Breast cancer survivors comprise the most prevalent cancer survivor population in the United States.¹ The number of breast cancer survivors is increasing because of early detection and diagnosis, and advances in treatment have resulted in increased life expectancy. Therefore, greater attention is needed to improve the long-term quality of life of these survivors and to help them re-adjust to normal life. For many women, although the medical treatment may have been completed, the recovery process may have not.² The prevalence of long-term mental and physical illness is significant among many breast cancer survivors. Long-term mental consequences may include memory problems, anxiety, depression, and fear of recurrence³, and long-term physical consequences may include pain, fatigue, and lymphedema, among others.⁴

El Paso, Texas, is the fourth most populous city in Texas and has a Hispanic majority. This provides an opportunity to conduct clinical research targeting participants of Hispanic descent. Several studies have noted the influence of race/ethnicity on the psychosocial function of breast cancer survivors.^5,6 We have previously reported that Hispanic breast cancer survivors might experience decreased mental and physical health-related quality of life (QoL) which limit their normal social functioning.⁶Other studies have similarly reported poor outcomes of breast cancer survivors and higher rates of fatigue and depression among Hispanic patients.⁷ However, there is a paucity of research addressing specific interventions needed to improve these outcomes and provide better QoL for breast cancer survivors.^8,9 In addition, a few survivorship care interventions have focused on minorities. We sought to assess whether a multidisciplinary cancer survivorship program in a primarily Hispanic populated area would lead to improved QoL and reduce anxiety and depressive symptoms among breast cancer survivors.

Methods

After obtaining Institutional Review Board approval, we recruited consecutive patients who were treated at our institution during October 2013-October 2014 and obtained informed consent from them. The participants were within the first 5 years after diagnosis with stages I-III breast cancer and had completed surgery, chemotherapy, and/or radiation therapy. We sought to determine whether breast cancer survivors would benefit from this intervention as determined by improvement of performance at 12 months compared with baseline based on the following self-reported validated questionnaires: Patient Health Questionnaire-9 (PHQ-9) for depression; General Anxiety Disorder-7 (GAD-7); and Short-Form Health Survey-36 (SF-36, version 2) for patient quality of life. The participants were enrolled in a comprehensive survivorship program staffed by an oncologist, an oncology nurse practitioner, a nutritionist, and a certified clinical psychologist who had trained in mindfulness-based stress reduction (MBSR).

Interventions

The participants received a one-on-one individual psychological consultation visit every 3 months for 20-45 minutes during which the psychologist addressed each patient’s emotional and psychological issues in depth, discussed relaxation techniques, and provided psychosocial counselling. In addition, all participants were asked to attend an 8-week-course (in Spanish or English) using MBSR, an interventional program in which participants receive training to promote reduction of stress by self-regulating mindfulness practice.^3,10 Our institution’s MBSR program consists of a weekly 2-hour class for 8 sessions or more. The program is provided 3 times a year, in English and Spanish. It includes the following components:

• Learning various mindfulness meditation techniques (eg, body scans, awareness of breathing, sitting/walking meditations);
• Practicing the mindfulness techniques in class; and
• Practicing techniques at home through audiorecordings of mindfulness meditation exercises and daily diary writing.

Participants were provided with a workbook on MBSR in their preferred language.¹¹ In addition to the psychological component, they were also provided with oncologic evaluations by an oncology nurse practitioner. The nurse practitioner met with participants every 3 months and provided each one with a personalized summary of all the treatments received and routine oncology follow-up care in consultation with the patients’ regular oncologists. This care also addresses the long-term sequelae of treatment, including arthritis and osteoporosis, referrals to receive screening for other cancers (eg, cervical and colon cancer), and genetic counselling as appropriate. In addition, a nutritionist provided general dietary advice in individual and group sessions every 3 months.

The self-administered questionnaires, PHQ-9, GAD-7, and SF-36, were completed at baseline, and every 3 months for 12 months. The scores were reviewed by the psychologist and the oncologist. The PHQ-9 was used to initially screen survivors for depression and monitor their improvement after the intervention. The PHQ-9 is a reliable and validated self-administered depression module.¹² The PQH-9 exclusively focuses on the 9 diagnostic criteria for DSM-IV depression disorder and it can be used as a useful measure for monitoring outcomes of depression therapy. A score of 5-14 suggests mild-moderate depression, and a score of >15 suggests severe depression

The survivors were screened for anxiety using the GAD-7, a brief 7-item self-report scale to identify probable cases of anxiety disorder that has been shown to be an efficient tool for screening and assessing the severity of anxiety.¹³ For GAD-7, a score of 5 or higher is suggestive of anxiety. Scores of 5, 10, and 15 represent cut-off points for mild, moderate, and severe anxiety, respectively.

Survivor QoL was evaluated using the SF-36 questionnaire, a multipurpose survey containing 36 questions. It ranges from 0-100 and a score that is <50.0 is considered low. The lower the score, the worse the mental or physical function.¹⁴ The SF-36 yields a patient profile of 8 health domains – vitality, physical functioning, bodily pain, general health perceptions, physical, emotional, and social role functioning; and mental health.^15,16 A score of 50.0 on either the Physical Component Summary (PCS – vitality, physical functioning, bodily pain, general health perceptions, physical role functioning) or Mental Component Summary (MCS – emotional and social role functioning, and mental health) is consistent with the US norm.

Statistical analysis

In this study, the primary objective was to use the MBSR survivorship program to improve the survivors’ outcomes at 12 months compared with baseline using the following measures: PHQ-9 for depression, GAD-7 for anxiety, and SF-36 for QoL using the PCS and MCS. Quantitative data were described using the mean and standard deviation, and categorical data were described using frequency and percentage. The outcome measures were compared between patients who completed 12-month follow-up and those who did not, using unpaired t test. The change in outcome measures at 12 months from baseline was evaluated using paired t test. The effect of intervention was summarized using relative percentage change. The “dose” of the intervention was categorized the number of MBSR sessions – ≤4 sessions, 5-7 sessions, or ≤8 sessions. The change in outcome measures were compared among three groups using 1-way analysis of variance (ANOVA) followed by post hoc multiple comparison using the Bonferroni adjustment. In addition, the effect of intervention on each outcome was evaluated by important baseline characteristics of patients. In each subgroup, the changes were compared with baseline measures using the paired t test, whereas changes in outcome between groups were compared using the unpaired t test. Statistical analyses were conducted using SAS 9.3. P-values less than 5% were considered to be significant.

Results

A total of 94 survivors of breast cancer were included in this study and 60 (63.8%) completed the 12 months of follow-up. The average age of the participants was 54.4 years (SD, 8.7), and 90.4% were Hispanic (Table 1). Tumor characteristics were as follows: invasive ductal carcinoma (84.04%), estrogen receptor–positive (ER-, 71.28%), progesterone receptor–positive (PR-, 58.51%), and HER2-neu–positive (20%). In regard to therapy received, 48% of the participants had received anthracycline- and taxane-based adjuvant chemotherapy and 23%, nonanthracycline-based chemotherapy; 71% had received anti-estrogen (hormonal) therapy and 80%, radiation therapy. In regard to surgery, half of the participants had a lumpectomy, and half, a mastectomy. The trends in the outcome measures over the follow-up period are show in the Figure 1.

The effect of the number of MBSR sessions attended on the outcome measures is summarized in Table 3. There were significant improvements in the 12-month MCS scores for patients who completed 5-7 sessions of MBSR or ≥8 sessions, compared with patients who completed ≤4 sessions of MBSR. There was an improvement observed in PCS scores only among patients who received at least 8 sessions of MBSR. There was a marked improvement observed in GAD-7 and PHQ-9 among patients who received ≥8 sessions. There was no statistically significant change in the GAD-7 or PHQ-9 scores between patients who received ≤4 sessions and 5-7 sessions. No significant association was obtained between number of MBSR sessions attended and BMI.

Discussion

In this study, we showed that a group of predominately Hispanic breast cancer survivors benefited from participating in a multidisciplinary cancer survivorship program that emphasized in-depth psychological care and MBSR. They also benefited from an education effort that included providing survivors with personalized summaries of their treatment and oncology survivorship care, addressing potential long-term side effects of treatment, referral for genetic counselling and screening for other cancers as appropriate, as well dietary advice. We found significant improvement compared with baseline in both mental and physical determinants of the patient-reported outcomes, including anxiety (GAD-7), depression (PHQ-9), and HR-QoL (PCS) and (MCS). Survivors demonstrated significant improvement on the MCS and PHQ-9 if they attended 5 or more sessions of the 8-week MBSR course, and attending 8 sessions was associated with significant improvement in GAD-7 and PCS. This might suggest that survivors who are more motivated do benefit the most from such program.

To our knowledge, this study is the first to address the benefit of the MBSR intervention in Hispanic breast cancer survivors. In a randomized controlled trial that included breast cancer survivors with stages 0-III breast cancer who completed surgery, adjunctive radiation, and/or chemotherapy, MBSR was shown to reduce the symptoms of depression and anxiety and increase energy and physical functioning compared with participants who received “usual care”.³ Furthermore, Bower and colleagues have reported improvements in sleep, fatigue, and pro-inflammatory signaling in younger survivors of breast cancer.¹⁷ A similar standardized MBSR program was tested on Danish women who had been treated for stage I-III breast cancer¹⁸ and the results showed reduced levels of anxiety and depression at the 12-month follow-up. A similar study by Hoffman and colleagues¹⁹ reported improved mood, breast- and endocrine-related quality of life, and well-being with MBSR compared with standard care in women with stage 0-III breast cancer.

