Physical activity has numerous physical, mental, and psychosocial benefits for cancer survivors, such as a reduction in the risk of mobility disability, depression, and anxiety, and improved patient quality of life.^1,2 In addition, higher levels of physical activity are associated with reduced cancer-specific and all-causes mortality as well as cancer-specific outcomes including reduced risk of cancer progression and recurrence and new primary cancers.^3-5 However, fewer than one-third of cancer survivors are meeting government and cancer-specific recommendations of 150 minutes a week of moderate to vigorous physical activity (MPVA; ≥3 metabolic equivalents [METs]).^6,7 Growing evidence also demonstrates a significant association between higher levels of sedentary behavior and many deleterious health effects after cancer, including an increased risk for decreased physical functioning and development of other chronic diseases such as cardiovascular disease or diabetes.⁸ Distinct from physical activity, sedentary behavior is defined as any waking activity resulting in low levels of energy expenditure (≤1.5 METs) while in a seated or reclined position.⁹ Increased sedentary behavior, even when controlling for moderate and vigorous physical activity (MVPA), is associated with poor quality of life and increased all-cause mortality in cancer survivors.^10,11 Given the associations observed between higher levels of physical activity, lower levels of sedentary behavior, and improved health and disease outcomes among the large and increasing number of cancer survivors in the United States, it is important to identify low-cost methods that can be used in a in a variety of settings (ie, research, clinical, community) to accurately and efficiently measure survivors’ lifestyle behaviors to identify high-risk survivors for early intervention, better understand the effects of these behaviors on survivors’ health outcomes and disease trajectories, and ultimately, improve survivors’ health and quality of life.^12,13

Two methods commonly used to capture physical activity and sedentary behavior across the lifespan are accelerometry (Actigraph, Pensacola, FL) and self-report questionnaires such as the Godin Leisure-Time Questionnaire (GLTEQ), International Physical Activity Questionnaire (IPAQ), and Sitting Time Questionnaire (STQ).^14-17 Each method has unique strengths and weaknesses. Sending accelerometers to multiple individuals at a single time point can be costly, particularly in large-scale epidemiological studies, and the accelerometer’s waist-worn, nonwaterproof design may prevent researchers from capturing certain activities such as swimming and resistance training. However, the accelerometer provides objective, precise assessments of most physical activities and may help remove response bias.¹⁸ Conversely, self-report questionnaires rely solely on individuals’ memories and often result in recall bias, inaccurate reporting, and under- or overestimation of physical activity engagement.^19,20 Nevertheless, these questionnaires can be widely disseminated at low cost in a variety of settings (eg, clinical, research, community) and are less of a burden to participants.

Recent studies comparing objective (eg, accelerometer) with subjective (eg, self-report) methods of measuring physical activity and sedentary behavior in healthy middle-aged adults and older adults have demonstrated mixed findings with no distinct trends in the degree to which these methods differ.^19,21,22 To date, little consideration has been given to the measurement of these lifestyle behaviors in cancer survivors. Boyle and colleagues recently investigated the concurrent validity of an accelerometer to the GLTEQ in colon cancer survivors, finding significant differences in estimated MVPA (~11 minutes). However, no studies, to our knowledge, have compared accelerometer and self-report measures in breast cancer survivors, so it remains unclear how these different measurement tools relate to each another in this population.

It is particularly important to compare these measurement tools among breast cancer survivors because evidence indicates this population’s behavioral habits, self-perceived activity, and sitting time and movement patterns may differ significantly from the general population and other survivor groups across the lifespan.^23,24 Further, previous studies examining these behaviors in cancer survivors focused primarily on sitting time and MVPA.^15,25,26 Examining other lower-intensity intensities (eg, light activity or lifestyle) in cancer survivors may also be important given that increased levels of activity are associated with health benefits, ranging from reduced disability and fatigue to improved cardiovascular health and quality of life, and that breast cancer survivors engage in fewer of these activities compared with noncancer controls.²³ These lower levels of physical activity may be more prevalent among cancer survivors of their high levels of fatigue and propensity toward increased sitting time during the first year of treatment,¹¹ so it is important to be able to accurately assess these activities in this population. The purpose of the present study was to compare estimates of time spent in light physical activity (LPA), MVPA, and sitting time (ST) obtained from an accelerometer and 3 self-report measurement tools (GLTEQ, IPAQ, STQ) in a large, US-based sample of breast cancer survivors. A secondary purpose was to determine whether estimate comparisons among measurements changed by participant characteristics.
 

Methods

Participants and procedures

This study consisted of a subsample of women who participated in a larger study whose findings have been reported elsewhere by Phillips and McAuley.²⁷ In that study, breast cancer survivors (n = 1,631) were recruited nationally to participate in a 6-month prospective study on quality of life. Eligibility criteria included being aged 18 years or older, having had a diagnosis of breast cancer, being English speaking, and having access to the internet. Once consented to participate in the study, 500 women were randomly selected to wear the accelerometer.

Participants in this group were mailed an accelerometer, an activity log, instructions for use, and a self-addressed stamped envelope to return the monitor. They were asked to wear the accelerometer during all waking hours for 7 consecutive days of usual activity. They were also sent a secure link to complete 3 activity questionnaires online. The questionnaires were to be completed by the end of the 7-day monitoring period. Only women with 3 or more valid days of accelerometer data and complete data on variables of interest (n = 414) were included in the present analyses. All of the participants consented to the study procedures approved by the University of Illinois Institutional Review Board.
 

Measures

Demographics. The participants self-reported their age, level of education, height, and weight. Their body mass index (BMI; kg/m²) was estimated using the standard equation. They also self-reported their health and cancer history, detailing breast cancer disease stage, time since diagnosis, treatment type, and whether they had had a cancer recurrence. They were also asked to report whether they had ever been diagnosed (Yes/No) with 18 chronic conditions (eg, diabetes, arthritis).

Godin Leisure-Time Exercise Questionnaire.¹⁶ The GLTEQ assessed participants’ weekly frequency and mean amount of time performing MVPA (moderate exercise, such as fast walking, combined with vigorous exercise, such as jogging), and LPA (light/mild exercise, eg, easy walking) during the previous 7 days. The mean daily duration (in minutes) for each intensity category (MVPA, LPA) was calculated using activity frequencies and the amount of time spent in each activity presented as minutes/day.

The International Physical Activity Questionnaire.¹⁴ The IPAQ evaluated participants’ physical activity of at least moderate intensity in 4 domains of everyday life: job-related physical activity, transportation, housework/caring for family, and leisure-time activity. Within each domain, participants were asked the number of days per week and time per day (hours and minutes) spent performing MVPA. To estimate sitting time, the questionnaire asks participants to report the total amount of time spent sitting per day in 2 conditions, during weekdays and during weekends. The present analysis averaged sitting time for a typical 7-day (5 week days, 2 weekend days) period. We multiplied reported minutes per day and frequency per week of each activity category (MVPA and ST) to calculate the mean number of minutes per day.^29,30

Sitting Time Questionnaire.^17,28 The STQ estimated the mean time (hours and minutes) participants spent sitting each day on weekdays and at weekends within 5 domains: while traveling to and from places, at work, watching television, using a computer at home, and at leisure, not including watching television (eg, visiting friends, movies, dining out). Mean minutes per day of ST were calculated using all sitting domains.

Actigraph accelerometer (model GT1M, Health One Technology, Fort Walton Beach, FL). The Actigraph GT1M is a reliable and objective measure of physical activity.^31-33 Participants wore the monitor on the right hip for 7 consecutive days during all waking hours, except when bathing or swimming. Activity data was analyzed in 1-minute intervals. A valid day of accelerometer wear time was defined as ≥600 minutes with no more than 60 minutes of consecutive zero-values, with allowance of 2 minutes or fewer of observations <100 counts/minute within the nonwear interval.³⁴ Each minute of wear time was classified according to intensity (counts/min) using the following cut-points:³⁴ sedentary, <100 counts/min; LPA, 100-2,019 counts/min; and MVPA, ≥2,020 count/min. Mean daily durations (min/day) spent in each behavior were estimated by dividing the number of minutes in each category by the number of valid days.

Statistical analysis

All statistical analyses were completed in SPSS Statistics 23 (IBM, Chicago, IL). Descriptive statistics were used to define participant characteristics. Rank-order correlation between the methods was assessed using Spearman’s rho (r_s) and results were interpreted as follows: r_s = 0.10, small; 0.30, moderate; and 0.50, strong.³⁵ Within each activity intensity group, we jointly modeled daily minutes of self-report and accelerometer data using a random-intercept mixed-effects regression model. Differences between measurement tools were assessed based on regression coefficients with accelerometer as the reference category. Finally, we did a post hoc analysis of leisure-time–only MVPA from the IPAQ to compare with other estimates of MVPA.

We calculated the measurement tool difference scores for each estimated intensity category (ST, LPA, MVPA), that is, accelerometer estimated ST minus STQ estimated ST, and GLTEQ estimated MVPA minus IPAQ estimated MVPA. We used these data in an exploratory analysis to examine whether there were statistically significant differences between measurement difference scores by demographic or disease characteristics using linear regression stratified analyses. For example, we were interested in whether there was a significant difference in measurement tool estimates for sitting time in older compared with younger survivors. Analyses were stratified by age (<60/≥60 years), body mass index (<25 kg/m²/≥25 kg/m²), race (white/people of color), disease stage (I and II/III and IV), years since diagnosis (≤5 years/>5 years), recurrence (Yes/No), received chemotherapy (Yes/No ), received radiation (Yes/No ), and the presence of 1 or more chronic diseases (Yes/No ).

Results

Participants

The mean age of the participants was 56.8 years [9.2], they were overweight (BMI, 26.2 kg/m² [5.4]), and predominantly white (96.7%; Table 1). Table 2 provides a summary of mean daily duration of activity estimates for ST, LPA, and MVPA and the estimate mean difference scores between measurements.

Moderate and vigorous physical activity

Accelerometer−GLTEQ. The mean difference in MVPA estimates between the accelerometer and GLTEQ was less than 5 minutes (M_{accelerometer} = 20.2 minutes; M_GLTEQ = 23.6 minutes), even though the difference was statistically significant (P = .02). Estimates of MVPA from the accelerometer and GLTEQ (r_s = 0.564, P < .001) showed a strong relationship. Stratified analyses showed that the difference scores between the GLTEQ and accelerometer were lower for older survivors (≥60 years) compared with younger survivors such that older survivors reported significantly less time in MVPA on the GLTEQ compared with accelerometer estimates (difference score [D] = 6.8 minutes less, P = .001).

Accelerometer−IPAQ. The accelerometer estimated significantly fewer minutes of MVPA per day when compared with the IPAQ (M_diff = -67.4; 95% confidence interval [CI], -78.6, -55.8; P < .001). Estimates of MVPA from the accelerometer and IPAQ (r_s = 0.011, P = .680) were poorly related. Differences between the IPAQ and accelerometer were greater for later-stage breast cancer, compared with early-stage diagnoses such that participants with late-stage disease reported significantly less MVPA on the IPAQ compared with accelerometer estimates (D = 41.8 minutes less than early-stage disease, P = .018). Finally, participants of color reported a greater difference in MVPA between the accelerometer and the IPAQ than did their white counterparts (D = 47.5 minutes, P = .033).

GLTEQ−IPAQ. GLTEQ estimated significantly fewer minutes of MVPA per day compared with the IPAQ (M_diff = -64.6; 95% CI, -76.6, -52.5; P < .001). The estimates of MVPA from the GLTEQ had a small correlation with IPAQ estimates (r_s = 0.128, P = .011).

IPAQ estimates showed almost triple the MVPA minutes per day as were estimated by the accelerometer and GLTEQ. As the MVPA estimate for the IPAQ include nonleisure activities, we conducted a post hoc analyses that only included the leisure-time items from the IPAQ. Leisure-time only IPAQ items, estimates indicated survivors spent a mean 18.5 [SD, 14.2] min/day in MVPA. Although the magnitude of the difference between the accelerometer and GLTEQ estimates (~10 minutes) was much smaller using the leisure-time only IPAQ items, a repeated measures analysis of variance revealed there was still a significant difference between these estimates (P < .05 for both) and negligible correlation.

Light intensity physical activity

Accelerometer−GLTEQ. There was a large and significant difference between LPA estimates from the GLTEQ and accelerometer (M_diff = 224.5; 95% CI, 218.2, 230.7; P < .001) with estimates from the accelerometer being higher than those for the GLTEQ. Additionally, the measurements showed a negligible correlation (r_s = 0.004, P = .94). Difference scores for GLTEQ and accelerometer estimated LPA were significantly different by age, with survivors aged 60 years or older demonstrating a difference that was 18.3 minutes shorter (P = .005) than the difference in younger survivors (<60 years).

Sitting time

Accelerometer−IPAQ. Mean IPAQ estimates were significantly lower (M = 303.8 [63.4]) than accelerometer estimates (M = 603.9 [78.0]). Rank-order correlations between IPAQ and accelerometer estimated ST was small (r_s =0.26, P < .001). Difference scores between IPAQ and accelerometer estimates were significantly greater for survivors who were 60 years or older, compared with those younger than 60 years (D = 47.6 minutes, P = .006), indicating that older survivors tended to self-report significantly more ST than estimated by the accelerometer.

Accelerometer−STQ. There was no significant difference in estimated mean ST minutes per day between the STQ and the accelerometer, but the correlation between estimates was low (r_s = 0.30, P < .001). Stratified analyses revealed estimates for the difference scores for mean daily ST between the STQ and accelerometer were greater for participants who were diagnosed with later-stage breast cancer (D= -158.3 minutes, P < .001) and those who had received chemotherapy (D= -61.7 minutes, P = .028; Table 2) than for those who were diagnosed with early-stage breast cancer or had not received chemotherapy. Women who had later-stage disease reported significantly less ST than did women diagnosed with early-stage disease, when compared with estimates by the accelerometer.

IPAQ−STQ. The estimated mean ST was significantly lower for IPAQ (M = 303.8 minutes [163.4]) than for the STQ (M = 605.2 minutes [296.2]). There were no significant estimate differences among the stratified groups.

Discussion

The purpose of the present study was to compare 4 measurement tools, an accelerometer-based activity monitor and 3 self-report questionnaires, to estimate ST, LPA, and MVPA in breast cancer survivors. Developing and evaluating accurate and precise measurement tools to assess physical activity and ST in breast cancer survivors remains a critical step toward better understanding the role of physical activity in cancer survivorship. Our results indicate that the congruency of the measurement tools examined was highly dependent on the activity intensity of interest and participants’ demographic or disease characteristics. Overall, the accelerometer estimated a greater amount of time spent sitting and engaging in LPA and less time in MVPA than was estimated on the STQ, GLTEQ, and IPAQ. In addition, our findings suggest significant subgroup differences that will be important in future development and implementation of physical activity measurement for breast cancer survivors.

MVPA has been the most commonly measured activity intensity among cancer survivors to date.^15,25,26 The present results indicate mean daily MVPA estimates were significantly higher for the GLTEQ compared with the accelerometer (M_diff = 2.8 min/d, P = .019), although the magnitude of these differences was relatively small. This difference is lower than in another study that compared these measures in colon cancer survivors and found the GLTEQ over-estimated MVPA by 10.6 min/day compared with the accelerometer (P < .01).¹⁵ However, the correlation between the 2 tools in our study was similar to that of Boyle and colleagues (r_s = 0.56 and r_s = 0.51, respectively). A possible explanation for the equivocal findings across these studies may lie in the difference in study sample demographics; a previous study results finding breast cancer survivors may be better at recalling their physical activities because they may be more attentive to activities they perform daily.²⁶

The IPAQ significantly estimated more than an hour more of MVPA minutes per day compared with the accelerometer and GLTEQ. There are a number of limitations to the reporting of MVPA on the IPAQ. These limitations have been previously reported in the literature and include cross-cultural differences as well as overreporting of nonleisure-time MVPA (eg, occupational or household activities). However, the IPAQ has consistently been shown to be a valid and reliable tool for physical activity surveillance in different populations across the world.^29,36,37 This shows that although MVPA was overestimated in our population, we do not mean to undermine the IPAQ value in other populations in which it has shown great utility for overall physical activity surveillance. When we excluded nonleisure-time MVPA, MVPA equated to about 18 min/day, which was closer in magnitude to the GLTEQ and accelerometer. These data highlight the importance of identifying the specific activity parameters of interest when selecting a measurement tool to ensure congruency between the tool and construct of interest.

The differences in MVPA estimation from the 3 tools have significant translational consequences, notably the potential for misclassification of meeting physical activity guidelines. For example, the percentage of women in the present sample that met physical activity guidelines ranged from 0% (using the accelerometer) to 19.5% (using the IPAQ), depending on the measurement tool used. These findings have meaningful implications for future physical activity assessment because multiple measurement tools are currently being used to estimate physical activity in breast cancer survivors and would provide useful information regarding how breast cancer survivors report their physical activity time.

For example, scores from the IPAQ may result in a survivor being classified as meeting physical activity guidelines when in fact they are not, and thereby missing the opportunity for intervention; or the accelerometer may classify an active survivor as inactive, which could result in using time and resources for a behavior change intervention that is not necessary. The clinical significance of these findings is to provide providers with data-based information on the strengths and limitations of the measurement tools so that they can accurately estimate physical activity and ST and appropriately optimize resources and treatments.

The degree of measurement tool congruence is likely influenced by a number of factors. First, survivors’ perceptions of the intensity of their activity are relative and subjective to their state of feeling during the activity. For example, breast cancer survivors with lower functional capacity may perceive activities with lower absolute intensity as having a higher relative intensity (ie, they think they are working at a moderate intensity so record an activity as such, but the activity is classified as light by the accelerometer). Second, although our self-report measures asked survivors to record the time they had spent active over the previous 7 days, survivors might report on what they consider a “usual” week, which may reflect the ideal rather than the reality. Third, the accelerometer cut-points used were derived from young, healthy adults on a treadmill. Thus, generalization to an older, sick, less active population that could be experiencing treatment-related side effects could lead to underestimation of time spent in MVPA. To better understand measurement congruency in breast cancer survivors, future research should investigate how functional capacity and activity intensity perceptions are influenced by a breast cancer diagnosis and how those factors may influence subjective and objective physical activity measurement. If those factors were found to have significant influence on activity in breast cancer survivors, it would warrant future development of breast-cancer–specific accelerometer reduction techniques.

The comparison of LPA presented another interesting significant contrast between self-report (GLTEQ) and accelerometry. Results indicated the GLTEQ underestimated LPA by 224.5 [3.2] min/day compared with the accelerometer. This equates to over 3.5 h/day of active time (or about 280 kcal/day) that was potentially unaccounted for by the GLTEQ. The difference between these estimates could be due to the fact that the GLTEQ was designed to measure exercise time and therefore may not be as sensitive as the accelerometer to nonexercise-related LPA. Light intensity activities typically span a large range of domains (ie, occupational, leisure time, household) and tend to occur in higher volumes than MVPA, which may lead to some challenges with recall. Expanding existing LPA questionnaires to encompass these domains would likely provide increased congruency between self-reported and accelerometer-derived estimates for LPA, as it may provide a better trigger for recalling these high volume activities. With increasing literature advocating the important role of LPA in adults’ health in concert with data suggesting survivors may engage in lower levels of LPA than healthy controls,²³, accurately accounting for these lower intensity activities to provide a “whole picture” of a survivor’s active day remains an important future research direction. Combining accelerometer and self-report data using ecological momentary assessment to capture these behaviors in real-time in the real world could provide a better understanding of the context in which LPA occurs as well as survivors’ perceptions of intensity to build more accurate and scalable measurement tools for LPA.

Our ST results indicate nonsignificant difference estimates from the accelerometer and the STQ (M_diff = 1.3 [15.3] min/day) with slightly higher estimates for the STQ versus accelerometer. This finding is consistent with the one other study that has examined these relationships in cancer survivors.¹⁵ However, our findings also indicate the IPAQ significantly underestimated ST compared with the accelerometer and the STQ by about half (Table 1). These differences may be because both the STQ and Marshall questionnaire used in the previous study measure multiple domains of sitting (ie, computer, television, travel) on both weekdays and weekends whereas the IPAQ uses only two recall items of overall sitting time (for weekday and weekend separately). The domain-specific, structured approach has been shown to improve recall and may help to prevent underestimation and general underreporting of the high volume, ubiquitous behavior of sitting.^17,38 Finally, we would be remiss to not acknowledge the known limitations to estimating ST using the count-based approach on the waist-worn accelerometer. Due to the monitor’s orientation at the hip, the accelerometer may misrepresent total ST by misclassifying standing still as sitting. However, Kozey-Keadle and colleagues have previously examined estimation of ST using waist-worn accelerometers and have shown the 100 count per minute cut off yields ST estimates within 5% range of accuracy for a seated position compared with direct observation.³⁹

Of further interest are our exploratory results indicating that age and disease stage may modify the congruency between activity and ST measures. Specifically, older survivors and those with more advanced disease stage generally reported more PA and less ST than were measured by the accelerometer. These differences raise the question of whether these subgroups are systematically reporting more time physically active, overestimating their intensity, or the accelerometer is misclassifying their activity intensity. These misclassifications could be due to their age, disease stage, fatigue status, functional status, cognitive function, occupational status, etc. and would be important next steps for exploration of measurement of physical activity in breast cancer survivors. Finally, the difference score for MVPA was greater for survivors of color than for white survivors, with survivors of color overreporting MVPA compared with accelerometer-derived estimates. This may be due in part to cultural differences between white survivors and survivors of color. Previous research has suggested that people of color may accumulate a majority of their activity in occupational or household-related domains, thus explaining lower levels of leisure-time MVPA but high levels of reported total MVPA from other nonleisure domains.²⁰ However, given the small number of survivors of color in the present study, these results should be interpreted with caution.

