In recent years, the American Board of Internal Medicine (ABIM) Foundation’s Choosing Wisely™ campaign has advanced the dialogue on cost-consciousness by identifying potential examples of overuse in clinical practice.¹ Eliminating low-value care can decrease costs, improve quality, and potentially decrease patient harm.² In fact, there is growing consensus among health leaders and educators on the need for a physician workforce that is conscious of high-value care.^3,4 The Institute of Medicine has issued a call-to-action for graduate medical education (GME) to emphasize value-based care,⁵ and the Accreditation Council for Graduate Medical Education has outlined expectations that residents receive formal and experiential training on overuse as a part of its Clinical Learning Environment Review.⁶

However, recent reports highlight a lack of emphasis on value-based care in medical education.⁷ For example, few residency program directors believe that residents are prepared to incorporate value and cost into their medical decisions.⁸ In 2012, only 15% of medicine residencies reported having formal curricula addressing value, although many were developing one.⁸ Of the curricula reported, most were didactic in nature and did not include an assessment component.⁸

Experiential learning through simulation is one promising method to teach clinicians-in-training to practice value-based care. Simulation-based training promotes situational awareness (defined as being cognizant of one’s working environment), a concept that is crucial for recognizing both low-value and unsafe care.^9,10 Simulated training exercises are often included in GME orientation “boot-camps,” which have typically addressed safety.¹¹ The incorporation of value into existing GME boot-camp exercises could provide a promising model for the addition of value-based training to GME.

At the University of Chicago, we had successfully implemented the “Room of Horrors,” a simulation for entering interns to promote the detection of patient safety hazards.¹¹ Here, we describe a modification to this simulation to embed low-value hazards in addition to traditional patient safety hazards. The aim of this study is to assess the entering interns’ recognition of low-value care and their ability to recognize unsafe care in a simulation designed to promote situational awareness.

Setting and Participants

The simulation was conducted during GME orientation at a large, urban academic medical institution. One hundred and twenty-five entering postgraduate year one (PGY1) interns participated in the simulation, which was a required component of a multiday orientation “boot-camp” experience. All eligible interns participated in the simulation, representing 13 specialty programs and 60 medical schools. Interns entering into pathology were excluded because of infrequent patient contact. Participating interns were divided into 7 specialty groups for analysis in order to preserve the anonymity of interns in smaller residency programs (surgical subspecialties combined with general surgery, medicine-pediatrics grouped with internal medicine). The University of Chicago Institutional Review Board deemed this study exempt from review.

Program Description

A simulation of an inpatient hospital room, known as the “Room of Horrors,” was constructed in collaboration with the University of Chicago Simulation Center and adapted from a previous version of the exercise.¹¹ The simulation consisted of a mock door chart highlighting the patient had been admitted for diarrhea (Clostridium difficile positive) following a recent hospitalization for pneumonia. A clinical scenario was constructed by using a patient mannequin and an accompanying door chart that listed information on the patient’s hospital course, allergies, and medications. In addition to the 8 patient safety hazards utilized in the prior version, our team selected 4 low-value hazards to be included in the simulation.

The 8 safety hazards have been detailed in a prior study and were previously selected from Medicare’s Hospital-Acquired Conditions (HAC) Reduction Program and Agency for Healthcare Research and Quality (AHRQ) Patient Safety Indicators.^11-13 Each of the hazards was represented either physically in the simulation room and/or was indicated on the patient’s chart. For example, the latex allergy hazard was represented by latex gloves at the bedside despite an allergy indicated on the patient’s chart and wristband. A complete list of the 8 safety hazards and their representations in the simulation is shown in Table 1.

The Choosing Wisely™ lists were reviewed to identify low-value hazards for addition to the simulation.¹⁴ Our team selected 3 low-value hazards from the Society of Hospital Medicine (SHM) list,¹⁵ including (1) arbitrary blood transfusion despite the patient’s stable hemoglobin level of 8.0 g/dL and absence of cardiac symptoms,¹⁶ (2) addition of a proton pump inhibitor (PPI) for stress ulcer prophylaxis in a patient without high risk for gastrointestinal (GI) complications who was not on a PPI prior to admission, and (3) placement of a urinary catheter without medical indication. We had originally selected continuous telemetry monitoring as a fourth hazard from the SHM list, but were unable to operationalize, as it was difficult to simulate continuous telemetry on a mannequin. Because many inpatients are older than 65 years, we reviewed the American Geriatrics Society list¹⁷ and selected our fourth low-value hazard: (4) unnecessary use of physical restraints to manage behavioral symptoms in a hospitalized patient with delirium. Several of these hazards were also quality and safety priorities at our institution, including the overuse of urinary catheters, physical restraints, and blood transfusions. All 4 low-value hazards were referenced in the patient’s door chart, and 3 were also physically represented in the room via presence of a hanging unit of blood, Foley catheter, and upper-arm restraints (Table 1). See Appendix for a photograph of the simulation setup.

Each intern was allowed 10 minutes inside the simulation room. During this time, they were instructed to read the 1-page door chart, inspect the simulation room, and write down as many potential low-value and safety hazards as they could identify on a free-response form (see Appendix). Upon exiting the room, they were allotted 5 additional minutes to complete their free-response answers and provide written feedback on the simulation. The simulation was conducted in 3 simulated hospital rooms over the course of 2 days, and the correct answers were provided via e-mail after all interns had completed the exercise.

To assess prior training and safety knowledge, interns were asked to complete a 3-question preassessment on a ScanTron^TM (Tustin, CA) form. The preassessment asked interns whether they had received training on hospital safety during medical school (yes, no, or unsure), if they were satisfied with the hospital safety training they received during medical school (strongly disagree to strongly agree on a Likert scale), and if they were confident in their ability to identify potential hazards in a hospital setting (strongly disagree to strongly agree). Interns were also given the opportunity to provide feedback on the simulation experience on the ScanTron^TM (Tustin, CA) form.

One month after participating in the simulation, interns were asked to complete an online follow-up survey on MedHub^TM (Ann Arbor, MI), which included 2 Likert-scale questions (strongly disagree to strongly agree) assessing the simulation’s impact on their experience mitigating hospital hazards during the first month of internship.

Data Analysis

Interns’ free-response answers were manually coded, and descriptive statistics were used to summarize the mean percent correct for each hazard. A paired t test was used to compare intern identification of low-value vs safety hazards. T tests were used to compare hazard identification for interns entering highly procedural-intensive specialties (ie, surgical specialties, emergency medicine, anesthesia, obstetrics/gynecology) and those entering less procedural-intensive specialties (ie, internal medicine, pediatrics, psychiatry), as well as among those graduating from “Top 30” medical schools (based on US News & World Report Medical School Rankings¹⁸) and our own institution. One-way analysis of variance (ANOVA) calculations were used to test for differences in hazard identification based on interns’ prior hospital safety training, with interns who rated their satisfaction with prior training or confidence in identifying hazards as a “4” or a “5” considered “satisfied” and “confident,” respectively. Responses to the MedHub^TM (Ann Arbor, MI) survey were dichotomized with “strongly agree” and “agree” considered positive responses. Statistical significance was defined at P < .05. All data analysis was conducted using Stata 14^TM software (College Station, TX).

Intern Characteristics

One hundred twenty-five entering PGY1 interns participated in the simulation, representing 60 medical schools and 7 different specialty groups (Table 2). Thirty-five percent (44/125) were graduates from “Top 30” medical schools, and 8.8% (11/125) graduated from our own institution. Seventy-four percent (89/121) had received prior hospital safety training during medical school, and 62.9% (56/89) were satisfied with their training. A majority of interns (64.2%, 79/123) felt confident in their ability to identify potential hazards in a hospital setting, although confidence was much higher among those with prior safety training (71.9%, 64/89) compared to those without prior training or who were unsure about their training (40.6%, 13/32; P = .09, t test).

Identification of Hazards

The mean percentage of hazards correctly identified by interns during the simulation was 50.4% (standard deviation [SD] 11.8%), with a normal distribution (Figure 1). Interns identified a significantly lower percentage of low-value hazards than safety hazards in the simulation (mean 19.2% [SD 18.6%] vs 66.0% [SD 16.0%], respectively; P < .001, paired t test). Interns also identified significantly more room-based errors than chart-based errors (mean 58.6% [SD 13.4%] vs 9.6% [SD 19.8%], respectively; P < .001, paired t test). The 3 most commonly identified hazards were unavailability of hand hygiene (120/125, 96.0%), presence of latex gloves despite the patient’s allergy (111/125, 88.8%), and fall risk due to the lowered bed rail (107/125, 85.6%). More than half of interns identified the incorrect name on the patient’s wristband and IV bag (91/125, 72.8%), a lack of isolation precautions (90/125, 72.0%), administration of penicillin despite the patient’s allergy (67/125, 53.6%), and unnecessary restraints (64/125, 51.2%). Less than half of interns identified the wrong medication being administered (50/125, 40.0%), unnecessary Foley catheter (25/125, 20.0%), and absence of venous thromboembolism (VTE) prophylaxis (24/125, 19.2%). Few interns identified the unnecessary blood transfusion (7/125, 5.6%), and no one identified the unnecessary stress ulcer prophylaxis (0/125, 0.0%; Figure 2).

Predictors of Hazard Identification

Interns who self-reported as confident in their ability to identify hazards were not any more likely to correctly identify hazards than those who were not confident (50.9% overall hazard identification vs 49.6%, respectively; P = .56, t test). Interns entering into less procedural-intensive specialties identified significantly more safety hazards than those entering highly procedural-intensive specialties (mean 69.1% [SD 16.9%] vs 61.8% [SD 13.7%], respectively; P = .01, t test). However, there was no statistically significant difference in their identification of low-value hazards (mean 19.8% [SD 18.3%] for less procedural-intensive vs 18.4% [SD 19.1%] for highly procedural-intensive; P = .68, t test). There was no statistically significant difference in hazard identification among graduates of “Top 30” medical schools or graduates of our own institution. Prior hospital safety training had no significant impact on interns’ ability to identify safety or low-value hazards. Overall, interns who were satisfied with their prior training identified a mean of 51.8% of hazards present (SD 11.8%), interns who were not satisfied with their prior training identified 51.5% (SD 12.7%), interns with no prior training identified 48.7% (SD 11.7%), and interns who were unsure about their prior training identified 47.4% (SD 11.5%) [F(3,117) = .79; P = .51, ANOVA]. There was also no significant association between prior training and the identification of any one of the 12 specific hazards (chi-square tests, all P values > .1).

Intern Feedback and Follow-Up Survey

Debriefing revealed that most interns passively assumed the patient’s chart was correct and did not think they should question the patient’s current care regimen. For example, many interns commented that they did not think to consider the patient’s blood transfusion as unnecessary, even though they were aware of the recommended hemoglobin cutoffs for stable patients.

Interns also provided formal feedback on the simulation through open-ended comments on their ScanTron^TM (Tustin, CA) form. For example, one intern wrote that they would “inherently approach every patient room ‘looking’ for safety issues, probably directly because of this exercise.” Another commented that the simulation was “more difficult than I expected, but very necessary to facilitate discussion and learning.” One intern wrote that “I wish I had done this earlier in my career.”

Ninety-six percent of participating interns (120/125) completed an online follow-up survey 1 month after beginning internship. In the survey, 68.9% (82/119) of interns indicated they were more aware of how to identify potential hazards facing hospitalized patients as a result of the simulation. Furthermore, 52.1% (62/119) of interns had taken action during internship to reduce a potential hazard that was present in the simulation.

While many GME orientations include simulation and safety training, this study is the first of its kind to incorporate low-value care from Choosing Wisely™ recommendations into simulated training. It is concerning that interns identified significantly fewer low-value hazards than safety hazards in the simulation. In some cases, no interns identified the low-value hazard. For example, while almost all interns identified the hand hygiene hazard, not one could identify the unnecessary stress ulcer prophylaxis. Furthermore, interns who self-reported as confident in their ability to identify hazards did not perform any better in the simulation. Interns entering less procedural-intensive specialties identified more safety hazards overall.

The simulation was well received by interns. Many commented that the experience was engaging, challenging, and effective in cultivating situational awareness towards low-value care. Our follow-up survey demonstrated the majority of interns reported taking action during their first month of internship to reduce a hazard included in the simulation. Most interns also reported a greater awareness of how to identify hospital hazards as a result of the simulation. These findings suggest that a brief simulation-based experience has the potential to create a lasting retention of situational awareness and behavior change.

It is worth exploring why interns identified significantly fewer low-value hazards than safety hazards in the simulation. One hypothesis is that interns were less attuned to low-value hazards, which may reflect a lacking emphasis on value-based care in undergraduate medical education (UME). It is especially concerning that so few interns identified the catheter-associated urinary tract infection (CAUTI) risk, as interns are primarily responsible for recognizing and removing an unnecessary catheter. Although the risks of low-value care should be apparent to most trainees, the process of recognizing and deliberately stopping or avoiding low-value care can be challenging for young clinicians.¹⁹ To promote value-based thinking among entering residents, UME programs should teach students to question the utility of the interventions their patients are receiving. One promising framework for doing so is the Subjective, Objective, Assessment, Plan- (SOAP)-V, in which a V for “Value” is added to the traditional SOAP note.²⁰ SOAP-V notes serve as a cognitive forcing function that requires students to pause and assess the value and cost-consciousness of their patients’ care.²⁰

The results from the “Room of Horrors” simulation can also guide health leaders and educators in identifying institutional areas of focus towards providing high-value and safe care. For example, at the University of Chicago we launched an initiative to improve the inappropriate use of urinary catheters after learning that few of our incoming interns recognized this during the simulation. Institutions could use this model to raise awareness of initiatives and redirect resources from areas that trainees perform well in (eg, hand hygiene) to areas that need improvement (eg, recognition of low-value care). Given the simulation’s low cost and minimal material requirements, it could be easily integrated into existing training programs with the support of an institution’s simulation center.

This study’s limitations include its conduction at single-institution, although the participants represented graduates of 60 different institutions. Furthermore, while the 12 hazards included in the simulation represent patient safety and value initiatives from a wide array of medical societies, they were not intended to be comprehensive and were not tailored to specific specialties. The simulation included only 4 low-value hazards, and future iterations of this exercise should aim to include an equal number of safety and low-value hazards. Furthermore, the evaluation of interns’ prior hospital safety training relied on self-reporting, and the specific context and content of each interns’ training was not examined. Finally, at this point we are unable to provide objective longitudinal data assessing the simulation’s impact on clinical practice and patient outcomes. Subsequent work will assess the sustained impact of the simulation by correlating with institutional data on measurable occurrences of low-value care.

In conclusion, interns identified significantly fewer low-value hazards than safety hazards in an inpatient simulation designed to promote situational awareness. Our results suggest that interns are on the lookout for errors of omission (eg, absence of hand hygiene, absence of isolation precautions) but are often blinded to errors of commission, such that when patients are started on therapies there is an assumption that the therapies are correct and necessary (eg, blood transfusions, stress ulcer prophylaxis). These findings suggest poor awareness of low-value care among incoming interns and highlight the need for additional training in both UME and GME to place a greater emphasis on preventing low-value care.

Disclosure

Dr. Arora is a member of the American Board of Medicine Board of Directors and has received grant funding from ABIM Foundation via Costs of Care for the Teaching Value Choosing Wisely™ Challenge. Dr. Farnan, Dr. Arora, and Ms. Hirsch receive grant funds from Accreditation Council of Graduate Medical Education as part of the Pursuing Excellence Initiative. Dr. Arora and Dr. Farnan also receive grant funds from the American Medical Association Accelerating Change in Medical Education initiative. Kathleen Wiest and Lukas Matern were funded through matching funds of the Pritzker Summer Research Program for NIA T35AG029795.

In recent years, the American Board of Internal Medicine (ABIM) Foundation’s Choosing Wisely™ campaign has advanced the dialogue on cost-consciousness by identifying potential examples of overuse in clinical practice.¹ Eliminating low-value care can decrease costs, improve quality, and potentially decrease patient harm.² In fact, there is growing consensus among health leaders and educators on the need for a physician workforce that is conscious of high-value care.^3,4 The Institute of Medicine has issued a call-to-action for graduate medical education (GME) to emphasize value-based care,⁵ and the Accreditation Council for Graduate Medical Education has outlined expectations that residents receive formal and experiential training on overuse as a part of its Clinical Learning Environment Review.⁶

However, recent reports highlight a lack of emphasis on value-based care in medical education.⁷ For example, few residency program directors believe that residents are prepared to incorporate value and cost into their medical decisions.⁸ In 2012, only 15% of medicine residencies reported having formal curricula addressing value, although many were developing one.⁸ Of the curricula reported, most were didactic in nature and did not include an assessment component.⁸

Experiential learning through simulation is one promising method to teach clinicians-in-training to practice value-based care. Simulation-based training promotes situational awareness (defined as being cognizant of one’s working environment), a concept that is crucial for recognizing both low-value and unsafe care.^9,10 Simulated training exercises are often included in GME orientation “boot-camps,” which have typically addressed safety.¹¹ The incorporation of value into existing GME boot-camp exercises could provide a promising model for the addition of value-based training to GME.

At the University of Chicago, we had successfully implemented the “Room of Horrors,” a simulation for entering interns to promote the detection of patient safety hazards.¹¹ Here, we describe a modification to this simulation to embed low-value hazards in addition to traditional patient safety hazards. The aim of this study is to assess the entering interns’ recognition of low-value care and their ability to recognize unsafe care in a simulation designed to promote situational awareness.

Setting and Participants

The simulation was conducted during GME orientation at a large, urban academic medical institution. One hundred and twenty-five entering postgraduate year one (PGY1) interns participated in the simulation, which was a required component of a multiday orientation “boot-camp” experience. All eligible interns participated in the simulation, representing 13 specialty programs and 60 medical schools. Interns entering into pathology were excluded because of infrequent patient contact. Participating interns were divided into 7 specialty groups for analysis in order to preserve the anonymity of interns in smaller residency programs (surgical subspecialties combined with general surgery, medicine-pediatrics grouped with internal medicine). The University of Chicago Institutional Review Board deemed this study exempt from review.

Program Description

A simulation of an inpatient hospital room, known as the “Room of Horrors,” was constructed in collaboration with the University of Chicago Simulation Center and adapted from a previous version of the exercise.¹¹ The simulation consisted of a mock door chart highlighting the patient had been admitted for diarrhea (Clostridium difficile positive) following a recent hospitalization for pneumonia. A clinical scenario was constructed by using a patient mannequin and an accompanying door chart that listed information on the patient’s hospital course, allergies, and medications. In addition to the 8 patient safety hazards utilized in the prior version, our team selected 4 low-value hazards to be included in the simulation.

The 8 safety hazards have been detailed in a prior study and were previously selected from Medicare’s Hospital-Acquired Conditions (HAC) Reduction Program and Agency for Healthcare Research and Quality (AHRQ) Patient Safety Indicators.^11-13 Each of the hazards was represented either physically in the simulation room and/or was indicated on the patient’s chart. For example, the latex allergy hazard was represented by latex gloves at the bedside despite an allergy indicated on the patient’s chart and wristband. A complete list of the 8 safety hazards and their representations in the simulation is shown in Table 1.

The Choosing Wisely™ lists were reviewed to identify low-value hazards for addition to the simulation.¹⁴ Our team selected 3 low-value hazards from the Society of Hospital Medicine (SHM) list,¹⁵ including (1) arbitrary blood transfusion despite the patient’s stable hemoglobin level of 8.0 g/dL and absence of cardiac symptoms,¹⁶ (2) addition of a proton pump inhibitor (PPI) for stress ulcer prophylaxis in a patient without high risk for gastrointestinal (GI) complications who was not on a PPI prior to admission, and (3) placement of a urinary catheter without medical indication. We had originally selected continuous telemetry monitoring as a fourth hazard from the SHM list, but were unable to operationalize, as it was difficult to simulate continuous telemetry on a mannequin. Because many inpatients are older than 65 years, we reviewed the American Geriatrics Society list¹⁷ and selected our fourth low-value hazard: (4) unnecessary use of physical restraints to manage behavioral symptoms in a hospitalized patient with delirium. Several of these hazards were also quality and safety priorities at our institution, including the overuse of urinary catheters, physical restraints, and blood transfusions. All 4 low-value hazards were referenced in the patient’s door chart, and 3 were also physically represented in the room via presence of a hanging unit of blood, Foley catheter, and upper-arm restraints (Table 1). See Appendix for a photograph of the simulation setup.

Each intern was allowed 10 minutes inside the simulation room. During this time, they were instructed to read the 1-page door chart, inspect the simulation room, and write down as many potential low-value and safety hazards as they could identify on a free-response form (see Appendix). Upon exiting the room, they were allotted 5 additional minutes to complete their free-response answers and provide written feedback on the simulation. The simulation was conducted in 3 simulated hospital rooms over the course of 2 days, and the correct answers were provided via e-mail after all interns had completed the exercise.

To assess prior training and safety knowledge, interns were asked to complete a 3-question preassessment on a ScanTron^TM (Tustin, CA) form. The preassessment asked interns whether they had received training on hospital safety during medical school (yes, no, or unsure), if they were satisfied with the hospital safety training they received during medical school (strongly disagree to strongly agree on a Likert scale), and if they were confident in their ability to identify potential hazards in a hospital setting (strongly disagree to strongly agree). Interns were also given the opportunity to provide feedback on the simulation experience on the ScanTron^TM (Tustin, CA) form.

One month after participating in the simulation, interns were asked to complete an online follow-up survey on MedHub^TM (Ann Arbor, MI), which included 2 Likert-scale questions (strongly disagree to strongly agree) assessing the simulation’s impact on their experience mitigating hospital hazards during the first month of internship.

Data Analysis

Interns’ free-response answers were manually coded, and descriptive statistics were used to summarize the mean percent correct for each hazard. A paired t test was used to compare intern identification of low-value vs safety hazards. T tests were used to compare hazard identification for interns entering highly procedural-intensive specialties (ie, surgical specialties, emergency medicine, anesthesia, obstetrics/gynecology) and those entering less procedural-intensive specialties (ie, internal medicine, pediatrics, psychiatry), as well as among those graduating from “Top 30” medical schools (based on US News & World Report Medical School Rankings¹⁸) and our own institution. One-way analysis of variance (ANOVA) calculations were used to test for differences in hazard identification based on interns’ prior hospital safety training, with interns who rated their satisfaction with prior training or confidence in identifying hazards as a “4” or a “5” considered “satisfied” and “confident,” respectively. Responses to the MedHub^TM (Ann Arbor, MI) survey were dichotomized with “strongly agree” and “agree” considered positive responses. Statistical significance was defined at P < .05. All data analysis was conducted using Stata 14^TM software (College Station, TX).

Intern Characteristics

One hundred twenty-five entering PGY1 interns participated in the simulation, representing 60 medical schools and 7 different specialty groups (Table 2). Thirty-five percent (44/125) were graduates from “Top 30” medical schools, and 8.8% (11/125) graduated from our own institution. Seventy-four percent (89/121) had received prior hospital safety training during medical school, and 62.9% (56/89) were satisfied with their training. A majority of interns (64.2%, 79/123) felt confident in their ability to identify potential hazards in a hospital setting, although confidence was much higher among those with prior safety training (71.9%, 64/89) compared to those without prior training or who were unsure about their training (40.6%, 13/32; P = .09, t test).

Identification of Hazards

The mean percentage of hazards correctly identified by interns during the simulation was 50.4% (standard deviation [SD] 11.8%), with a normal distribution (Figure 1). Interns identified a significantly lower percentage of low-value hazards than safety hazards in the simulation (mean 19.2% [SD 18.6%] vs 66.0% [SD 16.0%], respectively; P < .001, paired t test). Interns also identified significantly more room-based errors than chart-based errors (mean 58.6% [SD 13.4%] vs 9.6% [SD 19.8%], respectively; P < .001, paired t test). The 3 most commonly identified hazards were unavailability of hand hygiene (120/125, 96.0%), presence of latex gloves despite the patient’s allergy (111/125, 88.8%), and fall risk due to the lowered bed rail (107/125, 85.6%). More than half of interns identified the incorrect name on the patient’s wristband and IV bag (91/125, 72.8%), a lack of isolation precautions (90/125, 72.0%), administration of penicillin despite the patient’s allergy (67/125, 53.6%), and unnecessary restraints (64/125, 51.2%). Less than half of interns identified the wrong medication being administered (50/125, 40.0%), unnecessary Foley catheter (25/125, 20.0%), and absence of venous thromboembolism (VTE) prophylaxis (24/125, 19.2%). Few interns identified the unnecessary blood transfusion (7/125, 5.6%), and no one identified the unnecessary stress ulcer prophylaxis (0/125, 0.0%; Figure 2).

Predictors of Hazard Identification

Interns who self-reported as confident in their ability to identify hazards were not any more likely to correctly identify hazards than those who were not confident (50.9% overall hazard identification vs 49.6%, respectively; P = .56, t test). Interns entering into less procedural-intensive specialties identified significantly more safety hazards than those entering highly procedural-intensive specialties (mean 69.1% [SD 16.9%] vs 61.8% [SD 13.7%], respectively; P = .01, t test). However, there was no statistically significant difference in their identification of low-value hazards (mean 19.8% [SD 18.3%] for less procedural-intensive vs 18.4% [SD 19.1%] for highly procedural-intensive; P = .68, t test). There was no statistically significant difference in hazard identification among graduates of “Top 30” medical schools or graduates of our own institution. Prior hospital safety training had no significant impact on interns’ ability to identify safety or low-value hazards. Overall, interns who were satisfied with their prior training identified a mean of 51.8% of hazards present (SD 11.8%), interns who were not satisfied with their prior training identified 51.5% (SD 12.7%), interns with no prior training identified 48.7% (SD 11.7%), and interns who were unsure about their prior training identified 47.4% (SD 11.5%) [F(3,117) = .79; P = .51, ANOVA]. There was also no significant association between prior training and the identification of any one of the 12 specific hazards (chi-square tests, all P values > .1).

Intern Feedback and Follow-Up Survey

Debriefing revealed that most interns passively assumed the patient’s chart was correct and did not think they should question the patient’s current care regimen. For example, many interns commented that they did not think to consider the patient’s blood transfusion as unnecessary, even though they were aware of the recommended hemoglobin cutoffs for stable patients.

Interns also provided formal feedback on the simulation through open-ended comments on their ScanTron^TM (Tustin, CA) form. For example, one intern wrote that they would “inherently approach every patient room ‘looking’ for safety issues, probably directly because of this exercise.” Another commented that the simulation was “more difficult than I expected, but very necessary to facilitate discussion and learning.” One intern wrote that “I wish I had done this earlier in my career.”

Ninety-six percent of participating interns (120/125) completed an online follow-up survey 1 month after beginning internship. In the survey, 68.9% (82/119) of interns indicated they were more aware of how to identify potential hazards facing hospitalized patients as a result of the simulation. Furthermore, 52.1% (62/119) of interns had taken action during internship to reduce a potential hazard that was present in the simulation.

While many GME orientations include simulation and safety training, this study is the first of its kind to incorporate low-value care from Choosing Wisely™ recommendations into simulated training. It is concerning that interns identified significantly fewer low-value hazards than safety hazards in the simulation. In some cases, no interns identified the low-value hazard. For example, while almost all interns identified the hand hygiene hazard, not one could identify the unnecessary stress ulcer prophylaxis. Furthermore, interns who self-reported as confident in their ability to identify hazards did not perform any better in the simulation. Interns entering less procedural-intensive specialties identified more safety hazards overall.

