Puerto Rico to achieve the accreditation.

A comprehensive, patient-centered approach is required to accomplish cancer best standards of care.¹ This approach reflects the holistic conceptualization of health in which the physical, emotional, and social dimensions of the human being are considered when providing medical care. As a result, to look after all patient needs, interdisciplinary and well-coordinated interventions are recommended. Cancer patients should be provided not only with diagnostic, treatment, and follow-up clinical service, but also with the supportive assistance that may positively influence all aspects of their health.

To appraise physical, social, emotional and spiritual issues and to develop supportive interventional action plans, the National Comprehensive Cancer Network (NCCN) recommends screening all cancer patients for distress.² In particular, screening the emotional component of distress occupies a prominent place in this process because it is now recognized as the sixth vital sign in oncology.³ Even though the influence of emotional distress over cancer mortality rates and disease progression is still under scrutiny,⁴ its plausible implications over treatment compliance have been pointed out. Patients with higher levels of emotional distress show lower adherence to treatment and poorer health outcomes.⁵ Furthermore, prevalence rates of emotional distress in cancer patients from ambulatory settings⁶ and oncology surgical units have been studied and have provided justification for distress management.⁷ Studies have shown low ability among oncologists to identify patients in distress and oncologists’ tendency to judge distress higher than the patients themselves.⁸ As a consequence, to achieve systematic distress evaluations and appropriate referrals for care, guidelines for distress management should be implemented in clinical settings. It is recommended that tests are conducted to find brief screening instruments and procedures to assure accurate interventions according to patient specific needs.

This article presents the process of implementing a distress management program at HIMA-San Pablo Oncologic Hospital in Caguas, Puerto Rico, with particular emphasis on the management of emotional distress, which has been defined as the feeling of suffering that cancer patients may experience after diagnosis. In addition, we have included data from a pilot study that was completed for content validation of the Patient Health Questionnaire (PHQ-9) to estimate depression levels in Puerto Rican cancer patients.

Methods

HIMA-San Pablo operates a group of privately owned hospitals in Puerto Rico. It established a cancer center in Caguas in 2007, recruiting a multispecialty medical faculty to provide cancer care and bone marrow transplants for adult and pediatric patients. The cancer center, currently named HIMA-San Pablo Oncologic Hospital (HSPOH), is a hospital within a hospital licensed by the Puerto Rico Department of Health. In 2007, a cancer committee was established as the steering committee to ensure the delivery of cancer care according to best standards of care. The committee took responsibility for developing all activities needed to achieve the American College of Surgeons’ Commission on Cancer (CoC) accreditation under the category of Comprehensive Community Cancer Center. The committee established a psychosocial team to develop a protocol for the delivery of distress management for adult patients. (The psychosocial needs of pediatric patients are assessed through other procedures.)

To develop the protocol, principles of input-output model of research and quality analysis in health care were applied.⁹ The input-output model, with its origin in engineering, helped map systematic activities to transform empirical data on cancer psychosocial care into operational procedures. Focus was given to data gathering (input), information organization and analysis (throughput), and the schematization of emotional distress management care (output).

The input phase

In the input phase, elements of psychosocial care and operational definitions related to distress management in general were identified through literature review (Table 1). Basic parameters for distress management were clarified, resulting in a conceptual framework based in four remarks: First, according to NCCN, distress is a multifactorial unpleasant emotional experience of a psychological, social, and spiritual nature. It may interfere with the ability to cope effectively with cancer, its symptoms and its treatment. Its intensity may fluctuate from feelings of suffering and fear to incapacitating manifestations of anxiety and depression² and its severity may hamper patient quality of life and treatment compliance.

Second, distress management requires the intervention of an interdisciplinary team with both medical and allied health professionals. This may include mental health specialists and other professionals with training and experience in cancer-related issues, who work with reciprocal channels of communication for the exchange of patient information.

Third, NCCN recommends using the Distress Thermometer for patient initial distress screening.^10-12 It consists of a numeric scale ranging from 0 (no distress) to 10 (severe distress) in which patients classify their level of distress. The numeric scale is followed by a section in which patients identify areas of practical, familiar, emotional, spiritual/ religious, and physical concerns. Based on responses, interviews may follow to set distress management interventions.

Fourth, screening and assessment are different but sequential and complementary stages of distress management. Screening is viewed as a rapid strategy to identify cancer patients in distress. Assessment looks out for a broader appraisal and documentation of factors with repercussions over patient distress level and resiliency capability.¹³ In many instances, the patient’s emotional distress is better understood in the assessment phase.

The throughput phase

Within the throughput phase of information organization and analysis, an inventory of health professionals and other in-house consultants needed for distress management was completed. Roles and procedures for information sharing were determined, and we established collaborative agreements with professionals in the community who could contribute to distress management. Members of the psychosocial team held workshops to discuss elements of NCCN guidelines for distress management and to create an action plan for the implementation of the protocol. Data analyses were performed to create a demographic profile of the oncology population at the hospital and assess patient willingness to receive emotional support services,¹⁶ which led to the implementation of support group meetings at which additional substantive information was collected about issues affecting cancer patients’ emotions.

The NCCN Distress Thermometer for measuring distress was translated to Spanish. Its format was adapted, and it was identified as a distress screening tool (DST), which we named Distress Assessment Tool for Oncology Patients (Figure 1). The instrument helps for rapid screening of patient needs and proper determination of initial interventions. In addition, psychometric properties of several instruments were reviewed for instances when patient emotional distress could not be clearly determined. We decided to proceed with the validation of the 9-item Patient Health Questionnaire (PHQ-9) to estimate patient depression level. A proposal for content validation of the PHQ-9 was approved by the University of Puerto Rico institutional review board, and patients were recruited to participate in the pilot study.

The PHQ-9. The PHQ-9 is a self-report version of the PRIME-MD instrument developed to assess mental disorders in clinical settings. It is based on DSM-IV diagnostic criteria.¹⁷ The PHQ-9 is the depression module with nine depression symptoms to check off if they become the cause of emotional impairment. Respondents categorized depression symptoms in four frequency degrees representing numeric values: 0 (not at all), 1 (several days), 2 (more than half the days), 3 (nearly every day). Measures of depression severity are subsequently determined in a Likert-type scale according to numeric calculations of responses: 0-4 (none severe depression), 5-9 (mild), 10-14 (moderate), 15-19 (moderately severe), and 20-27 (severe-major depression).

The instrument is widely used because of its validity in small and large populations. It showed adequate reliability and validity in a small sample of head and neck cancer patients, with a Cronbach’s alpha of 0.80 and a correlation coefficient of 0.71.¹⁸ Similarly, it showed good performance in identifying major depression in 4264 cancer outpatients, with sensitivity of 93%, specificity of 81%, and a positive predictive value (PPV) of 25% and negative predictive value (NPV) of 99%.¹⁹ Even when administered on a touch screen computer, the instrument showed valid data of depression from patients in treatment.²⁰

The Beck Depression Inventory. We used the Beck Depression Inventory (BDI-II) Spanish version as the gold standard measure for the validation study. It is a 22-items inventory that measures attitudes and symptoms of depression.²¹ It can be administered in 10 minutes and has shown good psychometric measures when administered in Spain and Puerto Rico.^{22, 23}

The pilot study. In all, 44 cancer patients who were receiving outpatient treatment at the radiotherapy unit agreed to participate in the study. The participants signed a consent form after the confidentiality protection measures and the main objectives of the study had been explained to them. Patients were interviewed individually during November and December 2012, with the Spanish versions of the PHQ-9 and BDI-II administered by one of two interviewers. At the beginning of each interview, the patient was asked 10 questions so that we could gather demographic data and confirm participant eligibility: aged 21 years or older, born and raised in Puerto Rico, being a Spanish speaker, and having a primary cancer diagnosis with no previous disease. Three patients were excluded from the sample because they either had cancer previously or had a recurrence or metastasis. The final sample consisted of 41 outpatients (N = 41).

Data analysis for demographics was completed with STATA v.12 software. Measures of central tendency and dispersion as well as PHQ-9 internal consistency analysis were made through Cronbach alpha with SPSS.

From a total of 41 patients surveyed, 22 (54%) were men and 19 (46%) were women, with an overall median age of 61 years. Among the men, 15 (68%) had a prostate cancer diagnosis and among women, 9 (47.4%) had a breast cancer diagnosis. In regard to health insurance, 19 (46%) had Medicare or Veterans/federal insurance coverage, and 13 (32%) had Reforma, the Puerto Rican government health insurance program partially funded by Medicaid funds. In addition, 8 participants (20%) were unemployed or disabled. As previously stated, all of the patients were in ambulatory care. Only 3 (7%) were participating in support groups.

Of all the respondents, 16 (39%) reported some level of depression. In particular, 2 (5%) showed severe-major depression, 4 (10%) moderately severe depression, and 10 (24%) moderate depression. Of those with depression, 8 (50%) were women, 8 (50%) were men. All 6 of the patients with head and neck cancer showed moderate or moderately severe depression (Table 2).

When respondent PHQ-9 scoring reflected moderate to severe depression (>10), a letter was sent to the patient’s radio-oncologist for referral to counseling and clinical psychological evaluation. All participants had access to the support group program, to a radiotherapy education program meeting weekly, and written information about their cancer diagnosis and treatment. They also were interviewed by the psychosocial coordinator or patient navigator for further assessment.

The output phase

In the output phase, a graphic representing the process of emotional assessment at the institution was created and then modified. PHQ-9 was added to the process when it was found suitable to assess level of depression contributing to the identification of patients requiring psychological and psychiatric assistance which by other means would be missed. PHQ-9 was useful in the busy clinical setting as it was completed, scored and interpreted in minutes. It showed the potential for routine evaluations when looking to identify improvement or deterioration in depression levels thus helping to monitor responses to treatment and providing insights for follow up interventions. As stated by NCCN guidelines, distress should be monitored, documented and managed at all stages of the cancer continuum.

Results and discussion

The protocol for distress management at HSPOH is based on the 2013 NCCN guidelines. Cancer patients are screened for levels of distress in all settings (inpatients and outpatients). Screening is held with the DST Spanish translation at the moment of diagnosis or as soon as possible after a diagnosis is made. Screening for distress is also done before or after surgery, in recurrence or progression, and when clinically indicated. Patients are informed that distress management is an essential part of their care and are encouraged to provide information so that we can make a proper need assessment.

Patients are screened by the psychosocial coordinator or patient navigator who administers the DST followed by in-depth interviews for additional appraisal. An action plan is designed based on patient needs, which include their intervention and the intervention of other members of the psychosocial team from the institution and/or from the community. Additional in-house health professionals contributing in distress management include, but are not limited to: physicians; clinical psychologists; health educators; social workers; dietitians; chaplains; and physical, respiratory, speech, and/or swallow therapists. Follow-up and rescreening sessions are scheduled to assure coordination of services between those health professionals as well as to secure continuity of distress management during all stages of the cancer continuum.

The results of the DST are filed in patient medical records. Members of the psychosocial team also document their interventions in the patient medical record, which helps in the exchange of information among the cancer care team. The psychosocial team meets once a month – or as required for extraordinary cases – to review and discuss the cases, determine the best options for distress management, and identify areas for psychosocial care improvement. Those findings and the results of distress management in patient level of satisfaction are then reported and discussed quarterly by the psychosocial coordinator and the cancer committee.