With the multitude of physical activity and ST measurement tools available, many factors including cost, sample size, primary outcome of interest, and activity characteristics of interest (eg, duration, intensity, energy expenditure) need to be considered⁴⁰ when choosing a tool. Our findings may help inform these decisions for breast cancer survivors. For example, if LPA is of interest, an accelerometer may provide a more comprehensive assessment of these activities than the GLTEQ. In contrast, if MVPA is the activity of interest, our results suggest the GLTEQ and accelerometer were more congruent than the IPAQ was with either measure, therefore, if budgetary constraints are a concern, the more cost-efficient GLTEQ could provide similar results to an accelerometer. In addition to considering measurement congruency, it is also critically important to carefully consider the population (breast cancer survivors) and subsequent burden that accompanies the measurement tool of choice. Overall, our results indicate, when choosing a questionnaire for ST or LPA for breast cancer survivors, the more comprehensive the questions, to encompass multiple domains or time of day, the greater amount of time that will be captured within that activity category. Conversely, since the majority of MVPA is completed in leisure-time, dependent on the age and race of the population, a shorter questionnaire may be sufficient. Additionally, dependent on time since diagnosis and treatment received, activity recall or body movement patterns may be affected which could influence measurement tool selection.^23,24 Finally, it is also important to consider the setting in which measurement is taking place. In busy clinical settings, shorter, self-report measures may have a greater chance of being implemented than accelerometers or longer self-report measures and would still provide useful information regarding an overall snapshot of survivors’ MVPA or ST that could be used to initiate a conversation or referral for a program to help survivors positively change one or both of these behaviors.

Limitations

There were a few limitations within the current study that should be taken into account. First, the accelerometer cut-points used were developed with healthy, young adults; therefore using different cut-points may have yielded different results.³⁴ Given the large age range in our participants (23-84 years), we believe the use of these cut-points was justified, in lieu of population-specific (ie, older adults) cut-points. In addition, limitations to estimating activity from an accelerometer include the inability to capture certain activities such as swimming and cycling and the aforementioned inability to distinguish between body postures (ie, sitting vs standing).⁴¹ The participants were predominantly white, highly educated, and high earners (85.2% earned ≥$40,000 per year), therefore, the present results may not be generalizable to survivors from more diverse backgrounds. However, as far as we know, this is the first study to report the congruency of estimated ST, LPA, and MVPA across multiple measurement tools in a nationwide sample of breast cancer survivors who were heterogeneous in terms of disease characteristics (ie, stage, treatment, time since diagnosis).

Conclusions

Our findings suggest that physical activity and ST estimates in breast cancer survivors may be dependent on the measurement tool used. In addition, congruency of measurement tools was dependent on activity intensity of interest, and participant age, race, and disease history may also influence these factors. Therefore, researchers should consider the intended outcomes of interest, the context in which the tool is being used (ie, clinical versus research), the available resources, and the participant population before they select a measurement tool for estimating physical activity and sitting time in breast cancer survivors.

Acknowledgment
This work was supported by grant #F31AG034025 from the National Institute on Aging (Dr Phillips); Shahid and Ann Carlson Khan endowed professorship and grant #AG020118 from the National Institute on Aging (Dr McAuley). Dr Phillips is supported by the National Cancer Institute #K07CA196840, and Dr Welch is supported by National Institute of Health/National Cancer Institute training grant CA193193. All data for this study were collected at the University of Illinois Urbana Champaign.

Physical activity has numerous physical, mental, and psychosocial benefits for cancer survivors, such as a reduction in the risk of mobility disability, depression, and anxiety, and improved patient quality of life.^1,2 In addition, higher levels of physical activity are associated with reduced cancer-specific and all-causes mortality as well as cancer-specific outcomes including reduced risk of cancer progression and recurrence and new primary cancers.^3-5 However, fewer than one-third of cancer survivors are meeting government and cancer-specific recommendations of 150 minutes a week of moderate to vigorous physical activity (MPVA; ≥3 metabolic equivalents [METs]).^6,7 Growing evidence also demonstrates a significant association between higher levels of sedentary behavior and many deleterious health effects after cancer, including an increased risk for decreased physical functioning and development of other chronic diseases such as cardiovascular disease or diabetes.⁸ Distinct from physical activity, sedentary behavior is defined as any waking activity resulting in low levels of energy expenditure (≤1.5 METs) while in a seated or reclined position.⁹ Increased sedentary behavior, even when controlling for moderate and vigorous physical activity (MVPA), is associated with poor quality of life and increased all-cause mortality in cancer survivors.^10,11 Given the associations observed between higher levels of physical activity, lower levels of sedentary behavior, and improved health and disease outcomes among the large and increasing number of cancer survivors in the United States, it is important to identify low-cost methods that can be used in a in a variety of settings (ie, research, clinical, community) to accurately and efficiently measure survivors’ lifestyle behaviors to identify high-risk survivors for early intervention, better understand the effects of these behaviors on survivors’ health outcomes and disease trajectories, and ultimately, improve survivors’ health and quality of life.^12,13

Two methods commonly used to capture physical activity and sedentary behavior across the lifespan are accelerometry (Actigraph, Pensacola, FL) and self-report questionnaires such as the Godin Leisure-Time Questionnaire (GLTEQ), International Physical Activity Questionnaire (IPAQ), and Sitting Time Questionnaire (STQ).^14-17 Each method has unique strengths and weaknesses. Sending accelerometers to multiple individuals at a single time point can be costly, particularly in large-scale epidemiological studies, and the accelerometer’s waist-worn, nonwaterproof design may prevent researchers from capturing certain activities such as swimming and resistance training. However, the accelerometer provides objective, precise assessments of most physical activities and may help remove response bias.¹⁸ Conversely, self-report questionnaires rely solely on individuals’ memories and often result in recall bias, inaccurate reporting, and under- or overestimation of physical activity engagement.^19,20 Nevertheless, these questionnaires can be widely disseminated at low cost in a variety of settings (eg, clinical, research, community) and are less of a burden to participants.

Recent studies comparing objective (eg, accelerometer) with subjective (eg, self-report) methods of measuring physical activity and sedentary behavior in healthy middle-aged adults and older adults have demonstrated mixed findings with no distinct trends in the degree to which these methods differ.^19,21,22 To date, little consideration has been given to the measurement of these lifestyle behaviors in cancer survivors. Boyle and colleagues recently investigated the concurrent validity of an accelerometer to the GLTEQ in colon cancer survivors, finding significant differences in estimated MVPA (~11 minutes). However, no studies, to our knowledge, have compared accelerometer and self-report measures in breast cancer survivors, so it remains unclear how these different measurement tools relate to each another in this population.

It is particularly important to compare these measurement tools among breast cancer survivors because evidence indicates this population’s behavioral habits, self-perceived activity, and sitting time and movement patterns may differ significantly from the general population and other survivor groups across the lifespan.^23,24 Further, previous studies examining these behaviors in cancer survivors focused primarily on sitting time and MVPA.^15,25,26 Examining other lower-intensity intensities (eg, light activity or lifestyle) in cancer survivors may also be important given that increased levels of activity are associated with health benefits, ranging from reduced disability and fatigue to improved cardiovascular health and quality of life, and that breast cancer survivors engage in fewer of these activities compared with noncancer controls.²³ These lower levels of physical activity may be more prevalent among cancer survivors of their high levels of fatigue and propensity toward increased sitting time during the first year of treatment,¹¹ so it is important to be able to accurately assess these activities in this population. The purpose of the present study was to compare estimates of time spent in light physical activity (LPA), MVPA, and sitting time (ST) obtained from an accelerometer and 3 self-report measurement tools (GLTEQ, IPAQ, STQ) in a large, US-based sample of breast cancer survivors. A secondary purpose was to determine whether estimate comparisons among measurements changed by participant characteristics.
 

Methods

Participants and procedures

This study consisted of a subsample of women who participated in a larger study whose findings have been reported elsewhere by Phillips and McAuley.²⁷ In that study, breast cancer survivors (n = 1,631) were recruited nationally to participate in a 6-month prospective study on quality of life. Eligibility criteria included being aged 18 years or older, having had a diagnosis of breast cancer, being English speaking, and having access to the internet. Once consented to participate in the study, 500 women were randomly selected to wear the accelerometer.

Participants in this group were mailed an accelerometer, an activity log, instructions for use, and a self-addressed stamped envelope to return the monitor. They were asked to wear the accelerometer during all waking hours for 7 consecutive days of usual activity. They were also sent a secure link to complete 3 activity questionnaires online. The questionnaires were to be completed by the end of the 7-day monitoring period. Only women with 3 or more valid days of accelerometer data and complete data on variables of interest (n = 414) were included in the present analyses. All of the participants consented to the study procedures approved by the University of Illinois Institutional Review Board.
 

Measures

Demographics. The participants self-reported their age, level of education, height, and weight. Their body mass index (BMI; kg/m²) was estimated using the standard equation. They also self-reported their health and cancer history, detailing breast cancer disease stage, time since diagnosis, treatment type, and whether they had had a cancer recurrence. They were also asked to report whether they had ever been diagnosed (Yes/No) with 18 chronic conditions (eg, diabetes, arthritis).

Godin Leisure-Time Exercise Questionnaire.¹⁶ The GLTEQ assessed participants’ weekly frequency and mean amount of time performing MVPA (moderate exercise, such as fast walking, combined with vigorous exercise, such as jogging), and LPA (light/mild exercise, eg, easy walking) during the previous 7 days. The mean daily duration (in minutes) for each intensity category (MVPA, LPA) was calculated using activity frequencies and the amount of time spent in each activity presented as minutes/day.

The International Physical Activity Questionnaire.¹⁴ The IPAQ evaluated participants’ physical activity of at least moderate intensity in 4 domains of everyday life: job-related physical activity, transportation, housework/caring for family, and leisure-time activity. Within each domain, participants were asked the number of days per week and time per day (hours and minutes) spent performing MVPA. To estimate sitting time, the questionnaire asks participants to report the total amount of time spent sitting per day in 2 conditions, during weekdays and during weekends. The present analysis averaged sitting time for a typical 7-day (5 week days, 2 weekend days) period. We multiplied reported minutes per day and frequency per week of each activity category (MVPA and ST) to calculate the mean number of minutes per day.^29,30

Sitting Time Questionnaire.^17,28 The STQ estimated the mean time (hours and minutes) participants spent sitting each day on weekdays and at weekends within 5 domains: while traveling to and from places, at work, watching television, using a computer at home, and at leisure, not including watching television (eg, visiting friends, movies, dining out). Mean minutes per day of ST were calculated using all sitting domains.

Actigraph accelerometer (model GT1M, Health One Technology, Fort Walton Beach, FL). The Actigraph GT1M is a reliable and objective measure of physical activity.^31-33 Participants wore the monitor on the right hip for 7 consecutive days during all waking hours, except when bathing or swimming. Activity data was analyzed in 1-minute intervals. A valid day of accelerometer wear time was defined as ≥600 minutes with no more than 60 minutes of consecutive zero-values, with allowance of 2 minutes or fewer of observations <100 counts/minute within the nonwear interval.³⁴ Each minute of wear time was classified according to intensity (counts/min) using the following cut-points:³⁴ sedentary, <100 counts/min; LPA, 100-2,019 counts/min; and MVPA, ≥2,020 count/min. Mean daily durations (min/day) spent in each behavior were estimated by dividing the number of minutes in each category by the number of valid days.

Statistical analysis

All statistical analyses were completed in SPSS Statistics 23 (IBM, Chicago, IL). Descriptive statistics were used to define participant characteristics. Rank-order correlation between the methods was assessed using Spearman’s rho (r_s) and results were interpreted as follows: r_s = 0.10, small; 0.30, moderate; and 0.50, strong.³⁵ Within each activity intensity group, we jointly modeled daily minutes of self-report and accelerometer data using a random-intercept mixed-effects regression model. Differences between measurement tools were assessed based on regression coefficients with accelerometer as the reference category. Finally, we did a post hoc analysis of leisure-time–only MVPA from the IPAQ to compare with other estimates of MVPA.

We calculated the measurement tool difference scores for each estimated intensity category (ST, LPA, MVPA), that is, accelerometer estimated ST minus STQ estimated ST, and GLTEQ estimated MVPA minus IPAQ estimated MVPA. We used these data in an exploratory analysis to examine whether there were statistically significant differences between measurement difference scores by demographic or disease characteristics using linear regression stratified analyses. For example, we were interested in whether there was a significant difference in measurement tool estimates for sitting time in older compared with younger survivors. Analyses were stratified by age (<60/≥60 years), body mass index (<25 kg/m²/≥25 kg/m²), race (white/people of color), disease stage (I and II/III and IV), years since diagnosis (≤5 years/>5 years), recurrence (Yes/No), received chemotherapy (Yes/No ), received radiation (Yes/No ), and the presence of 1 or more chronic diseases (Yes/No ).

Results

Participants

The mean age of the participants was 56.8 years [9.2], they were overweight (BMI, 26.2 kg/m² [5.4]), and predominantly white (96.7%; Table 1). Table 2 provides a summary of mean daily duration of activity estimates for ST, LPA, and MVPA and the estimate mean difference scores between measurements.

Moderate and vigorous physical activity

Accelerometer−GLTEQ. The mean difference in MVPA estimates between the accelerometer and GLTEQ was less than 5 minutes (M_{accelerometer} = 20.2 minutes; M_GLTEQ = 23.6 minutes), even though the difference was statistically significant (P = .02). Estimates of MVPA from the accelerometer and GLTEQ (r_s = 0.564, P < .001) showed a strong relationship. Stratified analyses showed that the difference scores between the GLTEQ and accelerometer were lower for older survivors (≥60 years) compared with younger survivors such that older survivors reported significantly less time in MVPA on the GLTEQ compared with accelerometer estimates (difference score [D] = 6.8 minutes less, P = .001).

Accelerometer−IPAQ. The accelerometer estimated significantly fewer minutes of MVPA per day when compared with the IPAQ (M_diff = -67.4; 95% confidence interval [CI], -78.6, -55.8; P < .001). Estimates of MVPA from the accelerometer and IPAQ (r_s = 0.011, P = .680) were poorly related. Differences between the IPAQ and accelerometer were greater for later-stage breast cancer, compared with early-stage diagnoses such that participants with late-stage disease reported significantly less MVPA on the IPAQ compared with accelerometer estimates (D = 41.8 minutes less than early-stage disease, P = .018). Finally, participants of color reported a greater difference in MVPA between the accelerometer and the IPAQ than did their white counterparts (D = 47.5 minutes, P = .033).

GLTEQ−IPAQ. GLTEQ estimated significantly fewer minutes of MVPA per day compared with the IPAQ (M_diff = -64.6; 95% CI, -76.6, -52.5; P < .001). The estimates of MVPA from the GLTEQ had a small correlation with IPAQ estimates (r_s = 0.128, P = .011).

IPAQ estimates showed almost triple the MVPA minutes per day as were estimated by the accelerometer and GLTEQ. As the MVPA estimate for the IPAQ include nonleisure activities, we conducted a post hoc analyses that only included the leisure-time items from the IPAQ. Leisure-time only IPAQ items, estimates indicated survivors spent a mean 18.5 [SD, 14.2] min/day in MVPA. Although the magnitude of the difference between the accelerometer and GLTEQ estimates (~10 minutes) was much smaller using the leisure-time only IPAQ items, a repeated measures analysis of variance revealed there was still a significant difference between these estimates (P < .05 for both) and negligible correlation.

Light intensity physical activity

Accelerometer−GLTEQ. There was a large and significant difference between LPA estimates from the GLTEQ and accelerometer (M_diff = 224.5; 95% CI, 218.2, 230.7; P < .001) with estimates from the accelerometer being higher than those for the GLTEQ. Additionally, the measurements showed a negligible correlation (r_s = 0.004, P = .94). Difference scores for GLTEQ and accelerometer estimated LPA were significantly different by age, with survivors aged 60 years or older demonstrating a difference that was 18.3 minutes shorter (P = .005) than the difference in younger survivors (<60 years).

Sitting time

Accelerometer−IPAQ. Mean IPAQ estimates were significantly lower (M = 303.8 [63.4]) than accelerometer estimates (M = 603.9 [78.0]). Rank-order correlations between IPAQ and accelerometer estimated ST was small (r_s =0.26, P < .001). Difference scores between IPAQ and accelerometer estimates were significantly greater for survivors who were 60 years or older, compared with those younger than 60 years (D = 47.6 minutes, P = .006), indicating that older survivors tended to self-report significantly more ST than estimated by the accelerometer.

Accelerometer−STQ. There was no significant difference in estimated mean ST minutes per day between the STQ and the accelerometer, but the correlation between estimates was low (r_s = 0.30, P < .001). Stratified analyses revealed estimates for the difference scores for mean daily ST between the STQ and accelerometer were greater for participants who were diagnosed with later-stage breast cancer (D= -158.3 minutes, P < .001) and those who had received chemotherapy (D= -61.7 minutes, P = .028; Table 2) than for those who were diagnosed with early-stage breast cancer or had not received chemotherapy. Women who had later-stage disease reported significantly less ST than did women diagnosed with early-stage disease, when compared with estimates by the accelerometer.

IPAQ−STQ. The estimated mean ST was significantly lower for IPAQ (M = 303.8 minutes [163.4]) than for the STQ (M = 605.2 minutes [296.2]). There were no significant estimate differences among the stratified groups.

Discussion

The purpose of the present study was to compare 4 measurement tools, an accelerometer-based activity monitor and 3 self-report questionnaires, to estimate ST, LPA, and MVPA in breast cancer survivors. Developing and evaluating accurate and precise measurement tools to assess physical activity and ST in breast cancer survivors remains a critical step toward better understanding the role of physical activity in cancer survivorship. Our results indicate that the congruency of the measurement tools examined was highly dependent on the activity intensity of interest and participants’ demographic or disease characteristics. Overall, the accelerometer estimated a greater amount of time spent sitting and engaging in LPA and less time in MVPA than was estimated on the STQ, GLTEQ, and IPAQ. In addition, our findings suggest significant subgroup differences that will be important in future development and implementation of physical activity measurement for breast cancer survivors.

MVPA has been the most commonly measured activity intensity among cancer survivors to date.^15,25,26 The present results indicate mean daily MVPA estimates were significantly higher for the GLTEQ compared with the accelerometer (M_diff = 2.8 min/d, P = .019), although the magnitude of these differences was relatively small. This difference is lower than in another study that compared these measures in colon cancer survivors and found the GLTEQ over-estimated MVPA by 10.6 min/day compared with the accelerometer (P < .01).¹⁵ However, the correlation between the 2 tools in our study was similar to that of Boyle and colleagues (r_s = 0.56 and r_s = 0.51, respectively). A possible explanation for the equivocal findings across these studies may lie in the difference in study sample demographics; a previous study results finding breast cancer survivors may be better at recalling their physical activities because they may be more attentive to activities they perform daily.²⁶

The IPAQ significantly estimated more than an hour more of MVPA minutes per day compared with the accelerometer and GLTEQ. There are a number of limitations to the reporting of MVPA on the IPAQ. These limitations have been previously reported in the literature and include cross-cultural differences as well as overreporting of nonleisure-time MVPA (eg, occupational or household activities). However, the IPAQ has consistently been shown to be a valid and reliable tool for physical activity surveillance in different populations across the world.^29,36,37 This shows that although MVPA was overestimated in our population, we do not mean to undermine the IPAQ value in other populations in which it has shown great utility for overall physical activity surveillance. When we excluded nonleisure-time MVPA, MVPA equated to about 18 min/day, which was closer in magnitude to the GLTEQ and accelerometer. These data highlight the importance of identifying the specific activity parameters of interest when selecting a measurement tool to ensure congruency between the tool and construct of interest.

The differences in MVPA estimation from the 3 tools have significant translational consequences, notably the potential for misclassification of meeting physical activity guidelines. For example, the percentage of women in the present sample that met physical activity guidelines ranged from 0% (using the accelerometer) to 19.5% (using the IPAQ), depending on the measurement tool used. These findings have meaningful implications for future physical activity assessment because multiple measurement tools are currently being used to estimate physical activity in breast cancer survivors and would provide useful information regarding how breast cancer survivors report their physical activity time.

For example, scores from the IPAQ may result in a survivor being classified as meeting physical activity guidelines when in fact they are not, and thereby missing the opportunity for intervention; or the accelerometer may classify an active survivor as inactive, which could result in using time and resources for a behavior change intervention that is not necessary. The clinical significance of these findings is to provide providers with data-based information on the strengths and limitations of the measurement tools so that they can accurately estimate physical activity and ST and appropriately optimize resources and treatments.

The degree of measurement tool congruence is likely influenced by a number of factors. First, survivors’ perceptions of the intensity of their activity are relative and subjective to their state of feeling during the activity. For example, breast cancer survivors with lower functional capacity may perceive activities with lower absolute intensity as having a higher relative intensity (ie, they think they are working at a moderate intensity so record an activity as such, but the activity is classified as light by the accelerometer). Second, although our self-report measures asked survivors to record the time they had spent active over the previous 7 days, survivors might report on what they consider a “usual” week, which may reflect the ideal rather than the reality. Third, the accelerometer cut-points used were derived from young, healthy adults on a treadmill. Thus, generalization to an older, sick, less active population that could be experiencing treatment-related side effects could lead to underestimation of time spent in MVPA. To better understand measurement congruency in breast cancer survivors, future research should investigate how functional capacity and activity intensity perceptions are influenced by a breast cancer diagnosis and how those factors may influence subjective and objective physical activity measurement. If those factors were found to have significant influence on activity in breast cancer survivors, it would warrant future development of breast-cancer–specific accelerometer reduction techniques.