The simulation was well received by interns. Many commented that the experience was engaging, challenging, and effective in cultivating situational awareness towards low-value care. Our follow-up survey demonstrated the majority of interns reported taking action during their first month of internship to reduce a hazard included in the simulation. Most interns also reported a greater awareness of how to identify hospital hazards as a result of the simulation. These findings suggest that a brief simulation-based experience has the potential to create a lasting retention of situational awareness and behavior change.

It is worth exploring why interns identified significantly fewer low-value hazards than safety hazards in the simulation. One hypothesis is that interns were less attuned to low-value hazards, which may reflect a lacking emphasis on value-based care in undergraduate medical education (UME). It is especially concerning that so few interns identified the catheter-associated urinary tract infection (CAUTI) risk, as interns are primarily responsible for recognizing and removing an unnecessary catheter. Although the risks of low-value care should be apparent to most trainees, the process of recognizing and deliberately stopping or avoiding low-value care can be challenging for young clinicians.¹⁹ To promote value-based thinking among entering residents, UME programs should teach students to question the utility of the interventions their patients are receiving. One promising framework for doing so is the Subjective, Objective, Assessment, Plan- (SOAP)-V, in which a V for “Value” is added to the traditional SOAP note.²⁰ SOAP-V notes serve as a cognitive forcing function that requires students to pause and assess the value and cost-consciousness of their patients’ care.²⁰

The results from the “Room of Horrors” simulation can also guide health leaders and educators in identifying institutional areas of focus towards providing high-value and safe care. For example, at the University of Chicago we launched an initiative to improve the inappropriate use of urinary catheters after learning that few of our incoming interns recognized this during the simulation. Institutions could use this model to raise awareness of initiatives and redirect resources from areas that trainees perform well in (eg, hand hygiene) to areas that need improvement (eg, recognition of low-value care). Given the simulation’s low cost and minimal material requirements, it could be easily integrated into existing training programs with the support of an institution’s simulation center.

This study’s limitations include its conduction at single-institution, although the participants represented graduates of 60 different institutions. Furthermore, while the 12 hazards included in the simulation represent patient safety and value initiatives from a wide array of medical societies, they were not intended to be comprehensive and were not tailored to specific specialties. The simulation included only 4 low-value hazards, and future iterations of this exercise should aim to include an equal number of safety and low-value hazards. Furthermore, the evaluation of interns’ prior hospital safety training relied on self-reporting, and the specific context and content of each interns’ training was not examined. Finally, at this point we are unable to provide objective longitudinal data assessing the simulation’s impact on clinical practice and patient outcomes. Subsequent work will assess the sustained impact of the simulation by correlating with institutional data on measurable occurrences of low-value care.

In conclusion, interns identified significantly fewer low-value hazards than safety hazards in an inpatient simulation designed to promote situational awareness. Our results suggest that interns are on the lookout for errors of omission (eg, absence of hand hygiene, absence of isolation precautions) but are often blinded to errors of commission, such that when patients are started on therapies there is an assumption that the therapies are correct and necessary (eg, blood transfusions, stress ulcer prophylaxis). These findings suggest poor awareness of low-value care among incoming interns and highlight the need for additional training in both UME and GME to place a greater emphasis on preventing low-value care.

Disclosure

Dr. Arora is a member of the American Board of Medicine Board of Directors and has received grant funding from ABIM Foundation via Costs of Care for the Teaching Value Choosing Wisely™ Challenge. Dr. Farnan, Dr. Arora, and Ms. Hirsch receive grant funds from Accreditation Council of Graduate Medical Education as part of the Pursuing Excellence Initiative. Dr. Arora and Dr. Farnan also receive grant funds from the American Medical Association Accelerating Change in Medical Education initiative. Kathleen Wiest and Lukas Matern were funded through matching funds of the Pritzker Summer Research Program for NIA T35AG029795.

In recent years, the American Board of Internal Medicine (ABIM) Foundation’s Choosing Wisely™ campaign has advanced the dialogue on cost-consciousness by identifying potential examples of overuse in clinical practice.¹ Eliminating low-value care can decrease costs, improve quality, and potentially decrease patient harm.² In fact, there is growing consensus among health leaders and educators on the need for a physician workforce that is conscious of high-value care.^3,4 The Institute of Medicine has issued a call-to-action for graduate medical education (GME) to emphasize value-based care,⁵ and the Accreditation Council for Graduate Medical Education has outlined expectations that residents receive formal and experiential training on overuse as a part of its Clinical Learning Environment Review.⁶

However, recent reports highlight a lack of emphasis on value-based care in medical education.⁷ For example, few residency program directors believe that residents are prepared to incorporate value and cost into their medical decisions.⁸ In 2012, only 15% of medicine residencies reported having formal curricula addressing value, although many were developing one.⁸ Of the curricula reported, most were didactic in nature and did not include an assessment component.⁸

Experiential learning through simulation is one promising method to teach clinicians-in-training to practice value-based care. Simulation-based training promotes situational awareness (defined as being cognizant of one’s working environment), a concept that is crucial for recognizing both low-value and unsafe care.^9,10 Simulated training exercises are often included in GME orientation “boot-camps,” which have typically addressed safety.¹¹ The incorporation of value into existing GME boot-camp exercises could provide a promising model for the addition of value-based training to GME.

At the University of Chicago, we had successfully implemented the “Room of Horrors,” a simulation for entering interns to promote the detection of patient safety hazards.¹¹ Here, we describe a modification to this simulation to embed low-value hazards in addition to traditional patient safety hazards. The aim of this study is to assess the entering interns’ recognition of low-value care and their ability to recognize unsafe care in a simulation designed to promote situational awareness.

Setting and Participants

The simulation was conducted during GME orientation at a large, urban academic medical institution. One hundred and twenty-five entering postgraduate year one (PGY1) interns participated in the simulation, which was a required component of a multiday orientation “boot-camp” experience. All eligible interns participated in the simulation, representing 13 specialty programs and 60 medical schools. Interns entering into pathology were excluded because of infrequent patient contact. Participating interns were divided into 7 specialty groups for analysis in order to preserve the anonymity of interns in smaller residency programs (surgical subspecialties combined with general surgery, medicine-pediatrics grouped with internal medicine). The University of Chicago Institutional Review Board deemed this study exempt from review.

Program Description

A simulation of an inpatient hospital room, known as the “Room of Horrors,” was constructed in collaboration with the University of Chicago Simulation Center and adapted from a previous version of the exercise.¹¹ The simulation consisted of a mock door chart highlighting the patient had been admitted for diarrhea (Clostridium difficile positive) following a recent hospitalization for pneumonia. A clinical scenario was constructed by using a patient mannequin and an accompanying door chart that listed information on the patient’s hospital course, allergies, and medications. In addition to the 8 patient safety hazards utilized in the prior version, our team selected 4 low-value hazards to be included in the simulation.

The 8 safety hazards have been detailed in a prior study and were previously selected from Medicare’s Hospital-Acquired Conditions (HAC) Reduction Program and Agency for Healthcare Research and Quality (AHRQ) Patient Safety Indicators.^11-13 Each of the hazards was represented either physically in the simulation room and/or was indicated on the patient’s chart. For example, the latex allergy hazard was represented by latex gloves at the bedside despite an allergy indicated on the patient’s chart and wristband. A complete list of the 8 safety hazards and their representations in the simulation is shown in Table 1.

The Choosing Wisely™ lists were reviewed to identify low-value hazards for addition to the simulation.¹⁴ Our team selected 3 low-value hazards from the Society of Hospital Medicine (SHM) list,¹⁵ including (1) arbitrary blood transfusion despite the patient’s stable hemoglobin level of 8.0 g/dL and absence of cardiac symptoms,¹⁶ (2) addition of a proton pump inhibitor (PPI) for stress ulcer prophylaxis in a patient without high risk for gastrointestinal (GI) complications who was not on a PPI prior to admission, and (3) placement of a urinary catheter without medical indication. We had originally selected continuous telemetry monitoring as a fourth hazard from the SHM list, but were unable to operationalize, as it was difficult to simulate continuous telemetry on a mannequin. Because many inpatients are older than 65 years, we reviewed the American Geriatrics Society list¹⁷ and selected our fourth low-value hazard: (4) unnecessary use of physical restraints to manage behavioral symptoms in a hospitalized patient with delirium. Several of these hazards were also quality and safety priorities at our institution, including the overuse of urinary catheters, physical restraints, and blood transfusions. All 4 low-value hazards were referenced in the patient’s door chart, and 3 were also physically represented in the room via presence of a hanging unit of blood, Foley catheter, and upper-arm restraints (Table 1). See Appendix for a photograph of the simulation setup.

Each intern was allowed 10 minutes inside the simulation room. During this time, they were instructed to read the 1-page door chart, inspect the simulation room, and write down as many potential low-value and safety hazards as they could identify on a free-response form (see Appendix). Upon exiting the room, they were allotted 5 additional minutes to complete their free-response answers and provide written feedback on the simulation. The simulation was conducted in 3 simulated hospital rooms over the course of 2 days, and the correct answers were provided via e-mail after all interns had completed the exercise.

To assess prior training and safety knowledge, interns were asked to complete a 3-question preassessment on a ScanTron^TM (Tustin, CA) form. The preassessment asked interns whether they had received training on hospital safety during medical school (yes, no, or unsure), if they were satisfied with the hospital safety training they received during medical school (strongly disagree to strongly agree on a Likert scale), and if they were confident in their ability to identify potential hazards in a hospital setting (strongly disagree to strongly agree). Interns were also given the opportunity to provide feedback on the simulation experience on the ScanTron^TM (Tustin, CA) form.

One month after participating in the simulation, interns were asked to complete an online follow-up survey on MedHub^TM (Ann Arbor, MI), which included 2 Likert-scale questions (strongly disagree to strongly agree) assessing the simulation’s impact on their experience mitigating hospital hazards during the first month of internship.

Data Analysis

Interns’ free-response answers were manually coded, and descriptive statistics were used to summarize the mean percent correct for each hazard. A paired t test was used to compare intern identification of low-value vs safety hazards. T tests were used to compare hazard identification for interns entering highly procedural-intensive specialties (ie, surgical specialties, emergency medicine, anesthesia, obstetrics/gynecology) and those entering less procedural-intensive specialties (ie, internal medicine, pediatrics, psychiatry), as well as among those graduating from “Top 30” medical schools (based on US News & World Report Medical School Rankings¹⁸) and our own institution. One-way analysis of variance (ANOVA) calculations were used to test for differences in hazard identification based on interns’ prior hospital safety training, with interns who rated their satisfaction with prior training or confidence in identifying hazards as a “4” or a “5” considered “satisfied” and “confident,” respectively. Responses to the MedHub^TM (Ann Arbor, MI) survey were dichotomized with “strongly agree” and “agree” considered positive responses. Statistical significance was defined at P < .05. All data analysis was conducted using Stata 14^TM software (College Station, TX).

Intern Characteristics

One hundred twenty-five entering PGY1 interns participated in the simulation, representing 60 medical schools and 7 different specialty groups (Table 2). Thirty-five percent (44/125) were graduates from “Top 30” medical schools, and 8.8% (11/125) graduated from our own institution. Seventy-four percent (89/121) had received prior hospital safety training during medical school, and 62.9% (56/89) were satisfied with their training. A majority of interns (64.2%, 79/123) felt confident in their ability to identify potential hazards in a hospital setting, although confidence was much higher among those with prior safety training (71.9%, 64/89) compared to those without prior training or who were unsure about their training (40.6%, 13/32; P = .09, t test).

Identification of Hazards

The mean percentage of hazards correctly identified by interns during the simulation was 50.4% (standard deviation [SD] 11.8%), with a normal distribution (Figure 1). Interns identified a significantly lower percentage of low-value hazards than safety hazards in the simulation (mean 19.2% [SD 18.6%] vs 66.0% [SD 16.0%], respectively; P < .001, paired t test). Interns also identified significantly more room-based errors than chart-based errors (mean 58.6% [SD 13.4%] vs 9.6% [SD 19.8%], respectively; P < .001, paired t test). The 3 most commonly identified hazards were unavailability of hand hygiene (120/125, 96.0%), presence of latex gloves despite the patient’s allergy (111/125, 88.8%), and fall risk due to the lowered bed rail (107/125, 85.6%). More than half of interns identified the incorrect name on the patient’s wristband and IV bag (91/125, 72.8%), a lack of isolation precautions (90/125, 72.0%), administration of penicillin despite the patient’s allergy (67/125, 53.6%), and unnecessary restraints (64/125, 51.2%). Less than half of interns identified the wrong medication being administered (50/125, 40.0%), unnecessary Foley catheter (25/125, 20.0%), and absence of venous thromboembolism (VTE) prophylaxis (24/125, 19.2%). Few interns identified the unnecessary blood transfusion (7/125, 5.6%), and no one identified the unnecessary stress ulcer prophylaxis (0/125, 0.0%; Figure 2).

Predictors of Hazard Identification

Interns who self-reported as confident in their ability to identify hazards were not any more likely to correctly identify hazards than those who were not confident (50.9% overall hazard identification vs 49.6%, respectively; P = .56, t test). Interns entering into less procedural-intensive specialties identified significantly more safety hazards than those entering highly procedural-intensive specialties (mean 69.1% [SD 16.9%] vs 61.8% [SD 13.7%], respectively; P = .01, t test). However, there was no statistically significant difference in their identification of low-value hazards (mean 19.8% [SD 18.3%] for less procedural-intensive vs 18.4% [SD 19.1%] for highly procedural-intensive; P = .68, t test). There was no statistically significant difference in hazard identification among graduates of “Top 30” medical schools or graduates of our own institution. Prior hospital safety training had no significant impact on interns’ ability to identify safety or low-value hazards. Overall, interns who were satisfied with their prior training identified a mean of 51.8% of hazards present (SD 11.8%), interns who were not satisfied with their prior training identified 51.5% (SD 12.7%), interns with no prior training identified 48.7% (SD 11.7%), and interns who were unsure about their prior training identified 47.4% (SD 11.5%) [F(3,117) = .79; P = .51, ANOVA]. There was also no significant association between prior training and the identification of any one of the 12 specific hazards (chi-square tests, all P values > .1).

Intern Feedback and Follow-Up Survey

Debriefing revealed that most interns passively assumed the patient’s chart was correct and did not think they should question the patient’s current care regimen. For example, many interns commented that they did not think to consider the patient’s blood transfusion as unnecessary, even though they were aware of the recommended hemoglobin cutoffs for stable patients.

Interns also provided formal feedback on the simulation through open-ended comments on their ScanTron^TM (Tustin, CA) form. For example, one intern wrote that they would “inherently approach every patient room ‘looking’ for safety issues, probably directly because of this exercise.” Another commented that the simulation was “more difficult than I expected, but very necessary to facilitate discussion and learning.” One intern wrote that “I wish I had done this earlier in my career.”

Ninety-six percent of participating interns (120/125) completed an online follow-up survey 1 month after beginning internship. In the survey, 68.9% (82/119) of interns indicated they were more aware of how to identify potential hazards facing hospitalized patients as a result of the simulation. Furthermore, 52.1% (62/119) of interns had taken action during internship to reduce a potential hazard that was present in the simulation.

While many GME orientations include simulation and safety training, this study is the first of its kind to incorporate low-value care from Choosing Wisely™ recommendations into simulated training. It is concerning that interns identified significantly fewer low-value hazards than safety hazards in the simulation. In some cases, no interns identified the low-value hazard. For example, while almost all interns identified the hand hygiene hazard, not one could identify the unnecessary stress ulcer prophylaxis. Furthermore, interns who self-reported as confident in their ability to identify hazards did not perform any better in the simulation. Interns entering less procedural-intensive specialties identified more safety hazards overall.

The simulation was well received by interns. Many commented that the experience was engaging, challenging, and effective in cultivating situational awareness towards low-value care. Our follow-up survey demonstrated the majority of interns reported taking action during their first month of internship to reduce a hazard included in the simulation. Most interns also reported a greater awareness of how to identify hospital hazards as a result of the simulation. These findings suggest that a brief simulation-based experience has the potential to create a lasting retention of situational awareness and behavior change.

It is worth exploring why interns identified significantly fewer low-value hazards than safety hazards in the simulation. One hypothesis is that interns were less attuned to low-value hazards, which may reflect a lacking emphasis on value-based care in undergraduate medical education (UME). It is especially concerning that so few interns identified the catheter-associated urinary tract infection (CAUTI) risk, as interns are primarily responsible for recognizing and removing an unnecessary catheter. Although the risks of low-value care should be apparent to most trainees, the process of recognizing and deliberately stopping or avoiding low-value care can be challenging for young clinicians.¹⁹ To promote value-based thinking among entering residents, UME programs should teach students to question the utility of the interventions their patients are receiving. One promising framework for doing so is the Subjective, Objective, Assessment, Plan- (SOAP)-V, in which a V for “Value” is added to the traditional SOAP note.²⁰ SOAP-V notes serve as a cognitive forcing function that requires students to pause and assess the value and cost-consciousness of their patients’ care.²⁰

The results from the “Room of Horrors” simulation can also guide health leaders and educators in identifying institutional areas of focus towards providing high-value and safe care. For example, at the University of Chicago we launched an initiative to improve the inappropriate use of urinary catheters after learning that few of our incoming interns recognized this during the simulation. Institutions could use this model to raise awareness of initiatives and redirect resources from areas that trainees perform well in (eg, hand hygiene) to areas that need improvement (eg, recognition of low-value care). Given the simulation’s low cost and minimal material requirements, it could be easily integrated into existing training programs with the support of an institution’s simulation center.

This study’s limitations include its conduction at single-institution, although the participants represented graduates of 60 different institutions. Furthermore, while the 12 hazards included in the simulation represent patient safety and value initiatives from a wide array of medical societies, they were not intended to be comprehensive and were not tailored to specific specialties. The simulation included only 4 low-value hazards, and future iterations of this exercise should aim to include an equal number of safety and low-value hazards. Furthermore, the evaluation of interns’ prior hospital safety training relied on self-reporting, and the specific context and content of each interns’ training was not examined. Finally, at this point we are unable to provide objective longitudinal data assessing the simulation’s impact on clinical practice and patient outcomes. Subsequent work will assess the sustained impact of the simulation by correlating with institutional data on measurable occurrences of low-value care.

In conclusion, interns identified significantly fewer low-value hazards than safety hazards in an inpatient simulation designed to promote situational awareness. Our results suggest that interns are on the lookout for errors of omission (eg, absence of hand hygiene, absence of isolation precautions) but are often blinded to errors of commission, such that when patients are started on therapies there is an assumption that the therapies are correct and necessary (eg, blood transfusions, stress ulcer prophylaxis). These findings suggest poor awareness of low-value care among incoming interns and highlight the need for additional training in both UME and GME to place a greater emphasis on preventing low-value care.

Disclosure

Dr. Arora is a member of the American Board of Medicine Board of Directors and has received grant funding from ABIM Foundation via Costs of Care for the Teaching Value Choosing Wisely™ Challenge. Dr. Farnan, Dr. Arora, and Ms. Hirsch receive grant funds from Accreditation Council of Graduate Medical Education as part of the Pursuing Excellence Initiative. Dr. Arora and Dr. Farnan also receive grant funds from the American Medical Association Accelerating Change in Medical Education initiative. Kathleen Wiest and Lukas Matern were funded through matching funds of the Pritzker Summer Research Program for NIA T35AG029795.

Inherited mutations in a single gene may contribute to a severe form of atopic dermatitis (AD), a study of eight patients showed.

Investigators from the National Institute of Allergy and Infectious Diseases (NIAID) and elsewhere identified eight individuals with severe AD from four unrelated families. All of the patients had a mutation in the CARD11 gene, which is part of the nuclear factor–kappa B (NF-kB) pathway.

Courtesy National Institute of Allergy and Infectious Diseases

Inherited mutations in a single gene may contribute to a severe form of atopic dermatitis (AD), a study of eight patients showed.

Investigators from the National Institute of Allergy and Infectious Diseases (NIAID) and elsewhere identified eight individuals with severe AD from four unrelated families. All of the patients had a mutation in the CARD11 gene, which is part of the nuclear factor–kappa B (NF-kB) pathway.

Courtesy National Institute of Allergy and Infectious Diseases

Inherited mutations in a single gene may contribute to a severe form of atopic dermatitis (AD), a study of eight patients showed.

Investigators from the National Institute of Allergy and Infectious Diseases (NIAID) and elsewhere identified eight individuals with severe AD from four unrelated families. All of the patients had a mutation in the CARD11 gene, which is part of the nuclear factor–kappa B (NF-kB) pathway.

Courtesy National Institute of Allergy and Infectious Diseases

SEATTLE – As patient satisfaction becomes increasingly important for reimbursements, it might be a good idea to switch to propofol for colonoscopies.

The reason is because patients prefer propofol over standard-of-care fentanyl/midazolam as their anesthetic for outpatient colonoscopies, according to a randomized, blinded trial at a single center. Importantly, clinical assessment also showed that propofol outperformed fentanyl/midazolam in terms of hypoxia, pain, nausea, and procedural difficulties.

Copyright Eraxion/Thinkstock

Alex Otto/Frontline Medical News

[email protected]

SEATTLE – As patient satisfaction becomes increasingly important for reimbursements, it might be a good idea to switch to propofol for colonoscopies.

The reason is because patients prefer propofol over standard-of-care fentanyl/midazolam as their anesthetic for outpatient colonoscopies, according to a randomized, blinded trial at a single center. Importantly, clinical assessment also showed that propofol outperformed fentanyl/midazolam in terms of hypoxia, pain, nausea, and procedural difficulties.

Copyright Eraxion/Thinkstock

Alex Otto/Frontline Medical News

[email protected]

SEATTLE – As patient satisfaction becomes increasingly important for reimbursements, it might be a good idea to switch to propofol for colonoscopies.

The reason is because patients prefer propofol over standard-of-care fentanyl/midazolam as their anesthetic for outpatient colonoscopies, according to a randomized, blinded trial at a single center. Importantly, clinical assessment also showed that propofol outperformed fentanyl/midazolam in terms of hypoxia, pain, nausea, and procedural difficulties.

Copyright Eraxion/Thinkstock

Alex Otto/Frontline Medical News

[email protected]

Seven months into the first year of the Quality Payment Program, the new value-based payment plan set up by the Medicare Access and CHIP Reauthorization Act (MACRA), and doctors’ knowledge of the program is still light.

“Physicians, especially those in small practices, need more help in preparing” for participation in QPP either through the Merit-Based Incentive Payment System (MIPS) or advanced Alternative Payment Models (APMs), according to a new report issued by the American Medical Association and consulting firm KPMG.

TheaDesign/Thinkstock

[email protected]
 

Seven months into the first year of the Quality Payment Program, the new value-based payment plan set up by the Medicare Access and CHIP Reauthorization Act (MACRA), and doctors’ knowledge of the program is still light.

“Physicians, especially those in small practices, need more help in preparing” for participation in QPP either through the Merit-Based Incentive Payment System (MIPS) or advanced Alternative Payment Models (APMs), according to a new report issued by the American Medical Association and consulting firm KPMG.

TheaDesign/Thinkstock

[email protected]
 

Seven months into the first year of the Quality Payment Program, the new value-based payment plan set up by the Medicare Access and CHIP Reauthorization Act (MACRA), and doctors’ knowledge of the program is still light.

“Physicians, especially those in small practices, need more help in preparing” for participation in QPP either through the Merit-Based Incentive Payment System (MIPS) or advanced Alternative Payment Models (APMs), according to a new report issued by the American Medical Association and consulting firm KPMG.

TheaDesign/Thinkstock

[email protected]
 

Take a brand-new research facility, then add a neighboring U.S. Army base with one of the largest veteran populations of any health care network and a world-class team of researchers—that’s a “recipe for success,” says Dr. Michael Russell, director of the VA Center of Excellence for Research on Returning War Veterans in Waco, Texas.

The 53,000-square-foot center is designed to conduct state-of-the-art research on mental health problems associated with PTSD and TBI, “signature wounds” of conflicts in Afghanistan and the Middle East. The flagship study is named Project MAVEREX. Researchers will examine whether the inability of the regions in injured brains to communicate with one another worsens behavior outcomes. Using “cutting-edge data analysis techniques,” they hope to characterize the effects of TBI on brain structure and function “with very high precision,” says Dr. Evan Gordon, a cognitive neuroscientist working on MAVEREX.

The Center of Excellence is on the campus of the historic Doris Miller VAMC. The facility has space for 75 staff members and faculty as well as 25 trainees. It features multiple examination rooms, observation rooms, electrocardiography, electroencephalography, a 3 Tesla MRI, a transcranial magnetic stimulation suite, and a custom-built laboratory wing.

Take a brand-new research facility, then add a neighboring U.S. Army base with one of the largest veteran populations of any health care network and a world-class team of researchers—that’s a “recipe for success,” says Dr. Michael Russell, director of the VA Center of Excellence for Research on Returning War Veterans in Waco, Texas.

The 53,000-square-foot center is designed to conduct state-of-the-art research on mental health problems associated with PTSD and TBI, “signature wounds” of conflicts in Afghanistan and the Middle East. The flagship study is named Project MAVEREX. Researchers will examine whether the inability of the regions in injured brains to communicate with one another worsens behavior outcomes. Using “cutting-edge data analysis techniques,” they hope to characterize the effects of TBI on brain structure and function “with very high precision,” says Dr. Evan Gordon, a cognitive neuroscientist working on MAVEREX.

The Center of Excellence is on the campus of the historic Doris Miller VAMC. The facility has space for 75 staff members and faculty as well as 25 trainees. It features multiple examination rooms, observation rooms, electrocardiography, electroencephalography, a 3 Tesla MRI, a transcranial magnetic stimulation suite, and a custom-built laboratory wing.

Take a brand-new research facility, then add a neighboring U.S. Army base with one of the largest veteran populations of any health care network and a world-class team of researchers—that’s a “recipe for success,” says Dr. Michael Russell, director of the VA Center of Excellence for Research on Returning War Veterans in Waco, Texas.

The 53,000-square-foot center is designed to conduct state-of-the-art research on mental health problems associated with PTSD and TBI, “signature wounds” of conflicts in Afghanistan and the Middle East. The flagship study is named Project MAVEREX. Researchers will examine whether the inability of the regions in injured brains to communicate with one another worsens behavior outcomes. Using “cutting-edge data analysis techniques,” they hope to characterize the effects of TBI on brain structure and function “with very high precision,” says Dr. Evan Gordon, a cognitive neuroscientist working on MAVEREX.

The Center of Excellence is on the campus of the historic Doris Miller VAMC. The facility has space for 75 staff members and faculty as well as 25 trainees. It features multiple examination rooms, observation rooms, electrocardiography, electroencephalography, a 3 Tesla MRI, a transcranial magnetic stimulation suite, and a custom-built laboratory wing.

Lymphedema is the swelling of tissue caused by the accumulation of interstitial fluid in any area of the body where lymphatic flow has been compromised.¹ Secondary lymphedema is an acquired abnormality in lymph drainage^1,2 and is the type commonly seen in cancer patients. Secondary lymphedema can be described as external or internal. Internal lymphedema, swelling of deep structures and tissues, is very difficult to quantify.

