With hospital reimbursement increasingly being linked to patient satisfaction,¹ about half of US hospitals have embraced arts programs as a means of humanizing clinical environments and improving the patient experience.^2,3 There is emerging evidence that integrating such programs into clinical settings is associated with less pain, stress, and anxiety^4-10 as well as improved mood,¹¹ greater levels of interaction,¹² and feeling less institutionalized.¹³ However, it has been observed that existing studies have been undertaken with variable methodological rigor,¹⁴ and few randomized controlled trials (RCTs) have linked specific design features or interventions directly to healthcare outcomes. We designed a RCT to test the hypotheses that (1) placing a painting by a local artist in the line of vision of hospitalized patients would improve psychological and clinical outcomes and patient satisfaction and (2) letting patients choose their own painting would offer even greater benefit in these areas.

Outcomes and Measures

The primary outcomes were psychological and included the following: anxiety, mood, depression, and sense of control and/or influence. These were measured using the validated State-Trait Anxiety Inventory (STAI)¹⁵ an emotional thermometer instrument (ETI)¹⁶, and a self-designed instrument measuring one’s sense of control and influence over the environment. Secondary outcomes were clinical, encompassing pain, quality of life (QOL), length of stay (LOS), and related to perceptions of the hospital environment. These were assessed using data extracted from the electronic medical record (EMR) as well as the Room Assessment (RA) survey, a validated instrument used in prior clinical studies to assess inpatient settings.¹⁷ The RA survey uses the Semantic Differential scale, a rating scale designed to measure emotional associations by using paired attributes.¹⁸ In our scale, we listed 17 paired and polar opposite attributes, with one descriptor reflecting a more positive impression than the other. Anxiety, emotional state, and control and/or influence were assessed at baseline and prior to discharge; emotional state was assessed every 1 to 2 days; and perceptions of the room and overall patient experience were measured once, prior to discharge, using the RA survey.

Data Analysis

A sample of 180 participants were chosen, with a 2:1 ratio of art group to no-art control group to provide at least 80% power to detect a difference in anxiety score of 4 units, for the comparisons of interest among the groups. The calculations assumed a 2-sided test with α = 0.05.

Comparisons were made between (1) those with paintings versus those without and (2) those with a choice of paintings versus those with no choice. For the primary psychological outcome, the average anxiety score at discharge was compared between groups of interest by using analysis of covariance, with adjustment for baseline score. Items measuring mood, depression, control, and influence that were collected more frequently were compared between groups by using repeated measures analysis of covariance, with adjustment for corresponding score at baseline. For clinical outcomes, median LOS was compared between groups by using the Wilcoxon rank sum test due to the skewed distribution of data, and QOL and pain were compared between groups by using repeated measures analysis of covariance. The model for patient-reported pain included covariates for pain medication received and level of pain tolerance. Outcomes measuring perceptions of hospital environment were collected at a single time point and compared between groups by using the 2-sample t-test. Results were reported in terms of means and 95% confidence intervals or medians and quartiles. Significance was defined by P < .05. All facets of this study were approved by the Pennsylvania State University College of Medicine Institutional Review Board.

We approached 518 patients to participate in the study, and 203 elected to enroll. Seventeen patients withdrew from the study because they had been discharged from the hospital or were unable to continue. Of the 186 participants who completed the study, 74 chose the painting displayed in their rooms, 69 had paintings randomly selected for them, and 43 had no paintings in their rooms, only white boards in their line of vision. The average age of participants in the trial was 56 years, 49% were male, and 89% were Caucasian. There were no significant differences between participants and decliners in terms of race (P = .13) and mean age (P = .08). However, they did differ by gender, with 49% of participants being male compared with 68% of decliners (P < .001). There were no significant differences among the 3 study groups with respect to these demographic characteristics. No harms were observed for any patients; however, several patients in the group whose artwork was randomly selected expressed distaste for the image and/or color scheme of their painting.

Psychological Outcomes: Anxiety (STAI), Mood and Depression (ETI), and Sense of Control and/or Influence (Self-Designed Instrument)

There were no differences in anxiety for the primary comparison of artwork versus no artwork or the secondary comparison of choice versus no choice. Likewise, there were no differences in mood, depression, or sense of control and/or influence across the 3 groups.

Clinical Outcomes: Self-Reported Pain, LOS, and QOL (from EMR)

There were no differences in self-reported pain, LOS, or QOL across the 3 groups. With regard to LOS, the median (quartile 1 [Q1], quartile 3 [Q3]) stay was 6 days for the choice group (4.0, 12.0), 6 days for the no-choice group (5.0, 9.5), and 9.5 days for the group with no artwork (5.0, 20.0; see supplementary Table).

Perceptions of Hospital Environment (RA Survey)

While having paintings in cancer inpatient rooms did not affect the psychological or clinical outcomes we assessed, patients who had paintings in their rooms had more positive impressions of the hospital environment. Given that healthcare administrators are under strong pressures to control costs while increasing care quality and patient satisfaction to maximize reimbursement, integrating local artwork into inpatient rooms may represent a simple and relatively inexpensive way (approximately $90 per room) to humanize clinical environments, systematically improve perceptions of the institution, and perhaps contribute to increased patient satisfaction scores. While more work must be done to establish a positive link between access to artwork and improved standardized patient satisfaction outcomes, our results suggest that there may be potential benefit in giving patients an opportunity to engage artwork as a therapeutic resource during the physical, emotional, and spiritual challenges that arise during inpatient treatment.

These findings also have implications for inpatients with illnesses other than cancer. Though we did not explicitly study noncancer patients, we know that nearly 40 million Americans are admitted annually to institutional care (ie, acute hospitalizations, rehabilitation hospitals, and skilled nursing facilities) and often find themselves in environments that can be stark and medicalized. We would anticipate that providing art in these patients’ rooms would likewise improve perceptions of the institutions where they receive their inpatient medical care.

This study had several limitations that could affect the generalizability of our findings. First, it was difficult to enroll patients, with greater than 50% of persons approached declining to participate. Second, nonparticipants were more likely to be male, and this clearly provides a biased sample. Third, we have incomplete data for some patients who were unavailable or changed rooms during the study. Fourth, while each patient room had standardized features (eg, windows, televisions, etc.), there were logistical challenges with placing paintings in the exact same location (ie, in the patient’s direct line of vision) in every hospital room because the shape, size, and idiosyncratic decorating of hospital rooms varied, so we were not able to fully control for all room décor features. Fifth, the study was conducted at a single site and only among patients with cancer; other populations could respond very differently. It is possible that other confounding factors (such as prior hospital experience, patient predilection for artwork, and usage of digital devices during hospitalization) could have affected outcomes, but these were not measured in this study.

In conclusion, as patient satisfaction continues to influence hospital reimbursement, identifying novel and effective approaches to improving patient perceptions can play a meaningful role in patient care. Future research should focus on different inpatient populations and venues; new strategies to effectively evaluate relevant clinical outcomes; comparisons with other nonpharmacological, arts-based interventions in inpatient settings (eg, music, creation of artwork, etc.); and assessment of aggregate scores on standardized patient satisfaction instruments (eg, Press Ganey, Hospital Consumer Assessment of Healthcare Providers and Systems). There may also be an additive benefit in providing “coaching” to healthcare providers on how to engage with patients regarding the artwork they have chosen. Such approaches might also examine the value of giving patients control over multiple opportunities to influence the aesthetics in their room versus a single opportunity during the course of their stay.

Acknowledgments

The authors would like to acknowledge the contributions of Lorna Davis, Lori Snyder, and Renee Stewart to this work.

Disclosure 

This work was supported by funding from the National Endowment for the Arts (grant 14-3800-7008). ClinicalTrials.gov Identifier for Penn State Milton S. Hershey Medical Center Protocol Record STUDY00000378: NCT02357160. The authors report no conflicts of interest.

With hospital reimbursement increasingly being linked to patient satisfaction,¹ about half of US hospitals have embraced arts programs as a means of humanizing clinical environments and improving the patient experience.^2,3 There is emerging evidence that integrating such programs into clinical settings is associated with less pain, stress, and anxiety^4-10 as well as improved mood,¹¹ greater levels of interaction,¹² and feeling less institutionalized.¹³ However, it has been observed that existing studies have been undertaken with variable methodological rigor,¹⁴ and few randomized controlled trials (RCTs) have linked specific design features or interventions directly to healthcare outcomes. We designed a RCT to test the hypotheses that (1) placing a painting by a local artist in the line of vision of hospitalized patients would improve psychological and clinical outcomes and patient satisfaction and (2) letting patients choose their own painting would offer even greater benefit in these areas.

Outcomes and Measures

The primary outcomes were psychological and included the following: anxiety, mood, depression, and sense of control and/or influence. These were measured using the validated State-Trait Anxiety Inventory (STAI)¹⁵ an emotional thermometer instrument (ETI)¹⁶, and a self-designed instrument measuring one’s sense of control and influence over the environment. Secondary outcomes were clinical, encompassing pain, quality of life (QOL), length of stay (LOS), and related to perceptions of the hospital environment. These were assessed using data extracted from the electronic medical record (EMR) as well as the Room Assessment (RA) survey, a validated instrument used in prior clinical studies to assess inpatient settings.¹⁷ The RA survey uses the Semantic Differential scale, a rating scale designed to measure emotional associations by using paired attributes.¹⁸ In our scale, we listed 17 paired and polar opposite attributes, with one descriptor reflecting a more positive impression than the other. Anxiety, emotional state, and control and/or influence were assessed at baseline and prior to discharge; emotional state was assessed every 1 to 2 days; and perceptions of the room and overall patient experience were measured once, prior to discharge, using the RA survey.

Data Analysis

A sample of 180 participants were chosen, with a 2:1 ratio of art group to no-art control group to provide at least 80% power to detect a difference in anxiety score of 4 units, for the comparisons of interest among the groups. The calculations assumed a 2-sided test with α = 0.05.

Comparisons were made between (1) those with paintings versus those without and (2) those with a choice of paintings versus those with no choice. For the primary psychological outcome, the average anxiety score at discharge was compared between groups of interest by using analysis of covariance, with adjustment for baseline score. Items measuring mood, depression, control, and influence that were collected more frequently were compared between groups by using repeated measures analysis of covariance, with adjustment for corresponding score at baseline. For clinical outcomes, median LOS was compared between groups by using the Wilcoxon rank sum test due to the skewed distribution of data, and QOL and pain were compared between groups by using repeated measures analysis of covariance. The model for patient-reported pain included covariates for pain medication received and level of pain tolerance. Outcomes measuring perceptions of hospital environment were collected at a single time point and compared between groups by using the 2-sample t-test. Results were reported in terms of means and 95% confidence intervals or medians and quartiles. Significance was defined by P < .05. All facets of this study were approved by the Pennsylvania State University College of Medicine Institutional Review Board.

We approached 518 patients to participate in the study, and 203 elected to enroll. Seventeen patients withdrew from the study because they had been discharged from the hospital or were unable to continue. Of the 186 participants who completed the study, 74 chose the painting displayed in their rooms, 69 had paintings randomly selected for them, and 43 had no paintings in their rooms, only white boards in their line of vision. The average age of participants in the trial was 56 years, 49% were male, and 89% were Caucasian. There were no significant differences between participants and decliners in terms of race (P = .13) and mean age (P = .08). However, they did differ by gender, with 49% of participants being male compared with 68% of decliners (P < .001). There were no significant differences among the 3 study groups with respect to these demographic characteristics. No harms were observed for any patients; however, several patients in the group whose artwork was randomly selected expressed distaste for the image and/or color scheme of their painting.

Psychological Outcomes: Anxiety (STAI), Mood and Depression (ETI), and Sense of Control and/or Influence (Self-Designed Instrument)

There were no differences in anxiety for the primary comparison of artwork versus no artwork or the secondary comparison of choice versus no choice. Likewise, there were no differences in mood, depression, or sense of control and/or influence across the 3 groups.

Clinical Outcomes: Self-Reported Pain, LOS, and QOL (from EMR)

There were no differences in self-reported pain, LOS, or QOL across the 3 groups. With regard to LOS, the median (quartile 1 [Q1], quartile 3 [Q3]) stay was 6 days for the choice group (4.0, 12.0), 6 days for the no-choice group (5.0, 9.5), and 9.5 days for the group with no artwork (5.0, 20.0; see supplementary Table).

Perceptions of Hospital Environment (RA Survey)

While having paintings in cancer inpatient rooms did not affect the psychological or clinical outcomes we assessed, patients who had paintings in their rooms had more positive impressions of the hospital environment. Given that healthcare administrators are under strong pressures to control costs while increasing care quality and patient satisfaction to maximize reimbursement, integrating local artwork into inpatient rooms may represent a simple and relatively inexpensive way (approximately $90 per room) to humanize clinical environments, systematically improve perceptions of the institution, and perhaps contribute to increased patient satisfaction scores. While more work must be done to establish a positive link between access to artwork and improved standardized patient satisfaction outcomes, our results suggest that there may be potential benefit in giving patients an opportunity to engage artwork as a therapeutic resource during the physical, emotional, and spiritual challenges that arise during inpatient treatment.

These findings also have implications for inpatients with illnesses other than cancer. Though we did not explicitly study noncancer patients, we know that nearly 40 million Americans are admitted annually to institutional care (ie, acute hospitalizations, rehabilitation hospitals, and skilled nursing facilities) and often find themselves in environments that can be stark and medicalized. We would anticipate that providing art in these patients’ rooms would likewise improve perceptions of the institutions where they receive their inpatient medical care.

This study had several limitations that could affect the generalizability of our findings. First, it was difficult to enroll patients, with greater than 50% of persons approached declining to participate. Second, nonparticipants were more likely to be male, and this clearly provides a biased sample. Third, we have incomplete data for some patients who were unavailable or changed rooms during the study. Fourth, while each patient room had standardized features (eg, windows, televisions, etc.), there were logistical challenges with placing paintings in the exact same location (ie, in the patient’s direct line of vision) in every hospital room because the shape, size, and idiosyncratic decorating of hospital rooms varied, so we were not able to fully control for all room décor features. Fifth, the study was conducted at a single site and only among patients with cancer; other populations could respond very differently. It is possible that other confounding factors (such as prior hospital experience, patient predilection for artwork, and usage of digital devices during hospitalization) could have affected outcomes, but these were not measured in this study.

In conclusion, as patient satisfaction continues to influence hospital reimbursement, identifying novel and effective approaches to improving patient perceptions can play a meaningful role in patient care. Future research should focus on different inpatient populations and venues; new strategies to effectively evaluate relevant clinical outcomes; comparisons with other nonpharmacological, arts-based interventions in inpatient settings (eg, music, creation of artwork, etc.); and assessment of aggregate scores on standardized patient satisfaction instruments (eg, Press Ganey, Hospital Consumer Assessment of Healthcare Providers and Systems). There may also be an additive benefit in providing “coaching” to healthcare providers on how to engage with patients regarding the artwork they have chosen. Such approaches might also examine the value of giving patients control over multiple opportunities to influence the aesthetics in their room versus a single opportunity during the course of their stay.

Acknowledgments

The authors would like to acknowledge the contributions of Lorna Davis, Lori Snyder, and Renee Stewart to this work.

Disclosure 

This work was supported by funding from the National Endowment for the Arts (grant 14-3800-7008). ClinicalTrials.gov Identifier for Penn State Milton S. Hershey Medical Center Protocol Record STUDY00000378: NCT02357160. The authors report no conflicts of interest.

With hospital reimbursement increasingly being linked to patient satisfaction,¹ about half of US hospitals have embraced arts programs as a means of humanizing clinical environments and improving the patient experience.^2,3 There is emerging evidence that integrating such programs into clinical settings is associated with less pain, stress, and anxiety^4-10 as well as improved mood,¹¹ greater levels of interaction,¹² and feeling less institutionalized.¹³ However, it has been observed that existing studies have been undertaken with variable methodological rigor,¹⁴ and few randomized controlled trials (RCTs) have linked specific design features or interventions directly to healthcare outcomes. We designed a RCT to test the hypotheses that (1) placing a painting by a local artist in the line of vision of hospitalized patients would improve psychological and clinical outcomes and patient satisfaction and (2) letting patients choose their own painting would offer even greater benefit in these areas.

Outcomes and Measures

The primary outcomes were psychological and included the following: anxiety, mood, depression, and sense of control and/or influence. These were measured using the validated State-Trait Anxiety Inventory (STAI)¹⁵ an emotional thermometer instrument (ETI)¹⁶, and a self-designed instrument measuring one’s sense of control and influence over the environment. Secondary outcomes were clinical, encompassing pain, quality of life (QOL), length of stay (LOS), and related to perceptions of the hospital environment. These were assessed using data extracted from the electronic medical record (EMR) as well as the Room Assessment (RA) survey, a validated instrument used in prior clinical studies to assess inpatient settings.¹⁷ The RA survey uses the Semantic Differential scale, a rating scale designed to measure emotional associations by using paired attributes.¹⁸ In our scale, we listed 17 paired and polar opposite attributes, with one descriptor reflecting a more positive impression than the other. Anxiety, emotional state, and control and/or influence were assessed at baseline and prior to discharge; emotional state was assessed every 1 to 2 days; and perceptions of the room and overall patient experience were measured once, prior to discharge, using the RA survey.

Data Analysis

A sample of 180 participants were chosen, with a 2:1 ratio of art group to no-art control group to provide at least 80% power to detect a difference in anxiety score of 4 units, for the comparisons of interest among the groups. The calculations assumed a 2-sided test with α = 0.05.

Comparisons were made between (1) those with paintings versus those without and (2) those with a choice of paintings versus those with no choice. For the primary psychological outcome, the average anxiety score at discharge was compared between groups of interest by using analysis of covariance, with adjustment for baseline score. Items measuring mood, depression, control, and influence that were collected more frequently were compared between groups by using repeated measures analysis of covariance, with adjustment for corresponding score at baseline. For clinical outcomes, median LOS was compared between groups by using the Wilcoxon rank sum test due to the skewed distribution of data, and QOL and pain were compared between groups by using repeated measures analysis of covariance. The model for patient-reported pain included covariates for pain medication received and level of pain tolerance. Outcomes measuring perceptions of hospital environment were collected at a single time point and compared between groups by using the 2-sample t-test. Results were reported in terms of means and 95% confidence intervals or medians and quartiles. Significance was defined by P < .05. All facets of this study were approved by the Pennsylvania State University College of Medicine Institutional Review Board.

We approached 518 patients to participate in the study, and 203 elected to enroll. Seventeen patients withdrew from the study because they had been discharged from the hospital or were unable to continue. Of the 186 participants who completed the study, 74 chose the painting displayed in their rooms, 69 had paintings randomly selected for them, and 43 had no paintings in their rooms, only white boards in their line of vision. The average age of participants in the trial was 56 years, 49% were male, and 89% were Caucasian. There were no significant differences between participants and decliners in terms of race (P = .13) and mean age (P = .08). However, they did differ by gender, with 49% of participants being male compared with 68% of decliners (P < .001). There were no significant differences among the 3 study groups with respect to these demographic characteristics. No harms were observed for any patients; however, several patients in the group whose artwork was randomly selected expressed distaste for the image and/or color scheme of their painting.

Psychological Outcomes: Anxiety (STAI), Mood and Depression (ETI), and Sense of Control and/or Influence (Self-Designed Instrument)

There were no differences in anxiety for the primary comparison of artwork versus no artwork or the secondary comparison of choice versus no choice. Likewise, there were no differences in mood, depression, or sense of control and/or influence across the 3 groups.

Clinical Outcomes: Self-Reported Pain, LOS, and QOL (from EMR)

There were no differences in self-reported pain, LOS, or QOL across the 3 groups. With regard to LOS, the median (quartile 1 [Q1], quartile 3 [Q3]) stay was 6 days for the choice group (4.0, 12.0), 6 days for the no-choice group (5.0, 9.5), and 9.5 days for the group with no artwork (5.0, 20.0; see supplementary Table).

Perceptions of Hospital Environment (RA Survey)

While having paintings in cancer inpatient rooms did not affect the psychological or clinical outcomes we assessed, patients who had paintings in their rooms had more positive impressions of the hospital environment. Given that healthcare administrators are under strong pressures to control costs while increasing care quality and patient satisfaction to maximize reimbursement, integrating local artwork into inpatient rooms may represent a simple and relatively inexpensive way (approximately $90 per room) to humanize clinical environments, systematically improve perceptions of the institution, and perhaps contribute to increased patient satisfaction scores. While more work must be done to establish a positive link between access to artwork and improved standardized patient satisfaction outcomes, our results suggest that there may be potential benefit in giving patients an opportunity to engage artwork as a therapeutic resource during the physical, emotional, and spiritual challenges that arise during inpatient treatment.

These findings also have implications for inpatients with illnesses other than cancer. Though we did not explicitly study noncancer patients, we know that nearly 40 million Americans are admitted annually to institutional care (ie, acute hospitalizations, rehabilitation hospitals, and skilled nursing facilities) and often find themselves in environments that can be stark and medicalized. We would anticipate that providing art in these patients’ rooms would likewise improve perceptions of the institutions where they receive their inpatient medical care.

This study had several limitations that could affect the generalizability of our findings. First, it was difficult to enroll patients, with greater than 50% of persons approached declining to participate. Second, nonparticipants were more likely to be male, and this clearly provides a biased sample. Third, we have incomplete data for some patients who were unavailable or changed rooms during the study. Fourth, while each patient room had standardized features (eg, windows, televisions, etc.), there were logistical challenges with placing paintings in the exact same location (ie, in the patient’s direct line of vision) in every hospital room because the shape, size, and idiosyncratic decorating of hospital rooms varied, so we were not able to fully control for all room décor features. Fifth, the study was conducted at a single site and only among patients with cancer; other populations could respond very differently. It is possible that other confounding factors (such as prior hospital experience, patient predilection for artwork, and usage of digital devices during hospitalization) could have affected outcomes, but these were not measured in this study.

In conclusion, as patient satisfaction continues to influence hospital reimbursement, identifying novel and effective approaches to improving patient perceptions can play a meaningful role in patient care. Future research should focus on different inpatient populations and venues; new strategies to effectively evaluate relevant clinical outcomes; comparisons with other nonpharmacological, arts-based interventions in inpatient settings (eg, music, creation of artwork, etc.); and assessment of aggregate scores on standardized patient satisfaction instruments (eg, Press Ganey, Hospital Consumer Assessment of Healthcare Providers and Systems). There may also be an additive benefit in providing “coaching” to healthcare providers on how to engage with patients regarding the artwork they have chosen. Such approaches might also examine the value of giving patients control over multiple opportunities to influence the aesthetics in their room versus a single opportunity during the course of their stay.

Acknowledgments

The authors would like to acknowledge the contributions of Lorna Davis, Lori Snyder, and Renee Stewart to this work.

Disclosure 

This work was supported by funding from the National Endowment for the Arts (grant 14-3800-7008). ClinicalTrials.gov Identifier for Penn State Milton S. Hershey Medical Center Protocol Record STUDY00000378: NCT02357160. The authors report no conflicts of interest.

Reimbursement for hospitals and physicians is increasingly tied to performance.¹ Bundled payments, for example, require hospitals to share risk for patient outcomes. Medicare bundled payments are becoming mandatory for some surgical and medical conditions, including joint replacement, acute myocardial infarction, and coronary artery bypass graft surgery.² Value-based payment is anticipated to become the norm as Medicare and private payers strive to control costs and improve outcomes. Although value-based reimbursement for hospitals targets hospital-level costs and outcomes, we know that variations at the level of individual providers explain a considerable proportion of variation in utilization and outcomes.³ However, physicians often lack awareness of their own practice patterns and relative costs, and successful participation in new payment models may require an investment by hospitals in the infrastructure needed to measure and provide feedback on performance to individual providers to affect their behavior.^4,5

Electronic health record (EHR)-based reports or “dashboards” have been proposed as one potential tool to provide individualized feedback on provider performance.⁶ Individual provider performance profiles (IPPs) offer the potential to provide peer comparisons that may adjust individual behavior by correcting misperceptions about norms.⁷ Behavioral economic theory suggests that individual performance data, if combined with information on peer behavior and normative goals, may be effective in changing behavior.⁸ Several studies have reported the effects of specific efforts to use IPPs, showing that such reports can improve care in certain clinical areas. For example, individual provider dashboards have been associated with better outcomes for hospitalized patients, such as increased compliance with recommendations for prophylaxis of venous thromboembolism, although evidence in other areas of practice is mixed.^9,10 A randomized controlled trial of peer comparison feedback reduced inappropriate antibiotic prescribing for upper respiratory infections by 11% among internists.¹¹

Despite the promise of individualized feedback to optimize behavior, however, little has been reported on trends in the use of IPPs on a population level. It is unknown whether their use is common or rare, or what hospital characteristics are associated with adoption. Such information would help guide future efforts to promote IPP use and understand its effect on practice. We used data from a nationally representative survey of US hospitals to examine the use of individual provider-level performance profiles.

We used data from the American Hospital Association (AHA) Annual Survey Information Technology (IT) Supplement, which asked respondents to indicate whether they have used electronic clinical data from the EHR or other electronic system in their hospital to create IPPs. The AHA survey is sent annually to all US operating hospitals. Survey results are supplemented by data from the AHA registration database, US Census Bureau, hospital accrediting bodies, and other organizations. The AHA IT supplement is also sent yearly to each hospital’s chief executive officer, who assigns it to the most knowledgeable person in the institution to complete.¹²

We linked data on IPP use to AHA Annual Survey responses on hospital characteristics for all general adult and pediatric hospitals. Multivariable logistic regression was used to model the odds of individual provider performance profile use as a function of hospital characteristics, including ownership (nonprofit, for profit, or government), geographic region, teaching versus nonteaching status, rural versus urban location, size, expenditures per bed, proportion of patient days covered by Medicaid, and risk-sharing models of reimbursement (participation in a health maintenance organization or bundled payments program). Variables were chosen a priori to account for important characteristics of US hospitals (eg, size, teaching status, and geographic location). These were combined with variables representing risk-sharing arrangements based on the hypothesis that hospitals whose payments are at greater risk would be more likely to invest in tracking provider performance. We eliminated any variable with an item nonresponse rate greater than 15%, which resulted in elimination of 2 variables representing hospital revenue from capitated payments and any risk-sharing arrangement, respectively. All other variables had item nonresponse rates of 0%, except for 4.7% item nonresponse for the bundled payments variable.

We also measured the trend in individual provider performance report use between 2013 and 2015 by estimating the linear probability between IPP use and year. A P value less than .05 was considered statistically significant.

Because past work has demonstrated nonresponse bias in the AHA Survey and IT Supplement, we performed additional analyses using nonresponsive weights based on hospital characteristics. Weighting methodology was based on prior work with the AHA and AHA IT surveys.^13,14 Weighting exploits the fact that a number of hospital characteristics are derived from sources outside the survey and thus are available for both respondents and nonrespondents. We created nonresponse weights based on a logistic regression model of survey response as a function of hospital characteristics (ownership, size, teaching status, systems membership, critical access hospital, and geographic region). Our findings were similar for weighted and nonweighted models and nonweighted estimates are presented throughout.

The University of Pennsylvania Institutional Review Board exempted this study from review. Analyses were performed using Stata statistical software, version 14.0 (StataCorp, College Station, TX).

The table shows the association between hospital characteristics and the odds of individual provider performance report use. Report use was associated with nonprofit status (odds ratio [OR], 2.77; 95% confidence interval [CI], 1.94-3.95; P < .01) compared to for-profit, large hospital size (OR, 2.37; 95% CI, 1.56-3.60; P < .01) compared to small size, highest (OR, 2.09; 95% CI, 1.55-2.82; P < .01) and second highest (OR, 1.43; 95% CI, 1.08-1.89; P = .01) quartiles of bed-adjusted expenditures compared to the bottom quartile, and West geographic region compared to Northeast (OR, 2.07; 95% CI, 1.45-2.95; P < .01). Individual provider performance use was also independently associated with participation in a health maintenance organization (OR, 1.50; 95% CI, 1.17-1.90; P < .01) or bundled payment program (OR, 1.61; 95% CI, 1.18-2.19; P < .01), controlling for other covariates. Adjustment for nonresponse bias did not change any coefficients by more than 10% (supplementary Table).

The Medicare Access and Children Health Insurance Program Reauthorization Act is accelerating the shift from quantity based toward value-based reimbursement. The proficient adoption of IT by healthcare providers has been cited as an important factor in adapting to new payment models.¹⁵ Physicians, and in particular hospitalists, who practice in an inpatient environment, may not directly access financial incentives aimed to adapt performance for value-based reimbursement. They may also have difficulty assessing their performance relative to peers and longitudinally over time. Individualized EHR-based provider-level performance reports offer 1 option for hospitals to measure performance and provide comparative feedback at the individual physician level. Our findings show that, in fact, a majority of US hospitals have made investments in the infrastructure necessary to create such profiles.

Nevertheless, a third of the hospitals surveyed have not adopted individualized provider performance profiles. If meeting efficiency and outcomes goals for value-based payments necessitates changes to individual provider behavior, those hospitals may be less well positioned to benefit from value-based payment models that incentivize hospitals for efficiency and outcomes. Furthermore, while we observe widespread adoption of individual performance profiles, it is unclear whether those were used to provide feedback to providers, and if so, how the feedback provided may influence its effect on behavior. Behavioral economics theory suggests, for example, that publicly reporting performance compared to peers provides stronger incentives for behavior change than “blinded” personalized reports.¹⁶

Our study has important limitations. We cannot exclude the possibility that unmeasured variables help explain individual provider performance adoption. These omitted variables may confound the association between hospital characteristics and individual provider performance adoption observed in this study. We were also unable to establish causality between bundled payments and individual provider performance profile use. For instance, hospitals may elect to make investments in IT infrastructure to enable individual provider performance profile adoption in anticipation of bundled payment reforms. Alternatively, the availability of IPPs may have led hospitals to enter bundled payments reimbursement arrangements. In addition, we are unable to describe how individual provider performance use affects physician practice or healthcare delivery more broadly. Finally, we are also unable to account for other sources of performance data. For example, some physician may receive data from their physician practice groups.

Our study suggests several avenues for future research. First, more work is needed to understand why certain types of hospitals are more likely to use IPPs. Our findings indicate that IPP use may be partly a function of hospital size and resources. However, other factors not measured here may play an important role as well, such as institutional culture. Institutions with a focus on informatics and strong IT leadership may be more likely to use their EHR to monitor performance. Second, further research should explore in greater depth how profiles are used. Future research should evaluate, for example, how hospitals are using behavioral economic principles, such as peer comparison, to motivate behavior change, and if such techniques have successfully influenced practice and patient outcomes. Ultimately, multicentered, randomized evaluations of IPP use may be necessary to understand their risks and evaluate their effect on patient outcomes. This work is necessary to inform policy and practice as hospitals transition from fee-for-service to value-based reimbursement.

In sum, we observed increasing adoption of individualized electronic provider performance profiles by US hospitals from 2013 to 2015. Hospitals that did not use IPPs were more likely to be small, for profit, and less likely to participate in bundled payment programs. Those hospitals may be less well positioned to track provider performance and implement incentives for provider behavior changes needed to meet targets for value-based reimbursement.

Disclosure

Dr. Rolnick is a consultant to Tuple Health, Inc. and was a part-time employee of Acumen, LLC outside the submitted work. Dr. Ryskina has nothing to disclose.

Reimbursement for hospitals and physicians is increasingly tied to performance.¹ Bundled payments, for example, require hospitals to share risk for patient outcomes. Medicare bundled payments are becoming mandatory for some surgical and medical conditions, including joint replacement, acute myocardial infarction, and coronary artery bypass graft surgery.² Value-based payment is anticipated to become the norm as Medicare and private payers strive to control costs and improve outcomes. Although value-based reimbursement for hospitals targets hospital-level costs and outcomes, we know that variations at the level of individual providers explain a considerable proportion of variation in utilization and outcomes.³ However, physicians often lack awareness of their own practice patterns and relative costs, and successful participation in new payment models may require an investment by hospitals in the infrastructure needed to measure and provide feedback on performance to individual providers to affect their behavior.^4,5

Electronic health record (EHR)-based reports or “dashboards” have been proposed as one potential tool to provide individualized feedback on provider performance.⁶ Individual provider performance profiles (IPPs) offer the potential to provide peer comparisons that may adjust individual behavior by correcting misperceptions about norms.⁷ Behavioral economic theory suggests that individual performance data, if combined with information on peer behavior and normative goals, may be effective in changing behavior.⁸ Several studies have reported the effects of specific efforts to use IPPs, showing that such reports can improve care in certain clinical areas. For example, individual provider dashboards have been associated with better outcomes for hospitalized patients, such as increased compliance with recommendations for prophylaxis of venous thromboembolism, although evidence in other areas of practice is mixed.^9,10 A randomized controlled trial of peer comparison feedback reduced inappropriate antibiotic prescribing for upper respiratory infections by 11% among internists.¹¹

Despite the promise of individualized feedback to optimize behavior, however, little has been reported on trends in the use of IPPs on a population level. It is unknown whether their use is common or rare, or what hospital characteristics are associated with adoption. Such information would help guide future efforts to promote IPP use and understand its effect on practice. We used data from a nationally representative survey of US hospitals to examine the use of individual provider-level performance profiles.

We used data from the American Hospital Association (AHA) Annual Survey Information Technology (IT) Supplement, which asked respondents to indicate whether they have used electronic clinical data from the EHR or other electronic system in their hospital to create IPPs. The AHA survey is sent annually to all US operating hospitals. Survey results are supplemented by data from the AHA registration database, US Census Bureau, hospital accrediting bodies, and other organizations. The AHA IT supplement is also sent yearly to each hospital’s chief executive officer, who assigns it to the most knowledgeable person in the institution to complete.¹²

We linked data on IPP use to AHA Annual Survey responses on hospital characteristics for all general adult and pediatric hospitals. Multivariable logistic regression was used to model the odds of individual provider performance profile use as a function of hospital characteristics, including ownership (nonprofit, for profit, or government), geographic region, teaching versus nonteaching status, rural versus urban location, size, expenditures per bed, proportion of patient days covered by Medicaid, and risk-sharing models of reimbursement (participation in a health maintenance organization or bundled payments program). Variables were chosen a priori to account for important characteristics of US hospitals (eg, size, teaching status, and geographic location). These were combined with variables representing risk-sharing arrangements based on the hypothesis that hospitals whose payments are at greater risk would be more likely to invest in tracking provider performance. We eliminated any variable with an item nonresponse rate greater than 15%, which resulted in elimination of 2 variables representing hospital revenue from capitated payments and any risk-sharing arrangement, respectively. All other variables had item nonresponse rates of 0%, except for 4.7% item nonresponse for the bundled payments variable.

We also measured the trend in individual provider performance report use between 2013 and 2015 by estimating the linear probability between IPP use and year. A P value less than .05 was considered statistically significant.

Because past work has demonstrated nonresponse bias in the AHA Survey and IT Supplement, we performed additional analyses using nonresponsive weights based on hospital characteristics. Weighting methodology was based on prior work with the AHA and AHA IT surveys.^13,14 Weighting exploits the fact that a number of hospital characteristics are derived from sources outside the survey and thus are available for both respondents and nonrespondents. We created nonresponse weights based on a logistic regression model of survey response as a function of hospital characteristics (ownership, size, teaching status, systems membership, critical access hospital, and geographic region). Our findings were similar for weighted and nonweighted models and nonweighted estimates are presented throughout.

The University of Pennsylvania Institutional Review Board exempted this study from review. Analyses were performed using Stata statistical software, version 14.0 (StataCorp, College Station, TX).

The table shows the association between hospital characteristics and the odds of individual provider performance report use. Report use was associated with nonprofit status (odds ratio [OR], 2.77; 95% confidence interval [CI], 1.94-3.95; P < .01) compared to for-profit, large hospital size (OR, 2.37; 95% CI, 1.56-3.60; P < .01) compared to small size, highest (OR, 2.09; 95% CI, 1.55-2.82; P < .01) and second highest (OR, 1.43; 95% CI, 1.08-1.89; P = .01) quartiles of bed-adjusted expenditures compared to the bottom quartile, and West geographic region compared to Northeast (OR, 2.07; 95% CI, 1.45-2.95; P < .01). Individual provider performance use was also independently associated with participation in a health maintenance organization (OR, 1.50; 95% CI, 1.17-1.90; P < .01) or bundled payment program (OR, 1.61; 95% CI, 1.18-2.19; P < .01), controlling for other covariates. Adjustment for nonresponse bias did not change any coefficients by more than 10% (supplementary Table).

The Medicare Access and Children Health Insurance Program Reauthorization Act is accelerating the shift from quantity based toward value-based reimbursement. The proficient adoption of IT by healthcare providers has been cited as an important factor in adapting to new payment models.¹⁵ Physicians, and in particular hospitalists, who practice in an inpatient environment, may not directly access financial incentives aimed to adapt performance for value-based reimbursement. They may also have difficulty assessing their performance relative to peers and longitudinally over time. Individualized EHR-based provider-level performance reports offer 1 option for hospitals to measure performance and provide comparative feedback at the individual physician level. Our findings show that, in fact, a majority of US hospitals have made investments in the infrastructure necessary to create such profiles.

Nevertheless, a third of the hospitals surveyed have not adopted individualized provider performance profiles. If meeting efficiency and outcomes goals for value-based payments necessitates changes to individual provider behavior, those hospitals may be less well positioned to benefit from value-based payment models that incentivize hospitals for efficiency and outcomes. Furthermore, while we observe widespread adoption of individual performance profiles, it is unclear whether those were used to provide feedback to providers, and if so, how the feedback provided may influence its effect on behavior. Behavioral economics theory suggests, for example, that publicly reporting performance compared to peers provides stronger incentives for behavior change than “blinded” personalized reports.¹⁶

Our study has important limitations. We cannot exclude the possibility that unmeasured variables help explain individual provider performance adoption. These omitted variables may confound the association between hospital characteristics and individual provider performance adoption observed in this study. We were also unable to establish causality between bundled payments and individual provider performance profile use. For instance, hospitals may elect to make investments in IT infrastructure to enable individual provider performance profile adoption in anticipation of bundled payment reforms. Alternatively, the availability of IPPs may have led hospitals to enter bundled payments reimbursement arrangements. In addition, we are unable to describe how individual provider performance use affects physician practice or healthcare delivery more broadly. Finally, we are also unable to account for other sources of performance data. For example, some physician may receive data from their physician practice groups.

Our study suggests several avenues for future research. First, more work is needed to understand why certain types of hospitals are more likely to use IPPs. Our findings indicate that IPP use may be partly a function of hospital size and resources. However, other factors not measured here may play an important role as well, such as institutional culture. Institutions with a focus on informatics and strong IT leadership may be more likely to use their EHR to monitor performance. Second, further research should explore in greater depth how profiles are used. Future research should evaluate, for example, how hospitals are using behavioral economic principles, such as peer comparison, to motivate behavior change, and if such techniques have successfully influenced practice and patient outcomes. Ultimately, multicentered, randomized evaluations of IPP use may be necessary to understand their risks and evaluate their effect on patient outcomes. This work is necessary to inform policy and practice as hospitals transition from fee-for-service to value-based reimbursement.

In sum, we observed increasing adoption of individualized electronic provider performance profiles by US hospitals from 2013 to 2015. Hospitals that did not use IPPs were more likely to be small, for profit, and less likely to participate in bundled payment programs. Those hospitals may be less well positioned to track provider performance and implement incentives for provider behavior changes needed to meet targets for value-based reimbursement.

Disclosure

Dr. Rolnick is a consultant to Tuple Health, Inc. and was a part-time employee of Acumen, LLC outside the submitted work. Dr. Ryskina has nothing to disclose.

Reimbursement for hospitals and physicians is increasingly tied to performance.¹ Bundled payments, for example, require hospitals to share risk for patient outcomes. Medicare bundled payments are becoming mandatory for some surgical and medical conditions, including joint replacement, acute myocardial infarction, and coronary artery bypass graft surgery.² Value-based payment is anticipated to become the norm as Medicare and private payers strive to control costs and improve outcomes. Although value-based reimbursement for hospitals targets hospital-level costs and outcomes, we know that variations at the level of individual providers explain a considerable proportion of variation in utilization and outcomes.³ However, physicians often lack awareness of their own practice patterns and relative costs, and successful participation in new payment models may require an investment by hospitals in the infrastructure needed to measure and provide feedback on performance to individual providers to affect their behavior.^4,5

Electronic health record (EHR)-based reports or “dashboards” have been proposed as one potential tool to provide individualized feedback on provider performance.⁶ Individual provider performance profiles (IPPs) offer the potential to provide peer comparisons that may adjust individual behavior by correcting misperceptions about norms.⁷ Behavioral economic theory suggests that individual performance data, if combined with information on peer behavior and normative goals, may be effective in changing behavior.⁸ Several studies have reported the effects of specific efforts to use IPPs, showing that such reports can improve care in certain clinical areas. For example, individual provider dashboards have been associated with better outcomes for hospitalized patients, such as increased compliance with recommendations for prophylaxis of venous thromboembolism, although evidence in other areas of practice is mixed.^9,10 A randomized controlled trial of peer comparison feedback reduced inappropriate antibiotic prescribing for upper respiratory infections by 11% among internists.¹¹

Despite the promise of individualized feedback to optimize behavior, however, little has been reported on trends in the use of IPPs on a population level. It is unknown whether their use is common or rare, or what hospital characteristics are associated with adoption. Such information would help guide future efforts to promote IPP use and understand its effect on practice. We used data from a nationally representative survey of US hospitals to examine the use of individual provider-level performance profiles.

We used data from the American Hospital Association (AHA) Annual Survey Information Technology (IT) Supplement, which asked respondents to indicate whether they have used electronic clinical data from the EHR or other electronic system in their hospital to create IPPs. The AHA survey is sent annually to all US operating hospitals. Survey results are supplemented by data from the AHA registration database, US Census Bureau, hospital accrediting bodies, and other organizations. The AHA IT supplement is also sent yearly to each hospital’s chief executive officer, who assigns it to the most knowledgeable person in the institution to complete.¹²

We linked data on IPP use to AHA Annual Survey responses on hospital characteristics for all general adult and pediatric hospitals. Multivariable logistic regression was used to model the odds of individual provider performance profile use as a function of hospital characteristics, including ownership (nonprofit, for profit, or government), geographic region, teaching versus nonteaching status, rural versus urban location, size, expenditures per bed, proportion of patient days covered by Medicaid, and risk-sharing models of reimbursement (participation in a health maintenance organization or bundled payments program). Variables were chosen a priori to account for important characteristics of US hospitals (eg, size, teaching status, and geographic location). These were combined with variables representing risk-sharing arrangements based on the hypothesis that hospitals whose payments are at greater risk would be more likely to invest in tracking provider performance. We eliminated any variable with an item nonresponse rate greater than 15%, which resulted in elimination of 2 variables representing hospital revenue from capitated payments and any risk-sharing arrangement, respectively. All other variables had item nonresponse rates of 0%, except for 4.7% item nonresponse for the bundled payments variable.

We also measured the trend in individual provider performance report use between 2013 and 2015 by estimating the linear probability between IPP use and year. A P value less than .05 was considered statistically significant.

Because past work has demonstrated nonresponse bias in the AHA Survey and IT Supplement, we performed additional analyses using nonresponsive weights based on hospital characteristics. Weighting methodology was based on prior work with the AHA and AHA IT surveys.^13,14 Weighting exploits the fact that a number of hospital characteristics are derived from sources outside the survey and thus are available for both respondents and nonrespondents. We created nonresponse weights based on a logistic regression model of survey response as a function of hospital characteristics (ownership, size, teaching status, systems membership, critical access hospital, and geographic region). Our findings were similar for weighted and nonweighted models and nonweighted estimates are presented throughout.

The University of Pennsylvania Institutional Review Board exempted this study from review. Analyses were performed using Stata statistical software, version 14.0 (StataCorp, College Station, TX).

The table shows the association between hospital characteristics and the odds of individual provider performance report use. Report use was associated with nonprofit status (odds ratio [OR], 2.77; 95% confidence interval [CI], 1.94-3.95; P < .01) compared to for-profit, large hospital size (OR, 2.37; 95% CI, 1.56-3.60; P < .01) compared to small size, highest (OR, 2.09; 95% CI, 1.55-2.82; P < .01) and second highest (OR, 1.43; 95% CI, 1.08-1.89; P = .01) quartiles of bed-adjusted expenditures compared to the bottom quartile, and West geographic region compared to Northeast (OR, 2.07; 95% CI, 1.45-2.95; P < .01). Individual provider performance use was also independently associated with participation in a health maintenance organization (OR, 1.50; 95% CI, 1.17-1.90; P < .01) or bundled payment program (OR, 1.61; 95% CI, 1.18-2.19; P < .01), controlling for other covariates. Adjustment for nonresponse bias did not change any coefficients by more than 10% (supplementary Table).

The Medicare Access and Children Health Insurance Program Reauthorization Act is accelerating the shift from quantity based toward value-based reimbursement. The proficient adoption of IT by healthcare providers has been cited as an important factor in adapting to new payment models.¹⁵ Physicians, and in particular hospitalists, who practice in an inpatient environment, may not directly access financial incentives aimed to adapt performance for value-based reimbursement. They may also have difficulty assessing their performance relative to peers and longitudinally over time. Individualized EHR-based provider-level performance reports offer 1 option for hospitals to measure performance and provide comparative feedback at the individual physician level. Our findings show that, in fact, a majority of US hospitals have made investments in the infrastructure necessary to create such profiles.

Nevertheless, a third of the hospitals surveyed have not adopted individualized provider performance profiles. If meeting efficiency and outcomes goals for value-based payments necessitates changes to individual provider behavior, those hospitals may be less well positioned to benefit from value-based payment models that incentivize hospitals for efficiency and outcomes. Furthermore, while we observe widespread adoption of individual performance profiles, it is unclear whether those were used to provide feedback to providers, and if so, how the feedback provided may influence its effect on behavior. Behavioral economics theory suggests, for example, that publicly reporting performance compared to peers provides stronger incentives for behavior change than “blinded” personalized reports.¹⁶

Our study has important limitations. We cannot exclude the possibility that unmeasured variables help explain individual provider performance adoption. These omitted variables may confound the association between hospital characteristics and individual provider performance adoption observed in this study. We were also unable to establish causality between bundled payments and individual provider performance profile use. For instance, hospitals may elect to make investments in IT infrastructure to enable individual provider performance profile adoption in anticipation of bundled payment reforms. Alternatively, the availability of IPPs may have led hospitals to enter bundled payments reimbursement arrangements. In addition, we are unable to describe how individual provider performance use affects physician practice or healthcare delivery more broadly. Finally, we are also unable to account for other sources of performance data. For example, some physician may receive data from their physician practice groups.

Our study suggests several avenues for future research. First, more work is needed to understand why certain types of hospitals are more likely to use IPPs. Our findings indicate that IPP use may be partly a function of hospital size and resources. However, other factors not measured here may play an important role as well, such as institutional culture. Institutions with a focus on informatics and strong IT leadership may be more likely to use their EHR to monitor performance. Second, further research should explore in greater depth how profiles are used. Future research should evaluate, for example, how hospitals are using behavioral economic principles, such as peer comparison, to motivate behavior change, and if such techniques have successfully influenced practice and patient outcomes. Ultimately, multicentered, randomized evaluations of IPP use may be necessary to understand their risks and evaluate their effect on patient outcomes. This work is necessary to inform policy and practice as hospitals transition from fee-for-service to value-based reimbursement.