Figure 2 shows in what phase of emotional distress assessment the PHQ-9 was included. Patients reporting four or more of the six areas of concern related to emotional distress in the DST (Figure 1) are automatically referred to a mental health specialist. But when patients report three areas of concern with no clear data on their specific level of depression, PHQ-9 is administered to differentiate those who need a mental health specialist from those who could be adequately supported by health education and support group interventions. In this way detrimental outcomes such as duplicity and over or underuse of services and resources are reduced. In addition, it is recognized that using an interview after the administration of the DST to determine distress management actions does not always provide enough information about a patient’s emotional circumstances and previous comorbidities. Patient responses during interviews may be influenced by the patient’s level of literacy, verbal comprehension, and communication style,²⁴ so emotional distress can go unrecognized during interviews, resulting in delays for treatment and supportive care.

National guidelines in oncology consider such socio-ecological models emphasizing the delivery of patient-centered, interdisciplinary, and evidence-based care. That does not mean that institutions should apply protocols of psychosocial care as previously developed, but that they should test, review, adapt, and improve them during the implementation of the care. In fact, NCCN encourages conducting trials to examine protocols, screening instruments, and models of intervention to determine applicability to particular settings.²

Findings from a study by NCCN member institutions to evaluate progress of implementing distress management guidelines found that 53% (n = 8) of respondent institutions conducted routine distress screening. Of those, 37.5% (3) relied only on interviews. That finding is of concern because if interviews are not standardized and have not been systematically evaluated, then their sensitivity and specificity in identifying distressed patients is unknown.²⁶ Accordingly, the process described in this article and the PHQ-9 validation was an effort to standardize emotional distress management, and was underlined as an achievement during the CoC accreditation visit to the cancer center in December 2013. The hospital was accredited as a comprehensive community cancer center with gold commendations, becoming the first privately owned hospital in Puerto Rico to achieve the accreditation.

A comprehensive, patient-centered approach is required to accomplish cancer best standards of care.¹ This approach reflects the holistic conceptualization of health in which the physical, emotional, and social dimensions of the human being are considered when providing medical care. As a result, to look after all patient needs, interdisciplinary and well-coordinated interventions are recommended. Cancer patients should be provided not only with diagnostic, treatment, and follow-up clinical service, but also with the supportive assistance that may positively influence all aspects of their health.

To appraise physical, social, emotional and spiritual issues and to develop supportive interventional action plans, the National Comprehensive Cancer Network (NCCN) recommends screening all cancer patients for distress.² In particular, screening the emotional component of distress occupies a prominent place in this process because it is now recognized as the sixth vital sign in oncology.³ Even though the influence of emotional distress over cancer mortality rates and disease progression is still under scrutiny,⁴ its plausible implications over treatment compliance have been pointed out. Patients with higher levels of emotional distress show lower adherence to treatment and poorer health outcomes.⁵ Furthermore, prevalence rates of emotional distress in cancer patients from ambulatory settings⁶ and oncology surgical units have been studied and have provided justification for distress management.⁷ Studies have shown low ability among oncologists to identify patients in distress and oncologists’ tendency to judge distress higher than the patients themselves.⁸ As a consequence, to achieve systematic distress evaluations and appropriate referrals for care, guidelines for distress management should be implemented in clinical settings. It is recommended that tests are conducted to find brief screening instruments and procedures to assure accurate interventions according to patient specific needs.

This article presents the process of implementing a distress management program at HIMA-San Pablo Oncologic Hospital in Caguas, Puerto Rico, with particular emphasis on the management of emotional distress, which has been defined as the feeling of suffering that cancer patients may experience after diagnosis. In addition, we have included data from a pilot study that was completed for content validation of the Patient Health Questionnaire (PHQ-9) to estimate depression levels in Puerto Rican cancer patients.

Methods

HIMA-San Pablo operates a group of privately owned hospitals in Puerto Rico. It established a cancer center in Caguas in 2007, recruiting a multispecialty medical faculty to provide cancer care and bone marrow transplants for adult and pediatric patients. The cancer center, currently named HIMA-San Pablo Oncologic Hospital (HSPOH), is a hospital within a hospital licensed by the Puerto Rico Department of Health. In 2007, a cancer committee was established as the steering committee to ensure the delivery of cancer care according to best standards of care. The committee took responsibility for developing all activities needed to achieve the American College of Surgeons’ Commission on Cancer (CoC) accreditation under the category of Comprehensive Community Cancer Center. The committee established a psychosocial team to develop a protocol for the delivery of distress management for adult patients. (The psychosocial needs of pediatric patients are assessed through other procedures.)

To develop the protocol, principles of input-output model of research and quality analysis in health care were applied.⁹ The input-output model, with its origin in engineering, helped map systematic activities to transform empirical data on cancer psychosocial care into operational procedures. Focus was given to data gathering (input), information organization and analysis (throughput), and the schematization of emotional distress management care (output).

The input phase

In the input phase, elements of psychosocial care and operational definitions related to distress management in general were identified through literature review (Table 1). Basic parameters for distress management were clarified, resulting in a conceptual framework based in four remarks: First, according to NCCN, distress is a multifactorial unpleasant emotional experience of a psychological, social, and spiritual nature. It may interfere with the ability to cope effectively with cancer, its symptoms and its treatment. Its intensity may fluctuate from feelings of suffering and fear to incapacitating manifestations of anxiety and depression² and its severity may hamper patient quality of life and treatment compliance.

Second, distress management requires the intervention of an interdisciplinary team with both medical and allied health professionals. This may include mental health specialists and other professionals with training and experience in cancer-related issues, who work with reciprocal channels of communication for the exchange of patient information.

Third, NCCN recommends using the Distress Thermometer for patient initial distress screening.^10-12 It consists of a numeric scale ranging from 0 (no distress) to 10 (severe distress) in which patients classify their level of distress. The numeric scale is followed by a section in which patients identify areas of practical, familiar, emotional, spiritual/ religious, and physical concerns. Based on responses, interviews may follow to set distress management interventions.

Fourth, screening and assessment are different but sequential and complementary stages of distress management. Screening is viewed as a rapid strategy to identify cancer patients in distress. Assessment looks out for a broader appraisal and documentation of factors with repercussions over patient distress level and resiliency capability.¹³ In many instances, the patient’s emotional distress is better understood in the assessment phase.

The throughput phase

Within the throughput phase of information organization and analysis, an inventory of health professionals and other in-house consultants needed for distress management was completed. Roles and procedures for information sharing were determined, and we established collaborative agreements with professionals in the community who could contribute to distress management. Members of the psychosocial team held workshops to discuss elements of NCCN guidelines for distress management and to create an action plan for the implementation of the protocol. Data analyses were performed to create a demographic profile of the oncology population at the hospital and assess patient willingness to receive emotional support services,¹⁶ which led to the implementation of support group meetings at which additional substantive information was collected about issues affecting cancer patients’ emotions.

The NCCN Distress Thermometer for measuring distress was translated to Spanish. Its format was adapted, and it was identified as a distress screening tool (DST), which we named Distress Assessment Tool for Oncology Patients (Figure 1). The instrument helps for rapid screening of patient needs and proper determination of initial interventions. In addition, psychometric properties of several instruments were reviewed for instances when patient emotional distress could not be clearly determined. We decided to proceed with the validation of the 9-item Patient Health Questionnaire (PHQ-9) to estimate patient depression level. A proposal for content validation of the PHQ-9 was approved by the University of Puerto Rico institutional review board, and patients were recruited to participate in the pilot study.

The PHQ-9. The PHQ-9 is a self-report version of the PRIME-MD instrument developed to assess mental disorders in clinical settings. It is based on DSM-IV diagnostic criteria.¹⁷ The PHQ-9 is the depression module with nine depression symptoms to check off if they become the cause of emotional impairment. Respondents categorized depression symptoms in four frequency degrees representing numeric values: 0 (not at all), 1 (several days), 2 (more than half the days), 3 (nearly every day). Measures of depression severity are subsequently determined in a Likert-type scale according to numeric calculations of responses: 0-4 (none severe depression), 5-9 (mild), 10-14 (moderate), 15-19 (moderately severe), and 20-27 (severe-major depression).

The instrument is widely used because of its validity in small and large populations. It showed adequate reliability and validity in a small sample of head and neck cancer patients, with a Cronbach’s alpha of 0.80 and a correlation coefficient of 0.71.¹⁸ Similarly, it showed good performance in identifying major depression in 4264 cancer outpatients, with sensitivity of 93%, specificity of 81%, and a positive predictive value (PPV) of 25% and negative predictive value (NPV) of 99%.¹⁹ Even when administered on a touch screen computer, the instrument showed valid data of depression from patients in treatment.²⁰

The Beck Depression Inventory. We used the Beck Depression Inventory (BDI-II) Spanish version as the gold standard measure for the validation study. It is a 22-items inventory that measures attitudes and symptoms of depression.²¹ It can be administered in 10 minutes and has shown good psychometric measures when administered in Spain and Puerto Rico.^{22, 23}

The pilot study. In all, 44 cancer patients who were receiving outpatient treatment at the radiotherapy unit agreed to participate in the study. The participants signed a consent form after the confidentiality protection measures and the main objectives of the study had been explained to them. Patients were interviewed individually during November and December 2012, with the Spanish versions of the PHQ-9 and BDI-II administered by one of two interviewers. At the beginning of each interview, the patient was asked 10 questions so that we could gather demographic data and confirm participant eligibility: aged 21 years or older, born and raised in Puerto Rico, being a Spanish speaker, and having a primary cancer diagnosis with no previous disease. Three patients were excluded from the sample because they either had cancer previously or had a recurrence or metastasis. The final sample consisted of 41 outpatients (N = 41).

Data analysis for demographics was completed with STATA v.12 software. Measures of central tendency and dispersion as well as PHQ-9 internal consistency analysis were made through Cronbach alpha with SPSS.

From a total of 41 patients surveyed, 22 (54%) were men and 19 (46%) were women, with an overall median age of 61 years. Among the men, 15 (68%) had a prostate cancer diagnosis and among women, 9 (47.4%) had a breast cancer diagnosis. In regard to health insurance, 19 (46%) had Medicare or Veterans/federal insurance coverage, and 13 (32%) had Reforma, the Puerto Rican government health insurance program partially funded by Medicaid funds. In addition, 8 participants (20%) were unemployed or disabled. As previously stated, all of the patients were in ambulatory care. Only 3 (7%) were participating in support groups.

Of all the respondents, 16 (39%) reported some level of depression. In particular, 2 (5%) showed severe-major depression, 4 (10%) moderately severe depression, and 10 (24%) moderate depression. Of those with depression, 8 (50%) were women, 8 (50%) were men. All 6 of the patients with head and neck cancer showed moderate or moderately severe depression (Table 2).

When respondent PHQ-9 scoring reflected moderate to severe depression (>10), a letter was sent to the patient’s radio-oncologist for referral to counseling and clinical psychological evaluation. All participants had access to the support group program, to a radiotherapy education program meeting weekly, and written information about their cancer diagnosis and treatment. They also were interviewed by the psychosocial coordinator or patient navigator for further assessment.

The output phase

In the output phase, a graphic representing the process of emotional assessment at the institution was created and then modified. PHQ-9 was added to the process when it was found suitable to assess level of depression contributing to the identification of patients requiring psychological and psychiatric assistance which by other means would be missed. PHQ-9 was useful in the busy clinical setting as it was completed, scored and interpreted in minutes. It showed the potential for routine evaluations when looking to identify improvement or deterioration in depression levels thus helping to monitor responses to treatment and providing insights for follow up interventions. As stated by NCCN guidelines, distress should be monitored, documented and managed at all stages of the cancer continuum.