Several theories have been suggested to explain how MBSR reduces symptoms of depression, anxiety, and fear of recurrence in breast cancer survivors, one of which is that it provides supportive interaction between group members to practice meditation and apply mindfulness in daily situations.³ In addition, evidence is beginning to emerge that stress-reducing interventions such as MBSR may improve telomere length (TL) and telomerase activity (TA), the markers for cellular aging, psychological stress, and disease risk.^20-24 Lengacher and colleagues conducted a randomized controlled study to investigate the effects of MBSR on TL and TA in women with breast cancer, and suggested that MBSR increases telomere length and telomerase activity.²⁵ The 142 patients with stages 0-III breast cancer had completed adjuvant treatment with radiation and/or chemotherapy at least 2 weeks before enrollment and within 2 years of completion of treatment with lumpectomy and/or mastectomy. They were randomly assigned to either a 6-week MBSR for breast cancer program or usual care.²⁵ Assessments of TA and TL were obtained along with psychological measurements at baseline, 6 weeks, and 12 weeks after the patients had completed the MBSR program. The mean age of the participants was 55.3 years; 72% were non-Hispanic white; 78% had stage I or II cancer; and 36% received both chemotherapy and radiation. In analyses adjusted for baseline TA and psychological status, TA increased steadily by about 17% over 12 weeks in the MBSR group, compared with about 3% (P < .01) in the control group. No difference was observed for TL (P = .92). The authors concluded that the data provide preliminary evidence that MBSR increases TA in peripheral blood mononuclear cells from breast cancer patients and have implications for understanding how MBSR may extend cell longevity at the cellular level.

In another study among healthy volunteers who were randomly assigned to a 3-month meditation retreat or a control group, the 30 participants in the meditation group had higher TA compared with controls.²⁰ In a nonrandomized study among prostate cancer patients, TA increased and psychological stress decreased following a stress-reducing, lifestyle-modification program.²¹ The results of another intervention study among overweight women showed improvement in distress, eating behavior, and metabolic health in women participating in a MBSR program, all of which correlated with increases in TA.²² Most recently, researchers explored the impact on TA of a Kirtan Kriya yogic meditation intervention compared with exposure to relaxing music in 39 dementia family caregivers. The yogic-meditation intervention group had a 43% increase in TA after the 8-week intervention period compared with 3.7% the music group (P < .05).²³ Finally, among 22 patients with cervical cancer who were randomized to a psychosocial telephone counseling intervention,²⁴ investigators found a significant association between increased TL and changes in psychological distress.²⁰ Findings from other studies have assessed interventions to improve outcome of breast cancer survivors, such as the Taking CHARGE self-management intervention that is designed to facilitate the transition to survivorship after breast cancer treatment.⁸ Another intervention using home-based physical activity was shown in a randomized controlled trial to improve self-reported physical activity, body-mass index, and health-related QoL.⁹ Findings from another study suggested that a combined exercise and psychological counselling program might improve QoL more than a single entity intervention.²⁶ As noted previously, these studies did not focus on minority breast cancer survivors’ population, and it is not clear if they are generalizable to Hispanics.

In addition to the MBSR component, our program has also included one-on-one psychological assessment for long-term treatment complications and provided participants with appropriate care and follow-up plans, adding the benefits of self-awareness and self-attention for the survivors, which can effectively reduce the fear of recurrence.³ Furthermore, we included dietary consults based on general cancer survivor guidelines recommending a high fruit and vegetable diet that is low in fat and sugar.²⁷ Healthier dietary lifestyle has been reported to improve breast cancer prognosis, metabolic disease, and cardiovascular outcomes among Hispanic breast cancer survivors.²⁸

Our study has some limitations, including a relatively small sample size. It did not include an exercise program, which would have been helpful in addressing the issue of overweight and obesity we encountered in the most of the Hispanic breast cancer survivors (baseline average BMI, 31.32 kg/m²; obesity range, >30 kg/m²). Because of the small sample size and nonrandomized design of the study, it is hard to evaluate the confounding effect of time on intervention effect. However, a subgroup analysis by MBSR number of sessions showed that the survivors who completed the full course of MBSR sessions (8 sessions) achieved superior benefit, compared with those who did not complete the full course, which indicates that the intervention did weigh in regardless of time. Despite these limitations, the participants in this interventional program showed improved outcomes, including less anxiety and depression and improved MCS score of the SF-36. A larger and longer follow-up prospective, randomized study is needed to validate the findings of this study. Implementing cancer survivorship as an integral component of cancer care during and after treatment is essential to improve the quality of life of cancer survivors and empower them in their transition from cancer treatment to survivorship.

Breast cancer survivors comprise the most prevalent cancer survivor population in the United States.¹ The number of breast cancer survivors is increasing because of early detection and diagnosis, and advances in treatment have resulted in increased life expectancy. Therefore, greater attention is needed to improve the long-term quality of life of these survivors and to help them re-adjust to normal life. For many women, although the medical treatment may have been completed, the recovery process may have not.² The prevalence of long-term mental and physical illness is significant among many breast cancer survivors. Long-term mental consequences may include memory problems, anxiety, depression, and fear of recurrence³, and long-term physical consequences may include pain, fatigue, and lymphedema, among others.⁴

El Paso, Texas, is the fourth most populous city in Texas and has a Hispanic majority. This provides an opportunity to conduct clinical research targeting participants of Hispanic descent. Several studies have noted the influence of race/ethnicity on the psychosocial function of breast cancer survivors.^5,6 We have previously reported that Hispanic breast cancer survivors might experience decreased mental and physical health-related quality of life (QoL) which limit their normal social functioning.⁶Other studies have similarly reported poor outcomes of breast cancer survivors and higher rates of fatigue and depression among Hispanic patients.⁷ However, there is a paucity of research addressing specific interventions needed to improve these outcomes and provide better QoL for breast cancer survivors.^8,9 In addition, a few survivorship care interventions have focused on minorities. We sought to assess whether a multidisciplinary cancer survivorship program in a primarily Hispanic populated area would lead to improved QoL and reduce anxiety and depressive symptoms among breast cancer survivors.

Methods

After obtaining Institutional Review Board approval, we recruited consecutive patients who were treated at our institution during October 2013-October 2014 and obtained informed consent from them. The participants were within the first 5 years after diagnosis with stages I-III breast cancer and had completed surgery, chemotherapy, and/or radiation therapy. We sought to determine whether breast cancer survivors would benefit from this intervention as determined by improvement of performance at 12 months compared with baseline based on the following self-reported validated questionnaires: Patient Health Questionnaire-9 (PHQ-9) for depression; General Anxiety Disorder-7 (GAD-7); and Short-Form Health Survey-36 (SF-36, version 2) for patient quality of life. The participants were enrolled in a comprehensive survivorship program staffed by an oncologist, an oncology nurse practitioner, a nutritionist, and a certified clinical psychologist who had trained in mindfulness-based stress reduction (MBSR).

Interventions

The participants received a one-on-one individual psychological consultation visit every 3 months for 20-45 minutes during which the psychologist addressed each patient’s emotional and psychological issues in depth, discussed relaxation techniques, and provided psychosocial counselling. In addition, all participants were asked to attend an 8-week-course (in Spanish or English) using MBSR, an interventional program in which participants receive training to promote reduction of stress by self-regulating mindfulness practice.^3,10 Our institution’s MBSR program consists of a weekly 2-hour class for 8 sessions or more. The program is provided 3 times a year, in English and Spanish. It includes the following components:

• Learning various mindfulness meditation techniques (eg, body scans, awareness of breathing, sitting/walking meditations);
• Practicing the mindfulness techniques in class; and
• Practicing techniques at home through audiorecordings of mindfulness meditation exercises and daily diary writing.

Participants were provided with a workbook on MBSR in their preferred language.¹¹ In addition to the psychological component, they were also provided with oncologic evaluations by an oncology nurse practitioner. The nurse practitioner met with participants every 3 months and provided each one with a personalized summary of all the treatments received and routine oncology follow-up care in consultation with the patients’ regular oncologists. This care also addresses the long-term sequelae of treatment, including arthritis and osteoporosis, referrals to receive screening for other cancers (eg, cervical and colon cancer), and genetic counselling as appropriate. In addition, a nutritionist provided general dietary advice in individual and group sessions every 3 months.

The self-administered questionnaires, PHQ-9, GAD-7, and SF-36, were completed at baseline, and every 3 months for 12 months. The scores were reviewed by the psychologist and the oncologist. The PHQ-9 was used to initially screen survivors for depression and monitor their improvement after the intervention. The PHQ-9 is a reliable and validated self-administered depression module.¹² The PQH-9 exclusively focuses on the 9 diagnostic criteria for DSM-IV depression disorder and it can be used as a useful measure for monitoring outcomes of depression therapy. A score of 5-14 suggests mild-moderate depression, and a score of >15 suggests severe depression

The survivors were screened for anxiety using the GAD-7, a brief 7-item self-report scale to identify probable cases of anxiety disorder that has been shown to be an efficient tool for screening and assessing the severity of anxiety.¹³ For GAD-7, a score of 5 or higher is suggestive of anxiety. Scores of 5, 10, and 15 represent cut-off points for mild, moderate, and severe anxiety, respectively.