The comparison of LPA presented another interesting significant contrast between self-report (GLTEQ) and accelerometry. Results indicated the GLTEQ underestimated LPA by 224.5 [3.2] min/day compared with the accelerometer. This equates to over 3.5 h/day of active time (or about 280 kcal/day) that was potentially unaccounted for by the GLTEQ. The difference between these estimates could be due to the fact that the GLTEQ was designed to measure exercise time and therefore may not be as sensitive as the accelerometer to nonexercise-related LPA. Light intensity activities typically span a large range of domains (ie, occupational, leisure time, household) and tend to occur in higher volumes than MVPA, which may lead to some challenges with recall. Expanding existing LPA questionnaires to encompass these domains would likely provide increased congruency between self-reported and accelerometer-derived estimates for LPA, as it may provide a better trigger for recalling these high volume activities. With increasing literature advocating the important role of LPA in adults’ health in concert with data suggesting survivors may engage in lower levels of LPA than healthy controls,²³, accurately accounting for these lower intensity activities to provide a “whole picture” of a survivor’s active day remains an important future research direction. Combining accelerometer and self-report data using ecological momentary assessment to capture these behaviors in real-time in the real world could provide a better understanding of the context in which LPA occurs as well as survivors’ perceptions of intensity to build more accurate and scalable measurement tools for LPA.

Our ST results indicate nonsignificant difference estimates from the accelerometer and the STQ (M_diff = 1.3 [15.3] min/day) with slightly higher estimates for the STQ versus accelerometer. This finding is consistent with the one other study that has examined these relationships in cancer survivors.¹⁵ However, our findings also indicate the IPAQ significantly underestimated ST compared with the accelerometer and the STQ by about half (Table 1). These differences may be because both the STQ and Marshall questionnaire used in the previous study measure multiple domains of sitting (ie, computer, television, travel) on both weekdays and weekends whereas the IPAQ uses only two recall items of overall sitting time (for weekday and weekend separately). The domain-specific, structured approach has been shown to improve recall and may help to prevent underestimation and general underreporting of the high volume, ubiquitous behavior of sitting.^17,38 Finally, we would be remiss to not acknowledge the known limitations to estimating ST using the count-based approach on the waist-worn accelerometer. Due to the monitor’s orientation at the hip, the accelerometer may misrepresent total ST by misclassifying standing still as sitting. However, Kozey-Keadle and colleagues have previously examined estimation of ST using waist-worn accelerometers and have shown the 100 count per minute cut off yields ST estimates within 5% range of accuracy for a seated position compared with direct observation.³⁹

Of further interest are our exploratory results indicating that age and disease stage may modify the congruency between activity and ST measures. Specifically, older survivors and those with more advanced disease stage generally reported more PA and less ST than were measured by the accelerometer. These differences raise the question of whether these subgroups are systematically reporting more time physically active, overestimating their intensity, or the accelerometer is misclassifying their activity intensity. These misclassifications could be due to their age, disease stage, fatigue status, functional status, cognitive function, occupational status, etc. and would be important next steps for exploration of measurement of physical activity in breast cancer survivors. Finally, the difference score for MVPA was greater for survivors of color than for white survivors, with survivors of color overreporting MVPA compared with accelerometer-derived estimates. This may be due in part to cultural differences between white survivors and survivors of color. Previous research has suggested that people of color may accumulate a majority of their activity in occupational or household-related domains, thus explaining lower levels of leisure-time MVPA but high levels of reported total MVPA from other nonleisure domains.²⁰ However, given the small number of survivors of color in the present study, these results should be interpreted with caution.

With the multitude of physical activity and ST measurement tools available, many factors including cost, sample size, primary outcome of interest, and activity characteristics of interest (eg, duration, intensity, energy expenditure) need to be considered⁴⁰ when choosing a tool. Our findings may help inform these decisions for breast cancer survivors. For example, if LPA is of interest, an accelerometer may provide a more comprehensive assessment of these activities than the GLTEQ. In contrast, if MVPA is the activity of interest, our results suggest the GLTEQ and accelerometer were more congruent than the IPAQ was with either measure, therefore, if budgetary constraints are a concern, the more cost-efficient GLTEQ could provide similar results to an accelerometer. In addition to considering measurement congruency, it is also critically important to carefully consider the population (breast cancer survivors) and subsequent burden that accompanies the measurement tool of choice. Overall, our results indicate, when choosing a questionnaire for ST or LPA for breast cancer survivors, the more comprehensive the questions, to encompass multiple domains or time of day, the greater amount of time that will be captured within that activity category. Conversely, since the majority of MVPA is completed in leisure-time, dependent on the age and race of the population, a shorter questionnaire may be sufficient. Additionally, dependent on time since diagnosis and treatment received, activity recall or body movement patterns may be affected which could influence measurement tool selection.^23,24 Finally, it is also important to consider the setting in which measurement is taking place. In busy clinical settings, shorter, self-report measures may have a greater chance of being implemented than accelerometers or longer self-report measures and would still provide useful information regarding an overall snapshot of survivors’ MVPA or ST that could be used to initiate a conversation or referral for a program to help survivors positively change one or both of these behaviors.

Limitations

There were a few limitations within the current study that should be taken into account. First, the accelerometer cut-points used were developed with healthy, young adults; therefore using different cut-points may have yielded different results.³⁴ Given the large age range in our participants (23-84 years), we believe the use of these cut-points was justified, in lieu of population-specific (ie, older adults) cut-points. In addition, limitations to estimating activity from an accelerometer include the inability to capture certain activities such as swimming and cycling and the aforementioned inability to distinguish between body postures (ie, sitting vs standing).⁴¹ The participants were predominantly white, highly educated, and high earners (85.2% earned ≥$40,000 per year), therefore, the present results may not be generalizable to survivors from more diverse backgrounds. However, as far as we know, this is the first study to report the congruency of estimated ST, LPA, and MVPA across multiple measurement tools in a nationwide sample of breast cancer survivors who were heterogeneous in terms of disease characteristics (ie, stage, treatment, time since diagnosis).

Conclusions

Our findings suggest that physical activity and ST estimates in breast cancer survivors may be dependent on the measurement tool used. In addition, congruency of measurement tools was dependent on activity intensity of interest, and participant age, race, and disease history may also influence these factors. Therefore, researchers should consider the intended outcomes of interest, the context in which the tool is being used (ie, clinical versus research), the available resources, and the participant population before they select a measurement tool for estimating physical activity and sitting time in breast cancer survivors.

Acknowledgment
This work was supported by grant #F31AG034025 from the National Institute on Aging (Dr Phillips); Shahid and Ann Carlson Khan endowed professorship and grant #AG020118 from the National Institute on Aging (Dr McAuley). Dr Phillips is supported by the National Cancer Institute #K07CA196840, and Dr Welch is supported by National Institute of Health/National Cancer Institute training grant CA193193. All data for this study were collected at the University of Illinois Urbana Champaign.

Physical activity has numerous physical, mental, and psychosocial benefits for cancer survivors, such as a reduction in the risk of mobility disability, depression, and anxiety, and improved patient quality of life.^1,2 In addition, higher levels of physical activity are associated with reduced cancer-specific and all-causes mortality as well as cancer-specific outcomes including reduced risk of cancer progression and recurrence and new primary cancers.^3-5 However, fewer than one-third of cancer survivors are meeting government and cancer-specific recommendations of 150 minutes a week of moderate to vigorous physical activity (MPVA; ≥3 metabolic equivalents [METs]).^6,7 Growing evidence also demonstrates a significant association between higher levels of sedentary behavior and many deleterious health effects after cancer, including an increased risk for decreased physical functioning and development of other chronic diseases such as cardiovascular disease or diabetes.⁸ Distinct from physical activity, sedentary behavior is defined as any waking activity resulting in low levels of energy expenditure (≤1.5 METs) while in a seated or reclined position.⁹ Increased sedentary behavior, even when controlling for moderate and vigorous physical activity (MVPA), is associated with poor quality of life and increased all-cause mortality in cancer survivors.^10,11 Given the associations observed between higher levels of physical activity, lower levels of sedentary behavior, and improved health and disease outcomes among the large and increasing number of cancer survivors in the United States, it is important to identify low-cost methods that can be used in a in a variety of settings (ie, research, clinical, community) to accurately and efficiently measure survivors’ lifestyle behaviors to identify high-risk survivors for early intervention, better understand the effects of these behaviors on survivors’ health outcomes and disease trajectories, and ultimately, improve survivors’ health and quality of life.^12,13

Two methods commonly used to capture physical activity and sedentary behavior across the lifespan are accelerometry (Actigraph, Pensacola, FL) and self-report questionnaires such as the Godin Leisure-Time Questionnaire (GLTEQ), International Physical Activity Questionnaire (IPAQ), and Sitting Time Questionnaire (STQ).^14-17 Each method has unique strengths and weaknesses. Sending accelerometers to multiple individuals at a single time point can be costly, particularly in large-scale epidemiological studies, and the accelerometer’s waist-worn, nonwaterproof design may prevent researchers from capturing certain activities such as swimming and resistance training. However, the accelerometer provides objective, precise assessments of most physical activities and may help remove response bias.¹⁸ Conversely, self-report questionnaires rely solely on individuals’ memories and often result in recall bias, inaccurate reporting, and under- or overestimation of physical activity engagement.^19,20 Nevertheless, these questionnaires can be widely disseminated at low cost in a variety of settings (eg, clinical, research, community) and are less of a burden to participants.

Recent studies comparing objective (eg, accelerometer) with subjective (eg, self-report) methods of measuring physical activity and sedentary behavior in healthy middle-aged adults and older adults have demonstrated mixed findings with no distinct trends in the degree to which these methods differ.^19,21,22 To date, little consideration has been given to the measurement of these lifestyle behaviors in cancer survivors. Boyle and colleagues recently investigated the concurrent validity of an accelerometer to the GLTEQ in colon cancer survivors, finding significant differences in estimated MVPA (~11 minutes). However, no studies, to our knowledge, have compared accelerometer and self-report measures in breast cancer survivors, so it remains unclear how these different measurement tools relate to each another in this population.

It is particularly important to compare these measurement tools among breast cancer survivors because evidence indicates this population’s behavioral habits, self-perceived activity, and sitting time and movement patterns may differ significantly from the general population and other survivor groups across the lifespan.^23,24 Further, previous studies examining these behaviors in cancer survivors focused primarily on sitting time and MVPA.^15,25,26 Examining other lower-intensity intensities (eg, light activity or lifestyle) in cancer survivors may also be important given that increased levels of activity are associated with health benefits, ranging from reduced disability and fatigue to improved cardiovascular health and quality of life, and that breast cancer survivors engage in fewer of these activities compared with noncancer controls.²³ These lower levels of physical activity may be more prevalent among cancer survivors of their high levels of fatigue and propensity toward increased sitting time during the first year of treatment,¹¹ so it is important to be able to accurately assess these activities in this population. The purpose of the present study was to compare estimates of time spent in light physical activity (LPA), MVPA, and sitting time (ST) obtained from an accelerometer and 3 self-report measurement tools (GLTEQ, IPAQ, STQ) in a large, US-based sample of breast cancer survivors. A secondary purpose was to determine whether estimate comparisons among measurements changed by participant characteristics.
 

Methods

Participants and procedures

This study consisted of a subsample of women who participated in a larger study whose findings have been reported elsewhere by Phillips and McAuley.²⁷ In that study, breast cancer survivors (n = 1,631) were recruited nationally to participate in a 6-month prospective study on quality of life. Eligibility criteria included being aged 18 years or older, having had a diagnosis of breast cancer, being English speaking, and having access to the internet. Once consented to participate in the study, 500 women were randomly selected to wear the accelerometer.

Participants in this group were mailed an accelerometer, an activity log, instructions for use, and a self-addressed stamped envelope to return the monitor. They were asked to wear the accelerometer during all waking hours for 7 consecutive days of usual activity. They were also sent a secure link to complete 3 activity questionnaires online. The questionnaires were to be completed by the end of the 7-day monitoring period. Only women with 3 or more valid days of accelerometer data and complete data on variables of interest (n = 414) were included in the present analyses. All of the participants consented to the study procedures approved by the University of Illinois Institutional Review Board.
 

Measures

Demographics. The participants self-reported their age, level of education, height, and weight. Their body mass index (BMI; kg/m²) was estimated using the standard equation. They also self-reported their health and cancer history, detailing breast cancer disease stage, time since diagnosis, treatment type, and whether they had had a cancer recurrence. They were also asked to report whether they had ever been diagnosed (Yes/No) with 18 chronic conditions (eg, diabetes, arthritis).

Godin Leisure-Time Exercise Questionnaire.¹⁶ The GLTEQ assessed participants’ weekly frequency and mean amount of time performing MVPA (moderate exercise, such as fast walking, combined with vigorous exercise, such as jogging), and LPA (light/mild exercise, eg, easy walking) during the previous 7 days. The mean daily duration (in minutes) for each intensity category (MVPA, LPA) was calculated using activity frequencies and the amount of time spent in each activity presented as minutes/day.

The International Physical Activity Questionnaire.¹⁴ The IPAQ evaluated participants’ physical activity of at least moderate intensity in 4 domains of everyday life: job-related physical activity, transportation, housework/caring for family, and leisure-time activity. Within each domain, participants were asked the number of days per week and time per day (hours and minutes) spent performing MVPA. To estimate sitting time, the questionnaire asks participants to report the total amount of time spent sitting per day in 2 conditions, during weekdays and during weekends. The present analysis averaged sitting time for a typical 7-day (5 week days, 2 weekend days) period. We multiplied reported minutes per day and frequency per week of each activity category (MVPA and ST) to calculate the mean number of minutes per day.^29,30

Sitting Time Questionnaire.^17,28 The STQ estimated the mean time (hours and minutes) participants spent sitting each day on weekdays and at weekends within 5 domains: while traveling to and from places, at work, watching television, using a computer at home, and at leisure, not including watching television (eg, visiting friends, movies, dining out). Mean minutes per day of ST were calculated using all sitting domains.

Actigraph accelerometer (model GT1M, Health One Technology, Fort Walton Beach, FL). The Actigraph GT1M is a reliable and objective measure of physical activity.^31-33 Participants wore the monitor on the right hip for 7 consecutive days during all waking hours, except when bathing or swimming. Activity data was analyzed in 1-minute intervals. A valid day of accelerometer wear time was defined as ≥600 minutes with no more than 60 minutes of consecutive zero-values, with allowance of 2 minutes or fewer of observations <100 counts/minute within the nonwear interval.³⁴ Each minute of wear time was classified according to intensity (counts/min) using the following cut-points:³⁴ sedentary, <100 counts/min; LPA, 100-2,019 counts/min; and MVPA, ≥2,020 count/min. Mean daily durations (min/day) spent in each behavior were estimated by dividing the number of minutes in each category by the number of valid days.

Statistical analysis

All statistical analyses were completed in SPSS Statistics 23 (IBM, Chicago, IL). Descriptive statistics were used to define participant characteristics. Rank-order correlation between the methods was assessed using Spearman’s rho (r_s) and results were interpreted as follows: r_s = 0.10, small; 0.30, moderate; and 0.50, strong.³⁵ Within each activity intensity group, we jointly modeled daily minutes of self-report and accelerometer data using a random-intercept mixed-effects regression model. Differences between measurement tools were assessed based on regression coefficients with accelerometer as the reference category. Finally, we did a post hoc analysis of leisure-time–only MVPA from the IPAQ to compare with other estimates of MVPA.

We calculated the measurement tool difference scores for each estimated intensity category (ST, LPA, MVPA), that is, accelerometer estimated ST minus STQ estimated ST, and GLTEQ estimated MVPA minus IPAQ estimated MVPA. We used these data in an exploratory analysis to examine whether there were statistically significant differences between measurement difference scores by demographic or disease characteristics using linear regression stratified analyses. For example, we were interested in whether there was a significant difference in measurement tool estimates for sitting time in older compared with younger survivors. Analyses were stratified by age (<60/≥60 years), body mass index (<25 kg/m²/≥25 kg/m²), race (white/people of color), disease stage (I and II/III and IV), years since diagnosis (≤5 years/>5 years), recurrence (Yes/No), received chemotherapy (Yes/No ), received radiation (Yes/No ), and the presence of 1 or more chronic diseases (Yes/No ).

Results

Participants

The mean age of the participants was 56.8 years [9.2], they were overweight (BMI, 26.2 kg/m² [5.4]), and predominantly white (96.7%; Table 1). Table 2 provides a summary of mean daily duration of activity estimates for ST, LPA, and MVPA and the estimate mean difference scores between measurements.

Moderate and vigorous physical activity

Accelerometer−GLTEQ. The mean difference in MVPA estimates between the accelerometer and GLTEQ was less than 5 minutes (M_{accelerometer} = 20.2 minutes; M_GLTEQ = 23.6 minutes), even though the difference was statistically significant (P = .02). Estimates of MVPA from the accelerometer and GLTEQ (r_s = 0.564, P < .001) showed a strong relationship. Stratified analyses showed that the difference scores between the GLTEQ and accelerometer were lower for older survivors (≥60 years) compared with younger survivors such that older survivors reported significantly less time in MVPA on the GLTEQ compared with accelerometer estimates (difference score [D] = 6.8 minutes less, P = .001).

Accelerometer−IPAQ. The accelerometer estimated significantly fewer minutes of MVPA per day when compared with the IPAQ (M_diff = -67.4; 95% confidence interval [CI], -78.6, -55.8; P < .001). Estimates of MVPA from the accelerometer and IPAQ (r_s = 0.011, P = .680) were poorly related. Differences between the IPAQ and accelerometer were greater for later-stage breast cancer, compared with early-stage diagnoses such that participants with late-stage disease reported significantly less MVPA on the IPAQ compared with accelerometer estimates (D = 41.8 minutes less than early-stage disease, P = .018). Finally, participants of color reported a greater difference in MVPA between the accelerometer and the IPAQ than did their white counterparts (D = 47.5 minutes, P = .033).

GLTEQ−IPAQ. GLTEQ estimated significantly fewer minutes of MVPA per day compared with the IPAQ (M_diff = -64.6; 95% CI, -76.6, -52.5; P < .001). The estimates of MVPA from the GLTEQ had a small correlation with IPAQ estimates (r_s = 0.128, P = .011).

IPAQ estimates showed almost triple the MVPA minutes per day as were estimated by the accelerometer and GLTEQ. As the MVPA estimate for the IPAQ include nonleisure activities, we conducted a post hoc analyses that only included the leisure-time items from the IPAQ. Leisure-time only IPAQ items, estimates indicated survivors spent a mean 18.5 [SD, 14.2] min/day in MVPA. Although the magnitude of the difference between the accelerometer and GLTEQ estimates (~10 minutes) was much smaller using the leisure-time only IPAQ items, a repeated measures analysis of variance revealed there was still a significant difference between these estimates (P < .05 for both) and negligible correlation.

Light intensity physical activity

Accelerometer−GLTEQ. There was a large and significant difference between LPA estimates from the GLTEQ and accelerometer (M_diff = 224.5; 95% CI, 218.2, 230.7; P < .001) with estimates from the accelerometer being higher than those for the GLTEQ. Additionally, the measurements showed a negligible correlation (r_s = 0.004, P = .94). Difference scores for GLTEQ and accelerometer estimated LPA were significantly different by age, with survivors aged 60 years or older demonstrating a difference that was 18.3 minutes shorter (P = .005) than the difference in younger survivors (<60 years).

Sitting time

Accelerometer−IPAQ. Mean IPAQ estimates were significantly lower (M = 303.8 [63.4]) than accelerometer estimates (M = 603.9 [78.0]). Rank-order correlations between IPAQ and accelerometer estimated ST was small (r_s =0.26, P < .001). Difference scores between IPAQ and accelerometer estimates were significantly greater for survivors who were 60 years or older, compared with those younger than 60 years (D = 47.6 minutes, P = .006), indicating that older survivors tended to self-report significantly more ST than estimated by the accelerometer.

Accelerometer−STQ. There was no significant difference in estimated mean ST minutes per day between the STQ and the accelerometer, but the correlation between estimates was low (r_s = 0.30, P < .001). Stratified analyses revealed estimates for the difference scores for mean daily ST between the STQ and accelerometer were greater for participants who were diagnosed with later-stage breast cancer (D= -158.3 minutes, P < .001) and those who had received chemotherapy (D= -61.7 minutes, P = .028; Table 2) than for those who were diagnosed with early-stage breast cancer or had not received chemotherapy. Women who had later-stage disease reported significantly less ST than did women diagnosed with early-stage disease, when compared with estimates by the accelerometer.

IPAQ−STQ. The estimated mean ST was significantly lower for IPAQ (M = 303.8 minutes [163.4]) than for the STQ (M = 605.2 minutes [296.2]). There were no significant estimate differences among the stratified groups.

Discussion

The purpose of the present study was to compare 4 measurement tools, an accelerometer-based activity monitor and 3 self-report questionnaires, to estimate ST, LPA, and MVPA in breast cancer survivors. Developing and evaluating accurate and precise measurement tools to assess physical activity and ST in breast cancer survivors remains a critical step toward better understanding the role of physical activity in cancer survivorship. Our results indicate that the congruency of the measurement tools examined was highly dependent on the activity intensity of interest and participants’ demographic or disease characteristics. Overall, the accelerometer estimated a greater amount of time spent sitting and engaging in LPA and less time in MVPA than was estimated on the STQ, GLTEQ, and IPAQ. In addition, our findings suggest significant subgroup differences that will be important in future development and implementation of physical activity measurement for breast cancer survivors.