In sum, we observed increasing adoption of individualized electronic provider performance profiles by US hospitals from 2013 to 2015. Hospitals that did not use IPPs were more likely to be small, for profit, and less likely to participate in bundled payment programs. Those hospitals may be less well positioned to track provider performance and implement incentives for provider behavior changes needed to meet targets for value-based reimbursement.

Disclosure

Dr. Rolnick is a consultant to Tuple Health, Inc. and was a part-time employee of Acumen, LLC outside the submitted work. Dr. Ryskina has nothing to disclose.

Pediatric expertise is critical in caring for children during the perioperative and postoperative periods.^1,2 Some postoperative care models involve pediatric hospitalists (PH) as collaborators for global care (comanagement),³ as consultants for specific issues, or not at all.

Single-site studies in specific pediatric surgical populations^4-7and medically fragile adults⁸ suggest improved outcomes for patients and systems by using hospitalist-surgeon collaboration. However, including PH in the care of surgical patients may also disrupt systems. No studies have broadly examined the clinical relationships between surgeons and PH.

The aims of this cross-sectional survey of US pediatric surgeons (PS) and pediatric orthopedic surgeons (OS) were to understand (1) the prevalence and characteristics of surgical care models in pediatrics, specifically those involving PH, and (2) surgeons’ perceptions of PH in caring for surgical patients.

The target US surgeon population was the estimated 850 active PS and at least 600 pediatric OS.⁹ Most US PS (n = 606) are affiliated with the American Academy of Pediatrics (AAP) Section on Surgery (SoSu), representing at least 200 programs. Nearly all pediatric OS belong to the Pediatric Orthopedic Society of North America (POSNA) (n = 706), representing 340 programs; a subset (n = 130) also belong to the AAP SoSu.

Survey Development and Distribution

Survey questions were developed to elicit surgeons’ descriptions of their program structure and their perceptions of PH involvement. For programs with PH involvement, program variables included primary assignment of clinical responsibilities by service line (surgery, hospitalist, shared) and use of a written service agreement, which defines each service’s roles and responsibilities.

The web-based survey, created by using Survey Monkey (San Mateo, CA), was pilot tested for usability and clarity among 8 surgeons and 1 PH. The survey had logic points around involvement of hospitalists and multiple hospital affiliations (supplemental Appendix A). The survey request with a web-based link was e-mailed 3 times to surgical and orthopedic distribution outlets, endorsed by organizational leadership. Respondents’ hospital ZIP codes were used as a proxy for program. If there was more than 1 complete survey response per ZIP code, 1 response with complete data was randomly selected to ensure a unique entry per program.

Classification of Care Models

Each surgical program was classified into 1 of the following 3 categories based on reported care of primary surgical patients: (1) comanagement, described as PH writing orders and/or functioning as the primary service; (2) consultation, described as PH providing clinical recommendations only; and (3) no PH involvement, described as “rarely” or “never” involving PH.

Clinical Responsibility Score

To estimate the degree of hospitalist involvement, we devised and calculated a composite score of service responsibilities for each program. This score involved the following 7 clinical domains: management of fluids or nutrition, pain, comorbidities, antibiotics, medication dosing, wound care, and discharge planning. Scores were summed for each domain: 0 for surgical team primary responsibility, 1 for shared surgical and hospitalist responsibility, and 2 for hospitalist primary responsibility. Composite scores could range from 0 to 14; lower scores represented a stronger tendency for surgeon management, and higher scores represented a stronger tendency toward PH management.

Data Analysis

For data analysis, simple exploratory tests with χ² analysis and Student t tests were performed by using Stata 14.2 (StataCorp LLC, College Station, TX) to compare differences by surgical specialty programs and individuals by role assignment and perceptions of PH involvement.

The NYU School of Medicine Institutional Review Board approved this study.

Respondents and Programs

Among the unique 185 PS programs and 212 OS programs represented, PH were often engaged in the care of primary surgical patients (Table).

Roles of PH in Collaborative Programs

Among programs that reported any hospitalist involvement (PS, n = 100; OS, n = 157), few (≤15%) programs involved hospitalists with all patients. Pediatric OS programs were significantly more likely than pediatric surgical programs to involve PH for healthy patients with any high-risk surgery (27% vs 9%; P = .001). Most PS (64%) and OS (83%) reported involving PH for all medically complex patients, regardless of surgery risk (P = .003).

In programs involving PH, few PS (11%) or OS programs (16%) reported by using a written service agreement.

Care of Surgical Patients in PH-involved programs

Composite clinical responsibility scores ranged from 0 to 8, with a median score of 2.3 (interquartile range [IQR] 0-3) for consultation programs and 5 (IQR 1-7) for comanagement programs. Composite scores were higher for OS (7.4; SD 3.4) versus PS (3.3; SD 3.4) programs (P < .001; 95% CI, 3.3-5.5; supplemental Appendix C).

Surgeons’ Perspectives on Hospitalist Involvement

Surgeons in programs without PH involvement viewed PH overall impact less positively than those with PH (27% vs 58%). Among all surgeons surveyed, few perceived positive (agree/strongly agree) PH impact on pain management (<15%) or decreasing LOS (<15%; supplemental Appendix D).

Most surgeons (n = 355) believed that PH financial support should come from separate billing (“patient fee”) (48%) or hospital budget (36%). Only 17% endorsed PH receiving part of the surgical global fee, with no significant difference by surgical specialty or current PH involvement status.

This study is the first comprehensive assessment of surgeons’ perspectives on the involvement and effectiveness of PH in the postoperative care of children undergoing inpatient general or orthopedic surgeries. The high prevalence (>70%) of PH involvement among responding surgical programs suggests that PH comanagement of hospitalized patients merits attention from providers, systems, educators, and payors.

Collaboration and Roles are Correlated with Surgical Specialty and Setting

Forty percent of inpatient pediatric surgeries occur outside of children’s hospitals.¹⁰ We found that PH involvement was higher at smaller and general hospitals where PH may provide pediatric expertise when insufficient pediatric resources, like pain teams, exist.⁷ Alternately, some quaternary centers have dedicated surgical hospitalists. The extensive involvement of PH in the bulk of certain clinical care domains, especially care coordination, in OS and in many PS programs (Figure) suggests that PH are well integrated into many programs and provide essential clinical care.

In many large freestanding children’s hospitals, though, surgical teams may have sufficient depth and breadth to manage most aspects of care. There may be an exception for care coordination of medically complex patients. Care coordination is a patient- and family-centered care best practice,¹¹ encompasses integrating and aligning medical care among clinical services, and is focused on shared decision making and communication. High-quality care coordination processes are of great value to patients and families, especially in medically complex children,¹¹ and are associated with improved transitions from hospital to home.¹² Well-planned transitions likely decrease these special populations’ postoperative readmission risk, complications, and prolonged length of stay.¹³ Reimbursement for these services could integrate these contributions needed for safe and patient-centered pediatric inpatient surgical care.

Perceptions of PH Impact

The variation in perception of PH by surgical specialty, with higher prevalence as well as higher regard for PH among OS, is intriguing. This disparity may reflect current training and clinical expectations of each surgical specialty, with larger emphasis on medical management for surgical compared with orthopedic curricula (www.acgme.org).

While PS and OS respondents perceived that PH involvement did not influence length of stay, pain management, and resource use, single-site studies suggest otherwise.^4,8,14 Objective data on the impact of PH involvement on patient and systems outcomes may help elucidate whether this is a perceived or actual lack of impact. Future metrics might include pain scores, patient centered care measures on communication and coordination, patient complaints and/or lawsuits, resource utilization and/or cost, readmission, and medical errors.

This study has several limitations. There is likely a (self) selection bias by surgeons with either strongly positive or negative views of PH involvement. Future studies may target a random sampling of programs rather than a cross-sectional survey of individual providers. Relatively few respondents represented community hospitals, possibly because these facilities are staffed by general OS and general surgeons¹⁰ who were not included in this sample.

Given the high prevalence of PH involvement in caring for surgical pediatric patients in varied settings, the field of pediatric hospital medicine should support increased PH training and standardized practice around perioperative management, particularly for medically complex patients with increased care coordination needs. Surgical comanagement, including interdisciplinary communication skills, deserves inclusion as a PH core competency and as an entrustable professional activity for pediatric hospital medicine and pediatric graduate medical education programs,¹⁵ especially orthopedic surgeries.

Further research on effective and evidence-based pediatric postoperative care and collaboration models will help PH and surgeons to most effectively and respectfully partner to improve care.

Acknowledgments

The authors thank the members of the AAP Section on Hospital Medicine Surgical Care Subcommittee, AAP SOHM leadership, and Ms. Alexandra Case.

Disclosure 

The authors have no conflicts of interest relevant to this manuscript to report. This study was supported in part by the Agency for Health Care Research and Quality (LM, R00HS022198).

Pediatric expertise is critical in caring for children during the perioperative and postoperative periods.^1,2 Some postoperative care models involve pediatric hospitalists (PH) as collaborators for global care (comanagement),³ as consultants for specific issues, or not at all.

Single-site studies in specific pediatric surgical populations^4-7and medically fragile adults⁸ suggest improved outcomes for patients and systems by using hospitalist-surgeon collaboration. However, including PH in the care of surgical patients may also disrupt systems. No studies have broadly examined the clinical relationships between surgeons and PH.

The aims of this cross-sectional survey of US pediatric surgeons (PS) and pediatric orthopedic surgeons (OS) were to understand (1) the prevalence and characteristics of surgical care models in pediatrics, specifically those involving PH, and (2) surgeons’ perceptions of PH in caring for surgical patients.

The target US surgeon population was the estimated 850 active PS and at least 600 pediatric OS.⁹ Most US PS (n = 606) are affiliated with the American Academy of Pediatrics (AAP) Section on Surgery (SoSu), representing at least 200 programs. Nearly all pediatric OS belong to the Pediatric Orthopedic Society of North America (POSNA) (n = 706), representing 340 programs; a subset (n = 130) also belong to the AAP SoSu.

Survey Development and Distribution

Survey questions were developed to elicit surgeons’ descriptions of their program structure and their perceptions of PH involvement. For programs with PH involvement, program variables included primary assignment of clinical responsibilities by service line (surgery, hospitalist, shared) and use of a written service agreement, which defines each service’s roles and responsibilities.

The web-based survey, created by using Survey Monkey (San Mateo, CA), was pilot tested for usability and clarity among 8 surgeons and 1 PH. The survey had logic points around involvement of hospitalists and multiple hospital affiliations (supplemental Appendix A). The survey request with a web-based link was e-mailed 3 times to surgical and orthopedic distribution outlets, endorsed by organizational leadership. Respondents’ hospital ZIP codes were used as a proxy for program. If there was more than 1 complete survey response per ZIP code, 1 response with complete data was randomly selected to ensure a unique entry per program.

Classification of Care Models

Each surgical program was classified into 1 of the following 3 categories based on reported care of primary surgical patients: (1) comanagement, described as PH writing orders and/or functioning as the primary service; (2) consultation, described as PH providing clinical recommendations only; and (3) no PH involvement, described as “rarely” or “never” involving PH.

Clinical Responsibility Score

To estimate the degree of hospitalist involvement, we devised and calculated a composite score of service responsibilities for each program. This score involved the following 7 clinical domains: management of fluids or nutrition, pain, comorbidities, antibiotics, medication dosing, wound care, and discharge planning. Scores were summed for each domain: 0 for surgical team primary responsibility, 1 for shared surgical and hospitalist responsibility, and 2 for hospitalist primary responsibility. Composite scores could range from 0 to 14; lower scores represented a stronger tendency for surgeon management, and higher scores represented a stronger tendency toward PH management.

Data Analysis

For data analysis, simple exploratory tests with χ² analysis and Student t tests were performed by using Stata 14.2 (StataCorp LLC, College Station, TX) to compare differences by surgical specialty programs and individuals by role assignment and perceptions of PH involvement.

The NYU School of Medicine Institutional Review Board approved this study.

Respondents and Programs

Among the unique 185 PS programs and 212 OS programs represented, PH were often engaged in the care of primary surgical patients (Table).

Roles of PH in Collaborative Programs

Among programs that reported any hospitalist involvement (PS, n = 100; OS, n = 157), few (≤15%) programs involved hospitalists with all patients. Pediatric OS programs were significantly more likely than pediatric surgical programs to involve PH for healthy patients with any high-risk surgery (27% vs 9%; P = .001). Most PS (64%) and OS (83%) reported involving PH for all medically complex patients, regardless of surgery risk (P = .003).

In programs involving PH, few PS (11%) or OS programs (16%) reported by using a written service agreement.

Care of Surgical Patients in PH-involved programs

Composite clinical responsibility scores ranged from 0 to 8, with a median score of 2.3 (interquartile range [IQR] 0-3) for consultation programs and 5 (IQR 1-7) for comanagement programs. Composite scores were higher for OS (7.4; SD 3.4) versus PS (3.3; SD 3.4) programs (P < .001; 95% CI, 3.3-5.5; supplemental Appendix C).

Surgeons’ Perspectives on Hospitalist Involvement

Surgeons in programs without PH involvement viewed PH overall impact less positively than those with PH (27% vs 58%). Among all surgeons surveyed, few perceived positive (agree/strongly agree) PH impact on pain management (<15%) or decreasing LOS (<15%; supplemental Appendix D).

Most surgeons (n = 355) believed that PH financial support should come from separate billing (“patient fee”) (48%) or hospital budget (36%). Only 17% endorsed PH receiving part of the surgical global fee, with no significant difference by surgical specialty or current PH involvement status.

This study is the first comprehensive assessment of surgeons’ perspectives on the involvement and effectiveness of PH in the postoperative care of children undergoing inpatient general or orthopedic surgeries. The high prevalence (>70%) of PH involvement among responding surgical programs suggests that PH comanagement of hospitalized patients merits attention from providers, systems, educators, and payors.

Collaboration and Roles are Correlated with Surgical Specialty and Setting

Forty percent of inpatient pediatric surgeries occur outside of children’s hospitals.¹⁰ We found that PH involvement was higher at smaller and general hospitals where PH may provide pediatric expertise when insufficient pediatric resources, like pain teams, exist.⁷ Alternately, some quaternary centers have dedicated surgical hospitalists. The extensive involvement of PH in the bulk of certain clinical care domains, especially care coordination, in OS and in many PS programs (Figure) suggests that PH are well integrated into many programs and provide essential clinical care.

In many large freestanding children’s hospitals, though, surgical teams may have sufficient depth and breadth to manage most aspects of care. There may be an exception for care coordination of medically complex patients. Care coordination is a patient- and family-centered care best practice,¹¹ encompasses integrating and aligning medical care among clinical services, and is focused on shared decision making and communication. High-quality care coordination processes are of great value to patients and families, especially in medically complex children,¹¹ and are associated with improved transitions from hospital to home.¹² Well-planned transitions likely decrease these special populations’ postoperative readmission risk, complications, and prolonged length of stay.¹³ Reimbursement for these services could integrate these contributions needed for safe and patient-centered pediatric inpatient surgical care.

Perceptions of PH Impact

The variation in perception of PH by surgical specialty, with higher prevalence as well as higher regard for PH among OS, is intriguing. This disparity may reflect current training and clinical expectations of each surgical specialty, with larger emphasis on medical management for surgical compared with orthopedic curricula (www.acgme.org).

While PS and OS respondents perceived that PH involvement did not influence length of stay, pain management, and resource use, single-site studies suggest otherwise.^4,8,14 Objective data on the impact of PH involvement on patient and systems outcomes may help elucidate whether this is a perceived or actual lack of impact. Future metrics might include pain scores, patient centered care measures on communication and coordination, patient complaints and/or lawsuits, resource utilization and/or cost, readmission, and medical errors.

This study has several limitations. There is likely a (self) selection bias by surgeons with either strongly positive or negative views of PH involvement. Future studies may target a random sampling of programs rather than a cross-sectional survey of individual providers. Relatively few respondents represented community hospitals, possibly because these facilities are staffed by general OS and general surgeons¹⁰ who were not included in this sample.

Given the high prevalence of PH involvement in caring for surgical pediatric patients in varied settings, the field of pediatric hospital medicine should support increased PH training and standardized practice around perioperative management, particularly for medically complex patients with increased care coordination needs. Surgical comanagement, including interdisciplinary communication skills, deserves inclusion as a PH core competency and as an entrustable professional activity for pediatric hospital medicine and pediatric graduate medical education programs,¹⁵ especially orthopedic surgeries.

Further research on effective and evidence-based pediatric postoperative care and collaboration models will help PH and surgeons to most effectively and respectfully partner to improve care.

Acknowledgments

The authors thank the members of the AAP Section on Hospital Medicine Surgical Care Subcommittee, AAP SOHM leadership, and Ms. Alexandra Case.

Disclosure 

The authors have no conflicts of interest relevant to this manuscript to report. This study was supported in part by the Agency for Health Care Research and Quality (LM, R00HS022198).

Pediatric expertise is critical in caring for children during the perioperative and postoperative periods.^1,2 Some postoperative care models involve pediatric hospitalists (PH) as collaborators for global care (comanagement),³ as consultants for specific issues, or not at all.

Single-site studies in specific pediatric surgical populations^4-7and medically fragile adults⁸ suggest improved outcomes for patients and systems by using hospitalist-surgeon collaboration. However, including PH in the care of surgical patients may also disrupt systems. No studies have broadly examined the clinical relationships between surgeons and PH.

The aims of this cross-sectional survey of US pediatric surgeons (PS) and pediatric orthopedic surgeons (OS) were to understand (1) the prevalence and characteristics of surgical care models in pediatrics, specifically those involving PH, and (2) surgeons’ perceptions of PH in caring for surgical patients.

The target US surgeon population was the estimated 850 active PS and at least 600 pediatric OS.⁹ Most US PS (n = 606) are affiliated with the American Academy of Pediatrics (AAP) Section on Surgery (SoSu), representing at least 200 programs. Nearly all pediatric OS belong to the Pediatric Orthopedic Society of North America (POSNA) (n = 706), representing 340 programs; a subset (n = 130) also belong to the AAP SoSu.

Survey Development and Distribution

Survey questions were developed to elicit surgeons’ descriptions of their program structure and their perceptions of PH involvement. For programs with PH involvement, program variables included primary assignment of clinical responsibilities by service line (surgery, hospitalist, shared) and use of a written service agreement, which defines each service’s roles and responsibilities.

The web-based survey, created by using Survey Monkey (San Mateo, CA), was pilot tested for usability and clarity among 8 surgeons and 1 PH. The survey had logic points around involvement of hospitalists and multiple hospital affiliations (supplemental Appendix A). The survey request with a web-based link was e-mailed 3 times to surgical and orthopedic distribution outlets, endorsed by organizational leadership. Respondents’ hospital ZIP codes were used as a proxy for program. If there was more than 1 complete survey response per ZIP code, 1 response with complete data was randomly selected to ensure a unique entry per program.

Classification of Care Models

Each surgical program was classified into 1 of the following 3 categories based on reported care of primary surgical patients: (1) comanagement, described as PH writing orders and/or functioning as the primary service; (2) consultation, described as PH providing clinical recommendations only; and (3) no PH involvement, described as “rarely” or “never” involving PH.

Clinical Responsibility Score

To estimate the degree of hospitalist involvement, we devised and calculated a composite score of service responsibilities for each program. This score involved the following 7 clinical domains: management of fluids or nutrition, pain, comorbidities, antibiotics, medication dosing, wound care, and discharge planning. Scores were summed for each domain: 0 for surgical team primary responsibility, 1 for shared surgical and hospitalist responsibility, and 2 for hospitalist primary responsibility. Composite scores could range from 0 to 14; lower scores represented a stronger tendency for surgeon management, and higher scores represented a stronger tendency toward PH management.

Data Analysis

For data analysis, simple exploratory tests with χ² analysis and Student t tests were performed by using Stata 14.2 (StataCorp LLC, College Station, TX) to compare differences by surgical specialty programs and individuals by role assignment and perceptions of PH involvement.

The NYU School of Medicine Institutional Review Board approved this study.

Respondents and Programs

Among the unique 185 PS programs and 212 OS programs represented, PH were often engaged in the care of primary surgical patients (Table).

Roles of PH in Collaborative Programs

Among programs that reported any hospitalist involvement (PS, n = 100; OS, n = 157), few (≤15%) programs involved hospitalists with all patients. Pediatric OS programs were significantly more likely than pediatric surgical programs to involve PH for healthy patients with any high-risk surgery (27% vs 9%; P = .001). Most PS (64%) and OS (83%) reported involving PH for all medically complex patients, regardless of surgery risk (P = .003).

In programs involving PH, few PS (11%) or OS programs (16%) reported by using a written service agreement.

Care of Surgical Patients in PH-involved programs

Composite clinical responsibility scores ranged from 0 to 8, with a median score of 2.3 (interquartile range [IQR] 0-3) for consultation programs and 5 (IQR 1-7) for comanagement programs. Composite scores were higher for OS (7.4; SD 3.4) versus PS (3.3; SD 3.4) programs (P < .001; 95% CI, 3.3-5.5; supplemental Appendix C).

Surgeons’ Perspectives on Hospitalist Involvement

Surgeons in programs without PH involvement viewed PH overall impact less positively than those with PH (27% vs 58%). Among all surgeons surveyed, few perceived positive (agree/strongly agree) PH impact on pain management (<15%) or decreasing LOS (<15%; supplemental Appendix D).

Most surgeons (n = 355) believed that PH financial support should come from separate billing (“patient fee”) (48%) or hospital budget (36%). Only 17% endorsed PH receiving part of the surgical global fee, with no significant difference by surgical specialty or current PH involvement status.

This study is the first comprehensive assessment of surgeons’ perspectives on the involvement and effectiveness of PH in the postoperative care of children undergoing inpatient general or orthopedic surgeries. The high prevalence (>70%) of PH involvement among responding surgical programs suggests that PH comanagement of hospitalized patients merits attention from providers, systems, educators, and payors.

Collaboration and Roles are Correlated with Surgical Specialty and Setting

Forty percent of inpatient pediatric surgeries occur outside of children’s hospitals.¹⁰ We found that PH involvement was higher at smaller and general hospitals where PH may provide pediatric expertise when insufficient pediatric resources, like pain teams, exist.⁷ Alternately, some quaternary centers have dedicated surgical hospitalists. The extensive involvement of PH in the bulk of certain clinical care domains, especially care coordination, in OS and in many PS programs (Figure) suggests that PH are well integrated into many programs and provide essential clinical care.

In many large freestanding children’s hospitals, though, surgical teams may have sufficient depth and breadth to manage most aspects of care. There may be an exception for care coordination of medically complex patients. Care coordination is a patient- and family-centered care best practice,¹¹ encompasses integrating and aligning medical care among clinical services, and is focused on shared decision making and communication. High-quality care coordination processes are of great value to patients and families, especially in medically complex children,¹¹ and are associated with improved transitions from hospital to home.¹² Well-planned transitions likely decrease these special populations’ postoperative readmission risk, complications, and prolonged length of stay.¹³ Reimbursement for these services could integrate these contributions needed for safe and patient-centered pediatric inpatient surgical care.

Perceptions of PH Impact

The variation in perception of PH by surgical specialty, with higher prevalence as well as higher regard for PH among OS, is intriguing. This disparity may reflect current training and clinical expectations of each surgical specialty, with larger emphasis on medical management for surgical compared with orthopedic curricula (www.acgme.org).

While PS and OS respondents perceived that PH involvement did not influence length of stay, pain management, and resource use, single-site studies suggest otherwise.^4,8,14 Objective data on the impact of PH involvement on patient and systems outcomes may help elucidate whether this is a perceived or actual lack of impact. Future metrics might include pain scores, patient centered care measures on communication and coordination, patient complaints and/or lawsuits, resource utilization and/or cost, readmission, and medical errors.

This study has several limitations. There is likely a (self) selection bias by surgeons with either strongly positive or negative views of PH involvement. Future studies may target a random sampling of programs rather than a cross-sectional survey of individual providers. Relatively few respondents represented community hospitals, possibly because these facilities are staffed by general OS and general surgeons¹⁰ who were not included in this sample.

Given the high prevalence of PH involvement in caring for surgical pediatric patients in varied settings, the field of pediatric hospital medicine should support increased PH training and standardized practice around perioperative management, particularly for medically complex patients with increased care coordination needs. Surgical comanagement, including interdisciplinary communication skills, deserves inclusion as a PH core competency and as an entrustable professional activity for pediatric hospital medicine and pediatric graduate medical education programs,¹⁵ especially orthopedic surgeries.

Further research on effective and evidence-based pediatric postoperative care and collaboration models will help PH and surgeons to most effectively and respectfully partner to improve care.

Acknowledgments

The authors thank the members of the AAP Section on Hospital Medicine Surgical Care Subcommittee, AAP SOHM leadership, and Ms. Alexandra Case.

Disclosure 

The authors have no conflicts of interest relevant to this manuscript to report. This study was supported in part by the Agency for Health Care Research and Quality (LM, R00HS022198).

Since the Accreditation Council for Graduate Medical Education (ACGME) posed new duty hour regulations in 2003 and again in 2011, there have been concerns that the substantial compression of resident workload may have resulted in a negative learning environment.^1-3 Residents are now expected to complete more work in a reduced amount of time and with less flexibility.⁴ In addition to time constraints, the actual work of a resident today may differ from that of a resident in the past, especially in the area of clinical documentation.⁵ Restricting resident work hours without examining the workload may result in increased work intensity and counter the potential benefits of working fewer hours.⁶ Measuring workload, as well as electronic health record (EHR)–related stress, may also help combat burnout in internal medicine.⁷ There are many components that influence resident workload, including patient census, patient comorbidities and acuity,EHR data and other available documentation, and ancillary tasks and procedures.⁷ We define resident workload intensity as the responsibilities required to provide patient care within a specified time. There is a paucity of objective data regarding the workload intensity of residents, which are essential to graduate medical education reform and optimization. Patient census, ancillary responsibilities, number of procedures, and conference length and frequency are some of the variables that can be adjusted by each residency program. As a first step to objective measurement of resident workload intensity, we endeavored to evaluate the less easily residency program–controlled workload components of patient comorbidity and EHR data the time of patient admission.

We conducted an observational, retrospective assessment of all admissions to the Louis Stokes Cleveland VA Medical Center (LSCVAMC) internal medicine service from January 1, 2000 to December 31, 2015. The inclusion criteria were admission to non-ICU internal medicine services and an admission note written by a resident physician. Otherwise, there were no exclusions. Data were accessed using VA Informatics and Computing Infrastructure. This study was approved by the LSCVAMC institutional review board.

A total of 67,346 admissions were included in the analysis. All parameters increased from 2000 to 2015. Mean CCI increased from 1.60 in 2003 (95% CI, 1.54–1.65) to 3.05 in 2011 (95% CI, 2.97–3.13) and to 3.77 in 2015 (95% CI, 3.67–3.87). Mean number of comorbidities increased from 6.21 in 2003 (95% CI, 6.05–6.36) to 16.09 in 2011 (95% CI, 15.84–16.34) and to 19.89 in 2015 (95% CI, 19.57–20.21). Mean number of notes increased from 193 in 2003 (95% CI, 186–199) to 841 in 2011 (95% CI, 815–868) and to 1289 in 2015 (95% CI, 1243–1335). Mean number of medications increased from 8.37 in 2003 (95% CI, 8.15–8.59) to 16.89 in 2011 (95% CI 16.60–17.20) and decreased to 16.49 in 2015 (95% CI, 16.18–16.80). Mean number of discharge summaries available at admission increased from 2.29 in 2003 (95% CI, 2.19–2.38) to 4.42 in 2011 (95% CI, 4.27–4.58) and to 5.48 in 2015 (95% CI, 5.27–5.69).

This retrospective, observational study shows that patient comorbidity and EHR data burden have increased over time, both of which impact resident workload at the time of admission. These findings, combined with the duty hour regulations, suggest that resident workload intensity at the time of admission may be increasing over time.

Patient comorbidity has likely increased due to a combination of factors. Elective admissions have decreased, and demographics have changed consistent with an aging population. Trainee admissions patterns also have changed over time, with less-acute admissions often admitted to nonacademic providers. Additionally, there are more stringent requirements for inpatient admissions, resulting in higher acuity and comorbidity.

As EHRs have matured and documentation requirements have expanded, the amount of electronic data has grown per patient, substantially increasing the time required to review a patient’s medical record.^5,10 In our evaluation, all EHR metrics increased between 2003 and 2011. The only metric that did not increase between 2011 and 2015 was the mean number of medications. The number of notes per patient has shown a dramatic increase. Even in an EHR that has reached maturity (in use more than 10 years), the number of notes per patient still increased by greater than 50% between 2011 and 2015. The VA EHR has been in use for more than 15 years, making it an ideal resource to study data trends. As many EHRs are in their infancy in comparison, these data may serve as a predictor of how other EHRs will mature. While all notes are not reviewed at every admission, this illustrates how increasing data burden combined with poor usability can be time consuming and promote inefficient patient care.¹¹ Moreover, many argue that poor EHR usability also affects cognitive workflow and clinical decision making, a task that is of utmost value to patient quality and safety as well as resident education.¹²Common program requirements for internal medicine as set forth by the ACGME state that residency programs should give adequate attention to scheduling, work intensity, and work compression to optimize resident well-being and prevent burnout.¹³ Resident workload intensity is multifaceted and encompasses many elements, including patient census and acuity, EHR data assessment, components of patient complexity such as comorbidity and psychosocial situation, and time.¹³ The work intensity increases with increase in the overall patient census, complexity, acuity, or data burden. Similarly, work intensity increases with time restrictions for patient care (in the form of duty hours). In addition, work intensity is affected by the time allotted for nonclinical responsibilities, such as morning reports and conferences, as these decrease the amount of time a resident can spend providing patient care.

Many programs have responded to the duty hour restrictions by decreasing patient caps.¹⁴ Our data suggest that decreasing patient census alone may not adequately mitigate the workload intensity of residents. There are other alternatives to prevent the increasing workload intensity that may have already been employed by some institutions. One such method is that programs can take into account patient complexity or acuity when allocating patients to teaching teams.¹⁴ Another method is to adjust the time spent on ancillary tasks such as obtaining outside hospital records, transporting patients, and scheduling follow-up appointments. Foregoing routine conferences such as morning reports or noon conferences would decrease work intensity, although obviously at the expense of resident education. Geographic rounding can encourage more efficient use of clinical time. One of the most difficult, but potentially impactful strategies would be to streamline EHRs to simplify and speed documentation, refocus regulations, and support and build based on the view of clinicians.¹⁵

The main limitations of this study include its retrospective design, single-center site, and focus on the internal medicine admissions to a VA hospital. Therefore, these findings may not be generalizable to other patient populations and training programs. Another potential limitation may be that changes in documentation practices have led to “upcoding” of patient comorbidy within the EHR. In addition, in this study, we looked only at the data available at the time of admission. To get a more complete picture of true workload intensity, understanding the day-to-day metrics of inpatient care would be crucial.

Our study demonstrates that components of resident workload (patient comorbidity and EHR data burden), specifically at the time of admission, have increased over time. These findings, combined with the duty hour regulations, suggest resident workload intensity at the time of admission has increased over time. This can have significant implications regarding graduate medical education, patient safety, and burnout. To optimize resident workload, innovation will be required in the areas of workflow, informatics, and curriculum. Future studies to assess the workload and intensity of the course of the entire patient hospitalization are needed.

The authors thank Paul E. Drawz, MD, MHS, MS (University of Minnesota) for contributions in designing and reviewing the study.

Ethical approval: The study was approved by the Institutional Review Board at the LSCVAMC. The contents do not represent the views of the U.S. Department of Veterans Affairs or the U.S. government. This material is the result of work supported with resources and the use of facilities of the LSCVAMC.

Disclosures

The authors declare that they have no conflicts of interest to disclose.

Since the Accreditation Council for Graduate Medical Education (ACGME) posed new duty hour regulations in 2003 and again in 2011, there have been concerns that the substantial compression of resident workload may have resulted in a negative learning environment.^1-3 Residents are now expected to complete more work in a reduced amount of time and with less flexibility.⁴ In addition to time constraints, the actual work of a resident today may differ from that of a resident in the past, especially in the area of clinical documentation.⁵ Restricting resident work hours without examining the workload may result in increased work intensity and counter the potential benefits of working fewer hours.⁶ Measuring workload, as well as electronic health record (EHR)–related stress, may also help combat burnout in internal medicine.⁷ There are many components that influence resident workload, including patient census, patient comorbidities and acuity,EHR data and other available documentation, and ancillary tasks and procedures.⁷ We define resident workload intensity as the responsibilities required to provide patient care within a specified time. There is a paucity of objective data regarding the workload intensity of residents, which are essential to graduate medical education reform and optimization. Patient census, ancillary responsibilities, number of procedures, and conference length and frequency are some of the variables that can be adjusted by each residency program. As a first step to objective measurement of resident workload intensity, we endeavored to evaluate the less easily residency program–controlled workload components of patient comorbidity and EHR data the time of patient admission.

We conducted an observational, retrospective assessment of all admissions to the Louis Stokes Cleveland VA Medical Center (LSCVAMC) internal medicine service from January 1, 2000 to December 31, 2015. The inclusion criteria were admission to non-ICU internal medicine services and an admission note written by a resident physician. Otherwise, there were no exclusions. Data were accessed using VA Informatics and Computing Infrastructure. This study was approved by the LSCVAMC institutional review board.

A total of 67,346 admissions were included in the analysis. All parameters increased from 2000 to 2015. Mean CCI increased from 1.60 in 2003 (95% CI, 1.54–1.65) to 3.05 in 2011 (95% CI, 2.97–3.13) and to 3.77 in 2015 (95% CI, 3.67–3.87). Mean number of comorbidities increased from 6.21 in 2003 (95% CI, 6.05–6.36) to 16.09 in 2011 (95% CI, 15.84–16.34) and to 19.89 in 2015 (95% CI, 19.57–20.21). Mean number of notes increased from 193 in 2003 (95% CI, 186–199) to 841 in 2011 (95% CI, 815–868) and to 1289 in 2015 (95% CI, 1243–1335). Mean number of medications increased from 8.37 in 2003 (95% CI, 8.15–8.59) to 16.89 in 2011 (95% CI 16.60–17.20) and decreased to 16.49 in 2015 (95% CI, 16.18–16.80). Mean number of discharge summaries available at admission increased from 2.29 in 2003 (95% CI, 2.19–2.38) to 4.42 in 2011 (95% CI, 4.27–4.58) and to 5.48 in 2015 (95% CI, 5.27–5.69).

This retrospective, observational study shows that patient comorbidity and EHR data burden have increased over time, both of which impact resident workload at the time of admission. These findings, combined with the duty hour regulations, suggest that resident workload intensity at the time of admission may be increasing over time.

Patient comorbidity has likely increased due to a combination of factors. Elective admissions have decreased, and demographics have changed consistent with an aging population. Trainee admissions patterns also have changed over time, with less-acute admissions often admitted to nonacademic providers. Additionally, there are more stringent requirements for inpatient admissions, resulting in higher acuity and comorbidity.

As EHRs have matured and documentation requirements have expanded, the amount of electronic data has grown per patient, substantially increasing the time required to review a patient’s medical record.^5,10 In our evaluation, all EHR metrics increased between 2003 and 2011. The only metric that did not increase between 2011 and 2015 was the mean number of medications. The number of notes per patient has shown a dramatic increase. Even in an EHR that has reached maturity (in use more than 10 years), the number of notes per patient still increased by greater than 50% between 2011 and 2015. The VA EHR has been in use for more than 15 years, making it an ideal resource to study data trends. As many EHRs are in their infancy in comparison, these data may serve as a predictor of how other EHRs will mature. While all notes are not reviewed at every admission, this illustrates how increasing data burden combined with poor usability can be time consuming and promote inefficient patient care.¹¹ Moreover, many argue that poor EHR usability also affects cognitive workflow and clinical decision making, a task that is of utmost value to patient quality and safety as well as resident education.¹²Common program requirements for internal medicine as set forth by the ACGME state that residency programs should give adequate attention to scheduling, work intensity, and work compression to optimize resident well-being and prevent burnout.¹³ Resident workload intensity is multifaceted and encompasses many elements, including patient census and acuity, EHR data assessment, components of patient complexity such as comorbidity and psychosocial situation, and time.¹³ The work intensity increases with increase in the overall patient census, complexity, acuity, or data burden. Similarly, work intensity increases with time restrictions for patient care (in the form of duty hours). In addition, work intensity is affected by the time allotted for nonclinical responsibilities, such as morning reports and conferences, as these decrease the amount of time a resident can spend providing patient care.

Many programs have responded to the duty hour restrictions by decreasing patient caps.¹⁴ Our data suggest that decreasing patient census alone may not adequately mitigate the workload intensity of residents. There are other alternatives to prevent the increasing workload intensity that may have already been employed by some institutions. One such method is that programs can take into account patient complexity or acuity when allocating patients to teaching teams.¹⁴ Another method is to adjust the time spent on ancillary tasks such as obtaining outside hospital records, transporting patients, and scheduling follow-up appointments. Foregoing routine conferences such as morning reports or noon conferences would decrease work intensity, although obviously at the expense of resident education. Geographic rounding can encourage more efficient use of clinical time. One of the most difficult, but potentially impactful strategies would be to streamline EHRs to simplify and speed documentation, refocus regulations, and support and build based on the view of clinicians.¹⁵

The main limitations of this study include its retrospective design, single-center site, and focus on the internal medicine admissions to a VA hospital. Therefore, these findings may not be generalizable to other patient populations and training programs. Another potential limitation may be that changes in documentation practices have led to “upcoding” of patient comorbidy within the EHR. In addition, in this study, we looked only at the data available at the time of admission. To get a more complete picture of true workload intensity, understanding the day-to-day metrics of inpatient care would be crucial.

Our study demonstrates that components of resident workload (patient comorbidity and EHR data burden), specifically at the time of admission, have increased over time. These findings, combined with the duty hour regulations, suggest resident workload intensity at the time of admission has increased over time. This can have significant implications regarding graduate medical education, patient safety, and burnout. To optimize resident workload, innovation will be required in the areas of workflow, informatics, and curriculum. Future studies to assess the workload and intensity of the course of the entire patient hospitalization are needed.

The authors thank Paul E. Drawz, MD, MHS, MS (University of Minnesota) for contributions in designing and reviewing the study.

Ethical approval: The study was approved by the Institutional Review Board at the LSCVAMC. The contents do not represent the views of the U.S. Department of Veterans Affairs or the U.S. government. This material is the result of work supported with resources and the use of facilities of the LSCVAMC.

Disclosures

The authors declare that they have no conflicts of interest to disclose.

Since the Accreditation Council for Graduate Medical Education (ACGME) posed new duty hour regulations in 2003 and again in 2011, there have been concerns that the substantial compression of resident workload may have resulted in a negative learning environment.^1-3 Residents are now expected to complete more work in a reduced amount of time and with less flexibility.⁴ In addition to time constraints, the actual work of a resident today may differ from that of a resident in the past, especially in the area of clinical documentation.⁵ Restricting resident work hours without examining the workload may result in increased work intensity and counter the potential benefits of working fewer hours.⁶ Measuring workload, as well as electronic health record (EHR)–related stress, may also help combat burnout in internal medicine.⁷ There are many components that influence resident workload, including patient census, patient comorbidities and acuity,EHR data and other available documentation, and ancillary tasks and procedures.⁷ We define resident workload intensity as the responsibilities required to provide patient care within a specified time. There is a paucity of objective data regarding the workload intensity of residents, which are essential to graduate medical education reform and optimization. Patient census, ancillary responsibilities, number of procedures, and conference length and frequency are some of the variables that can be adjusted by each residency program. As a first step to objective measurement of resident workload intensity, we endeavored to evaluate the less easily residency program–controlled workload components of patient comorbidity and EHR data the time of patient admission.

We conducted an observational, retrospective assessment of all admissions to the Louis Stokes Cleveland VA Medical Center (LSCVAMC) internal medicine service from January 1, 2000 to December 31, 2015. The inclusion criteria were admission to non-ICU internal medicine services and an admission note written by a resident physician. Otherwise, there were no exclusions. Data were accessed using VA Informatics and Computing Infrastructure. This study was approved by the LSCVAMC institutional review board.

A total of 67,346 admissions were included in the analysis. All parameters increased from 2000 to 2015. Mean CCI increased from 1.60 in 2003 (95% CI, 1.54–1.65) to 3.05 in 2011 (95% CI, 2.97–3.13) and to 3.77 in 2015 (95% CI, 3.67–3.87). Mean number of comorbidities increased from 6.21 in 2003 (95% CI, 6.05–6.36) to 16.09 in 2011 (95% CI, 15.84–16.34) and to 19.89 in 2015 (95% CI, 19.57–20.21). Mean number of notes increased from 193 in 2003 (95% CI, 186–199) to 841 in 2011 (95% CI, 815–868) and to 1289 in 2015 (95% CI, 1243–1335). Mean number of medications increased from 8.37 in 2003 (95% CI, 8.15–8.59) to 16.89 in 2011 (95% CI 16.60–17.20) and decreased to 16.49 in 2015 (95% CI, 16.18–16.80). Mean number of discharge summaries available at admission increased from 2.29 in 2003 (95% CI, 2.19–2.38) to 4.42 in 2011 (95% CI, 4.27–4.58) and to 5.48 in 2015 (95% CI, 5.27–5.69).

This retrospective, observational study shows that patient comorbidity and EHR data burden have increased over time, both of which impact resident workload at the time of admission. These findings, combined with the duty hour regulations, suggest that resident workload intensity at the time of admission may be increasing over time.

Patient comorbidity has likely increased due to a combination of factors. Elective admissions have decreased, and demographics have changed consistent with an aging population. Trainee admissions patterns also have changed over time, with less-acute admissions often admitted to nonacademic providers. Additionally, there are more stringent requirements for inpatient admissions, resulting in higher acuity and comorbidity.

As EHRs have matured and documentation requirements have expanded, the amount of electronic data has grown per patient, substantially increasing the time required to review a patient’s medical record.^5,10 In our evaluation, all EHR metrics increased between 2003 and 2011. The only metric that did not increase between 2011 and 2015 was the mean number of medications. The number of notes per patient has shown a dramatic increase. Even in an EHR that has reached maturity (in use more than 10 years), the number of notes per patient still increased by greater than 50% between 2011 and 2015. The VA EHR has been in use for more than 15 years, making it an ideal resource to study data trends. As many EHRs are in their infancy in comparison, these data may serve as a predictor of how other EHRs will mature. While all notes are not reviewed at every admission, this illustrates how increasing data burden combined with poor usability can be time consuming and promote inefficient patient care.¹¹ Moreover, many argue that poor EHR usability also affects cognitive workflow and clinical decision making, a task that is of utmost value to patient quality and safety as well as resident education.¹²Common program requirements for internal medicine as set forth by the ACGME state that residency programs should give adequate attention to scheduling, work intensity, and work compression to optimize resident well-being and prevent burnout.¹³ Resident workload intensity is multifaceted and encompasses many elements, including patient census and acuity, EHR data assessment, components of patient complexity such as comorbidity and psychosocial situation, and time.¹³ The work intensity increases with increase in the overall patient census, complexity, acuity, or data burden. Similarly, work intensity increases with time restrictions for patient care (in the form of duty hours). In addition, work intensity is affected by the time allotted for nonclinical responsibilities, such as morning reports and conferences, as these decrease the amount of time a resident can spend providing patient care.

Many programs have responded to the duty hour restrictions by decreasing patient caps.¹⁴ Our data suggest that decreasing patient census alone may not adequately mitigate the workload intensity of residents. There are other alternatives to prevent the increasing workload intensity that may have already been employed by some institutions. One such method is that programs can take into account patient complexity or acuity when allocating patients to teaching teams.¹⁴ Another method is to adjust the time spent on ancillary tasks such as obtaining outside hospital records, transporting patients, and scheduling follow-up appointments. Foregoing routine conferences such as morning reports or noon conferences would decrease work intensity, although obviously at the expense of resident education. Geographic rounding can encourage more efficient use of clinical time. One of the most difficult, but potentially impactful strategies would be to streamline EHRs to simplify and speed documentation, refocus regulations, and support and build based on the view of clinicians.¹⁵

The main limitations of this study include its retrospective design, single-center site, and focus on the internal medicine admissions to a VA hospital. Therefore, these findings may not be generalizable to other patient populations and training programs. Another potential limitation may be that changes in documentation practices have led to “upcoding” of patient comorbidy within the EHR. In addition, in this study, we looked only at the data available at the time of admission. To get a more complete picture of true workload intensity, understanding the day-to-day metrics of inpatient care would be crucial.

Our study demonstrates that components of resident workload (patient comorbidity and EHR data burden), specifically at the time of admission, have increased over time. These findings, combined with the duty hour regulations, suggest resident workload intensity at the time of admission has increased over time. This can have significant implications regarding graduate medical education, patient safety, and burnout. To optimize resident workload, innovation will be required in the areas of workflow, informatics, and curriculum. Future studies to assess the workload and intensity of the course of the entire patient hospitalization are needed.

The authors thank Paul E. Drawz, MD, MHS, MS (University of Minnesota) for contributions in designing and reviewing the study.

Ethical approval: The study was approved by the Institutional Review Board at the LSCVAMC. The contents do not represent the views of the U.S. Department of Veterans Affairs or the U.S. government. This material is the result of work supported with resources and the use of facilities of the LSCVAMC.

Disclosures

The authors declare that they have no conflicts of interest to disclose.

The “Things We Do for No Reason” series reviews practices which have become common parts of hospital care but which may provide little value to our patients. Practices reviewed in the TWDFR series do not represent “black and white” conclusions or clinical practice standards, but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion. https://www.choosingwisely.org/

A 67-year-old man with acute myeloid leukemia who has recently completed a cycle of consolidation chemotherapy presents to the emergency room with fatigue and bruising. He is found to have pancytopenia due to chemotherapy. His absolute neutrophil count (ANC) is 380/mm³,and he has no symptoms or signs of infection. He is admitted for transfusion support and asks for a dinner tray. The provider reflexively prescribes a neutropenic diet.