Survivor QoL was evaluated using the SF-36 questionnaire, a multipurpose survey containing 36 questions. It ranges from 0-100 and a score that is <50.0 is considered low. The lower the score, the worse the mental or physical function.¹⁴ The SF-36 yields a patient profile of 8 health domains – vitality, physical functioning, bodily pain, general health perceptions, physical, emotional, and social role functioning; and mental health.^15,16 A score of 50.0 on either the Physical Component Summary (PCS – vitality, physical functioning, bodily pain, general health perceptions, physical role functioning) or Mental Component Summary (MCS – emotional and social role functioning, and mental health) is consistent with the US norm.

Statistical analysis

In this study, the primary objective was to use the MBSR survivorship program to improve the survivors’ outcomes at 12 months compared with baseline using the following measures: PHQ-9 for depression, GAD-7 for anxiety, and SF-36 for QoL using the PCS and MCS. Quantitative data were described using the mean and standard deviation, and categorical data were described using frequency and percentage. The outcome measures were compared between patients who completed 12-month follow-up and those who did not, using unpaired t test. The change in outcome measures at 12 months from baseline was evaluated using paired t test. The effect of intervention was summarized using relative percentage change. The “dose” of the intervention was categorized the number of MBSR sessions – ≤4 sessions, 5-7 sessions, or ≤8 sessions. The change in outcome measures were compared among three groups using 1-way analysis of variance (ANOVA) followed by post hoc multiple comparison using the Bonferroni adjustment. In addition, the effect of intervention on each outcome was evaluated by important baseline characteristics of patients. In each subgroup, the changes were compared with baseline measures using the paired t test, whereas changes in outcome between groups were compared using the unpaired t test. Statistical analyses were conducted using SAS 9.3. P-values less than 5% were considered to be significant.

Results

A total of 94 survivors of breast cancer were included in this study and 60 (63.8%) completed the 12 months of follow-up. The average age of the participants was 54.4 years (SD, 8.7), and 90.4% were Hispanic (Table 1). Tumor characteristics were as follows: invasive ductal carcinoma (84.04%), estrogen receptor–positive (ER-, 71.28%), progesterone receptor–positive (PR-, 58.51%), and HER2-neu–positive (20%). In regard to therapy received, 48% of the participants had received anthracycline- and taxane-based adjuvant chemotherapy and 23%, nonanthracycline-based chemotherapy; 71% had received anti-estrogen (hormonal) therapy and 80%, radiation therapy. In regard to surgery, half of the participants had a lumpectomy, and half, a mastectomy. The trends in the outcome measures over the follow-up period are show in the Figure 1.

The effect of the number of MBSR sessions attended on the outcome measures is summarized in Table 3. There were significant improvements in the 12-month MCS scores for patients who completed 5-7 sessions of MBSR or ≥8 sessions, compared with patients who completed ≤4 sessions of MBSR. There was an improvement observed in PCS scores only among patients who received at least 8 sessions of MBSR. There was a marked improvement observed in GAD-7 and PHQ-9 among patients who received ≥8 sessions. There was no statistically significant change in the GAD-7 or PHQ-9 scores between patients who received ≤4 sessions and 5-7 sessions. No significant association was obtained between number of MBSR sessions attended and BMI.

Discussion

In this study, we showed that a group of predominately Hispanic breast cancer survivors benefited from participating in a multidisciplinary cancer survivorship program that emphasized in-depth psychological care and MBSR. They also benefited from an education effort that included providing survivors with personalized summaries of their treatment and oncology survivorship care, addressing potential long-term side effects of treatment, referral for genetic counselling and screening for other cancers as appropriate, as well dietary advice. We found significant improvement compared with baseline in both mental and physical determinants of the patient-reported outcomes, including anxiety (GAD-7), depression (PHQ-9), and HR-QoL (PCS) and (MCS). Survivors demonstrated significant improvement on the MCS and PHQ-9 if they attended 5 or more sessions of the 8-week MBSR course, and attending 8 sessions was associated with significant improvement in GAD-7 and PCS. This might suggest that survivors who are more motivated do benefit the most from such program.

To our knowledge, this study is the first to address the benefit of the MBSR intervention in Hispanic breast cancer survivors. In a randomized controlled trial that included breast cancer survivors with stages 0-III breast cancer who completed surgery, adjunctive radiation, and/or chemotherapy, MBSR was shown to reduce the symptoms of depression and anxiety and increase energy and physical functioning compared with participants who received “usual care”.³ Furthermore, Bower and colleagues have reported improvements in sleep, fatigue, and pro-inflammatory signaling in younger survivors of breast cancer.¹⁷ A similar standardized MBSR program was tested on Danish women who had been treated for stage I-III breast cancer¹⁸ and the results showed reduced levels of anxiety and depression at the 12-month follow-up. A similar study by Hoffman and colleagues¹⁹ reported improved mood, breast- and endocrine-related quality of life, and well-being with MBSR compared with standard care in women with stage 0-III breast cancer.

Several theories have been suggested to explain how MBSR reduces symptoms of depression, anxiety, and fear of recurrence in breast cancer survivors, one of which is that it provides supportive interaction between group members to practice meditation and apply mindfulness in daily situations.³ In addition, evidence is beginning to emerge that stress-reducing interventions such as MBSR may improve telomere length (TL) and telomerase activity (TA), the markers for cellular aging, psychological stress, and disease risk.^20-24 Lengacher and colleagues conducted a randomized controlled study to investigate the effects of MBSR on TL and TA in women with breast cancer, and suggested that MBSR increases telomere length and telomerase activity.²⁵ The 142 patients with stages 0-III breast cancer had completed adjuvant treatment with radiation and/or chemotherapy at least 2 weeks before enrollment and within 2 years of completion of treatment with lumpectomy and/or mastectomy. They were randomly assigned to either a 6-week MBSR for breast cancer program or usual care.²⁵ Assessments of TA and TL were obtained along with psychological measurements at baseline, 6 weeks, and 12 weeks after the patients had completed the MBSR program. The mean age of the participants was 55.3 years; 72% were non-Hispanic white; 78% had stage I or II cancer; and 36% received both chemotherapy and radiation. In analyses adjusted for baseline TA and psychological status, TA increased steadily by about 17% over 12 weeks in the MBSR group, compared with about 3% (P < .01) in the control group. No difference was observed for TL (P = .92). The authors concluded that the data provide preliminary evidence that MBSR increases TA in peripheral blood mononuclear cells from breast cancer patients and have implications for understanding how MBSR may extend cell longevity at the cellular level.

In another study among healthy volunteers who were randomly assigned to a 3-month meditation retreat or a control group, the 30 participants in the meditation group had higher TA compared with controls.²⁰ In a nonrandomized study among prostate cancer patients, TA increased and psychological stress decreased following a stress-reducing, lifestyle-modification program.²¹ The results of another intervention study among overweight women showed improvement in distress, eating behavior, and metabolic health in women participating in a MBSR program, all of which correlated with increases in TA.²² Most recently, researchers explored the impact on TA of a Kirtan Kriya yogic meditation intervention compared with exposure to relaxing music in 39 dementia family caregivers. The yogic-meditation intervention group had a 43% increase in TA after the 8-week intervention period compared with 3.7% the music group (P < .05).²³ Finally, among 22 patients with cervical cancer who were randomized to a psychosocial telephone counseling intervention,²⁴ investigators found a significant association between increased TL and changes in psychological distress.²⁰ Findings from other studies have assessed interventions to improve outcome of breast cancer survivors, such as the Taking CHARGE self-management intervention that is designed to facilitate the transition to survivorship after breast cancer treatment.⁸ Another intervention using home-based physical activity was shown in a randomized controlled trial to improve self-reported physical activity, body-mass index, and health-related QoL.⁹ Findings from another study suggested that a combined exercise and psychological counselling program might improve QoL more than a single entity intervention.²⁶ As noted previously, these studies did not focus on minority breast cancer survivors’ population, and it is not clear if they are generalizable to Hispanics.

In addition to the MBSR component, our program has also included one-on-one psychological assessment for long-term treatment complications and provided participants with appropriate care and follow-up plans, adding the benefits of self-awareness and self-attention for the survivors, which can effectively reduce the fear of recurrence.³ Furthermore, we included dietary consults based on general cancer survivor guidelines recommending a high fruit and vegetable diet that is low in fat and sugar.²⁷ Healthier dietary lifestyle has been reported to improve breast cancer prognosis, metabolic disease, and cardiovascular outcomes among Hispanic breast cancer survivors.²⁸

Our study has some limitations, including a relatively small sample size. It did not include an exercise program, which would have been helpful in addressing the issue of overweight and obesity we encountered in the most of the Hispanic breast cancer survivors (baseline average BMI, 31.32 kg/m²; obesity range, >30 kg/m²). Because of the small sample size and nonrandomized design of the study, it is hard to evaluate the confounding effect of time on intervention effect. However, a subgroup analysis by MBSR number of sessions showed that the survivors who completed the full course of MBSR sessions (8 sessions) achieved superior benefit, compared with those who did not complete the full course, which indicates that the intervention did weigh in regardless of time. Despite these limitations, the participants in this interventional program showed improved outcomes, including less anxiety and depression and improved MCS score of the SF-36. A larger and longer follow-up prospective, randomized study is needed to validate the findings of this study. Implementing cancer survivorship as an integral component of cancer care during and after treatment is essential to improve the quality of life of cancer survivors and empower them in their transition from cancer treatment to survivorship.