MVPA has been the most commonly measured activity intensity among cancer survivors to date.^15,25,26 The present results indicate mean daily MVPA estimates were significantly higher for the GLTEQ compared with the accelerometer (M_diff = 2.8 min/d, P = .019), although the magnitude of these differences was relatively small. This difference is lower than in another study that compared these measures in colon cancer survivors and found the GLTEQ over-estimated MVPA by 10.6 min/day compared with the accelerometer (P < .01).¹⁵ However, the correlation between the 2 tools in our study was similar to that of Boyle and colleagues (r_s = 0.56 and r_s = 0.51, respectively). A possible explanation for the equivocal findings across these studies may lie in the difference in study sample demographics; a previous study results finding breast cancer survivors may be better at recalling their physical activities because they may be more attentive to activities they perform daily.²⁶

The IPAQ significantly estimated more than an hour more of MVPA minutes per day compared with the accelerometer and GLTEQ. There are a number of limitations to the reporting of MVPA on the IPAQ. These limitations have been previously reported in the literature and include cross-cultural differences as well as overreporting of nonleisure-time MVPA (eg, occupational or household activities). However, the IPAQ has consistently been shown to be a valid and reliable tool for physical activity surveillance in different populations across the world.^29,36,37 This shows that although MVPA was overestimated in our population, we do not mean to undermine the IPAQ value in other populations in which it has shown great utility for overall physical activity surveillance. When we excluded nonleisure-time MVPA, MVPA equated to about 18 min/day, which was closer in magnitude to the GLTEQ and accelerometer. These data highlight the importance of identifying the specific activity parameters of interest when selecting a measurement tool to ensure congruency between the tool and construct of interest.

The differences in MVPA estimation from the 3 tools have significant translational consequences, notably the potential for misclassification of meeting physical activity guidelines. For example, the percentage of women in the present sample that met physical activity guidelines ranged from 0% (using the accelerometer) to 19.5% (using the IPAQ), depending on the measurement tool used. These findings have meaningful implications for future physical activity assessment because multiple measurement tools are currently being used to estimate physical activity in breast cancer survivors and would provide useful information regarding how breast cancer survivors report their physical activity time.

For example, scores from the IPAQ may result in a survivor being classified as meeting physical activity guidelines when in fact they are not, and thereby missing the opportunity for intervention; or the accelerometer may classify an active survivor as inactive, which could result in using time and resources for a behavior change intervention that is not necessary. The clinical significance of these findings is to provide providers with data-based information on the strengths and limitations of the measurement tools so that they can accurately estimate physical activity and ST and appropriately optimize resources and treatments.

The degree of measurement tool congruence is likely influenced by a number of factors. First, survivors’ perceptions of the intensity of their activity are relative and subjective to their state of feeling during the activity. For example, breast cancer survivors with lower functional capacity may perceive activities with lower absolute intensity as having a higher relative intensity (ie, they think they are working at a moderate intensity so record an activity as such, but the activity is classified as light by the accelerometer). Second, although our self-report measures asked survivors to record the time they had spent active over the previous 7 days, survivors might report on what they consider a “usual” week, which may reflect the ideal rather than the reality. Third, the accelerometer cut-points used were derived from young, healthy adults on a treadmill. Thus, generalization to an older, sick, less active population that could be experiencing treatment-related side effects could lead to underestimation of time spent in MVPA. To better understand measurement congruency in breast cancer survivors, future research should investigate how functional capacity and activity intensity perceptions are influenced by a breast cancer diagnosis and how those factors may influence subjective and objective physical activity measurement. If those factors were found to have significant influence on activity in breast cancer survivors, it would warrant future development of breast-cancer–specific accelerometer reduction techniques.

The comparison of LPA presented another interesting significant contrast between self-report (GLTEQ) and accelerometry. Results indicated the GLTEQ underestimated LPA by 224.5 [3.2] min/day compared with the accelerometer. This equates to over 3.5 h/day of active time (or about 280 kcal/day) that was potentially unaccounted for by the GLTEQ. The difference between these estimates could be due to the fact that the GLTEQ was designed to measure exercise time and therefore may not be as sensitive as the accelerometer to nonexercise-related LPA. Light intensity activities typically span a large range of domains (ie, occupational, leisure time, household) and tend to occur in higher volumes than MVPA, which may lead to some challenges with recall. Expanding existing LPA questionnaires to encompass these domains would likely provide increased congruency between self-reported and accelerometer-derived estimates for LPA, as it may provide a better trigger for recalling these high volume activities. With increasing literature advocating the important role of LPA in adults’ health in concert with data suggesting survivors may engage in lower levels of LPA than healthy controls,²³, accurately accounting for these lower intensity activities to provide a “whole picture” of a survivor’s active day remains an important future research direction. Combining accelerometer and self-report data using ecological momentary assessment to capture these behaviors in real-time in the real world could provide a better understanding of the context in which LPA occurs as well as survivors’ perceptions of intensity to build more accurate and scalable measurement tools for LPA.

Our ST results indicate nonsignificant difference estimates from the accelerometer and the STQ (M_diff = 1.3 [15.3] min/day) with slightly higher estimates for the STQ versus accelerometer. This finding is consistent with the one other study that has examined these relationships in cancer survivors.¹⁵ However, our findings also indicate the IPAQ significantly underestimated ST compared with the accelerometer and the STQ by about half (Table 1). These differences may be because both the STQ and Marshall questionnaire used in the previous study measure multiple domains of sitting (ie, computer, television, travel) on both weekdays and weekends whereas the IPAQ uses only two recall items of overall sitting time (for weekday and weekend separately). The domain-specific, structured approach has been shown to improve recall and may help to prevent underestimation and general underreporting of the high volume, ubiquitous behavior of sitting.^17,38 Finally, we would be remiss to not acknowledge the known limitations to estimating ST using the count-based approach on the waist-worn accelerometer. Due to the monitor’s orientation at the hip, the accelerometer may misrepresent total ST by misclassifying standing still as sitting. However, Kozey-Keadle and colleagues have previously examined estimation of ST using waist-worn accelerometers and have shown the 100 count per minute cut off yields ST estimates within 5% range of accuracy for a seated position compared with direct observation.³⁹

Of further interest are our exploratory results indicating that age and disease stage may modify the congruency between activity and ST measures. Specifically, older survivors and those with more advanced disease stage generally reported more PA and less ST than were measured by the accelerometer. These differences raise the question of whether these subgroups are systematically reporting more time physically active, overestimating their intensity, or the accelerometer is misclassifying their activity intensity. These misclassifications could be due to their age, disease stage, fatigue status, functional status, cognitive function, occupational status, etc. and would be important next steps for exploration of measurement of physical activity in breast cancer survivors. Finally, the difference score for MVPA was greater for survivors of color than for white survivors, with survivors of color overreporting MVPA compared with accelerometer-derived estimates. This may be due in part to cultural differences between white survivors and survivors of color. Previous research has suggested that people of color may accumulate a majority of their activity in occupational or household-related domains, thus explaining lower levels of leisure-time MVPA but high levels of reported total MVPA from other nonleisure domains.²⁰ However, given the small number of survivors of color in the present study, these results should be interpreted with caution.

With the multitude of physical activity and ST measurement tools available, many factors including cost, sample size, primary outcome of interest, and activity characteristics of interest (eg, duration, intensity, energy expenditure) need to be considered⁴⁰ when choosing a tool. Our findings may help inform these decisions for breast cancer survivors. For example, if LPA is of interest, an accelerometer may provide a more comprehensive assessment of these activities than the GLTEQ. In contrast, if MVPA is the activity of interest, our results suggest the GLTEQ and accelerometer were more congruent than the IPAQ was with either measure, therefore, if budgetary constraints are a concern, the more cost-efficient GLTEQ could provide similar results to an accelerometer. In addition to considering measurement congruency, it is also critically important to carefully consider the population (breast cancer survivors) and subsequent burden that accompanies the measurement tool of choice. Overall, our results indicate, when choosing a questionnaire for ST or LPA for breast cancer survivors, the more comprehensive the questions, to encompass multiple domains or time of day, the greater amount of time that will be captured within that activity category. Conversely, since the majority of MVPA is completed in leisure-time, dependent on the age and race of the population, a shorter questionnaire may be sufficient. Additionally, dependent on time since diagnosis and treatment received, activity recall or body movement patterns may be affected which could influence measurement tool selection.^23,24 Finally, it is also important to consider the setting in which measurement is taking place. In busy clinical settings, shorter, self-report measures may have a greater chance of being implemented than accelerometers or longer self-report measures and would still provide useful information regarding an overall snapshot of survivors’ MVPA or ST that could be used to initiate a conversation or referral for a program to help survivors positively change one or both of these behaviors.

Limitations

There were a few limitations within the current study that should be taken into account. First, the accelerometer cut-points used were developed with healthy, young adults; therefore using different cut-points may have yielded different results.³⁴ Given the large age range in our participants (23-84 years), we believe the use of these cut-points was justified, in lieu of population-specific (ie, older adults) cut-points. In addition, limitations to estimating activity from an accelerometer include the inability to capture certain activities such as swimming and cycling and the aforementioned inability to distinguish between body postures (ie, sitting vs standing).⁴¹ The participants were predominantly white, highly educated, and high earners (85.2% earned ≥$40,000 per year), therefore, the present results may not be generalizable to survivors from more diverse backgrounds. However, as far as we know, this is the first study to report the congruency of estimated ST, LPA, and MVPA across multiple measurement tools in a nationwide sample of breast cancer survivors who were heterogeneous in terms of disease characteristics (ie, stage, treatment, time since diagnosis).

Conclusions

Our findings suggest that physical activity and ST estimates in breast cancer survivors may be dependent on the measurement tool used. In addition, congruency of measurement tools was dependent on activity intensity of interest, and participant age, race, and disease history may also influence these factors. Therefore, researchers should consider the intended outcomes of interest, the context in which the tool is being used (ie, clinical versus research), the available resources, and the participant population before they select a measurement tool for estimating physical activity and sitting time in breast cancer survivors.

Acknowledgment
This work was supported by grant #F31AG034025 from the National Institute on Aging (Dr Phillips); Shahid and Ann Carlson Khan endowed professorship and grant #AG020118 from the National Institute on Aging (Dr McAuley). Dr Phillips is supported by the National Cancer Institute #K07CA196840, and Dr Welch is supported by National Institute of Health/National Cancer Institute training grant CA193193. All data for this study were collected at the University of Illinois Urbana Champaign.

The fall 2017 approval by the US Food and Drug Administration (FDA) of abemaciclib made it the third cyclin-dependent kinase (CDK) inhibitor approved for the treatment of hormone receptor (HR)-positive breast cancer, and the first to receive an approved indication as monotherapy in that setting. Abemaciclib is a small-molecule inhibitor of the CDK4 and CDK6 proteins, which are key gatekeepers of the cell cycle and frequently dysregulated in HR-positive breast cancer. On the basis of the randomized, placebo-controlled, multicenter phase 3 MONARCH-2 trial, it was approved in combination with fulvestrant for the treatment of women with HR-positive, HER2-negative advanced or metastatic breast cancer who had progressed during endocrine therapy.¹

A total of 669 women aged 18 years and older, with any menopausal status, an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1, measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) or nonmeasurable bone-only disease, were enrolled. Patients had progressed during neoadjuvant or adjuvant endocrine therapy, within 12 months of adjuvant endocrine therapy, or during frontline endocrine treatment for metastatic disease.

Those who had received more than 1 endocrine therapy or any prior chemotherapy for metastatic breast cancer or prior treatment with everolimus or CDK4/6 inhibitors, as well as those with the presence of visceral crisis or evidence or history of central nervous system (CNS) metastases, were excluded from the study.

Patients were randomized 2:1 to receive 150 mg abemaciclib or placebo, both in combination with 500 mg fulvestrant. The initial dose of abemaciclib was 200 mg, but this was amended to 150mg after enrollment of the first 178 patients to alleviate diarrhea-related toxicity concerns. Randomization was stratified according to metastatic site (visceral, bone only, or other) and endocrine therapy resistance (primary or secondary).

Tumors were measured by computed tomography (CT) and magnetic-resonance imaging (MRI) according to RECIST-1.1 within 28 days before random assignment, every 8 weeks for the first year, every 12 weeks thereafter, and then within 2 weeks of clinical progression. Bone scintigraphy was also performed at baseline and then every 6th cycle starting with cycle 7. Hematologic and blood chemistry laboratory tests were performed centrally on days 1 and 15 of the first cycle and day 1 of all remaining cycles.

The primary endpoint was progression-free survival (PFS); median PFS was 16.4 months in the abemaciclib arm, compared with 9.3 months in the placebo arm in the intent-to-treat population (hazard ratio [HR], 0.553;P < .0000001), translating to a 45% reduction in the risk of disease progression or death with the combination. Objective response rate in the 2 groups among patients with measurable disease was 48.1% and 21.3%, respectively, which included a complete response rate of 3.5% in the abemaciclib arm. The median duration of response was not yet reached in the study group, compared with 25.6 months for placebo. Overall survival data were not yet mature.

The agency also approved abemaciclib as monotherapy for women and men with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. That approval was based on data from the single-arm MONARCH-1 trial of 132 patients who received 200 mg abemaciclib twice daily on a continuous schedule.²

Patients had adequate organ function, measurable disease per RECIST-1.1, and an ECOG performance status of 0 or 1. Patients must have progressed on or after previous endocrine therapy and have received prior treatment with at least 2 chemotherapy regimens, at least 1 of them, but no more than 2, having been administered in the metastatic setting. Exclusion criteria included prior receipt of a CDK inhibitor, major surgery within 14 days of the start of the study, and CNS metastases.

Tumor assessments were performed by CT or MRI according to RECIST-1.1 within the 4 weeks prior to the first dose of study drug and then subsequently at every other cycle. Responses were confirmed at least 4 weeks after the initial observation. The overall response rate was 19.7%, made up completely of partial responses. Median duration of response was 8.6 months, median PFS was 6 months and median OS was 17.7 months.
 

Adverse events

The most common adverse events experienced with the combination of abemaciclib and fulvestrant were neutropenia (23.6%) and diarrhea (13.4%). The rate of grade 4 neutropenia was higher in the combination arm (2.9% vs 0.4%) and there were 3 deaths with the combination that were linked to treatment-related AEs. In the monotherapy trial, abemaciclib treatment most commonly caused diarrhea (90.2%), fatigue (65.2%), nausea (64.4%), decreased appetite (45.5%), and abdominal pain (38.6%). Grade 3 diarrhea and fatigue occurred in 19.7% and 12.9% of patients, respectively. Serious AEs occurred in 24.2% of patients and AEs led to treatment discontinuation in 7.6% of patients.

Warnings and precautions

Abemaciclib is marketed as Verzenio by Eli Lilly and Company. Warnings and precautions relating to diarrhea, neutropenia, hepatotoxicity, venous thromboembolism (VTE), and embryofetal toxicity are detailed in the prescribing information. In the event of diarrhea, patients should be treated with antidiarrheal therapy and should increase oral fluids and notify their health care provider. Treatment should be interrupted for grade 3 or 4 diarrhea and then resumed at a lower dose upon return to grade 1.

To guard against neutropenia, complete blood counts should be performed prior to starting therapy, every 2 weeks for the first 2 months, monthly for the subsequent 2 months, and then as clinically indicated. Treatment should be interrupted or delayed or the dose reduced for grade 3 or 4 neutropenia and patients should report episodes of fever.

Liver function tests should be performed before starting abemaciclib, every 2 weeks for the first 2 months, monthly for the next 2 months, and then as clinically indicated. For patients who develop persistent or recurrent grade 2, 3 or 4 hepatic transaminase elevation, dose interruption, reduction, discontinuation, or delay should be considered.

Patients should be monitored for signs and symptoms of VTE and pulmonary embolism, and treated appropriately. Pregnant women should be advised of the potential risk to a fetus, and those of reproductive potential should be counselled on the importance of using effective contraception during treatment and for at least 3 weeks after the last dose.³

The fall 2017 approval by the US Food and Drug Administration (FDA) of abemaciclib made it the third cyclin-dependent kinase (CDK) inhibitor approved for the treatment of hormone receptor (HR)-positive breast cancer, and the first to receive an approved indication as monotherapy in that setting. Abemaciclib is a small-molecule inhibitor of the CDK4 and CDK6 proteins, which are key gatekeepers of the cell cycle and frequently dysregulated in HR-positive breast cancer. On the basis of the randomized, placebo-controlled, multicenter phase 3 MONARCH-2 trial, it was approved in combination with fulvestrant for the treatment of women with HR-positive, HER2-negative advanced or metastatic breast cancer who had progressed during endocrine therapy.¹

A total of 669 women aged 18 years and older, with any menopausal status, an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1, measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) or nonmeasurable bone-only disease, were enrolled. Patients had progressed during neoadjuvant or adjuvant endocrine therapy, within 12 months of adjuvant endocrine therapy, or during frontline endocrine treatment for metastatic disease.

Those who had received more than 1 endocrine therapy or any prior chemotherapy for metastatic breast cancer or prior treatment with everolimus or CDK4/6 inhibitors, as well as those with the presence of visceral crisis or evidence or history of central nervous system (CNS) metastases, were excluded from the study.

Patients were randomized 2:1 to receive 150 mg abemaciclib or placebo, both in combination with 500 mg fulvestrant. The initial dose of abemaciclib was 200 mg, but this was amended to 150mg after enrollment of the first 178 patients to alleviate diarrhea-related toxicity concerns. Randomization was stratified according to metastatic site (visceral, bone only, or other) and endocrine therapy resistance (primary or secondary).

Tumors were measured by computed tomography (CT) and magnetic-resonance imaging (MRI) according to RECIST-1.1 within 28 days before random assignment, every 8 weeks for the first year, every 12 weeks thereafter, and then within 2 weeks of clinical progression. Bone scintigraphy was also performed at baseline and then every 6th cycle starting with cycle 7. Hematologic and blood chemistry laboratory tests were performed centrally on days 1 and 15 of the first cycle and day 1 of all remaining cycles.

The primary endpoint was progression-free survival (PFS); median PFS was 16.4 months in the abemaciclib arm, compared with 9.3 months in the placebo arm in the intent-to-treat population (hazard ratio [HR], 0.553;P < .0000001), translating to a 45% reduction in the risk of disease progression or death with the combination. Objective response rate in the 2 groups among patients with measurable disease was 48.1% and 21.3%, respectively, which included a complete response rate of 3.5% in the abemaciclib arm. The median duration of response was not yet reached in the study group, compared with 25.6 months for placebo. Overall survival data were not yet mature.

The agency also approved abemaciclib as monotherapy for women and men with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. That approval was based on data from the single-arm MONARCH-1 trial of 132 patients who received 200 mg abemaciclib twice daily on a continuous schedule.²

Patients had adequate organ function, measurable disease per RECIST-1.1, and an ECOG performance status of 0 or 1. Patients must have progressed on or after previous endocrine therapy and have received prior treatment with at least 2 chemotherapy regimens, at least 1 of them, but no more than 2, having been administered in the metastatic setting. Exclusion criteria included prior receipt of a CDK inhibitor, major surgery within 14 days of the start of the study, and CNS metastases.

Tumor assessments were performed by CT or MRI according to RECIST-1.1 within the 4 weeks prior to the first dose of study drug and then subsequently at every other cycle. Responses were confirmed at least 4 weeks after the initial observation. The overall response rate was 19.7%, made up completely of partial responses. Median duration of response was 8.6 months, median PFS was 6 months and median OS was 17.7 months.
 

Adverse events

The most common adverse events experienced with the combination of abemaciclib and fulvestrant were neutropenia (23.6%) and diarrhea (13.4%). The rate of grade 4 neutropenia was higher in the combination arm (2.9% vs 0.4%) and there were 3 deaths with the combination that were linked to treatment-related AEs. In the monotherapy trial, abemaciclib treatment most commonly caused diarrhea (90.2%), fatigue (65.2%), nausea (64.4%), decreased appetite (45.5%), and abdominal pain (38.6%). Grade 3 diarrhea and fatigue occurred in 19.7% and 12.9% of patients, respectively. Serious AEs occurred in 24.2% of patients and AEs led to treatment discontinuation in 7.6% of patients.

Warnings and precautions

Abemaciclib is marketed as Verzenio by Eli Lilly and Company. Warnings and precautions relating to diarrhea, neutropenia, hepatotoxicity, venous thromboembolism (VTE), and embryofetal toxicity are detailed in the prescribing information. In the event of diarrhea, patients should be treated with antidiarrheal therapy and should increase oral fluids and notify their health care provider. Treatment should be interrupted for grade 3 or 4 diarrhea and then resumed at a lower dose upon return to grade 1.

To guard against neutropenia, complete blood counts should be performed prior to starting therapy, every 2 weeks for the first 2 months, monthly for the subsequent 2 months, and then as clinically indicated. Treatment should be interrupted or delayed or the dose reduced for grade 3 or 4 neutropenia and patients should report episodes of fever.

Liver function tests should be performed before starting abemaciclib, every 2 weeks for the first 2 months, monthly for the next 2 months, and then as clinically indicated. For patients who develop persistent or recurrent grade 2, 3 or 4 hepatic transaminase elevation, dose interruption, reduction, discontinuation, or delay should be considered.

Patients should be monitored for signs and symptoms of VTE and pulmonary embolism, and treated appropriately. Pregnant women should be advised of the potential risk to a fetus, and those of reproductive potential should be counselled on the importance of using effective contraception during treatment and for at least 3 weeks after the last dose.³

The fall 2017 approval by the US Food and Drug Administration (FDA) of abemaciclib made it the third cyclin-dependent kinase (CDK) inhibitor approved for the treatment of hormone receptor (HR)-positive breast cancer, and the first to receive an approved indication as monotherapy in that setting. Abemaciclib is a small-molecule inhibitor of the CDK4 and CDK6 proteins, which are key gatekeepers of the cell cycle and frequently dysregulated in HR-positive breast cancer. On the basis of the randomized, placebo-controlled, multicenter phase 3 MONARCH-2 trial, it was approved in combination with fulvestrant for the treatment of women with HR-positive, HER2-negative advanced or metastatic breast cancer who had progressed during endocrine therapy.¹

A total of 669 women aged 18 years and older, with any menopausal status, an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1, measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) or nonmeasurable bone-only disease, were enrolled. Patients had progressed during neoadjuvant or adjuvant endocrine therapy, within 12 months of adjuvant endocrine therapy, or during frontline endocrine treatment for metastatic disease.