Although aggressive chemotherapy regimens have significantly improved survival rates in patients with cancer, these intensive regimens put patients at risk for a number of complications, including severe, prolonged neutropenia. Patients with neutropenia, particularly those with ANC< 500/mm³, are at a significantly increased risk for infection. Common sites of infection include the blood stream, skin, lungs, urinary tract, and, particularly, the gastrointestinal tract.¹ Oncologists and dieticians first designed neutropenic diets, or low-bacteria diets, to limit the introduction of pathogenic microbes to the gastrointestinal system. Neutropenic diets typically limit the intake of fresh fruits, fresh vegetables, raw or undercooked meats and fish, and soft cheese made from unpasteurized milk. Despite the widespread recommendation of the neutropenic diet, no standardized guidelines exist, and the utilization of the diet and its contents vary widely among and within institutions.²

The neutropenic diet is a national phenomenon. A survey of 156 United States members of the Association of Community Cancer Centers revealed that 120 (78%) of the members had placed patients with neutropenia on restricted diets.² The triggers for prescription (neutropenia, or starting chemotherapy), ANC threshold for prescription, and duration of prescription (throughout chemotherapy or just when neutropenic) were not uniform. A majority of centers restricted fresh fruits, fresh vegetables, and raw eggs, while some locations also restricted tap water, herbs and spices, and alcoholic beverages.² Similarly, a study of practices in 29 countries across 6 continents found that 88% of centers have some version of a neutropenic diet guideline with significant heterogeneity in their prescription and content. For example, dried fruits were unrestricted in 23% of centers but were forbidden in 43%.³

The rationale behind the neutropenic diet is to limit the bacterial load delivered to the gut. Studies have shown that organisms such as Enterobacter, Pseudomonas, and Klebsiella have been isolated from food, particularly fruits and vegetables.^4,5 The ingestion of contaminated food products may serve as a source of pathogenic bacteria, which may cause potentially life-threatening infections. Mucositis, a common complication among cancer patients receiving therapy, predisposes patients to infection by disrupting the mucosal barrier, allowing bacteria to translocate from the gut to the bloodstream. Given that neutropenia and mucositis often occur simultaneously, these patients are at an increased risk of infections.⁶ Cooking destroys bacteria if present, rendering cooked foods safe. Thus, the avoidance of fresh fruits and vegetables and other foods considered to have high bacterial loads should theoretically decrease the risk of infections in these patients.

Researchers have investigated the ability of the neutropenic diet to reduce infection in adult and pediatric neutropenic patients. A study involving 153 patients receiving chemotherapy for acute myeloid leukemia or myelodysplastic syndrome randomized 78 patients to a diet that restricted raw fruits and vegetables and 75 patients to a diet that included those foods.⁸ The groups had similar rates of major infection (29% in the cooked group versus 35% in the raw group, P = .60) with no difference in mortality.⁷ In a randomized, multiinstitutional trial of 150 pediatric oncology patients, 77 patients received a neutropenic diet plus a diet based on the food safety guidelines approved by the Food and Drug Administration (FDA), while 73 children received a diet based on FDA-approved food safety guidelines.⁸ Infection rates between the groups were not significantly different (35% vs 33% respectively, P = .78).

Intensive conditioning regimens place hematopoietic stem-cell transplant (HSCT) recipients at an even greater risk of infectious complications than other patients and may increase gastrointestinal toxicity and prolong neutropenia. A study from a single academic US center included 726 HSCT recipients, 363 of whom received a neutropenic diet and 363 of whom received a general diet. Significantly fewer infections were observed in the general diet group than in the neutropenic diet group. Notably, this study was a retrospective trial, and approximately 75% of participants were autologous HSCT recipients, who traditionally have low risks of infection. A survey and analysis of nonpharmacologic anti-infective measures in 339 children with leukemia enrolled in the multicenter Acute Myeloid Leukemia Berlin-Frankfurt-Munster 2004 trial also did not show that the neutropenic diet has protective effects on infection rates.⁹ A metaanalysis that compiled data from the studies mentioned above found the hazard ratio for any infection (major or minor) and fever was actually higher in the neutropenic diet arm (relative risk 1.18, 95% confidence interval: 1.05-1.34, P = .007) relative to that in the unrestricted arm.¹⁰

The inefficacy of the neutropenic diet may be attributed to the fact that many of the organisms found on fresh fruits and vegetables are part of the normal flora in the gastrointestinal tract. A Dutch prospective randomized pilot study of 20 adult patients with acute myeloid leukemia undergoing chemotherapy compared the gut flora in patients on a low-bacteria diet versus that in patients on a normal hospital diet. Gut colonization by potential pathogens or infection rates were not significantly different between the 2 groups.¹¹

In addition to mucositis, the common gastrointestinal complications of chemotherapy include nausea, vomiting, diarrhea, food aversions, and changes in smells and taste, which limit oral intake.¹² Unnecessary dietary restrictions can place patients at further risk of inadequate intake and malnutrition.¹³ In the outpatient setting, compliance with the neutropenic diet is also problematic. In 1 study of 28 patients educated about the neutropenic diet, only 16 (57%) were compliant with the diet as revealed through telephone-based assessments at 6 and 12 weeks, and infection rates were not different between compliant versus noncompliant patients.¹⁴ Patients and family members reported that following the neutropenic diet requires considerably more effort than following a less restrictive diet.⁸ Maintaining nutrition in this patient population is already challenging, and the restriction of a wide variety of food items (fresh fruits, vegetables, dairy, certain meats, eggs) can cause malnutrition, low patient satisfaction, and poor quality of life.^13,14

Evidence shows no benefit of the neutropenic diet in any particular clinical scenario or patient population. However, despite the dearth of evidence to support neutropenic diets, the overall data regarding neutropenic diets are sparse. Randomized control trials to date have been limited by their small size with possible confounding by the type of malignancy and cancer therapy; use of prophylactic antibiotics, growth factors, and air-filtered rooms; variation in contents and adherence to the prescribed diet; and inpatient versus outpatient status. The study that included HSCT recipients was a retrospective trial, and a majority of patients were autologous HSCT recipients.¹⁵ Although no study has specifically investigated the neutropenic diet in preventing infection in patients with noncancer-related neutropenia, no reason exists to suspect that it is helpful. The FDA advises safe food-handling practices for other immunocompromised patients, such as transplant recipients and patients with human immunodeficiency virus/acquired immunodeficiency syndrome, and the same principles can likely be applied to patients with noncancer-related neutropenia.

WHAT WE SHOULD DO INSTEAD

Although the neutropenic diet has not been proven beneficial, the prevention of food-borne infection in this population remains important. FDA-published guidelines, which promote safe food handling to prevent food contamination in patients with cancer, should be followed in inpatient and outpatient settings.¹⁶ These guidelines allow for fresh fruits and vegetables as long as they have been adequately washed. Cleaning (eg, cleaning the lids of canned foods before opening, hand washing), separating raw meats from other foods, cooking to the right temperature (eg, cooking eggs until the yolk and white are firm), and chilling/refrigerating food appropriately are strongly emphasized. These guidelines are also recommended by the American Dietetic Association. Despite additional flexibility, patients following the FDA diet guidelines do not have increased risk of infection.⁸ At our hospitals, the neutropenic diet can no longer be ordered. Neutropenic patients are free to consume all items on the general hospital menu, including eggs, meat, soft cheeses, nuts, and washed raw fruits and vegetables. The National Comprehensive Cancer Network guidelines for the prevention and treatment of cancer-related infections do not specifically address diet.¹⁷ We call upon them to note the lack of benefit and potential harm of the neutropenic diet in the guidelines. Such an action may persuade more institutions to abandon this practice.

RECOMMENDATIONS

• Neutropenic diets, or low-bacteria diets, should not be prescribed to neutropenic patients.
• Properly handled and adequately washed fresh fruits and vegetables can safely be consumed by patients with neutropenia.
• Patients and hospitals should follow FDA-published safe food-handling guidelines to prevent food contamination.

A general diet can be safely ordered for our patient in the presented clinical scenario. Available data from individual studies and pooled data provide no evidence that neutropenic diets prevent infectious complications in patients with neutropenia.

Hospital kitchens must adhere to the food-handling guidelines issued by the FDA, and following these guidelines should provide adequate protection against food-borne infection, even in patients who are immunocompromised. Instead of restricting food groups, the FDA guidelines focus on safe food-handling practices. Less dietary restrictions provide patient’s additional opportunities for balanced nutrition and for food choices based on personal preferences or cultural practices.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason?” Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason” topics by emailing [email protected].Disclosures: There are no financial or other disclosures for any author.

Disclosures

There are no financial or other disclosures for any author.

The “Things We Do for No Reason” series reviews practices which have become common parts of hospital care but which may provide little value to our patients. Practices reviewed in the TWDFR series do not represent “black and white” conclusions or clinical practice standards, but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion. https://www.choosingwisely.org/

A 67-year-old man with acute myeloid leukemia who has recently completed a cycle of consolidation chemotherapy presents to the emergency room with fatigue and bruising. He is found to have pancytopenia due to chemotherapy. His absolute neutrophil count (ANC) is 380/mm³,and he has no symptoms or signs of infection. He is admitted for transfusion support and asks for a dinner tray. The provider reflexively prescribes a neutropenic diet.

Although aggressive chemotherapy regimens have significantly improved survival rates in patients with cancer, these intensive regimens put patients at risk for a number of complications, including severe, prolonged neutropenia. Patients with neutropenia, particularly those with ANC< 500/mm³, are at a significantly increased risk for infection. Common sites of infection include the blood stream, skin, lungs, urinary tract, and, particularly, the gastrointestinal tract.¹ Oncologists and dieticians first designed neutropenic diets, or low-bacteria diets, to limit the introduction of pathogenic microbes to the gastrointestinal system. Neutropenic diets typically limit the intake of fresh fruits, fresh vegetables, raw or undercooked meats and fish, and soft cheese made from unpasteurized milk. Despite the widespread recommendation of the neutropenic diet, no standardized guidelines exist, and the utilization of the diet and its contents vary widely among and within institutions.²

The neutropenic diet is a national phenomenon. A survey of 156 United States members of the Association of Community Cancer Centers revealed that 120 (78%) of the members had placed patients with neutropenia on restricted diets.² The triggers for prescription (neutropenia, or starting chemotherapy), ANC threshold for prescription, and duration of prescription (throughout chemotherapy or just when neutropenic) were not uniform. A majority of centers restricted fresh fruits, fresh vegetables, and raw eggs, while some locations also restricted tap water, herbs and spices, and alcoholic beverages.² Similarly, a study of practices in 29 countries across 6 continents found that 88% of centers have some version of a neutropenic diet guideline with significant heterogeneity in their prescription and content. For example, dried fruits were unrestricted in 23% of centers but were forbidden in 43%.³

The rationale behind the neutropenic diet is to limit the bacterial load delivered to the gut. Studies have shown that organisms such as Enterobacter, Pseudomonas, and Klebsiella have been isolated from food, particularly fruits and vegetables.^4,5 The ingestion of contaminated food products may serve as a source of pathogenic bacteria, which may cause potentially life-threatening infections. Mucositis, a common complication among cancer patients receiving therapy, predisposes patients to infection by disrupting the mucosal barrier, allowing bacteria to translocate from the gut to the bloodstream. Given that neutropenia and mucositis often occur simultaneously, these patients are at an increased risk of infections.⁶ Cooking destroys bacteria if present, rendering cooked foods safe. Thus, the avoidance of fresh fruits and vegetables and other foods considered to have high bacterial loads should theoretically decrease the risk of infections in these patients.

Researchers have investigated the ability of the neutropenic diet to reduce infection in adult and pediatric neutropenic patients. A study involving 153 patients receiving chemotherapy for acute myeloid leukemia or myelodysplastic syndrome randomized 78 patients to a diet that restricted raw fruits and vegetables and 75 patients to a diet that included those foods.⁸ The groups had similar rates of major infection (29% in the cooked group versus 35% in the raw group, P = .60) with no difference in mortality.⁷ In a randomized, multiinstitutional trial of 150 pediatric oncology patients, 77 patients received a neutropenic diet plus a diet based on the food safety guidelines approved by the Food and Drug Administration (FDA), while 73 children received a diet based on FDA-approved food safety guidelines.⁸ Infection rates between the groups were not significantly different (35% vs 33% respectively, P = .78).

Intensive conditioning regimens place hematopoietic stem-cell transplant (HSCT) recipients at an even greater risk of infectious complications than other patients and may increase gastrointestinal toxicity and prolong neutropenia. A study from a single academic US center included 726 HSCT recipients, 363 of whom received a neutropenic diet and 363 of whom received a general diet. Significantly fewer infections were observed in the general diet group than in the neutropenic diet group. Notably, this study was a retrospective trial, and approximately 75% of participants were autologous HSCT recipients, who traditionally have low risks of infection. A survey and analysis of nonpharmacologic anti-infective measures in 339 children with leukemia enrolled in the multicenter Acute Myeloid Leukemia Berlin-Frankfurt-Munster 2004 trial also did not show that the neutropenic diet has protective effects on infection rates.⁹ A metaanalysis that compiled data from the studies mentioned above found the hazard ratio for any infection (major or minor) and fever was actually higher in the neutropenic diet arm (relative risk 1.18, 95% confidence interval: 1.05-1.34, P = .007) relative to that in the unrestricted arm.¹⁰

The inefficacy of the neutropenic diet may be attributed to the fact that many of the organisms found on fresh fruits and vegetables are part of the normal flora in the gastrointestinal tract. A Dutch prospective randomized pilot study of 20 adult patients with acute myeloid leukemia undergoing chemotherapy compared the gut flora in patients on a low-bacteria diet versus that in patients on a normal hospital diet. Gut colonization by potential pathogens or infection rates were not significantly different between the 2 groups.¹¹

In addition to mucositis, the common gastrointestinal complications of chemotherapy include nausea, vomiting, diarrhea, food aversions, and changes in smells and taste, which limit oral intake.¹² Unnecessary dietary restrictions can place patients at further risk of inadequate intake and malnutrition.¹³ In the outpatient setting, compliance with the neutropenic diet is also problematic. In 1 study of 28 patients educated about the neutropenic diet, only 16 (57%) were compliant with the diet as revealed through telephone-based assessments at 6 and 12 weeks, and infection rates were not different between compliant versus noncompliant patients.¹⁴ Patients and family members reported that following the neutropenic diet requires considerably more effort than following a less restrictive diet.⁸ Maintaining nutrition in this patient population is already challenging, and the restriction of a wide variety of food items (fresh fruits, vegetables, dairy, certain meats, eggs) can cause malnutrition, low patient satisfaction, and poor quality of life.^13,14

Evidence shows no benefit of the neutropenic diet in any particular clinical scenario or patient population. However, despite the dearth of evidence to support neutropenic diets, the overall data regarding neutropenic diets are sparse. Randomized control trials to date have been limited by their small size with possible confounding by the type of malignancy and cancer therapy; use of prophylactic antibiotics, growth factors, and air-filtered rooms; variation in contents and adherence to the prescribed diet; and inpatient versus outpatient status. The study that included HSCT recipients was a retrospective trial, and a majority of patients were autologous HSCT recipients.¹⁵ Although no study has specifically investigated the neutropenic diet in preventing infection in patients with noncancer-related neutropenia, no reason exists to suspect that it is helpful. The FDA advises safe food-handling practices for other immunocompromised patients, such as transplant recipients and patients with human immunodeficiency virus/acquired immunodeficiency syndrome, and the same principles can likely be applied to patients with noncancer-related neutropenia.

WHAT WE SHOULD DO INSTEAD

Although the neutropenic diet has not been proven beneficial, the prevention of food-borne infection in this population remains important. FDA-published guidelines, which promote safe food handling to prevent food contamination in patients with cancer, should be followed in inpatient and outpatient settings.¹⁶ These guidelines allow for fresh fruits and vegetables as long as they have been adequately washed. Cleaning (eg, cleaning the lids of canned foods before opening, hand washing), separating raw meats from other foods, cooking to the right temperature (eg, cooking eggs until the yolk and white are firm), and chilling/refrigerating food appropriately are strongly emphasized. These guidelines are also recommended by the American Dietetic Association. Despite additional flexibility, patients following the FDA diet guidelines do not have increased risk of infection.⁸ At our hospitals, the neutropenic diet can no longer be ordered. Neutropenic patients are free to consume all items on the general hospital menu, including eggs, meat, soft cheeses, nuts, and washed raw fruits and vegetables. The National Comprehensive Cancer Network guidelines for the prevention and treatment of cancer-related infections do not specifically address diet.¹⁷ We call upon them to note the lack of benefit and potential harm of the neutropenic diet in the guidelines. Such an action may persuade more institutions to abandon this practice.

RECOMMENDATIONS

• Neutropenic diets, or low-bacteria diets, should not be prescribed to neutropenic patients.
• Properly handled and adequately washed fresh fruits and vegetables can safely be consumed by patients with neutropenia.
• Patients and hospitals should follow FDA-published safe food-handling guidelines to prevent food contamination.

A general diet can be safely ordered for our patient in the presented clinical scenario. Available data from individual studies and pooled data provide no evidence that neutropenic diets prevent infectious complications in patients with neutropenia.

Hospital kitchens must adhere to the food-handling guidelines issued by the FDA, and following these guidelines should provide adequate protection against food-borne infection, even in patients who are immunocompromised. Instead of restricting food groups, the FDA guidelines focus on safe food-handling practices. Less dietary restrictions provide patient’s additional opportunities for balanced nutrition and for food choices based on personal preferences or cultural practices.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason?” Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason” topics by emailing [email protected].Disclosures: There are no financial or other disclosures for any author.

Disclosures

There are no financial or other disclosures for any author.

The “Things We Do for No Reason” series reviews practices which have become common parts of hospital care but which may provide little value to our patients. Practices reviewed in the TWDFR series do not represent “black and white” conclusions or clinical practice standards, but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion. https://www.choosingwisely.org/

A 67-year-old man with acute myeloid leukemia who has recently completed a cycle of consolidation chemotherapy presents to the emergency room with fatigue and bruising. He is found to have pancytopenia due to chemotherapy. His absolute neutrophil count (ANC) is 380/mm³,and he has no symptoms or signs of infection. He is admitted for transfusion support and asks for a dinner tray. The provider reflexively prescribes a neutropenic diet.

Although aggressive chemotherapy regimens have significantly improved survival rates in patients with cancer, these intensive regimens put patients at risk for a number of complications, including severe, prolonged neutropenia. Patients with neutropenia, particularly those with ANC< 500/mm³, are at a significantly increased risk for infection. Common sites of infection include the blood stream, skin, lungs, urinary tract, and, particularly, the gastrointestinal tract.¹ Oncologists and dieticians first designed neutropenic diets, or low-bacteria diets, to limit the introduction of pathogenic microbes to the gastrointestinal system. Neutropenic diets typically limit the intake of fresh fruits, fresh vegetables, raw or undercooked meats and fish, and soft cheese made from unpasteurized milk. Despite the widespread recommendation of the neutropenic diet, no standardized guidelines exist, and the utilization of the diet and its contents vary widely among and within institutions.²

The neutropenic diet is a national phenomenon. A survey of 156 United States members of the Association of Community Cancer Centers revealed that 120 (78%) of the members had placed patients with neutropenia on restricted diets.² The triggers for prescription (neutropenia, or starting chemotherapy), ANC threshold for prescription, and duration of prescription (throughout chemotherapy or just when neutropenic) were not uniform. A majority of centers restricted fresh fruits, fresh vegetables, and raw eggs, while some locations also restricted tap water, herbs and spices, and alcoholic beverages.² Similarly, a study of practices in 29 countries across 6 continents found that 88% of centers have some version of a neutropenic diet guideline with significant heterogeneity in their prescription and content. For example, dried fruits were unrestricted in 23% of centers but were forbidden in 43%.³

The rationale behind the neutropenic diet is to limit the bacterial load delivered to the gut. Studies have shown that organisms such as Enterobacter, Pseudomonas, and Klebsiella have been isolated from food, particularly fruits and vegetables.^4,5 The ingestion of contaminated food products may serve as a source of pathogenic bacteria, which may cause potentially life-threatening infections. Mucositis, a common complication among cancer patients receiving therapy, predisposes patients to infection by disrupting the mucosal barrier, allowing bacteria to translocate from the gut to the bloodstream. Given that neutropenia and mucositis often occur simultaneously, these patients are at an increased risk of infections.⁶ Cooking destroys bacteria if present, rendering cooked foods safe. Thus, the avoidance of fresh fruits and vegetables and other foods considered to have high bacterial loads should theoretically decrease the risk of infections in these patients.

Researchers have investigated the ability of the neutropenic diet to reduce infection in adult and pediatric neutropenic patients. A study involving 153 patients receiving chemotherapy for acute myeloid leukemia or myelodysplastic syndrome randomized 78 patients to a diet that restricted raw fruits and vegetables and 75 patients to a diet that included those foods.⁸ The groups had similar rates of major infection (29% in the cooked group versus 35% in the raw group, P = .60) with no difference in mortality.⁷ In a randomized, multiinstitutional trial of 150 pediatric oncology patients, 77 patients received a neutropenic diet plus a diet based on the food safety guidelines approved by the Food and Drug Administration (FDA), while 73 children received a diet based on FDA-approved food safety guidelines.⁸ Infection rates between the groups were not significantly different (35% vs 33% respectively, P = .78).

Intensive conditioning regimens place hematopoietic stem-cell transplant (HSCT) recipients at an even greater risk of infectious complications than other patients and may increase gastrointestinal toxicity and prolong neutropenia. A study from a single academic US center included 726 HSCT recipients, 363 of whom received a neutropenic diet and 363 of whom received a general diet. Significantly fewer infections were observed in the general diet group than in the neutropenic diet group. Notably, this study was a retrospective trial, and approximately 75% of participants were autologous HSCT recipients, who traditionally have low risks of infection. A survey and analysis of nonpharmacologic anti-infective measures in 339 children with leukemia enrolled in the multicenter Acute Myeloid Leukemia Berlin-Frankfurt-Munster 2004 trial also did not show that the neutropenic diet has protective effects on infection rates.⁹ A metaanalysis that compiled data from the studies mentioned above found the hazard ratio for any infection (major or minor) and fever was actually higher in the neutropenic diet arm (relative risk 1.18, 95% confidence interval: 1.05-1.34, P = .007) relative to that in the unrestricted arm.¹⁰

The inefficacy of the neutropenic diet may be attributed to the fact that many of the organisms found on fresh fruits and vegetables are part of the normal flora in the gastrointestinal tract. A Dutch prospective randomized pilot study of 20 adult patients with acute myeloid leukemia undergoing chemotherapy compared the gut flora in patients on a low-bacteria diet versus that in patients on a normal hospital diet. Gut colonization by potential pathogens or infection rates were not significantly different between the 2 groups.¹¹

In addition to mucositis, the common gastrointestinal complications of chemotherapy include nausea, vomiting, diarrhea, food aversions, and changes in smells and taste, which limit oral intake.¹² Unnecessary dietary restrictions can place patients at further risk of inadequate intake and malnutrition.¹³ In the outpatient setting, compliance with the neutropenic diet is also problematic. In 1 study of 28 patients educated about the neutropenic diet, only 16 (57%) were compliant with the diet as revealed through telephone-based assessments at 6 and 12 weeks, and infection rates were not different between compliant versus noncompliant patients.¹⁴ Patients and family members reported that following the neutropenic diet requires considerably more effort than following a less restrictive diet.⁸ Maintaining nutrition in this patient population is already challenging, and the restriction of a wide variety of food items (fresh fruits, vegetables, dairy, certain meats, eggs) can cause malnutrition, low patient satisfaction, and poor quality of life.^13,14

Evidence shows no benefit of the neutropenic diet in any particular clinical scenario or patient population. However, despite the dearth of evidence to support neutropenic diets, the overall data regarding neutropenic diets are sparse. Randomized control trials to date have been limited by their small size with possible confounding by the type of malignancy and cancer therapy; use of prophylactic antibiotics, growth factors, and air-filtered rooms; variation in contents and adherence to the prescribed diet; and inpatient versus outpatient status. The study that included HSCT recipients was a retrospective trial, and a majority of patients were autologous HSCT recipients.¹⁵ Although no study has specifically investigated the neutropenic diet in preventing infection in patients with noncancer-related neutropenia, no reason exists to suspect that it is helpful. The FDA advises safe food-handling practices for other immunocompromised patients, such as transplant recipients and patients with human immunodeficiency virus/acquired immunodeficiency syndrome, and the same principles can likely be applied to patients with noncancer-related neutropenia.

WHAT WE SHOULD DO INSTEAD

Although the neutropenic diet has not been proven beneficial, the prevention of food-borne infection in this population remains important. FDA-published guidelines, which promote safe food handling to prevent food contamination in patients with cancer, should be followed in inpatient and outpatient settings.¹⁶ These guidelines allow for fresh fruits and vegetables as long as they have been adequately washed. Cleaning (eg, cleaning the lids of canned foods before opening, hand washing), separating raw meats from other foods, cooking to the right temperature (eg, cooking eggs until the yolk and white are firm), and chilling/refrigerating food appropriately are strongly emphasized. These guidelines are also recommended by the American Dietetic Association. Despite additional flexibility, patients following the FDA diet guidelines do not have increased risk of infection.⁸ At our hospitals, the neutropenic diet can no longer be ordered. Neutropenic patients are free to consume all items on the general hospital menu, including eggs, meat, soft cheeses, nuts, and washed raw fruits and vegetables. The National Comprehensive Cancer Network guidelines for the prevention and treatment of cancer-related infections do not specifically address diet.¹⁷ We call upon them to note the lack of benefit and potential harm of the neutropenic diet in the guidelines. Such an action may persuade more institutions to abandon this practice.

RECOMMENDATIONS

• Neutropenic diets, or low-bacteria diets, should not be prescribed to neutropenic patients.
• Properly handled and adequately washed fresh fruits and vegetables can safely be consumed by patients with neutropenia.
• Patients and hospitals should follow FDA-published safe food-handling guidelines to prevent food contamination.

A general diet can be safely ordered for our patient in the presented clinical scenario. Available data from individual studies and pooled data provide no evidence that neutropenic diets prevent infectious complications in patients with neutropenia.

Hospital kitchens must adhere to the food-handling guidelines issued by the FDA, and following these guidelines should provide adequate protection against food-borne infection, even in patients who are immunocompromised. Instead of restricting food groups, the FDA guidelines focus on safe food-handling practices. Less dietary restrictions provide patient’s additional opportunities for balanced nutrition and for food choices based on personal preferences or cultural practices.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason?” Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason” topics by emailing [email protected].Disclosures: There are no financial or other disclosures for any author.

Disclosures

There are no financial or other disclosures for any author.

A 70-year-old man presented to the emergency department with 5 days of decreased appetite, frequent urination, tremors, and memory difficulties. He also reported 9 months of malaise, generalized weakness, and weight loss. There was no history of fever, chills, nausea, diarrhea, constipation, pain, or focal neurologic complaints.

This patient exemplifies a common clinical challenge: an older adult with several possibly unrelated concerns. In many patients, a new presentation is usually either a different manifestation of a known condition (eg, a complication of an established malignancy) or the emergence of something they are at risk for based on health behavior or other characteristics (eg, lung cancer in a smoker). The diagnostic process in older adults can be complicated because many have, or are at risk for, multiple chronic conditions.

After reviewing the timeline of symptoms, the presence of 9 months of symptoms suggests a chronic and progressive underlying process, perhaps with subsequent superimposition of an acute problem. Although it is not certain whether chronic and acute symptoms are caused by the same process, this assumption is reasonable. The superimposition of acute symptoms on a chronic process may represent progression of the underlying condition or an acute complication of the underlying disease. However, the patient’s chronic symptoms of malaise, weakness, and weight loss are nonspecific.

Although malignancy is a consideration given the age of the patient and time course of symptoms, attributing the symptoms to a specific pattern of disease or building a cogent differential diagnosis is difficult until additional information is obtained. One strategy is to try to localize the findings to 1 or more organ systems; for example, given that tremors and memory difficulties localize to the central nervous system, neurodegenerative disorders, such as “Parkinson plus” syndromes, and cerebellar disease are possible. However, this tactic still leaves a relatively broad set of symptoms without an immediate and clear unifying cause.

The patient’s medical history included hyperlipidemia, peripheral neuropathy, prostate cancer, and papillary bladder cancer. The patient was admitted to the hospital 4 months earlier for severe sepsis presumed secondary to a urinary tract infection, although bacterial cultures were sterile. His social history was notable for a 50 pack-year smoking history. Outpatient medications included alfuzosin, gabapentin, simvastatin, hydrocodone, and cholecalciferol. He used a Bright Light Therapy lamp for 1 hour per week and occasionally used calcium carbonate for indigestion. The patient’s sister had a history of throat cancer.

On examination, the patient was detected with blood pressure of 104/56 mm Hg, pulse of 85 beats per minute, temperature of 98.2 °F, oxygen saturation of 97% on ambient air, and body mass index of 18 kg/m². The patient appeared frail with mildly decreased strength in the upper and lower extremities bilaterally. The remainder of the physical examination was normal. Reflexes were symmetric, no tremors or rigidity was noted, sensation was intact to light touch, and the response to the Romberg maneuver was normal.

Past medical history is the cornerstone of the diagnostic process. The history of 2 different malignancies is the most striking element in this case. Papillary bladder cancer is usually a local process, but additional information is needed regarding its stage and previous treatment, including whether or not the patient received Bacille Calmette Guerin (BCG) vaccine, which can rarely be associated with infectious and inflammatory complications. Metastatic prostate cancer could certainly account for his symptomatology, and bladder outlet obstruction could explain the history of urinary frequency and probable urosepsis. His medication list suggested no obvious causes to explain his presentation, except that cholecalciferol and calcium carbonate, which when taken in excess, can cause hypercalcemia. This finding is of particular importance given that many of the patient’s symptoms, including polyuria, malaise, weakness, tremor, memory difficulties, anorexia, acute kidney injury and (indirectly) hypotension and weight loss, are also seen in patients with hypercalcemia. The relatively normal result of the neurologic examination decreases the probability of a primary neurologic disorder and increases the likelihood that his neurologic symptoms are due to a global systemic process. The relative hypotension and weight loss similarly support the possibility that the patient is experiencing a chronic and progressive process.

The differential diagnosis remains broad. An underlying malignancy would explain the chronic progressive course, and superimposed hypercalcemia would explain the acute symptoms of polyuria, tremor, and memory changes. Endocrinopathies including hyperthyroidism or adrenal insufficiency are other possibilities. A chronic progressive infection, such as tuberculosis, is possible, although no epidemiologic factors that increase his risk for this disease are present.

The patient had serum calcium of 14.5 mg/dL, ionized calcium of 3.46 mEq/L, albumin of 3.6 g/dL, BUN of 62 mg/dL, and creatinine of 3.9 mg/dL (all values were normal 3 months prior). His electrolytes and liver function were otherwise normal. Moreover, he had hemoglobin level of 10.5 mg/dL, white blood cell count of 4.8 × 10⁹cells/L, and platelet count of 203 × 10⁹ cells/L.

Until this point, only nonspecific findings were identified, leading to a broad differential diagnosis with little specificity. However, laboratory examinations confirm the suspected diagnosis of hypercalcemia, provide an opportunity to explain the patient’s symptoms, and offer a “lens” to narrow the differential diagnosis and guide the diagnostic evaluation. Hypercalcemia is most commonly secondary to primary hyperparathyroidism or malignancy. Primary hyperparathyroidism is unlikely in this patient given the relatively acute onset of symptoms. The degree of hypercalcemia is also atypical for primary hyperparathyroidism because it rarely exceeds 13 mg/dL, although the use of concurrent vitamin D and calcium supplementation could explain the high calcium level. Malignancy seems more likely given the degree of hypercalcemia in the setting of weight loss, tobacco use, and history of malignancy. Malignancy may cause hypercalcemia through multiple disparate mechanisms, including development of osteolytic bone metastases, elaboration of parathyroid hormone-related Peptide (PTHrP), increased production of 1,25-dihydroxyvitamin D, or, very rarely, ectopic production of parathyroid hormone (PTH). However, none of these mechanisms are particularly common in bladder or prostate cancer, which are the known malignancies in the patient. Other less likely and less common causes of hypercalcemia are also possible given the clinical clues, including vitamin D toxicity and milk alkali syndrome (vitamin D and calcium carbonate supplementation), multiple endocrine neoplasia (a sister with “throat cancer”), and granulomatous disease (weight loss). At this point, further laboratory evaluations would be helpful, specifically determination of PTH and PTHrP levels and serum and urine protein electrophoresis.

With respect to the patient’s past medical history, his Gleason 3 + 3 prostate cancer was diagnosed 12 years prior to admission and treated with external beam radiation therapy and brachytherapy. His bladder cancer was diagnosed 3 years before admission and treated with tumor resection followed by 2 rounds of intravesical BCG (iBCG), 1 round of mitomycin C, and 2 additional rounds of iBCG over the course of treatment spanning 2 years and 6 months. The treatment was complicated by urethral strictures requiring dilation, ureteral outlet obstruction requiring left ureteral stent placement, and multiple urinary tract infections.

The patient’s last round of iBCG was delivered 6 months prior to his current presentation. The patient’s hospital admission 4 months earlier for severe sepsis was presumed secondary to a urologic source considering that significant pyuria was noted on urinalysis and he was treated with meropenem, although bacterial cultures of blood and urine were sterile. From the time of discharge until his current presentation, he experienced progressive weakness and an approximately 50 lb weight loss.

The prior cancers and associated treatments of the patient may be involved in his current presentation. The simplest explanation would be metastatic disease with resultant hypercalcemia, which is atypical of either prostate or bladder cancer. The history of genitourinary surgery could predispose the patient to a chronic infection of the urinary tract with indolent organisms, such as a fungus, especially given the prior sepsis without clear etiology. However, the history would not explain the presence of hypercalcemia. Tuberculosis must thus be considered given the weight loss, hypercalcemia, and “sterile pyuria” of the patient. A more intriguing possibility is whether or not the patient’s constellation of signs and symptoms might be a late effect of iBCG. Intravesical BCG for treatment of localized bladder cancer is occasionally associated with complications. BCG is a modified live form of Mycobacterium bovis which invokes an intense inflammatory reaction when instilled into the bladder. These complications include disseminated infection and local complications, such as genitourinary infections. BCG infection might also explain the severe sepsis of unclear etiology that the patient had experienced 4 months earlier. Most interestingly, hypercalcemia has been described in the setting of BCG infection. Diagnosis of disseminated BCG is best made via culture or polymerase chain reaction testing for M. bovis at potential sites of involvement, including the blood. Nevertheless, a common presentation of a common disorder is still most likely. If his current presentation is distilled down to a chronic presentation of weakness, weight loss, and hypercalcemia in the setting of known malignancy, then the underlying malignancy seems to offer the most unifying explanation. Given that neither of his known cancers are commonly associated with hypercalcemia, the possibility that he has developed a third malignancy must also be considered.

In the hospital, the patient received intravenous normal saline, furosemide, and pamidronate. Evaluation for hypercalcemia revealed appropriately suppressed PTH (8 mg/dL), and normal levels of PTHrP (<.74 pmol/L), prostate specific antigen (<.01 ng/mL), and morning cortisol (16.7 mcg/dL). Serum and urine electrophoresis did not show evidence for monoclonal gammopathy, and the 25-hydroxy vitamin D level (39.5 ng/mL) was within the normal limits (normal range 20.1-50.0 ng/mL). The patient had elevated levels of 1,25-dihydroxy vitamin D (122 ng/mL, normal range 19.9–79.3 pg/mL), lactate dehydrogenase (196 units/L, normal 50–150 units/L), and angiotensin-converting enzyme (153 units/L, normal 14–82 units/L).

The suppressed PTH level makes primary hyperparathyroidism unlikely, the low PTHrP level decreases the probability of a paraneoplastic process, and the normal protein electrophoresis makes multiple myeloma unlikely. The presence of a significantly elevated 1,25-dihydroxy vitamin D level with a normal 25-hydroxy vitamin D level indicates extrarenal conversion of 25-hydroxy vitamin D by 1-hydroxylase as the etiology of hypercalcemia. Increased activity of 1-hydroxylase is the most consistent with granulomatous diseases, including sarcoidosis, and, with the exception of lymphoma, would not be expected in hypercalcemia malignancy. This mechanism is also associated with tuberculosis, disseminated fungal infections, such as coccidioidomycosis and histoplasmosis, and as a late effect of BCG treatment, regardless of whether disseminated infection or granulomatous immune response. Elevated lactate dehydrogenase and angiotensin-converting enzyme levels may also be noted in many of these disorders.

Lymphoma would appear to be the most likely diagnosis as it accounts for most of the clinical findings observed in the patient and is a fairly common disorder. Sarcoidosis is also reasonably common and would explain the laboratory abnormalities but is not usually associated with weight loss and frailty. Disseminated infections, such as tuberculosis, histoplasmosis, and coccidioidomycosis, are all possible, but the patient lacks key risk factors for these infections. A complication of iBCG is the most intriguing possibility and could account for many of the patient’s clinical findings, including the septic episode, which is an event not clearly accounted for by the other diagnostic possibilities. However, disseminated BCG and hypersensitivity reactions to BCG leading to hypercalcemia are rare. When asked to choose between the most interesting possibility and the most common possibility, the most common will usually be the best (and safest) bet. Nonetheless, the effects of prior BCG treatment, including disseminated infection or diffuse immune-mediated granulomatous disease, would be near the top of the differential diagnosis in this case.

The bone survey was normal, the renal ultrasound examination showed nodular wall thickening of the bladder with areas of calcification, and the CT scan of the chest, abdomen, and pelvis showed an area of calcification in the superior portion of the bladder but no evidence of lymphadenopathy or masses to suggest lymphoma. Aerobic and anaerobic blood and urine cultures were sterile. The patient was discharged 12 days after admission with plans for further outpatient diagnostic evaluation. At this time, his serum calcium had stabilized at 10.5 mg/dL with pamidronate, diuretics, and aggressive oral hydration.

Hypercalcemia is a common finding in both hospital and ambulatory settings. The classic symptoms associated with hypercalcemia are aptly summarized with the mnemonic “bones, stones, abdominal groans, and psychiatric overtones” (to represent the associated skeletal involvement, renal disease, gastrointestinal symptoms, and effects on the nervous system). However, the severity and type of symptoms vary depending on the degree of hypercalcemia, acuity of onset, and underlying etiology. The vast majority (90%) of hypercalcemia cases are due to primary hyperparathyroidism and malignancy.³ Measuring the PTH level is a key step in the diagnostic evaluation process. An isolated elevation of PTH confirms the presence of primary or possibly tertiary hyperparathyroidism. Low PTH concentrations (<20 pg/mL) occur in the settings of PTHrP or vitamin-D-mediated hypercalcemia such as hypervitaminosis D, malignancy, or granulomatous disease.

Elevated PTHrP occurs most commonly in squamous cell, renal, bladder, and ovarian carcinomas.^3,4 Elevated levels of 25-hydroxy vitamin D can occur with excessive consumption of vitamin D-containing products and some herbal supplements. In this case, neither PTHrP nor 25-hydroxy vitamin D level was elevated, leading to an exhaustive search for other causes. Although iBCG treatment is a rare cause of hypercalcemia, 2 previous reports indicated the presence of hypercalcemia secondary to granuloma formation in treated patients.^5,6

The finding of an elevated 1,25-dihydroxy vitamin D level was unexpected. As the discussant mentioned, this finding is associated with lymphoma and with granulomatous disorders that were not initially strong diagnostic considerations in the patient. A variety of granulomatous diseases can cause hypercalcemia. Sarcoidosis and tuberculosis are the most common, but berylliosis, fungal infections, Crohn’s disease, silicone exposure, and granulomatosis with polyangiitis may also be associated with hypercalcemia.⁷ The mechanism for hypercalcemia in these situations is increased intestinal calcium absorption mediated by inappropriately increased, PTH-independent, extrarenal calcitriol (1,25-dihydroxy vitamin D) production. Activated monocytes upregulate 25(OH)D-alpha-hydroxylase, converting 25-hydroxy vitamin D to 1,25-dihydroxy vitamin D. Concurrently, the elevated levels of gamma-interferon render macrophages resistant to the normal regulatory feedback mechanisms, thereby promoting the production and inhibiting the degradation of 1,25-dihydroxy vitamin D.⁸

The tuberculosis vaccine BCG is an attenuated form of M. bovis and was originally developed by Albert Calmette and Camille Guérin at the Pasteur Institute in Paris in the early 20^th century. In addition to its use as a vaccine against tuberculosis, BCG can protect against other mycobacterial infections, help treat atopic conditions via stimulation of the Th1 cellular immune response, and has been used as an antineoplastic agent. To date, BCG remains the most effective agent available for intravesical treatment of superficial bladder cancer.^9,10 Although iBCG therapy is considered relatively safe and well-tolerated, rare complications do occur. Localized symptoms (bladder irritation, hematuria) and/or flu-like symptoms are common immediately after instillation and thought to be related to the cellular immune response and inflammatory cascade triggered by mycobacterial antigens.¹¹ Other adverse effects, such as infectious and noninfectious complications, may occur months to years after treatment with BCG, and the associated symptoms can be quite nonspecific. Infectious complications include mycobacterial prostatitis, orchiepididymitis, balantitis, pneumonia, hepatitis, nephritis, septic arthritis, osteomyelitis, infected orthopedic and vascular prostheses, endocarditis, and bacteremia. Traumatic catheterization is the most common risk factor for infection with BCG.^11-13 Noninfectious complications include reactive arthritis, hypersensitivity pneumonitis, hemophagocytic lymphohistiocytosis (HLH), and sterile granulomatous infiltration of solid organs.

The protean and nonspecific nature of the adverse effects of iBCG treatment and the fact that complications can present weeks to years after instillation can make diagnosis quite challenging.¹⁴ Even if clinical suspicion is high, it may be difficult to definitively identify BCG as the underlying etiology because acid fast staining, culture, and even PCR can lead to falsely negative results.^14,15 For this reason, biopsy and tissue culture are recommended to demonstrate granuloma formation and identify the presence of M. bovis.

Although no prospective studies have been conducted to assess the optimal therapy for BCG infection, opinion-based recommendations include cessation of BCG treatment, initiation of at least 3 tuberculostatic agents, and treatment for 3-12 months depending on the severity of the complications.^11,14 M. bovis is susceptible to isoniazid, rifampin, and ethambutol as well as to fluoroquinolones, clarithromycin, aminoglycosides, and doxycycline; however, this organism is highly resistant to pyrazinamide due to single-point mutation.^11,16Interestingly, imipenem is used to treat other nontuberculous mycobacterial diseases, such as those caused by M. abscessus, thereby raising the possibility that the patient’s exposure to meropenem during treatment for his prior sepsis may have partially treated an acute infection due to M. bovis.

Although treatment with steroids is a standard approach for management of hypercalcemia in other granulomatous disorders and leads to rapid reduction in circulating levels of 1,25-dihydroxy vitamin D and serum calcium., specific evidence has not been established to support its efficacy and effectiveness in treating hypercalcemia and other complications due to M. bovis.¹⁷ Nevertheless, some experts recommend the use of steroids in conjunction with a multidrug tuberculostatic regimen in cases of septicemia and multiorgan failure due to M. bovis.^12,14,18-20

In summary, this case illustrates the importance of making room in differential diagnosis to include iatrogenic complications. That is, when faced with an unclear diagnosis, the provider should consider common and uncommon immediate and delayed side effects of prior therapies.

Teaching Points

• Complications of intravesical BCG treatment include manifestations of granulomatous diseases, such as hypercalcemia.
• When generating a differential diagnosis, medical providers should not only consider the possibility of a new disease process or the progression of a known comorbidity but also the potential of an adverse effect related to prior treatments.
• Medical providers should be wary of accepting previously made diagnoses, particularly when key pieces of objective data are lacking.

Disclosures

 The authors have no financial or other conflicts of interest that might bias this work.

A 70-year-old man presented to the emergency department with 5 days of decreased appetite, frequent urination, tremors, and memory difficulties. He also reported 9 months of malaise, generalized weakness, and weight loss. There was no history of fever, chills, nausea, diarrhea, constipation, pain, or focal neurologic complaints.

This patient exemplifies a common clinical challenge: an older adult with several possibly unrelated concerns. In many patients, a new presentation is usually either a different manifestation of a known condition (eg, a complication of an established malignancy) or the emergence of something they are at risk for based on health behavior or other characteristics (eg, lung cancer in a smoker). The diagnostic process in older adults can be complicated because many have, or are at risk for, multiple chronic conditions.

After reviewing the timeline of symptoms, the presence of 9 months of symptoms suggests a chronic and progressive underlying process, perhaps with subsequent superimposition of an acute problem. Although it is not certain whether chronic and acute symptoms are caused by the same process, this assumption is reasonable. The superimposition of acute symptoms on a chronic process may represent progression of the underlying condition or an acute complication of the underlying disease. However, the patient’s chronic symptoms of malaise, weakness, and weight loss are nonspecific.

Although malignancy is a consideration given the age of the patient and time course of symptoms, attributing the symptoms to a specific pattern of disease or building a cogent differential diagnosis is difficult until additional information is obtained. One strategy is to try to localize the findings to 1 or more organ systems; for example, given that tremors and memory difficulties localize to the central nervous system, neurodegenerative disorders, such as “Parkinson plus” syndromes, and cerebellar disease are possible. However, this tactic still leaves a relatively broad set of symptoms without an immediate and clear unifying cause.

The patient’s medical history included hyperlipidemia, peripheral neuropathy, prostate cancer, and papillary bladder cancer. The patient was admitted to the hospital 4 months earlier for severe sepsis presumed secondary to a urinary tract infection, although bacterial cultures were sterile. His social history was notable for a 50 pack-year smoking history. Outpatient medications included alfuzosin, gabapentin, simvastatin, hydrocodone, and cholecalciferol. He used a Bright Light Therapy lamp for 1 hour per week and occasionally used calcium carbonate for indigestion. The patient’s sister had a history of throat cancer.

On examination, the patient was detected with blood pressure of 104/56 mm Hg, pulse of 85 beats per minute, temperature of 98.2 °F, oxygen saturation of 97% on ambient air, and body mass index of 18 kg/m². The patient appeared frail with mildly decreased strength in the upper and lower extremities bilaterally. The remainder of the physical examination was normal. Reflexes were symmetric, no tremors or rigidity was noted, sensation was intact to light touch, and the response to the Romberg maneuver was normal.

Past medical history is the cornerstone of the diagnostic process. The history of 2 different malignancies is the most striking element in this case. Papillary bladder cancer is usually a local process, but additional information is needed regarding its stage and previous treatment, including whether or not the patient received Bacille Calmette Guerin (BCG) vaccine, which can rarely be associated with infectious and inflammatory complications. Metastatic prostate cancer could certainly account for his symptomatology, and bladder outlet obstruction could explain the history of urinary frequency and probable urosepsis. His medication list suggested no obvious causes to explain his presentation, except that cholecalciferol and calcium carbonate, which when taken in excess, can cause hypercalcemia. This finding is of particular importance given that many of the patient’s symptoms, including polyuria, malaise, weakness, tremor, memory difficulties, anorexia, acute kidney injury and (indirectly) hypotension and weight loss, are also seen in patients with hypercalcemia. The relatively normal result of the neurologic examination decreases the probability of a primary neurologic disorder and increases the likelihood that his neurologic symptoms are due to a global systemic process. The relative hypotension and weight loss similarly support the possibility that the patient is experiencing a chronic and progressive process.

The differential diagnosis remains broad. An underlying malignancy would explain the chronic progressive course, and superimposed hypercalcemia would explain the acute symptoms of polyuria, tremor, and memory changes. Endocrinopathies including hyperthyroidism or adrenal insufficiency are other possibilities. A chronic progressive infection, such as tuberculosis, is possible, although no epidemiologic factors that increase his risk for this disease are present.

The patient had serum calcium of 14.5 mg/dL, ionized calcium of 3.46 mEq/L, albumin of 3.6 g/dL, BUN of 62 mg/dL, and creatinine of 3.9 mg/dL (all values were normal 3 months prior). His electrolytes and liver function were otherwise normal. Moreover, he had hemoglobin level of 10.5 mg/dL, white blood cell count of 4.8 × 10⁹cells/L, and platelet count of 203 × 10⁹ cells/L.