Results and discussion

The protocol for distress management at HSPOH is based on the 2013 NCCN guidelines. Cancer patients are screened for levels of distress in all settings (inpatients and outpatients). Screening is held with the DST Spanish translation at the moment of diagnosis or as soon as possible after a diagnosis is made. Screening for distress is also done before or after surgery, in recurrence or progression, and when clinically indicated. Patients are informed that distress management is an essential part of their care and are encouraged to provide information so that we can make a proper need assessment.

Patients are screened by the psychosocial coordinator or patient navigator who administers the DST followed by in-depth interviews for additional appraisal. An action plan is designed based on patient needs, which include their intervention and the intervention of other members of the psychosocial team from the institution and/or from the community. Additional in-house health professionals contributing in distress management include, but are not limited to: physicians; clinical psychologists; health educators; social workers; dietitians; chaplains; and physical, respiratory, speech, and/or swallow therapists. Follow-up and rescreening sessions are scheduled to assure coordination of services between those health professionals as well as to secure continuity of distress management during all stages of the cancer continuum.

The results of the DST are filed in patient medical records. Members of the psychosocial team also document their interventions in the patient medical record, which helps in the exchange of information among the cancer care team. The psychosocial team meets once a month – or as required for extraordinary cases – to review and discuss the cases, determine the best options for distress management, and identify areas for psychosocial care improvement. Those findings and the results of distress management in patient level of satisfaction are then reported and discussed quarterly by the psychosocial coordinator and the cancer committee.

Figure 2 shows in what phase of emotional distress assessment the PHQ-9 was included. Patients reporting four or more of the six areas of concern related to emotional distress in the DST (Figure 1) are automatically referred to a mental health specialist. But when patients report three areas of concern with no clear data on their specific level of depression, PHQ-9 is administered to differentiate those who need a mental health specialist from those who could be adequately supported by health education and support group interventions. In this way detrimental outcomes such as duplicity and over or underuse of services and resources are reduced. In addition, it is recognized that using an interview after the administration of the DST to determine distress management actions does not always provide enough information about a patient’s emotional circumstances and previous comorbidities. Patient responses during interviews may be influenced by the patient’s level of literacy, verbal comprehension, and communication style,²⁴ so emotional distress can go unrecognized during interviews, resulting in delays for treatment and supportive care.

National guidelines in oncology consider such socio-ecological models emphasizing the delivery of patient-centered, interdisciplinary, and evidence-based care. That does not mean that institutions should apply protocols of psychosocial care as previously developed, but that they should test, review, adapt, and improve them during the implementation of the care. In fact, NCCN encourages conducting trials to examine protocols, screening instruments, and models of intervention to determine applicability to particular settings.²

Findings from a study by NCCN member institutions to evaluate progress of implementing distress management guidelines found that 53% (n = 8) of respondent institutions conducted routine distress screening. Of those, 37.5% (3) relied only on interviews. That finding is of concern because if interviews are not standardized and have not been systematically evaluated, then their sensitivity and specificity in identifying distressed patients is unknown.²⁶ Accordingly, the process described in this article and the PHQ-9 validation was an effort to standardize emotional distress management, and was underlined as an achievement during the CoC accreditation visit to the cancer center in December 2013. The hospital was accredited as a comprehensive community cancer center with gold commendations, becoming the first privately owned hospital in Puerto Rico to achieve the accreditation.

Take-Home Points

• With EHR implementation there are small changes in the level of billing coding.
• Although these changes may be statistically significant they are relatively minor.
• In the general internal medicine department, level 4 coding increased by 1.2% while level 3 coding decreased by 0.5%.
• In the orthopedics department, level 4 coding increased by 3.3% while level 3 coding decreased by 3.1%.
• Reports in the lay media regarding dramatic up-coding after EHR implementation may be misleading.

The Health Information Technology for Economic and Clinical Health (HITECH) Act, which was signed into law in 2009, mandated that hospitals that care for Medicare patients either begin using electronic health records (EHRs) or pay a nontrivial penalty.¹ By now, the majority of orthopedic surgeons have implemented EHRs in their practices.² Despite ongoing debate in the orthopedic literature,³ EHRs are expected to improve coordination of care, reduce duplicate testing, and reduce costs over the long term as healthcare insurance coverage is extended to millions more Americans.

In early coverage, however, media reported that EHR implementation at some hospitals was correlated with substantial increases in Medicare payments.⁴ Journalists suggested the billion dollars more paid by Medicare to hospitals in 2010 than in 2005 were partly attributable to up-coding facilitated by EHRs.⁵ The secretary of the Department of Health and Human Services (DHHS) and the attorney general of the Department of Justice also weighed in on this controversy by expressing their concerns in a letter to the presidents of 5 hospital associations.⁶ The inspector general of DHHS also published a report critical of Medicare officials’ oversight of EHRs.⁷Responding to the critical reception of EHR implementations, investigators studied the validity of the early reports and anecdotes. Some initial reports cited the emergency department (ED) as an area at high risk for using the convenience of EHRs to up-code visits.⁵ The DHHS Office of the Inspector General noted that, between 2001 and 2010, the proportion of claims for lower reimbursement categories of American Medical Association Current Procedural Terminology (CPT) codes decreased while the proportion for higher-paid billing codes increased for all visit types.⁸ Addressing these concerns, the American Hospital Association⁹ issued a brief that noted that any observed coding increases were more likely attributable to more ED use by Medicare patients and increased average illness severity. In a thoughtful perspective, Pitts¹⁰ conceded that, though utilization and illness severity may explain part of the trend, the trend may also be related to technological innovations and changes in culture and practice style in the ED.

Because these studies and reports variously suggested that EHR implementation affects patient volume and up-coding, and because none of the reports specifically addressed orthopedics, we conducted a study to determine whether any significant up-coding or change in patient volumes occurred around the time of EHR implementation in ambulatory practices at our academic medical center. In a recent national study, Adler-Milstein and Jha¹¹ compared billing data of hospitals that adopted EHRs and hospitals that did not. Although both groups showed increased billing trends, the increases were not significantly different between the EHR adopters and nonadopters. To more effectively control for the confounding differences between groups of EHR adopters and nonadopters, we studied individual departments during EHR implementation at our institution.

Methods

In 2011, our academic medical center began the transition to EHRs (Epic). We examined our center’s trends in patient volumes and billing coding around the time of the transition in the outpatient practice of the general internal medicine (GIM) department (EHR transition, October 2011) and the outpatient practice of the orthopedics department (EHR transition, March 2012). These departments were chosen because they are representative of a GIM practice and a subspecialty practice, and because a recent study found that GIM practitioners and orthopedic surgeons were among those specialists who used EHRs the most.¹²

After this study was approved by our Human Investigations Committee, we began using CPT codes to identify all outpatient visits (new, consultation, and return) on a monthly basis. We compared the volume of patient visits and the billing coding level in the GIM and orthopedics departments before and after EHR implementation. Pearson χ² test was used when appropriate, and statistical analyses were performed with SPSS for Windows Version 16.0.

Results

In the GIM department, mean monthly volume of patient visits in the 12 months before EHR implementation was similar to that in the 12 months afterward (613 vs 587; P = .439). Even when normalized for changes in provider availability (maternity leave), the decrease in volume of patient visits after EHR implementation in the GIM department was not significant (6.9%; P = .107). Likewise, in the orthopedics department, mean monthly volume of patient visits in the 17 months before EHR implementation was similar to that in the 7 months afterward (2157 vs 2317; P = .156). In fact, patient volumes remained constant during the EHR transition (Figure 1).

EHR implementation brought small changes in billing coding levels. In the GIM department, the largest change was a 1.2% increase in level 4 billing coding—an increase accompanied by a 0.5% decrease in level 3 coding.

Discussion

It is remarkable that the volumes of patient visits in the GIM and orthopedics departments at our academic center were not affected by EHR implementation.

Rather than reduce scheduling during the EHR transition, surgeons in our practice either added or lengthened clinic sessions, and the level of ancillary staffing was adjusted accordingly. As staffing costs at any given time are multifactorial and vary widely, estimating the cost of these staffing changes during the EHR transition is difficult. We should note that extending ancillary staff hours during the transition very likely increased costs, and it is unclear whether they were higher or lower than the costs that would have been incurred had we reduced scheduling or tried some combination of these strategies.

Although billing coding levels changed with EHR implementation, the changes were small. In the GIM department, level 4 CPT coded visits as percentages of all visits increased to 59.5% from 58.3%, and level 5 visits increased to 6.2% from 6.0%; in the orthopedics department, level 4 visits increased to 40.2% from 37.1%, and level 5 visits increased to 5.5% from 3.8% (Table). The 1.2% and 0.2% absolute increases in level 4 and level 5 visits in the GIM department represent 2.1% and 3.3% relative increases in level 4 and level 5 visits, and the 3.3% and 1.7% absolute increases in the orthopedics department represent 8.4% and 44.7% relative increases in level 4 and level 5 visits after EHR implementation.

Although the absolute increases in level 4 and level 5 visits were relatively minor, popular media have raised the alarm about 43% and 82% relative increases in level 5 visits after EHR implementation in some hospitals’ EDs.⁴ Although our orthopedics department showed a 44.7% relative increase in level 5 visits after EHR implementation, this represented an increase of only 1.7% of patient visits overall. Our findings therefore indicate that lay media reports could be misleading. Nevertheless, the small changes we found were statistically significant.

One explanation for these small changes is that EHRs facilitate better documentation of services provided. Therefore, what seem to be billing coding changes could be more accurate reports of high-level care that is the same as before. In addition, because of meaningful use mandates that coincided with the requirement to implement EHRs, additional data elements are now being consistently collected and reviewed (these may not necessarily have been collected and reviewed before). In some patient encounters, these additional data elements may have contributed to higher levels of service, and this effect could be especially apparent in EDs.

Some have suggested a potential for large-scale up-coding during EHR transitions. Others have contended that coding level increases are a consequence of a time-intensive data entry process, collection and review of additional data, and more accurate reporting of services already being provided. We are not convinced that large coding changes are attributable solely to EHR implementation, as the changes at our center have been relatively small.

Nevertheless, minor coding level changes could translate to large changes in healthcare costs when scaled nationally. Although causes may be innocuous, any increases in national healthcare costs are concerning in our time of limited budgets and scrutinized healthcare utilization.

This study had its limitations. First, including billing data from only 2 departments at a single center may limit the generalizability of findings. However, we specifically selected a GIM department and a specialty (orthopedics) department in an attempt to capture a representative sample of practices. Another limitation is that we investigated billing codes over only 2 years, around the implementation of EHRs in these departments, and therefore may have captured only short-term changes. However, as patient volumes and billing are subject to many factors, including staffing changes (eg, new partners, new hires, retirements, other departures), we attempted to limit the effect of confounding variables by limiting the period of analysis.

Overall, changes in patient volume and coded level of service during EHR implementation at our institution were relatively small. Although the trend toward higher billing coding levels was statistically significant, these 0.2% and 1.7% increases in level 5 coding hardly deserve the negative attention from lay media. These small increases are unlikely caused by intentional up-coding, and more likely reflect better documentation of an already high level of care. We hope these findings allay the concern that up-coding increased dramatically with EHR implementation.