Those who had received more than 1 endocrine therapy or any prior chemotherapy for metastatic breast cancer or prior treatment with everolimus or CDK4/6 inhibitors, as well as those with the presence of visceral crisis or evidence or history of central nervous system (CNS) metastases, were excluded from the study.

Patients were randomized 2:1 to receive 150 mg abemaciclib or placebo, both in combination with 500 mg fulvestrant. The initial dose of abemaciclib was 200 mg, but this was amended to 150mg after enrollment of the first 178 patients to alleviate diarrhea-related toxicity concerns. Randomization was stratified according to metastatic site (visceral, bone only, or other) and endocrine therapy resistance (primary or secondary).

Tumors were measured by computed tomography (CT) and magnetic-resonance imaging (MRI) according to RECIST-1.1 within 28 days before random assignment, every 8 weeks for the first year, every 12 weeks thereafter, and then within 2 weeks of clinical progression. Bone scintigraphy was also performed at baseline and then every 6th cycle starting with cycle 7. Hematologic and blood chemistry laboratory tests were performed centrally on days 1 and 15 of the first cycle and day 1 of all remaining cycles.

The primary endpoint was progression-free survival (PFS); median PFS was 16.4 months in the abemaciclib arm, compared with 9.3 months in the placebo arm in the intent-to-treat population (hazard ratio [HR], 0.553;P < .0000001), translating to a 45% reduction in the risk of disease progression or death with the combination. Objective response rate in the 2 groups among patients with measurable disease was 48.1% and 21.3%, respectively, which included a complete response rate of 3.5% in the abemaciclib arm. The median duration of response was not yet reached in the study group, compared with 25.6 months for placebo. Overall survival data were not yet mature.

The agency also approved abemaciclib as monotherapy for women and men with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. That approval was based on data from the single-arm MONARCH-1 trial of 132 patients who received 200 mg abemaciclib twice daily on a continuous schedule.²

Patients had adequate organ function, measurable disease per RECIST-1.1, and an ECOG performance status of 0 or 1. Patients must have progressed on or after previous endocrine therapy and have received prior treatment with at least 2 chemotherapy regimens, at least 1 of them, but no more than 2, having been administered in the metastatic setting. Exclusion criteria included prior receipt of a CDK inhibitor, major surgery within 14 days of the start of the study, and CNS metastases.

Tumor assessments were performed by CT or MRI according to RECIST-1.1 within the 4 weeks prior to the first dose of study drug and then subsequently at every other cycle. Responses were confirmed at least 4 weeks after the initial observation. The overall response rate was 19.7%, made up completely of partial responses. Median duration of response was 8.6 months, median PFS was 6 months and median OS was 17.7 months.
 

Adverse events

The most common adverse events experienced with the combination of abemaciclib and fulvestrant were neutropenia (23.6%) and diarrhea (13.4%). The rate of grade 4 neutropenia was higher in the combination arm (2.9% vs 0.4%) and there were 3 deaths with the combination that were linked to treatment-related AEs. In the monotherapy trial, abemaciclib treatment most commonly caused diarrhea (90.2%), fatigue (65.2%), nausea (64.4%), decreased appetite (45.5%), and abdominal pain (38.6%). Grade 3 diarrhea and fatigue occurred in 19.7% and 12.9% of patients, respectively. Serious AEs occurred in 24.2% of patients and AEs led to treatment discontinuation in 7.6% of patients.

Warnings and precautions

Abemaciclib is marketed as Verzenio by Eli Lilly and Company. Warnings and precautions relating to diarrhea, neutropenia, hepatotoxicity, venous thromboembolism (VTE), and embryofetal toxicity are detailed in the prescribing information. In the event of diarrhea, patients should be treated with antidiarrheal therapy and should increase oral fluids and notify their health care provider. Treatment should be interrupted for grade 3 or 4 diarrhea and then resumed at a lower dose upon return to grade 1.

To guard against neutropenia, complete blood counts should be performed prior to starting therapy, every 2 weeks for the first 2 months, monthly for the subsequent 2 months, and then as clinically indicated. Treatment should be interrupted or delayed or the dose reduced for grade 3 or 4 neutropenia and patients should report episodes of fever.

Liver function tests should be performed before starting abemaciclib, every 2 weeks for the first 2 months, monthly for the next 2 months, and then as clinically indicated. For patients who develop persistent or recurrent grade 2, 3 or 4 hepatic transaminase elevation, dose interruption, reduction, discontinuation, or delay should be considered.

Patients should be monitored for signs and symptoms of VTE and pulmonary embolism, and treated appropriately. Pregnant women should be advised of the potential risk to a fetus, and those of reproductive potential should be counselled on the importance of using effective contraception during treatment and for at least 3 weeks after the last dose.³

Photo by Bill Branson

ORLANDO—Results of a pilot study suggest a web-based, reward-driven intervention can motivate adolescent cancer survivors to stay physically active.

Time spent performing moderate-to-vigorous physical activity (MVPA) increased by an average of 5 minutes a week for subjects who were randomized to the intervention.

For control subjects, MVPA decreased by an average of 24 minutes a week.

These findings were presented at the 2018 Cancer Survivorship Symposium (abstract 102).

“Compared to the general population, childhood cancer survivors have an increased risk for obesity and metabolic syndrome, conditions that can lead to heart disease, stroke, and diabetes, so it is really important that they are physically active,” said study investigator Carrie R. Howell, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“By intervening in this young age group, we hope to help kids develop healthy exercise habits for life.”

Dr Howell and her colleagues studied cancer survivors, ages 11 to 15, who were no longer receiving cancer treatment and were physically active less than 60 minutes a day.

The subjects were randomized to the intervention or to a control group. Controls received a wearable activity monitor and an educational handout with information about the importance of physical activity and examples of activities.

The intervention group received the handout and activity monitor but also had access to an interactive website. On at least a weekly basis, subjects would connect their monitor to a computer and log their activity through the website. Upon achieving certain thresholds of activity, they received rewards, such as T-shirts and gift cards by mail.

At the beginning and end of the study, participants visited St. Jude for an assessment of their physical fitness (strength, flexibility, and endurance) and neurocognitive measures (attention and memory), as well as health-related quality of life (assessed using the Pediatric Quality of Life Inventory questionnaire).

Results

Seventy-eight cancer survivors completed the 24-week study, 53 of them in the intervention group and 25 in the control group.

MVPA increased by an average of 4.7 minutes per week in the intervention group and decreased by an average of 24.3 minutes per week in the control group.

“In this age group, it is common to see a decrease in physical activity over time, even among healthy kids,” Dr Howell said. “Therefore, we are encouraged that our intervention was successful at maintaining physical activity levels, but a longer program may be needed to create lasting exercise habits.”

In addition to increases in MVPA, the intervention group had the following improvements in fitness:

• Increase in hand grip strength from an average of 19.9 kg to 21.0 kg
• Increase in number of push-ups from an average of 15 to 18
• Increase in number of sit-ups from an average of 11 to 14.

Furthermore, subjects in the intervention group saw their verbal fluency z-score increase by an average of 0.13 points and their general cognition z-score increase by an average of 0.23 points.

Their quality of life scores increased as well. Both overall quality of life and physical-function-related quality of life scores increased from an average of 74.2 to 78.0.

Control subjects had no significant changes in fitness, neurocognitive measures, or quality of life.

This study was supported by the National Cancer Institute, the American Lebanese Syrian Associated Charities, and HopeLab.

Based on the results of this study, the investigators have designed a larger trial (ALTE1631) to test a web-based physical activity intervention. They hope to enroll 384 survivors of childhood acute lymphoblastic leukemia at institutions across the US. The intervention will last a year, with follow-up at 18 months.

Further down the line, the investigators plan to explore the relationship between physical activity and cognition.

Photo by Bill Branson

ORLANDO—Results of a pilot study suggest a web-based, reward-driven intervention can motivate adolescent cancer survivors to stay physically active.

Time spent performing moderate-to-vigorous physical activity (MVPA) increased by an average of 5 minutes a week for subjects who were randomized to the intervention.

For control subjects, MVPA decreased by an average of 24 minutes a week.

These findings were presented at the 2018 Cancer Survivorship Symposium (abstract 102).

“Compared to the general population, childhood cancer survivors have an increased risk for obesity and metabolic syndrome, conditions that can lead to heart disease, stroke, and diabetes, so it is really important that they are physically active,” said study investigator Carrie R. Howell, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“By intervening in this young age group, we hope to help kids develop healthy exercise habits for life.”

Dr Howell and her colleagues studied cancer survivors, ages 11 to 15, who were no longer receiving cancer treatment and were physically active less than 60 minutes a day.

The subjects were randomized to the intervention or to a control group. Controls received a wearable activity monitor and an educational handout with information about the importance of physical activity and examples of activities.

The intervention group received the handout and activity monitor but also had access to an interactive website. On at least a weekly basis, subjects would connect their monitor to a computer and log their activity through the website. Upon achieving certain thresholds of activity, they received rewards, such as T-shirts and gift cards by mail.

At the beginning and end of the study, participants visited St. Jude for an assessment of their physical fitness (strength, flexibility, and endurance) and neurocognitive measures (attention and memory), as well as health-related quality of life (assessed using the Pediatric Quality of Life Inventory questionnaire).

Results

Seventy-eight cancer survivors completed the 24-week study, 53 of them in the intervention group and 25 in the control group.

MVPA increased by an average of 4.7 minutes per week in the intervention group and decreased by an average of 24.3 minutes per week in the control group.

“In this age group, it is common to see a decrease in physical activity over time, even among healthy kids,” Dr Howell said. “Therefore, we are encouraged that our intervention was successful at maintaining physical activity levels, but a longer program may be needed to create lasting exercise habits.”

In addition to increases in MVPA, the intervention group had the following improvements in fitness:

• Increase in hand grip strength from an average of 19.9 kg to 21.0 kg
• Increase in number of push-ups from an average of 15 to 18
• Increase in number of sit-ups from an average of 11 to 14.

Furthermore, subjects in the intervention group saw their verbal fluency z-score increase by an average of 0.13 points and their general cognition z-score increase by an average of 0.23 points.

Their quality of life scores increased as well. Both overall quality of life and physical-function-related quality of life scores increased from an average of 74.2 to 78.0.

Control subjects had no significant changes in fitness, neurocognitive measures, or quality of life.

This study was supported by the National Cancer Institute, the American Lebanese Syrian Associated Charities, and HopeLab.

Based on the results of this study, the investigators have designed a larger trial (ALTE1631) to test a web-based physical activity intervention. They hope to enroll 384 survivors of childhood acute lymphoblastic leukemia at institutions across the US. The intervention will last a year, with follow-up at 18 months.

Further down the line, the investigators plan to explore the relationship between physical activity and cognition.

Photo by Bill Branson

ORLANDO—Results of a pilot study suggest a web-based, reward-driven intervention can motivate adolescent cancer survivors to stay physically active.

Time spent performing moderate-to-vigorous physical activity (MVPA) increased by an average of 5 minutes a week for subjects who were randomized to the intervention.

For control subjects, MVPA decreased by an average of 24 minutes a week.

These findings were presented at the 2018 Cancer Survivorship Symposium (abstract 102).

“Compared to the general population, childhood cancer survivors have an increased risk for obesity and metabolic syndrome, conditions that can lead to heart disease, stroke, and diabetes, so it is really important that they are physically active,” said study investigator Carrie R. Howell, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“By intervening in this young age group, we hope to help kids develop healthy exercise habits for life.”

Dr Howell and her colleagues studied cancer survivors, ages 11 to 15, who were no longer receiving cancer treatment and were physically active less than 60 minutes a day.

The subjects were randomized to the intervention or to a control group. Controls received a wearable activity monitor and an educational handout with information about the importance of physical activity and examples of activities.

The intervention group received the handout and activity monitor but also had access to an interactive website. On at least a weekly basis, subjects would connect their monitor to a computer and log their activity through the website. Upon achieving certain thresholds of activity, they received rewards, such as T-shirts and gift cards by mail.

At the beginning and end of the study, participants visited St. Jude for an assessment of their physical fitness (strength, flexibility, and endurance) and neurocognitive measures (attention and memory), as well as health-related quality of life (assessed using the Pediatric Quality of Life Inventory questionnaire).

Results

Seventy-eight cancer survivors completed the 24-week study, 53 of them in the intervention group and 25 in the control group.

MVPA increased by an average of 4.7 minutes per week in the intervention group and decreased by an average of 24.3 minutes per week in the control group.

“In this age group, it is common to see a decrease in physical activity over time, even among healthy kids,” Dr Howell said. “Therefore, we are encouraged that our intervention was successful at maintaining physical activity levels, but a longer program may be needed to create lasting exercise habits.”

In addition to increases in MVPA, the intervention group had the following improvements in fitness:

• Increase in hand grip strength from an average of 19.9 kg to 21.0 kg
• Increase in number of push-ups from an average of 15 to 18
• Increase in number of sit-ups from an average of 11 to 14.

Furthermore, subjects in the intervention group saw their verbal fluency z-score increase by an average of 0.13 points and their general cognition z-score increase by an average of 0.23 points.

Their quality of life scores increased as well. Both overall quality of life and physical-function-related quality of life scores increased from an average of 74.2 to 78.0.

Control subjects had no significant changes in fitness, neurocognitive measures, or quality of life.

This study was supported by the National Cancer Institute, the American Lebanese Syrian Associated Charities, and HopeLab.

Based on the results of this study, the investigators have designed a larger trial (ALTE1631) to test a web-based physical activity intervention. They hope to enroll 384 survivors of childhood acute lymphoblastic leukemia at institutions across the US. The intervention will last a year, with follow-up at 18 months.

Further down the line, the investigators plan to explore the relationship between physical activity and cognition.

1. A 22-year-old woman dropped an iron on her toe yesterday. Today, the toe is painful at rest and worse with movement.

Diagnosis: The patient was diagnosed with a subungual hematoma and a possible fracture of the distal phalanx. In this case, the clinician offered to drain the hematoma but did not have access to an electrocautery unit. The patient consented to any procedure that would relieve the pain. An open paperclip, held in a hemostat and heated with a torch, was used to pierce the patient’s nail plate and drain the blood, providing immediate relief. Citing lack of insurance, the patient declined an x-ray, despite the possible fracture. The toe was bandaged, and the patient was instructed to keep it elevated and avoid weight-bearing activity. Her toe healed well, and no radiographs were taken.

For more information, see “Painful toe.” J Fam Pract. 2011;60(12).

2. For the past month, a man in his 50s has had a discolored right foot with increasing tenderness, as well as livedo reticularis on the sole and lateral aspect. He has a history of right-arm arterial thrombosis, multiple deep vein thromboses of the legs, ischemic stroke, atrial fibrillation, peripheral arterial disease, and long-term warfarin treatment. Pulses are palpable on exam.

Diagnosis: The patient was diagnosed with antiphospholipid syndrome. He remained on inpatient anticoagulation therapy with fondaparinux and was treated with pulse-dose IV corticosteroids followed by a slow oral taper: daily plasmapheresis for one week, three doses of IV immunoglobulin (0.5 g/kg), and four weekly doses of rituximab (375 mg/m²). His cutaneous findings slowly improved over the next several weeks.

For more information, see “Cyanosis of the Foot.” Cutis. 2017;100(4):206, 209-210.

3. A 35-year-old woman presents in January with purplish toes that are markedly tender to pressure. Recurrent over three successive winters, the initial symptom is an itchy, burning sensation in her toes. The discoloration and other symptoms are constant, not episodic. The condition resolves each year in late spring. Her distal pulses are normal.

Diagnosis: Pernio—also called perniosis or chilblains—is a common dermatologic condition associated with a cold, humid climate. The inflammatory lesions of pernio may be pruritic, painful, erythematous to violaceous plaques, papules, or nodules, which may have overlying blisters or ulcerations. The condition is frequently misdiagnosed; proper diagnosis relies on patient history and clinical picture. Histologic examination is typically not needed or definitive. This patient had moderately disabling pernio, which responded promptly to therapy with a calcium channel blocker.

For more information, see “Erythrocyanotic Discoloration of the Toes.” Cutis. 2000;65(4):223-226.

4. For three days, a 63-year-old man has had severe, sudden-onset pain in the right hallux and fifth toe. The patient has hypertension and hyperlipidemia and has not undergone any vascular procedures. Physical exam reveals cyanotic change with remarkable coldness on the affected toes and livedo reticularis on the underside of the toes. Pulses are palpable. A biopsy of the fifth toe reveals thrombotic arterioles with cholesterol clefts.

Diagnosis: There are a variety of causes for blue toe syndrome, including embolism, thrombosis, vasoconstrictive disorders, infectious and noninfectious inflammation, extensive venous thrombosis, and abnormal blood circulation. Among them, only emboli from atherosclerotic plaques give rise to cholesterol clefts on biopsy. Such atheroemboli are often an iatrogenic complication, especially those caused by invasive percutaneous procedures or damage to the arterial walls from vascular surgery. However, spontaneous plaque hemorrhage or shearing forces of the circulating blood can disrupt atheromatous plaques and cause embolization of cholesterol crystals—which was likely the case with this patient, since no preceding events were noted.

For more information, see “Painful Purple Toes.” Cutis. 2016;98(3):E8-E10.

1. A 22-year-old woman dropped an iron on her toe yesterday. Today, the toe is painful at rest and worse with movement.

Diagnosis: The patient was diagnosed with a subungual hematoma and a possible fracture of the distal phalanx. In this case, the clinician offered to drain the hematoma but did not have access to an electrocautery unit. The patient consented to any procedure that would relieve the pain. An open paperclip, held in a hemostat and heated with a torch, was used to pierce the patient’s nail plate and drain the blood, providing immediate relief. Citing lack of insurance, the patient declined an x-ray, despite the possible fracture. The toe was bandaged, and the patient was instructed to keep it elevated and avoid weight-bearing activity. Her toe healed well, and no radiographs were taken.

For more information, see “Painful toe.” J Fam Pract. 2011;60(12).

2. For the past month, a man in his 50s has had a discolored right foot with increasing tenderness, as well as livedo reticularis on the sole and lateral aspect. He has a history of right-arm arterial thrombosis, multiple deep vein thromboses of the legs, ischemic stroke, atrial fibrillation, peripheral arterial disease, and long-term warfarin treatment. Pulses are palpable on exam.

Diagnosis: The patient was diagnosed with antiphospholipid syndrome. He remained on inpatient anticoagulation therapy with fondaparinux and was treated with pulse-dose IV corticosteroids followed by a slow oral taper: daily plasmapheresis for one week, three doses of IV immunoglobulin (0.5 g/kg), and four weekly doses of rituximab (375 mg/m²). His cutaneous findings slowly improved over the next several weeks.

For more information, see “Cyanosis of the Foot.” Cutis. 2017;100(4):206, 209-210.

3. A 35-year-old woman presents in January with purplish toes that are markedly tender to pressure. Recurrent over three successive winters, the initial symptom is an itchy, burning sensation in her toes. The discoloration and other symptoms are constant, not episodic. The condition resolves each year in late spring. Her distal pulses are normal.

Diagnosis: Pernio—also called perniosis or chilblains—is a common dermatologic condition associated with a cold, humid climate. The inflammatory lesions of pernio may be pruritic, painful, erythematous to violaceous plaques, papules, or nodules, which may have overlying blisters or ulcerations. The condition is frequently misdiagnosed; proper diagnosis relies on patient history and clinical picture. Histologic examination is typically not needed or definitive. This patient had moderately disabling pernio, which responded promptly to therapy with a calcium channel blocker.

For more information, see “Erythrocyanotic Discoloration of the Toes.” Cutis. 2000;65(4):223-226.

4. For three days, a 63-year-old man has had severe, sudden-onset pain in the right hallux and fifth toe. The patient has hypertension and hyperlipidemia and has not undergone any vascular procedures. Physical exam reveals cyanotic change with remarkable coldness on the affected toes and livedo reticularis on the underside of the toes. Pulses are palpable. A biopsy of the fifth toe reveals thrombotic arterioles with cholesterol clefts.

Diagnosis: There are a variety of causes for blue toe syndrome, including embolism, thrombosis, vasoconstrictive disorders, infectious and noninfectious inflammation, extensive venous thrombosis, and abnormal blood circulation. Among them, only emboli from atherosclerotic plaques give rise to cholesterol clefts on biopsy. Such atheroemboli are often an iatrogenic complication, especially those caused by invasive percutaneous procedures or damage to the arterial walls from vascular surgery. However, spontaneous plaque hemorrhage or shearing forces of the circulating blood can disrupt atheromatous plaques and cause embolization of cholesterol crystals—which was likely the case with this patient, since no preceding events were noted.

For more information, see “Painful Purple Toes.” Cutis. 2016;98(3):E8-E10.

1. A 22-year-old woman dropped an iron on her toe yesterday. Today, the toe is painful at rest and worse with movement.

Diagnosis: The patient was diagnosed with a subungual hematoma and a possible fracture of the distal phalanx. In this case, the clinician offered to drain the hematoma but did not have access to an electrocautery unit. The patient consented to any procedure that would relieve the pain. An open paperclip, held in a hemostat and heated with a torch, was used to pierce the patient’s nail plate and drain the blood, providing immediate relief. Citing lack of insurance, the patient declined an x-ray, despite the possible fracture. The toe was bandaged, and the patient was instructed to keep it elevated and avoid weight-bearing activity. Her toe healed well, and no radiographs were taken.