Until this point, only nonspecific findings were identified, leading to a broad differential diagnosis with little specificity. However, laboratory examinations confirm the suspected diagnosis of hypercalcemia, provide an opportunity to explain the patient’s symptoms, and offer a “lens” to narrow the differential diagnosis and guide the diagnostic evaluation. Hypercalcemia is most commonly secondary to primary hyperparathyroidism or malignancy. Primary hyperparathyroidism is unlikely in this patient given the relatively acute onset of symptoms. The degree of hypercalcemia is also atypical for primary hyperparathyroidism because it rarely exceeds 13 mg/dL, although the use of concurrent vitamin D and calcium supplementation could explain the high calcium level. Malignancy seems more likely given the degree of hypercalcemia in the setting of weight loss, tobacco use, and history of malignancy. Malignancy may cause hypercalcemia through multiple disparate mechanisms, including development of osteolytic bone metastases, elaboration of parathyroid hormone-related Peptide (PTHrP), increased production of 1,25-dihydroxyvitamin D, or, very rarely, ectopic production of parathyroid hormone (PTH). However, none of these mechanisms are particularly common in bladder or prostate cancer, which are the known malignancies in the patient. Other less likely and less common causes of hypercalcemia are also possible given the clinical clues, including vitamin D toxicity and milk alkali syndrome (vitamin D and calcium carbonate supplementation), multiple endocrine neoplasia (a sister with “throat cancer”), and granulomatous disease (weight loss). At this point, further laboratory evaluations would be helpful, specifically determination of PTH and PTHrP levels and serum and urine protein electrophoresis.

With respect to the patient’s past medical history, his Gleason 3 + 3 prostate cancer was diagnosed 12 years prior to admission and treated with external beam radiation therapy and brachytherapy. His bladder cancer was diagnosed 3 years before admission and treated with tumor resection followed by 2 rounds of intravesical BCG (iBCG), 1 round of mitomycin C, and 2 additional rounds of iBCG over the course of treatment spanning 2 years and 6 months. The treatment was complicated by urethral strictures requiring dilation, ureteral outlet obstruction requiring left ureteral stent placement, and multiple urinary tract infections.

The patient’s last round of iBCG was delivered 6 months prior to his current presentation. The patient’s hospital admission 4 months earlier for severe sepsis was presumed secondary to a urologic source considering that significant pyuria was noted on urinalysis and he was treated with meropenem, although bacterial cultures of blood and urine were sterile. From the time of discharge until his current presentation, he experienced progressive weakness and an approximately 50 lb weight loss.

The prior cancers and associated treatments of the patient may be involved in his current presentation. The simplest explanation would be metastatic disease with resultant hypercalcemia, which is atypical of either prostate or bladder cancer. The history of genitourinary surgery could predispose the patient to a chronic infection of the urinary tract with indolent organisms, such as a fungus, especially given the prior sepsis without clear etiology. However, the history would not explain the presence of hypercalcemia. Tuberculosis must thus be considered given the weight loss, hypercalcemia, and “sterile pyuria” of the patient. A more intriguing possibility is whether or not the patient’s constellation of signs and symptoms might be a late effect of iBCG. Intravesical BCG for treatment of localized bladder cancer is occasionally associated with complications. BCG is a modified live form of Mycobacterium bovis which invokes an intense inflammatory reaction when instilled into the bladder. These complications include disseminated infection and local complications, such as genitourinary infections. BCG infection might also explain the severe sepsis of unclear etiology that the patient had experienced 4 months earlier. Most interestingly, hypercalcemia has been described in the setting of BCG infection. Diagnosis of disseminated BCG is best made via culture or polymerase chain reaction testing for M. bovis at potential sites of involvement, including the blood. Nevertheless, a common presentation of a common disorder is still most likely. If his current presentation is distilled down to a chronic presentation of weakness, weight loss, and hypercalcemia in the setting of known malignancy, then the underlying malignancy seems to offer the most unifying explanation. Given that neither of his known cancers are commonly associated with hypercalcemia, the possibility that he has developed a third malignancy must also be considered.

In the hospital, the patient received intravenous normal saline, furosemide, and pamidronate. Evaluation for hypercalcemia revealed appropriately suppressed PTH (8 mg/dL), and normal levels of PTHrP (<.74 pmol/L), prostate specific antigen (<.01 ng/mL), and morning cortisol (16.7 mcg/dL). Serum and urine electrophoresis did not show evidence for monoclonal gammopathy, and the 25-hydroxy vitamin D level (39.5 ng/mL) was within the normal limits (normal range 20.1-50.0 ng/mL). The patient had elevated levels of 1,25-dihydroxy vitamin D (122 ng/mL, normal range 19.9–79.3 pg/mL), lactate dehydrogenase (196 units/L, normal 50–150 units/L), and angiotensin-converting enzyme (153 units/L, normal 14–82 units/L).

The suppressed PTH level makes primary hyperparathyroidism unlikely, the low PTHrP level decreases the probability of a paraneoplastic process, and the normal protein electrophoresis makes multiple myeloma unlikely. The presence of a significantly elevated 1,25-dihydroxy vitamin D level with a normal 25-hydroxy vitamin D level indicates extrarenal conversion of 25-hydroxy vitamin D by 1-hydroxylase as the etiology of hypercalcemia. Increased activity of 1-hydroxylase is the most consistent with granulomatous diseases, including sarcoidosis, and, with the exception of lymphoma, would not be expected in hypercalcemia malignancy. This mechanism is also associated with tuberculosis, disseminated fungal infections, such as coccidioidomycosis and histoplasmosis, and as a late effect of BCG treatment, regardless of whether disseminated infection or granulomatous immune response. Elevated lactate dehydrogenase and angiotensin-converting enzyme levels may also be noted in many of these disorders.

Lymphoma would appear to be the most likely diagnosis as it accounts for most of the clinical findings observed in the patient and is a fairly common disorder. Sarcoidosis is also reasonably common and would explain the laboratory abnormalities but is not usually associated with weight loss and frailty. Disseminated infections, such as tuberculosis, histoplasmosis, and coccidioidomycosis, are all possible, but the patient lacks key risk factors for these infections. A complication of iBCG is the most intriguing possibility and could account for many of the patient’s clinical findings, including the septic episode, which is an event not clearly accounted for by the other diagnostic possibilities. However, disseminated BCG and hypersensitivity reactions to BCG leading to hypercalcemia are rare. When asked to choose between the most interesting possibility and the most common possibility, the most common will usually be the best (and safest) bet. Nonetheless, the effects of prior BCG treatment, including disseminated infection or diffuse immune-mediated granulomatous disease, would be near the top of the differential diagnosis in this case.

The bone survey was normal, the renal ultrasound examination showed nodular wall thickening of the bladder with areas of calcification, and the CT scan of the chest, abdomen, and pelvis showed an area of calcification in the superior portion of the bladder but no evidence of lymphadenopathy or masses to suggest lymphoma. Aerobic and anaerobic blood and urine cultures were sterile. The patient was discharged 12 days after admission with plans for further outpatient diagnostic evaluation. At this time, his serum calcium had stabilized at 10.5 mg/dL with pamidronate, diuretics, and aggressive oral hydration.

Hypercalcemia is a common finding in both hospital and ambulatory settings. The classic symptoms associated with hypercalcemia are aptly summarized with the mnemonic “bones, stones, abdominal groans, and psychiatric overtones” (to represent the associated skeletal involvement, renal disease, gastrointestinal symptoms, and effects on the nervous system). However, the severity and type of symptoms vary depending on the degree of hypercalcemia, acuity of onset, and underlying etiology. The vast majority (90%) of hypercalcemia cases are due to primary hyperparathyroidism and malignancy.³ Measuring the PTH level is a key step in the diagnostic evaluation process. An isolated elevation of PTH confirms the presence of primary or possibly tertiary hyperparathyroidism. Low PTH concentrations (<20 pg/mL) occur in the settings of PTHrP or vitamin-D-mediated hypercalcemia such as hypervitaminosis D, malignancy, or granulomatous disease.

Elevated PTHrP occurs most commonly in squamous cell, renal, bladder, and ovarian carcinomas.^3,4 Elevated levels of 25-hydroxy vitamin D can occur with excessive consumption of vitamin D-containing products and some herbal supplements. In this case, neither PTHrP nor 25-hydroxy vitamin D level was elevated, leading to an exhaustive search for other causes. Although iBCG treatment is a rare cause of hypercalcemia, 2 previous reports indicated the presence of hypercalcemia secondary to granuloma formation in treated patients.^5,6

The finding of an elevated 1,25-dihydroxy vitamin D level was unexpected. As the discussant mentioned, this finding is associated with lymphoma and with granulomatous disorders that were not initially strong diagnostic considerations in the patient. A variety of granulomatous diseases can cause hypercalcemia. Sarcoidosis and tuberculosis are the most common, but berylliosis, fungal infections, Crohn’s disease, silicone exposure, and granulomatosis with polyangiitis may also be associated with hypercalcemia.⁷ The mechanism for hypercalcemia in these situations is increased intestinal calcium absorption mediated by inappropriately increased, PTH-independent, extrarenal calcitriol (1,25-dihydroxy vitamin D) production. Activated monocytes upregulate 25(OH)D-alpha-hydroxylase, converting 25-hydroxy vitamin D to 1,25-dihydroxy vitamin D. Concurrently, the elevated levels of gamma-interferon render macrophages resistant to the normal regulatory feedback mechanisms, thereby promoting the production and inhibiting the degradation of 1,25-dihydroxy vitamin D.⁸

The tuberculosis vaccine BCG is an attenuated form of M. bovis and was originally developed by Albert Calmette and Camille Guérin at the Pasteur Institute in Paris in the early 20^th century. In addition to its use as a vaccine against tuberculosis, BCG can protect against other mycobacterial infections, help treat atopic conditions via stimulation of the Th1 cellular immune response, and has been used as an antineoplastic agent. To date, BCG remains the most effective agent available for intravesical treatment of superficial bladder cancer.^9,10 Although iBCG therapy is considered relatively safe and well-tolerated, rare complications do occur. Localized symptoms (bladder irritation, hematuria) and/or flu-like symptoms are common immediately after instillation and thought to be related to the cellular immune response and inflammatory cascade triggered by mycobacterial antigens.¹¹ Other adverse effects, such as infectious and noninfectious complications, may occur months to years after treatment with BCG, and the associated symptoms can be quite nonspecific. Infectious complications include mycobacterial prostatitis, orchiepididymitis, balantitis, pneumonia, hepatitis, nephritis, septic arthritis, osteomyelitis, infected orthopedic and vascular prostheses, endocarditis, and bacteremia. Traumatic catheterization is the most common risk factor for infection with BCG.^11-13 Noninfectious complications include reactive arthritis, hypersensitivity pneumonitis, hemophagocytic lymphohistiocytosis (HLH), and sterile granulomatous infiltration of solid organs.

The protean and nonspecific nature of the adverse effects of iBCG treatment and the fact that complications can present weeks to years after instillation can make diagnosis quite challenging.¹⁴ Even if clinical suspicion is high, it may be difficult to definitively identify BCG as the underlying etiology because acid fast staining, culture, and even PCR can lead to falsely negative results.^14,15 For this reason, biopsy and tissue culture are recommended to demonstrate granuloma formation and identify the presence of M. bovis.

Although no prospective studies have been conducted to assess the optimal therapy for BCG infection, opinion-based recommendations include cessation of BCG treatment, initiation of at least 3 tuberculostatic agents, and treatment for 3-12 months depending on the severity of the complications.^11,14 M. bovis is susceptible to isoniazid, rifampin, and ethambutol as well as to fluoroquinolones, clarithromycin, aminoglycosides, and doxycycline; however, this organism is highly resistant to pyrazinamide due to single-point mutation.^11,16Interestingly, imipenem is used to treat other nontuberculous mycobacterial diseases, such as those caused by M. abscessus, thereby raising the possibility that the patient’s exposure to meropenem during treatment for his prior sepsis may have partially treated an acute infection due to M. bovis.

Although treatment with steroids is a standard approach for management of hypercalcemia in other granulomatous disorders and leads to rapid reduction in circulating levels of 1,25-dihydroxy vitamin D and serum calcium., specific evidence has not been established to support its efficacy and effectiveness in treating hypercalcemia and other complications due to M. bovis.¹⁷ Nevertheless, some experts recommend the use of steroids in conjunction with a multidrug tuberculostatic regimen in cases of septicemia and multiorgan failure due to M. bovis.^12,14,18-20

In summary, this case illustrates the importance of making room in differential diagnosis to include iatrogenic complications. That is, when faced with an unclear diagnosis, the provider should consider common and uncommon immediate and delayed side effects of prior therapies.

Teaching Points

• Complications of intravesical BCG treatment include manifestations of granulomatous diseases, such as hypercalcemia.
• When generating a differential diagnosis, medical providers should not only consider the possibility of a new disease process or the progression of a known comorbidity but also the potential of an adverse effect related to prior treatments.
• Medical providers should be wary of accepting previously made diagnoses, particularly when key pieces of objective data are lacking.

Disclosures

 The authors have no financial or other conflicts of interest that might bias this work.

A 70-year-old man presented to the emergency department with 5 days of decreased appetite, frequent urination, tremors, and memory difficulties. He also reported 9 months of malaise, generalized weakness, and weight loss. There was no history of fever, chills, nausea, diarrhea, constipation, pain, or focal neurologic complaints.

This patient exemplifies a common clinical challenge: an older adult with several possibly unrelated concerns. In many patients, a new presentation is usually either a different manifestation of a known condition (eg, a complication of an established malignancy) or the emergence of something they are at risk for based on health behavior or other characteristics (eg, lung cancer in a smoker). The diagnostic process in older adults can be complicated because many have, or are at risk for, multiple chronic conditions.

After reviewing the timeline of symptoms, the presence of 9 months of symptoms suggests a chronic and progressive underlying process, perhaps with subsequent superimposition of an acute problem. Although it is not certain whether chronic and acute symptoms are caused by the same process, this assumption is reasonable. The superimposition of acute symptoms on a chronic process may represent progression of the underlying condition or an acute complication of the underlying disease. However, the patient’s chronic symptoms of malaise, weakness, and weight loss are nonspecific.

Although malignancy is a consideration given the age of the patient and time course of symptoms, attributing the symptoms to a specific pattern of disease or building a cogent differential diagnosis is difficult until additional information is obtained. One strategy is to try to localize the findings to 1 or more organ systems; for example, given that tremors and memory difficulties localize to the central nervous system, neurodegenerative disorders, such as “Parkinson plus” syndromes, and cerebellar disease are possible. However, this tactic still leaves a relatively broad set of symptoms without an immediate and clear unifying cause.

The patient’s medical history included hyperlipidemia, peripheral neuropathy, prostate cancer, and papillary bladder cancer. The patient was admitted to the hospital 4 months earlier for severe sepsis presumed secondary to a urinary tract infection, although bacterial cultures were sterile. His social history was notable for a 50 pack-year smoking history. Outpatient medications included alfuzosin, gabapentin, simvastatin, hydrocodone, and cholecalciferol. He used a Bright Light Therapy lamp for 1 hour per week and occasionally used calcium carbonate for indigestion. The patient’s sister had a history of throat cancer.

On examination, the patient was detected with blood pressure of 104/56 mm Hg, pulse of 85 beats per minute, temperature of 98.2 °F, oxygen saturation of 97% on ambient air, and body mass index of 18 kg/m². The patient appeared frail with mildly decreased strength in the upper and lower extremities bilaterally. The remainder of the physical examination was normal. Reflexes were symmetric, no tremors or rigidity was noted, sensation was intact to light touch, and the response to the Romberg maneuver was normal.

Past medical history is the cornerstone of the diagnostic process. The history of 2 different malignancies is the most striking element in this case. Papillary bladder cancer is usually a local process, but additional information is needed regarding its stage and previous treatment, including whether or not the patient received Bacille Calmette Guerin (BCG) vaccine, which can rarely be associated with infectious and inflammatory complications. Metastatic prostate cancer could certainly account for his symptomatology, and bladder outlet obstruction could explain the history of urinary frequency and probable urosepsis. His medication list suggested no obvious causes to explain his presentation, except that cholecalciferol and calcium carbonate, which when taken in excess, can cause hypercalcemia. This finding is of particular importance given that many of the patient’s symptoms, including polyuria, malaise, weakness, tremor, memory difficulties, anorexia, acute kidney injury and (indirectly) hypotension and weight loss, are also seen in patients with hypercalcemia. The relatively normal result of the neurologic examination decreases the probability of a primary neurologic disorder and increases the likelihood that his neurologic symptoms are due to a global systemic process. The relative hypotension and weight loss similarly support the possibility that the patient is experiencing a chronic and progressive process.

The differential diagnosis remains broad. An underlying malignancy would explain the chronic progressive course, and superimposed hypercalcemia would explain the acute symptoms of polyuria, tremor, and memory changes. Endocrinopathies including hyperthyroidism or adrenal insufficiency are other possibilities. A chronic progressive infection, such as tuberculosis, is possible, although no epidemiologic factors that increase his risk for this disease are present.

The patient had serum calcium of 14.5 mg/dL, ionized calcium of 3.46 mEq/L, albumin of 3.6 g/dL, BUN of 62 mg/dL, and creatinine of 3.9 mg/dL (all values were normal 3 months prior). His electrolytes and liver function were otherwise normal. Moreover, he had hemoglobin level of 10.5 mg/dL, white blood cell count of 4.8 × 10⁹cells/L, and platelet count of 203 × 10⁹ cells/L.

Until this point, only nonspecific findings were identified, leading to a broad differential diagnosis with little specificity. However, laboratory examinations confirm the suspected diagnosis of hypercalcemia, provide an opportunity to explain the patient’s symptoms, and offer a “lens” to narrow the differential diagnosis and guide the diagnostic evaluation. Hypercalcemia is most commonly secondary to primary hyperparathyroidism or malignancy. Primary hyperparathyroidism is unlikely in this patient given the relatively acute onset of symptoms. The degree of hypercalcemia is also atypical for primary hyperparathyroidism because it rarely exceeds 13 mg/dL, although the use of concurrent vitamin D and calcium supplementation could explain the high calcium level. Malignancy seems more likely given the degree of hypercalcemia in the setting of weight loss, tobacco use, and history of malignancy. Malignancy may cause hypercalcemia through multiple disparate mechanisms, including development of osteolytic bone metastases, elaboration of parathyroid hormone-related Peptide (PTHrP), increased production of 1,25-dihydroxyvitamin D, or, very rarely, ectopic production of parathyroid hormone (PTH). However, none of these mechanisms are particularly common in bladder or prostate cancer, which are the known malignancies in the patient. Other less likely and less common causes of hypercalcemia are also possible given the clinical clues, including vitamin D toxicity and milk alkali syndrome (vitamin D and calcium carbonate supplementation), multiple endocrine neoplasia (a sister with “throat cancer”), and granulomatous disease (weight loss). At this point, further laboratory evaluations would be helpful, specifically determination of PTH and PTHrP levels and serum and urine protein electrophoresis.

With respect to the patient’s past medical history, his Gleason 3 + 3 prostate cancer was diagnosed 12 years prior to admission and treated with external beam radiation therapy and brachytherapy. His bladder cancer was diagnosed 3 years before admission and treated with tumor resection followed by 2 rounds of intravesical BCG (iBCG), 1 round of mitomycin C, and 2 additional rounds of iBCG over the course of treatment spanning 2 years and 6 months. The treatment was complicated by urethral strictures requiring dilation, ureteral outlet obstruction requiring left ureteral stent placement, and multiple urinary tract infections.

The patient’s last round of iBCG was delivered 6 months prior to his current presentation. The patient’s hospital admission 4 months earlier for severe sepsis was presumed secondary to a urologic source considering that significant pyuria was noted on urinalysis and he was treated with meropenem, although bacterial cultures of blood and urine were sterile. From the time of discharge until his current presentation, he experienced progressive weakness and an approximately 50 lb weight loss.

The prior cancers and associated treatments of the patient may be involved in his current presentation. The simplest explanation would be metastatic disease with resultant hypercalcemia, which is atypical of either prostate or bladder cancer. The history of genitourinary surgery could predispose the patient to a chronic infection of the urinary tract with indolent organisms, such as a fungus, especially given the prior sepsis without clear etiology. However, the history would not explain the presence of hypercalcemia. Tuberculosis must thus be considered given the weight loss, hypercalcemia, and “sterile pyuria” of the patient. A more intriguing possibility is whether or not the patient’s constellation of signs and symptoms might be a late effect of iBCG. Intravesical BCG for treatment of localized bladder cancer is occasionally associated with complications. BCG is a modified live form of Mycobacterium bovis which invokes an intense inflammatory reaction when instilled into the bladder. These complications include disseminated infection and local complications, such as genitourinary infections. BCG infection might also explain the severe sepsis of unclear etiology that the patient had experienced 4 months earlier. Most interestingly, hypercalcemia has been described in the setting of BCG infection. Diagnosis of disseminated BCG is best made via culture or polymerase chain reaction testing for M. bovis at potential sites of involvement, including the blood. Nevertheless, a common presentation of a common disorder is still most likely. If his current presentation is distilled down to a chronic presentation of weakness, weight loss, and hypercalcemia in the setting of known malignancy, then the underlying malignancy seems to offer the most unifying explanation. Given that neither of his known cancers are commonly associated with hypercalcemia, the possibility that he has developed a third malignancy must also be considered.

In the hospital, the patient received intravenous normal saline, furosemide, and pamidronate. Evaluation for hypercalcemia revealed appropriately suppressed PTH (8 mg/dL), and normal levels of PTHrP (<.74 pmol/L), prostate specific antigen (<.01 ng/mL), and morning cortisol (16.7 mcg/dL). Serum and urine electrophoresis did not show evidence for monoclonal gammopathy, and the 25-hydroxy vitamin D level (39.5 ng/mL) was within the normal limits (normal range 20.1-50.0 ng/mL). The patient had elevated levels of 1,25-dihydroxy vitamin D (122 ng/mL, normal range 19.9–79.3 pg/mL), lactate dehydrogenase (196 units/L, normal 50–150 units/L), and angiotensin-converting enzyme (153 units/L, normal 14–82 units/L).

The suppressed PTH level makes primary hyperparathyroidism unlikely, the low PTHrP level decreases the probability of a paraneoplastic process, and the normal protein electrophoresis makes multiple myeloma unlikely. The presence of a significantly elevated 1,25-dihydroxy vitamin D level with a normal 25-hydroxy vitamin D level indicates extrarenal conversion of 25-hydroxy vitamin D by 1-hydroxylase as the etiology of hypercalcemia. Increased activity of 1-hydroxylase is the most consistent with granulomatous diseases, including sarcoidosis, and, with the exception of lymphoma, would not be expected in hypercalcemia malignancy. This mechanism is also associated with tuberculosis, disseminated fungal infections, such as coccidioidomycosis and histoplasmosis, and as a late effect of BCG treatment, regardless of whether disseminated infection or granulomatous immune response. Elevated lactate dehydrogenase and angiotensin-converting enzyme levels may also be noted in many of these disorders.

Lymphoma would appear to be the most likely diagnosis as it accounts for most of the clinical findings observed in the patient and is a fairly common disorder. Sarcoidosis is also reasonably common and would explain the laboratory abnormalities but is not usually associated with weight loss and frailty. Disseminated infections, such as tuberculosis, histoplasmosis, and coccidioidomycosis, are all possible, but the patient lacks key risk factors for these infections. A complication of iBCG is the most intriguing possibility and could account for many of the patient’s clinical findings, including the septic episode, which is an event not clearly accounted for by the other diagnostic possibilities. However, disseminated BCG and hypersensitivity reactions to BCG leading to hypercalcemia are rare. When asked to choose between the most interesting possibility and the most common possibility, the most common will usually be the best (and safest) bet. Nonetheless, the effects of prior BCG treatment, including disseminated infection or diffuse immune-mediated granulomatous disease, would be near the top of the differential diagnosis in this case.

The bone survey was normal, the renal ultrasound examination showed nodular wall thickening of the bladder with areas of calcification, and the CT scan of the chest, abdomen, and pelvis showed an area of calcification in the superior portion of the bladder but no evidence of lymphadenopathy or masses to suggest lymphoma. Aerobic and anaerobic blood and urine cultures were sterile. The patient was discharged 12 days after admission with plans for further outpatient diagnostic evaluation. At this time, his serum calcium had stabilized at 10.5 mg/dL with pamidronate, diuretics, and aggressive oral hydration.

Hypercalcemia is a common finding in both hospital and ambulatory settings. The classic symptoms associated with hypercalcemia are aptly summarized with the mnemonic “bones, stones, abdominal groans, and psychiatric overtones” (to represent the associated skeletal involvement, renal disease, gastrointestinal symptoms, and effects on the nervous system). However, the severity and type of symptoms vary depending on the degree of hypercalcemia, acuity of onset, and underlying etiology. The vast majority (90%) of hypercalcemia cases are due to primary hyperparathyroidism and malignancy.³ Measuring the PTH level is a key step in the diagnostic evaluation process. An isolated elevation of PTH confirms the presence of primary or possibly tertiary hyperparathyroidism. Low PTH concentrations (<20 pg/mL) occur in the settings of PTHrP or vitamin-D-mediated hypercalcemia such as hypervitaminosis D, malignancy, or granulomatous disease.

Elevated PTHrP occurs most commonly in squamous cell, renal, bladder, and ovarian carcinomas.^3,4 Elevated levels of 25-hydroxy vitamin D can occur with excessive consumption of vitamin D-containing products and some herbal supplements. In this case, neither PTHrP nor 25-hydroxy vitamin D level was elevated, leading to an exhaustive search for other causes. Although iBCG treatment is a rare cause of hypercalcemia, 2 previous reports indicated the presence of hypercalcemia secondary to granuloma formation in treated patients.^5,6

The finding of an elevated 1,25-dihydroxy vitamin D level was unexpected. As the discussant mentioned, this finding is associated with lymphoma and with granulomatous disorders that were not initially strong diagnostic considerations in the patient. A variety of granulomatous diseases can cause hypercalcemia. Sarcoidosis and tuberculosis are the most common, but berylliosis, fungal infections, Crohn’s disease, silicone exposure, and granulomatosis with polyangiitis may also be associated with hypercalcemia.⁷ The mechanism for hypercalcemia in these situations is increased intestinal calcium absorption mediated by inappropriately increased, PTH-independent, extrarenal calcitriol (1,25-dihydroxy vitamin D) production. Activated monocytes upregulate 25(OH)D-alpha-hydroxylase, converting 25-hydroxy vitamin D to 1,25-dihydroxy vitamin D. Concurrently, the elevated levels of gamma-interferon render macrophages resistant to the normal regulatory feedback mechanisms, thereby promoting the production and inhibiting the degradation of 1,25-dihydroxy vitamin D.⁸

The tuberculosis vaccine BCG is an attenuated form of M. bovis and was originally developed by Albert Calmette and Camille Guérin at the Pasteur Institute in Paris in the early 20^th century. In addition to its use as a vaccine against tuberculosis, BCG can protect against other mycobacterial infections, help treat atopic conditions via stimulation of the Th1 cellular immune response, and has been used as an antineoplastic agent. To date, BCG remains the most effective agent available for intravesical treatment of superficial bladder cancer.^9,10 Although iBCG therapy is considered relatively safe and well-tolerated, rare complications do occur. Localized symptoms (bladder irritation, hematuria) and/or flu-like symptoms are common immediately after instillation and thought to be related to the cellular immune response and inflammatory cascade triggered by mycobacterial antigens.¹¹ Other adverse effects, such as infectious and noninfectious complications, may occur months to years after treatment with BCG, and the associated symptoms can be quite nonspecific. Infectious complications include mycobacterial prostatitis, orchiepididymitis, balantitis, pneumonia, hepatitis, nephritis, septic arthritis, osteomyelitis, infected orthopedic and vascular prostheses, endocarditis, and bacteremia. Traumatic catheterization is the most common risk factor for infection with BCG.^11-13 Noninfectious complications include reactive arthritis, hypersensitivity pneumonitis, hemophagocytic lymphohistiocytosis (HLH), and sterile granulomatous infiltration of solid organs.

The protean and nonspecific nature of the adverse effects of iBCG treatment and the fact that complications can present weeks to years after instillation can make diagnosis quite challenging.¹⁴ Even if clinical suspicion is high, it may be difficult to definitively identify BCG as the underlying etiology because acid fast staining, culture, and even PCR can lead to falsely negative results.^14,15 For this reason, biopsy and tissue culture are recommended to demonstrate granuloma formation and identify the presence of M. bovis.

Although no prospective studies have been conducted to assess the optimal therapy for BCG infection, opinion-based recommendations include cessation of BCG treatment, initiation of at least 3 tuberculostatic agents, and treatment for 3-12 months depending on the severity of the complications.^11,14 M. bovis is susceptible to isoniazid, rifampin, and ethambutol as well as to fluoroquinolones, clarithromycin, aminoglycosides, and doxycycline; however, this organism is highly resistant to pyrazinamide due to single-point mutation.^11,16Interestingly, imipenem is used to treat other nontuberculous mycobacterial diseases, such as those caused by M. abscessus, thereby raising the possibility that the patient’s exposure to meropenem during treatment for his prior sepsis may have partially treated an acute infection due to M. bovis.

Although treatment with steroids is a standard approach for management of hypercalcemia in other granulomatous disorders and leads to rapid reduction in circulating levels of 1,25-dihydroxy vitamin D and serum calcium., specific evidence has not been established to support its efficacy and effectiveness in treating hypercalcemia and other complications due to M. bovis.¹⁷ Nevertheless, some experts recommend the use of steroids in conjunction with a multidrug tuberculostatic regimen in cases of septicemia and multiorgan failure due to M. bovis.^12,14,18-20

In summary, this case illustrates the importance of making room in differential diagnosis to include iatrogenic complications. That is, when faced with an unclear diagnosis, the provider should consider common and uncommon immediate and delayed side effects of prior therapies.

Teaching Points

• Complications of intravesical BCG treatment include manifestations of granulomatous diseases, such as hypercalcemia.
• When generating a differential diagnosis, medical providers should not only consider the possibility of a new disease process or the progression of a known comorbidity but also the potential of an adverse effect related to prior treatments.
• Medical providers should be wary of accepting previously made diagnoses, particularly when key pieces of objective data are lacking.

Disclosures

 The authors have no financial or other conflicts of interest that might bias this work.

Royer and colleagues¹ have performed a meta-analysis comparing shorter versus longer courses of antibiotics for treating infections in hospitalized patients. They conclude that shorter courses are safe. However, the authors do not address a flaw in the analysis; they included studies in which treatment with azithromycin was considered a short antibiotic course relative to treatment with another antibiotic. Azithromycin is a macrolide antibiotic that has a relatively long terminal serum half-life, which has been reported to be 35-96 hours.^2-4 Moreover, the half-life of azithromycin in lung tissue can be as long as 132 hours,⁴ which is important because tissue concentrations are thought to be more indicative of the clinical efficacy of macrolides.⁵ In 4 of 19 studies in the meta-analysis,¹ azithromycin was used as a short course for the treatment of pneumonia and compared with longer courses of antibiotics with a much shorter half-life. This implies that in these studies, the duration of the effective antibiotic tissue concentration in the short arms was probably not shorter than in the comparator arms. It could even be longer due to azithromycin’s favorable pharmacokinetics. In our view, these studies have unfairly contributed to the clinical efficacy of short courses, thereby threatening the validity of the overall conclusions. We think that effective antibiotic blood/tissue levels determine the clinical outcome, not just shorter or longer antibiotic courses.

Disclosures

The authors declare that they have no conflicts of interest to report.

Royer and colleagues¹ have performed a meta-analysis comparing shorter versus longer courses of antibiotics for treating infections in hospitalized patients. They conclude that shorter courses are safe. However, the authors do not address a flaw in the analysis; they included studies in which treatment with azithromycin was considered a short antibiotic course relative to treatment with another antibiotic. Azithromycin is a macrolide antibiotic that has a relatively long terminal serum half-life, which has been reported to be 35-96 hours.^2-4 Moreover, the half-life of azithromycin in lung tissue can be as long as 132 hours,⁴ which is important because tissue concentrations are thought to be more indicative of the clinical efficacy of macrolides.⁵ In 4 of 19 studies in the meta-analysis,¹ azithromycin was used as a short course for the treatment of pneumonia and compared with longer courses of antibiotics with a much shorter half-life. This implies that in these studies, the duration of the effective antibiotic tissue concentration in the short arms was probably not shorter than in the comparator arms. It could even be longer due to azithromycin’s favorable pharmacokinetics. In our view, these studies have unfairly contributed to the clinical efficacy of short courses, thereby threatening the validity of the overall conclusions. We think that effective antibiotic blood/tissue levels determine the clinical outcome, not just shorter or longer antibiotic courses.

Disclosures

The authors declare that they have no conflicts of interest to report.

Royer and colleagues¹ have performed a meta-analysis comparing shorter versus longer courses of antibiotics for treating infections in hospitalized patients. They conclude that shorter courses are safe. However, the authors do not address a flaw in the analysis; they included studies in which treatment with azithromycin was considered a short antibiotic course relative to treatment with another antibiotic. Azithromycin is a macrolide antibiotic that has a relatively long terminal serum half-life, which has been reported to be 35-96 hours.^2-4 Moreover, the half-life of azithromycin in lung tissue can be as long as 132 hours,⁴ which is important because tissue concentrations are thought to be more indicative of the clinical efficacy of macrolides.⁵ In 4 of 19 studies in the meta-analysis,¹ azithromycin was used as a short course for the treatment of pneumonia and compared with longer courses of antibiotics with a much shorter half-life. This implies that in these studies, the duration of the effective antibiotic tissue concentration in the short arms was probably not shorter than in the comparator arms. It could even be longer due to azithromycin’s favorable pharmacokinetics. In our view, these studies have unfairly contributed to the clinical efficacy of short courses, thereby threatening the validity of the overall conclusions. We think that effective antibiotic blood/tissue levels determine the clinical outcome, not just shorter or longer antibiotic courses.

Disclosures

The authors declare that they have no conflicts of interest to report.

We appreciate the interest in our review of antibiotic duration in hospitalized patients. Drs. Sikkens and van Agtmael comment that drug pharmacokinetics can alter true treatment duration.^1,2 Specifically, azithromycin has a long half-life in tissues.³ We did not consider pharmacokinetics in our prespecified protocol for study inclusion, nor require that studies compare the same drug between treatment groups. This is consistent with a systematic review of antibiotic duration in community-acquired pneumonia, which included 3 of the 4 studies comparing short-course azithromycin to a longer course of another antibiotic.⁴ Similarly, in a recent pilot study of antibiotic duration in bloodstream infections, only treatment duration was prespecified.⁵ We agree that the differing pharmacokinetics between drugs is a limitation to our findings.

To assess whether the inclusion of studies using short-course azithromycin biased our conclusions, we performed an additional meta-analysis for clinical efficacy excluding the 4 studies that compared azithromycin with another drug. This subgroup included 9 trials comprising 1270 patients. The overall risk difference was 0.3% (95% CI −2.7%, 3.3%), consistent with the primary findings that short-course antibiotic treatment is non-inferior to long-course antibiotic treatment. None of these 4 studies examined mortality; thus, the meta-analyses for short-term and long-term mortality are unaffected.

Disclosures

Dr. Royer holds stock in Pfizer. The authors have no other potential financial conflicts of interest to report.

Funding

This work was supported by K08 GM115859 [HCP]. This manuscript does not necessarily represent the position or policy of the US government or the Department of Veterans Affairs.

We appreciate the interest in our review of antibiotic duration in hospitalized patients. Drs. Sikkens and van Agtmael comment that drug pharmacokinetics can alter true treatment duration.^1,2 Specifically, azithromycin has a long half-life in tissues.³ We did not consider pharmacokinetics in our prespecified protocol for study inclusion, nor require that studies compare the same drug between treatment groups. This is consistent with a systematic review of antibiotic duration in community-acquired pneumonia, which included 3 of the 4 studies comparing short-course azithromycin to a longer course of another antibiotic.⁴ Similarly, in a recent pilot study of antibiotic duration in bloodstream infections, only treatment duration was prespecified.⁵ We agree that the differing pharmacokinetics between drugs is a limitation to our findings.

To assess whether the inclusion of studies using short-course azithromycin biased our conclusions, we performed an additional meta-analysis for clinical efficacy excluding the 4 studies that compared azithromycin with another drug. This subgroup included 9 trials comprising 1270 patients. The overall risk difference was 0.3% (95% CI −2.7%, 3.3%), consistent with the primary findings that short-course antibiotic treatment is non-inferior to long-course antibiotic treatment. None of these 4 studies examined mortality; thus, the meta-analyses for short-term and long-term mortality are unaffected.

Disclosures

Dr. Royer holds stock in Pfizer. The authors have no other potential financial conflicts of interest to report.

Funding

This work was supported by K08 GM115859 [HCP]. This manuscript does not necessarily represent the position or policy of the US government or the Department of Veterans Affairs.

We appreciate the interest in our review of antibiotic duration in hospitalized patients. Drs. Sikkens and van Agtmael comment that drug pharmacokinetics can alter true treatment duration.^1,2 Specifically, azithromycin has a long half-life in tissues.³ We did not consider pharmacokinetics in our prespecified protocol for study inclusion, nor require that studies compare the same drug between treatment groups. This is consistent with a systematic review of antibiotic duration in community-acquired pneumonia, which included 3 of the 4 studies comparing short-course azithromycin to a longer course of another antibiotic.⁴ Similarly, in a recent pilot study of antibiotic duration in bloodstream infections, only treatment duration was prespecified.⁵ We agree that the differing pharmacokinetics between drugs is a limitation to our findings.

To assess whether the inclusion of studies using short-course azithromycin biased our conclusions, we performed an additional meta-analysis for clinical efficacy excluding the 4 studies that compared azithromycin with another drug. This subgroup included 9 trials comprising 1270 patients. The overall risk difference was 0.3% (95% CI −2.7%, 3.3%), consistent with the primary findings that short-course antibiotic treatment is non-inferior to long-course antibiotic treatment. None of these 4 studies examined mortality; thus, the meta-analyses for short-term and long-term mortality are unaffected.

Disclosures

Dr. Royer holds stock in Pfizer. The authors have no other potential financial conflicts of interest to report.

Funding

This work was supported by K08 GM115859 [HCP]. This manuscript does not necessarily represent the position or policy of the US government or the Department of Veterans Affairs.

Introduction

Acute myeloid leukemia (AML) comprises a heterogeneous group of disorders characterized by proliferation of clonal, abnormally differentiated hematopoietic progenitor cells of myeloid lineage that infiltrate the bone marrow, blood, and other tissues.¹ In most cases, AML is rapidly fatal if left untreated. Over the past 2 decades, our understanding of the underlying disease biology responsible for the development of AML has improved substantially. We have learned that biological differences drive the various clinical, cytogenetic, and molecular subentities of AML; distinguishing among these subentities helps to identify optimal therapies, while offering improved clinical outcomes for select groups. After years of stagnation in therapeutic advances, 4 new drugs for treating AML were approved by the US Food and Drug Administration (FDA) in 2017. In this article, we review key features of AML diagnosis and management in the context of 2 case presentations.

Epidemiology and Risk Factors

An estimated 21,380 new cases of AML were diagnosed in the United States in 2017, constituting roughly 1.3% of all new cases of cancer.² Approximately 10,590 patients died of AML in 2017. The median age of patients at the time of diagnosis is 68 years, and the incidence is approximately 4.2 per 100,000 persons per year. The 5-year survival for AML has steadily risen from a meager 6.3% in 1975 to 17.3% in 1995 and 28.1% in 2009.² The cure rates for AML vary drastically with age. Long-term survival is achieved in approximately 35% to 40% of adults who present at age 60 years or younger, but only 5% to 15% of those older than 60 years at presentation will achieve long-term survival.³

Most cases of AML occur in the absence of any known risk factors. High-dose radiation exposure, chronic benzene exposure, chronic tobacco smoking, and certain chemotherapeutics are known to increase the risk for AML.⁴ Inconsistent correlations have also been made between exposure to organic solvents, petroleum products, radon, pesticides, and herbicides and the development of AML.⁴ Obesity may also increase AML risk.⁴

Two distinct subcategories of therapy-related AML (t-AML) are known. Patients who have been exposed to alkylating chemotherapeutics (eg, melphalan, cyclophosphamide, and nitrogen mustard) can develop t-AML with chromosomal 5 and/or 7 abnormalities after a latency period of approximately 4 to 8 years.⁵ In contrast, patients exposed to topoisomerase II inhibitors (notably etoposide) develop AML with abnormalities of 11q23 (leading to MLL gene rearrangement) or 21q22 (RUNX1) after a latency period of about 1 to 3 years.⁶ AML can also arise out of other myeloid disorders such as myelodysplastic syndrome and myeloproliferative neoplasms, and other bone marrow failure syndromes such as aplastic anemia.⁴ Various inherited or congenital conditions such as Down syndrome, Bloom syndrome, Fanconi anemia, neurofibromatosis 1, and dyskeratosis congenita can also predispose to the development of AML. A more detailed listing of conditions associated with AML can be found elsewhere.⁴

Molecular Landscape

The first cancer genome sequence was reported in an AML patient in 2008.⁷ Since then, various elegantly conducted studies have expanded our understanding of the molecular abnormalities in AML. The Cancer Genome Atlas Research Network analyzed the genomes of 200 cases of de novo AML in adults.⁸ Only 13 mutations were found on average, much fewer than the number of mutations in most adult cancers. Twenty-three genes were commonly mutated, and another 237 were mutated in 2 or more cases. Essentially, all cases had at least 1 nonsynonymous mutation in 1 of 9 categories of genes: transcription-factor fusions (18%), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation–related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), spliceosome-complex genes (14%), and cohesin-complex genes (13%).

In another study, samples from 1540 patients from 3 prospective trials of intensive chemotherapy were analyzed to understand how genetic diversity defines the pathophysiology of AML.⁹ The study authors identified 5234 driver mutations from 76 genes or genomic regions, with 2 or more drivers identified in 86% of the samples. Eleven classes of mutational events, each with distinct diagnostic features and clinical outcomes, were identified. Acting as an internal positive control in this analysis, previously recognized mutational and cytogenetic groups emerged as distinct entities, including the groups with biallelic CEBPA mutations, mutations in NPM1, MLL fusions, and the cytogenetic entities t(6;9), inv(3), t(8;21), t(15;17), and inv(16). Three additional categories emerged as distinct entities: AML with mutations in genes encoding chromatin, RNA splicing regulators, or both (18% of patients); AML with TP53 mutations, chromosomal aneuploidies, or both (13%); and, provisionally, AML with IDH2R172 mutations (1%). An additional level of complexity was also revealed within the subgroup of patients with NPM1 mutations, where gene–gene interactions identified co-mutational events associated with both favorable or adverse prognosis.

Further supporting this molecular classification of AML, a study that performed targeted mutational analysis of 194 patients with defined secondary AML (s-AML) or t-AML and 105 unselected AML patients found that the presence of mutations in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 (all members of the chromatin or RNA splicing families) was highly specific for the diagnosis of s-AML.¹⁰ These findings are particularly clinically useful in those without a known history of antecedent hematologic disorder. These mutations defining the AML ontogeny were found to occur early in leukemogenesis, persist in clonal remissions, and predict worse clinical outcomes. Mutations in genes involved in regulation of DNA modification and of chromatin state (commonly DNMT3A, ASXL1, and TET2) have also been shown to be present in preleukemic stem or progenitor cells and to occur early in leukemogenesis.³ Unsurprisingly, some of these same mutations, including those in epigenetic regulators (DNMT3A, ASXL1, and TET2) and less frequently in splicing factor genes (SF3B1, SRSF2), have been associated with clonal hematopoietic expansion in elderly, seemingly healthy adults, a condition termed clonal hematopoiesis of indeterminate potential (CHIP).^3,11,12 The presence of CHIP is associated with increased risk of hematologic neoplasms and all-cause mortality, the latter being possibly driven by a near doubling in the risk of coronary heart disease in humans and by accelerated atherosclerosis in a mouse model.^11,13,14

Clinical Presentation and Work-up

Case Patient 1

A 57-year-old woman with a history of hypertension presents to the emergency department with complaints of productive cough and fevers for the previous 3 days. Examination reveals conjunctival pallor, gingival hyperplasia, and decreased breath sounds at the posterior right lung field. Investigations reveal a white blood cell (WBC) count of 51,000/µL with 15% blasts, a hemoglobin of 7.8 g/dL, and a platelet count of 56 × 10³/µL. Peripheral blood smear is notable for large myeloblasts with occasional Auer rods. Chest radiograph shows a consolidation in the right lower lobe.

Case Patient 2

A 69-year-old man presents to his primary care physician for evaluation of worsening fatigue for the previous 4 months. Ten years prior to presentation, he had received 6 cycles of RCHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) as treatment for diffuse large B-cell lymphoma. Conjunctival pallor, patches of purpura over the extremities, and mucosal petechiae are noted on examination. Laboratory analyisis reveals a WBC count of 2400/µL with 12% blasts, hemoglobin of 9.0 g/dL, and platelet count of 10 × 10³/µL. Peripheral smear shows dysplastic myeloid cells and blasts.

Clinical Features

Patients with AML typically present with features secondary to proliferation of blasts (ie, findings of bone marrow failure and end organ damage).^4,5 Fatigue, pallor, dizziness, dyspnea, and headaches occur secondary to anemia. Easy and prolonged bruising, petechiae, epistaxis, gingival bleeding, and conjunctival hemorrhages result from thrombocytopenia. Bleeding from other sites such as the central nervous system and gastrointestinal tract occurs but is uncommon. Patients may also present with infections resulting from unrecognized neutropenia. Constitutional symptoms including anorexia, fevers, and weight loss are frequently reported, while organomegaly (hepatomegaly and/or splenomegaly) is seen in about a quarter of patients.⁴ Infiltration of blasts into almost every organ has been noted, a condition known as myeloid (or granulocytic) sarcoma.¹⁵ This condition is more commonly found in patients with blastic, monoblastic, or myelomonocytic variants of AML, and is known as isolated myeloid sarcoma if no concurrent marrow or blood involvement is identified. In the absence of induction chemotherapy, systemic involvement occurs in a matter of weeks to months following such presentation.¹⁶

Laboratory analysis will usually demonstrate derangements in peripheral blood cell lines. At least half of patients have a total WBC count less than 5000/µL, a platelet count less than 50 × 10³/µL, or both at the time of diagnosis.^4,17 Approximately 10% of patients present with hyperleukocytosis and a WBC count greater than 100,000/µL, which can be associated with leukostasis.⁵ Additionally, spontaneous electrolyte derangement consistent with tumor lysis syndrome and coagulation abnormalities found in disseminated intravascular coagulation may be noted, even before initiation of therapy.