Breast cancer survivors comprise the most prevalent cancer survivor population in the United States.¹ The number of breast cancer survivors is increasing because of early detection and diagnosis, and advances in treatment have resulted in increased life expectancy. Therefore, greater attention is needed to improve the long-term quality of life of these survivors and to help them re-adjust to normal life. For many women, although the medical treatment may have been completed, the recovery process may have not.² The prevalence of long-term mental and physical illness is significant among many breast cancer survivors. Long-term mental consequences may include memory problems, anxiety, depression, and fear of recurrence³, and long-term physical consequences may include pain, fatigue, and lymphedema, among others.⁴

El Paso, Texas, is the fourth most populous city in Texas and has a Hispanic majority. This provides an opportunity to conduct clinical research targeting participants of Hispanic descent. Several studies have noted the influence of race/ethnicity on the psychosocial function of breast cancer survivors.^5,6 We have previously reported that Hispanic breast cancer survivors might experience decreased mental and physical health-related quality of life (QoL) which limit their normal social functioning.⁶Other studies have similarly reported poor outcomes of breast cancer survivors and higher rates of fatigue and depression among Hispanic patients.⁷ However, there is a paucity of research addressing specific interventions needed to improve these outcomes and provide better QoL for breast cancer survivors.^8,9 In addition, a few survivorship care interventions have focused on minorities. We sought to assess whether a multidisciplinary cancer survivorship program in a primarily Hispanic populated area would lead to improved QoL and reduce anxiety and depressive symptoms among breast cancer survivors.

Methods

After obtaining Institutional Review Board approval, we recruited consecutive patients who were treated at our institution during October 2013-October 2014 and obtained informed consent from them. The participants were within the first 5 years after diagnosis with stages I-III breast cancer and had completed surgery, chemotherapy, and/or radiation therapy. We sought to determine whether breast cancer survivors would benefit from this intervention as determined by improvement of performance at 12 months compared with baseline based on the following self-reported validated questionnaires: Patient Health Questionnaire-9 (PHQ-9) for depression; General Anxiety Disorder-7 (GAD-7); and Short-Form Health Survey-36 (SF-36, version 2) for patient quality of life. The participants were enrolled in a comprehensive survivorship program staffed by an oncologist, an oncology nurse practitioner, a nutritionist, and a certified clinical psychologist who had trained in mindfulness-based stress reduction (MBSR).

Interventions

The participants received a one-on-one individual psychological consultation visit every 3 months for 20-45 minutes during which the psychologist addressed each patient’s emotional and psychological issues in depth, discussed relaxation techniques, and provided psychosocial counselling. In addition, all participants were asked to attend an 8-week-course (in Spanish or English) using MBSR, an interventional program in which participants receive training to promote reduction of stress by self-regulating mindfulness practice.^3,10 Our institution’s MBSR program consists of a weekly 2-hour class for 8 sessions or more. The program is provided 3 times a year, in English and Spanish. It includes the following components:

• Learning various mindfulness meditation techniques (eg, body scans, awareness of breathing, sitting/walking meditations);
• Practicing the mindfulness techniques in class; and
• Practicing techniques at home through audiorecordings of mindfulness meditation exercises and daily diary writing.

Participants were provided with a workbook on MBSR in their preferred language.¹¹ In addition to the psychological component, they were also provided with oncologic evaluations by an oncology nurse practitioner. The nurse practitioner met with participants every 3 months and provided each one with a personalized summary of all the treatments received and routine oncology follow-up care in consultation with the patients’ regular oncologists. This care also addresses the long-term sequelae of treatment, including arthritis and osteoporosis, referrals to receive screening for other cancers (eg, cervical and colon cancer), and genetic counselling as appropriate. In addition, a nutritionist provided general dietary advice in individual and group sessions every 3 months.

The self-administered questionnaires, PHQ-9, GAD-7, and SF-36, were completed at baseline, and every 3 months for 12 months. The scores were reviewed by the psychologist and the oncologist. The PHQ-9 was used to initially screen survivors for depression and monitor their improvement after the intervention. The PHQ-9 is a reliable and validated self-administered depression module.¹² The PQH-9 exclusively focuses on the 9 diagnostic criteria for DSM-IV depression disorder and it can be used as a useful measure for monitoring outcomes of depression therapy. A score of 5-14 suggests mild-moderate depression, and a score of >15 suggests severe depression

The survivors were screened for anxiety using the GAD-7, a brief 7-item self-report scale to identify probable cases of anxiety disorder that has been shown to be an efficient tool for screening and assessing the severity of anxiety.¹³ For GAD-7, a score of 5 or higher is suggestive of anxiety. Scores of 5, 10, and 15 represent cut-off points for mild, moderate, and severe anxiety, respectively.

Survivor QoL was evaluated using the SF-36 questionnaire, a multipurpose survey containing 36 questions. It ranges from 0-100 and a score that is <50.0 is considered low. The lower the score, the worse the mental or physical function.¹⁴ The SF-36 yields a patient profile of 8 health domains – vitality, physical functioning, bodily pain, general health perceptions, physical, emotional, and social role functioning; and mental health.^15,16 A score of 50.0 on either the Physical Component Summary (PCS – vitality, physical functioning, bodily pain, general health perceptions, physical role functioning) or Mental Component Summary (MCS – emotional and social role functioning, and mental health) is consistent with the US norm.

Statistical analysis

In this study, the primary objective was to use the MBSR survivorship program to improve the survivors’ outcomes at 12 months compared with baseline using the following measures: PHQ-9 for depression, GAD-7 for anxiety, and SF-36 for QoL using the PCS and MCS. Quantitative data were described using the mean and standard deviation, and categorical data were described using frequency and percentage. The outcome measures were compared between patients who completed 12-month follow-up and those who did not, using unpaired t test. The change in outcome measures at 12 months from baseline was evaluated using paired t test. The effect of intervention was summarized using relative percentage change. The “dose” of the intervention was categorized the number of MBSR sessions – ≤4 sessions, 5-7 sessions, or ≤8 sessions. The change in outcome measures were compared among three groups using 1-way analysis of variance (ANOVA) followed by post hoc multiple comparison using the Bonferroni adjustment. In addition, the effect of intervention on each outcome was evaluated by important baseline characteristics of patients. In each subgroup, the changes were compared with baseline measures using the paired t test, whereas changes in outcome between groups were compared using the unpaired t test. Statistical analyses were conducted using SAS 9.3. P-values less than 5% were considered to be significant.

Results

A total of 94 survivors of breast cancer were included in this study and 60 (63.8%) completed the 12 months of follow-up. The average age of the participants was 54.4 years (SD, 8.7), and 90.4% were Hispanic (Table 1). Tumor characteristics were as follows: invasive ductal carcinoma (84.04%), estrogen receptor–positive (ER-, 71.28%), progesterone receptor–positive (PR-, 58.51%), and HER2-neu–positive (20%). In regard to therapy received, 48% of the participants had received anthracycline- and taxane-based adjuvant chemotherapy and 23%, nonanthracycline-based chemotherapy; 71% had received anti-estrogen (hormonal) therapy and 80%, radiation therapy. In regard to surgery, half of the participants had a lumpectomy, and half, a mastectomy. The trends in the outcome measures over the follow-up period are show in the Figure 1.

The effect of the number of MBSR sessions attended on the outcome measures is summarized in Table 3. There were significant improvements in the 12-month MCS scores for patients who completed 5-7 sessions of MBSR or ≥8 sessions, compared with patients who completed ≤4 sessions of MBSR. There was an improvement observed in PCS scores only among patients who received at least 8 sessions of MBSR. There was a marked improvement observed in GAD-7 and PHQ-9 among patients who received ≥8 sessions. There was no statistically significant change in the GAD-7 or PHQ-9 scores between patients who received ≤4 sessions and 5-7 sessions. No significant association was obtained between number of MBSR sessions attended and BMI.

Discussion

In this study, we showed that a group of predominately Hispanic breast cancer survivors benefited from participating in a multidisciplinary cancer survivorship program that emphasized in-depth psychological care and MBSR. They also benefited from an education effort that included providing survivors with personalized summaries of their treatment and oncology survivorship care, addressing potential long-term side effects of treatment, referral for genetic counselling and screening for other cancers as appropriate, as well dietary advice. We found significant improvement compared with baseline in both mental and physical determinants of the patient-reported outcomes, including anxiety (GAD-7), depression (PHQ-9), and HR-QoL (PCS) and (MCS). Survivors demonstrated significant improvement on the MCS and PHQ-9 if they attended 5 or more sessions of the 8-week MBSR course, and attending 8 sessions was associated with significant improvement in GAD-7 and PCS. This might suggest that survivors who are more motivated do benefit the most from such program.

To our knowledge, this study is the first to address the benefit of the MBSR intervention in Hispanic breast cancer survivors. In a randomized controlled trial that included breast cancer survivors with stages 0-III breast cancer who completed surgery, adjunctive radiation, and/or chemotherapy, MBSR was shown to reduce the symptoms of depression and anxiety and increase energy and physical functioning compared with participants who received “usual care”.³ Furthermore, Bower and colleagues have reported improvements in sleep, fatigue, and pro-inflammatory signaling in younger survivors of breast cancer.¹⁷ A similar standardized MBSR program was tested on Danish women who had been treated for stage I-III breast cancer¹⁸ and the results showed reduced levels of anxiety and depression at the 12-month follow-up. A similar study by Hoffman and colleagues¹⁹ reported improved mood, breast- and endocrine-related quality of life, and well-being with MBSR compared with standard care in women with stage 0-III breast cancer.