Lymphedema in patients with head and neck cancers
Lymphedema is a complicating morbidity frequently seen in head and neck cancer patients who have undergone treatment with surgery, radiation, and chemotherapy. However, although it is one of the most prevalent side effects of treatment, it is both under-recognized and under-treated.³

In head and neck cancer patients, internal swelling may develop in the soft tissues of the upper aero-digestive tract,⁴ affecting articulation and swallowing. Currently, there does not seem to be an effective practical and reliable tool with which to measure internal lymphedema. In addition, it is generally accepted that there is no effective way to treat internal lymphedema. By contrast, external lymphedema is more readily observed, but both subjective and objective assessments are difficult. External swelling may occur in the face, jaw, and neck. However, the subjective scales currently available are insufficient to capture very important characteristics of external lymphedema.⁵ The Edge Task Force on Head and Neck Cancer in 2015 was not able to recommend any outcome measures for objectively quantifying external edema.⁶ Furthermore, objective measurements of head and neck lymphedema can be expensive and time consuming.

Extent and risk

A combination of both internal and external swelling is seen in more than 50% of patients.⁷ Risk factors include “throat” tumors, multicancer treatment approaches, higher total radiation dose, a greater number of radiation procedures, and radiation at the surgical site.⁵ More than 500,000 survivors of head and neck cancer in the United States are at risk of lymphedema.⁵ Although recent advances in treatment have reduced the incidence of other morbidities, 50% of patients who are treated for head and neck cancer may still develop lymphedema.^1,8 The reported incidence in some centers may be much higher, with up to 75% of patients developing lymphedema following treatment.⁹

Measurement modalities for clinical evaluation

There is little current research into lymphedema of the head and neck, despite the high prevalence of the condition.⁸ According to Deng and colleagues, measurement of head and neck lymphedema is a challenge, which has an impact on clinical assessment, diagnosis, and treatment of this under-recognized, under-reported and under-addressed problem in head and neck cancer patients.¹⁰ In a review of the literature, Deng and colleagues identified three measurement modalities available for clinical evaluation: patient-reported outcomes, clinician-reported outcomes, and technology.¹⁰ One major factor, though, in detecting lymphedema, is physician awareness: physicians, health care professionals, and even some lymphedema therapists are not well educated about this problem.⁸

Treatment

The effectiveness of traditional lymphedema treatment is not well defined.⁸ Currently, complete decongestive therapy (CDT), is considered the standard of care for lymphedema. The National Lymphedema Network has stated that modifications of CDT, especially manual lymphatic drainage and modified compressive garments for external lymphedema, have been shown to be beneficial for the treatment of lymphedema in head and neck cancer patients.¹¹ Most findings in lymphedema research, mainly in breast cancer patients, have shown that early intervention is the best management and yields the best outcomes. As with other chronic conditions, early identification and timely, appropriate treatment of lymphedema is critical to improve clinical outcomes, to decrease symptom burden and functional impairment, and to improve overall quality of life in head and neck cancer patients.¹⁰

Improving recognition and treatment

Head and neck oncologic treatment is increasingly offered outside the network of specialist academic hospitals, at hospitals serving more localized communities where the neediest, sickest patient groups may be receiving less than optimal care.³ This challenges community hospitals to provide optimal treatment, similar to that being offered at nationally recognized institutions. In January 2012, we implemented a prehabilitation program in our community hospital cancer center to provide early intervention for our patients based on the understanding that proper and prompt treatment for patients with early signs of lymphedema should be a priority.¹² In this article, we outline how we implemented the program and the describe improvements we observed before and after the implementation of the program.

The prehabilitation program

The role of the nurse navigator

Before the introduction of the prehabilitation program, our pattern of practice was to refer patients to oncology rehabilitation for lymphedema management after they had completed their medical treatment with surgery, radiation, and chemotherapy. In 2012, that was changed to a prehabilitation model of care that was overseen by a head and neck nurse navigator. This focus on prehabilitation begins with patients being referred to oncology rehabilitation at the time of cancer diagnosis for baseline assessment of head and neck swelling. In addition, there is assessment of the many possible other side effects associated with head and neck cancer and its treatment, namely loss of range of motion of the neck, jaw (trismus), and/or shoulders, postural deficits, functional loss, pain, balance dysfunction with fall risk, weakness, and fatigue. Therapeutic interventions are initiated as needed and appropriate. This process also raises awareness of a condition that has been described as under-recognized and under-treated.³

The nurse navigator sits in on each radiation oncology consultation and aids in “navigating” patients through their treatment. The nurse ensures that each patient is referred to different ancillary services from the outset, such as seeing a dietician, social worker, physical/occupational therapist and certified lymphedema therapist, speech pathologist, and financial assistance advisor, if necessary (Table 1).

Assessment of lymphedema

Measurement of head and neck lymphedema is a challenge.¹⁰ In our program, the physical therapy assessment also includes the evaluation of several other morbidities associated with head and neck cancer and its treatment, such as range of motion, weakness, fatigue, radiation fibrosis, balance dysfunction, and risk of falling (Table 2).

Although objective criteria for external lymphedema have not been established, simple measurements such as using a tape measure to record neck circumference, allow a useful longitudinal assessment. Digital photography may be effective in the documentation and subjective evaluation of changes of external lymphedema.^10,17 However, there are some limitations with photography because although external photographs (including digital photography and three-dimensional imaging) can capture some features, such as changes in contours, symmetry, and changes in skin quality and color, they do not detect changes in skin and soft tissue texture and compliance (Table 3).¹⁰

Impact on clinical outcomes

We retrospectively reviewed the medical records of 230 head and neck cancer patients who had been treated at our center between June 2008 and June 2015. Complete clinical data were available for 190 patients. The following information was extracted from each patient’s chart: whether they developed lymphedema, tumor stage, had surgery, radiation dose, type of chemotherapy given, their smoking history, if they had had a neck dissection and the primary site of the tumor (Table 3).

Incidence in different time periods. Of the 190 patients with complete records 78 (41%) were found to have lymphedema. These were all patients undergoing treatment for head and neck cancer during June 2008-June 2015. The prehabilitation program was initiated with the hiring of a nurse navigator for head and neck cancer, starting in January 2012. It is interesting to note that the incidence of lymphedema was 27% before the program was started, but after nurse navigator joined the team, the incidence increased significantly to 48% (P = .0002), in line with published expectations. This increase in recorded incidence may be attributable to the greater awareness of lymphedema intentionally fostered by the prehabilitation program.

Smoking history. Patients’ lifetime smoking history was retrieved from their medical records, based on their verbal admission of tobacco use. Most of the patients (n = 110) self-reported a history of smoking. Of those with a history of smoking, 36 (33%) developed external lymphedema after treatment for head and neck cancer, and 74 (67%) did not. However, this difference was not statistically significant. Hence, although smoking is a risk factor for head and neck cancer, it was not associated with the development of external lymphedema in our cohort of patients.

Type of tumor

Most of the patients (n = 156, 82%) had squamous cell carcinomas (SCC). Of those, 45% developed external lymphedema and 55% did not. Therefore, having SCC did not predispose to lymphedema. The other cancers were mixed type, mainly adenocaricoma, but their numbers were too small to draw statistical conclusions.

Stage of the tumor

About two thirds of the patients (n = 121, 64%) had stage 3 or 4 cancer. However, treatment of more advanced cancers was not associated with lymphedema development.

Site of the tumor

The literature suggests that patients with a primary tumor in the throat are at increased risk for lymphedema.⁵ The American Cancer Society has defined cancers of the oropharynx (throat) as including the base of the tongue (back third of the tongue), the soft palate, the tonsils, and the side and back walls of the throat.¹⁸ In our head and neck cancer cohort, patients with primary tumors of the oropharnyx were, perhaps, more susceptible to lymphedema (P = .044, Table 3). By contrast, in our cohort of patients, those with nasopharyngeal, hypopharyngeal, and parotid gland tumors were significantly less likely to develop lymphedema (Ps = .017, .04, .012, respectively).

No surgery

Half of our patients (n = 95) were not treated with surgery. In the patients who did not have surgery, 25 (26%) developed lymphedema, whereas 70 (74%) did not. Hence, although the incidence of lymphedema was significantly lower in patients who did not have surgery (P = .015), lymphedema did develop in patients who did not have a surgical procedure.

Resection of primary tumor without neck dissection

Of the 64 patients who had surgery, but without neck dissection, 35 (55%) developed external lymphedema. Compared with the no-surgery patients, the doubling of the incidence (from 26% to 55%) was highly significant (P = .0004). These findings are compatible with the literature reports that surgery increases the incidence of lymphedema, which is not surprising because surgery and subsequent scarring is known to compromise the lymphatic system.

Resection of primary tumor with neck dissection

The incidence of external lymphedema was increased to 69% when patients were subjected to both surgery and neck dissection. Compared with the June 2008-June 2015 cohort, there was a significant increase in the incidence of lymphedema in the neck dissection group (P = .007). Neck dissection involves the removal of lymph nodes and disruption of the lymphatic vessels, so it is not surprising that there is a higher incidence of external lymphedema. In our practice, neck dissections increased in frequency every year from June 2008 until December 2011, when 8 patients underwent neck dissections, 6 (75%) of whom developed lymphedema. Since January 2012, when the prehabilitation program was implemented, the number of neck dissections have declined, with more patients receiving chemoradiation and surgery being reserved for surgery. Hamoir and colleagues have reported that neck dissection is no longer justified unless there is clinically residual disease in the neck.¹⁹

Radiation

Lymphedema occurred in patients regardless of the dose of radiation received. Although the incidence of lymphedema seemed to be higher in patients who received more than 60 cGy, that difference was not statistically significant (Table 3). We had expected a relationship between radiation damage and greater lymphedema, but that was not evident in our patients.

Chemotherapy

The majority of patients (n = 131, 69%) received chemotherapy. The exposure to chemotherapy was not correlated with the risk of external lymphedema in our cohort of patients, with 58 of the 131 treated patients (44%) developing lymphedema, compared with 73 (56%) of treated patients who did not (Table 3).

Complete decongestive therapy

All patients with documented lymphedema were evaluated for complete decongestive therapy (CDT). Contraindications to CDT included congestive heart failure, renal failure, acute infection, peripheral artery disease, upper-quadrant deep vein thrombosis, and carotid artery stenosis. Eligible patients were referred to a certified lymphedema therapist for CDT. As the program evolved, patients at risk for lymphedema were referred for CDT early on, usually at the time of diagnosis, to improve early identification and surveillance of lymphedema.

CDT included manual lymph drainage, compression bandaging (Figure), decongestive exercises, skin care, and education in swelling self-management. Manual lymph drainage is a specialized light pressure hands-on technique that reduces swelling by enhancing lymphatic reabsorption and flow. Compressive bandaging/garments increase venous and lymphatic drainage and soften fibrotic tissue. Continued use of compression depends on progress. In head and neck cancer patients, the need for lifelong compression is not evident when they are treated early and there is good patient compliance.⁸ Therapeutic exercise enhances lymphatic and venous circulation, and good skin care reduces the risk of infection.

Communication and education

The head and neck cancer nurse navigator attends the cancer center’s multidisciplinary head and neck tumor board, which has representation from otolaryngology, diagnostic radiology, pathology, radiation oncology, medical oncology, reconstructive surgery, oncology rehabilitation (physical/occupational therapist), dietary services, speech pathology, social services and clinical research. This regular contact allows for earlier awareness about which patients are at greater risk for developing lymphedema, thus enabling early intervention (and patient education) in a timely manner.

Education of the patient, before cancer therapy, of the risks of lymphedema is very important. Before the implementation of the prehabilitation program, some patients did not fully comprehend what a painful and debilitating consequence of cancer treatment lymphedema could be.

Discussion

We introduced a prehabilitation program to detect and treat lymphedema in head and neck cancer patients in January 2012 part way through following an observation cohort from June2008 through June2015. Central to this, in our center, was the appointment of a nurse navigator whose primary focus was on head and neck cancer patients. We placed a high priority on the early detection and treatment of lymphedema because do so has been associated with better outcomes in other centers.

One immediate consequence of the inception of our program was the identification of more patients with external lymphedema. Our detected incidence rose significantly (P = .0002), from 27% in the period June 2008-December 20112010, before the program, to 48% during the January 2012-June 2015 period, after the inception of the program. This later incidence rate is in line with published incidence rates in most centers. However, it is still somewhat short of the 75% suggested in one center,⁹ which suggests we are either we are underdetecting lymphedema or there are differences in definition criteria or sensitivity levels for defining lymphedema.

There are currently no specific objective measures of lymphedema, so there is bound to be some variation in diagnosis rates. In our program, we rely heavily on the patient-reported outcome measures, the NDI instrument, and digital photography to detect and monitor lymphedema, starting with the pretreatment baseline values that are established for each patient.

The use of digital photography in our community hospital setting, which includes taking photographs before and after treatment and at each visit, motivates and encourages patients and provides a tool for clinical lymphedema therapists to visually document benefits of treatment. Patients’ motivation and compliance with their established home program for head and neck lymphedema self-management are essential. The elements of the home program may include self-manual lymph drainage, home-modified compression bandaging and garment wear, therapeutic exercises, and skin care. Patients with lymphedema who adhered closely with their therapy program were more than 8 times more likely to improve compared with noncompliant patients.¹⁷

Some groups of patients have a greater risk of developing lymphedema than others,⁵ so the development of an algorithm to predict lymphedema seemed possible. However, in our cohort of patients, only neck dissection, with its disruption of the lymphatic system of the neck, was strongly associated with external lymphedema (Table 3). It is important to note that some patients who did not undergo surgery developed lymphedema. In our patients, high doses of radiation alone did not seem to predispose to lymphedema. That suggests that no group of head and neck cancer patients should be ignored, which is why we did routine screening of all patients before, during, and after treatment.

Our protocol falls short in the detection of internal lymphedema. For example, information on swallowing gathered by our speech pathologists (in a different department) has not, so far, been included in our assessment. This is one opportunity to improve on our approach, especially because speech difficulties may be associated with internal lymphedema. In addition, we are not equipped for the requisite internal examinations. Unfortunately, there are no practical and successful treatments for patients suffering from internal swelling. This represents a challenge for the medical community to better meet this need. Therefore, although we are missing some assessments of internal lymphedema, this is of little therapeutic consequence at this time.

The increase in the detected incidence of external lymphedema points to a practice gap that has been resolved by the appointment of a dedicated nurse navigator who attends oncology reviews to share knowledge and information. Another educational effort has been made with the patients themselves to increase compliance and improve continuous care at home.

There is always room for improvement, however, either by feedback acquired from other institutions and hospitals or through the future introduction of more objective assessment techniques.

Conclusions

The introduction of the prehabilitation program at our center has coincided with a significantly improved detection rate for external lymphedema in head and neck cancer patients. It may be because the program emphasizes education about lymphedema that awareness of the condition has increased throughout the center. It is now widely recognized that all patients are at risk of lymphedema regardless of whether they fall into an acknowledged high-risk group. Our experience shows that there is no significant difference between treatment modalities apart from neck dissection. In our population, the use of this procedure is decreasing. External lymphedema can develop even in patients who do not have surgery. Therefore, there is no sound way to predict which patients are most likely to suffer from the accumulation of fluid in their head and neck after treatment for head and neck cancer. Thus, an assessment as described here, during and after treatment for all patients, is warranted. Patients are now being seen earlier as a part of the prehabilitation program, which facilitates access to complete decongestive treatment at an earlier stage, improves patient outcomes, and increases patient satisfaction with their treatment. Our prehabilitation program could serve as a model for other community hospital centers in achieving outcomes that are as good as those in academic centers.

Acknowledgments

The authors thank Irene Kadota and Heather Peters, from the Department of Radiation Oncology, and Julianne Courtenay, from the Department of Physical Therapy at the Disney Family Cancer Center, Burbank, California, for providing the original clinical data for analysis.

Lymphedema is the swelling of tissue caused by the accumulation of interstitial fluid in any area of the body where lymphatic flow has been compromised.¹ Secondary lymphedema is an acquired abnormality in lymph drainage^1,2 and is the type commonly seen in cancer patients. Secondary lymphedema can be described as external or internal. Internal lymphedema, swelling of deep structures and tissues, is very difficult to quantify.

Lymphedema in patients with head and neck cancers
Lymphedema is a complicating morbidity frequently seen in head and neck cancer patients who have undergone treatment with surgery, radiation, and chemotherapy. However, although it is one of the most prevalent side effects of treatment, it is both under-recognized and under-treated.³

In head and neck cancer patients, internal swelling may develop in the soft tissues of the upper aero-digestive tract,⁴ affecting articulation and swallowing. Currently, there does not seem to be an effective practical and reliable tool with which to measure internal lymphedema. In addition, it is generally accepted that there is no effective way to treat internal lymphedema. By contrast, external lymphedema is more readily observed, but both subjective and objective assessments are difficult. External swelling may occur in the face, jaw, and neck. However, the subjective scales currently available are insufficient to capture very important characteristics of external lymphedema.⁵ The Edge Task Force on Head and Neck Cancer in 2015 was not able to recommend any outcome measures for objectively quantifying external edema.⁶ Furthermore, objective measurements of head and neck lymphedema can be expensive and time consuming.

Extent and risk

A combination of both internal and external swelling is seen in more than 50% of patients.⁷ Risk factors include “throat” tumors, multicancer treatment approaches, higher total radiation dose, a greater number of radiation procedures, and radiation at the surgical site.⁵ More than 500,000 survivors of head and neck cancer in the United States are at risk of lymphedema.⁵ Although recent advances in treatment have reduced the incidence of other morbidities, 50% of patients who are treated for head and neck cancer may still develop lymphedema.^1,8 The reported incidence in some centers may be much higher, with up to 75% of patients developing lymphedema following treatment.⁹

Measurement modalities for clinical evaluation

There is little current research into lymphedema of the head and neck, despite the high prevalence of the condition.⁸ According to Deng and colleagues, measurement of head and neck lymphedema is a challenge, which has an impact on clinical assessment, diagnosis, and treatment of this under-recognized, under-reported and under-addressed problem in head and neck cancer patients.¹⁰ In a review of the literature, Deng and colleagues identified three measurement modalities available for clinical evaluation: patient-reported outcomes, clinician-reported outcomes, and technology.¹⁰ One major factor, though, in detecting lymphedema, is physician awareness: physicians, health care professionals, and even some lymphedema therapists are not well educated about this problem.⁸

Treatment

The effectiveness of traditional lymphedema treatment is not well defined.⁸ Currently, complete decongestive therapy (CDT), is considered the standard of care for lymphedema. The National Lymphedema Network has stated that modifications of CDT, especially manual lymphatic drainage and modified compressive garments for external lymphedema, have been shown to be beneficial for the treatment of lymphedema in head and neck cancer patients.¹¹ Most findings in lymphedema research, mainly in breast cancer patients, have shown that early intervention is the best management and yields the best outcomes. As with other chronic conditions, early identification and timely, appropriate treatment of lymphedema is critical to improve clinical outcomes, to decrease symptom burden and functional impairment, and to improve overall quality of life in head and neck cancer patients.¹⁰

Improving recognition and treatment

Head and neck oncologic treatment is increasingly offered outside the network of specialist academic hospitals, at hospitals serving more localized communities where the neediest, sickest patient groups may be receiving less than optimal care.³ This challenges community hospitals to provide optimal treatment, similar to that being offered at nationally recognized institutions. In January 2012, we implemented a prehabilitation program in our community hospital cancer center to provide early intervention for our patients based on the understanding that proper and prompt treatment for patients with early signs of lymphedema should be a priority.¹² In this article, we outline how we implemented the program and the describe improvements we observed before and after the implementation of the program.

The prehabilitation program

The role of the nurse navigator

Before the introduction of the prehabilitation program, our pattern of practice was to refer patients to oncology rehabilitation for lymphedema management after they had completed their medical treatment with surgery, radiation, and chemotherapy. In 2012, that was changed to a prehabilitation model of care that was overseen by a head and neck nurse navigator. This focus on prehabilitation begins with patients being referred to oncology rehabilitation at the time of cancer diagnosis for baseline assessment of head and neck swelling. In addition, there is assessment of the many possible other side effects associated with head and neck cancer and its treatment, namely loss of range of motion of the neck, jaw (trismus), and/or shoulders, postural deficits, functional loss, pain, balance dysfunction with fall risk, weakness, and fatigue. Therapeutic interventions are initiated as needed and appropriate. This process also raises awareness of a condition that has been described as under-recognized and under-treated.³

The nurse navigator sits in on each radiation oncology consultation and aids in “navigating” patients through their treatment. The nurse ensures that each patient is referred to different ancillary services from the outset, such as seeing a dietician, social worker, physical/occupational therapist and certified lymphedema therapist, speech pathologist, and financial assistance advisor, if necessary (Table 1).

Assessment of lymphedema

Measurement of head and neck lymphedema is a challenge.¹⁰ In our program, the physical therapy assessment also includes the evaluation of several other morbidities associated with head and neck cancer and its treatment, such as range of motion, weakness, fatigue, radiation fibrosis, balance dysfunction, and risk of falling (Table 2).

Although objective criteria for external lymphedema have not been established, simple measurements such as using a tape measure to record neck circumference, allow a useful longitudinal assessment. Digital photography may be effective in the documentation and subjective evaluation of changes of external lymphedema.^10,17 However, there are some limitations with photography because although external photographs (including digital photography and three-dimensional imaging) can capture some features, such as changes in contours, symmetry, and changes in skin quality and color, they do not detect changes in skin and soft tissue texture and compliance (Table 3).¹⁰

Impact on clinical outcomes

We retrospectively reviewed the medical records of 230 head and neck cancer patients who had been treated at our center between June 2008 and June 2015. Complete clinical data were available for 190 patients. The following information was extracted from each patient’s chart: whether they developed lymphedema, tumor stage, had surgery, radiation dose, type of chemotherapy given, their smoking history, if they had had a neck dissection and the primary site of the tumor (Table 3).

Incidence in different time periods. Of the 190 patients with complete records 78 (41%) were found to have lymphedema. These were all patients undergoing treatment for head and neck cancer during June 2008-June 2015. The prehabilitation program was initiated with the hiring of a nurse navigator for head and neck cancer, starting in January 2012. It is interesting to note that the incidence of lymphedema was 27% before the program was started, but after nurse navigator joined the team, the incidence increased significantly to 48% (P = .0002), in line with published expectations. This increase in recorded incidence may be attributable to the greater awareness of lymphedema intentionally fostered by the prehabilitation program.

Smoking history. Patients’ lifetime smoking history was retrieved from their medical records, based on their verbal admission of tobacco use. Most of the patients (n = 110) self-reported a history of smoking. Of those with a history of smoking, 36 (33%) developed external lymphedema after treatment for head and neck cancer, and 74 (67%) did not. However, this difference was not statistically significant. Hence, although smoking is a risk factor for head and neck cancer, it was not associated with the development of external lymphedema in our cohort of patients.

Type of tumor

Most of the patients (n = 156, 82%) had squamous cell carcinomas (SCC). Of those, 45% developed external lymphedema and 55% did not. Therefore, having SCC did not predispose to lymphedema. The other cancers were mixed type, mainly adenocaricoma, but their numbers were too small to draw statistical conclusions.

Stage of the tumor

About two thirds of the patients (n = 121, 64%) had stage 3 or 4 cancer. However, treatment of more advanced cancers was not associated with lymphedema development.

Site of the tumor

The literature suggests that patients with a primary tumor in the throat are at increased risk for lymphedema.⁵ The American Cancer Society has defined cancers of the oropharynx (throat) as including the base of the tongue (back third of the tongue), the soft palate, the tonsils, and the side and back walls of the throat.¹⁸ In our head and neck cancer cohort, patients with primary tumors of the oropharnyx were, perhaps, more susceptible to lymphedema (P = .044, Table 3). By contrast, in our cohort of patients, those with nasopharyngeal, hypopharyngeal, and parotid gland tumors were significantly less likely to develop lymphedema (Ps = .017, .04, .012, respectively).

No surgery

Half of our patients (n = 95) were not treated with surgery. In the patients who did not have surgery, 25 (26%) developed lymphedema, whereas 70 (74%) did not. Hence, although the incidence of lymphedema was significantly lower in patients who did not have surgery (P = .015), lymphedema did develop in patients who did not have a surgical procedure.

Resection of primary tumor without neck dissection

Of the 64 patients who had surgery, but without neck dissection, 35 (55%) developed external lymphedema. Compared with the no-surgery patients, the doubling of the incidence (from 26% to 55%) was highly significant (P = .0004). These findings are compatible with the literature reports that surgery increases the incidence of lymphedema, which is not surprising because surgery and subsequent scarring is known to compromise the lymphatic system.

Resection of primary tumor with neck dissection

The incidence of external lymphedema was increased to 69% when patients were subjected to both surgery and neck dissection. Compared with the June 2008-June 2015 cohort, there was a significant increase in the incidence of lymphedema in the neck dissection group (P = .007). Neck dissection involves the removal of lymph nodes and disruption of the lymphatic vessels, so it is not surprising that there is a higher incidence of external lymphedema. In our practice, neck dissections increased in frequency every year from June 2008 until December 2011, when 8 patients underwent neck dissections, 6 (75%) of whom developed lymphedema. Since January 2012, when the prehabilitation program was implemented, the number of neck dissections have declined, with more patients receiving chemoradiation and surgery being reserved for surgery. Hamoir and colleagues have reported that neck dissection is no longer justified unless there is clinically residual disease in the neck.¹⁹

Radiation

Lymphedema occurred in patients regardless of the dose of radiation received. Although the incidence of lymphedema seemed to be higher in patients who received more than 60 cGy, that difference was not statistically significant (Table 3). We had expected a relationship between radiation damage and greater lymphedema, but that was not evident in our patients.

Chemotherapy

The majority of patients (n = 131, 69%) received chemotherapy. The exposure to chemotherapy was not correlated with the risk of external lymphedema in our cohort of patients, with 58 of the 131 treated patients (44%) developing lymphedema, compared with 73 (56%) of treated patients who did not (Table 3).

Complete decongestive therapy

All patients with documented lymphedema were evaluated for complete decongestive therapy (CDT). Contraindications to CDT included congestive heart failure, renal failure, acute infection, peripheral artery disease, upper-quadrant deep vein thrombosis, and carotid artery stenosis. Eligible patients were referred to a certified lymphedema therapist for CDT. As the program evolved, patients at risk for lymphedema were referred for CDT early on, usually at the time of diagnosis, to improve early identification and surveillance of lymphedema.

CDT included manual lymph drainage, compression bandaging (Figure), decongestive exercises, skin care, and education in swelling self-management. Manual lymph drainage is a specialized light pressure hands-on technique that reduces swelling by enhancing lymphatic reabsorption and flow. Compressive bandaging/garments increase venous and lymphatic drainage and soften fibrotic tissue. Continued use of compression depends on progress. In head and neck cancer patients, the need for lifelong compression is not evident when they are treated early and there is good patient compliance.⁸ Therapeutic exercise enhances lymphatic and venous circulation, and good skin care reduces the risk of infection.

Communication and education

The head and neck cancer nurse navigator attends the cancer center’s multidisciplinary head and neck tumor board, which has representation from otolaryngology, diagnostic radiology, pathology, radiation oncology, medical oncology, reconstructive surgery, oncology rehabilitation (physical/occupational therapist), dietary services, speech pathology, social services and clinical research. This regular contact allows for earlier awareness about which patients are at greater risk for developing lymphedema, thus enabling early intervention (and patient education) in a timely manner.