Work-Up of Suspected AML

Bone marrow biopsy and aspirate, along with touch preparations of the core biopsy sample, are crucial in the workup of suspected AML. At least 200 WBCs on blood smears and 500 nucleated cells on spiculated marrow smears should be counted.³ Reactivity with specific histochemical stains (myeloperoxidase, Sudan black B, or naphthyl AS-D-chloroacetate), presence of Auer rods, and reactivity to monoclonal antibodies against epitopes present on myeloblasts (eg, CD13, CD33, CD117) help distinguish myeloblasts from lymphoblasts.⁴ Flow cytometric analysis helps in confirming myeloid lineage; blasts generally express CD34 and HLA-DR, markers of immature hematopoietic precursors, and dim CD45 (common leukocyte antigen). One or more lymphoid antigens may be aberrantly expressed as well. Of note, in about 2% to 3% of acute leukemia cases, immunohistochemistry and/or flow cytometry findings demonstrate immature cells with features of both myeloid and lymphoid lineages (biphenotypic) or different populations of myeloid and lymphoid leukemia cells (bilineal). These leukemias are termed mixed-phenotype acute leukemia and are typically treated with either AML or acute lymphoblastic leukemia regimens.¹⁸

Cytogenetics, as assessed through conventional karyotype and fluorescence in situ hybridization (FISH), constitutes an essential part of the work-up. Eight balanced translocations and inversions and their variants are included in the World Health Organization (WHO) category “AML with recurrent genetic abnormalities,” while 9 balanced rearrangements and multiple unbalanced abnormalities in the presence of a blast count ≥ 20% are sufficient to establish the diagnosis of “AML with myelodysplasia-related changes.”^3,19 Various other gene rearrangements thought to represent disease-initiating events are recognized as well, but these rearrangements do not yet formally define WHO disease categories.³ FISH can help detect RUNX1-RUNX1T1, CBFB-MYH11, KMT2A (MLL), and MECOM (EVI1) gene fusions, as well as chromosomal changes like 5q, 7q, or 17p, especially when fewer than 20 metaphases are assessable (due to failure of culture) by conventional cytogenetic methods.³

As certain molecular markers help with disease prognosis and the selection of personalized therapies, testing for these markers is recommended as part of a complete work-up of AML. The current standard of care is to test for nucleophosmin (NPM1), fms-like tyrosine kinase 3 (FLT3), and CEBPA mutations in all newly diagnosed patients.¹RUNX1 mutation analysis should also be considered as its presence defines a provisional WHO subcategory.¹⁹ In the case of FLT3, the analysis should include both internal tandem duplications (FLT3-ITD, associated with worse prognosis especially at high allelic ratio) and tyrosine-kinase domain mutations (FLT3-TKD; D835 and I836), especially now that FLT3 inhibitors are regularly used.²⁰ Most academic centers now routinely use next-generation sequencing–based panels to assess multiple mutations. 

Diagnosis and Classification

A marrow or blood blast (myeloblasts, monoblasts, megakaryoblasts, or promonocytes [considered blast equivalents]) count of ≥ 20% is required for AML diagnosis.^3,19 The presence of t(15;17), t(8;21), inv(16), or t(16;16), however, is considered diagnostic of AML irrespective of blast count.^3,19 The previously used French-American-British (FAB) classification scheme has been replaced by the WHO classification (Table 2), which takes into account the morphologic, cytogenetic, genetic, and clinical features of the leukemia. 

The category “AML with myelodysplasia-related changes” includes AML that has evolved out of an antecedent myelodysplastic syndrome, has ≥ 50% dysplasia in 2 or more lineages, or has myelodysplasia-related cytogenetic changes (eg, –5/del(5q), –7/del(7q), ≥ 3 cytogenetic abnormalities).¹⁹ “Therapy-related myeloid neoplasm,” or therapy-related AML, is diagnosed when the patient has previously received cytotoxic agents or ionizing radiation.¹⁹

Cases which do not meet the criteria for 1 of the previously mentioned categories are currently classified as “AML, not otherwise specified.” Further subclassification is pursued as per the older FAB scheme; however, no additional prognostic information is obtained in doing so.^3,19 Myeloid sarcoma is strictly not a subcategory of AML. Rather, it is an extramedullary mass of myeloid blasts that effaces the normal tissue architecture.¹⁶ Rarely, myeloid sarcoma can be present without systemic disease involvement; it is important to note that management of such cases is identical to management of overt AML.¹⁶

Finally, myeloid proliferations related to Down syndrome include 2 entities seen in children with Down syndrome.¹⁹ Transient abnormal myelopoiesis, seen in 10% to 30% of newborns with Down syndrome, presents with circulating blasts that resolve in a couple of months. Myeloid leukemia associated with Down syndrome is AML that occurs usually in the first 3 years of life and persists if not treated.¹⁹

Case 1 Continued

The presence of 15% blasts in the peripheral blood is concerning for, but not diagnostic of, AML. On the other hand, the presence of Auer rods is virtually pathognomonic for AML. Gingival hyperplasia in this patient may be reflective of extramedullary disease. Cytogenetics from the peripheral blood and marrow aspirate show inv(16) in 20 of 20 cells. Molecular panel is notable for mutation in c-KIT. As such, the patient is diagnosed with core-binding factor AML, which per the ELN classification is considered a favorable-risk AML. The presence of c-KIT mutation, however, confers a relatively worse outcome.

Case 2 Continued

Presence of pancytopenia in a patient who previously received cytotoxic chemotherapy is highly concerning for therapy-related myeloid neoplasm. The presence of 12% blasts in the peripheral blood does not meet the criteria for diagnosis of AML. However, marrow specimens show 40% blasts, thus meeting the criteria for an AML diagnosis. Additionally, cytogenetics are notable for the presence of monosomy 7, while a next-generation sequencing panel shows a mutation in TP53. Put together, this patient meets the criteria for therapy-related AML which is an adverse-risk AML according to the ELN classification.

Management

The 2 most significant factors that must be considered when selecting AML therapies are the patient’s suitability for intensive chemotherapy and the biological characteristics of the AML. The former is a nuanced decision that incorporates age, performance status, and existing comorbidities. Treatment-related mortality calculators can guide physicians when making therapy decisions, especially in older patients (≥ 65 years). Retrospective evidence from various studies suggests that older, medically fit patients may derive clinically comparable benefits from intensive and less intensive induction therapies.^25–27 The biological characteristics of the leukemia can be suggested by morphologic findings, cytogenetics, and molecular information, in addition to a history of antecedent myeloid neoplasms. Recently, an AML composite model incorporating an augmented Hematopoietic Cell Transplantation–specific Comorbidity Index (HCT-CI) score, age, and cytogenetic/molecular risks was shown to improve treatment decision-making about AML; this model potentially could be used to guide patient stratification in clinical trials as well.²⁸ The overall treatment model of AML is largely unchanged otherwise. It is generally divided into induction, consolidation, and maintenance therapies.

Induction Therapy

In patients who can tolerate intensive therapies, the role of anthracycline- and cytarabine-based treatment is well established. However, the choice of specific anthracycline is not well established. One study concluded that idarubicin and mitoxantrone led to better outcomes as compared to daunorubicin, while another showed no difference between these agents.^29,30 A pooled study of AML trials conducted in patients aged 50 years and older showed that while idarubicin led to a higher complete remission rate (69% versus 61%), the overall survival (OS) did not differ significantly.³¹ As for dosing, daunorubicin given at 45 mg/m² daily for 3 days has been shown to have lower complete remission rates and higher relapse rates than a dose of 90 mg/m² daily for 3 days in younger patients.^32–34 However, it is not clear whether the 90 mg/m² dose is superior to the frequently used dose of 60 mg/m².³⁵ A French study has shown comparable rates of complete remission, relapse, and OS between the 60 mg/m² and 90 mg/m² doses in patients with intermediate or unfavorable cytogenetics.³⁶

If idarubicin is used, a dose of 12 mg/m² for 3 days is considered the standard. In patients aged 50 to 70 years, there were no statistically significant differences in rates of relapse or OS between daunorubicin 80 mg/m² for 3 days versus idarubicin 12 mg/m² for 3 days versus idarubicin 12 mg/m² for 4 days.³⁷ As for cytarabine, the bulk of the evidence indicates that a dose of 1000 mg/m² or higher should not be used.³⁸ As such, the typical induction chemotherapy regimen of choice is 3 days of anthracycline (daunorubicin or idarubicin) and 7 days of cytarabine (100–200 mg/m² continuous infusion), also known as the 7+3 regimen, which was first pioneered in the 1970s. In a recent phase 3 trial, 309 patients aged 60 to 75 years with high-risk AML (AML with myelodysplasia-related changes or t-AML) were randomly assigned to either the 7+3 regimen or CPX-351 (ie, nano-liposomal encapsulation of cytarabine and daunorubicin in a 5:1 molar ratio).³⁹ A higher composite complete response rate (47.7% versus 33.3%; P = 0.016) and improved survival (9.56 months versus 5.95 months; hazard ratio [HR] 0.69, P = 0.005) were seen with CPX-351, leading to its approval by the FDA in patients with high-risk AML.

The 7+3 regimen has served as a backbone onto which other drugs have been added in clinical trials—the majority without any clinical benefits—for patients who can tolerate intensive therapy. In this context, the role of 2 therapies recently approved by the FDA must be discussed. In the RATIFY trial, 717 patients aged 18 to 59 years with AML and a FLT3 mutation were randomly assigned to receive standard chemotherapy (induction and consolidation therapy) plus either midostaurin or placebo; those who were in remission after consolidation therapy received either midostaurin or placebo in the maintenance phase.⁴⁰ The primary endpoint was met as midostaurin improved OS (HR 0.78, P = 0.009). The benefit of midostaurin was consistent across all FLT3 subtypes and mutant allele burdens, regardless of whether patients proceeded to allogeneic stem cell transplant (allo-SCT). Based on the results of RATIFY, midostaurin was approved by the FDA for treatment of AML patients who are positive for the FLT3 mutation. Whether more potent and selective FLT3 inhibitors like gilteritinib, quizartinib, or crenolanib improve the outcomes is currently under investigation in various clinical trials.²⁰

The development of gemtuzumab ozogamicin (GO) has been more complicated. GO, an antibody-drug conjugate comprised of a CD33-directed humanized monoclonal antibody linked covalently to the cytotoxic agent calicheamicin, binds CD33 present on the surface of myeloid leukemic blasts and immature normal cells of myelomonocytic lineage.⁴¹ The drug first received an accelerated approval in 2000 as monotherapy (2 doses of 9 mg/m² 14 days apart) for the treatment of patients 60 years of age and older with CD33-positive AML in first relapse based on the results of 3 open-label multicenter trials.^41,42 However, a confirmatory S0106 trial in which GO 6 mg/m² was added on day 4 in newly diagnosed AML patients was terminated early when an interim analysis showed an increased rate of death in induction (6% versus 1%) and lack of improvement in complete response, disease-free survival, or OS with the addition of GO.⁴³ This study led to the withdrawal of GO from the US market in 2010. However, 2 randomized trials that studied GO using a different dose and schedule suggested that the addition of GO to intensive chemotherapy improved survival outcomes in patients with favorable and intermediate-risk cytogenetics.^44,45 The results of the multicenter, open-label phase 3 ALFA-0701 trial, which randomly assigned 271 patients aged 50 to 70 years with newly diagnosed AML to daunorubicin and cytarabine alone or in combination with GO (3 mg/m² on days 1, 4, and 7 during induction and day 1 of 2 consolidation courses), showed a statistically significant improvement in event-free survival (17.3 months versus 9.5 months; HR 0.56 [95% confidence interval 0.42 to 0.76]).⁴⁵ Again, the survival benefits were more pronounced in patients with favorable or intermediate-risk cytogenetics than in those with unfavorable cytogenetics. The results of this trial led to the re-approval of GO in newly diagnosed AML patients. 


For patients who cannot tolerate intensive therapies, the 2 main therapeutic options are low-dose cytarabine (LDAC) and the hypomethylating agents (HMA) azacitidine and decitabine. A phase 3 trial of decitabine versus mostly LDAC (or best supportive care, BSC) demonstrated favorable survival with decitabine (7.7 months versus 5.0 months).⁴⁶ In the AZA-AML-001 trial, azacitidine improved median survival (10.4 months versus 6.5 months) in comparison to the control arm (LDAC, 7+3, BSC).⁴⁷ Emerging data has also suggested that HMAs may be particularly active in patients with unfavorable-risk AML, a group for which LDAC has been shown to be especially useless.⁴⁸ As such, HMA therapies are generally preferred over LDAC in practice. Finally, it is pertinent to note that GO can also be used as monotherapy based on the results of the open-label phase 3 AML-19 study in which GO demonstrated a survival advantage over BSC (4.9 months versus 3.6 months, P = 0.005).⁴⁹

Postremission or Consolidation Therapy

There is no standard consolidation therapy for AML at present. In general, for patients who received HMA in the induction phase, the same HMA should be continued indefinitely until disease progression or allo-SCT.³ For those who received intensive chemotherapy in the induction phase, the consensus is to use cytarabine-based consolidation therapies. Cytarabine given as a single agent in high-doses has generally led to similar outcomes as multiagent chemotherapy.⁵⁰ In this regard, cytarabine regimens, with or without anthracycline, at 3000 mg/m² have similar efficacy as an intermediate dose of 1000 mg/m².³⁸ A total of 2 to 4 cycles of post-remission therapy is considered standard.³ Intensified post-remission chemotherapy has not been associated with consistent benefit in older AML patients or those with poor-risk disease. In recent years, measurable residual disease (MRD) assessment has emerged as a potentially useful tool in risk stratification and treatment planning, with various studies suggesting that MRD status in complete remission is one of the most important prognostic factors.⁵¹ Prospective studies confirming the significance of MRD as a marker for therapy selection are awaited. Finally, maintenance chemotherapy is not part of standard AML treatment.³

Role of Stem Cell Transplant

AML is the most common indication for allo-SCT. The availability of alternative donor strategies, which include mismatched, unrelated, haplo-identical, and cord blood donor sources, and the development of non-myeloablative and reduced-intensity conditioning (RIC) regimens (which take advantage of graft-versus-leukemia effect while decreasing cytotoxicity from myeloablative regimens) have expanded the possibility of allo-SCT to most patients under the age of 75 years.³ The decision to perform transplant is now largely based upon assessment of the risk (nonrelapse mortality) to benefit (reduction in risk of relapse) ratio, as determined by both disease-related features (cytogenetics, molecular profile) and clinical characteristics of the donor (type, availability, match) and the recipient (comorbidities, performance status).³ In a meta-analysis of 24 prospective trials involving more than 6000 AML patients in first complete remission, allo-SCT was associated with a significant survival benefit in patients with intermediate- and poor-risk AML but not in patients with good-risk AML.⁵² In line with this, good-risk AML patients are generally not recommended for transplant in first complete remission. For patients with normal karyotype who were said to have de novo AML (historically an intermediate-risk AML group), superior OS was demonstrated with transplant over intensive chemotherapy in those patients with either FLT3-ITD mutations or those with the molecular profile characterized by negativity for mutations in NPM1/CEBPA/FLT3.⁵³ For patients with primary refractory disease and high-risk AML, transplant is probably the only curative option.

The choice of conditioning regimen is guided by several factors, including the subtype of AML, disease status, donor-recipient genetic disparity, graft source, comorbidities in the recipient (ie, tolerability for intensive conditioning regimen), as well as the reliance on graft-versus-leukemia effect as compared to cytotoxic effect of the regimen. The BMT CTN 0901 trial, which randomly assigned 218 patients aged 18 to 65 years to RIC (typically fludarabine/busulfan) or myeloablative regimens, showed an advantage for myeloablative regimens.⁵⁴ The trial demonstrated a lower risk of relapse (13.5% versus 48.3%, P < 0.01) and higher rates of relapse-free survival (67.7% versus 47.3%, P < 0.01) and OS (67.7% versus. 77.4%, P = 0.07) at 18 months despite higher treatment-related mortality (15.8% versus 4.4%, P = 0.02) and a higher rate of grade 2 to 4 acute graft-versus-host disease (44.7% versus 31.6%, P = 0.024). At present, a RIC regimen is generally recommended for older patients or those with a higher comorbidity burden, while the myeloablative regimen is recommended for younger, fit patients.

Relapsed/Refractory Disease

The treatment of relapsed and refractory AML constitutes a major challenge, with OS estimated around 10% at 3 years.⁵⁵ Currently, there is no standard salvage therapy in this setting, thus underscoring the need for clinical trials. For younger, fitter patients, the typical approach is to use intensive chemotherapy to achieve a second complete remission followed by a stem cell transplant. In younger patients, a second complete remission is achievable in about 55% of patients, although this rate is lower (~20%–30%) in more unselected patients.^56,57 About two thirds of those who achieve complete remission may be able to proceed to transplant.⁵⁷ For older patients where transplant is not possible, the goal is to use less intensive therapies that help with palliation. HMAs (azacitidine, decitabine) are used and have complete remission rates of 16% to 21% and median survival of 6 to 9 months in older patients.³ LDAC is another option in this setting. The recent approval of GO in this setting has further expanded the options. This approval was based on the outcomes of the phase 2 single-arm MyloFrance-1 study in which single-agent GO administered at 3 mg/m² on days 1, 4, and 7 led to complete remission in 15 of 57 patients.⁵⁸

With greater elucidation of the molecular characteristics of AML, the emergence of more effective targeted therapies is possible. Enasidenib, an inhibitor of mutant isocitrate dehydrogenase 2 (IDH2) protein that promotes differentiation of leukemic myeloblasts, recently received regulatory approval based on a single-arm trial. The overall response rate in this study was 38.5%, including a composite complete remission rate of 26.6% at a dose of 100 mg daily.⁵⁹ IDH differentiation syndrome, akin to the differentiation syndrome seen in acute promyelocytic leukemia, occurred in approximately 12% of the patients, with the most frequent manifestations being dyspnea, fever, pulmonary infiltrates, and hypoxia.⁶⁰

Survival of patients who relapse following transplant is particularly poor. A recent Center for International Blood and Marrow Transplant Research study found a 3-year OS ranging from a dismal 4% for those who present with early relapses (within 1 to 6 months) post-transplant to a more modest 38% for those who relapsed ≥ 3 years after their first transplant.⁶¹ The German Cooperative Transplant Study Group have suggested that azacitidine or chemotherapy followed by donor-lymphocyte infusions might improve responses over chemotherapy alone.⁶² Ipilimumab-based CTLA-4 blockade was reported to produce responses in a small cohort of patients, which was particularly notable in patients presenting with extramedullary manifestations of relapse.⁶³ In patients who are otherwise fit but have a florid relapse, a second transplant can sometimes be sought, but the value of a different donor for second transplant is unclear.³

Case 1 Conclusion

Given his relatively young age, suitability for intensive therapy, and the presence of a core- binding factor abnormality, the patient is treated with an induction regimen containing daunorubicin, cytarabine, and GO (7+3 + GO). He achieves complete remission. This is followed by consolidation chemotherapy with high-dose cytarabine and GO. Allo-SCT is reserved for later should the AML relapse. Note that dasatinib, a c-KIT inhibitor, can be added to the treatment regimens as per the results of the CALGB 10801 protocol.⁶⁴ Also, autologous SCT, instead of allo-SCT, can be considered in rare situations with relapsed core-binding factor AML (especially with inv(16) AML, younger patients, longer time in complete remission prior to relapse, and use of GO).

Case 2 Conclusion

The patient is deemed suitable for intensive chemotherapy. As such, CPX-351 is given in induction and consolidation and complete remission is achieved. Because he has adverse-risk AML, an allo-SCT is planned, but the patient relapses before it can be performed. Following 3 courses of decitabine therapy, the patient achieves complete remission once again but declines transplant. He maintains remission for an additional 4 months but then the leukemia progresses. Clinical trials are recommended to the patient, but he decides to pursue hospice care.

Conclusion

AML is the most common acute leukemia in adults. As defined currently, AML represents a group of related but distinct myeloid disorders that are characterized by various chromosomal, genetic, and epigenetic alterations. Early diagnosis and treatment can help prevent the emergence or manage the detrimental effects of its various complications such as leukostasis and tumor lysis syndrome. Improvements in supportive care, incremental treatment advances, and the wide adoption of allo-SCT for less than favorable cases have significantly improved survival of AML patients since the initial design of combinatorial (7+3) induction chemotherapy, particularly in patients presenting at a younger age. HMAs and the emergence of targeted therapies like FLT-3 and IDH2 inhibitors have added to our therapeutic armamentarium. Despite these advances, long-term survival rates in AML patients continue to be only approximately 40% to 50%. Older patients (particularly those over age 65 at the time of diagnosis), those with relapsed disease, and those with AML with certain unfavorable genetic abnormalities continue to have dismal outcomes. The design of newer targeted therapies, epigenetic agents, and immunotherapies will hopefully address this unmet need.

Introduction

Acute myeloid leukemia (AML) comprises a heterogeneous group of disorders characterized by proliferation of clonal, abnormally differentiated hematopoietic progenitor cells of myeloid lineage that infiltrate the bone marrow, blood, and other tissues.¹ In most cases, AML is rapidly fatal if left untreated. Over the past 2 decades, our understanding of the underlying disease biology responsible for the development of AML has improved substantially. We have learned that biological differences drive the various clinical, cytogenetic, and molecular subentities of AML; distinguishing among these subentities helps to identify optimal therapies, while offering improved clinical outcomes for select groups. After years of stagnation in therapeutic advances, 4 new drugs for treating AML were approved by the US Food and Drug Administration (FDA) in 2017. In this article, we review key features of AML diagnosis and management in the context of 2 case presentations.

Epidemiology and Risk Factors

An estimated 21,380 new cases of AML were diagnosed in the United States in 2017, constituting roughly 1.3% of all new cases of cancer.² Approximately 10,590 patients died of AML in 2017. The median age of patients at the time of diagnosis is 68 years, and the incidence is approximately 4.2 per 100,000 persons per year. The 5-year survival for AML has steadily risen from a meager 6.3% in 1975 to 17.3% in 1995 and 28.1% in 2009.² The cure rates for AML vary drastically with age. Long-term survival is achieved in approximately 35% to 40% of adults who present at age 60 years or younger, but only 5% to 15% of those older than 60 years at presentation will achieve long-term survival.³

Most cases of AML occur in the absence of any known risk factors. High-dose radiation exposure, chronic benzene exposure, chronic tobacco smoking, and certain chemotherapeutics are known to increase the risk for AML.⁴ Inconsistent correlations have also been made between exposure to organic solvents, petroleum products, radon, pesticides, and herbicides and the development of AML.⁴ Obesity may also increase AML risk.⁴

Two distinct subcategories of therapy-related AML (t-AML) are known. Patients who have been exposed to alkylating chemotherapeutics (eg, melphalan, cyclophosphamide, and nitrogen mustard) can develop t-AML with chromosomal 5 and/or 7 abnormalities after a latency period of approximately 4 to 8 years.⁵ In contrast, patients exposed to topoisomerase II inhibitors (notably etoposide) develop AML with abnormalities of 11q23 (leading to MLL gene rearrangement) or 21q22 (RUNX1) after a latency period of about 1 to 3 years.⁶ AML can also arise out of other myeloid disorders such as myelodysplastic syndrome and myeloproliferative neoplasms, and other bone marrow failure syndromes such as aplastic anemia.⁴ Various inherited or congenital conditions such as Down syndrome, Bloom syndrome, Fanconi anemia, neurofibromatosis 1, and dyskeratosis congenita can also predispose to the development of AML. A more detailed listing of conditions associated with AML can be found elsewhere.⁴

Molecular Landscape

The first cancer genome sequence was reported in an AML patient in 2008.⁷ Since then, various elegantly conducted studies have expanded our understanding of the molecular abnormalities in AML. The Cancer Genome Atlas Research Network analyzed the genomes of 200 cases of de novo AML in adults.⁸ Only 13 mutations were found on average, much fewer than the number of mutations in most adult cancers. Twenty-three genes were commonly mutated, and another 237 were mutated in 2 or more cases. Essentially, all cases had at least 1 nonsynonymous mutation in 1 of 9 categories of genes: transcription-factor fusions (18%), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation–related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), spliceosome-complex genes (14%), and cohesin-complex genes (13%).

In another study, samples from 1540 patients from 3 prospective trials of intensive chemotherapy were analyzed to understand how genetic diversity defines the pathophysiology of AML.⁹ The study authors identified 5234 driver mutations from 76 genes or genomic regions, with 2 or more drivers identified in 86% of the samples. Eleven classes of mutational events, each with distinct diagnostic features and clinical outcomes, were identified. Acting as an internal positive control in this analysis, previously recognized mutational and cytogenetic groups emerged as distinct entities, including the groups with biallelic CEBPA mutations, mutations in NPM1, MLL fusions, and the cytogenetic entities t(6;9), inv(3), t(8;21), t(15;17), and inv(16). Three additional categories emerged as distinct entities: AML with mutations in genes encoding chromatin, RNA splicing regulators, or both (18% of patients); AML with TP53 mutations, chromosomal aneuploidies, or both (13%); and, provisionally, AML with IDH2R172 mutations (1%). An additional level of complexity was also revealed within the subgroup of patients with NPM1 mutations, where gene–gene interactions identified co-mutational events associated with both favorable or adverse prognosis.

Further supporting this molecular classification of AML, a study that performed targeted mutational analysis of 194 patients with defined secondary AML (s-AML) or t-AML and 105 unselected AML patients found that the presence of mutations in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 (all members of the chromatin or RNA splicing families) was highly specific for the diagnosis of s-AML.¹⁰ These findings are particularly clinically useful in those without a known history of antecedent hematologic disorder. These mutations defining the AML ontogeny were found to occur early in leukemogenesis, persist in clonal remissions, and predict worse clinical outcomes. Mutations in genes involved in regulation of DNA modification and of chromatin state (commonly DNMT3A, ASXL1, and TET2) have also been shown to be present in preleukemic stem or progenitor cells and to occur early in leukemogenesis.³ Unsurprisingly, some of these same mutations, including those in epigenetic regulators (DNMT3A, ASXL1, and TET2) and less frequently in splicing factor genes (SF3B1, SRSF2), have been associated with clonal hematopoietic expansion in elderly, seemingly healthy adults, a condition termed clonal hematopoiesis of indeterminate potential (CHIP).^3,11,12 The presence of CHIP is associated with increased risk of hematologic neoplasms and all-cause mortality, the latter being possibly driven by a near doubling in the risk of coronary heart disease in humans and by accelerated atherosclerosis in a mouse model.^11,13,14

Clinical Presentation and Work-up

Case Patient 1

A 57-year-old woman with a history of hypertension presents to the emergency department with complaints of productive cough and fevers for the previous 3 days. Examination reveals conjunctival pallor, gingival hyperplasia, and decreased breath sounds at the posterior right lung field. Investigations reveal a white blood cell (WBC) count of 51,000/µL with 15% blasts, a hemoglobin of 7.8 g/dL, and a platelet count of 56 × 10³/µL. Peripheral blood smear is notable for large myeloblasts with occasional Auer rods. Chest radiograph shows a consolidation in the right lower lobe.

Case Patient 2

A 69-year-old man presents to his primary care physician for evaluation of worsening fatigue for the previous 4 months. Ten years prior to presentation, he had received 6 cycles of RCHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) as treatment for diffuse large B-cell lymphoma. Conjunctival pallor, patches of purpura over the extremities, and mucosal petechiae are noted on examination. Laboratory analyisis reveals a WBC count of 2400/µL with 12% blasts, hemoglobin of 9.0 g/dL, and platelet count of 10 × 10³/µL. Peripheral smear shows dysplastic myeloid cells and blasts.

Clinical Features

Patients with AML typically present with features secondary to proliferation of blasts (ie, findings of bone marrow failure and end organ damage).^4,5 Fatigue, pallor, dizziness, dyspnea, and headaches occur secondary to anemia. Easy and prolonged bruising, petechiae, epistaxis, gingival bleeding, and conjunctival hemorrhages result from thrombocytopenia. Bleeding from other sites such as the central nervous system and gastrointestinal tract occurs but is uncommon. Patients may also present with infections resulting from unrecognized neutropenia. Constitutional symptoms including anorexia, fevers, and weight loss are frequently reported, while organomegaly (hepatomegaly and/or splenomegaly) is seen in about a quarter of patients.⁴ Infiltration of blasts into almost every organ has been noted, a condition known as myeloid (or granulocytic) sarcoma.¹⁵ This condition is more commonly found in patients with blastic, monoblastic, or myelomonocytic variants of AML, and is known as isolated myeloid sarcoma if no concurrent marrow or blood involvement is identified. In the absence of induction chemotherapy, systemic involvement occurs in a matter of weeks to months following such presentation.¹⁶

Laboratory analysis will usually demonstrate derangements in peripheral blood cell lines. At least half of patients have a total WBC count less than 5000/µL, a platelet count less than 50 × 10³/µL, or both at the time of diagnosis.^4,17 Approximately 10% of patients present with hyperleukocytosis and a WBC count greater than 100,000/µL, which can be associated with leukostasis.⁵ Additionally, spontaneous electrolyte derangement consistent with tumor lysis syndrome and coagulation abnormalities found in disseminated intravascular coagulation may be noted, even before initiation of therapy.

Work-Up of Suspected AML

Bone marrow biopsy and aspirate, along with touch preparations of the core biopsy sample, are crucial in the workup of suspected AML. At least 200 WBCs on blood smears and 500 nucleated cells on spiculated marrow smears should be counted.³ Reactivity with specific histochemical stains (myeloperoxidase, Sudan black B, or naphthyl AS-D-chloroacetate), presence of Auer rods, and reactivity to monoclonal antibodies against epitopes present on myeloblasts (eg, CD13, CD33, CD117) help distinguish myeloblasts from lymphoblasts.⁴ Flow cytometric analysis helps in confirming myeloid lineage; blasts generally express CD34 and HLA-DR, markers of immature hematopoietic precursors, and dim CD45 (common leukocyte antigen). One or more lymphoid antigens may be aberrantly expressed as well. Of note, in about 2% to 3% of acute leukemia cases, immunohistochemistry and/or flow cytometry findings demonstrate immature cells with features of both myeloid and lymphoid lineages (biphenotypic) or different populations of myeloid and lymphoid leukemia cells (bilineal). These leukemias are termed mixed-phenotype acute leukemia and are typically treated with either AML or acute lymphoblastic leukemia regimens.¹⁸

Cytogenetics, as assessed through conventional karyotype and fluorescence in situ hybridization (FISH), constitutes an essential part of the work-up. Eight balanced translocations and inversions and their variants are included in the World Health Organization (WHO) category “AML with recurrent genetic abnormalities,” while 9 balanced rearrangements and multiple unbalanced abnormalities in the presence of a blast count ≥ 20% are sufficient to establish the diagnosis of “AML with myelodysplasia-related changes.”^3,19 Various other gene rearrangements thought to represent disease-initiating events are recognized as well, but these rearrangements do not yet formally define WHO disease categories.³ FISH can help detect RUNX1-RUNX1T1, CBFB-MYH11, KMT2A (MLL), and MECOM (EVI1) gene fusions, as well as chromosomal changes like 5q, 7q, or 17p, especially when fewer than 20 metaphases are assessable (due to failure of culture) by conventional cytogenetic methods.³

As certain molecular markers help with disease prognosis and the selection of personalized therapies, testing for these markers is recommended as part of a complete work-up of AML. The current standard of care is to test for nucleophosmin (NPM1), fms-like tyrosine kinase 3 (FLT3), and CEBPA mutations in all newly diagnosed patients.¹RUNX1 mutation analysis should also be considered as its presence defines a provisional WHO subcategory.¹⁹ In the case of FLT3, the analysis should include both internal tandem duplications (FLT3-ITD, associated with worse prognosis especially at high allelic ratio) and tyrosine-kinase domain mutations (FLT3-TKD; D835 and I836), especially now that FLT3 inhibitors are regularly used.²⁰ Most academic centers now routinely use next-generation sequencing–based panels to assess multiple mutations. 

Diagnosis and Classification

A marrow or blood blast (myeloblasts, monoblasts, megakaryoblasts, or promonocytes [considered blast equivalents]) count of ≥ 20% is required for AML diagnosis.^3,19 The presence of t(15;17), t(8;21), inv(16), or t(16;16), however, is considered diagnostic of AML irrespective of blast count.^3,19 The previously used French-American-British (FAB) classification scheme has been replaced by the WHO classification (Table 2), which takes into account the morphologic, cytogenetic, genetic, and clinical features of the leukemia. 

The category “AML with myelodysplasia-related changes” includes AML that has evolved out of an antecedent myelodysplastic syndrome, has ≥ 50% dysplasia in 2 or more lineages, or has myelodysplasia-related cytogenetic changes (eg, –5/del(5q), –7/del(7q), ≥ 3 cytogenetic abnormalities).¹⁹ “Therapy-related myeloid neoplasm,” or therapy-related AML, is diagnosed when the patient has previously received cytotoxic agents or ionizing radiation.¹⁹

Cases which do not meet the criteria for 1 of the previously mentioned categories are currently classified as “AML, not otherwise specified.” Further subclassification is pursued as per the older FAB scheme; however, no additional prognostic information is obtained in doing so.^3,19 Myeloid sarcoma is strictly not a subcategory of AML. Rather, it is an extramedullary mass of myeloid blasts that effaces the normal tissue architecture.¹⁶ Rarely, myeloid sarcoma can be present without systemic disease involvement; it is important to note that management of such cases is identical to management of overt AML.¹⁶

Finally, myeloid proliferations related to Down syndrome include 2 entities seen in children with Down syndrome.¹⁹ Transient abnormal myelopoiesis, seen in 10% to 30% of newborns with Down syndrome, presents with circulating blasts that resolve in a couple of months. Myeloid leukemia associated with Down syndrome is AML that occurs usually in the first 3 years of life and persists if not treated.¹⁹

Case 1 Continued

The presence of 15% blasts in the peripheral blood is concerning for, but not diagnostic of, AML. On the other hand, the presence of Auer rods is virtually pathognomonic for AML. Gingival hyperplasia in this patient may be reflective of extramedullary disease. Cytogenetics from the peripheral blood and marrow aspirate show inv(16) in 20 of 20 cells. Molecular panel is notable for mutation in c-KIT. As such, the patient is diagnosed with core-binding factor AML, which per the ELN classification is considered a favorable-risk AML. The presence of c-KIT mutation, however, confers a relatively worse outcome.

Case 2 Continued

Presence of pancytopenia in a patient who previously received cytotoxic chemotherapy is highly concerning for therapy-related myeloid neoplasm. The presence of 12% blasts in the peripheral blood does not meet the criteria for diagnosis of AML. However, marrow specimens show 40% blasts, thus meeting the criteria for an AML diagnosis. Additionally, cytogenetics are notable for the presence of monosomy 7, while a next-generation sequencing panel shows a mutation in TP53. Put together, this patient meets the criteria for therapy-related AML which is an adverse-risk AML according to the ELN classification.

Management

The 2 most significant factors that must be considered when selecting AML therapies are the patient’s suitability for intensive chemotherapy and the biological characteristics of the AML. The former is a nuanced decision that incorporates age, performance status, and existing comorbidities. Treatment-related mortality calculators can guide physicians when making therapy decisions, especially in older patients (≥ 65 years). Retrospective evidence from various studies suggests that older, medically fit patients may derive clinically comparable benefits from intensive and less intensive induction therapies.^25–27 The biological characteristics of the leukemia can be suggested by morphologic findings, cytogenetics, and molecular information, in addition to a history of antecedent myeloid neoplasms. Recently, an AML composite model incorporating an augmented Hematopoietic Cell Transplantation–specific Comorbidity Index (HCT-CI) score, age, and cytogenetic/molecular risks was shown to improve treatment decision-making about AML; this model potentially could be used to guide patient stratification in clinical trials as well.²⁸ The overall treatment model of AML is largely unchanged otherwise. It is generally divided into induction, consolidation, and maintenance therapies.

Induction Therapy

In patients who can tolerate intensive therapies, the role of anthracycline- and cytarabine-based treatment is well established. However, the choice of specific anthracycline is not well established. One study concluded that idarubicin and mitoxantrone led to better outcomes as compared to daunorubicin, while another showed no difference between these agents.^29,30 A pooled study of AML trials conducted in patients aged 50 years and older showed that while idarubicin led to a higher complete remission rate (69% versus 61%), the overall survival (OS) did not differ significantly.³¹ As for dosing, daunorubicin given at 45 mg/m² daily for 3 days has been shown to have lower complete remission rates and higher relapse rates than a dose of 90 mg/m² daily for 3 days in younger patients.^32–34 However, it is not clear whether the 90 mg/m² dose is superior to the frequently used dose of 60 mg/m².³⁵ A French study has shown comparable rates of complete remission, relapse, and OS between the 60 mg/m² and 90 mg/m² doses in patients with intermediate or unfavorable cytogenetics.³⁶

If idarubicin is used, a dose of 12 mg/m² for 3 days is considered the standard. In patients aged 50 to 70 years, there were no statistically significant differences in rates of relapse or OS between daunorubicin 80 mg/m² for 3 days versus idarubicin 12 mg/m² for 3 days versus idarubicin 12 mg/m² for 4 days.³⁷ As for cytarabine, the bulk of the evidence indicates that a dose of 1000 mg/m² or higher should not be used.³⁸ As such, the typical induction chemotherapy regimen of choice is 3 days of anthracycline (daunorubicin or idarubicin) and 7 days of cytarabine (100–200 mg/m² continuous infusion), also known as the 7+3 regimen, which was first pioneered in the 1970s. In a recent phase 3 trial, 309 patients aged 60 to 75 years with high-risk AML (AML with myelodysplasia-related changes or t-AML) were randomly assigned to either the 7+3 regimen or CPX-351 (ie, nano-liposomal encapsulation of cytarabine and daunorubicin in a 5:1 molar ratio).³⁹ A higher composite complete response rate (47.7% versus 33.3%; P = 0.016) and improved survival (9.56 months versus 5.95 months; hazard ratio [HR] 0.69, P = 0.005) were seen with CPX-351, leading to its approval by the FDA in patients with high-risk AML.

The 7+3 regimen has served as a backbone onto which other drugs have been added in clinical trials—the majority without any clinical benefits—for patients who can tolerate intensive therapy. In this context, the role of 2 therapies recently approved by the FDA must be discussed. In the RATIFY trial, 717 patients aged 18 to 59 years with AML and a FLT3 mutation were randomly assigned to receive standard chemotherapy (induction and consolidation therapy) plus either midostaurin or placebo; those who were in remission after consolidation therapy received either midostaurin or placebo in the maintenance phase.⁴⁰ The primary endpoint was met as midostaurin improved OS (HR 0.78, P = 0.009). The benefit of midostaurin was consistent across all FLT3 subtypes and mutant allele burdens, regardless of whether patients proceeded to allogeneic stem cell transplant (allo-SCT). Based on the results of RATIFY, midostaurin was approved by the FDA for treatment of AML patients who are positive for the FLT3 mutation. Whether more potent and selective FLT3 inhibitors like gilteritinib, quizartinib, or crenolanib improve the outcomes is currently under investigation in various clinical trials.²⁰

The development of gemtuzumab ozogamicin (GO) has been more complicated. GO, an antibody-drug conjugate comprised of a CD33-directed humanized monoclonal antibody linked covalently to the cytotoxic agent calicheamicin, binds CD33 present on the surface of myeloid leukemic blasts and immature normal cells of myelomonocytic lineage.⁴¹ The drug first received an accelerated approval in 2000 as monotherapy (2 doses of 9 mg/m² 14 days apart) for the treatment of patients 60 years of age and older with CD33-positive AML in first relapse based on the results of 3 open-label multicenter trials.^41,42 However, a confirmatory S0106 trial in which GO 6 mg/m² was added on day 4 in newly diagnosed AML patients was terminated early when an interim analysis showed an increased rate of death in induction (6% versus 1%) and lack of improvement in complete response, disease-free survival, or OS with the addition of GO.⁴³ This study led to the withdrawal of GO from the US market in 2010. However, 2 randomized trials that studied GO using a different dose and schedule suggested that the addition of GO to intensive chemotherapy improved survival outcomes in patients with favorable and intermediate-risk cytogenetics.^44,45 The results of the multicenter, open-label phase 3 ALFA-0701 trial, which randomly assigned 271 patients aged 50 to 70 years with newly diagnosed AML to daunorubicin and cytarabine alone or in combination with GO (3 mg/m² on days 1, 4, and 7 during induction and day 1 of 2 consolidation courses), showed a statistically significant improvement in event-free survival (17.3 months versus 9.5 months; HR 0.56 [95% confidence interval 0.42 to 0.76]).⁴⁵ Again, the survival benefits were more pronounced in patients with favorable or intermediate-risk cytogenetics than in those with unfavorable cytogenetics. The results of this trial led to the re-approval of GO in newly diagnosed AML patients. 


For patients who cannot tolerate intensive therapies, the 2 main therapeutic options are low-dose cytarabine (LDAC) and the hypomethylating agents (HMA) azacitidine and decitabine. A phase 3 trial of decitabine versus mostly LDAC (or best supportive care, BSC) demonstrated favorable survival with decitabine (7.7 months versus 5.0 months).⁴⁶ In the AZA-AML-001 trial, azacitidine improved median survival (10.4 months versus 6.5 months) in comparison to the control arm (LDAC, 7+3, BSC).⁴⁷ Emerging data has also suggested that HMAs may be particularly active in patients with unfavorable-risk AML, a group for which LDAC has been shown to be especially useless.⁴⁸ As such, HMA therapies are generally preferred over LDAC in practice. Finally, it is pertinent to note that GO can also be used as monotherapy based on the results of the open-label phase 3 AML-19 study in which GO demonstrated a survival advantage over BSC (4.9 months versus 3.6 months, P = 0.005).⁴⁹

Postremission or Consolidation Therapy

There is no standard consolidation therapy for AML at present. In general, for patients who received HMA in the induction phase, the same HMA should be continued indefinitely until disease progression or allo-SCT.³ For those who received intensive chemotherapy in the induction phase, the consensus is to use cytarabine-based consolidation therapies. Cytarabine given as a single agent in high-doses has generally led to similar outcomes as multiagent chemotherapy.⁵⁰ In this regard, cytarabine regimens, with or without anthracycline, at 3000 mg/m² have similar efficacy as an intermediate dose of 1000 mg/m².³⁸ A total of 2 to 4 cycles of post-remission therapy is considered standard.³ Intensified post-remission chemotherapy has not been associated with consistent benefit in older AML patients or those with poor-risk disease. In recent years, measurable residual disease (MRD) assessment has emerged as a potentially useful tool in risk stratification and treatment planning, with various studies suggesting that MRD status in complete remission is one of the most important prognostic factors.⁵¹ Prospective studies confirming the significance of MRD as a marker for therapy selection are awaited. Finally, maintenance chemotherapy is not part of standard AML treatment.³

Role of Stem Cell Transplant

AML is the most common indication for allo-SCT. The availability of alternative donor strategies, which include mismatched, unrelated, haplo-identical, and cord blood donor sources, and the development of non-myeloablative and reduced-intensity conditioning (RIC) regimens (which take advantage of graft-versus-leukemia effect while decreasing cytotoxicity from myeloablative regimens) have expanded the possibility of allo-SCT to most patients under the age of 75 years.³ The decision to perform transplant is now largely based upon assessment of the risk (nonrelapse mortality) to benefit (reduction in risk of relapse) ratio, as determined by both disease-related features (cytogenetics, molecular profile) and clinical characteristics of the donor (type, availability, match) and the recipient (comorbidities, performance status).³ In a meta-analysis of 24 prospective trials involving more than 6000 AML patients in first complete remission, allo-SCT was associated with a significant survival benefit in patients with intermediate- and poor-risk AML but not in patients with good-risk AML.⁵² In line with this, good-risk AML patients are generally not recommended for transplant in first complete remission. For patients with normal karyotype who were said to have de novo AML (historically an intermediate-risk AML group), superior OS was demonstrated with transplant over intensive chemotherapy in those patients with either FLT3-ITD mutations or those with the molecular profile characterized by negativity for mutations in NPM1/CEBPA/FLT3.⁵³ For patients with primary refractory disease and high-risk AML, transplant is probably the only curative option.

The choice of conditioning regimen is guided by several factors, including the subtype of AML, disease status, donor-recipient genetic disparity, graft source, comorbidities in the recipient (ie, tolerability for intensive conditioning regimen), as well as the reliance on graft-versus-leukemia effect as compared to cytotoxic effect of the regimen. The BMT CTN 0901 trial, which randomly assigned 218 patients aged 18 to 65 years to RIC (typically fludarabine/busulfan) or myeloablative regimens, showed an advantage for myeloablative regimens.⁵⁴ The trial demonstrated a lower risk of relapse (13.5% versus 48.3%, P < 0.01) and higher rates of relapse-free survival (67.7% versus 47.3%, P < 0.01) and OS (67.7% versus. 77.4%, P = 0.07) at 18 months despite higher treatment-related mortality (15.8% versus 4.4%, P = 0.02) and a higher rate of grade 2 to 4 acute graft-versus-host disease (44.7% versus 31.6%, P = 0.024). At present, a RIC regimen is generally recommended for older patients or those with a higher comorbidity burden, while the myeloablative regimen is recommended for younger, fit patients.

Relapsed/Refractory Disease

The treatment of relapsed and refractory AML constitutes a major challenge, with OS estimated around 10% at 3 years.⁵⁵ Currently, there is no standard salvage therapy in this setting, thus underscoring the need for clinical trials. For younger, fitter patients, the typical approach is to use intensive chemotherapy to achieve a second complete remission followed by a stem cell transplant. In younger patients, a second complete remission is achievable in about 55% of patients, although this rate is lower (~20%–30%) in more unselected patients.^56,57 About two thirds of those who achieve complete remission may be able to proceed to transplant.⁵⁷ For older patients where transplant is not possible, the goal is to use less intensive therapies that help with palliation. HMAs (azacitidine, decitabine) are used and have complete remission rates of 16% to 21% and median survival of 6 to 9 months in older patients.³ LDAC is another option in this setting. The recent approval of GO in this setting has further expanded the options. This approval was based on the outcomes of the phase 2 single-arm MyloFrance-1 study in which single-agent GO administered at 3 mg/m² on days 1, 4, and 7 led to complete remission in 15 of 57 patients.⁵⁸

With greater elucidation of the molecular characteristics of AML, the emergence of more effective targeted therapies is possible. Enasidenib, an inhibitor of mutant isocitrate dehydrogenase 2 (IDH2) protein that promotes differentiation of leukemic myeloblasts, recently received regulatory approval based on a single-arm trial. The overall response rate in this study was 38.5%, including a composite complete remission rate of 26.6% at a dose of 100 mg daily.⁵⁹ IDH differentiation syndrome, akin to the differentiation syndrome seen in acute promyelocytic leukemia, occurred in approximately 12% of the patients, with the most frequent manifestations being dyspnea, fever, pulmonary infiltrates, and hypoxia.⁶⁰

Survival of patients who relapse following transplant is particularly poor. A recent Center for International Blood and Marrow Transplant Research study found a 3-year OS ranging from a dismal 4% for those who present with early relapses (within 1 to 6 months) post-transplant to a more modest 38% for those who relapsed ≥ 3 years after their first transplant.⁶¹ The German Cooperative Transplant Study Group have suggested that azacitidine or chemotherapy followed by donor-lymphocyte infusions might improve responses over chemotherapy alone.⁶² Ipilimumab-based CTLA-4 blockade was reported to produce responses in a small cohort of patients, which was particularly notable in patients presenting with extramedullary manifestations of relapse.⁶³ In patients who are otherwise fit but have a florid relapse, a second transplant can sometimes be sought, but the value of a different donor for second transplant is unclear.³

Case 1 Conclusion

Given his relatively young age, suitability for intensive therapy, and the presence of a core- binding factor abnormality, the patient is treated with an induction regimen containing daunorubicin, cytarabine, and GO (7+3 + GO). He achieves complete remission. This is followed by consolidation chemotherapy with high-dose cytarabine and GO. Allo-SCT is reserved for later should the AML relapse. Note that dasatinib, a c-KIT inhibitor, can be added to the treatment regimens as per the results of the CALGB 10801 protocol.⁶⁴ Also, autologous SCT, instead of allo-SCT, can be considered in rare situations with relapsed core-binding factor AML (especially with inv(16) AML, younger patients, longer time in complete remission prior to relapse, and use of GO).