Several theories have been suggested to explain how MBSR reduces symptoms of depression, anxiety, and fear of recurrence in breast cancer survivors, one of which is that it provides supportive interaction between group members to practice meditation and apply mindfulness in daily situations.³ In addition, evidence is beginning to emerge that stress-reducing interventions such as MBSR may improve telomere length (TL) and telomerase activity (TA), the markers for cellular aging, psychological stress, and disease risk.^20-24 Lengacher and colleagues conducted a randomized controlled study to investigate the effects of MBSR on TL and TA in women with breast cancer, and suggested that MBSR increases telomere length and telomerase activity.²⁵ The 142 patients with stages 0-III breast cancer had completed adjuvant treatment with radiation and/or chemotherapy at least 2 weeks before enrollment and within 2 years of completion of treatment with lumpectomy and/or mastectomy. They were randomly assigned to either a 6-week MBSR for breast cancer program or usual care.²⁵ Assessments of TA and TL were obtained along with psychological measurements at baseline, 6 weeks, and 12 weeks after the patients had completed the MBSR program. The mean age of the participants was 55.3 years; 72% were non-Hispanic white; 78% had stage I or II cancer; and 36% received both chemotherapy and radiation. In analyses adjusted for baseline TA and psychological status, TA increased steadily by about 17% over 12 weeks in the MBSR group, compared with about 3% (P < .01) in the control group. No difference was observed for TL (P = .92). The authors concluded that the data provide preliminary evidence that MBSR increases TA in peripheral blood mononuclear cells from breast cancer patients and have implications for understanding how MBSR may extend cell longevity at the cellular level.

In another study among healthy volunteers who were randomly assigned to a 3-month meditation retreat or a control group, the 30 participants in the meditation group had higher TA compared with controls.²⁰ In a nonrandomized study among prostate cancer patients, TA increased and psychological stress decreased following a stress-reducing, lifestyle-modification program.²¹ The results of another intervention study among overweight women showed improvement in distress, eating behavior, and metabolic health in women participating in a MBSR program, all of which correlated with increases in TA.²² Most recently, researchers explored the impact on TA of a Kirtan Kriya yogic meditation intervention compared with exposure to relaxing music in 39 dementia family caregivers. The yogic-meditation intervention group had a 43% increase in TA after the 8-week intervention period compared with 3.7% the music group (P < .05).²³ Finally, among 22 patients with cervical cancer who were randomized to a psychosocial telephone counseling intervention,²⁴ investigators found a significant association between increased TL and changes in psychological distress.²⁰ Findings from other studies have assessed interventions to improve outcome of breast cancer survivors, such as the Taking CHARGE self-management intervention that is designed to facilitate the transition to survivorship after breast cancer treatment.⁸ Another intervention using home-based physical activity was shown in a randomized controlled trial to improve self-reported physical activity, body-mass index, and health-related QoL.⁹ Findings from another study suggested that a combined exercise and psychological counselling program might improve QoL more than a single entity intervention.²⁶ As noted previously, these studies did not focus on minority breast cancer survivors’ population, and it is not clear if they are generalizable to Hispanics.

In addition to the MBSR component, our program has also included one-on-one psychological assessment for long-term treatment complications and provided participants with appropriate care and follow-up plans, adding the benefits of self-awareness and self-attention for the survivors, which can effectively reduce the fear of recurrence.³ Furthermore, we included dietary consults based on general cancer survivor guidelines recommending a high fruit and vegetable diet that is low in fat and sugar.²⁷ Healthier dietary lifestyle has been reported to improve breast cancer prognosis, metabolic disease, and cardiovascular outcomes among Hispanic breast cancer survivors.²⁸

Our study has some limitations, including a relatively small sample size. It did not include an exercise program, which would have been helpful in addressing the issue of overweight and obesity we encountered in the most of the Hispanic breast cancer survivors (baseline average BMI, 31.32 kg/m²; obesity range, >30 kg/m²). Because of the small sample size and nonrandomized design of the study, it is hard to evaluate the confounding effect of time on intervention effect. However, a subgroup analysis by MBSR number of sessions showed that the survivors who completed the full course of MBSR sessions (8 sessions) achieved superior benefit, compared with those who did not complete the full course, which indicates that the intervention did weigh in regardless of time. Despite these limitations, the participants in this interventional program showed improved outcomes, including less anxiety and depression and improved MCS score of the SF-36. A larger and longer follow-up prospective, randomized study is needed to validate the findings of this study. Implementing cancer survivorship as an integral component of cancer care during and after treatment is essential to improve the quality of life of cancer survivors and empower them in their transition from cancer treatment to survivorship.

Goals-of-care conversations led by the oncologist are a key opportunity to improve advance care planning and end-of-life care,¹ but our patients are not understanding the essentials. Findings from a study of patients’ expectations about chemotherapy showed that more than two-thirds of patients with lung or colorectal cancers thought their palliative chemotherapy,² radiation, ³ and/or surgery⁴ could cure them. Failure to effectively educate patients can lead to end-of-life care associated with poor quality of care, including over-aggressive care, poor quality of life with suboptimal symptom management, caregiver distress, and other potentially preventable problems.⁵

Palliative care routinely includes goals-of-care (GoC) discussions as part of the standard note. At one large urban hospital, the 30-day readmission rate was 10% if palliative care consultation was done, compared with 15% if no consultation was obtained.⁶ Patients who had consultations that included GoC discussions in addition to a symptom management consultation had a lower hospital readmission rate of 5%, compared with 15% in patients who received symptom management consultations alone (adjusted odds ratio [AOR], 0.36; confidence interval [CI], 0.27-0.48; P < .001). ⁶ Findings from another study showed that the use of aggressive end-of-life care was reduced by one-third when the patient and provider had a GoC planning session close to the time of diagnosis, instead of at the end of life.⁷

We prepared a template to be incorporated into the electronic medical record (EMR) to facilitate GoC discussions between the oncologist and patient as part of a randomized phase 3 trial of early versus delayed palliative care for phase 1 clinical trial patients. Documentation is one of the most important elements of efforts to improve end-of-life care, along with advance care planning, GoC discussions, and understanding the system of care.⁸ Because we have found this approach useful in our everyday oncology practice, we are sharing this simple, doable template in the hope that others will find it effective.

The GoC template

What does it look like?

We developed a document for oncology GoC discussions that was incorporated into the EMR (Table). We use the GoC document in much the same way we’d review a computed-tomography scan with our patients and their families: we bring it up on the computer screen, show them the categories, and type in responses on the allotted spaces on the right-hand side of the document. The input can be done in real time or after the conversation, or even after the patient has left. In our practice, we access the Patient Instructions part of the EMR, use a SmartPhrase to copy the Word template into the chart, and start typing.

How do you use template?

It is critically important to make sure that the patient and family are ready for this discussion. To further facilitate the discussion, we have devised a temporary palliative care tattoo with a script, or prompts, for what questions to ask and in what order they should be asked (Figure). The easy-to-read tattoo is worn on the inner forearm so that it is readily visible to the oncologist or advanced practice nurse.¹²

We always start by asking, “How do you like to get medical information?” (Table, question 1) and follow up with something like, “Are you the sort of person who wants all the details, or not?” (Table). If the response is yes, they want all the details, then we follow up with another question, “Does that include talking about prognosis and what might happen?” (Table). Most patients will want full disclosure of their circumstances and prognosis, but some will not, and will feel overwhelmed and disempowered if you proceed.

After reviewing the answers to question 1 and any follow-up questions you may have asked, you will be able to gauge whether you should continue with questions 2-4 in the template. Once you know more about the patient and the family’s understanding of the situation (Table, question 2), what is important to them (question 3), what they are hoping for (question 4), and have spoken to them about disease progression, recapped their treatment to date, and checked to see if they might be eligible for any clinical trials (question 5), it will be easier to move on to the next questions, about progressive disease and advance care planning: “You are doing OK now, but have you thought about a time when you could be sicker [and need] a living will or advance directive [question 6, see next section of this article]?” For people unwilling to have this discussion, or have it at that moment, there is an excellent article that outlines the process to help practitioners increase prognostic awareness.¹⁴ Patient readiness will change over time as they adjust to the life changes forced by serious illness, and one can put off the discussion until they are more accepting. Just remember that patients are not likely to broach the subject themselves, and part of our job is to offer guidance.

As Singh and colleagues have noted, many patients with incurable disease have poor “prognosis awareness,” ¹⁵ so it is important for the oncologist to have a GoC conversation with the patient to be able to guage the patient’s understanding of the prognosis after a scan that shows progressive disease. Singh and his colleagues reported that of 64 taped oncologist-patient conversations about scan results, only 4 included frank discussions about prognosis. The authors suggested asking the question, “Would you like to talk about what this means?” after showing the patient the scan to allow the patient some control and to get permission to disclose crucial information based on the reading of the scan.¹⁵

Getting started on the GoC discussions may be the hardest part. Some useful introductory lines might include: “In my experience, it is easier to talk about our goals of care while people are still doing well. I know the future can be more uncertain. That’s why I want us to discuss these things now,” or “I am worried about you, after looking at these scans. I think it is time to have another discussion about what the future holds.”