Am J Orthop. 2017;46(3):E172-E176. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Take-Home Points

• With EHR implementation there are small changes in the level of billing coding.
• Although these changes may be statistically significant they are relatively minor.
• In the general internal medicine department, level 4 coding increased by 1.2% while level 3 coding decreased by 0.5%.
• In the orthopedics department, level 4 coding increased by 3.3% while level 3 coding decreased by 3.1%.
• Reports in the lay media regarding dramatic up-coding after EHR implementation may be misleading.

The Health Information Technology for Economic and Clinical Health (HITECH) Act, which was signed into law in 2009, mandated that hospitals that care for Medicare patients either begin using electronic health records (EHRs) or pay a nontrivial penalty.¹ By now, the majority of orthopedic surgeons have implemented EHRs in their practices.² Despite ongoing debate in the orthopedic literature,³ EHRs are expected to improve coordination of care, reduce duplicate testing, and reduce costs over the long term as healthcare insurance coverage is extended to millions more Americans.

In early coverage, however, media reported that EHR implementation at some hospitals was correlated with substantial increases in Medicare payments.⁴ Journalists suggested the billion dollars more paid by Medicare to hospitals in 2010 than in 2005 were partly attributable to up-coding facilitated by EHRs.⁵ The secretary of the Department of Health and Human Services (DHHS) and the attorney general of the Department of Justice also weighed in on this controversy by expressing their concerns in a letter to the presidents of 5 hospital associations.⁶ The inspector general of DHHS also published a report critical of Medicare officials’ oversight of EHRs.⁷Responding to the critical reception of EHR implementations, investigators studied the validity of the early reports and anecdotes. Some initial reports cited the emergency department (ED) as an area at high risk for using the convenience of EHRs to up-code visits.⁵ The DHHS Office of the Inspector General noted that, between 2001 and 2010, the proportion of claims for lower reimbursement categories of American Medical Association Current Procedural Terminology (CPT) codes decreased while the proportion for higher-paid billing codes increased for all visit types.⁸ Addressing these concerns, the American Hospital Association⁹ issued a brief that noted that any observed coding increases were more likely attributable to more ED use by Medicare patients and increased average illness severity. In a thoughtful perspective, Pitts¹⁰ conceded that, though utilization and illness severity may explain part of the trend, the trend may also be related to technological innovations and changes in culture and practice style in the ED.

Because these studies and reports variously suggested that EHR implementation affects patient volume and up-coding, and because none of the reports specifically addressed orthopedics, we conducted a study to determine whether any significant up-coding or change in patient volumes occurred around the time of EHR implementation in ambulatory practices at our academic medical center. In a recent national study, Adler-Milstein and Jha¹¹ compared billing data of hospitals that adopted EHRs and hospitals that did not. Although both groups showed increased billing trends, the increases were not significantly different between the EHR adopters and nonadopters. To more effectively control for the confounding differences between groups of EHR adopters and nonadopters, we studied individual departments during EHR implementation at our institution.

Methods

In 2011, our academic medical center began the transition to EHRs (Epic). We examined our center’s trends in patient volumes and billing coding around the time of the transition in the outpatient practice of the general internal medicine (GIM) department (EHR transition, October 2011) and the outpatient practice of the orthopedics department (EHR transition, March 2012). These departments were chosen because they are representative of a GIM practice and a subspecialty practice, and because a recent study found that GIM practitioners and orthopedic surgeons were among those specialists who used EHRs the most.¹²

After this study was approved by our Human Investigations Committee, we began using CPT codes to identify all outpatient visits (new, consultation, and return) on a monthly basis. We compared the volume of patient visits and the billing coding level in the GIM and orthopedics departments before and after EHR implementation. Pearson χ² test was used when appropriate, and statistical analyses were performed with SPSS for Windows Version 16.0.

Results

In the GIM department, mean monthly volume of patient visits in the 12 months before EHR implementation was similar to that in the 12 months afterward (613 vs 587; P = .439). Even when normalized for changes in provider availability (maternity leave), the decrease in volume of patient visits after EHR implementation in the GIM department was not significant (6.9%; P = .107). Likewise, in the orthopedics department, mean monthly volume of patient visits in the 17 months before EHR implementation was similar to that in the 7 months afterward (2157 vs 2317; P = .156). In fact, patient volumes remained constant during the EHR transition (Figure 1).

EHR implementation brought small changes in billing coding levels. In the GIM department, the largest change was a 1.2% increase in level 4 billing coding—an increase accompanied by a 0.5% decrease in level 3 coding.

Discussion

It is remarkable that the volumes of patient visits in the GIM and orthopedics departments at our academic center were not affected by EHR implementation.

Rather than reduce scheduling during the EHR transition, surgeons in our practice either added or lengthened clinic sessions, and the level of ancillary staffing was adjusted accordingly. As staffing costs at any given time are multifactorial and vary widely, estimating the cost of these staffing changes during the EHR transition is difficult. We should note that extending ancillary staff hours during the transition very likely increased costs, and it is unclear whether they were higher or lower than the costs that would have been incurred had we reduced scheduling or tried some combination of these strategies.

Although billing coding levels changed with EHR implementation, the changes were small. In the GIM department, level 4 CPT coded visits as percentages of all visits increased to 59.5% from 58.3%, and level 5 visits increased to 6.2% from 6.0%; in the orthopedics department, level 4 visits increased to 40.2% from 37.1%, and level 5 visits increased to 5.5% from 3.8% (Table). The 1.2% and 0.2% absolute increases in level 4 and level 5 visits in the GIM department represent 2.1% and 3.3% relative increases in level 4 and level 5 visits, and the 3.3% and 1.7% absolute increases in the orthopedics department represent 8.4% and 44.7% relative increases in level 4 and level 5 visits after EHR implementation.

Although the absolute increases in level 4 and level 5 visits were relatively minor, popular media have raised the alarm about 43% and 82% relative increases in level 5 visits after EHR implementation in some hospitals’ EDs.⁴ Although our orthopedics department showed a 44.7% relative increase in level 5 visits after EHR implementation, this represented an increase of only 1.7% of patient visits overall. Our findings therefore indicate that lay media reports could be misleading. Nevertheless, the small changes we found were statistically significant.

One explanation for these small changes is that EHRs facilitate better documentation of services provided. Therefore, what seem to be billing coding changes could be more accurate reports of high-level care that is the same as before. In addition, because of meaningful use mandates that coincided with the requirement to implement EHRs, additional data elements are now being consistently collected and reviewed (these may not necessarily have been collected and reviewed before). In some patient encounters, these additional data elements may have contributed to higher levels of service, and this effect could be especially apparent in EDs.

Some have suggested a potential for large-scale up-coding during EHR transitions. Others have contended that coding level increases are a consequence of a time-intensive data entry process, collection and review of additional data, and more accurate reporting of services already being provided. We are not convinced that large coding changes are attributable solely to EHR implementation, as the changes at our center have been relatively small.

Nevertheless, minor coding level changes could translate to large changes in healthcare costs when scaled nationally. Although causes may be innocuous, any increases in national healthcare costs are concerning in our time of limited budgets and scrutinized healthcare utilization.

This study had its limitations. First, including billing data from only 2 departments at a single center may limit the generalizability of findings. However, we specifically selected a GIM department and a specialty (orthopedics) department in an attempt to capture a representative sample of practices. Another limitation is that we investigated billing codes over only 2 years, around the implementation of EHRs in these departments, and therefore may have captured only short-term changes. However, as patient volumes and billing are subject to many factors, including staffing changes (eg, new partners, new hires, retirements, other departures), we attempted to limit the effect of confounding variables by limiting the period of analysis.

Overall, changes in patient volume and coded level of service during EHR implementation at our institution were relatively small. Although the trend toward higher billing coding levels was statistically significant, these 0.2% and 1.7% increases in level 5 coding hardly deserve the negative attention from lay media. These small increases are unlikely caused by intentional up-coding, and more likely reflect better documentation of an already high level of care. We hope these findings allay the concern that up-coding increased dramatically with EHR implementation.

Am J Orthop. 2017;46(3):E172-E176. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Take-Home Points

• With EHR implementation there are small changes in the level of billing coding.
• Although these changes may be statistically significant they are relatively minor.
• In the general internal medicine department, level 4 coding increased by 1.2% while level 3 coding decreased by 0.5%.
• In the orthopedics department, level 4 coding increased by 3.3% while level 3 coding decreased by 3.1%.
• Reports in the lay media regarding dramatic up-coding after EHR implementation may be misleading.

The Health Information Technology for Economic and Clinical Health (HITECH) Act, which was signed into law in 2009, mandated that hospitals that care for Medicare patients either begin using electronic health records (EHRs) or pay a nontrivial penalty.¹ By now, the majority of orthopedic surgeons have implemented EHRs in their practices.² Despite ongoing debate in the orthopedic literature,³ EHRs are expected to improve coordination of care, reduce duplicate testing, and reduce costs over the long term as healthcare insurance coverage is extended to millions more Americans.

In early coverage, however, media reported that EHR implementation at some hospitals was correlated with substantial increases in Medicare payments.⁴ Journalists suggested the billion dollars more paid by Medicare to hospitals in 2010 than in 2005 were partly attributable to up-coding facilitated by EHRs.⁵ The secretary of the Department of Health and Human Services (DHHS) and the attorney general of the Department of Justice also weighed in on this controversy by expressing their concerns in a letter to the presidents of 5 hospital associations.⁶ The inspector general of DHHS also published a report critical of Medicare officials’ oversight of EHRs.⁷Responding to the critical reception of EHR implementations, investigators studied the validity of the early reports and anecdotes. Some initial reports cited the emergency department (ED) as an area at high risk for using the convenience of EHRs to up-code visits.⁵ The DHHS Office of the Inspector General noted that, between 2001 and 2010, the proportion of claims for lower reimbursement categories of American Medical Association Current Procedural Terminology (CPT) codes decreased while the proportion for higher-paid billing codes increased for all visit types.⁸ Addressing these concerns, the American Hospital Association⁹ issued a brief that noted that any observed coding increases were more likely attributable to more ED use by Medicare patients and increased average illness severity. In a thoughtful perspective, Pitts¹⁰ conceded that, though utilization and illness severity may explain part of the trend, the trend may also be related to technological innovations and changes in culture and practice style in the ED.

Because these studies and reports variously suggested that EHR implementation affects patient volume and up-coding, and because none of the reports specifically addressed orthopedics, we conducted a study to determine whether any significant up-coding or change in patient volumes occurred around the time of EHR implementation in ambulatory practices at our academic medical center. In a recent national study, Adler-Milstein and Jha¹¹ compared billing data of hospitals that adopted EHRs and hospitals that did not. Although both groups showed increased billing trends, the increases were not significantly different between the EHR adopters and nonadopters. To more effectively control for the confounding differences between groups of EHR adopters and nonadopters, we studied individual departments during EHR implementation at our institution.

Methods

In 2011, our academic medical center began the transition to EHRs (Epic). We examined our center’s trends in patient volumes and billing coding around the time of the transition in the outpatient practice of the general internal medicine (GIM) department (EHR transition, October 2011) and the outpatient practice of the orthopedics department (EHR transition, March 2012). These departments were chosen because they are representative of a GIM practice and a subspecialty practice, and because a recent study found that GIM practitioners and orthopedic surgeons were among those specialists who used EHRs the most.¹²

After this study was approved by our Human Investigations Committee, we began using CPT codes to identify all outpatient visits (new, consultation, and return) on a monthly basis. We compared the volume of patient visits and the billing coding level in the GIM and orthopedics departments before and after EHR implementation. Pearson χ² test was used when appropriate, and statistical analyses were performed with SPSS for Windows Version 16.0.