Case 2 Conclusion

The patient is deemed suitable for intensive chemotherapy. As such, CPX-351 is given in induction and consolidation and complete remission is achieved. Because he has adverse-risk AML, an allo-SCT is planned, but the patient relapses before it can be performed. Following 3 courses of decitabine therapy, the patient achieves complete remission once again but declines transplant. He maintains remission for an additional 4 months but then the leukemia progresses. Clinical trials are recommended to the patient, but he decides to pursue hospice care.

Conclusion

AML is the most common acute leukemia in adults. As defined currently, AML represents a group of related but distinct myeloid disorders that are characterized by various chromosomal, genetic, and epigenetic alterations. Early diagnosis and treatment can help prevent the emergence or manage the detrimental effects of its various complications such as leukostasis and tumor lysis syndrome. Improvements in supportive care, incremental treatment advances, and the wide adoption of allo-SCT for less than favorable cases have significantly improved survival of AML patients since the initial design of combinatorial (7+3) induction chemotherapy, particularly in patients presenting at a younger age. HMAs and the emergence of targeted therapies like FLT-3 and IDH2 inhibitors have added to our therapeutic armamentarium. Despite these advances, long-term survival rates in AML patients continue to be only approximately 40% to 50%. Older patients (particularly those over age 65 at the time of diagnosis), those with relapsed disease, and those with AML with certain unfavorable genetic abnormalities continue to have dismal outcomes. The design of newer targeted therapies, epigenetic agents, and immunotherapies will hopefully address this unmet need.

Introduction

Acute myeloid leukemia (AML) comprises a heterogeneous group of disorders characterized by proliferation of clonal, abnormally differentiated hematopoietic progenitor cells of myeloid lineage that infiltrate the bone marrow, blood, and other tissues.¹ In most cases, AML is rapidly fatal if left untreated. Over the past 2 decades, our understanding of the underlying disease biology responsible for the development of AML has improved substantially. We have learned that biological differences drive the various clinical, cytogenetic, and molecular subentities of AML; distinguishing among these subentities helps to identify optimal therapies, while offering improved clinical outcomes for select groups. After years of stagnation in therapeutic advances, 4 new drugs for treating AML were approved by the US Food and Drug Administration (FDA) in 2017. In this article, we review key features of AML diagnosis and management in the context of 2 case presentations.

Epidemiology and Risk Factors

An estimated 21,380 new cases of AML were diagnosed in the United States in 2017, constituting roughly 1.3% of all new cases of cancer.² Approximately 10,590 patients died of AML in 2017. The median age of patients at the time of diagnosis is 68 years, and the incidence is approximately 4.2 per 100,000 persons per year. The 5-year survival for AML has steadily risen from a meager 6.3% in 1975 to 17.3% in 1995 and 28.1% in 2009.² The cure rates for AML vary drastically with age. Long-term survival is achieved in approximately 35% to 40% of adults who present at age 60 years or younger, but only 5% to 15% of those older than 60 years at presentation will achieve long-term survival.³

Most cases of AML occur in the absence of any known risk factors. High-dose radiation exposure, chronic benzene exposure, chronic tobacco smoking, and certain chemotherapeutics are known to increase the risk for AML.⁴ Inconsistent correlations have also been made between exposure to organic solvents, petroleum products, radon, pesticides, and herbicides and the development of AML.⁴ Obesity may also increase AML risk.⁴

Two distinct subcategories of therapy-related AML (t-AML) are known. Patients who have been exposed to alkylating chemotherapeutics (eg, melphalan, cyclophosphamide, and nitrogen mustard) can develop t-AML with chromosomal 5 and/or 7 abnormalities after a latency period of approximately 4 to 8 years.⁵ In contrast, patients exposed to topoisomerase II inhibitors (notably etoposide) develop AML with abnormalities of 11q23 (leading to MLL gene rearrangement) or 21q22 (RUNX1) after a latency period of about 1 to 3 years.⁶ AML can also arise out of other myeloid disorders such as myelodysplastic syndrome and myeloproliferative neoplasms, and other bone marrow failure syndromes such as aplastic anemia.⁴ Various inherited or congenital conditions such as Down syndrome, Bloom syndrome, Fanconi anemia, neurofibromatosis 1, and dyskeratosis congenita can also predispose to the development of AML. A more detailed listing of conditions associated with AML can be found elsewhere.⁴

Molecular Landscape

The first cancer genome sequence was reported in an AML patient in 2008.⁷ Since then, various elegantly conducted studies have expanded our understanding of the molecular abnormalities in AML. The Cancer Genome Atlas Research Network analyzed the genomes of 200 cases of de novo AML in adults.⁸ Only 13 mutations were found on average, much fewer than the number of mutations in most adult cancers. Twenty-three genes were commonly mutated, and another 237 were mutated in 2 or more cases. Essentially, all cases had at least 1 nonsynonymous mutation in 1 of 9 categories of genes: transcription-factor fusions (18%), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation–related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), spliceosome-complex genes (14%), and cohesin-complex genes (13%).

In another study, samples from 1540 patients from 3 prospective trials of intensive chemotherapy were analyzed to understand how genetic diversity defines the pathophysiology of AML.⁹ The study authors identified 5234 driver mutations from 76 genes or genomic regions, with 2 or more drivers identified in 86% of the samples. Eleven classes of mutational events, each with distinct diagnostic features and clinical outcomes, were identified. Acting as an internal positive control in this analysis, previously recognized mutational and cytogenetic groups emerged as distinct entities, including the groups with biallelic CEBPA mutations, mutations in NPM1, MLL fusions, and the cytogenetic entities t(6;9), inv(3), t(8;21), t(15;17), and inv(16). Three additional categories emerged as distinct entities: AML with mutations in genes encoding chromatin, RNA splicing regulators, or both (18% of patients); AML with TP53 mutations, chromosomal aneuploidies, or both (13%); and, provisionally, AML with IDH2R172 mutations (1%). An additional level of complexity was also revealed within the subgroup of patients with NPM1 mutations, where gene–gene interactions identified co-mutational events associated with both favorable or adverse prognosis.

Further supporting this molecular classification of AML, a study that performed targeted mutational analysis of 194 patients with defined secondary AML (s-AML) or t-AML and 105 unselected AML patients found that the presence of mutations in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 (all members of the chromatin or RNA splicing families) was highly specific for the diagnosis of s-AML.¹⁰ These findings are particularly clinically useful in those without a known history of antecedent hematologic disorder. These mutations defining the AML ontogeny were found to occur early in leukemogenesis, persist in clonal remissions, and predict worse clinical outcomes. Mutations in genes involved in regulation of DNA modification and of chromatin state (commonly DNMT3A, ASXL1, and TET2) have also been shown to be present in preleukemic stem or progenitor cells and to occur early in leukemogenesis.³ Unsurprisingly, some of these same mutations, including those in epigenetic regulators (DNMT3A, ASXL1, and TET2) and less frequently in splicing factor genes (SF3B1, SRSF2), have been associated with clonal hematopoietic expansion in elderly, seemingly healthy adults, a condition termed clonal hematopoiesis of indeterminate potential (CHIP).^3,11,12 The presence of CHIP is associated with increased risk of hematologic neoplasms and all-cause mortality, the latter being possibly driven by a near doubling in the risk of coronary heart disease in humans and by accelerated atherosclerosis in a mouse model.^11,13,14

Clinical Presentation and Work-up

Case Patient 1

A 57-year-old woman with a history of hypertension presents to the emergency department with complaints of productive cough and fevers for the previous 3 days. Examination reveals conjunctival pallor, gingival hyperplasia, and decreased breath sounds at the posterior right lung field. Investigations reveal a white blood cell (WBC) count of 51,000/µL with 15% blasts, a hemoglobin of 7.8 g/dL, and a platelet count of 56 × 10³/µL. Peripheral blood smear is notable for large myeloblasts with occasional Auer rods. Chest radiograph shows a consolidation in the right lower lobe.

Case Patient 2

A 69-year-old man presents to his primary care physician for evaluation of worsening fatigue for the previous 4 months. Ten years prior to presentation, he had received 6 cycles of RCHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) as treatment for diffuse large B-cell lymphoma. Conjunctival pallor, patches of purpura over the extremities, and mucosal petechiae are noted on examination. Laboratory analyisis reveals a WBC count of 2400/µL with 12% blasts, hemoglobin of 9.0 g/dL, and platelet count of 10 × 10³/µL. Peripheral smear shows dysplastic myeloid cells and blasts.

Clinical Features

Patients with AML typically present with features secondary to proliferation of blasts (ie, findings of bone marrow failure and end organ damage).^4,5 Fatigue, pallor, dizziness, dyspnea, and headaches occur secondary to anemia. Easy and prolonged bruising, petechiae, epistaxis, gingival bleeding, and conjunctival hemorrhages result from thrombocytopenia. Bleeding from other sites such as the central nervous system and gastrointestinal tract occurs but is uncommon. Patients may also present with infections resulting from unrecognized neutropenia. Constitutional symptoms including anorexia, fevers, and weight loss are frequently reported, while organomegaly (hepatomegaly and/or splenomegaly) is seen in about a quarter of patients.⁴ Infiltration of blasts into almost every organ has been noted, a condition known as myeloid (or granulocytic) sarcoma.¹⁵ This condition is more commonly found in patients with blastic, monoblastic, or myelomonocytic variants of AML, and is known as isolated myeloid sarcoma if no concurrent marrow or blood involvement is identified. In the absence of induction chemotherapy, systemic involvement occurs in a matter of weeks to months following such presentation.¹⁶

Laboratory analysis will usually demonstrate derangements in peripheral blood cell lines. At least half of patients have a total WBC count less than 5000/µL, a platelet count less than 50 × 10³/µL, or both at the time of diagnosis.^4,17 Approximately 10% of patients present with hyperleukocytosis and a WBC count greater than 100,000/µL, which can be associated with leukostasis.⁵ Additionally, spontaneous electrolyte derangement consistent with tumor lysis syndrome and coagulation abnormalities found in disseminated intravascular coagulation may be noted, even before initiation of therapy.

Work-Up of Suspected AML

Bone marrow biopsy and aspirate, along with touch preparations of the core biopsy sample, are crucial in the workup of suspected AML. At least 200 WBCs on blood smears and 500 nucleated cells on spiculated marrow smears should be counted.³ Reactivity with specific histochemical stains (myeloperoxidase, Sudan black B, or naphthyl AS-D-chloroacetate), presence of Auer rods, and reactivity to monoclonal antibodies against epitopes present on myeloblasts (eg, CD13, CD33, CD117) help distinguish myeloblasts from lymphoblasts.⁴ Flow cytometric analysis helps in confirming myeloid lineage; blasts generally express CD34 and HLA-DR, markers of immature hematopoietic precursors, and dim CD45 (common leukocyte antigen). One or more lymphoid antigens may be aberrantly expressed as well. Of note, in about 2% to 3% of acute leukemia cases, immunohistochemistry and/or flow cytometry findings demonstrate immature cells with features of both myeloid and lymphoid lineages (biphenotypic) or different populations of myeloid and lymphoid leukemia cells (bilineal). These leukemias are termed mixed-phenotype acute leukemia and are typically treated with either AML or acute lymphoblastic leukemia regimens.¹⁸

Cytogenetics, as assessed through conventional karyotype and fluorescence in situ hybridization (FISH), constitutes an essential part of the work-up. Eight balanced translocations and inversions and their variants are included in the World Health Organization (WHO) category “AML with recurrent genetic abnormalities,” while 9 balanced rearrangements and multiple unbalanced abnormalities in the presence of a blast count ≥ 20% are sufficient to establish the diagnosis of “AML with myelodysplasia-related changes.”^3,19 Various other gene rearrangements thought to represent disease-initiating events are recognized as well, but these rearrangements do not yet formally define WHO disease categories.³ FISH can help detect RUNX1-RUNX1T1, CBFB-MYH11, KMT2A (MLL), and MECOM (EVI1) gene fusions, as well as chromosomal changes like 5q, 7q, or 17p, especially when fewer than 20 metaphases are assessable (due to failure of culture) by conventional cytogenetic methods.³

As certain molecular markers help with disease prognosis and the selection of personalized therapies, testing for these markers is recommended as part of a complete work-up of AML. The current standard of care is to test for nucleophosmin (NPM1), fms-like tyrosine kinase 3 (FLT3), and CEBPA mutations in all newly diagnosed patients.¹RUNX1 mutation analysis should also be considered as its presence defines a provisional WHO subcategory.¹⁹ In the case of FLT3, the analysis should include both internal tandem duplications (FLT3-ITD, associated with worse prognosis especially at high allelic ratio) and tyrosine-kinase domain mutations (FLT3-TKD; D835 and I836), especially now that FLT3 inhibitors are regularly used.²⁰ Most academic centers now routinely use next-generation sequencing–based panels to assess multiple mutations. 

Diagnosis and Classification

A marrow or blood blast (myeloblasts, monoblasts, megakaryoblasts, or promonocytes [considered blast equivalents]) count of ≥ 20% is required for AML diagnosis.^3,19 The presence of t(15;17), t(8;21), inv(16), or t(16;16), however, is considered diagnostic of AML irrespective of blast count.^3,19 The previously used French-American-British (FAB) classification scheme has been replaced by the WHO classification (Table 2), which takes into account the morphologic, cytogenetic, genetic, and clinical features of the leukemia. 

The category “AML with myelodysplasia-related changes” includes AML that has evolved out of an antecedent myelodysplastic syndrome, has ≥ 50% dysplasia in 2 or more lineages, or has myelodysplasia-related cytogenetic changes (eg, –5/del(5q), –7/del(7q), ≥ 3 cytogenetic abnormalities).¹⁹ “Therapy-related myeloid neoplasm,” or therapy-related AML, is diagnosed when the patient has previously received cytotoxic agents or ionizing radiation.¹⁹

Cases which do not meet the criteria for 1 of the previously mentioned categories are currently classified as “AML, not otherwise specified.” Further subclassification is pursued as per the older FAB scheme; however, no additional prognostic information is obtained in doing so.^3,19 Myeloid sarcoma is strictly not a subcategory of AML. Rather, it is an extramedullary mass of myeloid blasts that effaces the normal tissue architecture.¹⁶ Rarely, myeloid sarcoma can be present without systemic disease involvement; it is important to note that management of such cases is identical to management of overt AML.¹⁶

Finally, myeloid proliferations related to Down syndrome include 2 entities seen in children with Down syndrome.¹⁹ Transient abnormal myelopoiesis, seen in 10% to 30% of newborns with Down syndrome, presents with circulating blasts that resolve in a couple of months. Myeloid leukemia associated with Down syndrome is AML that occurs usually in the first 3 years of life and persists if not treated.¹⁹

Case 1 Continued

The presence of 15% blasts in the peripheral blood is concerning for, but not diagnostic of, AML. On the other hand, the presence of Auer rods is virtually pathognomonic for AML. Gingival hyperplasia in this patient may be reflective of extramedullary disease. Cytogenetics from the peripheral blood and marrow aspirate show inv(16) in 20 of 20 cells. Molecular panel is notable for mutation in c-KIT. As such, the patient is diagnosed with core-binding factor AML, which per the ELN classification is considered a favorable-risk AML. The presence of c-KIT mutation, however, confers a relatively worse outcome.

Case 2 Continued

Presence of pancytopenia in a patient who previously received cytotoxic chemotherapy is highly concerning for therapy-related myeloid neoplasm. The presence of 12% blasts in the peripheral blood does not meet the criteria for diagnosis of AML. However, marrow specimens show 40% blasts, thus meeting the criteria for an AML diagnosis. Additionally, cytogenetics are notable for the presence of monosomy 7, while a next-generation sequencing panel shows a mutation in TP53. Put together, this patient meets the criteria for therapy-related AML which is an adverse-risk AML according to the ELN classification.

Management

The 2 most significant factors that must be considered when selecting AML therapies are the patient’s suitability for intensive chemotherapy and the biological characteristics of the AML. The former is a nuanced decision that incorporates age, performance status, and existing comorbidities. Treatment-related mortality calculators can guide physicians when making therapy decisions, especially in older patients (≥ 65 years). Retrospective evidence from various studies suggests that older, medically fit patients may derive clinically comparable benefits from intensive and less intensive induction therapies.^25–27 The biological characteristics of the leukemia can be suggested by morphologic findings, cytogenetics, and molecular information, in addition to a history of antecedent myeloid neoplasms. Recently, an AML composite model incorporating an augmented Hematopoietic Cell Transplantation–specific Comorbidity Index (HCT-CI) score, age, and cytogenetic/molecular risks was shown to improve treatment decision-making about AML; this model potentially could be used to guide patient stratification in clinical trials as well.²⁸ The overall treatment model of AML is largely unchanged otherwise. It is generally divided into induction, consolidation, and maintenance therapies.

Induction Therapy

In patients who can tolerate intensive therapies, the role of anthracycline- and cytarabine-based treatment is well established. However, the choice of specific anthracycline is not well established. One study concluded that idarubicin and mitoxantrone led to better outcomes as compared to daunorubicin, while another showed no difference between these agents.^29,30 A pooled study of AML trials conducted in patients aged 50 years and older showed that while idarubicin led to a higher complete remission rate (69% versus 61%), the overall survival (OS) did not differ significantly.³¹ As for dosing, daunorubicin given at 45 mg/m² daily for 3 days has been shown to have lower complete remission rates and higher relapse rates than a dose of 90 mg/m² daily for 3 days in younger patients.^32–34 However, it is not clear whether the 90 mg/m² dose is superior to the frequently used dose of 60 mg/m².³⁵ A French study has shown comparable rates of complete remission, relapse, and OS between the 60 mg/m² and 90 mg/m² doses in patients with intermediate or unfavorable cytogenetics.³⁶

If idarubicin is used, a dose of 12 mg/m² for 3 days is considered the standard. In patients aged 50 to 70 years, there were no statistically significant differences in rates of relapse or OS between daunorubicin 80 mg/m² for 3 days versus idarubicin 12 mg/m² for 3 days versus idarubicin 12 mg/m² for 4 days.³⁷ As for cytarabine, the bulk of the evidence indicates that a dose of 1000 mg/m² or higher should not be used.³⁸ As such, the typical induction chemotherapy regimen of choice is 3 days of anthracycline (daunorubicin or idarubicin) and 7 days of cytarabine (100–200 mg/m² continuous infusion), also known as the 7+3 regimen, which was first pioneered in the 1970s. In a recent phase 3 trial, 309 patients aged 60 to 75 years with high-risk AML (AML with myelodysplasia-related changes or t-AML) were randomly assigned to either the 7+3 regimen or CPX-351 (ie, nano-liposomal encapsulation of cytarabine and daunorubicin in a 5:1 molar ratio).³⁹ A higher composite complete response rate (47.7% versus 33.3%; P = 0.016) and improved survival (9.56 months versus 5.95 months; hazard ratio [HR] 0.69, P = 0.005) were seen with CPX-351, leading to its approval by the FDA in patients with high-risk AML.

The 7+3 regimen has served as a backbone onto which other drugs have been added in clinical trials—the majority without any clinical benefits—for patients who can tolerate intensive therapy. In this context, the role of 2 therapies recently approved by the FDA must be discussed. In the RATIFY trial, 717 patients aged 18 to 59 years with AML and a FLT3 mutation were randomly assigned to receive standard chemotherapy (induction and consolidation therapy) plus either midostaurin or placebo; those who were in remission after consolidation therapy received either midostaurin or placebo in the maintenance phase.⁴⁰ The primary endpoint was met as midostaurin improved OS (HR 0.78, P = 0.009). The benefit of midostaurin was consistent across all FLT3 subtypes and mutant allele burdens, regardless of whether patients proceeded to allogeneic stem cell transplant (allo-SCT). Based on the results of RATIFY, midostaurin was approved by the FDA for treatment of AML patients who are positive for the FLT3 mutation. Whether more potent and selective FLT3 inhibitors like gilteritinib, quizartinib, or crenolanib improve the outcomes is currently under investigation in various clinical trials.²⁰

The development of gemtuzumab ozogamicin (GO) has been more complicated. GO, an antibody-drug conjugate comprised of a CD33-directed humanized monoclonal antibody linked covalently to the cytotoxic agent calicheamicin, binds CD33 present on the surface of myeloid leukemic blasts and immature normal cells of myelomonocytic lineage.⁴¹ The drug first received an accelerated approval in 2000 as monotherapy (2 doses of 9 mg/m² 14 days apart) for the treatment of patients 60 years of age and older with CD33-positive AML in first relapse based on the results of 3 open-label multicenter trials.^41,42 However, a confirmatory S0106 trial in which GO 6 mg/m² was added on day 4 in newly diagnosed AML patients was terminated early when an interim analysis showed an increased rate of death in induction (6% versus 1%) and lack of improvement in complete response, disease-free survival, or OS with the addition of GO.⁴³ This study led to the withdrawal of GO from the US market in 2010. However, 2 randomized trials that studied GO using a different dose and schedule suggested that the addition of GO to intensive chemotherapy improved survival outcomes in patients with favorable and intermediate-risk cytogenetics.^44,45 The results of the multicenter, open-label phase 3 ALFA-0701 trial, which randomly assigned 271 patients aged 50 to 70 years with newly diagnosed AML to daunorubicin and cytarabine alone or in combination with GO (3 mg/m² on days 1, 4, and 7 during induction and day 1 of 2 consolidation courses), showed a statistically significant improvement in event-free survival (17.3 months versus 9.5 months; HR 0.56 [95% confidence interval 0.42 to 0.76]).⁴⁵ Again, the survival benefits were more pronounced in patients with favorable or intermediate-risk cytogenetics than in those with unfavorable cytogenetics. The results of this trial led to the re-approval of GO in newly diagnosed AML patients. 


For patients who cannot tolerate intensive therapies, the 2 main therapeutic options are low-dose cytarabine (LDAC) and the hypomethylating agents (HMA) azacitidine and decitabine. A phase 3 trial of decitabine versus mostly LDAC (or best supportive care, BSC) demonstrated favorable survival with decitabine (7.7 months versus 5.0 months).⁴⁶ In the AZA-AML-001 trial, azacitidine improved median survival (10.4 months versus 6.5 months) in comparison to the control arm (LDAC, 7+3, BSC).⁴⁷ Emerging data has also suggested that HMAs may be particularly active in patients with unfavorable-risk AML, a group for which LDAC has been shown to be especially useless.⁴⁸ As such, HMA therapies are generally preferred over LDAC in practice. Finally, it is pertinent to note that GO can also be used as monotherapy based on the results of the open-label phase 3 AML-19 study in which GO demonstrated a survival advantage over BSC (4.9 months versus 3.6 months, P = 0.005).⁴⁹

Postremission or Consolidation Therapy

There is no standard consolidation therapy for AML at present. In general, for patients who received HMA in the induction phase, the same HMA should be continued indefinitely until disease progression or allo-SCT.³ For those who received intensive chemotherapy in the induction phase, the consensus is to use cytarabine-based consolidation therapies. Cytarabine given as a single agent in high-doses has generally led to similar outcomes as multiagent chemotherapy.⁵⁰ In this regard, cytarabine regimens, with or without anthracycline, at 3000 mg/m² have similar efficacy as an intermediate dose of 1000 mg/m².³⁸ A total of 2 to 4 cycles of post-remission therapy is considered standard.³ Intensified post-remission chemotherapy has not been associated with consistent benefit in older AML patients or those with poor-risk disease. In recent years, measurable residual disease (MRD) assessment has emerged as a potentially useful tool in risk stratification and treatment planning, with various studies suggesting that MRD status in complete remission is one of the most important prognostic factors.⁵¹ Prospective studies confirming the significance of MRD as a marker for therapy selection are awaited. Finally, maintenance chemotherapy is not part of standard AML treatment.³

Role of Stem Cell Transplant

AML is the most common indication for allo-SCT. The availability of alternative donor strategies, which include mismatched, unrelated, haplo-identical, and cord blood donor sources, and the development of non-myeloablative and reduced-intensity conditioning (RIC) regimens (which take advantage of graft-versus-leukemia effect while decreasing cytotoxicity from myeloablative regimens) have expanded the possibility of allo-SCT to most patients under the age of 75 years.³ The decision to perform transplant is now largely based upon assessment of the risk (nonrelapse mortality) to benefit (reduction in risk of relapse) ratio, as determined by both disease-related features (cytogenetics, molecular profile) and clinical characteristics of the donor (type, availability, match) and the recipient (comorbidities, performance status).³ In a meta-analysis of 24 prospective trials involving more than 6000 AML patients in first complete remission, allo-SCT was associated with a significant survival benefit in patients with intermediate- and poor-risk AML but not in patients with good-risk AML.⁵² In line with this, good-risk AML patients are generally not recommended for transplant in first complete remission. For patients with normal karyotype who were said to have de novo AML (historically an intermediate-risk AML group), superior OS was demonstrated with transplant over intensive chemotherapy in those patients with either FLT3-ITD mutations or those with the molecular profile characterized by negativity for mutations in NPM1/CEBPA/FLT3.⁵³ For patients with primary refractory disease and high-risk AML, transplant is probably the only curative option.

The choice of conditioning regimen is guided by several factors, including the subtype of AML, disease status, donor-recipient genetic disparity, graft source, comorbidities in the recipient (ie, tolerability for intensive conditioning regimen), as well as the reliance on graft-versus-leukemia effect as compared to cytotoxic effect of the regimen. The BMT CTN 0901 trial, which randomly assigned 218 patients aged 18 to 65 years to RIC (typically fludarabine/busulfan) or myeloablative regimens, showed an advantage for myeloablative regimens.⁵⁴ The trial demonstrated a lower risk of relapse (13.5% versus 48.3%, P < 0.01) and higher rates of relapse-free survival (67.7% versus 47.3%, P < 0.01) and OS (67.7% versus. 77.4%, P = 0.07) at 18 months despite higher treatment-related mortality (15.8% versus 4.4%, P = 0.02) and a higher rate of grade 2 to 4 acute graft-versus-host disease (44.7% versus 31.6%, P = 0.024). At present, a RIC regimen is generally recommended for older patients or those with a higher comorbidity burden, while the myeloablative regimen is recommended for younger, fit patients.

Relapsed/Refractory Disease

The treatment of relapsed and refractory AML constitutes a major challenge, with OS estimated around 10% at 3 years.⁵⁵ Currently, there is no standard salvage therapy in this setting, thus underscoring the need for clinical trials. For younger, fitter patients, the typical approach is to use intensive chemotherapy to achieve a second complete remission followed by a stem cell transplant. In younger patients, a second complete remission is achievable in about 55% of patients, although this rate is lower (~20%–30%) in more unselected patients.^56,57 About two thirds of those who achieve complete remission may be able to proceed to transplant.⁵⁷ For older patients where transplant is not possible, the goal is to use less intensive therapies that help with palliation. HMAs (azacitidine, decitabine) are used and have complete remission rates of 16% to 21% and median survival of 6 to 9 months in older patients.³ LDAC is another option in this setting. The recent approval of GO in this setting has further expanded the options. This approval was based on the outcomes of the phase 2 single-arm MyloFrance-1 study in which single-agent GO administered at 3 mg/m² on days 1, 4, and 7 led to complete remission in 15 of 57 patients.⁵⁸

With greater elucidation of the molecular characteristics of AML, the emergence of more effective targeted therapies is possible. Enasidenib, an inhibitor of mutant isocitrate dehydrogenase 2 (IDH2) protein that promotes differentiation of leukemic myeloblasts, recently received regulatory approval based on a single-arm trial. The overall response rate in this study was 38.5%, including a composite complete remission rate of 26.6% at a dose of 100 mg daily.⁵⁹ IDH differentiation syndrome, akin to the differentiation syndrome seen in acute promyelocytic leukemia, occurred in approximately 12% of the patients, with the most frequent manifestations being dyspnea, fever, pulmonary infiltrates, and hypoxia.⁶⁰

Survival of patients who relapse following transplant is particularly poor. A recent Center for International Blood and Marrow Transplant Research study found a 3-year OS ranging from a dismal 4% for those who present with early relapses (within 1 to 6 months) post-transplant to a more modest 38% for those who relapsed ≥ 3 years after their first transplant.⁶¹ The German Cooperative Transplant Study Group have suggested that azacitidine or chemotherapy followed by donor-lymphocyte infusions might improve responses over chemotherapy alone.⁶² Ipilimumab-based CTLA-4 blockade was reported to produce responses in a small cohort of patients, which was particularly notable in patients presenting with extramedullary manifestations of relapse.⁶³ In patients who are otherwise fit but have a florid relapse, a second transplant can sometimes be sought, but the value of a different donor for second transplant is unclear.³

Case 1 Conclusion

Given his relatively young age, suitability for intensive therapy, and the presence of a core- binding factor abnormality, the patient is treated with an induction regimen containing daunorubicin, cytarabine, and GO (7+3 + GO). He achieves complete remission. This is followed by consolidation chemotherapy with high-dose cytarabine and GO. Allo-SCT is reserved for later should the AML relapse. Note that dasatinib, a c-KIT inhibitor, can be added to the treatment regimens as per the results of the CALGB 10801 protocol.⁶⁴ Also, autologous SCT, instead of allo-SCT, can be considered in rare situations with relapsed core-binding factor AML (especially with inv(16) AML, younger patients, longer time in complete remission prior to relapse, and use of GO).

Case 2 Conclusion

The patient is deemed suitable for intensive chemotherapy. As such, CPX-351 is given in induction and consolidation and complete remission is achieved. Because he has adverse-risk AML, an allo-SCT is planned, but the patient relapses before it can be performed. Following 3 courses of decitabine therapy, the patient achieves complete remission once again but declines transplant. He maintains remission for an additional 4 months but then the leukemia progresses. Clinical trials are recommended to the patient, but he decides to pursue hospice care.

Conclusion

AML is the most common acute leukemia in adults. As defined currently, AML represents a group of related but distinct myeloid disorders that are characterized by various chromosomal, genetic, and epigenetic alterations. Early diagnosis and treatment can help prevent the emergence or manage the detrimental effects of its various complications such as leukostasis and tumor lysis syndrome. Improvements in supportive care, incremental treatment advances, and the wide adoption of allo-SCT for less than favorable cases have significantly improved survival of AML patients since the initial design of combinatorial (7+3) induction chemotherapy, particularly in patients presenting at a younger age. HMAs and the emergence of targeted therapies like FLT-3 and IDH2 inhibitors have added to our therapeutic armamentarium. Despite these advances, long-term survival rates in AML patients continue to be only approximately 40% to 50%. Older patients (particularly those over age 65 at the time of diagnosis), those with relapsed disease, and those with AML with certain unfavorable genetic abnormalities continue to have dismal outcomes. The design of newer targeted therapies, epigenetic agents, and immunotherapies will hopefully address this unmet need.

Introduction

Colorectal cancer (CRC) is the fourth most common cancer in the United States and has a high prevalence among the older population.¹ In 2017, there were an estimated 135,430 new cases of CRC and 50,260 deaths due to CRC. It is the second leading cause of cancer death in the United States, and the death rate for patients with CRC increases with age (Figure).² 

Although elderly persons are more frequently diagnosed with CRC, they are underrepresented in clinical trials. This may be due in part to stringent eligibility criteria in prospective randomized controlled trials that exclude older patients with certain comorbidities and decreased functional status. Hutchins and colleagues compared the proportion of persons aged 65 years and older enrolled in Southwest Oncology Group (SWOG) clinical trials and the proportion of persons in this age group in the US population with the same cancer diagnoses.⁵ They found that while 72% of the US population with CRC were aged ≥ 65 years, persons in this age group comprised only 40% of patients enrolled in SWOG trials. An update on this study performed after Medicare policy changed in 2000 to include coverage of costs incurred due to clinical trials showed an upward trend in the accrual of older patients in SWOG trials, from 25% during the period 1993–1996 to 38% during the period 2001–2003; however, the percentage of older patients with CRC on clinical trials overall remained stable from 1993 to 2003.⁶

The underrepresentation of older adults with CRC in clinical trials presents oncologists with a challenging task when practicing evidence-based medicine in this patient population. Analysis of a large claims database demonstrated that the use of multi-agent chemotherapy for the treatment of metastatic CRC in older adults increased over time, while the use of single-agent 5-fluorouracil (5-FU) decreased.⁷ However, the adoption of combination therapy with irinotecan or oxaliplatin in older adults lagged behind the initial adoption of these agents in younger patients. This data demonstrates that as the field of medical oncology evolves, providers are becoming more comfortable treating older patients with multiple medical problems using standard approved regimens.

Geriatric Assessment

Before treating older patients with cancer, it is necessary to define the patient’s physiological age, ideally through a multidisciplinary team evaluation. Comprehensive geriatric assessment (CGA) is a multidisciplinary approach recommended for evaluation of an elderly person’s functional status, medical comorbidities, psychosocial status, cognitive function, and nutritional state.^8,9 CGA may uncover geriatric syndromes not otherwise detected by routine oncology evaluation. Functional status can vary greatly across geriatric patients in the same age group, with some older patients as robust as their younger counterparts and others more frail. The remainder of the population will likely fall along a continuum between the 2 extremes and may appear fit but have borderline reserve.¹⁰ Robust older adults have a better performance status and fewer comorbidities; identifying these fit older patients is important, as they are more likely to benefit from standard anticancer treatments.¹¹ Frail patients are more likely to have multiple comorbidities or other geriatric syndromes, such as cognitive impairment, depression, or gait disturbance, and are less likely to benefit from standard treatments.

The Eastern Cooperative Oncology Group performance status (ECOG PS) and Karnofsky Performance Status (KPS) are crude measures of functional status.¹² Generally, elderly patients with good ECOG PS or KPS scores are considered fit enough to receive standard therapy similar to their younger counterparts. Evaluation of functional status using these performance scores is often suboptimal, resulting in patients with a normal or adequate performance status score who may still experience poor outcomes, including decreased survival and inability to tolerate treatment. A study that explored parameters among older patients that predict for increased risk of chemotherapy-related toxicities found that physician-rated KPS score did not accurately predict the risk for adverse events.¹³ Therefore, a CGA represents a better way to evaluate functional status and other domains.

Functional status can also be evaluated by self-reported tools such as activities of daily living, which refer to basic self-care, and instrumental activities of daily living (IADLs), which are essential for independent living in the community.^14,15 Mobility, gait, and balance can also be measured using the “Timed Get Up and Go” test and gait speed. Klepin et al found that faster gait speed was associated with overall survival (OS) in patients with metastatic cancer.¹⁶

Cognitive function is an important component of the geriatric assessment in older patients with cancer, as dementia is a prognostic factor for survival in the overall geriatric population. In a retrospective review, patients with dementia were less likely to have a biopsy-proven diagnosis and were twice as likely to have their CRC diagnosed postmortem.¹⁷ In addition, establishing that the patient has intact cognitive function prior to initiating treatment is essential to ensure that the patient can comply with treatment and understands when to report adverse effects. Nutritional status is an important portion of the geriatric assessment because malnutrition is associated with increased mortality and decreased tolerance for chemotherapy.^18–20 Evaluating the patient’s psychosocial support is crucial as well because older patients are at greater risk of social isolation and depression.²¹ While the incidence of depression is lower in older adults with cancer than in younger adults with cancer, clinically significant depression is still noted in 3% to 25% of elderly cancer patients.²² Other critical components of the CGA are review of the patient’s comorbidities and medications to avoid complications of polypharmacy.

Both the Cancer and Aging Research Group (CARG) and Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) toxicity tools are valuable tools, as they predict chemotherapy tolerance in elderly patients.^13,23 These tools can help guide discussions between oncologists and patients as well as the formulation of an appropriate treatment plan.²⁴ Although toxicity tools can help to determine which patients are at risk for severe toxicity secondary to treatment, these tools do not replace the CGA. A prospective cohort study that evaluated the impact of CGA on tolerance to chemotherapy in older patients with cancer compared patients aged ≥ 70 years at the start of their treatment with chemotherapy (± radiation therapy) using geriatrician-delivered CGA versus standard care given by oncology.⁸ Patients who received geriatrician-guided CGA interventions tolerated chemotherapy better and completed treatments as planned (odds ratio 4.14 [95% confidence interval {CI} 1.50 to 11.42], P = 0.006) with fewer treatment modifications.

Unfortunately, the CGA is time-consuming to administer and difficult to incorporate into a busy oncology practice. Therefore, other screening models are used to identify patients who may benefit from a full CGA. The International Society of Geriatric Oncology performed a systematic review of screening tools used to identify older cancer patients in need of geriatric assessment and found that the 3 most studied screening tools are the G8, the Vulnerable Elders Survey-13 (VES-13), and the Flemish version of the Triage Risk Screening Tool.²⁵ Another study found that the G8 was more sensitive than the VES-13 (76.5% versus 68.7%, P = 0.0046), whereas the VES-13 was more specific than the G8 (74.3% versus 64.4%, P < 0.0001).²⁶ In addition to providing guidance to initiate a full geriatric assessment, these screening tools may assist in decision making for older cancer patients, especially those with advanced disease.

Surgery

Early-Stage Disease

When possible, surgical resection of colorectal tumors is the primary treatment in both the curative setting and to avoid complications, such as obstruction or perforation.²⁷ Multiple studies have shown that fit elderly patients benefit from curative surgery similarly to their younger counterparts.^27–29 With the growing population of persons aged 65 years or older, surgeons are becoming more comfortable with operating on the elderly.⁴ However, a large systematic review of 28 independent studies with a total of 34,194 patients showed that older patients were less likely to undergo curative surgery.³⁰ Eligibility for surgery should not be determined by age alone, but rather should be based on a full assessment of the patient’s health, including comorbidities, functional status, nutrition, cognition, social support, and psychological status. The impact of age on short-term outcomes after colorectal surgery in terms of 30-day postoperative morbidity and mortality rates was explored in a study that divided patients into 2 groups: those aged ≥ 80 years (mean age 85) and those aged < 80 years (mean age 55.3).³¹ There were no statistical differences in 30-day postoperative morbidity and mortality rates between the 2 groups, and preexisting comorbidities and urgent nature of surgery were important predictors of colorectal surgery outcomes in the older adults, results that have been seen in several other studies.^28,30 When possible, laparoscopic surgery is preferred as it is associated with less intraoperative blood loss, less postoperative pain, reduced postoperative ileus, a shorter hospital stay, and fewer cardiovascular and pulmonary complications.³² The Preoperative Assessment of Cancer in the Elderly (PACE), which combines surgical risk assessment tools with CGA tools, can assist surgeons in determining candidacy for surgery and help decrease unequal access to surgery in the geriatric population.³³

Metastasectomy

A large international multicenter cohort study explored the outcomes of patients aged ≥ 70 years who underwent liver resection of colorectal metastases. The study investigatorsfound that neoadjuvant chemotherapy was used less frequently and less extensive surgery was performed in elderly patients than in younger patients.³⁴ Sixty-day postoperative mortality was slightly higher (3.8% versus 1.6%, P < 0.001) and 3-year OS was slightly lower (57.1% versus 60.2%, P < 0.001) in the elderly group as compared to their younger counterparts, but overall the outcomes after liver surgery were similar. Therefore, the management of liver metastases in oligometastatic disease in elderly patients fit for surgery should be the same as that offered to younger patients. Since outcomes are comparable, older patients should be offered neoadjuvant chemotherapy, as several studies have shown similar response rates and OS in younger and older patients.^35,36

Rectal Cancer

The standard of care for locally advanced rectal cancer is combined modality treatment with radiation and chemotherapy followed by total mesorectal excision. However, given conflicting data regarding the ability of elderly patients to tolerate neoadjuvant 5-FU-based chemotherapy and radiation, elderly patients are treated with trimodality therapy less often than their younger counterparts.^37,38 A systematic review of 22 randomized trials involving 8507 patients with rectal cancer showed that adjuvant radiation therapy could reduce the risk of local recurrence and death from rectal cancer in patients of all ages.³⁹ However, the risk of noncancer-related death was increased in the older population. The Stockholm II trial showed similar benefits of preoperative radiation overall, but this benefit did not extend to patients older than 68 years because of an increased risk of morbidity and mortality.⁴⁰ In older patients, mortality from noncancer causes within the first 6 months after surgery was higher in the group that received perioperative radiation than in the group that did not receive radiation. Elderly patients (age > 68 years) accounted for most of the mortality, which was predominantly due to cardiovascular disease.

A retrospective study of 36 patients aged ≥ 70 years with rectal cancer evaluated the toxicity and feasibility of neoadjuvant 5-FU combined with pelvic radiation for treating locally advanced rectal cancer. Patients were classified as healthy and “fit” or “vulnerable” based on the presence of comorbidities.⁴¹ This study demonstrated that tolerability and response to neoadjuvant chemotherapy and radiation as well as ability to undergo surgery were similar in “vulnerable” patients and “fit” patients. Conversely, Margalit and colleagues studied the rate of treatment deviations in elderly patients with rectal cancer treated with combined modality therapy and found that most patients required early termination of treatment, treatment interruptions, or dose reductions.⁴² While trimodality treatment is the standard of care in rectal cancer, there is conflicting data from retrospective studies regarding the tolerability and feasibility of this approach. It is important to proceed with caution but to still consider fit older patients with locally advanced rectal cancer for neoadjuvant chemotherapy and radiation followed by surgery.

In patients who have a complete response (CR) to neoadjuvant chemoradiation, watchful waiting rather than proceeding to surgery may be a reasonable strategy, especially in older patients. A systematic review of 867 patients with locally advanced rectal cancer showed no statistically significant difference in OS between patients who were observed with watchful waiting and those who underwent surgery.⁴³ The International Watch and Wait Database includes 679 patients who were managed with a watch-and-wait regimen because they had a clinical CR after chemoradiation. An outcomes analysis of these patients showed that 25% had local regrowth, with 3-year OS of 91% overall and 87% in patients with local regrowth.⁴⁴ In most patients (84%), regrowth of the tumor occurred within the first 2 years of follow up.

In frail older adults, for whom longer courses of treatment are not feasible or chemotherapy is contraindicated, short-course radiation therapy can be considered either in the neoadjuvant setting or alone for palliation.⁴⁵ A randomized trial of short-course radiation versus long-course chemoradiation in patients with T3 rectal cancer found that the difference in 3-year local recurrence rates was not statistically significant.⁴⁶

Chemotherapy

An expected natural decline in function occurs with age, but given the great variability that exists between patients, it is important to focus on physiologic age rather than chronologic age to determine ability to receive and tolerate anticancer treatment. Decreases in renal and hepatic function, cognitive impairment, changes in gastrointestinal motility, decrements in cardiac and bone marrow reserves, as well as comorbidities and polypharmacy affect a patient’s ability to tolerate chemotherapy.^47,48 Toxicity tools such as CARG and CRASH can help to predict severity of toxicity with chemotherapy.^13,23 The information provided by these tools can help guide conversations between the oncologist and patient regarding treatment plans.

Adjuvant Chemotherapy for Early-Stage Disease

Stage II Disease

Defining treatment guidelines for older patients with stage II colon cancer is difficult due to lack of data that shows benefit in this population. The QUASAR (Quick and Simple and Reliable) group’s prospective study of adjuvant single-agent 5-FU in stage II colon cancer patients showed an absolute improvement in survival of 3.6% when 5-FU was given after surgery (95% CI 1.0 to 6.0).⁴⁹ The subgroup analysis of patients aged ≥ 70 years showed a limited benefit of adjuvant 5-FU (hazard ratio [HR] 1.13 [95% CI 0.74 to 1.75]). Given the limited benefit, adjuvant 5-FU for elderly patients with stage II colon cancer should be used judiciously as patients may have competing causes of morbidity or mortality.

The use of oxaliplatin-based therapy in the adjuvant setting for stage II disease was evaluated in a subgroup analysis of the MOSAIC study (Multicenter International Study of Oxaliplatin/5-FU/Leucovorin in the Adjuvant Treatment of Colon Cancer).⁵⁰ Adjuvant oxaliplatin-based treatment may be offered to patients with stage II colon cancer that carries high-risk features (poorly differentiated histology, lymphovascular invasion, bowel obstruction and/or perforation, < 12 lymph nodes sampled, perineural invasion, or indeterminate or positive margins) due to a trend toward improved disease-free survival (DFS) at 5 years. Patients in this group who received adjuvant FOLFOX (leucovorin, oxaliplatin, 5-FU) versus 5-FU/leucovorin had a DFS of 82.3% versus 74.6%, respectively (HR 0.72 [95% CI 0.50 to 1.02]), a difference that was not statistically significant. A subgroup analysis of 315 patients aged 70 to 75 years with stage II colon cancer enrolled in the MOSAIC study found no statistically significant DFS or OS benefit with the addition of oxaliplatin to 5-FU/leucovorin.⁵¹ Therefore, use of this platinum/fluoropyrimidine combination for adjuvant therapy for high-risk stage II disease in older patients remains controversial given its associated risks and the lack of definitive data demonstrating a benefit in this patient group. Decisions regarding this therapy should be made through a shared discussion with patients about its risks and benefits.

Microsatellite status is an important biomarker in the evaluation of stage II CRC. Microsatellite stability is a marker of a functioning DNA mismatch repair system. In patients with colon cancer, tumor microsatellite stability is classified based on the percentage of abnormal microsatellite regions.⁵² Several studies have shown that patients with tumors that display high microsatellite instability (MSI-H) have an improved prognosis over patients with microsatellite stable tumors.^53,54 While patients with stage II MSI-H colon cancer have better outcomes, MSI is associated with a reduced response to treatment with fluoropyrimidines, as demonstrated in a systematic review that found that patients with tumors with MSI obtained no benefit from adjuvant 5-FU (HR 1.24 [95% CI 0.72 to 2.14]).⁵⁵ Aparicio and colleagues reported an increased prevalence of MSI-H tumors with increasing age.⁵⁶ Therefore, mismatch repair phenotype should be considered when making adjuvant chemotherapy decisions in the older adult with colon cancer, as it may affect the decision to recommend single-agent 5-FU treatment.