Starting the hospice information visit

For patients with progressive disease, how do you know when to initiate a discussion about hospice and specifically, the hospice information visit, in a timely manner? It turns out oncologists are fairly adept at sensing when the prognosis has changed, but one useful tip is to routinely ask yourself the “surprise” question: “Would you be surprised if this patient were to die within the next 6 months?”.¹⁶ We have developed this hospice information visit practice to ensure that hospice is brought up as part of a natural transition to end-of-life care. We have not formally tested the tool, but every oncologist we know who has adopted the practice has continued it.

If the answer to the “surprise” question is, “No, I would not be surprised if the patient were to die within 6 months,” then we will make a referral to hospice for a hospice information visit. This allows for a timely, carefully planned transition to a known team, working with the oncologist, at some reasonably predictable point on the illness trajectory, usually while the patient is still on treatment. This transition can be difficult for patients and their families, and often they will voice concerns about feeling abandoned by the treating oncologist: “Dr Smith took care of us for seven years, and now – when Mom is the sickest and likely dying – he is sending us to someone whom we have never met before.” The timing of this transition is important, because the tendency is to delay for as long as possible, as demonstrated in a study by O’Connor and colleagues of admissions to hospice, which found that 16% of cancer patients were on hospice for 3 days or less.¹⁷

After we have discussed hospice care with the patient, we ask the hospice team to call the patient to set up the hospice information visit. We have been surprised to see that most patients, after the initial shock of talking about hospice care, have indicated that they found this planned transition visit with the hospice team informative and helpful.

One way in which you could broach the topic of hospice care with a patient to avoid the feelings of abandonment, is to say, “I want you to meet the people who will be helping me take care of you if and when we need them.” This emphasizes the continuity of care and the desire for a smooth, planned transition. We try to do this when we think the patient has about 6 months to live. Then, when the patient’s performance status changes or the disease progresses, we will activate the referral and will say, “Remember nurse Bob and the social worker Clare who came out to your house 3 months ago? I think it’s time we touch base with them again. It’s time to change goals from fighting the cancer to maintaining your quality of life. In my experience, hospice support will help us do just that.”

Adelson and colleagues developed standardized criteria (triggers or prompts) for use in palliative care consultation to help improve overall quality of care.¹⁸ The criteria included any solid tumor patient with: stage IV solid malignancy or stage III lung or pancreatic cancer; a hospitalization of >7 days; hospitalized in the last 30 days (not including routine chemotherapy); and uncontrolled symptoms (pain, nausea/vomiting, dyspnea, delirium, psychological distress). The investigators showed that use of the standardized criteria for palliative care consultation was associated with a decline in 30-day readmission rates (35% for the intervention group, 13% for the control group), the use of chemotherapy after discharge (18% and 44%, respectively), and use of support services after discharge.

Discussion

We see this approach with GoC discussions as part of our TEAM approach (Time, Education, Assessment, and Management) to care¹⁹ that is patient and family centered, education centered, and symptom centered. Other institutions where similar prompt systems have been used have also shown improvements in advance care planning. Temel and colleagues found in a 2010 retrospective review of the EMRs and longitudinal medical records of 2,498 patients with metastatic cancer that only 20% patients had a documented code status, despite their advanced disease state.²⁰ A second study at the same institution, also by Temel and colleagues, showed that during 2009-2011, e-mail prompts encouraging physicians to document their patients’ code status resulted in a doubling of the rate of code status documentation, from 14.5% for historical controls to 33.7% after introducing the prompt system.²¹

In a study of a disease-management pilot program in Medicare patients with cancer, US Oncology adopted the best practice model of appointing someone in the practice, usually a nurse, to review advance care planning within the first visits of diagnosis of a life-limiting illness, and increased advance care planning to more than 80%.²² In another US Oncology study, Neubauer and colleagues reported that the implementation of an ACP process at 38 member sites resulted in a 15.6% increase in the incidence of code status documentation, and although the incidence of documentation varied considerably, it was as high as 89% at some sites.²³

For how long should a terminally ill cancer patient be enrolled in hospice? Von Gunten has suggested increasing length of stay (LoS) in hospice as a quality improvement task. He reported on a study in which oncologists in Ohio were given the LoS recommendations from the state’s Oncology Clinical Guidance Council (LoS, 45-90 days), the national LoS average (43 days), and their peers (19.7 days) at baseline, including a chart showing the median LoS by oncologist. Follow-up with the medical oncologist after a year, showed that there was a doubling of hospice LoS, from the baseline 19.7 days to 39.6 days.²⁴

Patients who have timely end-of-life discussions addressing GoC and understanding of their illness, are more likely to be satisfied with their quality of care, receive care that is closer to their stated preferences, and die at the place of their choosing, and their family members will be less distressed.²⁵ In addition, Enzinger and colleagues have shown that patients who had prognostic discussions with their oncologists revised their self-reported estimates of their survival downward by 17.2 months, which brought them closer to a more realistic expectation of life expectancy, without having a negative impact on their emotional well-being (sadness, anxiety) or relationship with the physician.²⁶ However, it is important to remember, that we, as the oncologist, have to start the GoC, hospice, and EoL conversations, because patients understandably rarely bring it up of their own free will.

Goals-of-care conversations led by the oncologist are a key opportunity to improve advance care planning and end-of-life care,¹ but our patients are not understanding the essentials. Findings from a study of patients’ expectations about chemotherapy showed that more than two-thirds of patients with lung or colorectal cancers thought their palliative chemotherapy,² radiation, ³ and/or surgery⁴ could cure them. Failure to effectively educate patients can lead to end-of-life care associated with poor quality of care, including over-aggressive care, poor quality of life with suboptimal symptom management, caregiver distress, and other potentially preventable problems.⁵

Palliative care routinely includes goals-of-care (GoC) discussions as part of the standard note. At one large urban hospital, the 30-day readmission rate was 10% if palliative care consultation was done, compared with 15% if no consultation was obtained.⁶ Patients who had consultations that included GoC discussions in addition to a symptom management consultation had a lower hospital readmission rate of 5%, compared with 15% in patients who received symptom management consultations alone (adjusted odds ratio [AOR], 0.36; confidence interval [CI], 0.27-0.48; P < .001). ⁶ Findings from another study showed that the use of aggressive end-of-life care was reduced by one-third when the patient and provider had a GoC planning session close to the time of diagnosis, instead of at the end of life.⁷

We prepared a template to be incorporated into the electronic medical record (EMR) to facilitate GoC discussions between the oncologist and patient as part of a randomized phase 3 trial of early versus delayed palliative care for phase 1 clinical trial patients. Documentation is one of the most important elements of efforts to improve end-of-life care, along with advance care planning, GoC discussions, and understanding the system of care.⁸ Because we have found this approach useful in our everyday oncology practice, we are sharing this simple, doable template in the hope that others will find it effective.

The GoC template

What does it look like?

We developed a document for oncology GoC discussions that was incorporated into the EMR (Table). We use the GoC document in much the same way we’d review a computed-tomography scan with our patients and their families: we bring it up on the computer screen, show them the categories, and type in responses on the allotted spaces on the right-hand side of the document. The input can be done in real time or after the conversation, or even after the patient has left. In our practice, we access the Patient Instructions part of the EMR, use a SmartPhrase to copy the Word template into the chart, and start typing.

How do you use template?

It is critically important to make sure that the patient and family are ready for this discussion. To further facilitate the discussion, we have devised a temporary palliative care tattoo with a script, or prompts, for what questions to ask and in what order they should be asked (Figure). The easy-to-read tattoo is worn on the inner forearm so that it is readily visible to the oncologist or advanced practice nurse.¹²

We always start by asking, “How do you like to get medical information?” (Table, question 1) and follow up with something like, “Are you the sort of person who wants all the details, or not?” (Table). If the response is yes, they want all the details, then we follow up with another question, “Does that include talking about prognosis and what might happen?” (Table). Most patients will want full disclosure of their circumstances and prognosis, but some will not, and will feel overwhelmed and disempowered if you proceed.

After reviewing the answers to question 1 and any follow-up questions you may have asked, you will be able to gauge whether you should continue with questions 2-4 in the template. Once you know more about the patient and the family’s understanding of the situation (Table, question 2), what is important to them (question 3), what they are hoping for (question 4), and have spoken to them about disease progression, recapped their treatment to date, and checked to see if they might be eligible for any clinical trials (question 5), it will be easier to move on to the next questions, about progressive disease and advance care planning: “You are doing OK now, but have you thought about a time when you could be sicker [and need] a living will or advance directive [question 6, see next section of this article]?” For people unwilling to have this discussion, or have it at that moment, there is an excellent article that outlines the process to help practitioners increase prognostic awareness.¹⁴ Patient readiness will change over time as they adjust to the life changes forced by serious illness, and one can put off the discussion until they are more accepting. Just remember that patients are not likely to broach the subject themselves, and part of our job is to offer guidance.