Results

In the GIM department, mean monthly volume of patient visits in the 12 months before EHR implementation was similar to that in the 12 months afterward (613 vs 587; P = .439). Even when normalized for changes in provider availability (maternity leave), the decrease in volume of patient visits after EHR implementation in the GIM department was not significant (6.9%; P = .107). Likewise, in the orthopedics department, mean monthly volume of patient visits in the 17 months before EHR implementation was similar to that in the 7 months afterward (2157 vs 2317; P = .156). In fact, patient volumes remained constant during the EHR transition (Figure 1).

EHR implementation brought small changes in billing coding levels. In the GIM department, the largest change was a 1.2% increase in level 4 billing coding—an increase accompanied by a 0.5% decrease in level 3 coding.

Discussion

It is remarkable that the volumes of patient visits in the GIM and orthopedics departments at our academic center were not affected by EHR implementation.

Rather than reduce scheduling during the EHR transition, surgeons in our practice either added or lengthened clinic sessions, and the level of ancillary staffing was adjusted accordingly. As staffing costs at any given time are multifactorial and vary widely, estimating the cost of these staffing changes during the EHR transition is difficult. We should note that extending ancillary staff hours during the transition very likely increased costs, and it is unclear whether they were higher or lower than the costs that would have been incurred had we reduced scheduling or tried some combination of these strategies.

Although billing coding levels changed with EHR implementation, the changes were small. In the GIM department, level 4 CPT coded visits as percentages of all visits increased to 59.5% from 58.3%, and level 5 visits increased to 6.2% from 6.0%; in the orthopedics department, level 4 visits increased to 40.2% from 37.1%, and level 5 visits increased to 5.5% from 3.8% (Table). The 1.2% and 0.2% absolute increases in level 4 and level 5 visits in the GIM department represent 2.1% and 3.3% relative increases in level 4 and level 5 visits, and the 3.3% and 1.7% absolute increases in the orthopedics department represent 8.4% and 44.7% relative increases in level 4 and level 5 visits after EHR implementation.

Although the absolute increases in level 4 and level 5 visits were relatively minor, popular media have raised the alarm about 43% and 82% relative increases in level 5 visits after EHR implementation in some hospitals’ EDs.⁴ Although our orthopedics department showed a 44.7% relative increase in level 5 visits after EHR implementation, this represented an increase of only 1.7% of patient visits overall. Our findings therefore indicate that lay media reports could be misleading. Nevertheless, the small changes we found were statistically significant.

One explanation for these small changes is that EHRs facilitate better documentation of services provided. Therefore, what seem to be billing coding changes could be more accurate reports of high-level care that is the same as before. In addition, because of meaningful use mandates that coincided with the requirement to implement EHRs, additional data elements are now being consistently collected and reviewed (these may not necessarily have been collected and reviewed before). In some patient encounters, these additional data elements may have contributed to higher levels of service, and this effect could be especially apparent in EDs.

Some have suggested a potential for large-scale up-coding during EHR transitions. Others have contended that coding level increases are a consequence of a time-intensive data entry process, collection and review of additional data, and more accurate reporting of services already being provided. We are not convinced that large coding changes are attributable solely to EHR implementation, as the changes at our center have been relatively small.

Nevertheless, minor coding level changes could translate to large changes in healthcare costs when scaled nationally. Although causes may be innocuous, any increases in national healthcare costs are concerning in our time of limited budgets and scrutinized healthcare utilization.

This study had its limitations. First, including billing data from only 2 departments at a single center may limit the generalizability of findings. However, we specifically selected a GIM department and a specialty (orthopedics) department in an attempt to capture a representative sample of practices. Another limitation is that we investigated billing codes over only 2 years, around the implementation of EHRs in these departments, and therefore may have captured only short-term changes. However, as patient volumes and billing are subject to many factors, including staffing changes (eg, new partners, new hires, retirements, other departures), we attempted to limit the effect of confounding variables by limiting the period of analysis.

Overall, changes in patient volume and coded level of service during EHR implementation at our institution were relatively small. Although the trend toward higher billing coding levels was statistically significant, these 0.2% and 1.7% increases in level 5 coding hardly deserve the negative attention from lay media. These small increases are unlikely caused by intentional up-coding, and more likely reflect better documentation of an already high level of care. We hope these findings allay the concern that up-coding increased dramatically with EHR implementation.

Am J Orthop. 2017;46(3):E172-E176. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

A suggestion for Congress: keep what’s working in the Patient Protection and Affordable Care Act (PPACA), adjust what isn’t working – just make the whole thing better and call it what you will.

A good thing, but needing work

The PPACA, which is also referred to as Obama care, had a lot in it that any reasonable person would consider good. Let’s take a look. As Dr Valerie Arkoosh wrote in our journal in 2012,² the law attempted to expand access to health care to the embarrassingly large 30 million or more Americans who were not insured. How would it do this? By expanding Medicaid, enhancing consumer protections in the private health insurance market, requiring large employers to offer insurance or pay a fine, giving tax credits to increase affordability of insurance for small businesses, creating state-based competitive market places, and requiring individuals to purchase health insurance plans (the so-called insurance mandate), thereby creating a pool of large numbers of healthy people who would help defray the costs of those not so fortunate.The law also guaranteed insurability despite any preexisting condition, surely a step in the right direction. Likewise, the need for employers to provide health insurance, the state-based health insurance exchanges, and especially the individual mandate to buy insurance or pay a fine, were all steps in the right direction.

And the law went further – it also addressed preventive care. Medicare and all new insurance plans would have to cover, without copay, co-insurance, or deductible, high-certainty preventive services such as screening for breast, cervical, colorectal, lung, and skin cancers, the annual well-woman visit, breast cancer preventative medications, and many others.³ Medicare recipients would be eligible for one non-copay annual wellness visit to their caregiver. Beyond providing increased access to health care, the PPACA added incentives to caregivers who were coming out of training programs to serve in underserved areas and benefit from a decrease in their med school loans or in their loan repayments.

Finally, and especially important, under the PPACA, our age-old insurance system of fee for service, which tends to incentivize more care, would change to incentivizing high-quality, outcomes-based care , thus replacing “quantity of care” with quality of care. So what’s wrong with the features of the law outlined in the preceding paragraphs? Well, of course, for every 100 ideas, only a few will be implemented and actually pay off. Certainly some of the PPACA could have been better implemented, and perhaps the task now facing Congress, if it could ever abandon its current pitched-camp approach, should be to take the ideas that health care policy scientists have established as being valid and find a way to make them work. Surely that would be best for all players, rather than carping about the repeal-replace approach versus staying with the PPACA.

So my response to the repeal-replace assertion? Retain, review, and refine.

Practitioner-friendly content

Health care calamities notwithstanding, we have a line-up of articles in this issue that uniformly address some of the pressing needs many of us face in our daily practice. Barry and colleagues examined the patterns of care with regard to whole brain radiotherapy technique and delivery at US-based academic centers. Their results show some interesting differences in the way younger and older practitioners deliver that care, with older practitioners placing more importance on tumor histopathology when considering brain irradiation. Speaking of access to care in the context of health reform, how often do our cancer patients use the emergency department? Lash and colleagues looked at the ED-use numbers from two databases in California and found that patients go to the ED at higher rates than previously reported and with notable variability by cancer type. Now we need to examine the reasons for those visits and establish ways to identify predictors of ED use to improve patient quality of care and rein in the higher costs of ED use.

In regard to symptom management, we can never have enough about nausea and vomiting prevention. Schwartzberg and colleagues report on a trial in which they evaluated the clinical benefits of APF530, a subcutaneous formulation of granisetron, compared with ondansetron in patients who had received cisplatin therapy. This longer-acting formulation of granisetron performed very well against a standard of care and might give our patients another option in the clinic for highly emetogenic chemotherapy.

Still on the topic of symptom management, preventing and treating mTOR-inhibitor–associated stomatitis (mIAS) is the subject of a review by Ramchandran and colleagues. The inhibitors have been approved for treatment in renal cell, neuroendocrine, and breast cancers, but of course, many of our newer molecules have some associated toxicity. Based on their literature scan, the authors report that management of mIAS should focus on three major approaches: prevention, early aggressive treatment, and, when needed, more aggressive pain management. Early recognition and diagnosis of mIAS facilitate early intervention to limit potential sequelae of mIAS and minimize the need for mTOR inhibitor dose reduction and interruption.

In a way, stress management could also fall under the symptom management category. I often remember being told during my training that we should always discuss with your patients their level of anxiety and depression. But I think sometimes we are so busy addressing the cancer, its treatment, and treatment side effects, we overlook the fact that the patient is suffering psychologically and might need additional intervention in the form of talk therapy and/or medication. Ramírez-Solá and colleagues describe in our How We Do It section the process of developing and implementing a psychosocial distress management program at their institution in Puerto Rico. The authors also summarize the results of a pilot study to validate the Patient Health Questionnaire (PHQ-9) as a measure to improve the process of emotional distress management in particular.

In recent years, the number of approvals and new indications for therapies for different cancer types has increased significantly. We highlight two such approvals in this issue. One is the PARP inhibitor, rucaparib, which was approved in both the platinum-sensitive and -resistant settings for BRCA1- and BRCA2-mutant patients with ovarian cancer. The other is the new CD38 antibody daratumumab, which was originally approved as a single-agent therapy for relapsed myeloma and which has now received a second approval with demonstrated improvement of progression-free survival when given with the lenalidomide-dexamethasone or bortezomib-dexamethasone combinations.

When it comes to new therapies, immunotherapies are at the cutting edge. Who hasn’t heard of the new checkpoint inhibitor drugs for a range of cancers that have either been approved or are in trial? Until now, we have used these immunotherapies as single agents, but Jane de Lartigue writes of the potential of combining more than one immunotherapy drug and/or combining an immune checkpoint inhibitor with a chemotherapy drug. The key behind this concept is that the more antigenic differentiation and tumor infiltrating lymphocytes in the system, the better the immunotherapy might work.

In the previous issue of the journal, one of our Editors, Thomas Strouse, discussed the issue of physician aid in dying (PAD)⁴ and asserted he had come to view “active non-participation” in legal PAD as a “toxic form of patient abandonment.” This is, of course, a very challenging and complex topic, and one that we likely have to address on a weekly basis with some of our cancer patients: if palliative care and end-of-life is the goal, how can we most humanely achieve that ethically and legally in concert with our patients’ wishes? Is it right or wrong to aid in some way in the dying process? Dr Alva Weir responds to Dr Strouse’s editorial, taking the view point that physician-assisted suicide is toxic abandonment. Dr Strauss responds, and I encourage you to read this very interesting exchange that highlights the point-counterpoint views of physician involvement in the dying process.

We round off the issue with a bumper crop of Case Reports. They include two that document diagnostic challenges: one in a patient with pulmonary sarcomatoid carcinoma presenting as a necrotizing cavitary lung lesion and another in which atraumatic splenic rupture is the initial presentation of CML. Also included is a report on a case of primary cardiac prosthetic valve-associated lymphoma and another on how a collaborative effort between oncologists and dermatologists contributed to the resolution of palmoplantar exacerbation of psoriasis in a patient who had been treated with nivolumab.

Going digital

I will close by remarking that the Journal of Community and Supportive Oncology, or JCSO, will be going digital only after this print issue. We will continue publishing the same content as a bimonthly digital issue, posting articles directly to our website, and mailing out our regular electronic newsletters. So visit the website, www.jcso-online.com, where you can read the articles as soon as they are posted and also find instructions for downloading the app for the digital edition – it’s quick, easy, and free, in case you were wondering. For a shortcut to the download the app, you can also use http://bit.ly/2nCEPIa.