For more information, see “Painful toe.” J Fam Pract. 2011;60(12).

2. For the past month, a man in his 50s has had a discolored right foot with increasing tenderness, as well as livedo reticularis on the sole and lateral aspect. He has a history of right-arm arterial thrombosis, multiple deep vein thromboses of the legs, ischemic stroke, atrial fibrillation, peripheral arterial disease, and long-term warfarin treatment. Pulses are palpable on exam.

Diagnosis: The patient was diagnosed with antiphospholipid syndrome. He remained on inpatient anticoagulation therapy with fondaparinux and was treated with pulse-dose IV corticosteroids followed by a slow oral taper: daily plasmapheresis for one week, three doses of IV immunoglobulin (0.5 g/kg), and four weekly doses of rituximab (375 mg/m²). His cutaneous findings slowly improved over the next several weeks.

For more information, see “Cyanosis of the Foot.” Cutis. 2017;100(4):206, 209-210.

3. A 35-year-old woman presents in January with purplish toes that are markedly tender to pressure. Recurrent over three successive winters, the initial symptom is an itchy, burning sensation in her toes. The discoloration and other symptoms are constant, not episodic. The condition resolves each year in late spring. Her distal pulses are normal.

Diagnosis: Pernio—also called perniosis or chilblains—is a common dermatologic condition associated with a cold, humid climate. The inflammatory lesions of pernio may be pruritic, painful, erythematous to violaceous plaques, papules, or nodules, which may have overlying blisters or ulcerations. The condition is frequently misdiagnosed; proper diagnosis relies on patient history and clinical picture. Histologic examination is typically not needed or definitive. This patient had moderately disabling pernio, which responded promptly to therapy with a calcium channel blocker.

For more information, see “Erythrocyanotic Discoloration of the Toes.” Cutis. 2000;65(4):223-226.

4. For three days, a 63-year-old man has had severe, sudden-onset pain in the right hallux and fifth toe. The patient has hypertension and hyperlipidemia and has not undergone any vascular procedures. Physical exam reveals cyanotic change with remarkable coldness on the affected toes and livedo reticularis on the underside of the toes. Pulses are palpable. A biopsy of the fifth toe reveals thrombotic arterioles with cholesterol clefts.

Diagnosis: There are a variety of causes for blue toe syndrome, including embolism, thrombosis, vasoconstrictive disorders, infectious and noninfectious inflammation, extensive venous thrombosis, and abnormal blood circulation. Among them, only emboli from atherosclerotic plaques give rise to cholesterol clefts on biopsy. Such atheroemboli are often an iatrogenic complication, especially those caused by invasive percutaneous procedures or damage to the arterial walls from vascular surgery. However, spontaneous plaque hemorrhage or shearing forces of the circulating blood can disrupt atheromatous plaques and cause embolization of cholesterol crystals—which was likely the case with this patient, since no preceding events were noted.

For more information, see “Painful Purple Toes.” Cutis. 2016;98(3):E8-E10.

This video was filmed at Metabolic & Endocrine Disease Summit (MEDS). Click here to learn more.

This video was filmed at Metabolic & Endocrine Disease Summit (MEDS). Click here to learn more.

This video was filmed at Metabolic & Endocrine Disease Summit (MEDS). Click here to learn more.

Last spring, the US Food and Drug Administration (FDA) granted accelerated approval to 3 different immune checkpoint inhibitors for the treatment of patients with metastatic urothelial carcinoma in the second-line setting, bringing the total number of approved members of this drug class for this indication to 5.

Avelumab and durvalumab, like atezolizumab, are monoclonal antibodies that target the programmed cell death protein ligand-1 (PD-L1) and prevent it from binding to and activating the programmed cell death protein-1 (PD-1) and CD80 receptors, which transmit inhibitory signals into T cells. In this way, it is hypothesized that their use reactivates the anti-tumor immune response conducted by tumor-infiltrating T cells. Both drugs were approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are refractory to platinum-based chemotherapy, and the approvals provide additional treatment options for this group of patients who typically have poor prognosis.^1,2
 

Avelumab trial findings

The approval of avelumab was based on the urothelial cancer cohorts of the JAVELIN Solid Tumor trial, a phase 1, open-label, dose-escalation study.³ Patients aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (range, 0-5; 0, fully active, and 5, dead), life expectancy of at least 3 months, and cytologically or histologically confirmed metastatic or locally advanced solid tumors were eligible.

Patients were excluded from the study if they had a history of or active central nervous system metastases, had other malignancies within the previous 5 years, had undergone organ transplant, had conditions requiring immune suppression, had active HIV or hepatitis B or C infection, or had autoimmune diseases other than type 1 diabetes, vitiligo, psoriasis, or thyroid disease that does not require immunosuppressive treatment.

Patients were also required to have adequate end organ function (white blood cell count, ≥3 x 10⁹ cells/L; absolute neutrophil count, ≥1.5 x 10⁹ cells/L; lymphocyte count, ≥0.5 x 10⁹ cells/L; platelet count, ≥100 x 10⁹ platelets/L; hemoglobin, ≥9 g/dL; total bilirubin concentration, ≤1.5 x upper limit of normal [ULN] range; aspartate- and alanine- aminotransferase (ALT/AST) concentrations, ≤2.5 x ULN); and estimated creatinine clearance, >50 mL/min.

A total of 242 patients were treated with a 10 mg/kg intravenous dose of avelumab every 2 weeks until disease progression or unacceptable toxicity. Before avelumab infusion, all patients received premedication with an antihistamine and acetaminophen.

The primary endpoint was objective response rate (ORR), which was 13.3% among 226 patients followed for at least 13 weeks, including 4% complete response (CR) rate, and 16.1% among 161 patients followed for at least 6 months, including 5.6% CR rate. The median time to response was 2 months and the median response duration had not been reached at the time of data cut-off. PD-L1 expression was evaluable in 84% of patients and there was no discernable variation in the response rates according to the levels of PD-L1 expression on the tumor.

The most common adverse events (AEs) that occurred in at least 20% of patients included fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection (UTI). Serious AEs occurred in 41% of patients and most commonly involved UTI, abdominal pain, musculoskeletal pain, creatinine increase/renal failure, dehydration, hematuria, intestinal obstruction, and pyrexia. Deaths owing to AEs occurred in 6% of patients and were related to pneumonitis, respiratory failure, sepsis/urosepsis, cerebrovascular accident, or gastrointestinal AEs.

Durvalumab approval

The agency’s approval of durvalumab rested on the results of an ongoing single-arm phase 1/2 trial (Study 1108).⁴ Eligibility criteria were the same as for the avelumab study. Patients were ineligible for the trial if they had received any immunotherapy within the previous 4 weeks, any monoclonal antibody within the previous 6 weeks, or had received concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy.

Durvalumab was administered as an intravenous infusion at a dose of 10 mg/kg every 2 weeks, for up to 12 months or until disease progression or unacceptable toxicity. PD-L1 expression was evaluated by immunohistochemistry in tumor tissue obtained before treatment using the Ventana PD-L1 (SP263) assay (Ventana Medical Systems), which was approved by the FDA alongside durvalumab as a companion diagnostic. The first 20 patients were enrolled regardless of their PD-L1 expression, and the subsequent 43 patients were required to have PD-L1 expression of at least 5% of their tumor cells, but that requirement was removed at an interim analysis when objective responses occurred in patients with a PD-L1 expression of lessthan 5%.

In the most up-to-date analysis, published after FDA approval, a total of 191 patients had been treated. The ORR as assessed by blinded independent central review per RECIST-1.1, was 17.8%, including 7 CRs (3.7%). In patients with high PD-L1 expression, the ORR was 27.6%, compared with 5.1% in those with low or no PD-L1 expression. Responses were observed across all subgroups, including patients with a poor prognosis. The ORRs in patients with visceral and liver metastases were 15.3% and 7.3%, respectively. The median time to response was 1.41 months, and the median duration of response had not yet been reached.

The most common AEs experienced by patients treated with durvalumab included fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and UTI. Serious treatment-related AEs occurred in 4.7% of patients, and treatment-related AEs leading to death occurred in 2 patients owing to autoimmune hepatitis and pneumonitis.
 

Toxicities and warnings for both therapies

Avelumab is marketed as Bavencio by EMD Serono, and durvalumab as Imfinzi by AstraZeneca. According to the prescribing information for both drugs, the recommended dose is 10 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks.^5,6

Both drugs are associated with serious or potentially life-threatening toxicities for which warnings and precautions are detailed in the prescribing information, predominantly for immune-mediated toxicities such as pneumonitis, hepatitis, colitis, nephritis, and endocrinpathy. Patients should be monitored for signs and symptoms of these toxicities and managed appropriately. Avelumab and durvalumab should both be withheld for grade 2 or higher pneumonitis, hepatitis, colitis, severe or life-threatening adrenal insufficiency, thyroid disorders or hyperglycemia, and moderate or severe nephritis or renal dysfunction.

These drugs should be permanently discontinued in the event of life-threatening or recurrent AEs. Immune-mediated pneumonitis, colitis, and hepatitis and adrenal insufficiency can be managed with corticosteroids; hypothyroidism, with hormone-replacement therapy; and hyperglycemia, with hyperglycemics or insulin.

To manage infusion-related reactions, patients should be premedicated with antihistamines and acetaminophen before the first 4 infusions and closely monitored for symptoms such as pyrexia, chills, flushing, hypotension, and dyspnea. Infusion can be interrupted or slowed for mild to moderate infusion-related reactions, but should be stopped and the drug discontinued for severe or life-threatening reactions.

Durvalumab is also associated with a risk of infection and patients should be monitored for signs and symptoms of infection and treated with anti-infectives. Durvalumab should be withheld for grade 3 infections. Patients being treated with durvalumab or avelumab should also be warned of the potential for embryofetal toxicity and advised to take appropriate precautions.

Last spring, the US Food and Drug Administration (FDA) granted accelerated approval to 3 different immune checkpoint inhibitors for the treatment of patients with metastatic urothelial carcinoma in the second-line setting, bringing the total number of approved members of this drug class for this indication to 5.

Avelumab and durvalumab, like atezolizumab, are monoclonal antibodies that target the programmed cell death protein ligand-1 (PD-L1) and prevent it from binding to and activating the programmed cell death protein-1 (PD-1) and CD80 receptors, which transmit inhibitory signals into T cells. In this way, it is hypothesized that their use reactivates the anti-tumor immune response conducted by tumor-infiltrating T cells. Both drugs were approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are refractory to platinum-based chemotherapy, and the approvals provide additional treatment options for this group of patients who typically have poor prognosis.^1,2
 

Avelumab trial findings

The approval of avelumab was based on the urothelial cancer cohorts of the JAVELIN Solid Tumor trial, a phase 1, open-label, dose-escalation study.³ Patients aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (range, 0-5; 0, fully active, and 5, dead), life expectancy of at least 3 months, and cytologically or histologically confirmed metastatic or locally advanced solid tumors were eligible.

Patients were excluded from the study if they had a history of or active central nervous system metastases, had other malignancies within the previous 5 years, had undergone organ transplant, had conditions requiring immune suppression, had active HIV or hepatitis B or C infection, or had autoimmune diseases other than type 1 diabetes, vitiligo, psoriasis, or thyroid disease that does not require immunosuppressive treatment.

Patients were also required to have adequate end organ function (white blood cell count, ≥3 x 10⁹ cells/L; absolute neutrophil count, ≥1.5 x 10⁹ cells/L; lymphocyte count, ≥0.5 x 10⁹ cells/L; platelet count, ≥100 x 10⁹ platelets/L; hemoglobin, ≥9 g/dL; total bilirubin concentration, ≤1.5 x upper limit of normal [ULN] range; aspartate- and alanine- aminotransferase (ALT/AST) concentrations, ≤2.5 x ULN); and estimated creatinine clearance, >50 mL/min.

A total of 242 patients were treated with a 10 mg/kg intravenous dose of avelumab every 2 weeks until disease progression or unacceptable toxicity. Before avelumab infusion, all patients received premedication with an antihistamine and acetaminophen.

The primary endpoint was objective response rate (ORR), which was 13.3% among 226 patients followed for at least 13 weeks, including 4% complete response (CR) rate, and 16.1% among 161 patients followed for at least 6 months, including 5.6% CR rate. The median time to response was 2 months and the median response duration had not been reached at the time of data cut-off. PD-L1 expression was evaluable in 84% of patients and there was no discernable variation in the response rates according to the levels of PD-L1 expression on the tumor.

The most common adverse events (AEs) that occurred in at least 20% of patients included fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection (UTI). Serious AEs occurred in 41% of patients and most commonly involved UTI, abdominal pain, musculoskeletal pain, creatinine increase/renal failure, dehydration, hematuria, intestinal obstruction, and pyrexia. Deaths owing to AEs occurred in 6% of patients and were related to pneumonitis, respiratory failure, sepsis/urosepsis, cerebrovascular accident, or gastrointestinal AEs.

Durvalumab approval

The agency’s approval of durvalumab rested on the results of an ongoing single-arm phase 1/2 trial (Study 1108).⁴ Eligibility criteria were the same as for the avelumab study. Patients were ineligible for the trial if they had received any immunotherapy within the previous 4 weeks, any monoclonal antibody within the previous 6 weeks, or had received concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy.

Durvalumab was administered as an intravenous infusion at a dose of 10 mg/kg every 2 weeks, for up to 12 months or until disease progression or unacceptable toxicity. PD-L1 expression was evaluated by immunohistochemistry in tumor tissue obtained before treatment using the Ventana PD-L1 (SP263) assay (Ventana Medical Systems), which was approved by the FDA alongside durvalumab as a companion diagnostic. The first 20 patients were enrolled regardless of their PD-L1 expression, and the subsequent 43 patients were required to have PD-L1 expression of at least 5% of their tumor cells, but that requirement was removed at an interim analysis when objective responses occurred in patients with a PD-L1 expression of lessthan 5%.

In the most up-to-date analysis, published after FDA approval, a total of 191 patients had been treated. The ORR as assessed by blinded independent central review per RECIST-1.1, was 17.8%, including 7 CRs (3.7%). In patients with high PD-L1 expression, the ORR was 27.6%, compared with 5.1% in those with low or no PD-L1 expression. Responses were observed across all subgroups, including patients with a poor prognosis. The ORRs in patients with visceral and liver metastases were 15.3% and 7.3%, respectively. The median time to response was 1.41 months, and the median duration of response had not yet been reached.

The most common AEs experienced by patients treated with durvalumab included fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and UTI. Serious treatment-related AEs occurred in 4.7% of patients, and treatment-related AEs leading to death occurred in 2 patients owing to autoimmune hepatitis and pneumonitis.
 

Toxicities and warnings for both therapies

Avelumab is marketed as Bavencio by EMD Serono, and durvalumab as Imfinzi by AstraZeneca. According to the prescribing information for both drugs, the recommended dose is 10 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks.^5,6

Both drugs are associated with serious or potentially life-threatening toxicities for which warnings and precautions are detailed in the prescribing information, predominantly for immune-mediated toxicities such as pneumonitis, hepatitis, colitis, nephritis, and endocrinpathy. Patients should be monitored for signs and symptoms of these toxicities and managed appropriately. Avelumab and durvalumab should both be withheld for grade 2 or higher pneumonitis, hepatitis, colitis, severe or life-threatening adrenal insufficiency, thyroid disorders or hyperglycemia, and moderate or severe nephritis or renal dysfunction.

These drugs should be permanently discontinued in the event of life-threatening or recurrent AEs. Immune-mediated pneumonitis, colitis, and hepatitis and adrenal insufficiency can be managed with corticosteroids; hypothyroidism, with hormone-replacement therapy; and hyperglycemia, with hyperglycemics or insulin.

To manage infusion-related reactions, patients should be premedicated with antihistamines and acetaminophen before the first 4 infusions and closely monitored for symptoms such as pyrexia, chills, flushing, hypotension, and dyspnea. Infusion can be interrupted or slowed for mild to moderate infusion-related reactions, but should be stopped and the drug discontinued for severe or life-threatening reactions.

Durvalumab is also associated with a risk of infection and patients should be monitored for signs and symptoms of infection and treated with anti-infectives. Durvalumab should be withheld for grade 3 infections. Patients being treated with durvalumab or avelumab should also be warned of the potential for embryofetal toxicity and advised to take appropriate precautions.

Last spring, the US Food and Drug Administration (FDA) granted accelerated approval to 3 different immune checkpoint inhibitors for the treatment of patients with metastatic urothelial carcinoma in the second-line setting, bringing the total number of approved members of this drug class for this indication to 5.

Avelumab and durvalumab, like atezolizumab, are monoclonal antibodies that target the programmed cell death protein ligand-1 (PD-L1) and prevent it from binding to and activating the programmed cell death protein-1 (PD-1) and CD80 receptors, which transmit inhibitory signals into T cells. In this way, it is hypothesized that their use reactivates the anti-tumor immune response conducted by tumor-infiltrating T cells. Both drugs were approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are refractory to platinum-based chemotherapy, and the approvals provide additional treatment options for this group of patients who typically have poor prognosis.^1,2
 

Avelumab trial findings

The approval of avelumab was based on the urothelial cancer cohorts of the JAVELIN Solid Tumor trial, a phase 1, open-label, dose-escalation study.³ Patients aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (range, 0-5; 0, fully active, and 5, dead), life expectancy of at least 3 months, and cytologically or histologically confirmed metastatic or locally advanced solid tumors were eligible.

Patients were excluded from the study if they had a history of or active central nervous system metastases, had other malignancies within the previous 5 years, had undergone organ transplant, had conditions requiring immune suppression, had active HIV or hepatitis B or C infection, or had autoimmune diseases other than type 1 diabetes, vitiligo, psoriasis, or thyroid disease that does not require immunosuppressive treatment.

Patients were also required to have adequate end organ function (white blood cell count, ≥3 x 10⁹ cells/L; absolute neutrophil count, ≥1.5 x 10⁹ cells/L; lymphocyte count, ≥0.5 x 10⁹ cells/L; platelet count, ≥100 x 10⁹ platelets/L; hemoglobin, ≥9 g/dL; total bilirubin concentration, ≤1.5 x upper limit of normal [ULN] range; aspartate- and alanine- aminotransferase (ALT/AST) concentrations, ≤2.5 x ULN); and estimated creatinine clearance, >50 mL/min.

A total of 242 patients were treated with a 10 mg/kg intravenous dose of avelumab every 2 weeks until disease progression or unacceptable toxicity. Before avelumab infusion, all patients received premedication with an antihistamine and acetaminophen.

The primary endpoint was objective response rate (ORR), which was 13.3% among 226 patients followed for at least 13 weeks, including 4% complete response (CR) rate, and 16.1% among 161 patients followed for at least 6 months, including 5.6% CR rate. The median time to response was 2 months and the median response duration had not been reached at the time of data cut-off. PD-L1 expression was evaluable in 84% of patients and there was no discernable variation in the response rates according to the levels of PD-L1 expression on the tumor.

The most common adverse events (AEs) that occurred in at least 20% of patients included fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection (UTI). Serious AEs occurred in 41% of patients and most commonly involved UTI, abdominal pain, musculoskeletal pain, creatinine increase/renal failure, dehydration, hematuria, intestinal obstruction, and pyrexia. Deaths owing to AEs occurred in 6% of patients and were related to pneumonitis, respiratory failure, sepsis/urosepsis, cerebrovascular accident, or gastrointestinal AEs.

Durvalumab approval

The agency’s approval of durvalumab rested on the results of an ongoing single-arm phase 1/2 trial (Study 1108).⁴ Eligibility criteria were the same as for the avelumab study. Patients were ineligible for the trial if they had received any immunotherapy within the previous 4 weeks, any monoclonal antibody within the previous 6 weeks, or had received concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy.

Durvalumab was administered as an intravenous infusion at a dose of 10 mg/kg every 2 weeks, for up to 12 months or until disease progression or unacceptable toxicity. PD-L1 expression was evaluated by immunohistochemistry in tumor tissue obtained before treatment using the Ventana PD-L1 (SP263) assay (Ventana Medical Systems), which was approved by the FDA alongside durvalumab as a companion diagnostic. The first 20 patients were enrolled regardless of their PD-L1 expression, and the subsequent 43 patients were required to have PD-L1 expression of at least 5% of their tumor cells, but that requirement was removed at an interim analysis when objective responses occurred in patients with a PD-L1 expression of lessthan 5%.

In the most up-to-date analysis, published after FDA approval, a total of 191 patients had been treated. The ORR as assessed by blinded independent central review per RECIST-1.1, was 17.8%, including 7 CRs (3.7%). In patients with high PD-L1 expression, the ORR was 27.6%, compared with 5.1% in those with low or no PD-L1 expression. Responses were observed across all subgroups, including patients with a poor prognosis. The ORRs in patients with visceral and liver metastases were 15.3% and 7.3%, respectively. The median time to response was 1.41 months, and the median duration of response had not yet been reached.

The most common AEs experienced by patients treated with durvalumab included fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and UTI. Serious treatment-related AEs occurred in 4.7% of patients, and treatment-related AEs leading to death occurred in 2 patients owing to autoimmune hepatitis and pneumonitis.
 

Toxicities and warnings for both therapies

Avelumab is marketed as Bavencio by EMD Serono, and durvalumab as Imfinzi by AstraZeneca. According to the prescribing information for both drugs, the recommended dose is 10 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks.^5,6

Both drugs are associated with serious or potentially life-threatening toxicities for which warnings and precautions are detailed in the prescribing information, predominantly for immune-mediated toxicities such as pneumonitis, hepatitis, colitis, nephritis, and endocrinpathy. Patients should be monitored for signs and symptoms of these toxicities and managed appropriately. Avelumab and durvalumab should both be withheld for grade 2 or higher pneumonitis, hepatitis, colitis, severe or life-threatening adrenal insufficiency, thyroid disorders or hyperglycemia, and moderate or severe nephritis or renal dysfunction.