As Singh and colleagues have noted, many patients with incurable disease have poor “prognosis awareness,” ¹⁵ so it is important for the oncologist to have a GoC conversation with the patient to be able to guage the patient’s understanding of the prognosis after a scan that shows progressive disease. Singh and his colleagues reported that of 64 taped oncologist-patient conversations about scan results, only 4 included frank discussions about prognosis. The authors suggested asking the question, “Would you like to talk about what this means?” after showing the patient the scan to allow the patient some control and to get permission to disclose crucial information based on the reading of the scan.¹⁵

Getting started on the GoC discussions may be the hardest part. Some useful introductory lines might include: “In my experience, it is easier to talk about our goals of care while people are still doing well. I know the future can be more uncertain. That’s why I want us to discuss these things now,” or “I am worried about you, after looking at these scans. I think it is time to have another discussion about what the future holds.”

Starting the hospice information visit

For patients with progressive disease, how do you know when to initiate a discussion about hospice and specifically, the hospice information visit, in a timely manner? It turns out oncologists are fairly adept at sensing when the prognosis has changed, but one useful tip is to routinely ask yourself the “surprise” question: “Would you be surprised if this patient were to die within the next 6 months?”.¹⁶ We have developed this hospice information visit practice to ensure that hospice is brought up as part of a natural transition to end-of-life care. We have not formally tested the tool, but every oncologist we know who has adopted the practice has continued it.

If the answer to the “surprise” question is, “No, I would not be surprised if the patient were to die within 6 months,” then we will make a referral to hospice for a hospice information visit. This allows for a timely, carefully planned transition to a known team, working with the oncologist, at some reasonably predictable point on the illness trajectory, usually while the patient is still on treatment. This transition can be difficult for patients and their families, and often they will voice concerns about feeling abandoned by the treating oncologist: “Dr Smith took care of us for seven years, and now – when Mom is the sickest and likely dying – he is sending us to someone whom we have never met before.” The timing of this transition is important, because the tendency is to delay for as long as possible, as demonstrated in a study by O’Connor and colleagues of admissions to hospice, which found that 16% of cancer patients were on hospice for 3 days or less.¹⁷

After we have discussed hospice care with the patient, we ask the hospice team to call the patient to set up the hospice information visit. We have been surprised to see that most patients, after the initial shock of talking about hospice care, have indicated that they found this planned transition visit with the hospice team informative and helpful.

One way in which you could broach the topic of hospice care with a patient to avoid the feelings of abandonment, is to say, “I want you to meet the people who will be helping me take care of you if and when we need them.” This emphasizes the continuity of care and the desire for a smooth, planned transition. We try to do this when we think the patient has about 6 months to live. Then, when the patient’s performance status changes or the disease progresses, we will activate the referral and will say, “Remember nurse Bob and the social worker Clare who came out to your house 3 months ago? I think it’s time we touch base with them again. It’s time to change goals from fighting the cancer to maintaining your quality of life. In my experience, hospice support will help us do just that.”

Adelson and colleagues developed standardized criteria (triggers or prompts) for use in palliative care consultation to help improve overall quality of care.¹⁸ The criteria included any solid tumor patient with: stage IV solid malignancy or stage III lung or pancreatic cancer; a hospitalization of >7 days; hospitalized in the last 30 days (not including routine chemotherapy); and uncontrolled symptoms (pain, nausea/vomiting, dyspnea, delirium, psychological distress). The investigators showed that use of the standardized criteria for palliative care consultation was associated with a decline in 30-day readmission rates (35% for the intervention group, 13% for the control group), the use of chemotherapy after discharge (18% and 44%, respectively), and use of support services after discharge.

Discussion

We see this approach with GoC discussions as part of our TEAM approach (Time, Education, Assessment, and Management) to care¹⁹ that is patient and family centered, education centered, and symptom centered. Other institutions where similar prompt systems have been used have also shown improvements in advance care planning. Temel and colleagues found in a 2010 retrospective review of the EMRs and longitudinal medical records of 2,498 patients with metastatic cancer that only 20% patients had a documented code status, despite their advanced disease state.²⁰ A second study at the same institution, also by Temel and colleagues, showed that during 2009-2011, e-mail prompts encouraging physicians to document their patients’ code status resulted in a doubling of the rate of code status documentation, from 14.5% for historical controls to 33.7% after introducing the prompt system.²¹

In a study of a disease-management pilot program in Medicare patients with cancer, US Oncology adopted the best practice model of appointing someone in the practice, usually a nurse, to review advance care planning within the first visits of diagnosis of a life-limiting illness, and increased advance care planning to more than 80%.²² In another US Oncology study, Neubauer and colleagues reported that the implementation of an ACP process at 38 member sites resulted in a 15.6% increase in the incidence of code status documentation, and although the incidence of documentation varied considerably, it was as high as 89% at some sites.²³

For how long should a terminally ill cancer patient be enrolled in hospice? Von Gunten has suggested increasing length of stay (LoS) in hospice as a quality improvement task. He reported on a study in which oncologists in Ohio were given the LoS recommendations from the state’s Oncology Clinical Guidance Council (LoS, 45-90 days), the national LoS average (43 days), and their peers (19.7 days) at baseline, including a chart showing the median LoS by oncologist. Follow-up with the medical oncologist after a year, showed that there was a doubling of hospice LoS, from the baseline 19.7 days to 39.6 days.²⁴

Patients who have timely end-of-life discussions addressing GoC and understanding of their illness, are more likely to be satisfied with their quality of care, receive care that is closer to their stated preferences, and die at the place of their choosing, and their family members will be less distressed.²⁵ In addition, Enzinger and colleagues have shown that patients who had prognostic discussions with their oncologists revised their self-reported estimates of their survival downward by 17.2 months, which brought them closer to a more realistic expectation of life expectancy, without having a negative impact on their emotional well-being (sadness, anxiety) or relationship with the physician.²⁶ However, it is important to remember, that we, as the oncologist, have to start the GoC, hospice, and EoL conversations, because patients understandably rarely bring it up of their own free will.

Goals-of-care conversations led by the oncologist are a key opportunity to improve advance care planning and end-of-life care,¹ but our patients are not understanding the essentials. Findings from a study of patients’ expectations about chemotherapy showed that more than two-thirds of patients with lung or colorectal cancers thought their palliative chemotherapy,² radiation, ³ and/or surgery⁴ could cure them. Failure to effectively educate patients can lead to end-of-life care associated with poor quality of care, including over-aggressive care, poor quality of life with suboptimal symptom management, caregiver distress, and other potentially preventable problems.⁵

Palliative care routinely includes goals-of-care (GoC) discussions as part of the standard note. At one large urban hospital, the 30-day readmission rate was 10% if palliative care consultation was done, compared with 15% if no consultation was obtained.⁶ Patients who had consultations that included GoC discussions in addition to a symptom management consultation had a lower hospital readmission rate of 5%, compared with 15% in patients who received symptom management consultations alone (adjusted odds ratio [AOR], 0.36; confidence interval [CI], 0.27-0.48; P < .001). ⁶ Findings from another study showed that the use of aggressive end-of-life care was reduced by one-third when the patient and provider had a GoC planning session close to the time of diagnosis, instead of at the end of life.⁷

We prepared a template to be incorporated into the electronic medical record (EMR) to facilitate GoC discussions between the oncologist and patient as part of a randomized phase 3 trial of early versus delayed palliative care for phase 1 clinical trial patients. Documentation is one of the most important elements of efforts to improve end-of-life care, along with advance care planning, GoC discussions, and understanding the system of care.⁸ Because we have found this approach useful in our everyday oncology practice, we are sharing this simple, doable template in the hope that others will find it effective.

The GoC template

What does it look like?

We developed a document for oncology GoC discussions that was incorporated into the EMR (Table). We use the GoC document in much the same way we’d review a computed-tomography scan with our patients and their families: we bring it up on the computer screen, show them the categories, and type in responses on the allotted spaces on the right-hand side of the document. The input can be done in real time or after the conversation, or even after the patient has left. In our practice, we access the Patient Instructions part of the EMR, use a SmartPhrase to copy the Word template into the chart, and start typing.

How do you use template?

It is critically important to make sure that the patient and family are ready for this discussion. To further facilitate the discussion, we have devised a temporary palliative care tattoo with a script, or prompts, for what questions to ask and in what order they should be asked (Figure). The easy-to-read tattoo is worn on the inner forearm so that it is readily visible to the oncologist or advanced practice nurse.¹²

We always start by asking, “How do you like to get medical information?” (Table, question 1) and follow up with something like, “Are you the sort of person who wants all the details, or not?” (Table). If the response is yes, they want all the details, then we follow up with another question, “Does that include talking about prognosis and what might happen?” (Table). Most patients will want full disclosure of their circumstances and prognosis, but some will not, and will feel overwhelmed and disempowered if you proceed.

After reviewing the answers to question 1 and any follow-up questions you may have asked, you will be able to gauge whether you should continue with questions 2-4 in the template. Once you know more about the patient and the family’s understanding of the situation (Table, question 2), what is important to them (question 3), what they are hoping for (question 4), and have spoken to them about disease progression, recapped their treatment to date, and checked to see if they might be eligible for any clinical trials (question 5), it will be easier to move on to the next questions, about progressive disease and advance care planning: “You are doing OK now, but have you thought about a time when you could be sicker [and need] a living will or advance directive [question 6, see next section of this article]?” For people unwilling to have this discussion, or have it at that moment, there is an excellent article that outlines the process to help practitioners increase prognostic awareness.¹⁴ Patient readiness will change over time as they adjust to the life changes forced by serious illness, and one can put off the discussion until they are more accepting. Just remember that patients are not likely to broach the subject themselves, and part of our job is to offer guidance.