Finally, if you would like to submit a paper to us for consideration for publication, you can do so by going to www.editorialmanager.com/jso/. We will consider submissions in original research, reviews, How We Do It, case reports, and tumor board summaries – you’ll find all the information you need to submit a paper at the EditorialManager platform. And let’s not forget social media – we’re on Twitter where our handle is @jcs_onc, my personal Twitter handle is @davidhenrymd, so connect with us – follow us, like us, and retweet us.

A suggestion for Congress: keep what’s working in the Patient Protection and Affordable Care Act (PPACA), adjust what isn’t working – just make the whole thing better and call it what you will.

A good thing, but needing work

The PPACA, which is also referred to as Obama care, had a lot in it that any reasonable person would consider good. Let’s take a look. As Dr Valerie Arkoosh wrote in our journal in 2012,² the law attempted to expand access to health care to the embarrassingly large 30 million or more Americans who were not insured. How would it do this? By expanding Medicaid, enhancing consumer protections in the private health insurance market, requiring large employers to offer insurance or pay a fine, giving tax credits to increase affordability of insurance for small businesses, creating state-based competitive market places, and requiring individuals to purchase health insurance plans (the so-called insurance mandate), thereby creating a pool of large numbers of healthy people who would help defray the costs of those not so fortunate.The law also guaranteed insurability despite any preexisting condition, surely a step in the right direction. Likewise, the need for employers to provide health insurance, the state-based health insurance exchanges, and especially the individual mandate to buy insurance or pay a fine, were all steps in the right direction.

And the law went further – it also addressed preventive care. Medicare and all new insurance plans would have to cover, without copay, co-insurance, or deductible, high-certainty preventive services such as screening for breast, cervical, colorectal, lung, and skin cancers, the annual well-woman visit, breast cancer preventative medications, and many others.³ Medicare recipients would be eligible for one non-copay annual wellness visit to their caregiver. Beyond providing increased access to health care, the PPACA added incentives to caregivers who were coming out of training programs to serve in underserved areas and benefit from a decrease in their med school loans or in their loan repayments.

Finally, and especially important, under the PPACA, our age-old insurance system of fee for service, which tends to incentivize more care, would change to incentivizing high-quality, outcomes-based care , thus replacing “quantity of care” with quality of care. So what’s wrong with the features of the law outlined in the preceding paragraphs? Well, of course, for every 100 ideas, only a few will be implemented and actually pay off. Certainly some of the PPACA could have been better implemented, and perhaps the task now facing Congress, if it could ever abandon its current pitched-camp approach, should be to take the ideas that health care policy scientists have established as being valid and find a way to make them work. Surely that would be best for all players, rather than carping about the repeal-replace approach versus staying with the PPACA.

So my response to the repeal-replace assertion? Retain, review, and refine.

Practitioner-friendly content

Health care calamities notwithstanding, we have a line-up of articles in this issue that uniformly address some of the pressing needs many of us face in our daily practice. Barry and colleagues examined the patterns of care with regard to whole brain radiotherapy technique and delivery at US-based academic centers. Their results show some interesting differences in the way younger and older practitioners deliver that care, with older practitioners placing more importance on tumor histopathology when considering brain irradiation. Speaking of access to care in the context of health reform, how often do our cancer patients use the emergency department? Lash and colleagues looked at the ED-use numbers from two databases in California and found that patients go to the ED at higher rates than previously reported and with notable variability by cancer type. Now we need to examine the reasons for those visits and establish ways to identify predictors of ED use to improve patient quality of care and rein in the higher costs of ED use.

In regard to symptom management, we can never have enough about nausea and vomiting prevention. Schwartzberg and colleagues report on a trial in which they evaluated the clinical benefits of APF530, a subcutaneous formulation of granisetron, compared with ondansetron in patients who had received cisplatin therapy. This longer-acting formulation of granisetron performed very well against a standard of care and might give our patients another option in the clinic for highly emetogenic chemotherapy.

Still on the topic of symptom management, preventing and treating mTOR-inhibitor–associated stomatitis (mIAS) is the subject of a review by Ramchandran and colleagues. The inhibitors have been approved for treatment in renal cell, neuroendocrine, and breast cancers, but of course, many of our newer molecules have some associated toxicity. Based on their literature scan, the authors report that management of mIAS should focus on three major approaches: prevention, early aggressive treatment, and, when needed, more aggressive pain management. Early recognition and diagnosis of mIAS facilitate early intervention to limit potential sequelae of mIAS and minimize the need for mTOR inhibitor dose reduction and interruption.

In a way, stress management could also fall under the symptom management category. I often remember being told during my training that we should always discuss with your patients their level of anxiety and depression. But I think sometimes we are so busy addressing the cancer, its treatment, and treatment side effects, we overlook the fact that the patient is suffering psychologically and might need additional intervention in the form of talk therapy and/or medication. Ramírez-Solá and colleagues describe in our How We Do It section the process of developing and implementing a psychosocial distress management program at their institution in Puerto Rico. The authors also summarize the results of a pilot study to validate the Patient Health Questionnaire (PHQ-9) as a measure to improve the process of emotional distress management in particular.

In recent years, the number of approvals and new indications for therapies for different cancer types has increased significantly. We highlight two such approvals in this issue. One is the PARP inhibitor, rucaparib, which was approved in both the platinum-sensitive and -resistant settings for BRCA1- and BRCA2-mutant patients with ovarian cancer. The other is the new CD38 antibody daratumumab, which was originally approved as a single-agent therapy for relapsed myeloma and which has now received a second approval with demonstrated improvement of progression-free survival when given with the lenalidomide-dexamethasone or bortezomib-dexamethasone combinations.

When it comes to new therapies, immunotherapies are at the cutting edge. Who hasn’t heard of the new checkpoint inhibitor drugs for a range of cancers that have either been approved or are in trial? Until now, we have used these immunotherapies as single agents, but Jane de Lartigue writes of the potential of combining more than one immunotherapy drug and/or combining an immune checkpoint inhibitor with a chemotherapy drug. The key behind this concept is that the more antigenic differentiation and tumor infiltrating lymphocytes in the system, the better the immunotherapy might work.

In the previous issue of the journal, one of our Editors, Thomas Strouse, discussed the issue of physician aid in dying (PAD)⁴ and asserted he had come to view “active non-participation” in legal PAD as a “toxic form of patient abandonment.” This is, of course, a very challenging and complex topic, and one that we likely have to address on a weekly basis with some of our cancer patients: if palliative care and end-of-life is the goal, how can we most humanely achieve that ethically and legally in concert with our patients’ wishes? Is it right or wrong to aid in some way in the dying process? Dr Alva Weir responds to Dr Strouse’s editorial, taking the view point that physician-assisted suicide is toxic abandonment. Dr Strauss responds, and I encourage you to read this very interesting exchange that highlights the point-counterpoint views of physician involvement in the dying process.

We round off the issue with a bumper crop of Case Reports. They include two that document diagnostic challenges: one in a patient with pulmonary sarcomatoid carcinoma presenting as a necrotizing cavitary lung lesion and another in which atraumatic splenic rupture is the initial presentation of CML. Also included is a report on a case of primary cardiac prosthetic valve-associated lymphoma and another on how a collaborative effort between oncologists and dermatologists contributed to the resolution of palmoplantar exacerbation of psoriasis in a patient who had been treated with nivolumab.

Going digital

I will close by remarking that the Journal of Community and Supportive Oncology, or JCSO, will be going digital only after this print issue. We will continue publishing the same content as a bimonthly digital issue, posting articles directly to our website, and mailing out our regular electronic newsletters. So visit the website, www.jcso-online.com, where you can read the articles as soon as they are posted and also find instructions for downloading the app for the digital edition – it’s quick, easy, and free, in case you were wondering. For a shortcut to the download the app, you can also use http://bit.ly/2nCEPIa.

Finally, if you would like to submit a paper to us for consideration for publication, you can do so by going to www.editorialmanager.com/jso/. We will consider submissions in original research, reviews, How We Do It, case reports, and tumor board summaries – you’ll find all the information you need to submit a paper at the EditorialManager platform. And let’s not forget social media – we’re on Twitter where our handle is @jcs_onc, my personal Twitter handle is @davidhenrymd, so connect with us – follow us, like us, and retweet us.

A suggestion for Congress: keep what’s working in the Patient Protection and Affordable Care Act (PPACA), adjust what isn’t working – just make the whole thing better and call it what you will.

A good thing, but needing work

The PPACA, which is also referred to as Obama care, had a lot in it that any reasonable person would consider good. Let’s take a look. As Dr Valerie Arkoosh wrote in our journal in 2012,² the law attempted to expand access to health care to the embarrassingly large 30 million or more Americans who were not insured. How would it do this? By expanding Medicaid, enhancing consumer protections in the private health insurance market, requiring large employers to offer insurance or pay a fine, giving tax credits to increase affordability of insurance for small businesses, creating state-based competitive market places, and requiring individuals to purchase health insurance plans (the so-called insurance mandate), thereby creating a pool of large numbers of healthy people who would help defray the costs of those not so fortunate.The law also guaranteed insurability despite any preexisting condition, surely a step in the right direction. Likewise, the need for employers to provide health insurance, the state-based health insurance exchanges, and especially the individual mandate to buy insurance or pay a fine, were all steps in the right direction.

And the law went further – it also addressed preventive care. Medicare and all new insurance plans would have to cover, without copay, co-insurance, or deductible, high-certainty preventive services such as screening for breast, cervical, colorectal, lung, and skin cancers, the annual well-woman visit, breast cancer preventative medications, and many others.³ Medicare recipients would be eligible for one non-copay annual wellness visit to their caregiver. Beyond providing increased access to health care, the PPACA added incentives to caregivers who were coming out of training programs to serve in underserved areas and benefit from a decrease in their med school loans or in their loan repayments.

Finally, and especially important, under the PPACA, our age-old insurance system of fee for service, which tends to incentivize more care, would change to incentivizing high-quality, outcomes-based care , thus replacing “quantity of care” with quality of care. So what’s wrong with the features of the law outlined in the preceding paragraphs? Well, of course, for every 100 ideas, only a few will be implemented and actually pay off. Certainly some of the PPACA could have been better implemented, and perhaps the task now facing Congress, if it could ever abandon its current pitched-camp approach, should be to take the ideas that health care policy scientists have established as being valid and find a way to make them work. Surely that would be best for all players, rather than carping about the repeal-replace approach versus staying with the PPACA.

So my response to the repeal-replace assertion? Retain, review, and refine.

Practitioner-friendly content

Health care calamities notwithstanding, we have a line-up of articles in this issue that uniformly address some of the pressing needs many of us face in our daily practice. Barry and colleagues examined the patterns of care with regard to whole brain radiotherapy technique and delivery at US-based academic centers. Their results show some interesting differences in the way younger and older practitioners deliver that care, with older practitioners placing more importance on tumor histopathology when considering brain irradiation. Speaking of access to care in the context of health reform, how often do our cancer patients use the emergency department? Lash and colleagues looked at the ED-use numbers from two databases in California and found that patients go to the ED at higher rates than previously reported and with notable variability by cancer type. Now we need to examine the reasons for those visits and establish ways to identify predictors of ED use to improve patient quality of care and rein in the higher costs of ED use.