Education of the patient, before cancer therapy, of the risks of lymphedema is very important. Before the implementation of the prehabilitation program, some patients did not fully comprehend what a painful and debilitating consequence of cancer treatment lymphedema could be.

Discussion

We introduced a prehabilitation program to detect and treat lymphedema in head and neck cancer patients in January 2012 part way through following an observation cohort from June2008 through June2015. Central to this, in our center, was the appointment of a nurse navigator whose primary focus was on head and neck cancer patients. We placed a high priority on the early detection and treatment of lymphedema because do so has been associated with better outcomes in other centers.

One immediate consequence of the inception of our program was the identification of more patients with external lymphedema. Our detected incidence rose significantly (P = .0002), from 27% in the period June 2008-December 20112010, before the program, to 48% during the January 2012-June 2015 period, after the inception of the program. This later incidence rate is in line with published incidence rates in most centers. However, it is still somewhat short of the 75% suggested in one center,⁹ which suggests we are either we are underdetecting lymphedema or there are differences in definition criteria or sensitivity levels for defining lymphedema.

There are currently no specific objective measures of lymphedema, so there is bound to be some variation in diagnosis rates. In our program, we rely heavily on the patient-reported outcome measures, the NDI instrument, and digital photography to detect and monitor lymphedema, starting with the pretreatment baseline values that are established for each patient.

The use of digital photography in our community hospital setting, which includes taking photographs before and after treatment and at each visit, motivates and encourages patients and provides a tool for clinical lymphedema therapists to visually document benefits of treatment. Patients’ motivation and compliance with their established home program for head and neck lymphedema self-management are essential. The elements of the home program may include self-manual lymph drainage, home-modified compression bandaging and garment wear, therapeutic exercises, and skin care. Patients with lymphedema who adhered closely with their therapy program were more than 8 times more likely to improve compared with noncompliant patients.¹⁷

Some groups of patients have a greater risk of developing lymphedema than others,⁵ so the development of an algorithm to predict lymphedema seemed possible. However, in our cohort of patients, only neck dissection, with its disruption of the lymphatic system of the neck, was strongly associated with external lymphedema (Table 3). It is important to note that some patients who did not undergo surgery developed lymphedema. In our patients, high doses of radiation alone did not seem to predispose to lymphedema. That suggests that no group of head and neck cancer patients should be ignored, which is why we did routine screening of all patients before, during, and after treatment.

Our protocol falls short in the detection of internal lymphedema. For example, information on swallowing gathered by our speech pathologists (in a different department) has not, so far, been included in our assessment. This is one opportunity to improve on our approach, especially because speech difficulties may be associated with internal lymphedema. In addition, we are not equipped for the requisite internal examinations. Unfortunately, there are no practical and successful treatments for patients suffering from internal swelling. This represents a challenge for the medical community to better meet this need. Therefore, although we are missing some assessments of internal lymphedema, this is of little therapeutic consequence at this time.

The increase in the detected incidence of external lymphedema points to a practice gap that has been resolved by the appointment of a dedicated nurse navigator who attends oncology reviews to share knowledge and information. Another educational effort has been made with the patients themselves to increase compliance and improve continuous care at home.

There is always room for improvement, however, either by feedback acquired from other institutions and hospitals or through the future introduction of more objective assessment techniques.

Conclusions

The introduction of the prehabilitation program at our center has coincided with a significantly improved detection rate for external lymphedema in head and neck cancer patients. It may be because the program emphasizes education about lymphedema that awareness of the condition has increased throughout the center. It is now widely recognized that all patients are at risk of lymphedema regardless of whether they fall into an acknowledged high-risk group. Our experience shows that there is no significant difference between treatment modalities apart from neck dissection. In our population, the use of this procedure is decreasing. External lymphedema can develop even in patients who do not have surgery. Therefore, there is no sound way to predict which patients are most likely to suffer from the accumulation of fluid in their head and neck after treatment for head and neck cancer. Thus, an assessment as described here, during and after treatment for all patients, is warranted. Patients are now being seen earlier as a part of the prehabilitation program, which facilitates access to complete decongestive treatment at an earlier stage, improves patient outcomes, and increases patient satisfaction with their treatment. Our prehabilitation program could serve as a model for other community hospital centers in achieving outcomes that are as good as those in academic centers.

Acknowledgments

The authors thank Irene Kadota and Heather Peters, from the Department of Radiation Oncology, and Julianne Courtenay, from the Department of Physical Therapy at the Disney Family Cancer Center, Burbank, California, for providing the original clinical data for analysis.

Lymphedema is the swelling of tissue caused by the accumulation of interstitial fluid in any area of the body where lymphatic flow has been compromised.¹ Secondary lymphedema is an acquired abnormality in lymph drainage^1,2 and is the type commonly seen in cancer patients. Secondary lymphedema can be described as external or internal. Internal lymphedema, swelling of deep structures and tissues, is very difficult to quantify.

Lymphedema in patients with head and neck cancers
Lymphedema is a complicating morbidity frequently seen in head and neck cancer patients who have undergone treatment with surgery, radiation, and chemotherapy. However, although it is one of the most prevalent side effects of treatment, it is both under-recognized and under-treated.³

In head and neck cancer patients, internal swelling may develop in the soft tissues of the upper aero-digestive tract,⁴ affecting articulation and swallowing. Currently, there does not seem to be an effective practical and reliable tool with which to measure internal lymphedema. In addition, it is generally accepted that there is no effective way to treat internal lymphedema. By contrast, external lymphedema is more readily observed, but both subjective and objective assessments are difficult. External swelling may occur in the face, jaw, and neck. However, the subjective scales currently available are insufficient to capture very important characteristics of external lymphedema.⁵ The Edge Task Force on Head and Neck Cancer in 2015 was not able to recommend any outcome measures for objectively quantifying external edema.⁶ Furthermore, objective measurements of head and neck lymphedema can be expensive and time consuming.

Extent and risk

A combination of both internal and external swelling is seen in more than 50% of patients.⁷ Risk factors include “throat” tumors, multicancer treatment approaches, higher total radiation dose, a greater number of radiation procedures, and radiation at the surgical site.⁵ More than 500,000 survivors of head and neck cancer in the United States are at risk of lymphedema.⁵ Although recent advances in treatment have reduced the incidence of other morbidities, 50% of patients who are treated for head and neck cancer may still develop lymphedema.^1,8 The reported incidence in some centers may be much higher, with up to 75% of patients developing lymphedema following treatment.⁹

Measurement modalities for clinical evaluation

There is little current research into lymphedema of the head and neck, despite the high prevalence of the condition.⁸ According to Deng and colleagues, measurement of head and neck lymphedema is a challenge, which has an impact on clinical assessment, diagnosis, and treatment of this under-recognized, under-reported and under-addressed problem in head and neck cancer patients.¹⁰ In a review of the literature, Deng and colleagues identified three measurement modalities available for clinical evaluation: patient-reported outcomes, clinician-reported outcomes, and technology.¹⁰ One major factor, though, in detecting lymphedema, is physician awareness: physicians, health care professionals, and even some lymphedema therapists are not well educated about this problem.⁸

Treatment

The effectiveness of traditional lymphedema treatment is not well defined.⁸ Currently, complete decongestive therapy (CDT), is considered the standard of care for lymphedema. The National Lymphedema Network has stated that modifications of CDT, especially manual lymphatic drainage and modified compressive garments for external lymphedema, have been shown to be beneficial for the treatment of lymphedema in head and neck cancer patients.¹¹ Most findings in lymphedema research, mainly in breast cancer patients, have shown that early intervention is the best management and yields the best outcomes. As with other chronic conditions, early identification and timely, appropriate treatment of lymphedema is critical to improve clinical outcomes, to decrease symptom burden and functional impairment, and to improve overall quality of life in head and neck cancer patients.¹⁰

Improving recognition and treatment

Head and neck oncologic treatment is increasingly offered outside the network of specialist academic hospitals, at hospitals serving more localized communities where the neediest, sickest patient groups may be receiving less than optimal care.³ This challenges community hospitals to provide optimal treatment, similar to that being offered at nationally recognized institutions. In January 2012, we implemented a prehabilitation program in our community hospital cancer center to provide early intervention for our patients based on the understanding that proper and prompt treatment for patients with early signs of lymphedema should be a priority.¹² In this article, we outline how we implemented the program and the describe improvements we observed before and after the implementation of the program.

The prehabilitation program

The role of the nurse navigator

Before the introduction of the prehabilitation program, our pattern of practice was to refer patients to oncology rehabilitation for lymphedema management after they had completed their medical treatment with surgery, radiation, and chemotherapy. In 2012, that was changed to a prehabilitation model of care that was overseen by a head and neck nurse navigator. This focus on prehabilitation begins with patients being referred to oncology rehabilitation at the time of cancer diagnosis for baseline assessment of head and neck swelling. In addition, there is assessment of the many possible other side effects associated with head and neck cancer and its treatment, namely loss of range of motion of the neck, jaw (trismus), and/or shoulders, postural deficits, functional loss, pain, balance dysfunction with fall risk, weakness, and fatigue. Therapeutic interventions are initiated as needed and appropriate. This process also raises awareness of a condition that has been described as under-recognized and under-treated.³

The nurse navigator sits in on each radiation oncology consultation and aids in “navigating” patients through their treatment. The nurse ensures that each patient is referred to different ancillary services from the outset, such as seeing a dietician, social worker, physical/occupational therapist and certified lymphedema therapist, speech pathologist, and financial assistance advisor, if necessary (Table 1).

Assessment of lymphedema

Measurement of head and neck lymphedema is a challenge.¹⁰ In our program, the physical therapy assessment also includes the evaluation of several other morbidities associated with head and neck cancer and its treatment, such as range of motion, weakness, fatigue, radiation fibrosis, balance dysfunction, and risk of falling (Table 2).

Although objective criteria for external lymphedema have not been established, simple measurements such as using a tape measure to record neck circumference, allow a useful longitudinal assessment. Digital photography may be effective in the documentation and subjective evaluation of changes of external lymphedema.^10,17 However, there are some limitations with photography because although external photographs (including digital photography and three-dimensional imaging) can capture some features, such as changes in contours, symmetry, and changes in skin quality and color, they do not detect changes in skin and soft tissue texture and compliance (Table 3).¹⁰

Impact on clinical outcomes

We retrospectively reviewed the medical records of 230 head and neck cancer patients who had been treated at our center between June 2008 and June 2015. Complete clinical data were available for 190 patients. The following information was extracted from each patient’s chart: whether they developed lymphedema, tumor stage, had surgery, radiation dose, type of chemotherapy given, their smoking history, if they had had a neck dissection and the primary site of the tumor (Table 3).

Incidence in different time periods. Of the 190 patients with complete records 78 (41%) were found to have lymphedema. These were all patients undergoing treatment for head and neck cancer during June 2008-June 2015. The prehabilitation program was initiated with the hiring of a nurse navigator for head and neck cancer, starting in January 2012. It is interesting to note that the incidence of lymphedema was 27% before the program was started, but after nurse navigator joined the team, the incidence increased significantly to 48% (P = .0002), in line with published expectations. This increase in recorded incidence may be attributable to the greater awareness of lymphedema intentionally fostered by the prehabilitation program.

Smoking history. Patients’ lifetime smoking history was retrieved from their medical records, based on their verbal admission of tobacco use. Most of the patients (n = 110) self-reported a history of smoking. Of those with a history of smoking, 36 (33%) developed external lymphedema after treatment for head and neck cancer, and 74 (67%) did not. However, this difference was not statistically significant. Hence, although smoking is a risk factor for head and neck cancer, it was not associated with the development of external lymphedema in our cohort of patients.

Type of tumor

Most of the patients (n = 156, 82%) had squamous cell carcinomas (SCC). Of those, 45% developed external lymphedema and 55% did not. Therefore, having SCC did not predispose to lymphedema. The other cancers were mixed type, mainly adenocaricoma, but their numbers were too small to draw statistical conclusions.

Stage of the tumor

About two thirds of the patients (n = 121, 64%) had stage 3 or 4 cancer. However, treatment of more advanced cancers was not associated with lymphedema development.

Site of the tumor

The literature suggests that patients with a primary tumor in the throat are at increased risk for lymphedema.⁵ The American Cancer Society has defined cancers of the oropharynx (throat) as including the base of the tongue (back third of the tongue), the soft palate, the tonsils, and the side and back walls of the throat.¹⁸ In our head and neck cancer cohort, patients with primary tumors of the oropharnyx were, perhaps, more susceptible to lymphedema (P = .044, Table 3). By contrast, in our cohort of patients, those with nasopharyngeal, hypopharyngeal, and parotid gland tumors were significantly less likely to develop lymphedema (Ps = .017, .04, .012, respectively).

No surgery

Half of our patients (n = 95) were not treated with surgery. In the patients who did not have surgery, 25 (26%) developed lymphedema, whereas 70 (74%) did not. Hence, although the incidence of lymphedema was significantly lower in patients who did not have surgery (P = .015), lymphedema did develop in patients who did not have a surgical procedure.

Resection of primary tumor without neck dissection

Of the 64 patients who had surgery, but without neck dissection, 35 (55%) developed external lymphedema. Compared with the no-surgery patients, the doubling of the incidence (from 26% to 55%) was highly significant (P = .0004). These findings are compatible with the literature reports that surgery increases the incidence of lymphedema, which is not surprising because surgery and subsequent scarring is known to compromise the lymphatic system.

Resection of primary tumor with neck dissection

The incidence of external lymphedema was increased to 69% when patients were subjected to both surgery and neck dissection. Compared with the June 2008-June 2015 cohort, there was a significant increase in the incidence of lymphedema in the neck dissection group (P = .007). Neck dissection involves the removal of lymph nodes and disruption of the lymphatic vessels, so it is not surprising that there is a higher incidence of external lymphedema. In our practice, neck dissections increased in frequency every year from June 2008 until December 2011, when 8 patients underwent neck dissections, 6 (75%) of whom developed lymphedema. Since January 2012, when the prehabilitation program was implemented, the number of neck dissections have declined, with more patients receiving chemoradiation and surgery being reserved for surgery. Hamoir and colleagues have reported that neck dissection is no longer justified unless there is clinically residual disease in the neck.¹⁹

Radiation

Lymphedema occurred in patients regardless of the dose of radiation received. Although the incidence of lymphedema seemed to be higher in patients who received more than 60 cGy, that difference was not statistically significant (Table 3). We had expected a relationship between radiation damage and greater lymphedema, but that was not evident in our patients.

Chemotherapy

The majority of patients (n = 131, 69%) received chemotherapy. The exposure to chemotherapy was not correlated with the risk of external lymphedema in our cohort of patients, with 58 of the 131 treated patients (44%) developing lymphedema, compared with 73 (56%) of treated patients who did not (Table 3).

Complete decongestive therapy

All patients with documented lymphedema were evaluated for complete decongestive therapy (CDT). Contraindications to CDT included congestive heart failure, renal failure, acute infection, peripheral artery disease, upper-quadrant deep vein thrombosis, and carotid artery stenosis. Eligible patients were referred to a certified lymphedema therapist for CDT. As the program evolved, patients at risk for lymphedema were referred for CDT early on, usually at the time of diagnosis, to improve early identification and surveillance of lymphedema.

CDT included manual lymph drainage, compression bandaging (Figure), decongestive exercises, skin care, and education in swelling self-management. Manual lymph drainage is a specialized light pressure hands-on technique that reduces swelling by enhancing lymphatic reabsorption and flow. Compressive bandaging/garments increase venous and lymphatic drainage and soften fibrotic tissue. Continued use of compression depends on progress. In head and neck cancer patients, the need for lifelong compression is not evident when they are treated early and there is good patient compliance.⁸ Therapeutic exercise enhances lymphatic and venous circulation, and good skin care reduces the risk of infection.

Communication and education

The head and neck cancer nurse navigator attends the cancer center’s multidisciplinary head and neck tumor board, which has representation from otolaryngology, diagnostic radiology, pathology, radiation oncology, medical oncology, reconstructive surgery, oncology rehabilitation (physical/occupational therapist), dietary services, speech pathology, social services and clinical research. This regular contact allows for earlier awareness about which patients are at greater risk for developing lymphedema, thus enabling early intervention (and patient education) in a timely manner.

Education of the patient, before cancer therapy, of the risks of lymphedema is very important. Before the implementation of the prehabilitation program, some patients did not fully comprehend what a painful and debilitating consequence of cancer treatment lymphedema could be.

Discussion

We introduced a prehabilitation program to detect and treat lymphedema in head and neck cancer patients in January 2012 part way through following an observation cohort from June2008 through June2015. Central to this, in our center, was the appointment of a nurse navigator whose primary focus was on head and neck cancer patients. We placed a high priority on the early detection and treatment of lymphedema because do so has been associated with better outcomes in other centers.

One immediate consequence of the inception of our program was the identification of more patients with external lymphedema. Our detected incidence rose significantly (P = .0002), from 27% in the period June 2008-December 20112010, before the program, to 48% during the January 2012-June 2015 period, after the inception of the program. This later incidence rate is in line with published incidence rates in most centers. However, it is still somewhat short of the 75% suggested in one center,⁹ which suggests we are either we are underdetecting lymphedema or there are differences in definition criteria or sensitivity levels for defining lymphedema.

There are currently no specific objective measures of lymphedema, so there is bound to be some variation in diagnosis rates. In our program, we rely heavily on the patient-reported outcome measures, the NDI instrument, and digital photography to detect and monitor lymphedema, starting with the pretreatment baseline values that are established for each patient.

The use of digital photography in our community hospital setting, which includes taking photographs before and after treatment and at each visit, motivates and encourages patients and provides a tool for clinical lymphedema therapists to visually document benefits of treatment. Patients’ motivation and compliance with their established home program for head and neck lymphedema self-management are essential. The elements of the home program may include self-manual lymph drainage, home-modified compression bandaging and garment wear, therapeutic exercises, and skin care. Patients with lymphedema who adhered closely with their therapy program were more than 8 times more likely to improve compared with noncompliant patients.¹⁷

Some groups of patients have a greater risk of developing lymphedema than others,⁵ so the development of an algorithm to predict lymphedema seemed possible. However, in our cohort of patients, only neck dissection, with its disruption of the lymphatic system of the neck, was strongly associated with external lymphedema (Table 3). It is important to note that some patients who did not undergo surgery developed lymphedema. In our patients, high doses of radiation alone did not seem to predispose to lymphedema. That suggests that no group of head and neck cancer patients should be ignored, which is why we did routine screening of all patients before, during, and after treatment.

Our protocol falls short in the detection of internal lymphedema. For example, information on swallowing gathered by our speech pathologists (in a different department) has not, so far, been included in our assessment. This is one opportunity to improve on our approach, especially because speech difficulties may be associated with internal lymphedema. In addition, we are not equipped for the requisite internal examinations. Unfortunately, there are no practical and successful treatments for patients suffering from internal swelling. This represents a challenge for the medical community to better meet this need. Therefore, although we are missing some assessments of internal lymphedema, this is of little therapeutic consequence at this time.

The increase in the detected incidence of external lymphedema points to a practice gap that has been resolved by the appointment of a dedicated nurse navigator who attends oncology reviews to share knowledge and information. Another educational effort has been made with the patients themselves to increase compliance and improve continuous care at home.

There is always room for improvement, however, either by feedback acquired from other institutions and hospitals or through the future introduction of more objective assessment techniques.

Conclusions

The introduction of the prehabilitation program at our center has coincided with a significantly improved detection rate for external lymphedema in head and neck cancer patients. It may be because the program emphasizes education about lymphedema that awareness of the condition has increased throughout the center. It is now widely recognized that all patients are at risk of lymphedema regardless of whether they fall into an acknowledged high-risk group. Our experience shows that there is no significant difference between treatment modalities apart from neck dissection. In our population, the use of this procedure is decreasing. External lymphedema can develop even in patients who do not have surgery. Therefore, there is no sound way to predict which patients are most likely to suffer from the accumulation of fluid in their head and neck after treatment for head and neck cancer. Thus, an assessment as described here, during and after treatment for all patients, is warranted. Patients are now being seen earlier as a part of the prehabilitation program, which facilitates access to complete decongestive treatment at an earlier stage, improves patient outcomes, and increases patient satisfaction with their treatment. Our prehabilitation program could serve as a model for other community hospital centers in achieving outcomes that are as good as those in academic centers.

Acknowledgments

The authors thank Irene Kadota and Heather Peters, from the Department of Radiation Oncology, and Julianne Courtenay, from the Department of Physical Therapy at the Disney Family Cancer Center, Burbank, California, for providing the original clinical data for analysis.

DR CARVER [JC]

A typical example is a patient who had Hodgkin disease in his teens and received mediastinal mantle radiation. Fifteen to 25 years later, the patient has a pacemaker for heart block, coronary artery disease that requires a stent, and most recently has two valves replaced—so aortic and mitral valve replacement because of late radiation effects. This scenario is typical for the “old” days. The 20-year cumulative incidence of radiation-induced cardiac toxicity is 15%-20% (Table, Figure).¹ Sitting with a patient about to begin chest radiation, the absolute risks are unknown but presumed to be less as treatment is delivered according to the modern techniques that you described in the question.

DH They’re so much better now, so this is less common.
JC With the shielding and breath-holding techniques and position changes, doing upright radiation rather than supine, and because the technology has improved both in the delivery of radiation and the technology in understanding where all the radiation is going, in today’s world, we can calculate pretty precisely how much radiation the heart actually receives. Ultimately, with the protective mechanisms that are in place going forward, the risks that I described for that survivor are probably exponentially less than what’s reported in the literature and what we see clinically. Radiation has become much, much safer. There is still probably some small risk of development of late changes, but I don’t think we know what that risk is today because the shielding and things we do to protect the heart have not yet been studied in the long term.

DH Of course, the patient is breathing and there’ll be some movement of the target. Some of the radiation techniques can follow the target despite the breathing?
JC Yes, definitely true. Radiation delivery is much more precise today. Not only has the delivery changed, but so has what we know about the location of potential arterial disease. For example, if you read any textbook, it says that for the coronaries, that it’s ostial and proximal disease of the left main, or the left anterior descending, or the right coronary artery. Today, somebody who gets chest/mediastinal radiation, for either breast cancer, lymphoma, or for a mediastinal tumor, the location of potential disease is more likely to mimic the location of classic coronary disease in the mid-portion of the left anterior descending artery rather than at the ostium. It’s going to be a different disease going forward.^2,3

With administration of the anthracyclines, we try to do whatever protective things we can do. There are some people who believe that continuous infusion is safer for the heart than bolus injection. It’s pretty controversial. Dexrazoxane, which is a chelating agent, has been shown to reduce cardiotoxicity, and using a lipophilic anthracycline preparation may also have less cardiac toxicity.

DH I have a population in which a lot of liposomal doxorubicin is used and I’ve given a lot and rarely if ever get cardiac toxicity. You see that as well?
JC Yes. There’s a significant financial difference between doxorubicin and liposomal doxorubicin; the latter is more expensive. From the standpoint of safety, and from the standpoint of if I ever needed doxorubicin, I would probably jump on that and ask for the liposomal preparation and/or dexrazoxane.

DH For trastuzumab, we are getting echo- cardiograms every 9 weeks. That seems awfully simple, but there’s a whole algorithm we follow for particular change in ejection fraction and watch the drug or stop the drug. Are we doing that correctly?
JC The first statement I would make about that is that there are too many women who need trastuzumab whose therapy has been prematurely stopped because of just looking at the ejection fractions. So, there has to be more to decision-making other than just the number of the ejection fraction. We’re pretty aggressive and tend to try to get women to get the full dose and whatever dose-effective dose they need, especially with curative intent in the adjuvant setting that we make decisions based not only on the ejection fraction.

We also have, I would say, a handful of our medical breast oncologists who do not follow the package insert. We don’t get ejection fractions every 3 cycles. We have substituted a little bit by following biomarkers so that we use N-terminal pro b-type natriuretic peptide (NT-proBNP) to monitor people, either with each cycle or every third cycle. The benefit of BNP is its negative predictive value. If it’s normal, it’s hard to have any clinically significant myocardial dysfunction.

What we’re going to see over – I would hope – the next year or two is that the recommendations about getting echocardiograms frequently will go away.
 

DH That would be welcome because in our electronic medical records, it’s 9 weeks, stop, do this, etc. How about a comment on infusional 5-FU and possibly its cousins, such as capecitabine, and any coronary issues?
JC Let me come back, just one more thing about trastuzumab. For metastatic disease, we do whatever is necessary to continue effective cancer therapy and in the absence of any cardiac symptoms or abnormal physical findings, we continue cancer treatment without any serial echocardiographic monitoring.

DH You think the NT-proBNP might be useful? I know that’s excreted by the kidneys, so that might rise in renal failure, but we can adjust for that.
JC The negative predictive value of having a normal BNP is helpful. I think what I wanted to say was that screening echocardiograms and looking at ejection fraction in low-risk populations probably is clearly not cost-effective. It probably never alters decision making. If you have a 30-year-old person with no cardiac risk factors and no past cardiac history who develops B-cell lymphoma and is going to get anthracycline-based chemotherapy, the likelihood of finding a reason not to give that therapy based on an echocardiogram is quite small. I would even go further and say close to zero. We’ve begun to look at this. There is literature that supports the concept. Also, that in low-risk people – if you can define the low-risk population in an accurate way – for lymphoma patients or women with breast cancer getting either anthracyclines, trastuzumab, or the other human epidermal growth factor receptor-2 (HER2)-directed therapies, there’s probably little yield to even getting a baseline study.

DH Very interesting. I would agree with you.
JC We’re going to talk about 5-FU, of course. The 5-FU thing has become a passion of mine. Over the last two to two-and-a- half years we have gotten very aggressive with treating coronary spasm that’s induced by the fluoropyrimidines. That’s 5-FU and capecitabine, the oral version.

There is an incidence that the literature says is less than 1%. It probably is somewhere between 3% and 5%. It’s a little bit more common than has been reported. The reason is the way that it presents has classically been described in the literature as different than what occurs in real life. It is a phenomenon. It’s the most common cardiac side effect. Sometimes it is large epicardial coronary artery spasm. Sometimes it’s small vessel spasm. You can have chest pain with no electrocardiographic changes or ECG changes without chest pain (so-called silent ischemia). The description doesn’t always sound like classic angina but symptoms are temporally related to getting the drug.

So, we’ve developed a protocol to treat documented spasm as an outpatient to be able to continue those drugs to their logical conclusion from an oncologic standpoint. In fact, we just submitted a manuscript to the American Journal of Cardiology describing our experience and the algorithm of how we treat people. We’re uniquely aggressive in re-challenging patients who’ve had spasm.
 

DH Finally, it occurred to me that we cause problems with radiation. We cause problems with chemotherapy and other infusions. Are there particular cancers that you think of or you’re called in to see that you worry about cardiac involvement by their location? What comes to mind are cases I’ve had in which there is pericardial involvement and tamponade or restrictive pericarditis.
JC We see metastatic disease to the pericardium with breast cancer, lung cancer, and lymphoma. Renal cell has an interesting predilection to go to the pericardium. We’ve seen in the last probably 6 months 2 cases of bladder cancer with pericardial metastases. When we reviewed the literature, we were only able to find 9 or 10 case reports. It’s rare, but it occurs.