Stage III Disease

The use of single-agent 5-FU for stage III resected CRC has been evaluated in multiple studies. Sargent et al performed a pooled analysis of 3351 patients from 7 randomized phase 3 trials comparing surgery and adjuvant 5-FU-based chemotherapy versus surgery alone in stage II or III colon cancer patients.⁵⁷ Adjuvant chemotherapy was associated with improvement in both OS and time to tumor recurrence (HR 0.76 and 0.68, respectively). The 5-year OS was 71% for those who received adjuvant treatment and 64% for those who were treated with surgery alone. The benefit of adjuvant treatment was independent of age, and there was no difference in toxicity across age groups, except for 1 study which showed increased rates of leukopenia in the elderly. The oral fluoropyrimidine capecitabine was shown to be an effective alternative to 5-FU plus leucovorin as adjuvant treatment for those with resected stage III colon cancer.⁵⁸ However, in the subgroup analysis of DFS in the intention-to-treat group, the improvement in DFS was not statistically significant in those aged ≥ 70 years. This study justified the phase 3 Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) trial, which compared capecitabine and 5-FU/leucovorin as adjuvant therapy in patients with resected stage III colon cancer.⁵⁹ The X-ACT trial showed no significant effect of age on DFS or OS.

The addition of oxaliplatin to 5-FU in the adjuvant setting for stage III tumors has been studied and debated in the elderly population in multiple trials. The MOSAIC trial investigated FOLFOX versus 5-FU/leucovorin in the adjuvant setting.⁵⁰ The addition of oxaliplatin was associated with a DFS and OS benefit, with a 20% reduction in risk of colon cancer recurrence and 16% reduction in risk of death in all patients. The National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trial then studied 2409 patients with stage II or III colon cancer treated with weekly bolus 5-FU/leucovorin with or without oxaliplatin.⁶⁰ In this study, OS was significantly improved with the addition of oxaliplatin in patients younger than 70 years, but OS at 5 years was 4.7% worse for patients aged ≥ 70 years treated with weekly 5-FU/leucovorin and oxaliplatin compared with those treated with weekly 5-FU/leucovorin (71.6% versus 76.3%, respectively). In contrast, the XELOXA trial (NO16968), which randomly assigned stage III colon cancer patients to capecitabine and oxaliplatin (XELOX) or bolus 5-FU/leucovorin (standard of care at study start), showed an efficacy benefit, albeit not statistically significant, in patients aged ≥ 70 years (HR 0.87 [95% CI 0.63 to 1.18]).^61–63

The Adjuvant Colon Cancer Endpoints (ACCENT) database included 7 randomized trials totaling 14,528 patients with stage II or III colon cancer treated with adjuvant 5-FU with or without oxaliplatin or irinotecan.⁶⁴ Subgroup analysis of patients aged ≥ 70 years (n = 2575) showed no benefit with an oxaliplatin-based regimen in DFS (HR 0.94 [95% CI 0.78 to 1.13]) or OS (HR 1.04 [95% CI, 0.85 to 1.27]). Based on these studies and the increased toxicity with oxaliplatin, oxaliplatin-based adjuvant chemotherapy is utilized less often than single-agent 5-FU in geriatric patients with early-stage colon cancer.⁶⁵ Conversely, a recent pooled analysis of individual patient data from 4 randomized trials (NSABP C-08, XELOXA, X-ACT, and AVANT) showed improved DFS and OS with adjuvant XELOX or FOLFOX over single-agent 5-FU in patients aged ≥ 70 years (DFS HR 0.77 [95% CI 0.62 to 0.95], P = 0.014; OS HR 0.78 [95% CI 0.61 to 0.99], P = 0.045).⁶⁶ This analysis also showed that grade 3 and 4 adverse events related to oxaliplatin were similar across age groups.

These data come from post-hoc analyses, and there is no prospective data to steer decision making in elderly patients with early-stage CRC (Table). 

It is well established that patients with stage III colon cancer benefit from oxaliplatin-based adjuvant chemotherapy after curative surgical resection.⁶⁸ However, older patients are less likely to be referred to oncology as compared with their younger counterparts, due to the conflicting data regarding the benefit of this approach in older adults. Studies have shown that when the referral is placed, the geriatric population is less likely to receive chemotherapy.⁶⁹ Sanoff et al analyzed 4 data sets (SEER-Medicare, National Comprehensive Cancer Network, New York State Cancer Registry, and Cancer Care Outcomes Research and Surveillance Consortium) to assess the benefit of adjuvant chemotherapy for resected stage III CRC among patients aged ≥ 75 years. Their analysis showed that only 40% of patients evaluated received adjuvant chemotherapy for stage III CRC after surgical resection.⁷⁰

Summary

Prospective data to guide the treatment of older patients with early-stage CRC in the adjuvant setting is lacking. For fit older patients with stage II disease, limited benefit will be derived from single-agent 5-FU. For those with stage III CRC, the benefit and toxicities of fluoropyrimidines as adjuvant therapy appear to be similar regardless of age. The addition of oxaliplatin to fluoropyrimidines in patients aged ≥ 70 years has not been proven to improve DFS or OS and could result in an incremental toxicity profile. Therefore, treatment plans must be individualized, and decisions should be made through an informed discussion evaluating the overall risk/benefit ratio of each approach.

Metastatic Disease

Palliative Chemotherapy

Approximately 20% of patients with CRC are diagnosed with metastatic disease at presentation, and 35% to 40% develop metastatic disease following surgery and adjuvant therapy.² The mainstay of treatment in this population is systemic therapy in the form of chemotherapy with or without biologic agents. In this setting, several prospective studies specific to older adults have been completed, providing more evidence-based guidance to oncologists who see these patients. Folprecht et al retrospectively reviewed data from 22 clinical trials evaluating 5-FU-based palliative chemotherapy in 3825 patients with metastatic CRC, including 629 patients aged ≥ 70 years.⁷¹ OS in elderly patients (10.8 months [95% CI 9.7 to 11.8]) was equivalent to that in younger patients (11.3 months [95% CI 10.9 to 11.7], P = 0.31). Similarly, relative risk and progression-free survival (PFS) were comparable irrespective of age.

Standard of care for most patients with metastatic colon cancer consists of 5-FU/leucovorin in combination with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) with a monoclonal antibody.⁷² A retrospective pooled analysis of patients with metastatic CRC compared the safety and efficacy of FOLFOX4 in patients aged < 70 years versus those aged ≥ 70 years.⁷³ While age ≥ 70 years was associated with an increased rate of grade ≥ 3 hematologic toxicity, it was not associated with increased rates of severe neurologic events, diarrhea, nausea, vomiting, infection, 60-day mortality, or overall incidence of grade ≥ 3 toxicity. The benefit of treatment was consistent across both age groups; therefore, age alone should not exclude an otherwise healthy individual from receiving FOLFOX.

These post-hoc analyses show that fit older patients who were candidates for trial participation tolerated these treatments well; however, these treatments may be more challenging for less fit older adults. The UK Medical Research Council FOCUS2 (Fluorouracil, Oxaliplatin, CPT11 [irinotecan]: Use and Sequencing) study was a prospective phase 3 trial that included 459 patients with metastatic CRC who were deemed too frail or not fit enough for standard-dose chemotherapy by their oncologists.⁷⁴ In this group, 43% of patients were older than 75 years and 13% were older than 80 years. Patients were randomly assigned to receive infusional 5-FU with levofolinate; oxaliplatin and 5-FU; capecitabine; or oxaliplatin and capecitabine; all regimens were initiated with an empiric 20% dose reduction. The addition of oxaliplatin suggested some improvement in PFS, but this was not significant (5.8 months versus 4.5 months, HR 0.84 [95% CI 0.69 to 1.01], P = 0.07). Oxaliplatin was not associated with increased grade 3 or 4 toxicities. Capecitabine is often viewed as less toxic because it is taken by mouth, but this study found that replacement of 5-FU with capecitabine did not improve quality of life. Grade 3 or 4 toxicities were seen more frequently in those receiving capecitabine than in those receiving 5-FU (40% versus 30%, P = 0.03) in this older and frailer group of patients. As the patients on this study were frail and treatment dose was reduced, this data may not apply to fit older adults who are candidates for standard therapy.

When managing an older patient with metastatic CRC, it is important to tailor therapy based on goals of care, toxicity of proposed treatment, other comorbidities, and the patient’s functional status. One approach to minimizing toxicity in the older population is the stop-and-go strategy. The OPTIMOX1 study showed that stopping oxaliplatin after 6 cycles of FOLFOX7 and continuing maintenance therapy with infusional 5-FU/leucovorin alone for 12 cycles prior to reintroducing FOLFOX7 achieved efficacy similar to continuous FOLFOX4 with decreased toxicity.⁷⁵ Figer et al studied an exploratory cohort of 37 patients aged 76 to 80 years who were included in the OPTIMOX1 study.⁷⁶ The overall relative risk, median PFS, and median OS did not differ between the older patients in this cohort and younger patients studied in the original study. Older patients did experience more neutropenia, neurotoxicity, and overall grade 3 to 4 toxicity, but there were no toxic deaths in patients older than 75 years. The approach of giving treatment breaks, as in OPTIMOX2, may also provide patients with better quality of life, but perhaps at the expense of cancer-related survival.⁷⁷

The combination of irinotecan and 5-FU has also been studied as treatment for patients with metastatic CRC. A pooled analysis of 2691 patients aged ≥ 70 years with metastatic CRC across 4 phase 3 randomized trials investigating irinotecan and 5-FU demonstrated that irinotecan-containing chemotherapy provided similar benefits to both older and younger patients with similar risk of toxicity.⁷⁸ A phase 2 trial studying FOLFIRI as first-line treatment in older metastatic CRC patients showed this to be a safe and active regimen with manageable toxicity.⁷⁹ Another randomized phase 3 trial for older patients compared 5-FU/leucovorin with or without irinotecan for first-line treatment of metastatic CRC (FFCD 2001-02).⁸⁰ The study accrued 282 patients aged ≥ 75 years (median age 80 years), and found that the addition of irinotecan to infusional 5-FU–based chemotherapy did not significantly increase either PFS or OS. Aparicio et al performed a substudy of baseline geriatric evaluation prior to treatment in the FFCD 2001-02 study and assessed the value of geriatric parameters for predicting outcomes (objective response rate [ORR], PFS, and OS).⁸¹ Multivariate analysis showed that none of the geriatric parameters were predictive of ORR or PFS but that normal IADL was associated with better OS. This combination may still be appropriate for some older patients with metastatic disease, while single- agent 5-FU may be more appropriate in frail patients.

Biologic Agents

VEGF Inhibitors

Targeted biologic agents have been studied in the treatment of metastatic CRC. Bevacizumab is a recombinant, humanized monoclonal antibody against vascular endothelial growth factor (VEGF) that is approved in the first-line setting for treatment of metastatic CRC. A pooled analysis examined 439 patients 65 years of age and older with metastatic CRC who received bevacizumab plus chemotherapy versus placebo plus chemotherapy.⁸² In this analysis, the addition of bevacizumab was associated with an improvement in OS (19.3 months versus 14.3 months, HR 0.7 [95% CI 0.55 to 0.90], P = 0.006) and in PFS (9.2 months versus 6.2 months, HR 0.52 [95% CI 0.40 to 0.67], P < 0.0001). Known adverse events associated with bevacizumab were seen in the bevacizumab plus chemotherapy group but not at increased rates in the older population compared to their younger counterparts. Conversely, another pooled analysis found that while there was a PFS and OS benefit in older patients receiving bevacizumab, there was an increased incidence of thrombotic events in patients older than 65 years.⁸³ The BEAT (Bevacizumab Expanded Access Trial) and BRiTE (Bevacizumab Regimens Investigation of Treatment Effects) studies showed similar clinical outcomes across all age groups.^84,85 While older patients experienced more arterial thromboembolic events with the addition of bevacizumab, other factors such as ECOG PS, prior anticoagulation, and history of arterial disease were more predictive of these adverse events than age.

The randomized phase 3 AVEX study explored the efficacy and tolerability of capecitabine plus bevacizumab versus capecitabine alone in 280 frail patients aged ≥ 70 years.⁸⁶ PFS in the capecitabine/bevacizumab arm was 9.1 months versus 5.1 months in the capecitabine alone arm. While the OS difference was not statistically significant, patients in the capecitabine/bevacizumab arm had an OS of 20.7 months versus 16.8 months in the capecitabine alone group. As reported in prior studies, patients in the capecitabine/bevacizumab arm had increased rates of toxic events (40%) compared with those who received capecitabine alone (22%), with reports of hypertension, hand-foot syndrome, bleeding, and thrombotic events. More recently, the phase 2 PRODIGE 20 trial studied the addition of bevacizumab to chemotherapy (5-FU, FOLFOX, or FOLFIRI) based on physician choice in untreated metastatic CRC patients aged ≥ 75 years (median age 80 years).⁸⁷ They found that the addition of bevacizumab to standard of care chemotherapy was both safe and effective. The adverse events seen with bevacizumab, such as hypertension and thrombotic events, were consistent with prior studies.

A newer antiangiogenic agent, ziv-aflibercept, has been approved for the second-line treatment of metastatic CRC. The VELOUR trial demonstrated that the addition of ziv-aflibercept to FOLFIRI benefited patients across all age groups compared with FOLFIRI plus placebo in patients who had failed prior oxaliplatin-based chemotherapy.^88,89 Ramucirumab is a human IgG-1 monoclonal antibody approved in second-line treatment in combination with FOLFIRI. A subgroup analysis of the RAISE study showed that the survival benefit was similar in patients aged ≥ 65 years versus those < 65 years.⁹⁰ Based on the above data, the use of a VEGF inhibitor in combination with chemotherapy should be considered in older patients with metastatic CRC. Furthermore, based on the conflicting data regarding the benefit of FOLFOX/FOLFIRI over single-agent 5-FU discussed above, the combination of capecitabine plus bevacizumab may be considered a front-line treatment option in older patients based on the AVEX study.

EGFR Inhibitors

Cetuximab and panitumumab are anti-epidermal growth factor receptor (EGFR) antibodies approved for the treatment of RAS wild-type metastatic CRC. Data regarding the use of EGFR inhibitors in the geriatric population is scarce and the data that does exist is conflicting.^91,92 The PRIME study demonstrated that panitumumab plus FOLFOX had a PFS benefit compared to FOLFOX alone in KRAS wild-type metastatic CRC patients.⁹² While the study met its primary endpoint, the benefit did not translate to patients aged ≥ 65 years in subgroup analysis. Conversely, a retrospective study of the efficacy and safety of cetuximab in elderly patients with heavily pretreated metastatic CRC found similar efficacy in older and younger patients as well as no increased adverse events in the older population.⁹¹ A phase 2 trial investigating cetuximab as single-agent first-line treatment of metastatic CRC in fit older patients found cetuximab to be safe with moderate activity in this population, but did not support the use of cetuximab as first-line single-agent treatment in fit geriatric patients who may be candidates for combination therapy.⁹³ Our group studied the patterns of use and tolerance of anti-EGFR antibodies in 117 older adults with metastatic CRC with a median age of 73 years.⁹⁴ The study showed that older age at the time of treatment was associated with administration of anti-EGFR antibody as monotherapy rather than in combination with chemotherapy (P = 0.0009). We found no association between age and presence of grade 3 or higher toxicity. In addition, the toxicity profile seen in older patients was similar to what has been demonstrated in prior studies involving a younger patient population. Given the discordance seen between studies, additional prospective trials are needed to elucidate the efficacy and safety of EGFR inhibitors in the geriatric population.

Other Agents

Two newer agents approved in the treatment of metastatic CRC are regorafenib, a multikinase inhibitor, and trifluridine/tipiracil (TFD/TPI), a nucleoside analog combined with an inhibitor of thymidine phosphorylase. The phase 3 CORRECT trial studied regorafenib as monotherapy in previously treated metastatic CRC and found an OS benefit of 1.4 months and minimal PFS benefit.⁹⁵ Van Cutsem et al performed a subgroup analysis by age and found similar OS benefit in patients < 65 years of age and ≥ 65 years.⁹⁶ The most frequent adverse events grade 3 or higher were hand-foot syndrome, fatigue, diarrhea, hypertension, and desquamation/rash, which were seen at similar rates in both age groups. More recently, the phase 2 Regorafenib Dose Optimization Study (ReDOS) found that weekly dose escalation of regorafenib from 80 mg to 160 mg daily over 3 weeks was superior to the standard 160 mg daily dosing in patients with metastatic CRC.⁹⁷ The dose escalation group had a longer median OS, although this difference was not statistically significant, as well as a more favorable toxicity profile. Therefore, this new dosing strategy may be a reasonable option for older patients with pretreated metastatic CRC. A study of TFD/TPI versus placebo in refractory metastatic CRC found an OS benefit of 7.1 months versus 5.3 months.⁹⁸ In subgroup analyses, the OS benefit extended to both patients < 65 years and ≥ 65 years. Given the sparse data on these newer agents in the geriatric population and the modest benefit they provide to those with refractory metastatic CRC, more data is needed to determine their utility in elderly patients. The decision to use these agents in the older patients warrants a thorough discussion with the patient regarding risks, benefit, and treatment goals.

Immunotherapy

Between 3.5% and 6.5% of stage IV colorectal cancers are MSI-H and have deficient mismatch repair (dMMR).^99–101 A recent phase 2 trial studied the use of pembrolizumab, an IgG4 monoclonal antibody against PD-1 (programmed cell death-1), in heavily pretreated patients with dMMR metastatic CRC, MMR-proficient (pMMR) metastatic CRC, and noncolorectal dMMR metastatic cancer.¹⁰² Patients with dMMR metastatic CRC had a 50% ORR and 89% disease control rate (DCR), as compared with an ORR of 0% and DCR of 16% in patients with pMMR metastatic CRC. There was also an OS and PFS benefit seen in the dMMR CRC group as compared with the pMMR CRC group. Another phase 2 study, CheckMate 142, studied the anti-PD-1 monoclonal antibody nivolumab with or without ipilimumab (a monoclonal antibody against cytotoxic T-lymphocyte antigen 4) in patients with dMMR and pMMR metastatic CRC.¹⁰³ In the interim analysis, nivolumab was found to provide both disease control and durable response in patients with dMMR metastatic CRC.

While these studies led to the FDA approval of pembrolizumab and nivolumab for management of previously treated MSI-H or dMMR metastatic CRC, data on the use of immunotherapy in older adults is scarce. Immunosenescence, or the gradual deterioration of the immune system that comes with aging, may impact the efficacy of immune checkpoint inhibitors (ICI) in older patients with advanced cancer.¹⁰⁴ There is conflicting data on the efficacy of PD-1 and programmed death ligand-1) PD-L1 inhibitors in older patients across different cancers. A meta-analysis of immunotherapy in older adults with a variety of malignancies showed overall efficacy comparable to that seen in adults younger than 65 years.¹⁰⁵ However, another review found ICIs to be less effective in older patients with head and neck, non-small cell lung cancer, and renal cell carcinoma compared with their younger counterparts.¹⁰⁴ Regarding the toxicity profile of ICIs in the elderly, similar rates of grade 3 or higher adverse events in patients younger than 65 years and older than 65 years have been reported.¹⁰⁶ However, patients aged ≥ 70 years had increased rates of grade 3 to 5 adverse events as compared to patients younger than 65 years (71.7% versus 58.4%, respectively). Given the scant data on ICIs in older patients with MSI-H or dMMR metastatic CRC, more clinical trials inclusive of this population are needed in order to determine the efficacy and safety of immunotherapy.

Palliative Care

The incorporation of palliative care early following the diagnosis of cancer has been shown to improve quality of life, decrease depression, and help with symptom management.¹⁰⁷ The triggers for geriatric patients to initiate palliative care may be different from those of younger patients, as older patients may have different goals of care.¹⁰⁸ Older patients will often choose quality over quantity of life when making treatment decisions.¹⁰⁹ The ideal medical treatment for the frail patient with colorectal cancer would focus on treating disease while providing palliative measures to help support the patient and improve quality of life. It is paramount that patients maintain functional independence as loss of independence is recognized as a major threat to an older patient’s quality of life.¹¹⁰ The optimal way to achieve these goals is through the efforts of a multidisciplinary care team including not only physicians and nurses, but also social workers, nutritionists, physical therapists, and family who can provide support for the patient’s psychosocial, cognitive, and medical needs.¹¹¹ Although cancer and noncancer–related death occur more frequently in the geriatric population, data to guide a specific palliative care approach to the elderly population is lacking.¹⁰⁸

Conclusion

Colorectal cancer is a disease of older adults with a median age at diagnosis of 67 years.¹ With the aging population, oncologists will be faced with treating increasing numbers of older patients, and must adjust their practice to accommodate this population of patients. Treating geriatric patients is challenging given the lack of available data to guide the treatment approach. Although several prospective elderly-specific studies have been conducted evaluating treatments for metastatic CRC, most treatment decisions are made based on the available retrospective studies and pooled analyses. Oncologists must carefully consider and evaluate each patient based on physiologic age rather than chronologic age.¹¹² Overall, older patients should be given the opportunity to receive standard of care treatments in the appropriate setting. The decision to modify treatment plans should be made after a thorough evaluation by a multidisciplinary team and a discussion with the patient regarding their goals and the risks and benefits of the treatment. Geriatric assessment tools can help the care team identify patients with various geriatric syndromes that may not be detected on routine oncology evaluation. This type of evaluation is time consuming and is rarely done in a busy oncology practice. Ongoing studies are aiming to develop a method to incorporate geriatric assessments into the care of older adults.Additional prospective trials targeting older, more frail patients are essential to improve upon our knowledge so we can provide best care for this growing elderly population.

Introduction

Colorectal cancer (CRC) is the fourth most common cancer in the United States and has a high prevalence among the older population.¹ In 2017, there were an estimated 135,430 new cases of CRC and 50,260 deaths due to CRC. It is the second leading cause of cancer death in the United States, and the death rate for patients with CRC increases with age (Figure).² 

Although elderly persons are more frequently diagnosed with CRC, they are underrepresented in clinical trials. This may be due in part to stringent eligibility criteria in prospective randomized controlled trials that exclude older patients with certain comorbidities and decreased functional status. Hutchins and colleagues compared the proportion of persons aged 65 years and older enrolled in Southwest Oncology Group (SWOG) clinical trials and the proportion of persons in this age group in the US population with the same cancer diagnoses.⁵ They found that while 72% of the US population with CRC were aged ≥ 65 years, persons in this age group comprised only 40% of patients enrolled in SWOG trials. An update on this study performed after Medicare policy changed in 2000 to include coverage of costs incurred due to clinical trials showed an upward trend in the accrual of older patients in SWOG trials, from 25% during the period 1993–1996 to 38% during the period 2001–2003; however, the percentage of older patients with CRC on clinical trials overall remained stable from 1993 to 2003.⁶

The underrepresentation of older adults with CRC in clinical trials presents oncologists with a challenging task when practicing evidence-based medicine in this patient population. Analysis of a large claims database demonstrated that the use of multi-agent chemotherapy for the treatment of metastatic CRC in older adults increased over time, while the use of single-agent 5-fluorouracil (5-FU) decreased.⁷ However, the adoption of combination therapy with irinotecan or oxaliplatin in older adults lagged behind the initial adoption of these agents in younger patients. This data demonstrates that as the field of medical oncology evolves, providers are becoming more comfortable treating older patients with multiple medical problems using standard approved regimens.

Geriatric Assessment

Before treating older patients with cancer, it is necessary to define the patient’s physiological age, ideally through a multidisciplinary team evaluation. Comprehensive geriatric assessment (CGA) is a multidisciplinary approach recommended for evaluation of an elderly person’s functional status, medical comorbidities, psychosocial status, cognitive function, and nutritional state.^8,9 CGA may uncover geriatric syndromes not otherwise detected by routine oncology evaluation. Functional status can vary greatly across geriatric patients in the same age group, with some older patients as robust as their younger counterparts and others more frail. The remainder of the population will likely fall along a continuum between the 2 extremes and may appear fit but have borderline reserve.¹⁰ Robust older adults have a better performance status and fewer comorbidities; identifying these fit older patients is important, as they are more likely to benefit from standard anticancer treatments.¹¹ Frail patients are more likely to have multiple comorbidities or other geriatric syndromes, such as cognitive impairment, depression, or gait disturbance, and are less likely to benefit from standard treatments.

The Eastern Cooperative Oncology Group performance status (ECOG PS) and Karnofsky Performance Status (KPS) are crude measures of functional status.¹² Generally, elderly patients with good ECOG PS or KPS scores are considered fit enough to receive standard therapy similar to their younger counterparts. Evaluation of functional status using these performance scores is often suboptimal, resulting in patients with a normal or adequate performance status score who may still experience poor outcomes, including decreased survival and inability to tolerate treatment. A study that explored parameters among older patients that predict for increased risk of chemotherapy-related toxicities found that physician-rated KPS score did not accurately predict the risk for adverse events.¹³ Therefore, a CGA represents a better way to evaluate functional status and other domains.

Functional status can also be evaluated by self-reported tools such as activities of daily living, which refer to basic self-care, and instrumental activities of daily living (IADLs), which are essential for independent living in the community.^14,15 Mobility, gait, and balance can also be measured using the “Timed Get Up and Go” test and gait speed. Klepin et al found that faster gait speed was associated with overall survival (OS) in patients with metastatic cancer.¹⁶

Cognitive function is an important component of the geriatric assessment in older patients with cancer, as dementia is a prognostic factor for survival in the overall geriatric population. In a retrospective review, patients with dementia were less likely to have a biopsy-proven diagnosis and were twice as likely to have their CRC diagnosed postmortem.¹⁷ In addition, establishing that the patient has intact cognitive function prior to initiating treatment is essential to ensure that the patient can comply with treatment and understands when to report adverse effects. Nutritional status is an important portion of the geriatric assessment because malnutrition is associated with increased mortality and decreased tolerance for chemotherapy.^18–20 Evaluating the patient’s psychosocial support is crucial as well because older patients are at greater risk of social isolation and depression.²¹ While the incidence of depression is lower in older adults with cancer than in younger adults with cancer, clinically significant depression is still noted in 3% to 25% of elderly cancer patients.²² Other critical components of the CGA are review of the patient’s comorbidities and medications to avoid complications of polypharmacy.

Both the Cancer and Aging Research Group (CARG) and Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) toxicity tools are valuable tools, as they predict chemotherapy tolerance in elderly patients.^13,23 These tools can help guide discussions between oncologists and patients as well as the formulation of an appropriate treatment plan.²⁴ Although toxicity tools can help to determine which patients are at risk for severe toxicity secondary to treatment, these tools do not replace the CGA. A prospective cohort study that evaluated the impact of CGA on tolerance to chemotherapy in older patients with cancer compared patients aged ≥ 70 years at the start of their treatment with chemotherapy (± radiation therapy) using geriatrician-delivered CGA versus standard care given by oncology.⁸ Patients who received geriatrician-guided CGA interventions tolerated chemotherapy better and completed treatments as planned (odds ratio 4.14 [95% confidence interval {CI} 1.50 to 11.42], P = 0.006) with fewer treatment modifications.

Unfortunately, the CGA is time-consuming to administer and difficult to incorporate into a busy oncology practice. Therefore, other screening models are used to identify patients who may benefit from a full CGA. The International Society of Geriatric Oncology performed a systematic review of screening tools used to identify older cancer patients in need of geriatric assessment and found that the 3 most studied screening tools are the G8, the Vulnerable Elders Survey-13 (VES-13), and the Flemish version of the Triage Risk Screening Tool.²⁵ Another study found that the G8 was more sensitive than the VES-13 (76.5% versus 68.7%, P = 0.0046), whereas the VES-13 was more specific than the G8 (74.3% versus 64.4%, P < 0.0001).²⁶ In addition to providing guidance to initiate a full geriatric assessment, these screening tools may assist in decision making for older cancer patients, especially those with advanced disease.

Surgery

Early-Stage Disease

When possible, surgical resection of colorectal tumors is the primary treatment in both the curative setting and to avoid complications, such as obstruction or perforation.²⁷ Multiple studies have shown that fit elderly patients benefit from curative surgery similarly to their younger counterparts.^27–29 With the growing population of persons aged 65 years or older, surgeons are becoming more comfortable with operating on the elderly.⁴ However, a large systematic review of 28 independent studies with a total of 34,194 patients showed that older patients were less likely to undergo curative surgery.³⁰ Eligibility for surgery should not be determined by age alone, but rather should be based on a full assessment of the patient’s health, including comorbidities, functional status, nutrition, cognition, social support, and psychological status. The impact of age on short-term outcomes after colorectal surgery in terms of 30-day postoperative morbidity and mortality rates was explored in a study that divided patients into 2 groups: those aged ≥ 80 years (mean age 85) and those aged < 80 years (mean age 55.3).³¹ There were no statistical differences in 30-day postoperative morbidity and mortality rates between the 2 groups, and preexisting comorbidities and urgent nature of surgery were important predictors of colorectal surgery outcomes in the older adults, results that have been seen in several other studies.^28,30 When possible, laparoscopic surgery is preferred as it is associated with less intraoperative blood loss, less postoperative pain, reduced postoperative ileus, a shorter hospital stay, and fewer cardiovascular and pulmonary complications.³² The Preoperative Assessment of Cancer in the Elderly (PACE), which combines surgical risk assessment tools with CGA tools, can assist surgeons in determining candidacy for surgery and help decrease unequal access to surgery in the geriatric population.³³

Metastasectomy

A large international multicenter cohort study explored the outcomes of patients aged ≥ 70 years who underwent liver resection of colorectal metastases. The study investigatorsfound that neoadjuvant chemotherapy was used less frequently and less extensive surgery was performed in elderly patients than in younger patients.³⁴ Sixty-day postoperative mortality was slightly higher (3.8% versus 1.6%, P < 0.001) and 3-year OS was slightly lower (57.1% versus 60.2%, P < 0.001) in the elderly group as compared to their younger counterparts, but overall the outcomes after liver surgery were similar. Therefore, the management of liver metastases in oligometastatic disease in elderly patients fit for surgery should be the same as that offered to younger patients. Since outcomes are comparable, older patients should be offered neoadjuvant chemotherapy, as several studies have shown similar response rates and OS in younger and older patients.^35,36

Rectal Cancer

The standard of care for locally advanced rectal cancer is combined modality treatment with radiation and chemotherapy followed by total mesorectal excision. However, given conflicting data regarding the ability of elderly patients to tolerate neoadjuvant 5-FU-based chemotherapy and radiation, elderly patients are treated with trimodality therapy less often than their younger counterparts.^37,38 A systematic review of 22 randomized trials involving 8507 patients with rectal cancer showed that adjuvant radiation therapy could reduce the risk of local recurrence and death from rectal cancer in patients of all ages.³⁹ However, the risk of noncancer-related death was increased in the older population. The Stockholm II trial showed similar benefits of preoperative radiation overall, but this benefit did not extend to patients older than 68 years because of an increased risk of morbidity and mortality.⁴⁰ In older patients, mortality from noncancer causes within the first 6 months after surgery was higher in the group that received perioperative radiation than in the group that did not receive radiation. Elderly patients (age > 68 years) accounted for most of the mortality, which was predominantly due to cardiovascular disease.

A retrospective study of 36 patients aged ≥ 70 years with rectal cancer evaluated the toxicity and feasibility of neoadjuvant 5-FU combined with pelvic radiation for treating locally advanced rectal cancer. Patients were classified as healthy and “fit” or “vulnerable” based on the presence of comorbidities.⁴¹ This study demonstrated that tolerability and response to neoadjuvant chemotherapy and radiation as well as ability to undergo surgery were similar in “vulnerable” patients and “fit” patients. Conversely, Margalit and colleagues studied the rate of treatment deviations in elderly patients with rectal cancer treated with combined modality therapy and found that most patients required early termination of treatment, treatment interruptions, or dose reductions.⁴² While trimodality treatment is the standard of care in rectal cancer, there is conflicting data from retrospective studies regarding the tolerability and feasibility of this approach. It is important to proceed with caution but to still consider fit older patients with locally advanced rectal cancer for neoadjuvant chemotherapy and radiation followed by surgery.

In patients who have a complete response (CR) to neoadjuvant chemoradiation, watchful waiting rather than proceeding to surgery may be a reasonable strategy, especially in older patients. A systematic review of 867 patients with locally advanced rectal cancer showed no statistically significant difference in OS between patients who were observed with watchful waiting and those who underwent surgery.⁴³ The International Watch and Wait Database includes 679 patients who were managed with a watch-and-wait regimen because they had a clinical CR after chemoradiation. An outcomes analysis of these patients showed that 25% had local regrowth, with 3-year OS of 91% overall and 87% in patients with local regrowth.⁴⁴ In most patients (84%), regrowth of the tumor occurred within the first 2 years of follow up.

In frail older adults, for whom longer courses of treatment are not feasible or chemotherapy is contraindicated, short-course radiation therapy can be considered either in the neoadjuvant setting or alone for palliation.⁴⁵ A randomized trial of short-course radiation versus long-course chemoradiation in patients with T3 rectal cancer found that the difference in 3-year local recurrence rates was not statistically significant.⁴⁶

Chemotherapy

An expected natural decline in function occurs with age, but given the great variability that exists between patients, it is important to focus on physiologic age rather than chronologic age to determine ability to receive and tolerate anticancer treatment. Decreases in renal and hepatic function, cognitive impairment, changes in gastrointestinal motility, decrements in cardiac and bone marrow reserves, as well as comorbidities and polypharmacy affect a patient’s ability to tolerate chemotherapy.^47,48 Toxicity tools such as CARG and CRASH can help to predict severity of toxicity with chemotherapy.^13,23 The information provided by these tools can help guide conversations between the oncologist and patient regarding treatment plans.

Adjuvant Chemotherapy for Early-Stage Disease

Stage II Disease

Defining treatment guidelines for older patients with stage II colon cancer is difficult due to lack of data that shows benefit in this population. The QUASAR (Quick and Simple and Reliable) group’s prospective study of adjuvant single-agent 5-FU in stage II colon cancer patients showed an absolute improvement in survival of 3.6% when 5-FU was given after surgery (95% CI 1.0 to 6.0).⁴⁹ The subgroup analysis of patients aged ≥ 70 years showed a limited benefit of adjuvant 5-FU (hazard ratio [HR] 1.13 [95% CI 0.74 to 1.75]). Given the limited benefit, adjuvant 5-FU for elderly patients with stage II colon cancer should be used judiciously as patients may have competing causes of morbidity or mortality.

The use of oxaliplatin-based therapy in the adjuvant setting for stage II disease was evaluated in a subgroup analysis of the MOSAIC study (Multicenter International Study of Oxaliplatin/5-FU/Leucovorin in the Adjuvant Treatment of Colon Cancer).⁵⁰ Adjuvant oxaliplatin-based treatment may be offered to patients with stage II colon cancer that carries high-risk features (poorly differentiated histology, lymphovascular invasion, bowel obstruction and/or perforation, < 12 lymph nodes sampled, perineural invasion, or indeterminate or positive margins) due to a trend toward improved disease-free survival (DFS) at 5 years. Patients in this group who received adjuvant FOLFOX (leucovorin, oxaliplatin, 5-FU) versus 5-FU/leucovorin had a DFS of 82.3% versus 74.6%, respectively (HR 0.72 [95% CI 0.50 to 1.02]), a difference that was not statistically significant. A subgroup analysis of 315 patients aged 70 to 75 years with stage II colon cancer enrolled in the MOSAIC study found no statistically significant DFS or OS benefit with the addition of oxaliplatin to 5-FU/leucovorin.⁵¹ Therefore, use of this platinum/fluoropyrimidine combination for adjuvant therapy for high-risk stage II disease in older patients remains controversial given its associated risks and the lack of definitive data demonstrating a benefit in this patient group. Decisions regarding this therapy should be made through a shared discussion with patients about its risks and benefits.

Microsatellite status is an important biomarker in the evaluation of stage II CRC. Microsatellite stability is a marker of a functioning DNA mismatch repair system. In patients with colon cancer, tumor microsatellite stability is classified based on the percentage of abnormal microsatellite regions.⁵² Several studies have shown that patients with tumors that display high microsatellite instability (MSI-H) have an improved prognosis over patients with microsatellite stable tumors.^53,54 While patients with stage II MSI-H colon cancer have better outcomes, MSI is associated with a reduced response to treatment with fluoropyrimidines, as demonstrated in a systematic review that found that patients with tumors with MSI obtained no benefit from adjuvant 5-FU (HR 1.24 [95% CI 0.72 to 2.14]).⁵⁵ Aparicio and colleagues reported an increased prevalence of MSI-H tumors with increasing age.⁵⁶ Therefore, mismatch repair phenotype should be considered when making adjuvant chemotherapy decisions in the older adult with colon cancer, as it may affect the decision to recommend single-agent 5-FU treatment.

Stage III Disease

The use of single-agent 5-FU for stage III resected CRC has been evaluated in multiple studies. Sargent et al performed a pooled analysis of 3351 patients from 7 randomized phase 3 trials comparing surgery and adjuvant 5-FU-based chemotherapy versus surgery alone in stage II or III colon cancer patients.⁵⁷ Adjuvant chemotherapy was associated with improvement in both OS and time to tumor recurrence (HR 0.76 and 0.68, respectively). The 5-year OS was 71% for those who received adjuvant treatment and 64% for those who were treated with surgery alone. The benefit of adjuvant treatment was independent of age, and there was no difference in toxicity across age groups, except for 1 study which showed increased rates of leukopenia in the elderly. The oral fluoropyrimidine capecitabine was shown to be an effective alternative to 5-FU plus leucovorin as adjuvant treatment for those with resected stage III colon cancer.⁵⁸ However, in the subgroup analysis of DFS in the intention-to-treat group, the improvement in DFS was not statistically significant in those aged ≥ 70 years. This study justified the phase 3 Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) trial, which compared capecitabine and 5-FU/leucovorin as adjuvant therapy in patients with resected stage III colon cancer.⁵⁹ The X-ACT trial showed no significant effect of age on DFS or OS.

The addition of oxaliplatin to 5-FU in the adjuvant setting for stage III tumors has been studied and debated in the elderly population in multiple trials. The MOSAIC trial investigated FOLFOX versus 5-FU/leucovorin in the adjuvant setting.⁵⁰ The addition of oxaliplatin was associated with a DFS and OS benefit, with a 20% reduction in risk of colon cancer recurrence and 16% reduction in risk of death in all patients. The National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trial then studied 2409 patients with stage II or III colon cancer treated with weekly bolus 5-FU/leucovorin with or without oxaliplatin.⁶⁰ In this study, OS was significantly improved with the addition of oxaliplatin in patients younger than 70 years, but OS at 5 years was 4.7% worse for patients aged ≥ 70 years treated with weekly 5-FU/leucovorin and oxaliplatin compared with those treated with weekly 5-FU/leucovorin (71.6% versus 76.3%, respectively). In contrast, the XELOXA trial (NO16968), which randomly assigned stage III colon cancer patients to capecitabine and oxaliplatin (XELOX) or bolus 5-FU/leucovorin (standard of care at study start), showed an efficacy benefit, albeit not statistically significant, in patients aged ≥ 70 years (HR 0.87 [95% CI 0.63 to 1.18]).^61–63

The Adjuvant Colon Cancer Endpoints (ACCENT) database included 7 randomized trials totaling 14,528 patients with stage II or III colon cancer treated with adjuvant 5-FU with or without oxaliplatin or irinotecan.⁶⁴ Subgroup analysis of patients aged ≥ 70 years (n = 2575) showed no benefit with an oxaliplatin-based regimen in DFS (HR 0.94 [95% CI 0.78 to 1.13]) or OS (HR 1.04 [95% CI, 0.85 to 1.27]). Based on these studies and the increased toxicity with oxaliplatin, oxaliplatin-based adjuvant chemotherapy is utilized less often than single-agent 5-FU in geriatric patients with early-stage colon cancer.⁶⁵ Conversely, a recent pooled analysis of individual patient data from 4 randomized trials (NSABP C-08, XELOXA, X-ACT, and AVANT) showed improved DFS and OS with adjuvant XELOX or FOLFOX over single-agent 5-FU in patients aged ≥ 70 years (DFS HR 0.77 [95% CI 0.62 to 0.95], P = 0.014; OS HR 0.78 [95% CI 0.61 to 0.99], P = 0.045).⁶⁶ This analysis also showed that grade 3 and 4 adverse events related to oxaliplatin were similar across age groups.

These data come from post-hoc analyses, and there is no prospective data to steer decision making in elderly patients with early-stage CRC (Table). 

It is well established that patients with stage III colon cancer benefit from oxaliplatin-based adjuvant chemotherapy after curative surgical resection.⁶⁸ However, older patients are less likely to be referred to oncology as compared with their younger counterparts, due to the conflicting data regarding the benefit of this approach in older adults. Studies have shown that when the referral is placed, the geriatric population is less likely to receive chemotherapy.⁶⁹ Sanoff et al analyzed 4 data sets (SEER-Medicare, National Comprehensive Cancer Network, New York State Cancer Registry, and Cancer Care Outcomes Research and Surveillance Consortium) to assess the benefit of adjuvant chemotherapy for resected stage III CRC among patients aged ≥ 75 years. Their analysis showed that only 40% of patients evaluated received adjuvant chemotherapy for stage III CRC after surgical resection.⁷⁰

Summary

Prospective data to guide the treatment of older patients with early-stage CRC in the adjuvant setting is lacking. For fit older patients with stage II disease, limited benefit will be derived from single-agent 5-FU. For those with stage III CRC, the benefit and toxicities of fluoropyrimidines as adjuvant therapy appear to be similar regardless of age. The addition of oxaliplatin to fluoropyrimidines in patients aged ≥ 70 years has not been proven to improve DFS or OS and could result in an incremental toxicity profile. Therefore, treatment plans must be individualized, and decisions should be made through an informed discussion evaluating the overall risk/benefit ratio of each approach.

Metastatic Disease

Palliative Chemotherapy

Approximately 20% of patients with CRC are diagnosed with metastatic disease at presentation, and 35% to 40% develop metastatic disease following surgery and adjuvant therapy.² The mainstay of treatment in this population is systemic therapy in the form of chemotherapy with or without biologic agents. In this setting, several prospective studies specific to older adults have been completed, providing more evidence-based guidance to oncologists who see these patients. Folprecht et al retrospectively reviewed data from 22 clinical trials evaluating 5-FU-based palliative chemotherapy in 3825 patients with metastatic CRC, including 629 patients aged ≥ 70 years.⁷¹ OS in elderly patients (10.8 months [95% CI 9.7 to 11.8]) was equivalent to that in younger patients (11.3 months [95% CI 10.9 to 11.7], P = 0.31). Similarly, relative risk and progression-free survival (PFS) were comparable irrespective of age.

Standard of care for most patients with metastatic colon cancer consists of 5-FU/leucovorin in combination with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) with a monoclonal antibody.⁷² A retrospective pooled analysis of patients with metastatic CRC compared the safety and efficacy of FOLFOX4 in patients aged < 70 years versus those aged ≥ 70 years.⁷³ While age ≥ 70 years was associated with an increased rate of grade ≥ 3 hematologic toxicity, it was not associated with increased rates of severe neurologic events, diarrhea, nausea, vomiting, infection, 60-day mortality, or overall incidence of grade ≥ 3 toxicity. The benefit of treatment was consistent across both age groups; therefore, age alone should not exclude an otherwise healthy individual from receiving FOLFOX.

These post-hoc analyses show that fit older patients who were candidates for trial participation tolerated these treatments well; however, these treatments may be more challenging for less fit older adults. The UK Medical Research Council FOCUS2 (Fluorouracil, Oxaliplatin, CPT11 [irinotecan]: Use and Sequencing) study was a prospective phase 3 trial that included 459 patients with metastatic CRC who were deemed too frail or not fit enough for standard-dose chemotherapy by their oncologists.⁷⁴ In this group, 43% of patients were older than 75 years and 13% were older than 80 years. Patients were randomly assigned to receive infusional 5-FU with levofolinate; oxaliplatin and 5-FU; capecitabine; or oxaliplatin and capecitabine; all regimens were initiated with an empiric 20% dose reduction. The addition of oxaliplatin suggested some improvement in PFS, but this was not significant (5.8 months versus 4.5 months, HR 0.84 [95% CI 0.69 to 1.01], P = 0.07). Oxaliplatin was not associated with increased grade 3 or 4 toxicities. Capecitabine is often viewed as less toxic because it is taken by mouth, but this study found that replacement of 5-FU with capecitabine did not improve quality of life. Grade 3 or 4 toxicities were seen more frequently in those receiving capecitabine than in those receiving 5-FU (40% versus 30%, P = 0.03) in this older and frailer group of patients. As the patients on this study were frail and treatment dose was reduced, this data may not apply to fit older adults who are candidates for standard therapy.

When managing an older patient with metastatic CRC, it is important to tailor therapy based on goals of care, toxicity of proposed treatment, other comorbidities, and the patient’s functional status. One approach to minimizing toxicity in the older population is the stop-and-go strategy. The OPTIMOX1 study showed that stopping oxaliplatin after 6 cycles of FOLFOX7 and continuing maintenance therapy with infusional 5-FU/leucovorin alone for 12 cycles prior to reintroducing FOLFOX7 achieved efficacy similar to continuous FOLFOX4 with decreased toxicity.⁷⁵ Figer et al studied an exploratory cohort of 37 patients aged 76 to 80 years who were included in the OPTIMOX1 study.⁷⁶ The overall relative risk, median PFS, and median OS did not differ between the older patients in this cohort and younger patients studied in the original study. Older patients did experience more neutropenia, neurotoxicity, and overall grade 3 to 4 toxicity, but there were no toxic deaths in patients older than 75 years. The approach of giving treatment breaks, as in OPTIMOX2, may also provide patients with better quality of life, but perhaps at the expense of cancer-related survival.⁷⁷

The combination of irinotecan and 5-FU has also been studied as treatment for patients with metastatic CRC. A pooled analysis of 2691 patients aged ≥ 70 years with metastatic CRC across 4 phase 3 randomized trials investigating irinotecan and 5-FU demonstrated that irinotecan-containing chemotherapy provided similar benefits to both older and younger patients with similar risk of toxicity.⁷⁸ A phase 2 trial studying FOLFIRI as first-line treatment in older metastatic CRC patients showed this to be a safe and active regimen with manageable toxicity.⁷⁹ Another randomized phase 3 trial for older patients compared 5-FU/leucovorin with or without irinotecan for first-line treatment of metastatic CRC (FFCD 2001-02).⁸⁰ The study accrued 282 patients aged ≥ 75 years (median age 80 years), and found that the addition of irinotecan to infusional 5-FU–based chemotherapy did not significantly increase either PFS or OS. Aparicio et al performed a substudy of baseline geriatric evaluation prior to treatment in the FFCD 2001-02 study and assessed the value of geriatric parameters for predicting outcomes (objective response rate [ORR], PFS, and OS).⁸¹ Multivariate analysis showed that none of the geriatric parameters were predictive of ORR or PFS but that normal IADL was associated with better OS. This combination may still be appropriate for some older patients with metastatic disease, while single- agent 5-FU may be more appropriate in frail patients.