These drugs should be permanently discontinued in the event of life-threatening or recurrent AEs. Immune-mediated pneumonitis, colitis, and hepatitis and adrenal insufficiency can be managed with corticosteroids; hypothyroidism, with hormone-replacement therapy; and hyperglycemia, with hyperglycemics or insulin.

To manage infusion-related reactions, patients should be premedicated with antihistamines and acetaminophen before the first 4 infusions and closely monitored for symptoms such as pyrexia, chills, flushing, hypotension, and dyspnea. Infusion can be interrupted or slowed for mild to moderate infusion-related reactions, but should be stopped and the drug discontinued for severe or life-threatening reactions.

Durvalumab is also associated with a risk of infection and patients should be monitored for signs and symptoms of infection and treated with anti-infectives. Durvalumab should be withheld for grade 3 infections. Patients being treated with durvalumab or avelumab should also be warned of the potential for embryofetal toxicity and advised to take appropriate precautions.

Immune checkpoint inhibitors, including anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) and anti-programmed cell death protein-1 (anti-PD-1) antibodies, have demonstrated clinical and survival benefits in a variety of malignancies, which has led to an expansion in their role in oncology. In melanoma, the anti-CTLA-4 antibody, ipilimumab, has demonstrated a survival benefit in patients with advanced metastatic melanoma and in patients with resectable disease with lymph node involvement.^1,2

Ipilimumab exerts its effect by binding CTLA-4 on conventional and regulatory T cells, thus blocking inhibitory signals on T cells, which leads to an antitumor response.³ The increased immune response counteracts the immune-evading mechanisms of the tumor. With increased use of these agents, immune-related adverse events (irAEs) have become more prevalent. The most common irAEs secondary to ipilimumab are skin rash, colitis/diarrhea, hepatitis, pneumonitis, and various endocrinopathies.⁴ In a phase 3 trial of adjuvant ipilimumab in patients with resected stage III melanoma, grade 3 or 4 adverse events occurred in 54.1% of participants in the ipilimumab arm, the most common being diarrhea and colitis (9.8% and 6.8%, respectively).²Recognition and management of irAEs has led to the implementation of treatment guidelines.^4,5 Management of irAEs includes checkpoint inhibitor discontinuation and reversal of the immune response by institution of immunosuppression with corticosteroids. Here we present the case of a patient with stage IIIB, BRAF V600E-positive melanoma, who developed colitis refractory to standard therapy after treatment with ipilimumab and whose clinical course was complicated by cytomegalovirus (CMV) reactivation and bowel perforation.

Case presentation and summary

A 40-year-old white woman with stage IIIB BRAF V600E-positive melanoma presented with diarrhea refractory to high-dose prednisone (1 mg/kg BID). She had recently undergone wide local excision and sentinel node biopsy and received her inaugural dose of ipilimumab (10 mg/kg).

The patient first presented with loose, watery stools that had begun 8 days after she had received her first dose of adjuvant ipilimumab. She was admitted to the hospital, and intravenous methylprednisolone was initiated along with empiric ciprofloxacin (400 mg, IVPB Q12h) and metronidazole (500 mg, IVPB Q8h) as infectious causes were concurrently ruled out. During this initial admission, the patient’s stool was negative for Clostridium difficile toxin, ova, and parasites, as well as enteric pathogens by culture. After infectious causes were excluded, she was diagnosed with ipilimumab-induced colitis. Antibiotics were discontinued, and the patient ultimately noted improvement in her symptoms. On hospital day 7, she was experiencing only 2 bowel movements a day and was discharged on 80 mg of prednisone twice daily.

After discharge the patient noted persistence of her symptoms. At her follow-up, 9 days after discharge, the patient noted continued symptoms of low-grade diarrhea. She failed a trial of steroid tapering due to exacerbation of her abdominal pain and frequency of diarrhea. Further investigation was negative for C. diff toxin and a computed-tomography scan was consistent with continuing colitis. The patient’s symptoms continued to worsen, with recurrence of grade 3 diarrhea, and she was ultimately readmitted 17 days after her earlier discharge (36 days after her first ipilimumab dosing).

On re-admission, the patient was again given intravenous methylprednisolone and experienced interval improvement in the frequency of diarrhea. A gastroenterology expert was consulted, and the patient underwent a flexible sigmoidoscopy that demonstrated findings of diffuse and severe inflammation and biopsies were obtained (Figure 1). After several days of continued symptoms, the patient received infliximab 5 mg/kg for treatment of her adverse autoimmune reaction. After administration, the patient noted improvement in the frequency and volume of diarrhea, however, her symptoms still persisted.

Discussion

Diarrhea and colitis are common irAEs attributable to checkpoint-inhibitor therapy used for the treatment of melanoma. This case of ipilimumab-induced colitis refractory to high-dose oral steroids demonstrates the risks associated with management of anti-CTLA-4 induced colitis. In particular, the high-dose corticosteroids required to treat the autoimmune component of this patient’s colitis increased her susceptibility to CMV reactivation.

The diagnosis of colitis secondary to ipilimumab is made primarily in the appropriate clinical setting, and typically onsets during the induction period (within 12 weeks of initial dosing) and most resolve within 6-8 weeks.⁶ Histopathologically, there is lymphoplasmacytic expansion of lamina propria, increased intraepithelial lymphocytes, and increased epithelial apoptosis of crypts. One can also see acute cryptitis and crypt abscesses. Reactive epithelial changes with mucin depletion are also often seen in epithelial cells.

Findings from immunohistochemical studies have shown the increased intraepithelial lymphocytes to be predominantly CD8-positive T cells, while the lamina propria contains an increase in the mixture of CD4- and CD8-positive T cells. In addition, small intestinal samples show villous blunting. There is an absence of significant architectural distortion and well-developed basal lymphoplasmacytic infiltrates characteristic of chronic mucosal injury, such as idiopathic inflammatory bowel disease.⁷ Granulomas are also absent in most series, though they have been reported in some cases.⁸ The features are similar to those seen in autoimmune enteropathy, but goblet and endocrine cells remain preserved. Graft-versus-host disease has similar histologic features, however, the clinical setting usually makes the distinction between these obvious.

Current treatment algorithms for ipilimumab-related diarrhea, begin with immediate treatment with intravenous methylprednisolone (125 mg once). This is followed with oral prednisone at a dose of 1-2 mg/kg tapered over 4 to 8 weeks.⁴ In patients with persistent symptoms despite adequate doses of corticosteroids, infliximab (5 mg/kg every 2 weeks) is recommended until the resolution of symptoms, and a longer taper of prednisone is often necessary.

Institution of high-dose corticosteroids to treat grade 3 or 4 irAEs can increase the risk for infection, including opportunistic infections. One retrospective review of patients administered checkpoint inhibitors at a single institution revealed that 7.3% of 740 patients developed a severe infection that lead to hospitalization or treatment with intravenous antibiotics.⁹ In that patient cohort, only 0.6% had a serious infection secondary to a viral etiology, and 1 patient developed CMV enterocolitis. Most patients who developed an infection in this cohort had received corticosteroids (46/54 patients, 85%) and/or infliximab (13/54 patients, 24%).⁹

CMV is a member of the Herpesviridae family. After a primary infection, which can often go unrecognized in an immunocompetent host, CMV can persist in a latent state.¹⁰ In a study by Bate and colleagues, the age-adjusted seropositivity of CMV was found to be 50.4%.¹¹ Based on those results, immunosuppression in a patient who has previously been infected with CMV can lead to a risk of reactivation or even reinfection. In the era of checkpoint-inhibitor therapy, reactivation of CMV has been described previously in a case of CMV hepatitis and a report of CMV colitis.^12,13 Immunosuppression, such as that caused by corticosteroids, is a risk factor for CMV infection.¹⁴ Colitis caused by CMV usually presents with abdominal pain, diarrhea, and bloody diarrhea.¹⁵ In suspected cases of CMV colitis, endoscopy should be pursued with biopsy for tissue examination. A tissue diagnosis is required for CMV colitis because serum PCR can be negative in isolated cases of gastrointestinal CMV infection.¹⁵

Conclusion

Despite appropriate treatment with ganciclovir and the noted response in the patient’s serum CMV PCR, symptom exacerbation was observed with the transition to oral prednisone. The requirement for intravenous corticosteroids in the present case demonstrates the prolonged effects exerted by irAEs secondary to checkpoint-inhibitor therapy. Those effects are attributable to the design of the antibody – ipilimumab is a fully humanized monoclonal antibody and has a plasma half-life of about 15 days.^1,4

By the identification of CMV histopathologically, this case, along with the case presented by Lankes and colleagues,¹³ illustrates the importance of considering CMV colitis in patients who are being treated with ipilimumab and who develop persistent or worsening diarrhea after initial treatment with high-dose steroids.

Early recognition of possible coexistent CMV colitis in patients with a history of treatment with ipilimumab can have important clinical consequences. It can lead to quicker implementation of proper antiviral therapy and minimization of immune suppression to levels required to maintain control of the patient’s symptoms.

Immune checkpoint inhibitors, including anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) and anti-programmed cell death protein-1 (anti-PD-1) antibodies, have demonstrated clinical and survival benefits in a variety of malignancies, which has led to an expansion in their role in oncology. In melanoma, the anti-CTLA-4 antibody, ipilimumab, has demonstrated a survival benefit in patients with advanced metastatic melanoma and in patients with resectable disease with lymph node involvement.^1,2

Ipilimumab exerts its effect by binding CTLA-4 on conventional and regulatory T cells, thus blocking inhibitory signals on T cells, which leads to an antitumor response.³ The increased immune response counteracts the immune-evading mechanisms of the tumor. With increased use of these agents, immune-related adverse events (irAEs) have become more prevalent. The most common irAEs secondary to ipilimumab are skin rash, colitis/diarrhea, hepatitis, pneumonitis, and various endocrinopathies.⁴ In a phase 3 trial of adjuvant ipilimumab in patients with resected stage III melanoma, grade 3 or 4 adverse events occurred in 54.1% of participants in the ipilimumab arm, the most common being diarrhea and colitis (9.8% and 6.8%, respectively).²Recognition and management of irAEs has led to the implementation of treatment guidelines.^4,5 Management of irAEs includes checkpoint inhibitor discontinuation and reversal of the immune response by institution of immunosuppression with corticosteroids. Here we present the case of a patient with stage IIIB, BRAF V600E-positive melanoma, who developed colitis refractory to standard therapy after treatment with ipilimumab and whose clinical course was complicated by cytomegalovirus (CMV) reactivation and bowel perforation.

Case presentation and summary

A 40-year-old white woman with stage IIIB BRAF V600E-positive melanoma presented with diarrhea refractory to high-dose prednisone (1 mg/kg BID). She had recently undergone wide local excision and sentinel node biopsy and received her inaugural dose of ipilimumab (10 mg/kg).

The patient first presented with loose, watery stools that had begun 8 days after she had received her first dose of adjuvant ipilimumab. She was admitted to the hospital, and intravenous methylprednisolone was initiated along with empiric ciprofloxacin (400 mg, IVPB Q12h) and metronidazole (500 mg, IVPB Q8h) as infectious causes were concurrently ruled out. During this initial admission, the patient’s stool was negative for Clostridium difficile toxin, ova, and parasites, as well as enteric pathogens by culture. After infectious causes were excluded, she was diagnosed with ipilimumab-induced colitis. Antibiotics were discontinued, and the patient ultimately noted improvement in her symptoms. On hospital day 7, she was experiencing only 2 bowel movements a day and was discharged on 80 mg of prednisone twice daily.

After discharge the patient noted persistence of her symptoms. At her follow-up, 9 days after discharge, the patient noted continued symptoms of low-grade diarrhea. She failed a trial of steroid tapering due to exacerbation of her abdominal pain and frequency of diarrhea. Further investigation was negative for C. diff toxin and a computed-tomography scan was consistent with continuing colitis. The patient’s symptoms continued to worsen, with recurrence of grade 3 diarrhea, and she was ultimately readmitted 17 days after her earlier discharge (36 days after her first ipilimumab dosing).

On re-admission, the patient was again given intravenous methylprednisolone and experienced interval improvement in the frequency of diarrhea. A gastroenterology expert was consulted, and the patient underwent a flexible sigmoidoscopy that demonstrated findings of diffuse and severe inflammation and biopsies were obtained (Figure 1). After several days of continued symptoms, the patient received infliximab 5 mg/kg for treatment of her adverse autoimmune reaction. After administration, the patient noted improvement in the frequency and volume of diarrhea, however, her symptoms still persisted.

Discussion

Diarrhea and colitis are common irAEs attributable to checkpoint-inhibitor therapy used for the treatment of melanoma. This case of ipilimumab-induced colitis refractory to high-dose oral steroids demonstrates the risks associated with management of anti-CTLA-4 induced colitis. In particular, the high-dose corticosteroids required to treat the autoimmune component of this patient’s colitis increased her susceptibility to CMV reactivation.

The diagnosis of colitis secondary to ipilimumab is made primarily in the appropriate clinical setting, and typically onsets during the induction period (within 12 weeks of initial dosing) and most resolve within 6-8 weeks.⁶ Histopathologically, there is lymphoplasmacytic expansion of lamina propria, increased intraepithelial lymphocytes, and increased epithelial apoptosis of crypts. One can also see acute cryptitis and crypt abscesses. Reactive epithelial changes with mucin depletion are also often seen in epithelial cells.

Findings from immunohistochemical studies have shown the increased intraepithelial lymphocytes to be predominantly CD8-positive T cells, while the lamina propria contains an increase in the mixture of CD4- and CD8-positive T cells. In addition, small intestinal samples show villous blunting. There is an absence of significant architectural distortion and well-developed basal lymphoplasmacytic infiltrates characteristic of chronic mucosal injury, such as idiopathic inflammatory bowel disease.⁷ Granulomas are also absent in most series, though they have been reported in some cases.⁸ The features are similar to those seen in autoimmune enteropathy, but goblet and endocrine cells remain preserved. Graft-versus-host disease has similar histologic features, however, the clinical setting usually makes the distinction between these obvious.

Current treatment algorithms for ipilimumab-related diarrhea, begin with immediate treatment with intravenous methylprednisolone (125 mg once). This is followed with oral prednisone at a dose of 1-2 mg/kg tapered over 4 to 8 weeks.⁴ In patients with persistent symptoms despite adequate doses of corticosteroids, infliximab (5 mg/kg every 2 weeks) is recommended until the resolution of symptoms, and a longer taper of prednisone is often necessary.

Institution of high-dose corticosteroids to treat grade 3 or 4 irAEs can increase the risk for infection, including opportunistic infections. One retrospective review of patients administered checkpoint inhibitors at a single institution revealed that 7.3% of 740 patients developed a severe infection that lead to hospitalization or treatment with intravenous antibiotics.⁹ In that patient cohort, only 0.6% had a serious infection secondary to a viral etiology, and 1 patient developed CMV enterocolitis. Most patients who developed an infection in this cohort had received corticosteroids (46/54 patients, 85%) and/or infliximab (13/54 patients, 24%).⁹

CMV is a member of the Herpesviridae family. After a primary infection, which can often go unrecognized in an immunocompetent host, CMV can persist in a latent state.¹⁰ In a study by Bate and colleagues, the age-adjusted seropositivity of CMV was found to be 50.4%.¹¹ Based on those results, immunosuppression in a patient who has previously been infected with CMV can lead to a risk of reactivation or even reinfection. In the era of checkpoint-inhibitor therapy, reactivation of CMV has been described previously in a case of CMV hepatitis and a report of CMV colitis.^12,13 Immunosuppression, such as that caused by corticosteroids, is a risk factor for CMV infection.¹⁴ Colitis caused by CMV usually presents with abdominal pain, diarrhea, and bloody diarrhea.¹⁵ In suspected cases of CMV colitis, endoscopy should be pursued with biopsy for tissue examination. A tissue diagnosis is required for CMV colitis because serum PCR can be negative in isolated cases of gastrointestinal CMV infection.¹⁵

Conclusion

Despite appropriate treatment with ganciclovir and the noted response in the patient’s serum CMV PCR, symptom exacerbation was observed with the transition to oral prednisone. The requirement for intravenous corticosteroids in the present case demonstrates the prolonged effects exerted by irAEs secondary to checkpoint-inhibitor therapy. Those effects are attributable to the design of the antibody – ipilimumab is a fully humanized monoclonal antibody and has a plasma half-life of about 15 days.^1,4

By the identification of CMV histopathologically, this case, along with the case presented by Lankes and colleagues,¹³ illustrates the importance of considering CMV colitis in patients who are being treated with ipilimumab and who develop persistent or worsening diarrhea after initial treatment with high-dose steroids.

Early recognition of possible coexistent CMV colitis in patients with a history of treatment with ipilimumab can have important clinical consequences. It can lead to quicker implementation of proper antiviral therapy and minimization of immune suppression to levels required to maintain control of the patient’s symptoms.

Immune checkpoint inhibitors, including anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) and anti-programmed cell death protein-1 (anti-PD-1) antibodies, have demonstrated clinical and survival benefits in a variety of malignancies, which has led to an expansion in their role in oncology. In melanoma, the anti-CTLA-4 antibody, ipilimumab, has demonstrated a survival benefit in patients with advanced metastatic melanoma and in patients with resectable disease with lymph node involvement.^1,2

Ipilimumab exerts its effect by binding CTLA-4 on conventional and regulatory T cells, thus blocking inhibitory signals on T cells, which leads to an antitumor response.³ The increased immune response counteracts the immune-evading mechanisms of the tumor. With increased use of these agents, immune-related adverse events (irAEs) have become more prevalent. The most common irAEs secondary to ipilimumab are skin rash, colitis/diarrhea, hepatitis, pneumonitis, and various endocrinopathies.⁴ In a phase 3 trial of adjuvant ipilimumab in patients with resected stage III melanoma, grade 3 or 4 adverse events occurred in 54.1% of participants in the ipilimumab arm, the most common being diarrhea and colitis (9.8% and 6.8%, respectively).²Recognition and management of irAEs has led to the implementation of treatment guidelines.^4,5 Management of irAEs includes checkpoint inhibitor discontinuation and reversal of the immune response by institution of immunosuppression with corticosteroids. Here we present the case of a patient with stage IIIB, BRAF V600E-positive melanoma, who developed colitis refractory to standard therapy after treatment with ipilimumab and whose clinical course was complicated by cytomegalovirus (CMV) reactivation and bowel perforation.

Case presentation and summary

A 40-year-old white woman with stage IIIB BRAF V600E-positive melanoma presented with diarrhea refractory to high-dose prednisone (1 mg/kg BID). She had recently undergone wide local excision and sentinel node biopsy and received her inaugural dose of ipilimumab (10 mg/kg).

The patient first presented with loose, watery stools that had begun 8 days after she had received her first dose of adjuvant ipilimumab. She was admitted to the hospital, and intravenous methylprednisolone was initiated along with empiric ciprofloxacin (400 mg, IVPB Q12h) and metronidazole (500 mg, IVPB Q8h) as infectious causes were concurrently ruled out. During this initial admission, the patient’s stool was negative for Clostridium difficile toxin, ova, and parasites, as well as enteric pathogens by culture. After infectious causes were excluded, she was diagnosed with ipilimumab-induced colitis. Antibiotics were discontinued, and the patient ultimately noted improvement in her symptoms. On hospital day 7, she was experiencing only 2 bowel movements a day and was discharged on 80 mg of prednisone twice daily.

After discharge the patient noted persistence of her symptoms. At her follow-up, 9 days after discharge, the patient noted continued symptoms of low-grade diarrhea. She failed a trial of steroid tapering due to exacerbation of her abdominal pain and frequency of diarrhea. Further investigation was negative for C. diff toxin and a computed-tomography scan was consistent with continuing colitis. The patient’s symptoms continued to worsen, with recurrence of grade 3 diarrhea, and she was ultimately readmitted 17 days after her earlier discharge (36 days after her first ipilimumab dosing).

On re-admission, the patient was again given intravenous methylprednisolone and experienced interval improvement in the frequency of diarrhea. A gastroenterology expert was consulted, and the patient underwent a flexible sigmoidoscopy that demonstrated findings of diffuse and severe inflammation and biopsies were obtained (Figure 1). After several days of continued symptoms, the patient received infliximab 5 mg/kg for treatment of her adverse autoimmune reaction. After administration, the patient noted improvement in the frequency and volume of diarrhea, however, her symptoms still persisted.

Discussion

Diarrhea and colitis are common irAEs attributable to checkpoint-inhibitor therapy used for the treatment of melanoma. This case of ipilimumab-induced colitis refractory to high-dose oral steroids demonstrates the risks associated with management of anti-CTLA-4 induced colitis. In particular, the high-dose corticosteroids required to treat the autoimmune component of this patient’s colitis increased her susceptibility to CMV reactivation.

The diagnosis of colitis secondary to ipilimumab is made primarily in the appropriate clinical setting, and typically onsets during the induction period (within 12 weeks of initial dosing) and most resolve within 6-8 weeks.⁶ Histopathologically, there is lymphoplasmacytic expansion of lamina propria, increased intraepithelial lymphocytes, and increased epithelial apoptosis of crypts. One can also see acute cryptitis and crypt abscesses. Reactive epithelial changes with mucin depletion are also often seen in epithelial cells.

Findings from immunohistochemical studies have shown the increased intraepithelial lymphocytes to be predominantly CD8-positive T cells, while the lamina propria contains an increase in the mixture of CD4- and CD8-positive T cells. In addition, small intestinal samples show villous blunting. There is an absence of significant architectural distortion and well-developed basal lymphoplasmacytic infiltrates characteristic of chronic mucosal injury, such as idiopathic inflammatory bowel disease.⁷ Granulomas are also absent in most series, though they have been reported in some cases.⁸ The features are similar to those seen in autoimmune enteropathy, but goblet and endocrine cells remain preserved. Graft-versus-host disease has similar histologic features, however, the clinical setting usually makes the distinction between these obvious.