Fluid in the pericardium with and without tamponade is increasingly common, and because we do a better job in treating complicated cancer, people successively can receive cycles of sequential chemotherapeutic regimens – they are living longer, their cancer can get more complicated and/or resistant and with it, there’s more time for metastatic disease to occur. Tamponade is a common phenomenon. We always say that at 4 o’clock on Friday we always see somebody who has tamponade. We see a lot of pericardial disease.

Then, another area of a concern is the tyrosine kinase inhibitors that can cause hypertension, which is very common. We’ve become pretty aggressive. The oncologists recognize the importance of being able to follow and treat blood pressures to allow patients to get these treatments. I guess we couldn’t end without talking about checkpoint inhibitors and the recent lay press flurry about reporting myocarditis.
 

DH I haven’t personally experienced that. How common is that, and how do we watch for it?
JC Personally, I’ve seen probably four or five people who were referred because of heart failure on checkpoint inhibitors. For each of them, there was historically something as a preexisting problem before the checkpoint inhibitor. It was coincident that with either fluid changes or blood pressure changes associated with the treatment that they had a flare-up of heart failure.

We have not seen, fortunately, the dynamics that were reported in the New England Journal of Medicine of three people with just rampant failure, incessant ventricular arrhythmias, and death.⁵ There’s probably some signal that may act as a cofactor. We’ve actually joined in a registry with Vanderbilt University in Nashville to try to understand this a little bit better.
 

DH Well, certainly with the proliferation of the checkpoint inhibitors, and so many different tumors, and so much widespread use, it looks like there is a small safety signal there but still yet to be defined. How common is that, and what should we watch for?
JC Actually, it’s serendipitous that yesterday I was walking to the parking lot with one of the nurse practitioners who takes care of the melanoma population. She said to me, “Now, do you think that we should be getting BNP levels on everybody who is getting a checkpoint inhibitor?”

I don’t think that we’re there. Just the awareness to ask the right questions when you see a patient and before starting ask, is this somebody who, in the absence of a checkpoint inhibitor, could be at risk for myocardial disease? Recognize that and use the cardiology and oncology community to work together and try to make sure that you do whatever cardioprotective things you can do and to monitor them a little bit more closely. I’m not sure that everybody who is going to start a checkpoint inhibitor needs a cardiac evaluation, doesn’t need an echocardiogram, and doesn’t need baseline biomarkers to decide if there’s a potential cardiotoxicity problem.
 

DH Well certainly, you’ve raised my awareness. It was not something that I had been thinking of with checkpoint inhibitors. Now, I certainly would if the patient has some comorbid illness that involves the heart, maybe think about it, wait to see how these reports develop, and what you and the registry do.
JC You’ve seen people who get this sort of immunologic reaction that they require steroids for fluid accumulation, rash, or other things that are in this constellation. I wouldn’t be surprised if that group might have some subclinical myocarditis that just gets better when they get treated for the other things.

We have actually been trying to get a quick look at the left ventricle when patients on checkpoint inhibitors present with systemic, noncardiac symptoms to see if there is a cardiac signal we are missing. We have a handheld portable echocardiogram device called a Vscan (General Electric Company, Fairfield, CT). It’s not much bigger than the larger cellphones that are available. We’ve been going to the bedside when people have the reaction and sticking the transducer on to get a feeling of what the ventricle looks like. There’s a lot that we don’t know. It’s a fertile ground for investigation.

DH Well, I couldn’t ask you to end on a higher note than covering the checkpoint inhibitors, which are so popular and so interesting and used everywhere. We’re still managing that whole concept. I want to thank you very much.
JC It was a great pleasure. Thank you.

DR CARVER [JC]

A typical example is a patient who had Hodgkin disease in his teens and received mediastinal mantle radiation. Fifteen to 25 years later, the patient has a pacemaker for heart block, coronary artery disease that requires a stent, and most recently has two valves replaced—so aortic and mitral valve replacement because of late radiation effects. This scenario is typical for the “old” days. The 20-year cumulative incidence of radiation-induced cardiac toxicity is 15%-20% (Table, Figure).¹ Sitting with a patient about to begin chest radiation, the absolute risks are unknown but presumed to be less as treatment is delivered according to the modern techniques that you described in the question.

DH They’re so much better now, so this is less common.
JC With the shielding and breath-holding techniques and position changes, doing upright radiation rather than supine, and because the technology has improved both in the delivery of radiation and the technology in understanding where all the radiation is going, in today’s world, we can calculate pretty precisely how much radiation the heart actually receives. Ultimately, with the protective mechanisms that are in place going forward, the risks that I described for that survivor are probably exponentially less than what’s reported in the literature and what we see clinically. Radiation has become much, much safer. There is still probably some small risk of development of late changes, but I don’t think we know what that risk is today because the shielding and things we do to protect the heart have not yet been studied in the long term.

DH Of course, the patient is breathing and there’ll be some movement of the target. Some of the radiation techniques can follow the target despite the breathing?
JC Yes, definitely true. Radiation delivery is much more precise today. Not only has the delivery changed, but so has what we know about the location of potential arterial disease. For example, if you read any textbook, it says that for the coronaries, that it’s ostial and proximal disease of the left main, or the left anterior descending, or the right coronary artery. Today, somebody who gets chest/mediastinal radiation, for either breast cancer, lymphoma, or for a mediastinal tumor, the location of potential disease is more likely to mimic the location of classic coronary disease in the mid-portion of the left anterior descending artery rather than at the ostium. It’s going to be a different disease going forward.^2,3

With administration of the anthracyclines, we try to do whatever protective things we can do. There are some people who believe that continuous infusion is safer for the heart than bolus injection. It’s pretty controversial. Dexrazoxane, which is a chelating agent, has been shown to reduce cardiotoxicity, and using a lipophilic anthracycline preparation may also have less cardiac toxicity.

DH I have a population in which a lot of liposomal doxorubicin is used and I’ve given a lot and rarely if ever get cardiac toxicity. You see that as well?
JC Yes. There’s a significant financial difference between doxorubicin and liposomal doxorubicin; the latter is more expensive. From the standpoint of safety, and from the standpoint of if I ever needed doxorubicin, I would probably jump on that and ask for the liposomal preparation and/or dexrazoxane.

DH For trastuzumab, we are getting echo- cardiograms every 9 weeks. That seems awfully simple, but there’s a whole algorithm we follow for particular change in ejection fraction and watch the drug or stop the drug. Are we doing that correctly?
JC The first statement I would make about that is that there are too many women who need trastuzumab whose therapy has been prematurely stopped because of just looking at the ejection fractions. So, there has to be more to decision-making other than just the number of the ejection fraction. We’re pretty aggressive and tend to try to get women to get the full dose and whatever dose-effective dose they need, especially with curative intent in the adjuvant setting that we make decisions based not only on the ejection fraction.

We also have, I would say, a handful of our medical breast oncologists who do not follow the package insert. We don’t get ejection fractions every 3 cycles. We have substituted a little bit by following biomarkers so that we use N-terminal pro b-type natriuretic peptide (NT-proBNP) to monitor people, either with each cycle or every third cycle. The benefit of BNP is its negative predictive value. If it’s normal, it’s hard to have any clinically significant myocardial dysfunction.

What we’re going to see over – I would hope – the next year or two is that the recommendations about getting echocardiograms frequently will go away.
 

DH That would be welcome because in our electronic medical records, it’s 9 weeks, stop, do this, etc. How about a comment on infusional 5-FU and possibly its cousins, such as capecitabine, and any coronary issues?
JC Let me come back, just one more thing about trastuzumab. For metastatic disease, we do whatever is necessary to continue effective cancer therapy and in the absence of any cardiac symptoms or abnormal physical findings, we continue cancer treatment without any serial echocardiographic monitoring.

DH You think the NT-proBNP might be useful? I know that’s excreted by the kidneys, so that might rise in renal failure, but we can adjust for that.
JC The negative predictive value of having a normal BNP is helpful. I think what I wanted to say was that screening echocardiograms and looking at ejection fraction in low-risk populations probably is clearly not cost-effective. It probably never alters decision making. If you have a 30-year-old person with no cardiac risk factors and no past cardiac history who develops B-cell lymphoma and is going to get anthracycline-based chemotherapy, the likelihood of finding a reason not to give that therapy based on an echocardiogram is quite small. I would even go further and say close to zero. We’ve begun to look at this. There is literature that supports the concept. Also, that in low-risk people – if you can define the low-risk population in an accurate way – for lymphoma patients or women with breast cancer getting either anthracyclines, trastuzumab, or the other human epidermal growth factor receptor-2 (HER2)-directed therapies, there’s probably little yield to even getting a baseline study.

DH Very interesting. I would agree with you.
JC We’re going to talk about 5-FU, of course. The 5-FU thing has become a passion of mine. Over the last two to two-and-a- half years we have gotten very aggressive with treating coronary spasm that’s induced by the fluoropyrimidines. That’s 5-FU and capecitabine, the oral version.

There is an incidence that the literature says is less than 1%. It probably is somewhere between 3% and 5%. It’s a little bit more common than has been reported. The reason is the way that it presents has classically been described in the literature as different than what occurs in real life. It is a phenomenon. It’s the most common cardiac side effect. Sometimes it is large epicardial coronary artery spasm. Sometimes it’s small vessel spasm. You can have chest pain with no electrocardiographic changes or ECG changes without chest pain (so-called silent ischemia). The description doesn’t always sound like classic angina but symptoms are temporally related to getting the drug.

So, we’ve developed a protocol to treat documented spasm as an outpatient to be able to continue those drugs to their logical conclusion from an oncologic standpoint. In fact, we just submitted a manuscript to the American Journal of Cardiology describing our experience and the algorithm of how we treat people. We’re uniquely aggressive in re-challenging patients who’ve had spasm.
 

DH Finally, it occurred to me that we cause problems with radiation. We cause problems with chemotherapy and other infusions. Are there particular cancers that you think of or you’re called in to see that you worry about cardiac involvement by their location? What comes to mind are cases I’ve had in which there is pericardial involvement and tamponade or restrictive pericarditis.
JC We see metastatic disease to the pericardium with breast cancer, lung cancer, and lymphoma. Renal cell has an interesting predilection to go to the pericardium. We’ve seen in the last probably 6 months 2 cases of bladder cancer with pericardial metastases. When we reviewed the literature, we were only able to find 9 or 10 case reports. It’s rare, but it occurs.

Fluid in the pericardium with and without tamponade is increasingly common, and because we do a better job in treating complicated cancer, people successively can receive cycles of sequential chemotherapeutic regimens – they are living longer, their cancer can get more complicated and/or resistant and with it, there’s more time for metastatic disease to occur. Tamponade is a common phenomenon. We always say that at 4 o’clock on Friday we always see somebody who has tamponade. We see a lot of pericardial disease.

Then, another area of a concern is the tyrosine kinase inhibitors that can cause hypertension, which is very common. We’ve become pretty aggressive. The oncologists recognize the importance of being able to follow and treat blood pressures to allow patients to get these treatments. I guess we couldn’t end without talking about checkpoint inhibitors and the recent lay press flurry about reporting myocarditis.
 

DH I haven’t personally experienced that. How common is that, and how do we watch for it?
JC Personally, I’ve seen probably four or five people who were referred because of heart failure on checkpoint inhibitors. For each of them, there was historically something as a preexisting problem before the checkpoint inhibitor. It was coincident that with either fluid changes or blood pressure changes associated with the treatment that they had a flare-up of heart failure.

We have not seen, fortunately, the dynamics that were reported in the New England Journal of Medicine of three people with just rampant failure, incessant ventricular arrhythmias, and death.⁵ There’s probably some signal that may act as a cofactor. We’ve actually joined in a registry with Vanderbilt University in Nashville to try to understand this a little bit better.
 

DH Well, certainly with the proliferation of the checkpoint inhibitors, and so many different tumors, and so much widespread use, it looks like there is a small safety signal there but still yet to be defined. How common is that, and what should we watch for?
JC Actually, it’s serendipitous that yesterday I was walking to the parking lot with one of the nurse practitioners who takes care of the melanoma population. She said to me, “Now, do you think that we should be getting BNP levels on everybody who is getting a checkpoint inhibitor?”

I don’t think that we’re there. Just the awareness to ask the right questions when you see a patient and before starting ask, is this somebody who, in the absence of a checkpoint inhibitor, could be at risk for myocardial disease? Recognize that and use the cardiology and oncology community to work together and try to make sure that you do whatever cardioprotective things you can do and to monitor them a little bit more closely. I’m not sure that everybody who is going to start a checkpoint inhibitor needs a cardiac evaluation, doesn’t need an echocardiogram, and doesn’t need baseline biomarkers to decide if there’s a potential cardiotoxicity problem.
 

DH Well certainly, you’ve raised my awareness. It was not something that I had been thinking of with checkpoint inhibitors. Now, I certainly would if the patient has some comorbid illness that involves the heart, maybe think about it, wait to see how these reports develop, and what you and the registry do.
JC You’ve seen people who get this sort of immunologic reaction that they require steroids for fluid accumulation, rash, or other things that are in this constellation. I wouldn’t be surprised if that group might have some subclinical myocarditis that just gets better when they get treated for the other things.

We have actually been trying to get a quick look at the left ventricle when patients on checkpoint inhibitors present with systemic, noncardiac symptoms to see if there is a cardiac signal we are missing. We have a handheld portable echocardiogram device called a Vscan (General Electric Company, Fairfield, CT). It’s not much bigger than the larger cellphones that are available. We’ve been going to the bedside when people have the reaction and sticking the transducer on to get a feeling of what the ventricle looks like. There’s a lot that we don’t know. It’s a fertile ground for investigation.

DH Well, I couldn’t ask you to end on a higher note than covering the checkpoint inhibitors, which are so popular and so interesting and used everywhere. We’re still managing that whole concept. I want to thank you very much.
JC It was a great pleasure. Thank you.

DR CARVER [JC]

A typical example is a patient who had Hodgkin disease in his teens and received mediastinal mantle radiation. Fifteen to 25 years later, the patient has a pacemaker for heart block, coronary artery disease that requires a stent, and most recently has two valves replaced—so aortic and mitral valve replacement because of late radiation effects. This scenario is typical for the “old” days. The 20-year cumulative incidence of radiation-induced cardiac toxicity is 15%-20% (Table, Figure).¹ Sitting with a patient about to begin chest radiation, the absolute risks are unknown but presumed to be less as treatment is delivered according to the modern techniques that you described in the question.

DH They’re so much better now, so this is less common.
JC With the shielding and breath-holding techniques and position changes, doing upright radiation rather than supine, and because the technology has improved both in the delivery of radiation and the technology in understanding where all the radiation is going, in today’s world, we can calculate pretty precisely how much radiation the heart actually receives. Ultimately, with the protective mechanisms that are in place going forward, the risks that I described for that survivor are probably exponentially less than what’s reported in the literature and what we see clinically. Radiation has become much, much safer. There is still probably some small risk of development of late changes, but I don’t think we know what that risk is today because the shielding and things we do to protect the heart have not yet been studied in the long term.

DH Of course, the patient is breathing and there’ll be some movement of the target. Some of the radiation techniques can follow the target despite the breathing?
JC Yes, definitely true. Radiation delivery is much more precise today. Not only has the delivery changed, but so has what we know about the location of potential arterial disease. For example, if you read any textbook, it says that for the coronaries, that it’s ostial and proximal disease of the left main, or the left anterior descending, or the right coronary artery. Today, somebody who gets chest/mediastinal radiation, for either breast cancer, lymphoma, or for a mediastinal tumor, the location of potential disease is more likely to mimic the location of classic coronary disease in the mid-portion of the left anterior descending artery rather than at the ostium. It’s going to be a different disease going forward.^2,3

With administration of the anthracyclines, we try to do whatever protective things we can do. There are some people who believe that continuous infusion is safer for the heart than bolus injection. It’s pretty controversial. Dexrazoxane, which is a chelating agent, has been shown to reduce cardiotoxicity, and using a lipophilic anthracycline preparation may also have less cardiac toxicity.

DH I have a population in which a lot of liposomal doxorubicin is used and I’ve given a lot and rarely if ever get cardiac toxicity. You see that as well?
JC Yes. There’s a significant financial difference between doxorubicin and liposomal doxorubicin; the latter is more expensive. From the standpoint of safety, and from the standpoint of if I ever needed doxorubicin, I would probably jump on that and ask for the liposomal preparation and/or dexrazoxane.

DH For trastuzumab, we are getting echo- cardiograms every 9 weeks. That seems awfully simple, but there’s a whole algorithm we follow for particular change in ejection fraction and watch the drug or stop the drug. Are we doing that correctly?
JC The first statement I would make about that is that there are too many women who need trastuzumab whose therapy has been prematurely stopped because of just looking at the ejection fractions. So, there has to be more to decision-making other than just the number of the ejection fraction. We’re pretty aggressive and tend to try to get women to get the full dose and whatever dose-effective dose they need, especially with curative intent in the adjuvant setting that we make decisions based not only on the ejection fraction.

We also have, I would say, a handful of our medical breast oncologists who do not follow the package insert. We don’t get ejection fractions every 3 cycles. We have substituted a little bit by following biomarkers so that we use N-terminal pro b-type natriuretic peptide (NT-proBNP) to monitor people, either with each cycle or every third cycle. The benefit of BNP is its negative predictive value. If it’s normal, it’s hard to have any clinically significant myocardial dysfunction.

What we’re going to see over – I would hope – the next year or two is that the recommendations about getting echocardiograms frequently will go away.
 

DH That would be welcome because in our electronic medical records, it’s 9 weeks, stop, do this, etc. How about a comment on infusional 5-FU and possibly its cousins, such as capecitabine, and any coronary issues?
JC Let me come back, just one more thing about trastuzumab. For metastatic disease, we do whatever is necessary to continue effective cancer therapy and in the absence of any cardiac symptoms or abnormal physical findings, we continue cancer treatment without any serial echocardiographic monitoring.

DH You think the NT-proBNP might be useful? I know that’s excreted by the kidneys, so that might rise in renal failure, but we can adjust for that.
JC The negative predictive value of having a normal BNP is helpful. I think what I wanted to say was that screening echocardiograms and looking at ejection fraction in low-risk populations probably is clearly not cost-effective. It probably never alters decision making. If you have a 30-year-old person with no cardiac risk factors and no past cardiac history who develops B-cell lymphoma and is going to get anthracycline-based chemotherapy, the likelihood of finding a reason not to give that therapy based on an echocardiogram is quite small. I would even go further and say close to zero. We’ve begun to look at this. There is literature that supports the concept. Also, that in low-risk people – if you can define the low-risk population in an accurate way – for lymphoma patients or women with breast cancer getting either anthracyclines, trastuzumab, or the other human epidermal growth factor receptor-2 (HER2)-directed therapies, there’s probably little yield to even getting a baseline study.

DH Very interesting. I would agree with you.
JC We’re going to talk about 5-FU, of course. The 5-FU thing has become a passion of mine. Over the last two to two-and-a- half years we have gotten very aggressive with treating coronary spasm that’s induced by the fluoropyrimidines. That’s 5-FU and capecitabine, the oral version.

There is an incidence that the literature says is less than 1%. It probably is somewhere between 3% and 5%. It’s a little bit more common than has been reported. The reason is the way that it presents has classically been described in the literature as different than what occurs in real life. It is a phenomenon. It’s the most common cardiac side effect. Sometimes it is large epicardial coronary artery spasm. Sometimes it’s small vessel spasm. You can have chest pain with no electrocardiographic changes or ECG changes without chest pain (so-called silent ischemia). The description doesn’t always sound like classic angina but symptoms are temporally related to getting the drug.

So, we’ve developed a protocol to treat documented spasm as an outpatient to be able to continue those drugs to their logical conclusion from an oncologic standpoint. In fact, we just submitted a manuscript to the American Journal of Cardiology describing our experience and the algorithm of how we treat people. We’re uniquely aggressive in re-challenging patients who’ve had spasm.
 

DH Finally, it occurred to me that we cause problems with radiation. We cause problems with chemotherapy and other infusions. Are there particular cancers that you think of or you’re called in to see that you worry about cardiac involvement by their location? What comes to mind are cases I’ve had in which there is pericardial involvement and tamponade or restrictive pericarditis.
JC We see metastatic disease to the pericardium with breast cancer, lung cancer, and lymphoma. Renal cell has an interesting predilection to go to the pericardium. We’ve seen in the last probably 6 months 2 cases of bladder cancer with pericardial metastases. When we reviewed the literature, we were only able to find 9 or 10 case reports. It’s rare, but it occurs.

Fluid in the pericardium with and without tamponade is increasingly common, and because we do a better job in treating complicated cancer, people successively can receive cycles of sequential chemotherapeutic regimens – they are living longer, their cancer can get more complicated and/or resistant and with it, there’s more time for metastatic disease to occur. Tamponade is a common phenomenon. We always say that at 4 o’clock on Friday we always see somebody who has tamponade. We see a lot of pericardial disease.

Then, another area of a concern is the tyrosine kinase inhibitors that can cause hypertension, which is very common. We’ve become pretty aggressive. The oncologists recognize the importance of being able to follow and treat blood pressures to allow patients to get these treatments. I guess we couldn’t end without talking about checkpoint inhibitors and the recent lay press flurry about reporting myocarditis.
 

DH I haven’t personally experienced that. How common is that, and how do we watch for it?
JC Personally, I’ve seen probably four or five people who were referred because of heart failure on checkpoint inhibitors. For each of them, there was historically something as a preexisting problem before the checkpoint inhibitor. It was coincident that with either fluid changes or blood pressure changes associated with the treatment that they had a flare-up of heart failure.

We have not seen, fortunately, the dynamics that were reported in the New England Journal of Medicine of three people with just rampant failure, incessant ventricular arrhythmias, and death.⁵ There’s probably some signal that may act as a cofactor. We’ve actually joined in a registry with Vanderbilt University in Nashville to try to understand this a little bit better.
 

DH Well, certainly with the proliferation of the checkpoint inhibitors, and so many different tumors, and so much widespread use, it looks like there is a small safety signal there but still yet to be defined. How common is that, and what should we watch for?
JC Actually, it’s serendipitous that yesterday I was walking to the parking lot with one of the nurse practitioners who takes care of the melanoma population. She said to me, “Now, do you think that we should be getting BNP levels on everybody who is getting a checkpoint inhibitor?”

I don’t think that we’re there. Just the awareness to ask the right questions when you see a patient and before starting ask, is this somebody who, in the absence of a checkpoint inhibitor, could be at risk for myocardial disease? Recognize that and use the cardiology and oncology community to work together and try to make sure that you do whatever cardioprotective things you can do and to monitor them a little bit more closely. I’m not sure that everybody who is going to start a checkpoint inhibitor needs a cardiac evaluation, doesn’t need an echocardiogram, and doesn’t need baseline biomarkers to decide if there’s a potential cardiotoxicity problem.
 

DH Well certainly, you’ve raised my awareness. It was not something that I had been thinking of with checkpoint inhibitors. Now, I certainly would if the patient has some comorbid illness that involves the heart, maybe think about it, wait to see how these reports develop, and what you and the registry do.
JC You’ve seen people who get this sort of immunologic reaction that they require steroids for fluid accumulation, rash, or other things that are in this constellation. I wouldn’t be surprised if that group might have some subclinical myocarditis that just gets better when they get treated for the other things.

We have actually been trying to get a quick look at the left ventricle when patients on checkpoint inhibitors present with systemic, noncardiac symptoms to see if there is a cardiac signal we are missing. We have a handheld portable echocardiogram device called a Vscan (General Electric Company, Fairfield, CT). It’s not much bigger than the larger cellphones that are available. We’ve been going to the bedside when people have the reaction and sticking the transducer on to get a feeling of what the ventricle looks like. There’s a lot that we don’t know. It’s a fertile ground for investigation.

DH Well, I couldn’t ask you to end on a higher note than covering the checkpoint inhibitors, which are so popular and so interesting and used everywhere. We’re still managing that whole concept. I want to thank you very much.
JC It was a great pleasure. Thank you.

After cancer treatment, a new challenge emerges as patients negotiate reentry into their everyday lives. These patients often need multifaceted, simultaneous, and ongoing help with physical, emotional, and psychological issues. And they’re often dealing with a multiplicity of health care providers.

Researchers from University of Zurich and Centres for Addiction Medicine in Zurich, Switzerland, saw similarities between these needs and those of patients with chronic medical conditions. They hypothesized that case management—like that for chronic diseases—could work for cancer survivors perhaps even better than usual care. Among other duties, case managers can assess individual needs, identify barriers, ensure coordination among care providers, and perhaps most important, promote empowering self-management skills and self-efficacy. All of which could help cancer survivors cope with the long-term consequences of cancer and improve health-related quality of life (QOL).

Related: Putting the Focus on Quality of Life in Cancer Care

The researchers designed an intervention study in which 5 oncology nurse case managers met with 95 patients at least once a month for 3 months, then conducted telephone follow-ups for 9 months. Questionnaires measured health-related QOL at 12 months via the Functional Assessment of Cancer Therapy-General (FACT-G), self-efficacy, and concordance of received care with the Patient Assessment of Chronic Illness Care (PACIC).

Although the researchers’ study did not show a significant absolute difference between the groups in FACT-G after 12 months, all scores improved in the case management group compared with the usual care group. Overall, case management clearly boosted QOL and self-efficacy and aligned health care with the chronic care model.

Related: Quality of Supportive Care for Patients With Advanced Lung Cancer in the VHA

According to the researchers, their study is the first, to their knowledge, to examine the effect of case management on the QOL of early cancer survivors. Several factors help explain the intervention’s success: (1) The case managers provided important information on long-term symptoms and available services and therapies; (2) They offered a continuity of care when treatment appointments ceased and medical follow-up visits were less frequent; and (3) They offered support to cope with the psychological issues of the reentry phase.

All in all, the researchers say their findings show case management is a practical approach to bridging a “fragmented oncological health care system” and addressing the heterogenic needs of cancer survivors.

Source:

Scherz N, Bachmann-Mettler I, Chmiel C. BMC Cancer. 2017;17(1):223.

doi: 10.1186/s12885-017-3213-9.

After cancer treatment, a new challenge emerges as patients negotiate reentry into their everyday lives. These patients often need multifaceted, simultaneous, and ongoing help with physical, emotional, and psychological issues. And they’re often dealing with a multiplicity of health care providers.

Researchers from University of Zurich and Centres for Addiction Medicine in Zurich, Switzerland, saw similarities between these needs and those of patients with chronic medical conditions. They hypothesized that case management—like that for chronic diseases—could work for cancer survivors perhaps even better than usual care. Among other duties, case managers can assess individual needs, identify barriers, ensure coordination among care providers, and perhaps most important, promote empowering self-management skills and self-efficacy. All of which could help cancer survivors cope with the long-term consequences of cancer and improve health-related quality of life (QOL).

Related: Putting the Focus on Quality of Life in Cancer Care

The researchers designed an intervention study in which 5 oncology nurse case managers met with 95 patients at least once a month for 3 months, then conducted telephone follow-ups for 9 months. Questionnaires measured health-related QOL at 12 months via the Functional Assessment of Cancer Therapy-General (FACT-G), self-efficacy, and concordance of received care with the Patient Assessment of Chronic Illness Care (PACIC).

Although the researchers’ study did not show a significant absolute difference between the groups in FACT-G after 12 months, all scores improved in the case management group compared with the usual care group. Overall, case management clearly boosted QOL and self-efficacy and aligned health care with the chronic care model.