Biologic Agents

VEGF Inhibitors

Targeted biologic agents have been studied in the treatment of metastatic CRC. Bevacizumab is a recombinant, humanized monoclonal antibody against vascular endothelial growth factor (VEGF) that is approved in the first-line setting for treatment of metastatic CRC. A pooled analysis examined 439 patients 65 years of age and older with metastatic CRC who received bevacizumab plus chemotherapy versus placebo plus chemotherapy.⁸² In this analysis, the addition of bevacizumab was associated with an improvement in OS (19.3 months versus 14.3 months, HR 0.7 [95% CI 0.55 to 0.90], P = 0.006) and in PFS (9.2 months versus 6.2 months, HR 0.52 [95% CI 0.40 to 0.67], P < 0.0001). Known adverse events associated with bevacizumab were seen in the bevacizumab plus chemotherapy group but not at increased rates in the older population compared to their younger counterparts. Conversely, another pooled analysis found that while there was a PFS and OS benefit in older patients receiving bevacizumab, there was an increased incidence of thrombotic events in patients older than 65 years.⁸³ The BEAT (Bevacizumab Expanded Access Trial) and BRiTE (Bevacizumab Regimens Investigation of Treatment Effects) studies showed similar clinical outcomes across all age groups.^84,85 While older patients experienced more arterial thromboembolic events with the addition of bevacizumab, other factors such as ECOG PS, prior anticoagulation, and history of arterial disease were more predictive of these adverse events than age.

The randomized phase 3 AVEX study explored the efficacy and tolerability of capecitabine plus bevacizumab versus capecitabine alone in 280 frail patients aged ≥ 70 years.⁸⁶ PFS in the capecitabine/bevacizumab arm was 9.1 months versus 5.1 months in the capecitabine alone arm. While the OS difference was not statistically significant, patients in the capecitabine/bevacizumab arm had an OS of 20.7 months versus 16.8 months in the capecitabine alone group. As reported in prior studies, patients in the capecitabine/bevacizumab arm had increased rates of toxic events (40%) compared with those who received capecitabine alone (22%), with reports of hypertension, hand-foot syndrome, bleeding, and thrombotic events. More recently, the phase 2 PRODIGE 20 trial studied the addition of bevacizumab to chemotherapy (5-FU, FOLFOX, or FOLFIRI) based on physician choice in untreated metastatic CRC patients aged ≥ 75 years (median age 80 years).⁸⁷ They found that the addition of bevacizumab to standard of care chemotherapy was both safe and effective. The adverse events seen with bevacizumab, such as hypertension and thrombotic events, were consistent with prior studies.

A newer antiangiogenic agent, ziv-aflibercept, has been approved for the second-line treatment of metastatic CRC. The VELOUR trial demonstrated that the addition of ziv-aflibercept to FOLFIRI benefited patients across all age groups compared with FOLFIRI plus placebo in patients who had failed prior oxaliplatin-based chemotherapy.^88,89 Ramucirumab is a human IgG-1 monoclonal antibody approved in second-line treatment in combination with FOLFIRI. A subgroup analysis of the RAISE study showed that the survival benefit was similar in patients aged ≥ 65 years versus those < 65 years.⁹⁰ Based on the above data, the use of a VEGF inhibitor in combination with chemotherapy should be considered in older patients with metastatic CRC. Furthermore, based on the conflicting data regarding the benefit of FOLFOX/FOLFIRI over single-agent 5-FU discussed above, the combination of capecitabine plus bevacizumab may be considered a front-line treatment option in older patients based on the AVEX study.

EGFR Inhibitors

Cetuximab and panitumumab are anti-epidermal growth factor receptor (EGFR) antibodies approved for the treatment of RAS wild-type metastatic CRC. Data regarding the use of EGFR inhibitors in the geriatric population is scarce and the data that does exist is conflicting.^91,92 The PRIME study demonstrated that panitumumab plus FOLFOX had a PFS benefit compared to FOLFOX alone in KRAS wild-type metastatic CRC patients.⁹² While the study met its primary endpoint, the benefit did not translate to patients aged ≥ 65 years in subgroup analysis. Conversely, a retrospective study of the efficacy and safety of cetuximab in elderly patients with heavily pretreated metastatic CRC found similar efficacy in older and younger patients as well as no increased adverse events in the older population.⁹¹ A phase 2 trial investigating cetuximab as single-agent first-line treatment of metastatic CRC in fit older patients found cetuximab to be safe with moderate activity in this population, but did not support the use of cetuximab as first-line single-agent treatment in fit geriatric patients who may be candidates for combination therapy.⁹³ Our group studied the patterns of use and tolerance of anti-EGFR antibodies in 117 older adults with metastatic CRC with a median age of 73 years.⁹⁴ The study showed that older age at the time of treatment was associated with administration of anti-EGFR antibody as monotherapy rather than in combination with chemotherapy (P = 0.0009). We found no association between age and presence of grade 3 or higher toxicity. In addition, the toxicity profile seen in older patients was similar to what has been demonstrated in prior studies involving a younger patient population. Given the discordance seen between studies, additional prospective trials are needed to elucidate the efficacy and safety of EGFR inhibitors in the geriatric population.

Other Agents

Two newer agents approved in the treatment of metastatic CRC are regorafenib, a multikinase inhibitor, and trifluridine/tipiracil (TFD/TPI), a nucleoside analog combined with an inhibitor of thymidine phosphorylase. The phase 3 CORRECT trial studied regorafenib as monotherapy in previously treated metastatic CRC and found an OS benefit of 1.4 months and minimal PFS benefit.⁹⁵ Van Cutsem et al performed a subgroup analysis by age and found similar OS benefit in patients < 65 years of age and ≥ 65 years.⁹⁶ The most frequent adverse events grade 3 or higher were hand-foot syndrome, fatigue, diarrhea, hypertension, and desquamation/rash, which were seen at similar rates in both age groups. More recently, the phase 2 Regorafenib Dose Optimization Study (ReDOS) found that weekly dose escalation of regorafenib from 80 mg to 160 mg daily over 3 weeks was superior to the standard 160 mg daily dosing in patients with metastatic CRC.⁹⁷ The dose escalation group had a longer median OS, although this difference was not statistically significant, as well as a more favorable toxicity profile. Therefore, this new dosing strategy may be a reasonable option for older patients with pretreated metastatic CRC. A study of TFD/TPI versus placebo in refractory metastatic CRC found an OS benefit of 7.1 months versus 5.3 months.⁹⁸ In subgroup analyses, the OS benefit extended to both patients < 65 years and ≥ 65 years. Given the sparse data on these newer agents in the geriatric population and the modest benefit they provide to those with refractory metastatic CRC, more data is needed to determine their utility in elderly patients. The decision to use these agents in the older patients warrants a thorough discussion with the patient regarding risks, benefit, and treatment goals.

Immunotherapy

Between 3.5% and 6.5% of stage IV colorectal cancers are MSI-H and have deficient mismatch repair (dMMR).^99–101 A recent phase 2 trial studied the use of pembrolizumab, an IgG4 monoclonal antibody against PD-1 (programmed cell death-1), in heavily pretreated patients with dMMR metastatic CRC, MMR-proficient (pMMR) metastatic CRC, and noncolorectal dMMR metastatic cancer.¹⁰² Patients with dMMR metastatic CRC had a 50% ORR and 89% disease control rate (DCR), as compared with an ORR of 0% and DCR of 16% in patients with pMMR metastatic CRC. There was also an OS and PFS benefit seen in the dMMR CRC group as compared with the pMMR CRC group. Another phase 2 study, CheckMate 142, studied the anti-PD-1 monoclonal antibody nivolumab with or without ipilimumab (a monoclonal antibody against cytotoxic T-lymphocyte antigen 4) in patients with dMMR and pMMR metastatic CRC.¹⁰³ In the interim analysis, nivolumab was found to provide both disease control and durable response in patients with dMMR metastatic CRC.

While these studies led to the FDA approval of pembrolizumab and nivolumab for management of previously treated MSI-H or dMMR metastatic CRC, data on the use of immunotherapy in older adults is scarce. Immunosenescence, or the gradual deterioration of the immune system that comes with aging, may impact the efficacy of immune checkpoint inhibitors (ICI) in older patients with advanced cancer.¹⁰⁴ There is conflicting data on the efficacy of PD-1 and programmed death ligand-1) PD-L1 inhibitors in older patients across different cancers. A meta-analysis of immunotherapy in older adults with a variety of malignancies showed overall efficacy comparable to that seen in adults younger than 65 years.¹⁰⁵ However, another review found ICIs to be less effective in older patients with head and neck, non-small cell lung cancer, and renal cell carcinoma compared with their younger counterparts.¹⁰⁴ Regarding the toxicity profile of ICIs in the elderly, similar rates of grade 3 or higher adverse events in patients younger than 65 years and older than 65 years have been reported.¹⁰⁶ However, patients aged ≥ 70 years had increased rates of grade 3 to 5 adverse events as compared to patients younger than 65 years (71.7% versus 58.4%, respectively). Given the scant data on ICIs in older patients with MSI-H or dMMR metastatic CRC, more clinical trials inclusive of this population are needed in order to determine the efficacy and safety of immunotherapy.

Palliative Care

The incorporation of palliative care early following the diagnosis of cancer has been shown to improve quality of life, decrease depression, and help with symptom management.¹⁰⁷ The triggers for geriatric patients to initiate palliative care may be different from those of younger patients, as older patients may have different goals of care.¹⁰⁸ Older patients will often choose quality over quantity of life when making treatment decisions.¹⁰⁹ The ideal medical treatment for the frail patient with colorectal cancer would focus on treating disease while providing palliative measures to help support the patient and improve quality of life. It is paramount that patients maintain functional independence as loss of independence is recognized as a major threat to an older patient’s quality of life.¹¹⁰ The optimal way to achieve these goals is through the efforts of a multidisciplinary care team including not only physicians and nurses, but also social workers, nutritionists, physical therapists, and family who can provide support for the patient’s psychosocial, cognitive, and medical needs.¹¹¹ Although cancer and noncancer–related death occur more frequently in the geriatric population, data to guide a specific palliative care approach to the elderly population is lacking.¹⁰⁸

Conclusion

Colorectal cancer is a disease of older adults with a median age at diagnosis of 67 years.¹ With the aging population, oncologists will be faced with treating increasing numbers of older patients, and must adjust their practice to accommodate this population of patients. Treating geriatric patients is challenging given the lack of available data to guide the treatment approach. Although several prospective elderly-specific studies have been conducted evaluating treatments for metastatic CRC, most treatment decisions are made based on the available retrospective studies and pooled analyses. Oncologists must carefully consider and evaluate each patient based on physiologic age rather than chronologic age.¹¹² Overall, older patients should be given the opportunity to receive standard of care treatments in the appropriate setting. The decision to modify treatment plans should be made after a thorough evaluation by a multidisciplinary team and a discussion with the patient regarding their goals and the risks and benefits of the treatment. Geriatric assessment tools can help the care team identify patients with various geriatric syndromes that may not be detected on routine oncology evaluation. This type of evaluation is time consuming and is rarely done in a busy oncology practice. Ongoing studies are aiming to develop a method to incorporate geriatric assessments into the care of older adults.Additional prospective trials targeting older, more frail patients are essential to improve upon our knowledge so we can provide best care for this growing elderly population.

Introduction

Colorectal cancer (CRC) is the fourth most common cancer in the United States and has a high prevalence among the older population.¹ In 2017, there were an estimated 135,430 new cases of CRC and 50,260 deaths due to CRC. It is the second leading cause of cancer death in the United States, and the death rate for patients with CRC increases with age (Figure).² 

Although elderly persons are more frequently diagnosed with CRC, they are underrepresented in clinical trials. This may be due in part to stringent eligibility criteria in prospective randomized controlled trials that exclude older patients with certain comorbidities and decreased functional status. Hutchins and colleagues compared the proportion of persons aged 65 years and older enrolled in Southwest Oncology Group (SWOG) clinical trials and the proportion of persons in this age group in the US population with the same cancer diagnoses.⁵ They found that while 72% of the US population with CRC were aged ≥ 65 years, persons in this age group comprised only 40% of patients enrolled in SWOG trials. An update on this study performed after Medicare policy changed in 2000 to include coverage of costs incurred due to clinical trials showed an upward trend in the accrual of older patients in SWOG trials, from 25% during the period 1993–1996 to 38% during the period 2001–2003; however, the percentage of older patients with CRC on clinical trials overall remained stable from 1993 to 2003.⁶

The underrepresentation of older adults with CRC in clinical trials presents oncologists with a challenging task when practicing evidence-based medicine in this patient population. Analysis of a large claims database demonstrated that the use of multi-agent chemotherapy for the treatment of metastatic CRC in older adults increased over time, while the use of single-agent 5-fluorouracil (5-FU) decreased.⁷ However, the adoption of combination therapy with irinotecan or oxaliplatin in older adults lagged behind the initial adoption of these agents in younger patients. This data demonstrates that as the field of medical oncology evolves, providers are becoming more comfortable treating older patients with multiple medical problems using standard approved regimens.

Geriatric Assessment

Before treating older patients with cancer, it is necessary to define the patient’s physiological age, ideally through a multidisciplinary team evaluation. Comprehensive geriatric assessment (CGA) is a multidisciplinary approach recommended for evaluation of an elderly person’s functional status, medical comorbidities, psychosocial status, cognitive function, and nutritional state.^8,9 CGA may uncover geriatric syndromes not otherwise detected by routine oncology evaluation. Functional status can vary greatly across geriatric patients in the same age group, with some older patients as robust as their younger counterparts and others more frail. The remainder of the population will likely fall along a continuum between the 2 extremes and may appear fit but have borderline reserve.¹⁰ Robust older adults have a better performance status and fewer comorbidities; identifying these fit older patients is important, as they are more likely to benefit from standard anticancer treatments.¹¹ Frail patients are more likely to have multiple comorbidities or other geriatric syndromes, such as cognitive impairment, depression, or gait disturbance, and are less likely to benefit from standard treatments.

The Eastern Cooperative Oncology Group performance status (ECOG PS) and Karnofsky Performance Status (KPS) are crude measures of functional status.¹² Generally, elderly patients with good ECOG PS or KPS scores are considered fit enough to receive standard therapy similar to their younger counterparts. Evaluation of functional status using these performance scores is often suboptimal, resulting in patients with a normal or adequate performance status score who may still experience poor outcomes, including decreased survival and inability to tolerate treatment. A study that explored parameters among older patients that predict for increased risk of chemotherapy-related toxicities found that physician-rated KPS score did not accurately predict the risk for adverse events.¹³ Therefore, a CGA represents a better way to evaluate functional status and other domains.

Functional status can also be evaluated by self-reported tools such as activities of daily living, which refer to basic self-care, and instrumental activities of daily living (IADLs), which are essential for independent living in the community.^14,15 Mobility, gait, and balance can also be measured using the “Timed Get Up and Go” test and gait speed. Klepin et al found that faster gait speed was associated with overall survival (OS) in patients with metastatic cancer.¹⁶

Cognitive function is an important component of the geriatric assessment in older patients with cancer, as dementia is a prognostic factor for survival in the overall geriatric population. In a retrospective review, patients with dementia were less likely to have a biopsy-proven diagnosis and were twice as likely to have their CRC diagnosed postmortem.¹⁷ In addition, establishing that the patient has intact cognitive function prior to initiating treatment is essential to ensure that the patient can comply with treatment and understands when to report adverse effects. Nutritional status is an important portion of the geriatric assessment because malnutrition is associated with increased mortality and decreased tolerance for chemotherapy.^18–20 Evaluating the patient’s psychosocial support is crucial as well because older patients are at greater risk of social isolation and depression.²¹ While the incidence of depression is lower in older adults with cancer than in younger adults with cancer, clinically significant depression is still noted in 3% to 25% of elderly cancer patients.²² Other critical components of the CGA are review of the patient’s comorbidities and medications to avoid complications of polypharmacy.

Both the Cancer and Aging Research Group (CARG) and Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) toxicity tools are valuable tools, as they predict chemotherapy tolerance in elderly patients.^13,23 These tools can help guide discussions between oncologists and patients as well as the formulation of an appropriate treatment plan.²⁴ Although toxicity tools can help to determine which patients are at risk for severe toxicity secondary to treatment, these tools do not replace the CGA. A prospective cohort study that evaluated the impact of CGA on tolerance to chemotherapy in older patients with cancer compared patients aged ≥ 70 years at the start of their treatment with chemotherapy (± radiation therapy) using geriatrician-delivered CGA versus standard care given by oncology.⁸ Patients who received geriatrician-guided CGA interventions tolerated chemotherapy better and completed treatments as planned (odds ratio 4.14 [95% confidence interval {CI} 1.50 to 11.42], P = 0.006) with fewer treatment modifications.

Unfortunately, the CGA is time-consuming to administer and difficult to incorporate into a busy oncology practice. Therefore, other screening models are used to identify patients who may benefit from a full CGA. The International Society of Geriatric Oncology performed a systematic review of screening tools used to identify older cancer patients in need of geriatric assessment and found that the 3 most studied screening tools are the G8, the Vulnerable Elders Survey-13 (VES-13), and the Flemish version of the Triage Risk Screening Tool.²⁵ Another study found that the G8 was more sensitive than the VES-13 (76.5% versus 68.7%, P = 0.0046), whereas the VES-13 was more specific than the G8 (74.3% versus 64.4%, P < 0.0001).²⁶ In addition to providing guidance to initiate a full geriatric assessment, these screening tools may assist in decision making for older cancer patients, especially those with advanced disease.

Surgery

Early-Stage Disease

When possible, surgical resection of colorectal tumors is the primary treatment in both the curative setting and to avoid complications, such as obstruction or perforation.²⁷ Multiple studies have shown that fit elderly patients benefit from curative surgery similarly to their younger counterparts.^27–29 With the growing population of persons aged 65 years or older, surgeons are becoming more comfortable with operating on the elderly.⁴ However, a large systematic review of 28 independent studies with a total of 34,194 patients showed that older patients were less likely to undergo curative surgery.³⁰ Eligibility for surgery should not be determined by age alone, but rather should be based on a full assessment of the patient’s health, including comorbidities, functional status, nutrition, cognition, social support, and psychological status. The impact of age on short-term outcomes after colorectal surgery in terms of 30-day postoperative morbidity and mortality rates was explored in a study that divided patients into 2 groups: those aged ≥ 80 years (mean age 85) and those aged < 80 years (mean age 55.3).³¹ There were no statistical differences in 30-day postoperative morbidity and mortality rates between the 2 groups, and preexisting comorbidities and urgent nature of surgery were important predictors of colorectal surgery outcomes in the older adults, results that have been seen in several other studies.^28,30 When possible, laparoscopic surgery is preferred as it is associated with less intraoperative blood loss, less postoperative pain, reduced postoperative ileus, a shorter hospital stay, and fewer cardiovascular and pulmonary complications.³² The Preoperative Assessment of Cancer in the Elderly (PACE), which combines surgical risk assessment tools with CGA tools, can assist surgeons in determining candidacy for surgery and help decrease unequal access to surgery in the geriatric population.³³

Metastasectomy

A large international multicenter cohort study explored the outcomes of patients aged ≥ 70 years who underwent liver resection of colorectal metastases. The study investigatorsfound that neoadjuvant chemotherapy was used less frequently and less extensive surgery was performed in elderly patients than in younger patients.³⁴ Sixty-day postoperative mortality was slightly higher (3.8% versus 1.6%, P < 0.001) and 3-year OS was slightly lower (57.1% versus 60.2%, P < 0.001) in the elderly group as compared to their younger counterparts, but overall the outcomes after liver surgery were similar. Therefore, the management of liver metastases in oligometastatic disease in elderly patients fit for surgery should be the same as that offered to younger patients. Since outcomes are comparable, older patients should be offered neoadjuvant chemotherapy, as several studies have shown similar response rates and OS in younger and older patients.^35,36

Rectal Cancer

The standard of care for locally advanced rectal cancer is combined modality treatment with radiation and chemotherapy followed by total mesorectal excision. However, given conflicting data regarding the ability of elderly patients to tolerate neoadjuvant 5-FU-based chemotherapy and radiation, elderly patients are treated with trimodality therapy less often than their younger counterparts.^37,38 A systematic review of 22 randomized trials involving 8507 patients with rectal cancer showed that adjuvant radiation therapy could reduce the risk of local recurrence and death from rectal cancer in patients of all ages.³⁹ However, the risk of noncancer-related death was increased in the older population. The Stockholm II trial showed similar benefits of preoperative radiation overall, but this benefit did not extend to patients older than 68 years because of an increased risk of morbidity and mortality.⁴⁰ In older patients, mortality from noncancer causes within the first 6 months after surgery was higher in the group that received perioperative radiation than in the group that did not receive radiation. Elderly patients (age > 68 years) accounted for most of the mortality, which was predominantly due to cardiovascular disease.

A retrospective study of 36 patients aged ≥ 70 years with rectal cancer evaluated the toxicity and feasibility of neoadjuvant 5-FU combined with pelvic radiation for treating locally advanced rectal cancer. Patients were classified as healthy and “fit” or “vulnerable” based on the presence of comorbidities.⁴¹ This study demonstrated that tolerability and response to neoadjuvant chemotherapy and radiation as well as ability to undergo surgery were similar in “vulnerable” patients and “fit” patients. Conversely, Margalit and colleagues studied the rate of treatment deviations in elderly patients with rectal cancer treated with combined modality therapy and found that most patients required early termination of treatment, treatment interruptions, or dose reductions.⁴² While trimodality treatment is the standard of care in rectal cancer, there is conflicting data from retrospective studies regarding the tolerability and feasibility of this approach. It is important to proceed with caution but to still consider fit older patients with locally advanced rectal cancer for neoadjuvant chemotherapy and radiation followed by surgery.

In patients who have a complete response (CR) to neoadjuvant chemoradiation, watchful waiting rather than proceeding to surgery may be a reasonable strategy, especially in older patients. A systematic review of 867 patients with locally advanced rectal cancer showed no statistically significant difference in OS between patients who were observed with watchful waiting and those who underwent surgery.⁴³ The International Watch and Wait Database includes 679 patients who were managed with a watch-and-wait regimen because they had a clinical CR after chemoradiation. An outcomes analysis of these patients showed that 25% had local regrowth, with 3-year OS of 91% overall and 87% in patients with local regrowth.⁴⁴ In most patients (84%), regrowth of the tumor occurred within the first 2 years of follow up.

In frail older adults, for whom longer courses of treatment are not feasible or chemotherapy is contraindicated, short-course radiation therapy can be considered either in the neoadjuvant setting or alone for palliation.⁴⁵ A randomized trial of short-course radiation versus long-course chemoradiation in patients with T3 rectal cancer found that the difference in 3-year local recurrence rates was not statistically significant.⁴⁶

Chemotherapy

An expected natural decline in function occurs with age, but given the great variability that exists between patients, it is important to focus on physiologic age rather than chronologic age to determine ability to receive and tolerate anticancer treatment. Decreases in renal and hepatic function, cognitive impairment, changes in gastrointestinal motility, decrements in cardiac and bone marrow reserves, as well as comorbidities and polypharmacy affect a patient’s ability to tolerate chemotherapy.^47,48 Toxicity tools such as CARG and CRASH can help to predict severity of toxicity with chemotherapy.^13,23 The information provided by these tools can help guide conversations between the oncologist and patient regarding treatment plans.

Adjuvant Chemotherapy for Early-Stage Disease

Stage II Disease

Defining treatment guidelines for older patients with stage II colon cancer is difficult due to lack of data that shows benefit in this population. The QUASAR (Quick and Simple and Reliable) group’s prospective study of adjuvant single-agent 5-FU in stage II colon cancer patients showed an absolute improvement in survival of 3.6% when 5-FU was given after surgery (95% CI 1.0 to 6.0).⁴⁹ The subgroup analysis of patients aged ≥ 70 years showed a limited benefit of adjuvant 5-FU (hazard ratio [HR] 1.13 [95% CI 0.74 to 1.75]). Given the limited benefit, adjuvant 5-FU for elderly patients with stage II colon cancer should be used judiciously as patients may have competing causes of morbidity or mortality.

The use of oxaliplatin-based therapy in the adjuvant setting for stage II disease was evaluated in a subgroup analysis of the MOSAIC study (Multicenter International Study of Oxaliplatin/5-FU/Leucovorin in the Adjuvant Treatment of Colon Cancer).⁵⁰ Adjuvant oxaliplatin-based treatment may be offered to patients with stage II colon cancer that carries high-risk features (poorly differentiated histology, lymphovascular invasion, bowel obstruction and/or perforation, < 12 lymph nodes sampled, perineural invasion, or indeterminate or positive margins) due to a trend toward improved disease-free survival (DFS) at 5 years. Patients in this group who received adjuvant FOLFOX (leucovorin, oxaliplatin, 5-FU) versus 5-FU/leucovorin had a DFS of 82.3% versus 74.6%, respectively (HR 0.72 [95% CI 0.50 to 1.02]), a difference that was not statistically significant. A subgroup analysis of 315 patients aged 70 to 75 years with stage II colon cancer enrolled in the MOSAIC study found no statistically significant DFS or OS benefit with the addition of oxaliplatin to 5-FU/leucovorin.⁵¹ Therefore, use of this platinum/fluoropyrimidine combination for adjuvant therapy for high-risk stage II disease in older patients remains controversial given its associated risks and the lack of definitive data demonstrating a benefit in this patient group. Decisions regarding this therapy should be made through a shared discussion with patients about its risks and benefits.

Microsatellite status is an important biomarker in the evaluation of stage II CRC. Microsatellite stability is a marker of a functioning DNA mismatch repair system. In patients with colon cancer, tumor microsatellite stability is classified based on the percentage of abnormal microsatellite regions.⁵² Several studies have shown that patients with tumors that display high microsatellite instability (MSI-H) have an improved prognosis over patients with microsatellite stable tumors.^53,54 While patients with stage II MSI-H colon cancer have better outcomes, MSI is associated with a reduced response to treatment with fluoropyrimidines, as demonstrated in a systematic review that found that patients with tumors with MSI obtained no benefit from adjuvant 5-FU (HR 1.24 [95% CI 0.72 to 2.14]).⁵⁵ Aparicio and colleagues reported an increased prevalence of MSI-H tumors with increasing age.⁵⁶ Therefore, mismatch repair phenotype should be considered when making adjuvant chemotherapy decisions in the older adult with colon cancer, as it may affect the decision to recommend single-agent 5-FU treatment.

Stage III Disease

The use of single-agent 5-FU for stage III resected CRC has been evaluated in multiple studies. Sargent et al performed a pooled analysis of 3351 patients from 7 randomized phase 3 trials comparing surgery and adjuvant 5-FU-based chemotherapy versus surgery alone in stage II or III colon cancer patients.⁵⁷ Adjuvant chemotherapy was associated with improvement in both OS and time to tumor recurrence (HR 0.76 and 0.68, respectively). The 5-year OS was 71% for those who received adjuvant treatment and 64% for those who were treated with surgery alone. The benefit of adjuvant treatment was independent of age, and there was no difference in toxicity across age groups, except for 1 study which showed increased rates of leukopenia in the elderly. The oral fluoropyrimidine capecitabine was shown to be an effective alternative to 5-FU plus leucovorin as adjuvant treatment for those with resected stage III colon cancer.⁵⁸ However, in the subgroup analysis of DFS in the intention-to-treat group, the improvement in DFS was not statistically significant in those aged ≥ 70 years. This study justified the phase 3 Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) trial, which compared capecitabine and 5-FU/leucovorin as adjuvant therapy in patients with resected stage III colon cancer.⁵⁹ The X-ACT trial showed no significant effect of age on DFS or OS.

The addition of oxaliplatin to 5-FU in the adjuvant setting for stage III tumors has been studied and debated in the elderly population in multiple trials. The MOSAIC trial investigated FOLFOX versus 5-FU/leucovorin in the adjuvant setting.⁵⁰ The addition of oxaliplatin was associated with a DFS and OS benefit, with a 20% reduction in risk of colon cancer recurrence and 16% reduction in risk of death in all patients. The National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trial then studied 2409 patients with stage II or III colon cancer treated with weekly bolus 5-FU/leucovorin with or without oxaliplatin.⁶⁰ In this study, OS was significantly improved with the addition of oxaliplatin in patients younger than 70 years, but OS at 5 years was 4.7% worse for patients aged ≥ 70 years treated with weekly 5-FU/leucovorin and oxaliplatin compared with those treated with weekly 5-FU/leucovorin (71.6% versus 76.3%, respectively). In contrast, the XELOXA trial (NO16968), which randomly assigned stage III colon cancer patients to capecitabine and oxaliplatin (XELOX) or bolus 5-FU/leucovorin (standard of care at study start), showed an efficacy benefit, albeit not statistically significant, in patients aged ≥ 70 years (HR 0.87 [95% CI 0.63 to 1.18]).^61–63

The Adjuvant Colon Cancer Endpoints (ACCENT) database included 7 randomized trials totaling 14,528 patients with stage II or III colon cancer treated with adjuvant 5-FU with or without oxaliplatin or irinotecan.⁶⁴ Subgroup analysis of patients aged ≥ 70 years (n = 2575) showed no benefit with an oxaliplatin-based regimen in DFS (HR 0.94 [95% CI 0.78 to 1.13]) or OS (HR 1.04 [95% CI, 0.85 to 1.27]). Based on these studies and the increased toxicity with oxaliplatin, oxaliplatin-based adjuvant chemotherapy is utilized less often than single-agent 5-FU in geriatric patients with early-stage colon cancer.⁶⁵ Conversely, a recent pooled analysis of individual patient data from 4 randomized trials (NSABP C-08, XELOXA, X-ACT, and AVANT) showed improved DFS and OS with adjuvant XELOX or FOLFOX over single-agent 5-FU in patients aged ≥ 70 years (DFS HR 0.77 [95% CI 0.62 to 0.95], P = 0.014; OS HR 0.78 [95% CI 0.61 to 0.99], P = 0.045).⁶⁶ This analysis also showed that grade 3 and 4 adverse events related to oxaliplatin were similar across age groups.

These data come from post-hoc analyses, and there is no prospective data to steer decision making in elderly patients with early-stage CRC (Table). 

It is well established that patients with stage III colon cancer benefit from oxaliplatin-based adjuvant chemotherapy after curative surgical resection.⁶⁸ However, older patients are less likely to be referred to oncology as compared with their younger counterparts, due to the conflicting data regarding the benefit of this approach in older adults. Studies have shown that when the referral is placed, the geriatric population is less likely to receive chemotherapy.⁶⁹ Sanoff et al analyzed 4 data sets (SEER-Medicare, National Comprehensive Cancer Network, New York State Cancer Registry, and Cancer Care Outcomes Research and Surveillance Consortium) to assess the benefit of adjuvant chemotherapy for resected stage III CRC among patients aged ≥ 75 years. Their analysis showed that only 40% of patients evaluated received adjuvant chemotherapy for stage III CRC after surgical resection.⁷⁰

Summary

Prospective data to guide the treatment of older patients with early-stage CRC in the adjuvant setting is lacking. For fit older patients with stage II disease, limited benefit will be derived from single-agent 5-FU. For those with stage III CRC, the benefit and toxicities of fluoropyrimidines as adjuvant therapy appear to be similar regardless of age. The addition of oxaliplatin to fluoropyrimidines in patients aged ≥ 70 years has not been proven to improve DFS or OS and could result in an incremental toxicity profile. Therefore, treatment plans must be individualized, and decisions should be made through an informed discussion evaluating the overall risk/benefit ratio of each approach.

Metastatic Disease

Palliative Chemotherapy

Approximately 20% of patients with CRC are diagnosed with metastatic disease at presentation, and 35% to 40% develop metastatic disease following surgery and adjuvant therapy.² The mainstay of treatment in this population is systemic therapy in the form of chemotherapy with or without biologic agents. In this setting, several prospective studies specific to older adults have been completed, providing more evidence-based guidance to oncologists who see these patients. Folprecht et al retrospectively reviewed data from 22 clinical trials evaluating 5-FU-based palliative chemotherapy in 3825 patients with metastatic CRC, including 629 patients aged ≥ 70 years.⁷¹ OS in elderly patients (10.8 months [95% CI 9.7 to 11.8]) was equivalent to that in younger patients (11.3 months [95% CI 10.9 to 11.7], P = 0.31). Similarly, relative risk and progression-free survival (PFS) were comparable irrespective of age.

Standard of care for most patients with metastatic colon cancer consists of 5-FU/leucovorin in combination with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) with a monoclonal antibody.⁷² A retrospective pooled analysis of patients with metastatic CRC compared the safety and efficacy of FOLFOX4 in patients aged < 70 years versus those aged ≥ 70 years.⁷³ While age ≥ 70 years was associated with an increased rate of grade ≥ 3 hematologic toxicity, it was not associated with increased rates of severe neurologic events, diarrhea, nausea, vomiting, infection, 60-day mortality, or overall incidence of grade ≥ 3 toxicity. The benefit of treatment was consistent across both age groups; therefore, age alone should not exclude an otherwise healthy individual from receiving FOLFOX.

These post-hoc analyses show that fit older patients who were candidates for trial participation tolerated these treatments well; however, these treatments may be more challenging for less fit older adults. The UK Medical Research Council FOCUS2 (Fluorouracil, Oxaliplatin, CPT11 [irinotecan]: Use and Sequencing) study was a prospective phase 3 trial that included 459 patients with metastatic CRC who were deemed too frail or not fit enough for standard-dose chemotherapy by their oncologists.⁷⁴ In this group, 43% of patients were older than 75 years and 13% were older than 80 years. Patients were randomly assigned to receive infusional 5-FU with levofolinate; oxaliplatin and 5-FU; capecitabine; or oxaliplatin and capecitabine; all regimens were initiated with an empiric 20% dose reduction. The addition of oxaliplatin suggested some improvement in PFS, but this was not significant (5.8 months versus 4.5 months, HR 0.84 [95% CI 0.69 to 1.01], P = 0.07). Oxaliplatin was not associated with increased grade 3 or 4 toxicities. Capecitabine is often viewed as less toxic because it is taken by mouth, but this study found that replacement of 5-FU with capecitabine did not improve quality of life. Grade 3 or 4 toxicities were seen more frequently in those receiving capecitabine than in those receiving 5-FU (40% versus 30%, P = 0.03) in this older and frailer group of patients. As the patients on this study were frail and treatment dose was reduced, this data may not apply to fit older adults who are candidates for standard therapy.

When managing an older patient with metastatic CRC, it is important to tailor therapy based on goals of care, toxicity of proposed treatment, other comorbidities, and the patient’s functional status. One approach to minimizing toxicity in the older population is the stop-and-go strategy. The OPTIMOX1 study showed that stopping oxaliplatin after 6 cycles of FOLFOX7 and continuing maintenance therapy with infusional 5-FU/leucovorin alone for 12 cycles prior to reintroducing FOLFOX7 achieved efficacy similar to continuous FOLFOX4 with decreased toxicity.⁷⁵ Figer et al studied an exploratory cohort of 37 patients aged 76 to 80 years who were included in the OPTIMOX1 study.⁷⁶ The overall relative risk, median PFS, and median OS did not differ between the older patients in this cohort and younger patients studied in the original study. Older patients did experience more neutropenia, neurotoxicity, and overall grade 3 to 4 toxicity, but there were no toxic deaths in patients older than 75 years. The approach of giving treatment breaks, as in OPTIMOX2, may also provide patients with better quality of life, but perhaps at the expense of cancer-related survival.⁷⁷

The combination of irinotecan and 5-FU has also been studied as treatment for patients with metastatic CRC. A pooled analysis of 2691 patients aged ≥ 70 years with metastatic CRC across 4 phase 3 randomized trials investigating irinotecan and 5-FU demonstrated that irinotecan-containing chemotherapy provided similar benefits to both older and younger patients with similar risk of toxicity.⁷⁸ A phase 2 trial studying FOLFIRI as first-line treatment in older metastatic CRC patients showed this to be a safe and active regimen with manageable toxicity.⁷⁹ Another randomized phase 3 trial for older patients compared 5-FU/leucovorin with or without irinotecan for first-line treatment of metastatic CRC (FFCD 2001-02).⁸⁰ The study accrued 282 patients aged ≥ 75 years (median age 80 years), and found that the addition of irinotecan to infusional 5-FU–based chemotherapy did not significantly increase either PFS or OS. Aparicio et al performed a substudy of baseline geriatric evaluation prior to treatment in the FFCD 2001-02 study and assessed the value of geriatric parameters for predicting outcomes (objective response rate [ORR], PFS, and OS).⁸¹ Multivariate analysis showed that none of the geriatric parameters were predictive of ORR or PFS but that normal IADL was associated with better OS. This combination may still be appropriate for some older patients with metastatic disease, while single- agent 5-FU may be more appropriate in frail patients.

Biologic Agents

VEGF Inhibitors

Targeted biologic agents have been studied in the treatment of metastatic CRC. Bevacizumab is a recombinant, humanized monoclonal antibody against vascular endothelial growth factor (VEGF) that is approved in the first-line setting for treatment of metastatic CRC. A pooled analysis examined 439 patients 65 years of age and older with metastatic CRC who received bevacizumab plus chemotherapy versus placebo plus chemotherapy.⁸² In this analysis, the addition of bevacizumab was associated with an improvement in OS (19.3 months versus 14.3 months, HR 0.7 [95% CI 0.55 to 0.90], P = 0.006) and in PFS (9.2 months versus 6.2 months, HR 0.52 [95% CI 0.40 to 0.67], P < 0.0001). Known adverse events associated with bevacizumab were seen in the bevacizumab plus chemotherapy group but not at increased rates in the older population compared to their younger counterparts. Conversely, another pooled analysis found that while there was a PFS and OS benefit in older patients receiving bevacizumab, there was an increased incidence of thrombotic events in patients older than 65 years.⁸³ The BEAT (Bevacizumab Expanded Access Trial) and BRiTE (Bevacizumab Regimens Investigation of Treatment Effects) studies showed similar clinical outcomes across all age groups.^84,85 While older patients experienced more arterial thromboembolic events with the addition of bevacizumab, other factors such as ECOG PS, prior anticoagulation, and history of arterial disease were more predictive of these adverse events than age.

The randomized phase 3 AVEX study explored the efficacy and tolerability of capecitabine plus bevacizumab versus capecitabine alone in 280 frail patients aged ≥ 70 years.⁸⁶ PFS in the capecitabine/bevacizumab arm was 9.1 months versus 5.1 months in the capecitabine alone arm. While the OS difference was not statistically significant, patients in the capecitabine/bevacizumab arm had an OS of 20.7 months versus 16.8 months in the capecitabine alone group. As reported in prior studies, patients in the capecitabine/bevacizumab arm had increased rates of toxic events (40%) compared with those who received capecitabine alone (22%), with reports of hypertension, hand-foot syndrome, bleeding, and thrombotic events. More recently, the phase 2 PRODIGE 20 trial studied the addition of bevacizumab to chemotherapy (5-FU, FOLFOX, or FOLFIRI) based on physician choice in untreated metastatic CRC patients aged ≥ 75 years (median age 80 years).⁸⁷ They found that the addition of bevacizumab to standard of care chemotherapy was both safe and effective. The adverse events seen with bevacizumab, such as hypertension and thrombotic events, were consistent with prior studies.

A newer antiangiogenic agent, ziv-aflibercept, has been approved for the second-line treatment of metastatic CRC. The VELOUR trial demonstrated that the addition of ziv-aflibercept to FOLFIRI benefited patients across all age groups compared with FOLFIRI plus placebo in patients who had failed prior oxaliplatin-based chemotherapy.^88,89 Ramucirumab is a human IgG-1 monoclonal antibody approved in second-line treatment in combination with FOLFIRI. A subgroup analysis of the RAISE study showed that the survival benefit was similar in patients aged ≥ 65 years versus those < 65 years.⁹⁰ Based on the above data, the use of a VEGF inhibitor in combination with chemotherapy should be considered in older patients with metastatic CRC. Furthermore, based on the conflicting data regarding the benefit of FOLFOX/FOLFIRI over single-agent 5-FU discussed above, the combination of capecitabine plus bevacizumab may be considered a front-line treatment option in older patients based on the AVEX study.

EGFR Inhibitors

Cetuximab and panitumumab are anti-epidermal growth factor receptor (EGFR) antibodies approved for the treatment of RAS wild-type metastatic CRC. Data regarding the use of EGFR inhibitors in the geriatric population is scarce and the data that does exist is conflicting.^91,92 The PRIME study demonstrated that panitumumab plus FOLFOX had a PFS benefit compared to FOLFOX alone in KRAS wild-type metastatic CRC patients.⁹² While the study met its primary endpoint, the benefit did not translate to patients aged ≥ 65 years in subgroup analysis. Conversely, a retrospective study of the efficacy and safety of cetuximab in elderly patients with heavily pretreated metastatic CRC found similar efficacy in older and younger patients as well as no increased adverse events in the older population.⁹¹ A phase 2 trial investigating cetuximab as single-agent first-line treatment of metastatic CRC in fit older patients found cetuximab to be safe with moderate activity in this population, but did not support the use of cetuximab as first-line single-agent treatment in fit geriatric patients who may be candidates for combination therapy.⁹³ Our group studied the patterns of use and tolerance of anti-EGFR antibodies in 117 older adults with metastatic CRC with a median age of 73 years.⁹⁴ The study showed that older age at the time of treatment was associated with administration of anti-EGFR antibody as monotherapy rather than in combination with chemotherapy (P = 0.0009). We found no association between age and presence of grade 3 or higher toxicity. In addition, the toxicity profile seen in older patients was similar to what has been demonstrated in prior studies involving a younger patient population. Given the discordance seen between studies, additional prospective trials are needed to elucidate the efficacy and safety of EGFR inhibitors in the geriatric population.

Other Agents

Two newer agents approved in the treatment of metastatic CRC are regorafenib, a multikinase inhibitor, and trifluridine/tipiracil (TFD/TPI), a nucleoside analog combined with an inhibitor of thymidine phosphorylase. The phase 3 CORRECT trial studied regorafenib as monotherapy in previously treated metastatic CRC and found an OS benefit of 1.4 months and minimal PFS benefit.⁹⁵ Van Cutsem et al performed a subgroup analysis by age and found similar OS benefit in patients < 65 years of age and ≥ 65 years.⁹⁶ The most frequent adverse events grade 3 or higher were hand-foot syndrome, fatigue, diarrhea, hypertension, and desquamation/rash, which were seen at similar rates in both age groups. More recently, the phase 2 Regorafenib Dose Optimization Study (ReDOS) found that weekly dose escalation of regorafenib from 80 mg to 160 mg daily over 3 weeks was superior to the standard 160 mg daily dosing in patients with metastatic CRC.⁹⁷ The dose escalation group had a longer median OS, although this difference was not statistically significant, as well as a more favorable toxicity profile. Therefore, this new dosing strategy may be a reasonable option for older patients with pretreated metastatic CRC. A study of TFD/TPI versus placebo in refractory metastatic CRC found an OS benefit of 7.1 months versus 5.3 months.⁹⁸ In subgroup analyses, the OS benefit extended to both patients < 65 years and ≥ 65 years. Given the sparse data on these newer agents in the geriatric population and the modest benefit they provide to those with refractory metastatic CRC, more data is needed to determine their utility in elderly patients. The decision to use these agents in the older patients warrants a thorough discussion with the patient regarding risks, benefit, and treatment goals.

Immunotherapy

Between 3.5% and 6.5% of stage IV colorectal cancers are MSI-H and have deficient mismatch repair (dMMR).^99–101 A recent phase 2 trial studied the use of pembrolizumab, an IgG4 monoclonal antibody against PD-1 (programmed cell death-1), in heavily pretreated patients with dMMR metastatic CRC, MMR-proficient (pMMR) metastatic CRC, and noncolorectal dMMR metastatic cancer.¹⁰² Patients with dMMR metastatic CRC had a 50% ORR and 89% disease control rate (DCR), as compared with an ORR of 0% and DCR of 16% in patients with pMMR metastatic CRC. There was also an OS and PFS benefit seen in the dMMR CRC group as compared with the pMMR CRC group. Another phase 2 study, CheckMate 142, studied the anti-PD-1 monoclonal antibody nivolumab with or without ipilimumab (a monoclonal antibody against cytotoxic T-lymphocyte antigen 4) in patients with dMMR and pMMR metastatic CRC.¹⁰³ In the interim analysis, nivolumab was found to provide both disease control and durable response in patients with dMMR metastatic CRC.

While these studies led to the FDA approval of pembrolizumab and nivolumab for management of previously treated MSI-H or dMMR metastatic CRC, data on the use of immunotherapy in older adults is scarce. Immunosenescence, or the gradual deterioration of the immune system that comes with aging, may impact the efficacy of immune checkpoint inhibitors (ICI) in older patients with advanced cancer.¹⁰⁴ There is conflicting data on the efficacy of PD-1 and programmed death ligand-1) PD-L1 inhibitors in older patients across different cancers. A meta-analysis of immunotherapy in older adults with a variety of malignancies showed overall efficacy comparable to that seen in adults younger than 65 years.¹⁰⁵ However, another review found ICIs to be less effective in older patients with head and neck, non-small cell lung cancer, and renal cell carcinoma compared with their younger counterparts.¹⁰⁴ Regarding the toxicity profile of ICIs in the elderly, similar rates of grade 3 or higher adverse events in patients younger than 65 years and older than 65 years have been reported.¹⁰⁶ However, patients aged ≥ 70 years had increased rates of grade 3 to 5 adverse events as compared to patients younger than 65 years (71.7% versus 58.4%, respectively). Given the scant data on ICIs in older patients with MSI-H or dMMR metastatic CRC, more clinical trials inclusive of this population are needed in order to determine the efficacy and safety of immunotherapy.

Palliative Care

The incorporation of palliative care early following the diagnosis of cancer has been shown to improve quality of life, decrease depression, and help with symptom management.¹⁰⁷ The triggers for geriatric patients to initiate palliative care may be different from those of younger patients, as older patients may have different goals of care.¹⁰⁸ Older patients will often choose quality over quantity of life when making treatment decisions.¹⁰⁹ The ideal medical treatment for the frail patient with colorectal cancer would focus on treating disease while providing palliative measures to help support the patient and improve quality of life. It is paramount that patients maintain functional independence as loss of independence is recognized as a major threat to an older patient’s quality of life.¹¹⁰ The optimal way to achieve these goals is through the efforts of a multidisciplinary care team including not only physicians and nurses, but also social workers, nutritionists, physical therapists, and family who can provide support for the patient’s psychosocial, cognitive, and medical needs.¹¹¹ Although cancer and noncancer–related death occur more frequently in the geriatric population, data to guide a specific palliative care approach to the elderly population is lacking.¹⁰⁸

Conclusion

Colorectal cancer is a disease of older adults with a median age at diagnosis of 67 years.¹ With the aging population, oncologists will be faced with treating increasing numbers of older patients, and must adjust their practice to accommodate this population of patients. Treating geriatric patients is challenging given the lack of available data to guide the treatment approach. Although several prospective elderly-specific studies have been conducted evaluating treatments for metastatic CRC, most treatment decisions are made based on the available retrospective studies and pooled analyses. Oncologists must carefully consider and evaluate each patient based on physiologic age rather than chronologic age.¹¹² Overall, older patients should be given the opportunity to receive standard of care treatments in the appropriate setting. The decision to modify treatment plans should be made after a thorough evaluation by a multidisciplinary team and a discussion with the patient regarding their goals and the risks and benefits of the treatment. Geriatric assessment tools can help the care team identify patients with various geriatric syndromes that may not be detected on routine oncology evaluation. This type of evaluation is time consuming and is rarely done in a busy oncology practice. Ongoing studies are aiming to develop a method to incorporate geriatric assessments into the care of older adults.Additional prospective trials targeting older, more frail patients are essential to improve upon our knowledge so we can provide best care for this growing elderly population.