Current treatment algorithms for ipilimumab-related diarrhea, begin with immediate treatment with intravenous methylprednisolone (125 mg once). This is followed with oral prednisone at a dose of 1-2 mg/kg tapered over 4 to 8 weeks.⁴ In patients with persistent symptoms despite adequate doses of corticosteroids, infliximab (5 mg/kg every 2 weeks) is recommended until the resolution of symptoms, and a longer taper of prednisone is often necessary.

Institution of high-dose corticosteroids to treat grade 3 or 4 irAEs can increase the risk for infection, including opportunistic infections. One retrospective review of patients administered checkpoint inhibitors at a single institution revealed that 7.3% of 740 patients developed a severe infection that lead to hospitalization or treatment with intravenous antibiotics.⁹ In that patient cohort, only 0.6% had a serious infection secondary to a viral etiology, and 1 patient developed CMV enterocolitis. Most patients who developed an infection in this cohort had received corticosteroids (46/54 patients, 85%) and/or infliximab (13/54 patients, 24%).⁹

CMV is a member of the Herpesviridae family. After a primary infection, which can often go unrecognized in an immunocompetent host, CMV can persist in a latent state.¹⁰ In a study by Bate and colleagues, the age-adjusted seropositivity of CMV was found to be 50.4%.¹¹ Based on those results, immunosuppression in a patient who has previously been infected with CMV can lead to a risk of reactivation or even reinfection. In the era of checkpoint-inhibitor therapy, reactivation of CMV has been described previously in a case of CMV hepatitis and a report of CMV colitis.^12,13 Immunosuppression, such as that caused by corticosteroids, is a risk factor for CMV infection.¹⁴ Colitis caused by CMV usually presents with abdominal pain, diarrhea, and bloody diarrhea.¹⁵ In suspected cases of CMV colitis, endoscopy should be pursued with biopsy for tissue examination. A tissue diagnosis is required for CMV colitis because serum PCR can be negative in isolated cases of gastrointestinal CMV infection.¹⁵

Conclusion

Despite appropriate treatment with ganciclovir and the noted response in the patient’s serum CMV PCR, symptom exacerbation was observed with the transition to oral prednisone. The requirement for intravenous corticosteroids in the present case demonstrates the prolonged effects exerted by irAEs secondary to checkpoint-inhibitor therapy. Those effects are attributable to the design of the antibody – ipilimumab is a fully humanized monoclonal antibody and has a plasma half-life of about 15 days.^1,4

By the identification of CMV histopathologically, this case, along with the case presented by Lankes and colleagues,¹³ illustrates the importance of considering CMV colitis in patients who are being treated with ipilimumab and who develop persistent or worsening diarrhea after initial treatment with high-dose steroids.

Early recognition of possible coexistent CMV colitis in patients with a history of treatment with ipilimumab can have important clinical consequences. It can lead to quicker implementation of proper antiviral therapy and minimization of immune suppression to levels required to maintain control of the patient’s symptoms.

Worldwide, head and neck cancers account for more than half a million cases annually and nearly 400,000 deaths.¹ Although the exact incidence of metastatic disease of these primarily squamous cell tumors is difficult to determine, the incidence is thought to be much lower than that of other solid tumors.² When the different sites of metastatic disease of these tumors have been studied previously, the most common have been (in descending order of frequency) the lungs, bones, liver, skin, mediastinum, and bone marrow.^2,3 It is extremely rare area for head and neck squamous cell cancers to metastasize to the retroperitoneum. To our knowledge, only 2 other such cases have been reported in the literature.^4,5 In those two cases, the metastatic recurrence occurred at 6 and 13 months after definitive treatment of the primary cancer.

Case presentation and summary

The patient in this case is a 60-year-old man with a history of stage IV moderately differentiated invasive squamous cell carcinoma (p16 negative, Bcl-2 negative, EGFR positive) of the hypopharynx that had been initially diagnosed in 2012. At that time, he underwent a total laryngectomy, partial pharyngectomy, and total thyroidectomy. A 2-centimeter mediastinal mass was also identified on a computed-tomography scan of the thorax and resected during the initial curative surgery. Final surgical pathology on the primary hypopharygeal tumor revealed a 4.1-cm moderately differentiated squamous cell carcinoma with negative margins, but positive lymphovascular invasion (Figure 1). The 2-cm mediastinal mass also revealed the same squamous cell carcinoma as the hypopharyngeal primary. Final surgical margins were negative.

In early 2017, the patient presented with fatigue, abdominal pain, and back pain during the previous month. CT imaging revealed a left retroperitoneal mass of 8.8 x 4.0 x 6.6 cm, with bony destruction of L3-L4 causing left hydronephrosis (Figure 2 and Figure 3). Other staging work-up and imaging did not reveal any other distant disease or locoregional disease recurrence in the head and neck. Lab work was significant for an acute kidney injury that was likely secondary to mass effect from the tumor.

Discussion

Masses of the retroperitoneum have a wide differential diagnosis.⁶ Primary malignancies including lymphomas, sarcomas, neurogenic tumors, and germ cell tumors may all present primarily as retroperitoneal masses.^6,7 Nonmalignant processes such as retroperitoneal fibrosis may also present in this manner.⁷ Certain tumors are known to metastasize to the retroperitoneum, namely carcinomas of the gastrointestinal tract and ovary as well as lung cancer or melanoma.^5,8 Some primary retroperitoneal masses in women have been described in the literature as being HPV-associated squamous cell cancers of unknown primaries.⁹

When head and neck cancers metastasize they typically metastasize to the lungs, bone, liver, mediastinum, skin, and bone marrow. Most metastasis is pulmonary in origin, with the literature indicating it accounts for 52%-66% of head and neck cancer metastases, with bone metastases next in frequency at 12%-22%.^2,3,10 In general, the incidence of distant metastatic disease in head and neck cancers is not as common as its other solid tumor counterparts, and even metastasis to other lymph node groups other than locoregional cervical nodes is rare.¹¹ Furthermore, late metastasis occurring more than 2 years after definitive treatment is also an infrequent occurrence.¹²

When discussing distant metastatic disease in head and neck cancer, previous literature has described an increasing likelihood of distant metastases when there is locoregional disease recurrence.¹³ Moreover, the retroperitoneum is an exceedingly rare site of distant metastatic disease for head and neck cancer. There have been only 2 previous cases that have described this phenomenon, and in both cases the metastases occurred within or close to 1 year of definitive locoregional treatment.^4,5

Conclusion

We present our case to present an exceedingly rare case of distant metastatic, recurrent disease from head and neck cancer to the retroperitoneum (without locoregional recurrence) that occurred 4 years after definitive treatment. We believe this to be the first case of its kind to be described when taking into consideration the site of metastases, when the metastatic recurrence occurred and that it happened without loco-regional disease recurrence. This case highlights the importance of keeping a wide differential diagnosis when encountering a retroperitoneal mass in a patient with even a remote history of head and neck cancer.

Acknowledgments

The authors thank the following members of the Department of Pathology at the University of Texas Medical Branch: Asad Ahmad, MD; Eduardo Eyzaguirre, MD; Timothy C Allen, MD, JD, FACP; and Suimmin Qiu, MD, PHD.

Worldwide, head and neck cancers account for more than half a million cases annually and nearly 400,000 deaths.¹ Although the exact incidence of metastatic disease of these primarily squamous cell tumors is difficult to determine, the incidence is thought to be much lower than that of other solid tumors.² When the different sites of metastatic disease of these tumors have been studied previously, the most common have been (in descending order of frequency) the lungs, bones, liver, skin, mediastinum, and bone marrow.^2,3 It is extremely rare area for head and neck squamous cell cancers to metastasize to the retroperitoneum. To our knowledge, only 2 other such cases have been reported in the literature.^4,5 In those two cases, the metastatic recurrence occurred at 6 and 13 months after definitive treatment of the primary cancer.

Case presentation and summary

The patient in this case is a 60-year-old man with a history of stage IV moderately differentiated invasive squamous cell carcinoma (p16 negative, Bcl-2 negative, EGFR positive) of the hypopharynx that had been initially diagnosed in 2012. At that time, he underwent a total laryngectomy, partial pharyngectomy, and total thyroidectomy. A 2-centimeter mediastinal mass was also identified on a computed-tomography scan of the thorax and resected during the initial curative surgery. Final surgical pathology on the primary hypopharygeal tumor revealed a 4.1-cm moderately differentiated squamous cell carcinoma with negative margins, but positive lymphovascular invasion (Figure 1). The 2-cm mediastinal mass also revealed the same squamous cell carcinoma as the hypopharyngeal primary. Final surgical margins were negative.

In early 2017, the patient presented with fatigue, abdominal pain, and back pain during the previous month. CT imaging revealed a left retroperitoneal mass of 8.8 x 4.0 x 6.6 cm, with bony destruction of L3-L4 causing left hydronephrosis (Figure 2 and Figure 3). Other staging work-up and imaging did not reveal any other distant disease or locoregional disease recurrence in the head and neck. Lab work was significant for an acute kidney injury that was likely secondary to mass effect from the tumor.

Discussion

Masses of the retroperitoneum have a wide differential diagnosis.⁶ Primary malignancies including lymphomas, sarcomas, neurogenic tumors, and germ cell tumors may all present primarily as retroperitoneal masses.^6,7 Nonmalignant processes such as retroperitoneal fibrosis may also present in this manner.⁷ Certain tumors are known to metastasize to the retroperitoneum, namely carcinomas of the gastrointestinal tract and ovary as well as lung cancer or melanoma.^5,8 Some primary retroperitoneal masses in women have been described in the literature as being HPV-associated squamous cell cancers of unknown primaries.⁹

When head and neck cancers metastasize they typically metastasize to the lungs, bone, liver, mediastinum, skin, and bone marrow. Most metastasis is pulmonary in origin, with the literature indicating it accounts for 52%-66% of head and neck cancer metastases, with bone metastases next in frequency at 12%-22%.^2,3,10 In general, the incidence of distant metastatic disease in head and neck cancers is not as common as its other solid tumor counterparts, and even metastasis to other lymph node groups other than locoregional cervical nodes is rare.¹¹ Furthermore, late metastasis occurring more than 2 years after definitive treatment is also an infrequent occurrence.¹²

When discussing distant metastatic disease in head and neck cancer, previous literature has described an increasing likelihood of distant metastases when there is locoregional disease recurrence.¹³ Moreover, the retroperitoneum is an exceedingly rare site of distant metastatic disease for head and neck cancer. There have been only 2 previous cases that have described this phenomenon, and in both cases the metastases occurred within or close to 1 year of definitive locoregional treatment.^4,5

Conclusion

We present our case to present an exceedingly rare case of distant metastatic, recurrent disease from head and neck cancer to the retroperitoneum (without locoregional recurrence) that occurred 4 years after definitive treatment. We believe this to be the first case of its kind to be described when taking into consideration the site of metastases, when the metastatic recurrence occurred and that it happened without loco-regional disease recurrence. This case highlights the importance of keeping a wide differential diagnosis when encountering a retroperitoneal mass in a patient with even a remote history of head and neck cancer.

Acknowledgments

The authors thank the following members of the Department of Pathology at the University of Texas Medical Branch: Asad Ahmad, MD; Eduardo Eyzaguirre, MD; Timothy C Allen, MD, JD, FACP; and Suimmin Qiu, MD, PHD.

Worldwide, head and neck cancers account for more than half a million cases annually and nearly 400,000 deaths.¹ Although the exact incidence of metastatic disease of these primarily squamous cell tumors is difficult to determine, the incidence is thought to be much lower than that of other solid tumors.² When the different sites of metastatic disease of these tumors have been studied previously, the most common have been (in descending order of frequency) the lungs, bones, liver, skin, mediastinum, and bone marrow.^2,3 It is extremely rare area for head and neck squamous cell cancers to metastasize to the retroperitoneum. To our knowledge, only 2 other such cases have been reported in the literature.^4,5 In those two cases, the metastatic recurrence occurred at 6 and 13 months after definitive treatment of the primary cancer.

Case presentation and summary

The patient in this case is a 60-year-old man with a history of stage IV moderately differentiated invasive squamous cell carcinoma (p16 negative, Bcl-2 negative, EGFR positive) of the hypopharynx that had been initially diagnosed in 2012. At that time, he underwent a total laryngectomy, partial pharyngectomy, and total thyroidectomy. A 2-centimeter mediastinal mass was also identified on a computed-tomography scan of the thorax and resected during the initial curative surgery. Final surgical pathology on the primary hypopharygeal tumor revealed a 4.1-cm moderately differentiated squamous cell carcinoma with negative margins, but positive lymphovascular invasion (Figure 1). The 2-cm mediastinal mass also revealed the same squamous cell carcinoma as the hypopharyngeal primary. Final surgical margins were negative.

In early 2017, the patient presented with fatigue, abdominal pain, and back pain during the previous month. CT imaging revealed a left retroperitoneal mass of 8.8 x 4.0 x 6.6 cm, with bony destruction of L3-L4 causing left hydronephrosis (Figure 2 and Figure 3). Other staging work-up and imaging did not reveal any other distant disease or locoregional disease recurrence in the head and neck. Lab work was significant for an acute kidney injury that was likely secondary to mass effect from the tumor.

Discussion

Masses of the retroperitoneum have a wide differential diagnosis.⁶ Primary malignancies including lymphomas, sarcomas, neurogenic tumors, and germ cell tumors may all present primarily as retroperitoneal masses.^6,7 Nonmalignant processes such as retroperitoneal fibrosis may also present in this manner.⁷ Certain tumors are known to metastasize to the retroperitoneum, namely carcinomas of the gastrointestinal tract and ovary as well as lung cancer or melanoma.^5,8 Some primary retroperitoneal masses in women have been described in the literature as being HPV-associated squamous cell cancers of unknown primaries.⁹

When head and neck cancers metastasize they typically metastasize to the lungs, bone, liver, mediastinum, skin, and bone marrow. Most metastasis is pulmonary in origin, with the literature indicating it accounts for 52%-66% of head and neck cancer metastases, with bone metastases next in frequency at 12%-22%.^2,3,10 In general, the incidence of distant metastatic disease in head and neck cancers is not as common as its other solid tumor counterparts, and even metastasis to other lymph node groups other than locoregional cervical nodes is rare.¹¹ Furthermore, late metastasis occurring more than 2 years after definitive treatment is also an infrequent occurrence.¹²

When discussing distant metastatic disease in head and neck cancer, previous literature has described an increasing likelihood of distant metastases when there is locoregional disease recurrence.¹³ Moreover, the retroperitoneum is an exceedingly rare site of distant metastatic disease for head and neck cancer. There have been only 2 previous cases that have described this phenomenon, and in both cases the metastases occurred within or close to 1 year of definitive locoregional treatment.^4,5

Conclusion

We present our case to present an exceedingly rare case of distant metastatic, recurrent disease from head and neck cancer to the retroperitoneum (without locoregional recurrence) that occurred 4 years after definitive treatment. We believe this to be the first case of its kind to be described when taking into consideration the site of metastases, when the metastatic recurrence occurred and that it happened without loco-regional disease recurrence. This case highlights the importance of keeping a wide differential diagnosis when encountering a retroperitoneal mass in a patient with even a remote history of head and neck cancer.

Acknowledgments

The authors thank the following members of the Department of Pathology at the University of Texas Medical Branch: Asad Ahmad, MD; Eduardo Eyzaguirre, MD; Timothy C Allen, MD, JD, FACP; and Suimmin Qiu, MD, PHD.

Patients with painful skin conditions need pain management that is provided by their dermatologists, Robert G. Micheletti, MD, contended in a presentation at the annual meeting of the American Academy of Dermatology.

Dermatologists are the experts when it comes to treating painful skin conditions like pyoderma gangrenosum, hidradenitis suppurativa, calciphylaxis, and vasculopathies. “We should be willing to treat the pain that goes with (these conditions), at least within our scope of practice,” said Dr. Micheletti, co-director of the Inpatient Dermatology Consult Service at the University of Pennsylvania, Philadelphia. “At the same time, we know opioids should be prescribed only when necessary, at the lowest effective dose, and for the shortest possible duration.”

In our exclusive video interview, Dr. Micheletti outlined the keys to successful care of patients with painful skin disease. He described patient characteristics that influence prescribing choices and tips for accurately assessing pain needs with a preference for a conservative regimen that utilizes non-opioids and avoids over-reliance on narcotics.

Source: Micheletti, R., Session F013

Patients with painful skin conditions need pain management that is provided by their dermatologists, Robert G. Micheletti, MD, contended in a presentation at the annual meeting of the American Academy of Dermatology.

Dermatologists are the experts when it comes to treating painful skin conditions like pyoderma gangrenosum, hidradenitis suppurativa, calciphylaxis, and vasculopathies. “We should be willing to treat the pain that goes with (these conditions), at least within our scope of practice,” said Dr. Micheletti, co-director of the Inpatient Dermatology Consult Service at the University of Pennsylvania, Philadelphia. “At the same time, we know opioids should be prescribed only when necessary, at the lowest effective dose, and for the shortest possible duration.”

In our exclusive video interview, Dr. Micheletti outlined the keys to successful care of patients with painful skin disease. He described patient characteristics that influence prescribing choices and tips for accurately assessing pain needs with a preference for a conservative regimen that utilizes non-opioids and avoids over-reliance on narcotics.

Source: Micheletti, R., Session F013

Patients with painful skin conditions need pain management that is provided by their dermatologists, Robert G. Micheletti, MD, contended in a presentation at the annual meeting of the American Academy of Dermatology.

Dermatologists are the experts when it comes to treating painful skin conditions like pyoderma gangrenosum, hidradenitis suppurativa, calciphylaxis, and vasculopathies. “We should be willing to treat the pain that goes with (these conditions), at least within our scope of practice,” said Dr. Micheletti, co-director of the Inpatient Dermatology Consult Service at the University of Pennsylvania, Philadelphia. “At the same time, we know opioids should be prescribed only when necessary, at the lowest effective dose, and for the shortest possible duration.”

In our exclusive video interview, Dr. Micheletti outlined the keys to successful care of patients with painful skin disease. He described patient characteristics that influence prescribing choices and tips for accurately assessing pain needs with a preference for a conservative regimen that utilizes non-opioids and avoids over-reliance on narcotics.

Source: Micheletti, R., Session F013

SAN DIEGO – The path to successful treatment of patients with imagined skin disorders is paved with compassion, according to John Koo, MD, a dermatologist and psychiatrist with the University of California at San Francisco.

When a patient presents with delusional parasitosis -- horror stories about imagined infestations of parasites or bugs – the key to successful treatment is a positive attitude and validation, not denial, Dr. Koo said in a presentation at the annual meeting of the American Academy of Dermatology.

"I cannot afford to go in (the exam room) with a long face," he said. "If I go in and I’m not looking happy, things can deteriorate quickly. So I make sure I go in with the biggest smile on my face like I'm meeting my favorite Hollywood star."

"When I say something like 'It's like a living hell, isn't it,' patients are really touched, he said. The patient’s response is typically 'You're the first dermatologist to understand what I'm going through.' You cannot endorse their delusion, but you can endorse their suffering."

In our video interview, Dr. Koo delved into techniques for the successful work-up and evaluation of patients with delusional parasitosis, the varying degrees of the condition, medications used for treatment, and the prospects for eventual drug-free relief.

Dr. Koo reports no relevant financial disclosures.

SAN DIEGO – The path to successful treatment of patients with imagined skin disorders is paved with compassion, according to John Koo, MD, a dermatologist and psychiatrist with the University of California at San Francisco.

When a patient presents with delusional parasitosis -- horror stories about imagined infestations of parasites or bugs – the key to successful treatment is a positive attitude and validation, not denial, Dr. Koo said in a presentation at the annual meeting of the American Academy of Dermatology.

"I cannot afford to go in (the exam room) with a long face," he said. "If I go in and I’m not looking happy, things can deteriorate quickly. So I make sure I go in with the biggest smile on my face like I'm meeting my favorite Hollywood star."

"When I say something like 'It's like a living hell, isn't it,' patients are really touched, he said. The patient’s response is typically 'You're the first dermatologist to understand what I'm going through.' You cannot endorse their delusion, but you can endorse their suffering."

In our video interview, Dr. Koo delved into techniques for the successful work-up and evaluation of patients with delusional parasitosis, the varying degrees of the condition, medications used for treatment, and the prospects for eventual drug-free relief.

Dr. Koo reports no relevant financial disclosures.

SAN DIEGO – The path to successful treatment of patients with imagined skin disorders is paved with compassion, according to John Koo, MD, a dermatologist and psychiatrist with the University of California at San Francisco.

When a patient presents with delusional parasitosis -- horror stories about imagined infestations of parasites or bugs – the key to successful treatment is a positive attitude and validation, not denial, Dr. Koo said in a presentation at the annual meeting of the American Academy of Dermatology.

"I cannot afford to go in (the exam room) with a long face," he said. "If I go in and I’m not looking happy, things can deteriorate quickly. So I make sure I go in with the biggest smile on my face like I'm meeting my favorite Hollywood star."

"When I say something like 'It's like a living hell, isn't it,' patients are really touched, he said. The patient’s response is typically 'You're the first dermatologist to understand what I'm going through.' You cannot endorse their delusion, but you can endorse their suffering."

In our video interview, Dr. Koo delved into techniques for the successful work-up and evaluation of patients with delusional parasitosis, the varying degrees of the condition, medications used for treatment, and the prospects for eventual drug-free relief.

Dr. Koo reports no relevant financial disclosures.