Related: Quality of Supportive Care for Patients With Advanced Lung Cancer in the VHA

According to the researchers, their study is the first, to their knowledge, to examine the effect of case management on the QOL of early cancer survivors. Several factors help explain the intervention’s success: (1) The case managers provided important information on long-term symptoms and available services and therapies; (2) They offered a continuity of care when treatment appointments ceased and medical follow-up visits were less frequent; and (3) They offered support to cope with the psychological issues of the reentry phase.

All in all, the researchers say their findings show case management is a practical approach to bridging a “fragmented oncological health care system” and addressing the heterogenic needs of cancer survivors.

Source:

Scherz N, Bachmann-Mettler I, Chmiel C. BMC Cancer. 2017;17(1):223.

doi: 10.1186/s12885-017-3213-9.

After cancer treatment, a new challenge emerges as patients negotiate reentry into their everyday lives. These patients often need multifaceted, simultaneous, and ongoing help with physical, emotional, and psychological issues. And they’re often dealing with a multiplicity of health care providers.

Researchers from University of Zurich and Centres for Addiction Medicine in Zurich, Switzerland, saw similarities between these needs and those of patients with chronic medical conditions. They hypothesized that case management—like that for chronic diseases—could work for cancer survivors perhaps even better than usual care. Among other duties, case managers can assess individual needs, identify barriers, ensure coordination among care providers, and perhaps most important, promote empowering self-management skills and self-efficacy. All of which could help cancer survivors cope with the long-term consequences of cancer and improve health-related quality of life (QOL).

Related: Putting the Focus on Quality of Life in Cancer Care

The researchers designed an intervention study in which 5 oncology nurse case managers met with 95 patients at least once a month for 3 months, then conducted telephone follow-ups for 9 months. Questionnaires measured health-related QOL at 12 months via the Functional Assessment of Cancer Therapy-General (FACT-G), self-efficacy, and concordance of received care with the Patient Assessment of Chronic Illness Care (PACIC).

Although the researchers’ study did not show a significant absolute difference between the groups in FACT-G after 12 months, all scores improved in the case management group compared with the usual care group. Overall, case management clearly boosted QOL and self-efficacy and aligned health care with the chronic care model.

Related: Quality of Supportive Care for Patients With Advanced Lung Cancer in the VHA

According to the researchers, their study is the first, to their knowledge, to examine the effect of case management on the QOL of early cancer survivors. Several factors help explain the intervention’s success: (1) The case managers provided important information on long-term symptoms and available services and therapies; (2) They offered a continuity of care when treatment appointments ceased and medical follow-up visits were less frequent; and (3) They offered support to cope with the psychological issues of the reentry phase.

All in all, the researchers say their findings show case management is a practical approach to bridging a “fragmented oncological health care system” and addressing the heterogenic needs of cancer survivors.

Source:

Scherz N, Bachmann-Mettler I, Chmiel C. BMC Cancer. 2017;17(1):223.

doi: 10.1186/s12885-017-3213-9.

Cancer drugs are becoming available at an unprecedented rate. In 2015 alone, the US Food and Drug Administration (FDA) approved 18 new agents.¹ Although many of those agents have adverse event profiles that are more favorable than those seen with conventional chemotherapy, nausea and vomiting still occur. In fact, nausea and vomiting continue to be ranked as among the most common and distressing of cancer symptoms.^2,3 In a 2004 study, Grunberg and colleagues reported that as many as 75% of health care providers misjudge the risk for chemotherapy-induced nausea and vomiting (CINV), even when prescribing cancer drugs that have been available for years,⁴ thus amplifying concerns that such risk assessment might be even worse when new cancer agents are prescribed for the first time.

In this study, we hypothesized that patients prescribed a new cancer drug, trifluridine-tipiracil, would be at risk for CINV because of poor guideline adherence on the part of health care providers. The correct matching of antiemetics to chemotherapy is important. Inadequate antiemetic prophylaxis predisposes to nausea and vomiting with dehydration and metabolic and electrolyte derangements – complications that can occur in up to one-third of patients who receive moderately or highly emetogenic chemotherapy and who have been reported to achieve poor symptom control.⁴ Over-prophylaxis also has drawbacks. For example, antiemetics are expensive and, at times, they can induce their own adverse events, such as lethargy, dyskinesia, constipation, headaches, hiccups, fatigue, and even cardiac arrhythmias.⁵ The best approach is to appropriately match the antiemetic to the chemotherapy. Indeed, adherence to evidence-based guidelines has yielded success in symptom control, but the guidelines work on the assumption that the emetogenic potential of new chemotherapy agents has been accurately determined and then disseminated to and acted upon by health care providers.^6,7 To our knowledge, no previous studies have tested that assumption, as we do in the present study.

Trifluridine-tipiracil was selected as the focus of this project and as illustrative of other newly approved chemotherapy agents for two reasons. First, it became available for routine prescribing in pretreated patients with metastatic colorectal cancer in the United States in September 2015.¹ That timing allowed us to analyze much of the early prescribing period, both during the 9 months before approval, when the drug was available on a compassionate-use basis at our institution, and the 3 months after approval. Second, trifluridine-tipiracil has classifiably low emetogenic potential, and mismatching of antiemetics tends to occur more often with low emetogenic chemotherapy.⁹ Trifluridine-tipiracil and placebo patients manifest rates of nausea at 48% and 24%, respectively, and rates of vomiting at 28% and 14%, respectively.⁸

Hence, the goal of this study was to explore whether a guideline-based prophylactic antiemetic regimen was appropriately matched to the new chemotherapy agent, trifluridine-tipiracil, to report whether such symptoms of nausea and vomiting are kept at bay, and to identify a potentially vulnerable interval – immediately after drug approval – when cancer patients may be at risk for CINV because of poor adherence to antiemetic guideline prescribing practices by health care providers.

Methods

Overview

The Mayo Clinic Institutional Review Board approved this study. We obtained the identifying information of all patients treated with trifluridine-tipiracil at our institution from the Mayo Clinic Specialty Pharmacy, which uses an electronic prescribing system that contributed to the comprehensiveness of the data set. Patients included those who had participated in a colorectal cancer compassionate-use program before the September 2015 approval of the drug and those who received the drug shortly after its approval. In essence, this retrospective, single-institution study included every patient who received trifluridine-tipiracil for metastatic colorectal cancer in 2015 (January through December); this approach enabled us to systematically report on early first-cycle prescribing practices 9 months before and 3 months after the drug’s approval in September of 2015.

Determination of guideline adherence

This project relied on the National Comprehensive Cancer Network (NCCN) Guidelines (v1.2015, behind paywall) because they had been updated in 2015 (and hence coincided with this project’s study dates) to incorporate recommendations specific to oral chemotherapy and because they seemed concordant with other guidelines.^10,11

Antiemetic prophylaxis for a specific patient was deemed guideline adherent if a version of the recommended NCCN antiemetic regimen had been prescribed during the first cycle of chemotherapy. This regimen consisted of metoclopramide, prochlorperazine, haloperidol, or a 5-hydroxytryptamine receptor antagonist. In contrast, if a patient had been prescribed a more aggressive or less aggressive regimen, such prescribing practices were deemed non–guideline adherent/aggressive (received more prophylaxis than called for) or non–guideline adherent/less aggressive (including no antiemetics), respectively. Again, medical record prescribing determined adherence.

Data reporting

The primary goal of this study was to report the percentage of patients who had been prescribed a first-cycle antiemetic prophylaxis regimen concordant with NCCN guidelines. Secondary goals included reporting the incidence of nausea and vomiting, the use of rescue antiemetics other than those prescribed up front, the need for an unplanned medical encounter to address nausea and vomiting, and change in antiemetic prescribing before the second chemotherapy cycle. Confidence intervals were calculated with JMP Pro 10.0.0. This study was too limited in sample size to assess sex-based differences in outcomes.

Results

Demographics

This report focuses on 44 patients who received first-cycle trifluridine-tipiracil during the first calendar year of the drug’s FDA approval. All patients had metastatic colorectal cancer and had previous exposures to other chemotherapy agents (Table 1). Of note, 28 patients (64%) had experienced CINV before starting trifluridine-tipiracil and all these patients had been heavily pretreated with multiple lines of chemotherapy.

Guideline adherence

Patients were most commonly prescribed prochlorperazine and ondansetron prophylaxis for CINV before the first chemotherapy cycle of trifluridine-tipiracil (Table 2): 15 patients were prescribed combination antiemetic therapy, typically two of the most commonly prescribed single agents with different mechanisms of action. Twenty-five patients (57%; 95% confidence interval (CI): 42%, 70%) were prescribed antiemetics in a manner consistent with guidelines; 15 (34%; 95% CI: 22%, 49%) were prescribed antiemetics in a non–guideline-adherent/more aggressive manner (received more prophylaxis than called for); and 4 (9%; 95% CI: 4%, 21%) were prescribed them in a non–guideline-adherent/less aggressive manner.

Clinical outcomes based on guideline adherence

In guideline-adherent patients, first-cycle nausea and vomiting occurred in 13 patients (52%) and 6 patients (24%), respectively, with 1 patient requiring an unscheduled clinic visit and another an emergency department visit and hospital admission – all for nausea and vomiting (Table 3). In non–guideline-adherent/more aggressive patients, those symptoms occurred in 5 patients (33%, nausea) and 4 patients (27%, vomiting), with 1 patient requiring a clinic visit and emergency department visit and another an emergency department visit – again, all for nausea and vomiting. In non–guideline-adherent/less aggressive patients, no nausea or vomiting was reported.

Discussion

This study examined adherence to antiemetic guidelines in the setting of a soon-to-be-approved or newly approved antineoplastic agent. As hypothesized, a substantial proportion of patients (43% in this study) were prescribed antiemetics in a nonadherent manner with respect to guidelines, thus identifying the period shortly before and after FDA approval as a particularly vulnerable interval with respect to antiemetic guideline adherence. It is possible that our institution’s practice of testing novel chemotherapy agents for the treatment of colorectal cancer prompted a heightened awareness of potential adverse events, leading to greater guideline adherence than might have occurred in other settings and resulting in judicious straying from guideline adherence only when appropriate.^12-14 Thus, these high rates of poor adherence may in fact represent an underestimate of what one might see in other clinical practices; and, similarly, these rates of symptom control might also be more favorable than those one might see in other clinical practices. To our knowledge, antiemetic prescribing practices with newer chemotherapy agents have not been explored before now, and our data underscore a clear need to do so – particularly during this limited interval when health care providers begin to prescribe new chemotherapy agents for the first time.

It is worth noting that despite the high rates of guideline nonadherence, rates of nausea and vomiting seemed to be comparable in patients prescribed antiemetics in a guideline-adherent manner and those prescribed antiemetics in a non–guideline-adherent/aggressive manner.A small number of patients in both the guideline-adherent and non–guideline-adherent/aggressive groups required rescue medications, unscheduled medical visits for nausea and vomiting, and additional antiemetics during the second cycle of chemotherapy. Of note,none of those interventions occurred in patients who were prescribed antiemetics in a non–guideline-adherent/less aggressive manner. These findings might reflect the fact that the patients had proven themselves to be at risk for nausea and vomiting with previous chemotherapy. Before they became candidates for trifluridine-tipiracil, patients had been heavily pretreated with other chemotherapy agents, most had experienced CINV, and many were therefore highly predisposed to nausea and vomiting. These observations underscore the fact that guidelines – even those that are well accepted and widely used – should be implemented in concert with good clinical judgment.^10,11 This study has shortcomings, most notably its small sample size. However, had we extended our study beyond 3 months of the FDA approval to include more patients, our findings would have reflected more experienced prescribing practices and we thereby would have deviated from our primary goal of assessing antiemetic prescribing practices with only recently-approved and available chemotherapy agents. In this context, this limited sample size aptly serves a primary role of capturing outcomes within a fleeting but critical interval of new drug availability.In summary, this study found a notable rate of poor guideline adherence when prescribing antiemetics for trifluridine-tipiracil, a new chemotherapy agent of low emetogenic potential. Although the resultant rates of nausea and vomiting suggest that good clinical judgment might have influenced whether or not guidelines were adhered to, these findings nonetheless underscore the need to assess adherence to antiemetic guidelines when new chemotherapy drugs become available and potentially to put in place institutional infrastructure rapidly to promote improved adherence. Such an assessment should be deliberate, formalized, and prompt within individual oncology clinics and cancer centers after a new cancer drug becomes available. In conjunction with clinical judgment, such measures might lead to improved symptom control.

Acknowledgment

This paper is based on a poster that was presented at the 2016 Palliative Care in Oncology Symposium, on September 10, 2016: Adherence to antiemetic guidelines with a newly approved chemotherapy agent, trifluridine-tipiracil (TAS-102): a single-institution study. Daniel Childs and Aminah Jatoi, Mayo Clinic, Rochester, MN. http://meetinglibrary.asco.org/record/136444/abstract. J Clin Oncol. 2016;34(suppl 26S):abstract 221.

Cancer drugs are becoming available at an unprecedented rate. In 2015 alone, the US Food and Drug Administration (FDA) approved 18 new agents.¹ Although many of those agents have adverse event profiles that are more favorable than those seen with conventional chemotherapy, nausea and vomiting still occur. In fact, nausea and vomiting continue to be ranked as among the most common and distressing of cancer symptoms.^2,3 In a 2004 study, Grunberg and colleagues reported that as many as 75% of health care providers misjudge the risk for chemotherapy-induced nausea and vomiting (CINV), even when prescribing cancer drugs that have been available for years,⁴ thus amplifying concerns that such risk assessment might be even worse when new cancer agents are prescribed for the first time.

In this study, we hypothesized that patients prescribed a new cancer drug, trifluridine-tipiracil, would be at risk for CINV because of poor guideline adherence on the part of health care providers. The correct matching of antiemetics to chemotherapy is important. Inadequate antiemetic prophylaxis predisposes to nausea and vomiting with dehydration and metabolic and electrolyte derangements – complications that can occur in up to one-third of patients who receive moderately or highly emetogenic chemotherapy and who have been reported to achieve poor symptom control.⁴ Over-prophylaxis also has drawbacks. For example, antiemetics are expensive and, at times, they can induce their own adverse events, such as lethargy, dyskinesia, constipation, headaches, hiccups, fatigue, and even cardiac arrhythmias.⁵ The best approach is to appropriately match the antiemetic to the chemotherapy. Indeed, adherence to evidence-based guidelines has yielded success in symptom control, but the guidelines work on the assumption that the emetogenic potential of new chemotherapy agents has been accurately determined and then disseminated to and acted upon by health care providers.^6,7 To our knowledge, no previous studies have tested that assumption, as we do in the present study.

Trifluridine-tipiracil was selected as the focus of this project and as illustrative of other newly approved chemotherapy agents for two reasons. First, it became available for routine prescribing in pretreated patients with metastatic colorectal cancer in the United States in September 2015.¹ That timing allowed us to analyze much of the early prescribing period, both during the 9 months before approval, when the drug was available on a compassionate-use basis at our institution, and the 3 months after approval. Second, trifluridine-tipiracil has classifiably low emetogenic potential, and mismatching of antiemetics tends to occur more often with low emetogenic chemotherapy.⁹ Trifluridine-tipiracil and placebo patients manifest rates of nausea at 48% and 24%, respectively, and rates of vomiting at 28% and 14%, respectively.⁸

Hence, the goal of this study was to explore whether a guideline-based prophylactic antiemetic regimen was appropriately matched to the new chemotherapy agent, trifluridine-tipiracil, to report whether such symptoms of nausea and vomiting are kept at bay, and to identify a potentially vulnerable interval – immediately after drug approval – when cancer patients may be at risk for CINV because of poor adherence to antiemetic guideline prescribing practices by health care providers.

Methods

Overview

The Mayo Clinic Institutional Review Board approved this study. We obtained the identifying information of all patients treated with trifluridine-tipiracil at our institution from the Mayo Clinic Specialty Pharmacy, which uses an electronic prescribing system that contributed to the comprehensiveness of the data set. Patients included those who had participated in a colorectal cancer compassionate-use program before the September 2015 approval of the drug and those who received the drug shortly after its approval. In essence, this retrospective, single-institution study included every patient who received trifluridine-tipiracil for metastatic colorectal cancer in 2015 (January through December); this approach enabled us to systematically report on early first-cycle prescribing practices 9 months before and 3 months after the drug’s approval in September of 2015.

Determination of guideline adherence

This project relied on the National Comprehensive Cancer Network (NCCN) Guidelines (v1.2015, behind paywall) because they had been updated in 2015 (and hence coincided with this project’s study dates) to incorporate recommendations specific to oral chemotherapy and because they seemed concordant with other guidelines.^10,11

Antiemetic prophylaxis for a specific patient was deemed guideline adherent if a version of the recommended NCCN antiemetic regimen had been prescribed during the first cycle of chemotherapy. This regimen consisted of metoclopramide, prochlorperazine, haloperidol, or a 5-hydroxytryptamine receptor antagonist. In contrast, if a patient had been prescribed a more aggressive or less aggressive regimen, such prescribing practices were deemed non–guideline adherent/aggressive (received more prophylaxis than called for) or non–guideline adherent/less aggressive (including no antiemetics), respectively. Again, medical record prescribing determined adherence.

Data reporting

The primary goal of this study was to report the percentage of patients who had been prescribed a first-cycle antiemetic prophylaxis regimen concordant with NCCN guidelines. Secondary goals included reporting the incidence of nausea and vomiting, the use of rescue antiemetics other than those prescribed up front, the need for an unplanned medical encounter to address nausea and vomiting, and change in antiemetic prescribing before the second chemotherapy cycle. Confidence intervals were calculated with JMP Pro 10.0.0. This study was too limited in sample size to assess sex-based differences in outcomes.

Results

Demographics

This report focuses on 44 patients who received first-cycle trifluridine-tipiracil during the first calendar year of the drug’s FDA approval. All patients had metastatic colorectal cancer and had previous exposures to other chemotherapy agents (Table 1). Of note, 28 patients (64%) had experienced CINV before starting trifluridine-tipiracil and all these patients had been heavily pretreated with multiple lines of chemotherapy.

Guideline adherence

Patients were most commonly prescribed prochlorperazine and ondansetron prophylaxis for CINV before the first chemotherapy cycle of trifluridine-tipiracil (Table 2): 15 patients were prescribed combination antiemetic therapy, typically two of the most commonly prescribed single agents with different mechanisms of action. Twenty-five patients (57%; 95% confidence interval (CI): 42%, 70%) were prescribed antiemetics in a manner consistent with guidelines; 15 (34%; 95% CI: 22%, 49%) were prescribed antiemetics in a non–guideline-adherent/more aggressive manner (received more prophylaxis than called for); and 4 (9%; 95% CI: 4%, 21%) were prescribed them in a non–guideline-adherent/less aggressive manner.

Clinical outcomes based on guideline adherence

In guideline-adherent patients, first-cycle nausea and vomiting occurred in 13 patients (52%) and 6 patients (24%), respectively, with 1 patient requiring an unscheduled clinic visit and another an emergency department visit and hospital admission – all for nausea and vomiting (Table 3). In non–guideline-adherent/more aggressive patients, those symptoms occurred in 5 patients (33%, nausea) and 4 patients (27%, vomiting), with 1 patient requiring a clinic visit and emergency department visit and another an emergency department visit – again, all for nausea and vomiting. In non–guideline-adherent/less aggressive patients, no nausea or vomiting was reported.

Discussion

This study examined adherence to antiemetic guidelines in the setting of a soon-to-be-approved or newly approved antineoplastic agent. As hypothesized, a substantial proportion of patients (43% in this study) were prescribed antiemetics in a nonadherent manner with respect to guidelines, thus identifying the period shortly before and after FDA approval as a particularly vulnerable interval with respect to antiemetic guideline adherence. It is possible that our institution’s practice of testing novel chemotherapy agents for the treatment of colorectal cancer prompted a heightened awareness of potential adverse events, leading to greater guideline adherence than might have occurred in other settings and resulting in judicious straying from guideline adherence only when appropriate.^12-14 Thus, these high rates of poor adherence may in fact represent an underestimate of what one might see in other clinical practices; and, similarly, these rates of symptom control might also be more favorable than those one might see in other clinical practices. To our knowledge, antiemetic prescribing practices with newer chemotherapy agents have not been explored before now, and our data underscore a clear need to do so – particularly during this limited interval when health care providers begin to prescribe new chemotherapy agents for the first time.

It is worth noting that despite the high rates of guideline nonadherence, rates of nausea and vomiting seemed to be comparable in patients prescribed antiemetics in a guideline-adherent manner and those prescribed antiemetics in a non–guideline-adherent/aggressive manner.A small number of patients in both the guideline-adherent and non–guideline-adherent/aggressive groups required rescue medications, unscheduled medical visits for nausea and vomiting, and additional antiemetics during the second cycle of chemotherapy. Of note,none of those interventions occurred in patients who were prescribed antiemetics in a non–guideline-adherent/less aggressive manner. These findings might reflect the fact that the patients had proven themselves to be at risk for nausea and vomiting with previous chemotherapy. Before they became candidates for trifluridine-tipiracil, patients had been heavily pretreated with other chemotherapy agents, most had experienced CINV, and many were therefore highly predisposed to nausea and vomiting. These observations underscore the fact that guidelines – even those that are well accepted and widely used – should be implemented in concert with good clinical judgment.^10,11 This study has shortcomings, most notably its small sample size. However, had we extended our study beyond 3 months of the FDA approval to include more patients, our findings would have reflected more experienced prescribing practices and we thereby would have deviated from our primary goal of assessing antiemetic prescribing practices with only recently-approved and available chemotherapy agents. In this context, this limited sample size aptly serves a primary role of capturing outcomes within a fleeting but critical interval of new drug availability.In summary, this study found a notable rate of poor guideline adherence when prescribing antiemetics for trifluridine-tipiracil, a new chemotherapy agent of low emetogenic potential. Although the resultant rates of nausea and vomiting suggest that good clinical judgment might have influenced whether or not guidelines were adhered to, these findings nonetheless underscore the need to assess adherence to antiemetic guidelines when new chemotherapy drugs become available and potentially to put in place institutional infrastructure rapidly to promote improved adherence. Such an assessment should be deliberate, formalized, and prompt within individual oncology clinics and cancer centers after a new cancer drug becomes available. In conjunction with clinical judgment, such measures might lead to improved symptom control.

Acknowledgment

This paper is based on a poster that was presented at the 2016 Palliative Care in Oncology Symposium, on September 10, 2016: Adherence to antiemetic guidelines with a newly approved chemotherapy agent, trifluridine-tipiracil (TAS-102): a single-institution study. Daniel Childs and Aminah Jatoi, Mayo Clinic, Rochester, MN. http://meetinglibrary.asco.org/record/136444/abstract. J Clin Oncol. 2016;34(suppl 26S):abstract 221.

Cancer drugs are becoming available at an unprecedented rate. In 2015 alone, the US Food and Drug Administration (FDA) approved 18 new agents.¹ Although many of those agents have adverse event profiles that are more favorable than those seen with conventional chemotherapy, nausea and vomiting still occur. In fact, nausea and vomiting continue to be ranked as among the most common and distressing of cancer symptoms.^2,3 In a 2004 study, Grunberg and colleagues reported that as many as 75% of health care providers misjudge the risk for chemotherapy-induced nausea and vomiting (CINV), even when prescribing cancer drugs that have been available for years,⁴ thus amplifying concerns that such risk assessment might be even worse when new cancer agents are prescribed for the first time.

In this study, we hypothesized that patients prescribed a new cancer drug, trifluridine-tipiracil, would be at risk for CINV because of poor guideline adherence on the part of health care providers. The correct matching of antiemetics to chemotherapy is important. Inadequate antiemetic prophylaxis predisposes to nausea and vomiting with dehydration and metabolic and electrolyte derangements – complications that can occur in up to one-third of patients who receive moderately or highly emetogenic chemotherapy and who have been reported to achieve poor symptom control.⁴ Over-prophylaxis also has drawbacks. For example, antiemetics are expensive and, at times, they can induce their own adverse events, such as lethargy, dyskinesia, constipation, headaches, hiccups, fatigue, and even cardiac arrhythmias.⁵ The best approach is to appropriately match the antiemetic to the chemotherapy. Indeed, adherence to evidence-based guidelines has yielded success in symptom control, but the guidelines work on the assumption that the emetogenic potential of new chemotherapy agents has been accurately determined and then disseminated to and acted upon by health care providers.^6,7 To our knowledge, no previous studies have tested that assumption, as we do in the present study.

Trifluridine-tipiracil was selected as the focus of this project and as illustrative of other newly approved chemotherapy agents for two reasons. First, it became available for routine prescribing in pretreated patients with metastatic colorectal cancer in the United States in September 2015.¹ That timing allowed us to analyze much of the early prescribing period, both during the 9 months before approval, when the drug was available on a compassionate-use basis at our institution, and the 3 months after approval. Second, trifluridine-tipiracil has classifiably low emetogenic potential, and mismatching of antiemetics tends to occur more often with low emetogenic chemotherapy.⁹ Trifluridine-tipiracil and placebo patients manifest rates of nausea at 48% and 24%, respectively, and rates of vomiting at 28% and 14%, respectively.⁸

Hence, the goal of this study was to explore whether a guideline-based prophylactic antiemetic regimen was appropriately matched to the new chemotherapy agent, trifluridine-tipiracil, to report whether such symptoms of nausea and vomiting are kept at bay, and to identify a potentially vulnerable interval – immediately after drug approval – when cancer patients may be at risk for CINV because of poor adherence to antiemetic guideline prescribing practices by health care providers.

Methods

Overview

The Mayo Clinic Institutional Review Board approved this study. We obtained the identifying information of all patients treated with trifluridine-tipiracil at our institution from the Mayo Clinic Specialty Pharmacy, which uses an electronic prescribing system that contributed to the comprehensiveness of the data set. Patients included those who had participated in a colorectal cancer compassionate-use program before the September 2015 approval of the drug and those who received the drug shortly after its approval. In essence, this retrospective, single-institution study included every patient who received trifluridine-tipiracil for metastatic colorectal cancer in 2015 (January through December); this approach enabled us to systematically report on early first-cycle prescribing practices 9 months before and 3 months after the drug’s approval in September of 2015.

Determination of guideline adherence

This project relied on the National Comprehensive Cancer Network (NCCN) Guidelines (v1.2015, behind paywall) because they had been updated in 2015 (and hence coincided with this project’s study dates) to incorporate recommendations specific to oral chemotherapy and because they seemed concordant with other guidelines.^10,11

Antiemetic prophylaxis for a specific patient was deemed guideline adherent if a version of the recommended NCCN antiemetic regimen had been prescribed during the first cycle of chemotherapy. This regimen consisted of metoclopramide, prochlorperazine, haloperidol, or a 5-hydroxytryptamine receptor antagonist. In contrast, if a patient had been prescribed a more aggressive or less aggressive regimen, such prescribing practices were deemed non–guideline adherent/aggressive (received more prophylaxis than called for) or non–guideline adherent/less aggressive (including no antiemetics), respectively. Again, medical record prescribing determined adherence.