In regard to symptom management, we can never have enough about nausea and vomiting prevention. Schwartzberg and colleagues report on a trial in which they evaluated the clinical benefits of APF530, a subcutaneous formulation of granisetron, compared with ondansetron in patients who had received cisplatin therapy. This longer-acting formulation of granisetron performed very well against a standard of care and might give our patients another option in the clinic for highly emetogenic chemotherapy.

Still on the topic of symptom management, preventing and treating mTOR-inhibitor–associated stomatitis (mIAS) is the subject of a review by Ramchandran and colleagues. The inhibitors have been approved for treatment in renal cell, neuroendocrine, and breast cancers, but of course, many of our newer molecules have some associated toxicity. Based on their literature scan, the authors report that management of mIAS should focus on three major approaches: prevention, early aggressive treatment, and, when needed, more aggressive pain management. Early recognition and diagnosis of mIAS facilitate early intervention to limit potential sequelae of mIAS and minimize the need for mTOR inhibitor dose reduction and interruption.

In a way, stress management could also fall under the symptom management category. I often remember being told during my training that we should always discuss with your patients their level of anxiety and depression. But I think sometimes we are so busy addressing the cancer, its treatment, and treatment side effects, we overlook the fact that the patient is suffering psychologically and might need additional intervention in the form of talk therapy and/or medication. Ramírez-Solá and colleagues describe in our How We Do It section the process of developing and implementing a psychosocial distress management program at their institution in Puerto Rico. The authors also summarize the results of a pilot study to validate the Patient Health Questionnaire (PHQ-9) as a measure to improve the process of emotional distress management in particular.

In recent years, the number of approvals and new indications for therapies for different cancer types has increased significantly. We highlight two such approvals in this issue. One is the PARP inhibitor, rucaparib, which was approved in both the platinum-sensitive and -resistant settings for BRCA1- and BRCA2-mutant patients with ovarian cancer. The other is the new CD38 antibody daratumumab, which was originally approved as a single-agent therapy for relapsed myeloma and which has now received a second approval with demonstrated improvement of progression-free survival when given with the lenalidomide-dexamethasone or bortezomib-dexamethasone combinations.

When it comes to new therapies, immunotherapies are at the cutting edge. Who hasn’t heard of the new checkpoint inhibitor drugs for a range of cancers that have either been approved or are in trial? Until now, we have used these immunotherapies as single agents, but Jane de Lartigue writes of the potential of combining more than one immunotherapy drug and/or combining an immune checkpoint inhibitor with a chemotherapy drug. The key behind this concept is that the more antigenic differentiation and tumor infiltrating lymphocytes in the system, the better the immunotherapy might work.

In the previous issue of the journal, one of our Editors, Thomas Strouse, discussed the issue of physician aid in dying (PAD)⁴ and asserted he had come to view “active non-participation” in legal PAD as a “toxic form of patient abandonment.” This is, of course, a very challenging and complex topic, and one that we likely have to address on a weekly basis with some of our cancer patients: if palliative care and end-of-life is the goal, how can we most humanely achieve that ethically and legally in concert with our patients’ wishes? Is it right or wrong to aid in some way in the dying process? Dr Alva Weir responds to Dr Strouse’s editorial, taking the view point that physician-assisted suicide is toxic abandonment. Dr Strauss responds, and I encourage you to read this very interesting exchange that highlights the point-counterpoint views of physician involvement in the dying process.

We round off the issue with a bumper crop of Case Reports. They include two that document diagnostic challenges: one in a patient with pulmonary sarcomatoid carcinoma presenting as a necrotizing cavitary lung lesion and another in which atraumatic splenic rupture is the initial presentation of CML. Also included is a report on a case of primary cardiac prosthetic valve-associated lymphoma and another on how a collaborative effort between oncologists and dermatologists contributed to the resolution of palmoplantar exacerbation of psoriasis in a patient who had been treated with nivolumab.

Going digital

I will close by remarking that the Journal of Community and Supportive Oncology, or JCSO, will be going digital only after this print issue. We will continue publishing the same content as a bimonthly digital issue, posting articles directly to our website, and mailing out our regular electronic newsletters. So visit the website, www.jcso-online.com, where you can read the articles as soon as they are posted and also find instructions for downloading the app for the digital edition – it’s quick, easy, and free, in case you were wondering. For a shortcut to the download the app, you can also use http://bit.ly/2nCEPIa.

Finally, if you would like to submit a paper to us for consideration for publication, you can do so by going to www.editorialmanager.com/jso/. We will consider submissions in original research, reviews, How We Do It, case reports, and tumor board summaries – you’ll find all the information you need to submit a paper at the EditorialManager platform. And let’s not forget social media – we’re on Twitter where our handle is @jcs_onc, my personal Twitter handle is @davidhenrymd, so connect with us – follow us, like us, and retweet us.

BOSTON – Prior Epstein-Barr virus (EBV) infection and prior herpes simplex virus (HSV) infection each appear to be associated with development of pediatric-onset multiple sclerosis (MS), according to findings from a large national case-control study.

Samples from 360 children with MS or clinically isolated syndrome and 496 frequency-matched controls recruited from 16 pediatric MS centers across the United States were tested for EBV, cytomegalovirus (CMV), and HSV antibodies and for 25-(OH)-vitamin D levels. After adjusting for age, sex, and race/ethnicity, evidence of a remote infection with EBV was strongly associated with higher risk of pediatric-onset MS (odds ratio, 3.6), Bardia Nourbakhsh, MD, reported at the annual meeting of the American Academy of Neurology.

copyright Zerbor/Thinkstock

[email protected]

BOSTON – Prior Epstein-Barr virus (EBV) infection and prior herpes simplex virus (HSV) infection each appear to be associated with development of pediatric-onset multiple sclerosis (MS), according to findings from a large national case-control study.

Samples from 360 children with MS or clinically isolated syndrome and 496 frequency-matched controls recruited from 16 pediatric MS centers across the United States were tested for EBV, cytomegalovirus (CMV), and HSV antibodies and for 25-(OH)-vitamin D levels. After adjusting for age, sex, and race/ethnicity, evidence of a remote infection with EBV was strongly associated with higher risk of pediatric-onset MS (odds ratio, 3.6), Bardia Nourbakhsh, MD, reported at the annual meeting of the American Academy of Neurology.

copyright Zerbor/Thinkstock

[email protected]

BOSTON – Prior Epstein-Barr virus (EBV) infection and prior herpes simplex virus (HSV) infection each appear to be associated with development of pediatric-onset multiple sclerosis (MS), according to findings from a large national case-control study.

Samples from 360 children with MS or clinically isolated syndrome and 496 frequency-matched controls recruited from 16 pediatric MS centers across the United States were tested for EBV, cytomegalovirus (CMV), and HSV antibodies and for 25-(OH)-vitamin D levels. After adjusting for age, sex, and race/ethnicity, evidence of a remote infection with EBV was strongly associated with higher risk of pediatric-onset MS (odds ratio, 3.6), Bardia Nourbakhsh, MD, reported at the annual meeting of the American Academy of Neurology.

copyright Zerbor/Thinkstock

[email protected]

I recently read with interest Dr Thomas Strouse’s article written to support physician aid in dying. Within the article he made the following statement: “I have come to view ‘active non-participation’ in legal PAD [physician aid in dying] – that is, decisions by individual physicians and/or health systems not only to not provide, but also not refer patients to possibly willing providers and systems without regard for specific clinical contexts – as a toxic form of patient abandonment.”¹ Within the article, Dr Strouse lays out for us thoughtful precautions in the aid-in-dying laws, attempting to demonstrate that no vulnerable population is abused. Such precautions are important but provide the same result for all participants: the death of a patient. This is the central problem with aid in dying. Certainly there is nothing wrong with dying, and we all will have that opportunity. Though most of us would choose to put that moment off a while, for some, the suffering in this life makes death seem a welcome relief.

What is a physician’s central responsibility in the care of his or her patients near the end of their lives?

As program director for the hematology and oncology fellowship at my institution, I impress upon my fellows the importance of goal-oriented decision-making. I specifically teach them that there are only four goals worth achieving in any therapeutic or diagnostic decision making: to cure the disease; to help patients live longer despite the disease; to maximize the patient’s quality of life, and to prevent impending disasters. I know of no other worthwhile goal in any decision we are to make for our patients. I can point to none of these goals that physician aid in dying achieves. When it comes to physician-assisted suicide, some would argue that selecting an early death is a way of “maximizing quality of life.” And certainly our task is to make life the best it can be for our patients while they live through the dying process, but I am unaware of any published quality of life formula that calculates the end of life as a positive measure.

The question for us is the role of the doctor. Dr Strouse raises two issues with those whom he accuses of toxic abandonment. The first is whether physicians should provide aid in death, and the second is whether physicians should refer for the same service if they believe it is wrong for their patients.

It certainly has not been well established that physician-assisted suicide is a good thing rather than a tragic thing. A 2012 statement from the Ethics, Professionalism and Human Rights Committee of the American College of Physicians suggests otherwise: “After much consideration, the College concluded that making physician-assisted suicide legal raised serious ethical, clinical and social concerns and that the practice might undermine patient trust; distract from reform in end-of-life care; and be used in vulnerable patients, including those who are poor, are disabled, or are unable to speak for themselves or minority groups who have experienced discrimination.”² The disability rights group, Not Dead Yet, has agreed with the ACP: “It cannot be seriously maintained that assisted suicide laws can or do limit assisted suicide to people who are imminently dying, and voluntarily request and consume a lethal dose, free of inappropriate pressures from family or society. Rather, assisted suicide laws ensure legal immunity for physicians who already devalue the lives of older and disabled people and have significant economic incentives to at least agree with their suicides, if not encourage them, or worse.”³

Such statements sound prophetic within both our present cost containment health care culture and in the real world of personal family economic pressures that can lead a patient toward the understanding that a right to die is actually a “duty to die.”

As society is driving physicians to be technicians to carry out their bidding, physicians should be clinging tightly to their role as trusted advocates for their patients. Certainly our patients have fears and pain that would at times lead them to prefer death to living, but a patient’s move to nonexistence is not the task of the physician. Our task as physicians was well described recently by Yang and Curlin: “Many patients with terminal illnesses fear unbearable pain or other symptoms. The physician’s role is to care for them in their illness so as to relieve pain or otherwise help them bear up under the symptoms they endure. Many patients loathe the prospect of abject debility. The physician’s role is to maintain solidarity with those whose health is diminished, not to not to imply that debility renders a patient’s life not worth living.”⁴

Statements such as these by reasoned people suggest we, as a country, have no consensus for the question whether aid in dying is possibly good or seriously bad for our patients. So it is quite reasonable for compassionate physicians to refuse to administer lethal medicines to their patients in order to “do no harm.”

The second question Dr Strouse explores is whether physicians who disapprove of physician-assisted suicide are abandoning their patients because they do not refer them to a provider who will provide such services. Dr Edmund Pelligrino, a well-respected medical ethicist, in his discussion of moral absolutes in medicine establishes the moral absolute, “Do not kill” and then addresses the ethical problem of complicity in killing. “Formal cooperation is absolutely and always, forbidden. This is the case when the physician shares the evil intent, partakes directly and freely, or in any way facilitates an intrinsically evil act like abortion or assisted suicide.”⁵ Though personally I would not use the word, “evil,” as he does, since evil implies motive; I would substitute the word “harm” and suggest that we should never be complicit in an act that we feel brings the harm of death to our patients. I would suggest that the expectation that physicians referring for aid in dying is analogous with the patient who comes to me demanding a chemotherapy that I know would cause her harm. I would refuse to give it to her and refuse to send her to a doctor who would be willing to give to her. Referral to produce harm is complicity with causing the harm itself. Our society should never go there. Our society should never ask a physician to cross the boundary line of conscience that is the ultimate protection for vulnerable patients.