Data reporting

The primary goal of this study was to report the percentage of patients who had been prescribed a first-cycle antiemetic prophylaxis regimen concordant with NCCN guidelines. Secondary goals included reporting the incidence of nausea and vomiting, the use of rescue antiemetics other than those prescribed up front, the need for an unplanned medical encounter to address nausea and vomiting, and change in antiemetic prescribing before the second chemotherapy cycle. Confidence intervals were calculated with JMP Pro 10.0.0. This study was too limited in sample size to assess sex-based differences in outcomes.

Results

Demographics

This report focuses on 44 patients who received first-cycle trifluridine-tipiracil during the first calendar year of the drug’s FDA approval. All patients had metastatic colorectal cancer and had previous exposures to other chemotherapy agents (Table 1). Of note, 28 patients (64%) had experienced CINV before starting trifluridine-tipiracil and all these patients had been heavily pretreated with multiple lines of chemotherapy.

Guideline adherence

Patients were most commonly prescribed prochlorperazine and ondansetron prophylaxis for CINV before the first chemotherapy cycle of trifluridine-tipiracil (Table 2): 15 patients were prescribed combination antiemetic therapy, typically two of the most commonly prescribed single agents with different mechanisms of action. Twenty-five patients (57%; 95% confidence interval (CI): 42%, 70%) were prescribed antiemetics in a manner consistent with guidelines; 15 (34%; 95% CI: 22%, 49%) were prescribed antiemetics in a non–guideline-adherent/more aggressive manner (received more prophylaxis than called for); and 4 (9%; 95% CI: 4%, 21%) were prescribed them in a non–guideline-adherent/less aggressive manner.

Clinical outcomes based on guideline adherence

In guideline-adherent patients, first-cycle nausea and vomiting occurred in 13 patients (52%) and 6 patients (24%), respectively, with 1 patient requiring an unscheduled clinic visit and another an emergency department visit and hospital admission – all for nausea and vomiting (Table 3). In non–guideline-adherent/more aggressive patients, those symptoms occurred in 5 patients (33%, nausea) and 4 patients (27%, vomiting), with 1 patient requiring a clinic visit and emergency department visit and another an emergency department visit – again, all for nausea and vomiting. In non–guideline-adherent/less aggressive patients, no nausea or vomiting was reported.

Discussion

This study examined adherence to antiemetic guidelines in the setting of a soon-to-be-approved or newly approved antineoplastic agent. As hypothesized, a substantial proportion of patients (43% in this study) were prescribed antiemetics in a nonadherent manner with respect to guidelines, thus identifying the period shortly before and after FDA approval as a particularly vulnerable interval with respect to antiemetic guideline adherence. It is possible that our institution’s practice of testing novel chemotherapy agents for the treatment of colorectal cancer prompted a heightened awareness of potential adverse events, leading to greater guideline adherence than might have occurred in other settings and resulting in judicious straying from guideline adherence only when appropriate.^12-14 Thus, these high rates of poor adherence may in fact represent an underestimate of what one might see in other clinical practices; and, similarly, these rates of symptom control might also be more favorable than those one might see in other clinical practices. To our knowledge, antiemetic prescribing practices with newer chemotherapy agents have not been explored before now, and our data underscore a clear need to do so – particularly during this limited interval when health care providers begin to prescribe new chemotherapy agents for the first time.

It is worth noting that despite the high rates of guideline nonadherence, rates of nausea and vomiting seemed to be comparable in patients prescribed antiemetics in a guideline-adherent manner and those prescribed antiemetics in a non–guideline-adherent/aggressive manner.A small number of patients in both the guideline-adherent and non–guideline-adherent/aggressive groups required rescue medications, unscheduled medical visits for nausea and vomiting, and additional antiemetics during the second cycle of chemotherapy. Of note,none of those interventions occurred in patients who were prescribed antiemetics in a non–guideline-adherent/less aggressive manner. These findings might reflect the fact that the patients had proven themselves to be at risk for nausea and vomiting with previous chemotherapy. Before they became candidates for trifluridine-tipiracil, patients had been heavily pretreated with other chemotherapy agents, most had experienced CINV, and many were therefore highly predisposed to nausea and vomiting. These observations underscore the fact that guidelines – even those that are well accepted and widely used – should be implemented in concert with good clinical judgment.^10,11 This study has shortcomings, most notably its small sample size. However, had we extended our study beyond 3 months of the FDA approval to include more patients, our findings would have reflected more experienced prescribing practices and we thereby would have deviated from our primary goal of assessing antiemetic prescribing practices with only recently-approved and available chemotherapy agents. In this context, this limited sample size aptly serves a primary role of capturing outcomes within a fleeting but critical interval of new drug availability.In summary, this study found a notable rate of poor guideline adherence when prescribing antiemetics for trifluridine-tipiracil, a new chemotherapy agent of low emetogenic potential. Although the resultant rates of nausea and vomiting suggest that good clinical judgment might have influenced whether or not guidelines were adhered to, these findings nonetheless underscore the need to assess adherence to antiemetic guidelines when new chemotherapy drugs become available and potentially to put in place institutional infrastructure rapidly to promote improved adherence. Such an assessment should be deliberate, formalized, and prompt within individual oncology clinics and cancer centers after a new cancer drug becomes available. In conjunction with clinical judgment, such measures might lead to improved symptom control.

Acknowledgment

This paper is based on a poster that was presented at the 2016 Palliative Care in Oncology Symposium, on September 10, 2016: Adherence to antiemetic guidelines with a newly approved chemotherapy agent, trifluridine-tipiracil (TAS-102): a single-institution study. Daniel Childs and Aminah Jatoi, Mayo Clinic, Rochester, MN. http://meetinglibrary.asco.org/record/136444/abstract. J Clin Oncol. 2016;34(suppl 26S):abstract 221.

Lung cancer is the leading cause of cancer death in the United States. It is estimated that there will be 222,500 new cases of lung cancer and 155,870 deaths from lung cancer in 2017. Non–small-cell lung carcinoma (NSCLC) accounts for 80%-85% of lung cancers, with adenocarcinoma being the most common histologic subtype. Other less common subtypes include squamous-cell carcinoma, large-cell carcinoma, and NSCLC that cannot be further classified.¹ Nearly 70% of patients present with locally advanced or metastatic disease at the time of diagnosis and are not candidates for surgical resection.² For that group of patients, the mainstay of treatment is platinum-based chemotherapy with or without radiation therapy. Patients who are chemotherapy naive often experience a modest response, however; durable remission is short lived, and the 5-year survival rate remains staggeringly low.³ Improved understanding of the molecular pathways that drive malignancy in NSCLC has led to the development of drugs that target specific molecular pathways.⁴ By definition, these driver mutations facilitate oncogenesis by conferring a selective advantage during clonal evolution.⁵ Moreover, agents targeting these pathways are extremely active and induce durable responses in many patients.^6,7,8

Predictive biomarkers in NSCLC include anaplastic lymphoma kinase (ALK) fusion oncogene and sensitizing epidermal growth factor receptor (EGFR) mutations. Mutations in the EGFR tyrosine kinase are observed in about 15%-20% of NSCLC adenocarcinomas in the United States and upward of 60% in Asian populations. They are also found more frequently in nonsmokers and women.⁶ The two most prevalent mutations in the EGFR tyrosine kinase domain are in-frame deletions of exon 19 and L858R substitution in exon 21, representing about 45% and 40% of mutations, respectively.⁹ Both mutations result in activation of the tyrosine kinase domain, and both are associated with sensitivity to the small-molecule tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib, and afatinib.¹⁰ Other drug-sensitive mutations include point mutations at exon 21 (L861Q) and exon 18 (G719X).¹¹ Targeted therapy produces durable responses in the majority of patients.^12,13,14 Unfortunately, most patients develop acquired resistance to these therapies, which leads to disease progression.^4,15-17

ALK gene rearrangements, although less prevalent, are another important molecular target in NSCLC and are seen in 2%-7% of cases in the United States.⁷ As with EGFR mutations, these mutations are more prevalent in nonsmokers, and they are found more commonly in younger patients and in men.⁸

Identification of driver mutations early in the course of disease and acquired resistance mutations later are crucial for the optimal management of advanced NSCLC. DNA analysis using polymerase chain reaction (PCR) and next-generation sequencing is the preferred method for testing for EGFR mutations, and ALK rearrangements are generally tested either by flourescence in situ hybridization (FISH) or immunohistochemistry.^18,19 Newer blood-based assays have shown great promise, and clinicians may soon have the ability to monitor subtle genetic changes, identify resistance patterns, and change therapy when acquired resistance occurs.²⁰

The American College of Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology have proposed guidelines for molecular testing in lung cancer. It is recommended that all advanced squamous and nonsquamous cell lung cancers with an adenocarcinoma component should be tested for EGFR and ALK mutations independent of age, sex, ethnicity, or smoking history. In the setting of smaller lung cancer specimens (eg, from biopsies, cytology) where an adenocarcinoma component cannot be completely excluded, EGFR and ALK testing may be performed in cases showing squamous or small cell histology but clinical criteria (eg, young age, lack of smoking history) may be useful in selecting a subset of these samples for testing. Samples obtained through surgical resection, open biopsy, endoscopy, transthoracic needle biopsy, fine-needle aspiration, and thoracentesis are all considered suitable for testing, but large biopsy samples are generally preferred over small biopsy samples, cell-blocks, and cytology samples.²¹ Despite this recommendation, not all patients who are eligible for mutation analysis are tested. At our institution, preliminary observations suggested that the percentage of patients being tested and the prevalence of driver mutations were significantly lower compared with published data. The purpose of this study was to evaluate physician attitudes about molecular testing, and to determine the rate of testing, the effect of biopsy sample size on rate of testing, and the prevalence of driver mutations at our institution.

Methods

In this retrospective clinical study, we identified 206 cases of advanced nsNSCLC from the tumor registry (February 2011-February 2013). Registry data was obtained from three hospitals within our health network – two academic tertiary care centers, and one community-based hospital. The other hospitals in the network were excluded because their EHR systems were not integrated with the rest of the hospitals and/or there was a lack of registry data. The testing rates for driver mutations, prevalence of driver mutations, and the tissue procurement techniques were obtained from individual chart review. Surgical specimens, core biopsy samples, and large volume thoracentesis specimens were categorized as large biopsy samples, and samples obtained by fine-needle aspiration, bronchial washing, and bronchial brushing were considered small biopsy samples. We used a chi-square analysis to compare mutation testing rates between the large and small biopsy sample groups. The prevalence of driver mutations was determined, excluding unknown or inadequate samples.

EGFR analysis had been conducted at Integrated Oncology, using formalin-fixed, paraffin-embedded tissue. Genomic DNA was isolated, and EGFR mutation analysis was performed using SNaPShot multiplex PCR, primer extension assay for exons 18-21; samples with >4mm² and ≥50% tumor content were preferred. Macrodissection was used to enrich for tumor cells when samples had lower tumor cellularity and content. ALK rearrangements were tested in the hospital using the Vysis ALK Break Apart FISH probe kit (Abott Molecular Inc, Des Plaines, IL).

We conducted a web-based, 20-question survey about molecular profiling among 110 practitioners to gauge their knowledge and opinions about molecular testing. The practitioners included medical oncologists, thoracic surgeons, pulmonologists, and interventional radiologists. Each received an initial e-mail informing them of the study, inviting them to complete survey, and providing a link to it, and two reminder e-mails at biweekly intervals to maximize survey participation and responses. The questions were aimed at understanding the challenges surrounding molecular testing within our network. Apart from the questions gathering demographic information about the respondents, the questions were intended to highlight the disparities between guideline recommendations and physician practices; to gauge the perceived importance of molecular evaluation; to identify individual, subspecialty, and hospital-based challenges; and to assess physician attitudes toward alternatives to traditional tissue-based testing (Table 1, p. e150). Nineteen of the questions were structured as single or best answer, whereas Question 9, which was aimed at identifying system-based challenges, allowed for multiple answer selections.

Results

There were a total of 206 cases of advanced stage IIIb or IV nsNSCLC identified at three hospitals during 2011-2013. Of those 206 cases, 161 (78.2%) were recorded at the two large academic medical centers, and 45 (21.9%) were recorded at the smaller community-based hospital. Of the total, there were 145 (70.4%) large biopsy specimens and 61 (29.6%) small biopsy specimens. We found that 89 of the 206 cases (43.2 %) had been tested for EGFR mutations, and 49 (23.8%) had been tested for ALK rearrangements (Figure, A and C). In all, 70 (48.3%) large-sample biopsies and 19 (31.1%) small-sample biopsies were submitted for EGFR analysis (Figure, B), and 42 (29%) large-sample biopsies and 7 (11.5%) small-sample biopsies were tested for ALK rearrangements (Figure, D). Large-sample biopsies were more likely to be analyzed for EGFR mutations and ALK rearrangements, with the results reaching statistical significance (P = .023 and P = .007, respectively). Across all samples, a total of 7 EGFR mutations and 1 ALK rearrangement were identified, yielding a prevalence of 7.9% and 2% respectively (Figure, A and C).

The average age at diagnosis of the patients in the cases that were analyzed was 69.3 years. Most of the patients (83.9%) identified as white, 3.8% were African American, and 12.6% were in the Unknown category. Of the total number of patients, 11 were identified as never-smokers (5.3%), 50 (24.3%) had a 1-15 pack-year smoking history, 104 (50.5%) had a 16-45 pack-year smoking history, and 41 (19.9%) had a >45 pack-year smoking history.

In regard to the survey, 46 of the 110 physicians asked to participate in the survey responded, representing a response rate of 41.8% (range across medical specialties, 26%-45%, Table 4). Of those respondents, 38 (82.6%) indicated they believed molecular evaluation was a very important aspect of NSCLC care, with the remainder indicating it was somewhat important. 91.4% of the respondents who routinely ordered molecular testing agreed that stage IIIb or IV nsNSCLC should undergo molecular evaluation.

Discussion

The treatment of advanced nsNSCLC has evolved significantly over the past decade. Molecular profiling is now an essential part of initial evaluation, and larger-sample biopsies are needed to ensure accurate evaluation and appropriate treatment. The detection of EGFR and EML4-ALK driver mutations are associated with increased response to tyrosine kinase inhibitors and are associated with improvement in progression-free survival, patient quality of life, and even overall survival in some studies.^12,22,23,24 Early identification of these driver mutations is crucial, however, preliminary observation in our network suggested that a large percentage of patients with advanced nsNSCLC in were not being appropriately evaluated for those mutations. To evaluate our molecular profiling rates, we conducted a retrospective study and reviewed 3 years of registry data at 3 hospitals within our health system. Two of the hospitals included in our analysis were large tertiary academic centers, and one was a community hospital. Our findings confirmed that a large percentage of our patients who are eligible for molecular evaluation are not tested: 56.7% of cases were not tested for EGFR mutations, and 76.2% of cases were not tested for ALK rearrangements.

In a similar study, the Association for Community Cancer Centers conducted a project aimed at understanding the landscape and current challenges for molecular profiling in NSCLC. Eight institutions participated in the study, and baseline testing rates were analyzed. The findings demonstrated that high-volume institutions (treating >100 lung cancer patients a year tested 62% and 60% of advanced lung cancer patients for EGFR and EML4-ALK, respectively, and low-volume institutions (treating <100 lung cancer patients a year tested 52% and 47% for EGFR and EML4-ALK, respectively.^25,26 In a recent international physician self-reported survey, Spicer and colleagues found that EGFR testing was requested before first-line therapy in patients with stage IIIB or IV disease in 81% of cases, and mutation results were available before start of therapy in 77% of the cases.²⁷ Those percentages are relatively low, given that current guidelines recommend that molecular testing should be done for all patients with stage IIIB or IV nsNSCLC. This highlights the need for objective performance feedback so oncologists can make the necessary practice changes so that molecular testing is done before the start of therapy to ensure high-quality cancer care that will translate into better, cost-effective outcomes and improved patient quality of life.

Our study findings showed that the prevalence of EGFR and ALK mutations is substantially lower among the patients we treat in our network compared with other published data on prevalence. The reason for those low rates is not clear, but it is likely multifactorial. First, Western Pennsylvania, the region our network serves, has a large proportion of older adults – 17.3% of the population is older than 65 years (national average, 14.5%) and advanced age might have contributed to the lower EGFR and ALK rates measured in our study.²⁸ Second, the smoking rate in Pennsylvania is higher than the national average, 20%-24% compared with 18%, respectively.²⁹ Third, the air quality in Western Pennsylvania has historically been very poor as a result of the large steel and coal mining industries. Even though the air quality has improved in recent decades, the American Lung Association’s 2017 State of the Air report ranked Pittsburgh and surrounding areas in Western Pennsylvania among the top 25 most air polluted areas in the United States.³⁰ It is not certain whether air pollution and air quality have any impact on driver mutation rates, but the correlation with smoking, ethnicity, and geographic distribution highlight the need for further epidemiologic studies.

Biopsy sufficiency – getting an adequate amount of sample tissue during biopsy – is a known challenge to molecular profiling, and we found that biopsy sample size had an impact on the testing rates in a large percentage of our cases. To fully understand the impact of biopsy sufficiency, we conducted a subset analysis and compared the testing rates between our large and small biopsy samples. Our analysis showed that larger-sample biopsies were more likely to be tested for mutations than were smaller-sample biopsies (EGFR: P = .023; ALK: P = .007).

Those results suggest that larger-sample biopsies should be encouraged, but procedural risks, tumor location, and patient age and wishes need to be considered before tissue acquisition.²¹ Furthermore, clinicians who are responsible for tissue procurement need to be properly educated on the tissue sample requirements and the impact these results have on treatment decisions.³¹ Our institution, like many others, has adopted rapid onsite evaluation (ROSE) of biopsy samples, whereby a trained cytopathologist reviews sample adequacy at the time of tissue procurement. Although there is scant data directly comparing molecular testing success rates with and without the ROSE protocol, a meta-analysis conducted by Schmidt and colleagues concluded that ROSE improved the adequacy rate of fine-needle aspiration cytology by 12%.^32,33 Given that molecular profiling depends on both the absolute and relative amount of tumor cells present in the sample, the ROSE protocol likely enhances the procedural success rate and reduces the need for repeat and subsequent biopsies.

It is interesting to note that our data also demonstrated that we are obtaining large-sample biopsies in most of our patients (about 70%). However, we are still failing to test more than half of our cases for driver mutations (Figure, A and C). This strongly suggests there are additional factors beyond tissue adequacy that are contributing to our high failure rate. It is essential to understand the dynamics and system practices that influence testing rates if we are to improve the care and outcomes of our cancer patients. To better understand those barriers, we surveyed 110 practitioners (including medical oncologists, pulmonologists, thoracic surgeons, and interventional radiologists) about the molecular profiling process and their responses highlighted several important areas that deserve special attention (Tables 1, 4, 5).

In our institution, testing initiation is primarily the responsibility of the treating medical oncologist. This presents a challenge because there is often a significant delay between tissue acquisition, histologic confirmation, and oncologic review. Many institutions have adopted pathology-driven reflex testing to help overcome such delays. Automatic testing after pathologic confirmation streamlines the process, increases testing rates, and eliminates unnecessary delay between the time of diagnosis and the time of test ordering.³⁴ It also allows for the molecular and histologic diagnosis to be integrated into a single pathology report before therapy is initiated.

Another barrier to timely testing according to the respondents, was the CMS’s 14-day rule. The 14-day rule requires hospitals to wait 14 days after the patient is discharged for the lab to receive reimbursement for molecular testing and was frequently identified as a cause for significant delay in testing and having an impact on first-line treatment decisions.^35,36

Often clinicians will choose to defer testing until this time has elapsed to reduce the financial burden placed on the hospital but by that time, they might well have initiated treatment without knowing if the patient has a mutation. This is a significant challenge identified by many of our oncologists, and is a limitation to our analysis above as it is unclear what percentage of patients received follow up testing once care was established at an outside facility and once the 14-day time period had elapsed.

The data from our institution suggests there is discordance between physician attitudes and molecular testing practices. However, there are several limitations in our study. First, most of the survey respondents agreed that molecular testing is an important aspect of treating advanced lung cancer patients, but the retrospective nature of the study made it difficult to identify why testing was deferred or never conducted. Second, the absence of a centralized reporting system for molecular testing results at our institution, may have resulted in an overestimation of our testing failure rate in cases where results were not integrated our electronic medical record.

Third, the low survey response rate only allowed us to make generalizations regarding the conclusions, although it does provide a framework for future process improvements.

We believe the poor testing rates observed in our study are not isolated to our institution and reflect a significant challenge within the broader oncology community.²⁷ A system of best practices is essential for capturing this subset of patients who are never tested. There is agreement among oncologists that improving our current testing rates will require a multidisciplinary approach, a refined process for molecular evaluation, a push toward reflex testing, and standardization of biopsy techniques and tissue handling procedures. In our institution, we have initiated a Lean Six Sigma and PDSA (plan, do, study, act) initiative to improve our current molecular testing process. In addition, because obtaining larger-sample biopsies or additional biopsies is often not feasible for many of our advanced cancer patients, we have started using whole blood circulating tumor cells (CTC) and plasma ctDNA (cell-free circulating DNA) for molecular testing. Recent studies have shown high concordance (89%) between tissue biopsies and blood-based mutation testing, which will likely have a positive impact on the cancer care of our patients and help to capture a subset of patients who are not candidates for traditional biopsies.³⁷

Conclusions

Despite current guidelines for testing driver mutations in advanced nsNSCLC, a large segment of our patients are not being tested for those genetic aberrations. There are several barriers that continue to thwart the recommendation, including failure to integrate driver mutation testing into routine pathology practice (ie, reflex testing), insufficient tissue obtained from biopsy, and difficulty in obtaining tissue because of tumor location or risk of complications from the biopsy procedure. More important, these trends are not isolated to our institution and reflect a significant challenge within the oncology community. Our data show that for the purpose of driver mutation testing, larger-sample biopsies, such as surgical/core biopsies, are better than small-sample biopsies, such as needle aspiration. We have also demonstrated that the prevalence of driver mutations is lower in Western Pennsylvania, which is served by our network, than elsewhere in the United States.

Lung cancer is the leading cause of cancer death in the United States. It is estimated that there will be 222,500 new cases of lung cancer and 155,870 deaths from lung cancer in 2017. Non–small-cell lung carcinoma (NSCLC) accounts for 80%-85% of lung cancers, with adenocarcinoma being the most common histologic subtype. Other less common subtypes include squamous-cell carcinoma, large-cell carcinoma, and NSCLC that cannot be further classified.¹ Nearly 70% of patients present with locally advanced or metastatic disease at the time of diagnosis and are not candidates for surgical resection.² For that group of patients, the mainstay of treatment is platinum-based chemotherapy with or without radiation therapy. Patients who are chemotherapy naive often experience a modest response, however; durable remission is short lived, and the 5-year survival rate remains staggeringly low.³ Improved understanding of the molecular pathways that drive malignancy in NSCLC has led to the development of drugs that target specific molecular pathways.⁴ By definition, these driver mutations facilitate oncogenesis by conferring a selective advantage during clonal evolution.⁵ Moreover, agents targeting these pathways are extremely active and induce durable responses in many patients.^6,7,8

Predictive biomarkers in NSCLC include anaplastic lymphoma kinase (ALK) fusion oncogene and sensitizing epidermal growth factor receptor (EGFR) mutations. Mutations in the EGFR tyrosine kinase are observed in about 15%-20% of NSCLC adenocarcinomas in the United States and upward of 60% in Asian populations. They are also found more frequently in nonsmokers and women.⁶ The two most prevalent mutations in the EGFR tyrosine kinase domain are in-frame deletions of exon 19 and L858R substitution in exon 21, representing about 45% and 40% of mutations, respectively.⁹ Both mutations result in activation of the tyrosine kinase domain, and both are associated with sensitivity to the small-molecule tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib, and afatinib.¹⁰ Other drug-sensitive mutations include point mutations at exon 21 (L861Q) and exon 18 (G719X).¹¹ Targeted therapy produces durable responses in the majority of patients.^12,13,14 Unfortunately, most patients develop acquired resistance to these therapies, which leads to disease progression.^4,15-17

ALK gene rearrangements, although less prevalent, are another important molecular target in NSCLC and are seen in 2%-7% of cases in the United States.⁷ As with EGFR mutations, these mutations are more prevalent in nonsmokers, and they are found more commonly in younger patients and in men.⁸

Identification of driver mutations early in the course of disease and acquired resistance mutations later are crucial for the optimal management of advanced NSCLC. DNA analysis using polymerase chain reaction (PCR) and next-generation sequencing is the preferred method for testing for EGFR mutations, and ALK rearrangements are generally tested either by flourescence in situ hybridization (FISH) or immunohistochemistry.^18,19 Newer blood-based assays have shown great promise, and clinicians may soon have the ability to monitor subtle genetic changes, identify resistance patterns, and change therapy when acquired resistance occurs.²⁰

The American College of Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology have proposed guidelines for molecular testing in lung cancer. It is recommended that all advanced squamous and nonsquamous cell lung cancers with an adenocarcinoma component should be tested for EGFR and ALK mutations independent of age, sex, ethnicity, or smoking history. In the setting of smaller lung cancer specimens (eg, from biopsies, cytology) where an adenocarcinoma component cannot be completely excluded, EGFR and ALK testing may be performed in cases showing squamous or small cell histology but clinical criteria (eg, young age, lack of smoking history) may be useful in selecting a subset of these samples for testing. Samples obtained through surgical resection, open biopsy, endoscopy, transthoracic needle biopsy, fine-needle aspiration, and thoracentesis are all considered suitable for testing, but large biopsy samples are generally preferred over small biopsy samples, cell-blocks, and cytology samples.²¹ Despite this recommendation, not all patients who are eligible for mutation analysis are tested. At our institution, preliminary observations suggested that the percentage of patients being tested and the prevalence of driver mutations were significantly lower compared with published data. The purpose of this study was to evaluate physician attitudes about molecular testing, and to determine the rate of testing, the effect of biopsy sample size on rate of testing, and the prevalence of driver mutations at our institution.

Methods

In this retrospective clinical study, we identified 206 cases of advanced nsNSCLC from the tumor registry (February 2011-February 2013). Registry data was obtained from three hospitals within our health network – two academic tertiary care centers, and one community-based hospital. The other hospitals in the network were excluded because their EHR systems were not integrated with the rest of the hospitals and/or there was a lack of registry data. The testing rates for driver mutations, prevalence of driver mutations, and the tissue procurement techniques were obtained from individual chart review. Surgical specimens, core biopsy samples, and large volume thoracentesis specimens were categorized as large biopsy samples, and samples obtained by fine-needle aspiration, bronchial washing, and bronchial brushing were considered small biopsy samples. We used a chi-square analysis to compare mutation testing rates between the large and small biopsy sample groups. The prevalence of driver mutations was determined, excluding unknown or inadequate samples.

EGFR analysis had been conducted at Integrated Oncology, using formalin-fixed, paraffin-embedded tissue. Genomic DNA was isolated, and EGFR mutation analysis was performed using SNaPShot multiplex PCR, primer extension assay for exons 18-21; samples with >4mm² and ≥50% tumor content were preferred. Macrodissection was used to enrich for tumor cells when samples had lower tumor cellularity and content. ALK rearrangements were tested in the hospital using the Vysis ALK Break Apart FISH probe kit (Abott Molecular Inc, Des Plaines, IL).