I know what it is like to watch our patients suffer. I know what it is like to watch our loved ones suffer. I pushed the morphine at my father’s bedside until he quit screaming in pain. But I did not kill him. I cared for him. Such is the physician’s role. If society decides to allow patients the autonomy to end their lives early and wishes to provide skilled technical help in doing so, let it do so at their peril. But let it choose and train technicians to do it. Do not compromise the one person whom our patients should trust totally to never do them harm.

Alva B Weir, III, MD, FACP ([email protected])
West Cancer Center, Memphis, Tennessee

I recently read with interest Dr Thomas Strouse’s article written to support physician aid in dying. Within the article he made the following statement: “I have come to view ‘active non-participation’ in legal PAD [physician aid in dying] – that is, decisions by individual physicians and/or health systems not only to not provide, but also not refer patients to possibly willing providers and systems without regard for specific clinical contexts – as a toxic form of patient abandonment.”¹ Within the article, Dr Strouse lays out for us thoughtful precautions in the aid-in-dying laws, attempting to demonstrate that no vulnerable population is abused. Such precautions are important but provide the same result for all participants: the death of a patient. This is the central problem with aid in dying. Certainly there is nothing wrong with dying, and we all will have that opportunity. Though most of us would choose to put that moment off a while, for some, the suffering in this life makes death seem a welcome relief.

What is a physician’s central responsibility in the care of his or her patients near the end of their lives?

As program director for the hematology and oncology fellowship at my institution, I impress upon my fellows the importance of goal-oriented decision-making. I specifically teach them that there are only four goals worth achieving in any therapeutic or diagnostic decision making: to cure the disease; to help patients live longer despite the disease; to maximize the patient’s quality of life, and to prevent impending disasters. I know of no other worthwhile goal in any decision we are to make for our patients. I can point to none of these goals that physician aid in dying achieves. When it comes to physician-assisted suicide, some would argue that selecting an early death is a way of “maximizing quality of life.” And certainly our task is to make life the best it can be for our patients while they live through the dying process, but I am unaware of any published quality of life formula that calculates the end of life as a positive measure.

The question for us is the role of the doctor. Dr Strouse raises two issues with those whom he accuses of toxic abandonment. The first is whether physicians should provide aid in death, and the second is whether physicians should refer for the same service if they believe it is wrong for their patients.

It certainly has not been well established that physician-assisted suicide is a good thing rather than a tragic thing. A 2012 statement from the Ethics, Professionalism and Human Rights Committee of the American College of Physicians suggests otherwise: “After much consideration, the College concluded that making physician-assisted suicide legal raised serious ethical, clinical and social concerns and that the practice might undermine patient trust; distract from reform in end-of-life care; and be used in vulnerable patients, including those who are poor, are disabled, or are unable to speak for themselves or minority groups who have experienced discrimination.”² The disability rights group, Not Dead Yet, has agreed with the ACP: “It cannot be seriously maintained that assisted suicide laws can or do limit assisted suicide to people who are imminently dying, and voluntarily request and consume a lethal dose, free of inappropriate pressures from family or society. Rather, assisted suicide laws ensure legal immunity for physicians who already devalue the lives of older and disabled people and have significant economic incentives to at least agree with their suicides, if not encourage them, or worse.”³

Such statements sound prophetic within both our present cost containment health care culture and in the real world of personal family economic pressures that can lead a patient toward the understanding that a right to die is actually a “duty to die.”

As society is driving physicians to be technicians to carry out their bidding, physicians should be clinging tightly to their role as trusted advocates for their patients. Certainly our patients have fears and pain that would at times lead them to prefer death to living, but a patient’s move to nonexistence is not the task of the physician. Our task as physicians was well described recently by Yang and Curlin: “Many patients with terminal illnesses fear unbearable pain or other symptoms. The physician’s role is to care for them in their illness so as to relieve pain or otherwise help them bear up under the symptoms they endure. Many patients loathe the prospect of abject debility. The physician’s role is to maintain solidarity with those whose health is diminished, not to not to imply that debility renders a patient’s life not worth living.”⁴

Statements such as these by reasoned people suggest we, as a country, have no consensus for the question whether aid in dying is possibly good or seriously bad for our patients. So it is quite reasonable for compassionate physicians to refuse to administer lethal medicines to their patients in order to “do no harm.”

The second question Dr Strouse explores is whether physicians who disapprove of physician-assisted suicide are abandoning their patients because they do not refer them to a provider who will provide such services. Dr Edmund Pelligrino, a well-respected medical ethicist, in his discussion of moral absolutes in medicine establishes the moral absolute, “Do not kill” and then addresses the ethical problem of complicity in killing. “Formal cooperation is absolutely and always, forbidden. This is the case when the physician shares the evil intent, partakes directly and freely, or in any way facilitates an intrinsically evil act like abortion or assisted suicide.”⁵ Though personally I would not use the word, “evil,” as he does, since evil implies motive; I would substitute the word “harm” and suggest that we should never be complicit in an act that we feel brings the harm of death to our patients. I would suggest that the expectation that physicians referring for aid in dying is analogous with the patient who comes to me demanding a chemotherapy that I know would cause her harm. I would refuse to give it to her and refuse to send her to a doctor who would be willing to give to her. Referral to produce harm is complicity with causing the harm itself. Our society should never go there. Our society should never ask a physician to cross the boundary line of conscience that is the ultimate protection for vulnerable patients.

I know what it is like to watch our patients suffer. I know what it is like to watch our loved ones suffer. I pushed the morphine at my father’s bedside until he quit screaming in pain. But I did not kill him. I cared for him. Such is the physician’s role. If society decides to allow patients the autonomy to end their lives early and wishes to provide skilled technical help in doing so, let it do so at their peril. But let it choose and train technicians to do it. Do not compromise the one person whom our patients should trust totally to never do them harm.

Alva B Weir, III, MD, FACP ([email protected])
West Cancer Center, Memphis, Tennessee

I recently read with interest Dr Thomas Strouse’s article written to support physician aid in dying. Within the article he made the following statement: “I have come to view ‘active non-participation’ in legal PAD [physician aid in dying] – that is, decisions by individual physicians and/or health systems not only to not provide, but also not refer patients to possibly willing providers and systems without regard for specific clinical contexts – as a toxic form of patient abandonment.”¹ Within the article, Dr Strouse lays out for us thoughtful precautions in the aid-in-dying laws, attempting to demonstrate that no vulnerable population is abused. Such precautions are important but provide the same result for all participants: the death of a patient. This is the central problem with aid in dying. Certainly there is nothing wrong with dying, and we all will have that opportunity. Though most of us would choose to put that moment off a while, for some, the suffering in this life makes death seem a welcome relief.

What is a physician’s central responsibility in the care of his or her patients near the end of their lives?

As program director for the hematology and oncology fellowship at my institution, I impress upon my fellows the importance of goal-oriented decision-making. I specifically teach them that there are only four goals worth achieving in any therapeutic or diagnostic decision making: to cure the disease; to help patients live longer despite the disease; to maximize the patient’s quality of life, and to prevent impending disasters. I know of no other worthwhile goal in any decision we are to make for our patients. I can point to none of these goals that physician aid in dying achieves. When it comes to physician-assisted suicide, some would argue that selecting an early death is a way of “maximizing quality of life.” And certainly our task is to make life the best it can be for our patients while they live through the dying process, but I am unaware of any published quality of life formula that calculates the end of life as a positive measure.

The question for us is the role of the doctor. Dr Strouse raises two issues with those whom he accuses of toxic abandonment. The first is whether physicians should provide aid in death, and the second is whether physicians should refer for the same service if they believe it is wrong for their patients.

It certainly has not been well established that physician-assisted suicide is a good thing rather than a tragic thing. A 2012 statement from the Ethics, Professionalism and Human Rights Committee of the American College of Physicians suggests otherwise: “After much consideration, the College concluded that making physician-assisted suicide legal raised serious ethical, clinical and social concerns and that the practice might undermine patient trust; distract from reform in end-of-life care; and be used in vulnerable patients, including those who are poor, are disabled, or are unable to speak for themselves or minority groups who have experienced discrimination.”² The disability rights group, Not Dead Yet, has agreed with the ACP: “It cannot be seriously maintained that assisted suicide laws can or do limit assisted suicide to people who are imminently dying, and voluntarily request and consume a lethal dose, free of inappropriate pressures from family or society. Rather, assisted suicide laws ensure legal immunity for physicians who already devalue the lives of older and disabled people and have significant economic incentives to at least agree with their suicides, if not encourage them, or worse.”³

Such statements sound prophetic within both our present cost containment health care culture and in the real world of personal family economic pressures that can lead a patient toward the understanding that a right to die is actually a “duty to die.”

As society is driving physicians to be technicians to carry out their bidding, physicians should be clinging tightly to their role as trusted advocates for their patients. Certainly our patients have fears and pain that would at times lead them to prefer death to living, but a patient’s move to nonexistence is not the task of the physician. Our task as physicians was well described recently by Yang and Curlin: “Many patients with terminal illnesses fear unbearable pain or other symptoms. The physician’s role is to care for them in their illness so as to relieve pain or otherwise help them bear up under the symptoms they endure. Many patients loathe the prospect of abject debility. The physician’s role is to maintain solidarity with those whose health is diminished, not to not to imply that debility renders a patient’s life not worth living.”⁴

Statements such as these by reasoned people suggest we, as a country, have no consensus for the question whether aid in dying is possibly good or seriously bad for our patients. So it is quite reasonable for compassionate physicians to refuse to administer lethal medicines to their patients in order to “do no harm.”

The second question Dr Strouse explores is whether physicians who disapprove of physician-assisted suicide are abandoning their patients because they do not refer them to a provider who will provide such services. Dr Edmund Pelligrino, a well-respected medical ethicist, in his discussion of moral absolutes in medicine establishes the moral absolute, “Do not kill” and then addresses the ethical problem of complicity in killing. “Formal cooperation is absolutely and always, forbidden. This is the case when the physician shares the evil intent, partakes directly and freely, or in any way facilitates an intrinsically evil act like abortion or assisted suicide.”⁵ Though personally I would not use the word, “evil,” as he does, since evil implies motive; I would substitute the word “harm” and suggest that we should never be complicit in an act that we feel brings the harm of death to our patients. I would suggest that the expectation that physicians referring for aid in dying is analogous with the patient who comes to me demanding a chemotherapy that I know would cause her harm. I would refuse to give it to her and refuse to send her to a doctor who would be willing to give to her. Referral to produce harm is complicity with causing the harm itself. Our society should never go there. Our society should never ask a physician to cross the boundary line of conscience that is the ultimate protection for vulnerable patients.

I know what it is like to watch our patients suffer. I know what it is like to watch our loved ones suffer. I pushed the morphine at my father’s bedside until he quit screaming in pain. But I did not kill him. I cared for him. Such is the physician’s role. If society decides to allow patients the autonomy to end their lives early and wishes to provide skilled technical help in doing so, let it do so at their peril. But let it choose and train technicians to do it. Do not compromise the one person whom our patients should trust totally to never do them harm.

Alva B Weir, III, MD, FACP ([email protected])
West Cancer Center, Memphis, Tennessee