We conducted a web-based, 20-question survey about molecular profiling among 110 practitioners to gauge their knowledge and opinions about molecular testing. The practitioners included medical oncologists, thoracic surgeons, pulmonologists, and interventional radiologists. Each received an initial e-mail informing them of the study, inviting them to complete survey, and providing a link to it, and two reminder e-mails at biweekly intervals to maximize survey participation and responses. The questions were aimed at understanding the challenges surrounding molecular testing within our network. Apart from the questions gathering demographic information about the respondents, the questions were intended to highlight the disparities between guideline recommendations and physician practices; to gauge the perceived importance of molecular evaluation; to identify individual, subspecialty, and hospital-based challenges; and to assess physician attitudes toward alternatives to traditional tissue-based testing (Table 1, p. e150). Nineteen of the questions were structured as single or best answer, whereas Question 9, which was aimed at identifying system-based challenges, allowed for multiple answer selections.

Results

There were a total of 206 cases of advanced stage IIIb or IV nsNSCLC identified at three hospitals during 2011-2013. Of those 206 cases, 161 (78.2%) were recorded at the two large academic medical centers, and 45 (21.9%) were recorded at the smaller community-based hospital. Of the total, there were 145 (70.4%) large biopsy specimens and 61 (29.6%) small biopsy specimens. We found that 89 of the 206 cases (43.2 %) had been tested for EGFR mutations, and 49 (23.8%) had been tested for ALK rearrangements (Figure, A and C). In all, 70 (48.3%) large-sample biopsies and 19 (31.1%) small-sample biopsies were submitted for EGFR analysis (Figure, B), and 42 (29%) large-sample biopsies and 7 (11.5%) small-sample biopsies were tested for ALK rearrangements (Figure, D). Large-sample biopsies were more likely to be analyzed for EGFR mutations and ALK rearrangements, with the results reaching statistical significance (P = .023 and P = .007, respectively). Across all samples, a total of 7 EGFR mutations and 1 ALK rearrangement were identified, yielding a prevalence of 7.9% and 2% respectively (Figure, A and C).

The average age at diagnosis of the patients in the cases that were analyzed was 69.3 years. Most of the patients (83.9%) identified as white, 3.8% were African American, and 12.6% were in the Unknown category. Of the total number of patients, 11 were identified as never-smokers (5.3%), 50 (24.3%) had a 1-15 pack-year smoking history, 104 (50.5%) had a 16-45 pack-year smoking history, and 41 (19.9%) had a >45 pack-year smoking history.

In regard to the survey, 46 of the 110 physicians asked to participate in the survey responded, representing a response rate of 41.8% (range across medical specialties, 26%-45%, Table 4). Of those respondents, 38 (82.6%) indicated they believed molecular evaluation was a very important aspect of NSCLC care, with the remainder indicating it was somewhat important. 91.4% of the respondents who routinely ordered molecular testing agreed that stage IIIb or IV nsNSCLC should undergo molecular evaluation.

Discussion

The treatment of advanced nsNSCLC has evolved significantly over the past decade. Molecular profiling is now an essential part of initial evaluation, and larger-sample biopsies are needed to ensure accurate evaluation and appropriate treatment. The detection of EGFR and EML4-ALK driver mutations are associated with increased response to tyrosine kinase inhibitors and are associated with improvement in progression-free survival, patient quality of life, and even overall survival in some studies.^12,22,23,24 Early identification of these driver mutations is crucial, however, preliminary observation in our network suggested that a large percentage of patients with advanced nsNSCLC in were not being appropriately evaluated for those mutations. To evaluate our molecular profiling rates, we conducted a retrospective study and reviewed 3 years of registry data at 3 hospitals within our health system. Two of the hospitals included in our analysis were large tertiary academic centers, and one was a community hospital. Our findings confirmed that a large percentage of our patients who are eligible for molecular evaluation are not tested: 56.7% of cases were not tested for EGFR mutations, and 76.2% of cases were not tested for ALK rearrangements.

In a similar study, the Association for Community Cancer Centers conducted a project aimed at understanding the landscape and current challenges for molecular profiling in NSCLC. Eight institutions participated in the study, and baseline testing rates were analyzed. The findings demonstrated that high-volume institutions (treating >100 lung cancer patients a year tested 62% and 60% of advanced lung cancer patients for EGFR and EML4-ALK, respectively, and low-volume institutions (treating <100 lung cancer patients a year tested 52% and 47% for EGFR and EML4-ALK, respectively.^25,26 In a recent international physician self-reported survey, Spicer and colleagues found that EGFR testing was requested before first-line therapy in patients with stage IIIB or IV disease in 81% of cases, and mutation results were available before start of therapy in 77% of the cases.²⁷ Those percentages are relatively low, given that current guidelines recommend that molecular testing should be done for all patients with stage IIIB or IV nsNSCLC. This highlights the need for objective performance feedback so oncologists can make the necessary practice changes so that molecular testing is done before the start of therapy to ensure high-quality cancer care that will translate into better, cost-effective outcomes and improved patient quality of life.

Our study findings showed that the prevalence of EGFR and ALK mutations is substantially lower among the patients we treat in our network compared with other published data on prevalence. The reason for those low rates is not clear, but it is likely multifactorial. First, Western Pennsylvania, the region our network serves, has a large proportion of older adults – 17.3% of the population is older than 65 years (national average, 14.5%) and advanced age might have contributed to the lower EGFR and ALK rates measured in our study.²⁸ Second, the smoking rate in Pennsylvania is higher than the national average, 20%-24% compared with 18%, respectively.²⁹ Third, the air quality in Western Pennsylvania has historically been very poor as a result of the large steel and coal mining industries. Even though the air quality has improved in recent decades, the American Lung Association’s 2017 State of the Air report ranked Pittsburgh and surrounding areas in Western Pennsylvania among the top 25 most air polluted areas in the United States.³⁰ It is not certain whether air pollution and air quality have any impact on driver mutation rates, but the correlation with smoking, ethnicity, and geographic distribution highlight the need for further epidemiologic studies.

Biopsy sufficiency – getting an adequate amount of sample tissue during biopsy – is a known challenge to molecular profiling, and we found that biopsy sample size had an impact on the testing rates in a large percentage of our cases. To fully understand the impact of biopsy sufficiency, we conducted a subset analysis and compared the testing rates between our large and small biopsy samples. Our analysis showed that larger-sample biopsies were more likely to be tested for mutations than were smaller-sample biopsies (EGFR: P = .023; ALK: P = .007).

Those results suggest that larger-sample biopsies should be encouraged, but procedural risks, tumor location, and patient age and wishes need to be considered before tissue acquisition.²¹ Furthermore, clinicians who are responsible for tissue procurement need to be properly educated on the tissue sample requirements and the impact these results have on treatment decisions.³¹ Our institution, like many others, has adopted rapid onsite evaluation (ROSE) of biopsy samples, whereby a trained cytopathologist reviews sample adequacy at the time of tissue procurement. Although there is scant data directly comparing molecular testing success rates with and without the ROSE protocol, a meta-analysis conducted by Schmidt and colleagues concluded that ROSE improved the adequacy rate of fine-needle aspiration cytology by 12%.^32,33 Given that molecular profiling depends on both the absolute and relative amount of tumor cells present in the sample, the ROSE protocol likely enhances the procedural success rate and reduces the need for repeat and subsequent biopsies.

It is interesting to note that our data also demonstrated that we are obtaining large-sample biopsies in most of our patients (about 70%). However, we are still failing to test more than half of our cases for driver mutations (Figure, A and C). This strongly suggests there are additional factors beyond tissue adequacy that are contributing to our high failure rate. It is essential to understand the dynamics and system practices that influence testing rates if we are to improve the care and outcomes of our cancer patients. To better understand those barriers, we surveyed 110 practitioners (including medical oncologists, pulmonologists, thoracic surgeons, and interventional radiologists) about the molecular profiling process and their responses highlighted several important areas that deserve special attention (Tables 1, 4, 5).

In our institution, testing initiation is primarily the responsibility of the treating medical oncologist. This presents a challenge because there is often a significant delay between tissue acquisition, histologic confirmation, and oncologic review. Many institutions have adopted pathology-driven reflex testing to help overcome such delays. Automatic testing after pathologic confirmation streamlines the process, increases testing rates, and eliminates unnecessary delay between the time of diagnosis and the time of test ordering.³⁴ It also allows for the molecular and histologic diagnosis to be integrated into a single pathology report before therapy is initiated.

Another barrier to timely testing according to the respondents, was the CMS’s 14-day rule. The 14-day rule requires hospitals to wait 14 days after the patient is discharged for the lab to receive reimbursement for molecular testing and was frequently identified as a cause for significant delay in testing and having an impact on first-line treatment decisions.^35,36

Often clinicians will choose to defer testing until this time has elapsed to reduce the financial burden placed on the hospital but by that time, they might well have initiated treatment without knowing if the patient has a mutation. This is a significant challenge identified by many of our oncologists, and is a limitation to our analysis above as it is unclear what percentage of patients received follow up testing once care was established at an outside facility and once the 14-day time period had elapsed.

The data from our institution suggests there is discordance between physician attitudes and molecular testing practices. However, there are several limitations in our study. First, most of the survey respondents agreed that molecular testing is an important aspect of treating advanced lung cancer patients, but the retrospective nature of the study made it difficult to identify why testing was deferred or never conducted. Second, the absence of a centralized reporting system for molecular testing results at our institution, may have resulted in an overestimation of our testing failure rate in cases where results were not integrated our electronic medical record.

Third, the low survey response rate only allowed us to make generalizations regarding the conclusions, although it does provide a framework for future process improvements.

We believe the poor testing rates observed in our study are not isolated to our institution and reflect a significant challenge within the broader oncology community.²⁷ A system of best practices is essential for capturing this subset of patients who are never tested. There is agreement among oncologists that improving our current testing rates will require a multidisciplinary approach, a refined process for molecular evaluation, a push toward reflex testing, and standardization of biopsy techniques and tissue handling procedures. In our institution, we have initiated a Lean Six Sigma and PDSA (plan, do, study, act) initiative to improve our current molecular testing process. In addition, because obtaining larger-sample biopsies or additional biopsies is often not feasible for many of our advanced cancer patients, we have started using whole blood circulating tumor cells (CTC) and plasma ctDNA (cell-free circulating DNA) for molecular testing. Recent studies have shown high concordance (89%) between tissue biopsies and blood-based mutation testing, which will likely have a positive impact on the cancer care of our patients and help to capture a subset of patients who are not candidates for traditional biopsies.³⁷

Conclusions

Despite current guidelines for testing driver mutations in advanced nsNSCLC, a large segment of our patients are not being tested for those genetic aberrations. There are several barriers that continue to thwart the recommendation, including failure to integrate driver mutation testing into routine pathology practice (ie, reflex testing), insufficient tissue obtained from biopsy, and difficulty in obtaining tissue because of tumor location or risk of complications from the biopsy procedure. More important, these trends are not isolated to our institution and reflect a significant challenge within the oncology community. Our data show that for the purpose of driver mutation testing, larger-sample biopsies, such as surgical/core biopsies, are better than small-sample biopsies, such as needle aspiration. We have also demonstrated that the prevalence of driver mutations is lower in Western Pennsylvania, which is served by our network, than elsewhere in the United States.

Lung cancer is the leading cause of cancer death in the United States. It is estimated that there will be 222,500 new cases of lung cancer and 155,870 deaths from lung cancer in 2017. Non–small-cell lung carcinoma (NSCLC) accounts for 80%-85% of lung cancers, with adenocarcinoma being the most common histologic subtype. Other less common subtypes include squamous-cell carcinoma, large-cell carcinoma, and NSCLC that cannot be further classified.¹ Nearly 70% of patients present with locally advanced or metastatic disease at the time of diagnosis and are not candidates for surgical resection.² For that group of patients, the mainstay of treatment is platinum-based chemotherapy with or without radiation therapy. Patients who are chemotherapy naive often experience a modest response, however; durable remission is short lived, and the 5-year survival rate remains staggeringly low.³ Improved understanding of the molecular pathways that drive malignancy in NSCLC has led to the development of drugs that target specific molecular pathways.⁴ By definition, these driver mutations facilitate oncogenesis by conferring a selective advantage during clonal evolution.⁵ Moreover, agents targeting these pathways are extremely active and induce durable responses in many patients.^6,7,8

Predictive biomarkers in NSCLC include anaplastic lymphoma kinase (ALK) fusion oncogene and sensitizing epidermal growth factor receptor (EGFR) mutations. Mutations in the EGFR tyrosine kinase are observed in about 15%-20% of NSCLC adenocarcinomas in the United States and upward of 60% in Asian populations. They are also found more frequently in nonsmokers and women.⁶ The two most prevalent mutations in the EGFR tyrosine kinase domain are in-frame deletions of exon 19 and L858R substitution in exon 21, representing about 45% and 40% of mutations, respectively.⁹ Both mutations result in activation of the tyrosine kinase domain, and both are associated with sensitivity to the small-molecule tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib, and afatinib.¹⁰ Other drug-sensitive mutations include point mutations at exon 21 (L861Q) and exon 18 (G719X).¹¹ Targeted therapy produces durable responses in the majority of patients.^12,13,14 Unfortunately, most patients develop acquired resistance to these therapies, which leads to disease progression.^4,15-17

ALK gene rearrangements, although less prevalent, are another important molecular target in NSCLC and are seen in 2%-7% of cases in the United States.⁷ As with EGFR mutations, these mutations are more prevalent in nonsmokers, and they are found more commonly in younger patients and in men.⁸

Identification of driver mutations early in the course of disease and acquired resistance mutations later are crucial for the optimal management of advanced NSCLC. DNA analysis using polymerase chain reaction (PCR) and next-generation sequencing is the preferred method for testing for EGFR mutations, and ALK rearrangements are generally tested either by flourescence in situ hybridization (FISH) or immunohistochemistry.^18,19 Newer blood-based assays have shown great promise, and clinicians may soon have the ability to monitor subtle genetic changes, identify resistance patterns, and change therapy when acquired resistance occurs.²⁰

The American College of Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology have proposed guidelines for molecular testing in lung cancer. It is recommended that all advanced squamous and nonsquamous cell lung cancers with an adenocarcinoma component should be tested for EGFR and ALK mutations independent of age, sex, ethnicity, or smoking history. In the setting of smaller lung cancer specimens (eg, from biopsies, cytology) where an adenocarcinoma component cannot be completely excluded, EGFR and ALK testing may be performed in cases showing squamous or small cell histology but clinical criteria (eg, young age, lack of smoking history) may be useful in selecting a subset of these samples for testing. Samples obtained through surgical resection, open biopsy, endoscopy, transthoracic needle biopsy, fine-needle aspiration, and thoracentesis are all considered suitable for testing, but large biopsy samples are generally preferred over small biopsy samples, cell-blocks, and cytology samples.²¹ Despite this recommendation, not all patients who are eligible for mutation analysis are tested. At our institution, preliminary observations suggested that the percentage of patients being tested and the prevalence of driver mutations were significantly lower compared with published data. The purpose of this study was to evaluate physician attitudes about molecular testing, and to determine the rate of testing, the effect of biopsy sample size on rate of testing, and the prevalence of driver mutations at our institution.

Methods

In this retrospective clinical study, we identified 206 cases of advanced nsNSCLC from the tumor registry (February 2011-February 2013). Registry data was obtained from three hospitals within our health network – two academic tertiary care centers, and one community-based hospital. The other hospitals in the network were excluded because their EHR systems were not integrated with the rest of the hospitals and/or there was a lack of registry data. The testing rates for driver mutations, prevalence of driver mutations, and the tissue procurement techniques were obtained from individual chart review. Surgical specimens, core biopsy samples, and large volume thoracentesis specimens were categorized as large biopsy samples, and samples obtained by fine-needle aspiration, bronchial washing, and bronchial brushing were considered small biopsy samples. We used a chi-square analysis to compare mutation testing rates between the large and small biopsy sample groups. The prevalence of driver mutations was determined, excluding unknown or inadequate samples.

EGFR analysis had been conducted at Integrated Oncology, using formalin-fixed, paraffin-embedded tissue. Genomic DNA was isolated, and EGFR mutation analysis was performed using SNaPShot multiplex PCR, primer extension assay for exons 18-21; samples with >4mm² and ≥50% tumor content were preferred. Macrodissection was used to enrich for tumor cells when samples had lower tumor cellularity and content. ALK rearrangements were tested in the hospital using the Vysis ALK Break Apart FISH probe kit (Abott Molecular Inc, Des Plaines, IL).

We conducted a web-based, 20-question survey about molecular profiling among 110 practitioners to gauge their knowledge and opinions about molecular testing. The practitioners included medical oncologists, thoracic surgeons, pulmonologists, and interventional radiologists. Each received an initial e-mail informing them of the study, inviting them to complete survey, and providing a link to it, and two reminder e-mails at biweekly intervals to maximize survey participation and responses. The questions were aimed at understanding the challenges surrounding molecular testing within our network. Apart from the questions gathering demographic information about the respondents, the questions were intended to highlight the disparities between guideline recommendations and physician practices; to gauge the perceived importance of molecular evaluation; to identify individual, subspecialty, and hospital-based challenges; and to assess physician attitudes toward alternatives to traditional tissue-based testing (Table 1, p. e150). Nineteen of the questions were structured as single or best answer, whereas Question 9, which was aimed at identifying system-based challenges, allowed for multiple answer selections.

Results

There were a total of 206 cases of advanced stage IIIb or IV nsNSCLC identified at three hospitals during 2011-2013. Of those 206 cases, 161 (78.2%) were recorded at the two large academic medical centers, and 45 (21.9%) were recorded at the smaller community-based hospital. Of the total, there were 145 (70.4%) large biopsy specimens and 61 (29.6%) small biopsy specimens. We found that 89 of the 206 cases (43.2 %) had been tested for EGFR mutations, and 49 (23.8%) had been tested for ALK rearrangements (Figure, A and C). In all, 70 (48.3%) large-sample biopsies and 19 (31.1%) small-sample biopsies were submitted for EGFR analysis (Figure, B), and 42 (29%) large-sample biopsies and 7 (11.5%) small-sample biopsies were tested for ALK rearrangements (Figure, D). Large-sample biopsies were more likely to be analyzed for EGFR mutations and ALK rearrangements, with the results reaching statistical significance (P = .023 and P = .007, respectively). Across all samples, a total of 7 EGFR mutations and 1 ALK rearrangement were identified, yielding a prevalence of 7.9% and 2% respectively (Figure, A and C).

The average age at diagnosis of the patients in the cases that were analyzed was 69.3 years. Most of the patients (83.9%) identified as white, 3.8% were African American, and 12.6% were in the Unknown category. Of the total number of patients, 11 were identified as never-smokers (5.3%), 50 (24.3%) had a 1-15 pack-year smoking history, 104 (50.5%) had a 16-45 pack-year smoking history, and 41 (19.9%) had a >45 pack-year smoking history.

In regard to the survey, 46 of the 110 physicians asked to participate in the survey responded, representing a response rate of 41.8% (range across medical specialties, 26%-45%, Table 4). Of those respondents, 38 (82.6%) indicated they believed molecular evaluation was a very important aspect of NSCLC care, with the remainder indicating it was somewhat important. 91.4% of the respondents who routinely ordered molecular testing agreed that stage IIIb or IV nsNSCLC should undergo molecular evaluation.

Discussion

The treatment of advanced nsNSCLC has evolved significantly over the past decade. Molecular profiling is now an essential part of initial evaluation, and larger-sample biopsies are needed to ensure accurate evaluation and appropriate treatment. The detection of EGFR and EML4-ALK driver mutations are associated with increased response to tyrosine kinase inhibitors and are associated with improvement in progression-free survival, patient quality of life, and even overall survival in some studies.^12,22,23,24 Early identification of these driver mutations is crucial, however, preliminary observation in our network suggested that a large percentage of patients with advanced nsNSCLC in were not being appropriately evaluated for those mutations. To evaluate our molecular profiling rates, we conducted a retrospective study and reviewed 3 years of registry data at 3 hospitals within our health system. Two of the hospitals included in our analysis were large tertiary academic centers, and one was a community hospital. Our findings confirmed that a large percentage of our patients who are eligible for molecular evaluation are not tested: 56.7% of cases were not tested for EGFR mutations, and 76.2% of cases were not tested for ALK rearrangements.

In a similar study, the Association for Community Cancer Centers conducted a project aimed at understanding the landscape and current challenges for molecular profiling in NSCLC. Eight institutions participated in the study, and baseline testing rates were analyzed. The findings demonstrated that high-volume institutions (treating >100 lung cancer patients a year tested 62% and 60% of advanced lung cancer patients for EGFR and EML4-ALK, respectively, and low-volume institutions (treating <100 lung cancer patients a year tested 52% and 47% for EGFR and EML4-ALK, respectively.^25,26 In a recent international physician self-reported survey, Spicer and colleagues found that EGFR testing was requested before first-line therapy in patients with stage IIIB or IV disease in 81% of cases, and mutation results were available before start of therapy in 77% of the cases.²⁷ Those percentages are relatively low, given that current guidelines recommend that molecular testing should be done for all patients with stage IIIB or IV nsNSCLC. This highlights the need for objective performance feedback so oncologists can make the necessary practice changes so that molecular testing is done before the start of therapy to ensure high-quality cancer care that will translate into better, cost-effective outcomes and improved patient quality of life.

Our study findings showed that the prevalence of EGFR and ALK mutations is substantially lower among the patients we treat in our network compared with other published data on prevalence. The reason for those low rates is not clear, but it is likely multifactorial. First, Western Pennsylvania, the region our network serves, has a large proportion of older adults – 17.3% of the population is older than 65 years (national average, 14.5%) and advanced age might have contributed to the lower EGFR and ALK rates measured in our study.²⁸ Second, the smoking rate in Pennsylvania is higher than the national average, 20%-24% compared with 18%, respectively.²⁹ Third, the air quality in Western Pennsylvania has historically been very poor as a result of the large steel and coal mining industries. Even though the air quality has improved in recent decades, the American Lung Association’s 2017 State of the Air report ranked Pittsburgh and surrounding areas in Western Pennsylvania among the top 25 most air polluted areas in the United States.³⁰ It is not certain whether air pollution and air quality have any impact on driver mutation rates, but the correlation with smoking, ethnicity, and geographic distribution highlight the need for further epidemiologic studies.

Biopsy sufficiency – getting an adequate amount of sample tissue during biopsy – is a known challenge to molecular profiling, and we found that biopsy sample size had an impact on the testing rates in a large percentage of our cases. To fully understand the impact of biopsy sufficiency, we conducted a subset analysis and compared the testing rates between our large and small biopsy samples. Our analysis showed that larger-sample biopsies were more likely to be tested for mutations than were smaller-sample biopsies (EGFR: P = .023; ALK: P = .007).

Those results suggest that larger-sample biopsies should be encouraged, but procedural risks, tumor location, and patient age and wishes need to be considered before tissue acquisition.²¹ Furthermore, clinicians who are responsible for tissue procurement need to be properly educated on the tissue sample requirements and the impact these results have on treatment decisions.³¹ Our institution, like many others, has adopted rapid onsite evaluation (ROSE) of biopsy samples, whereby a trained cytopathologist reviews sample adequacy at the time of tissue procurement. Although there is scant data directly comparing molecular testing success rates with and without the ROSE protocol, a meta-analysis conducted by Schmidt and colleagues concluded that ROSE improved the adequacy rate of fine-needle aspiration cytology by 12%.^32,33 Given that molecular profiling depends on both the absolute and relative amount of tumor cells present in the sample, the ROSE protocol likely enhances the procedural success rate and reduces the need for repeat and subsequent biopsies.

It is interesting to note that our data also demonstrated that we are obtaining large-sample biopsies in most of our patients (about 70%). However, we are still failing to test more than half of our cases for driver mutations (Figure, A and C). This strongly suggests there are additional factors beyond tissue adequacy that are contributing to our high failure rate. It is essential to understand the dynamics and system practices that influence testing rates if we are to improve the care and outcomes of our cancer patients. To better understand those barriers, we surveyed 110 practitioners (including medical oncologists, pulmonologists, thoracic surgeons, and interventional radiologists) about the molecular profiling process and their responses highlighted several important areas that deserve special attention (Tables 1, 4, 5).

In our institution, testing initiation is primarily the responsibility of the treating medical oncologist. This presents a challenge because there is often a significant delay between tissue acquisition, histologic confirmation, and oncologic review. Many institutions have adopted pathology-driven reflex testing to help overcome such delays. Automatic testing after pathologic confirmation streamlines the process, increases testing rates, and eliminates unnecessary delay between the time of diagnosis and the time of test ordering.³⁴ It also allows for the molecular and histologic diagnosis to be integrated into a single pathology report before therapy is initiated.

Another barrier to timely testing according to the respondents, was the CMS’s 14-day rule. The 14-day rule requires hospitals to wait 14 days after the patient is discharged for the lab to receive reimbursement for molecular testing and was frequently identified as a cause for significant delay in testing and having an impact on first-line treatment decisions.^35,36

Often clinicians will choose to defer testing until this time has elapsed to reduce the financial burden placed on the hospital but by that time, they might well have initiated treatment without knowing if the patient has a mutation. This is a significant challenge identified by many of our oncologists, and is a limitation to our analysis above as it is unclear what percentage of patients received follow up testing once care was established at an outside facility and once the 14-day time period had elapsed.

The data from our institution suggests there is discordance between physician attitudes and molecular testing practices. However, there are several limitations in our study. First, most of the survey respondents agreed that molecular testing is an important aspect of treating advanced lung cancer patients, but the retrospective nature of the study made it difficult to identify why testing was deferred or never conducted. Second, the absence of a centralized reporting system for molecular testing results at our institution, may have resulted in an overestimation of our testing failure rate in cases where results were not integrated our electronic medical record.

Third, the low survey response rate only allowed us to make generalizations regarding the conclusions, although it does provide a framework for future process improvements.

We believe the poor testing rates observed in our study are not isolated to our institution and reflect a significant challenge within the broader oncology community.²⁷ A system of best practices is essential for capturing this subset of patients who are never tested. There is agreement among oncologists that improving our current testing rates will require a multidisciplinary approach, a refined process for molecular evaluation, a push toward reflex testing, and standardization of biopsy techniques and tissue handling procedures. In our institution, we have initiated a Lean Six Sigma and PDSA (plan, do, study, act) initiative to improve our current molecular testing process. In addition, because obtaining larger-sample biopsies or additional biopsies is often not feasible for many of our advanced cancer patients, we have started using whole blood circulating tumor cells (CTC) and plasma ctDNA (cell-free circulating DNA) for molecular testing. Recent studies have shown high concordance (89%) between tissue biopsies and blood-based mutation testing, which will likely have a positive impact on the cancer care of our patients and help to capture a subset of patients who are not candidates for traditional biopsies.³⁷

Conclusions

Despite current guidelines for testing driver mutations in advanced nsNSCLC, a large segment of our patients are not being tested for those genetic aberrations. There are several barriers that continue to thwart the recommendation, including failure to integrate driver mutation testing into routine pathology practice (ie, reflex testing), insufficient tissue obtained from biopsy, and difficulty in obtaining tissue because of tumor location or risk of complications from the biopsy procedure. More important, these trends are not isolated to our institution and reflect a significant challenge within the oncology community. Our data show that for the purpose of driver mutation testing, larger-sample biopsies, such as surgical/core biopsies, are better than small-sample biopsies, such as needle aspiration. We have also demonstrated that the prevalence of driver mutations is lower in Western Pennsylvania, which is served by our network, than elsewhere in the United States.