As Singh and colleagues have noted, many patients with incurable disease have poor “prognosis awareness,” ¹⁵ so it is important for the oncologist to have a GoC conversation with the patient to be able to guage the patient’s understanding of the prognosis after a scan that shows progressive disease. Singh and his colleagues reported that of 64 taped oncologist-patient conversations about scan results, only 4 included frank discussions about prognosis. The authors suggested asking the question, “Would you like to talk about what this means?” after showing the patient the scan to allow the patient some control and to get permission to disclose crucial information based on the reading of the scan.¹⁵

Getting started on the GoC discussions may be the hardest part. Some useful introductory lines might include: “In my experience, it is easier to talk about our goals of care while people are still doing well. I know the future can be more uncertain. That’s why I want us to discuss these things now,” or “I am worried about you, after looking at these scans. I think it is time to have another discussion about what the future holds.”

Starting the hospice information visit

For patients with progressive disease, how do you know when to initiate a discussion about hospice and specifically, the hospice information visit, in a timely manner? It turns out oncologists are fairly adept at sensing when the prognosis has changed, but one useful tip is to routinely ask yourself the “surprise” question: “Would you be surprised if this patient were to die within the next 6 months?”.¹⁶ We have developed this hospice information visit practice to ensure that hospice is brought up as part of a natural transition to end-of-life care. We have not formally tested the tool, but every oncologist we know who has adopted the practice has continued it.

If the answer to the “surprise” question is, “No, I would not be surprised if the patient were to die within 6 months,” then we will make a referral to hospice for a hospice information visit. This allows for a timely, carefully planned transition to a known team, working with the oncologist, at some reasonably predictable point on the illness trajectory, usually while the patient is still on treatment. This transition can be difficult for patients and their families, and often they will voice concerns about feeling abandoned by the treating oncologist: “Dr Smith took care of us for seven years, and now – when Mom is the sickest and likely dying – he is sending us to someone whom we have never met before.” The timing of this transition is important, because the tendency is to delay for as long as possible, as demonstrated in a study by O’Connor and colleagues of admissions to hospice, which found that 16% of cancer patients were on hospice for 3 days or less.¹⁷

After we have discussed hospice care with the patient, we ask the hospice team to call the patient to set up the hospice information visit. We have been surprised to see that most patients, after the initial shock of talking about hospice care, have indicated that they found this planned transition visit with the hospice team informative and helpful.

One way in which you could broach the topic of hospice care with a patient to avoid the feelings of abandonment, is to say, “I want you to meet the people who will be helping me take care of you if and when we need them.” This emphasizes the continuity of care and the desire for a smooth, planned transition. We try to do this when we think the patient has about 6 months to live. Then, when the patient’s performance status changes or the disease progresses, we will activate the referral and will say, “Remember nurse Bob and the social worker Clare who came out to your house 3 months ago? I think it’s time we touch base with them again. It’s time to change goals from fighting the cancer to maintaining your quality of life. In my experience, hospice support will help us do just that.”

Adelson and colleagues developed standardized criteria (triggers or prompts) for use in palliative care consultation to help improve overall quality of care.¹⁸ The criteria included any solid tumor patient with: stage IV solid malignancy or stage III lung or pancreatic cancer; a hospitalization of >7 days; hospitalized in the last 30 days (not including routine chemotherapy); and uncontrolled symptoms (pain, nausea/vomiting, dyspnea, delirium, psychological distress). The investigators showed that use of the standardized criteria for palliative care consultation was associated with a decline in 30-day readmission rates (35% for the intervention group, 13% for the control group), the use of chemotherapy after discharge (18% and 44%, respectively), and use of support services after discharge.

Discussion

We see this approach with GoC discussions as part of our TEAM approach (Time, Education, Assessment, and Management) to care¹⁹ that is patient and family centered, education centered, and symptom centered. Other institutions where similar prompt systems have been used have also shown improvements in advance care planning. Temel and colleagues found in a 2010 retrospective review of the EMRs and longitudinal medical records of 2,498 patients with metastatic cancer that only 20% patients had a documented code status, despite their advanced disease state.²⁰ A second study at the same institution, also by Temel and colleagues, showed that during 2009-2011, e-mail prompts encouraging physicians to document their patients’ code status resulted in a doubling of the rate of code status documentation, from 14.5% for historical controls to 33.7% after introducing the prompt system.²¹

In a study of a disease-management pilot program in Medicare patients with cancer, US Oncology adopted the best practice model of appointing someone in the practice, usually a nurse, to review advance care planning within the first visits of diagnosis of a life-limiting illness, and increased advance care planning to more than 80%.²² In another US Oncology study, Neubauer and colleagues reported that the implementation of an ACP process at 38 member sites resulted in a 15.6% increase in the incidence of code status documentation, and although the incidence of documentation varied considerably, it was as high as 89% at some sites.²³

For how long should a terminally ill cancer patient be enrolled in hospice? Von Gunten has suggested increasing length of stay (LoS) in hospice as a quality improvement task. He reported on a study in which oncologists in Ohio were given the LoS recommendations from the state’s Oncology Clinical Guidance Council (LoS, 45-90 days), the national LoS average (43 days), and their peers (19.7 days) at baseline, including a chart showing the median LoS by oncologist. Follow-up with the medical oncologist after a year, showed that there was a doubling of hospice LoS, from the baseline 19.7 days to 39.6 days.²⁴

Patients who have timely end-of-life discussions addressing GoC and understanding of their illness, are more likely to be satisfied with their quality of care, receive care that is closer to their stated preferences, and die at the place of their choosing, and their family members will be less distressed.²⁵ In addition, Enzinger and colleagues have shown that patients who had prognostic discussions with their oncologists revised their self-reported estimates of their survival downward by 17.2 months, which brought them closer to a more realistic expectation of life expectancy, without having a negative impact on their emotional well-being (sadness, anxiety) or relationship with the physician.²⁶ However, it is important to remember, that we, as the oncologist, have to start the GoC, hospice, and EoL conversations, because patients understandably rarely bring it up of their own free will.

As we head into vacation season and the dog days of summer, let’s reflect for a few minutes on some of the very important advances we heard about at this year’s annual meeting of the American Society of Clinical Oncology in Chicago. Nearly 40,000 individuals registered for the conference, an indication of both the interest and the excitement around the new agents and the emerging clinical trial data. Scientific sessions dedicated to the use of combination immunotherapy, the role of antibody drug conjugates, and targeting molecular aberrations with small molecules were among the most popular (p. e236).

As we head into vacation season and the dog days of summer, let’s reflect for a few minutes on some of the very important advances we heard about at this year’s annual meeting of the American Society of Clinical Oncology in Chicago. Nearly 40,000 individuals registered for the conference, an indication of both the interest and the excitement around the new agents and the emerging clinical trial data. Scientific sessions dedicated to the use of combination immunotherapy, the role of antibody drug conjugates, and targeting molecular aberrations with small molecules were among the most popular (p. e236).

As we head into vacation season and the dog days of summer, let’s reflect for a few minutes on some of the very important advances we heard about at this year’s annual meeting of the American Society of Clinical Oncology in Chicago. Nearly 40,000 individuals registered for the conference, an indication of both the interest and the excitement around the new agents and the emerging clinical trial data. Scientific sessions dedicated to the use of combination immunotherapy, the role of antibody drug conjugates, and targeting molecular aberrations with small molecules were among the most popular (p. e236).

Photo from AstraZeneca

The US Food and Drug Administration (FDA) has placed a partial clinical hold on 5 trials and a full clinical hold on 1 trial of the anti-PD-L1 antibody durvalumab (Imfinzi™).

In these trials, researchers are testing durvalumab in combination with immunomodulatory and chemotherapy agents in patients with multiple myeloma (MM) and lymphomas.

At present, no new patients can be enrolled in any of the 6 trials.

Patients enrolled in the trials on partial clinical hold can remain on treatment if they are receiving clinical benefit.

Patients enrolled in the trial on full clinical hold will discontinue the study treatment.

The FDA’s decision to place these trials on hold is related to risks identified in trials studying another anti-PD-1 agent, pembrolizumab, in MM patients.

Data from the pembrolizumab trials indicate the risks outweigh the benefits when PD-1/PD-L1 treatment is given to MM patients in combination with dexamethasone and pomalidomide or lenalidomide.

In addition, there may be an unfavorable risk-benefit ratio for MM patients receiving PD-1/PD-L1 treatments alone or in other combinations.

With this in mind, the FDA placed the MEDI4736-MM-002 trial on full clinical hold.

MEDI4736-MM-002 is a phase 1b study designed to determine the recommended dose and regimen of durvalumab in combination with lenalidomide, with and without low-dose dexamethasone, in patients with newly diagnosed MM.

The FDA also placed the following trials on partial clinical hold:

• MEDI4736-MM-001: A phase 1b study to determine the recommended dose and regimen of durvalumab either as monotherapy or in combination with pomalidomide, with or without low-dose dexamethasone, in patients with relapsed and refractory MM
• MEDI4736-MM-003: A phase 2 study to determine the safety and efficacy of the combination of durvalumab and daratumumab in patients with relapsed and refractory MM
• MEDI4736-MM-005: A phase 2 study to determine the efficacy of the combination of durvalumab plus daratumumab in patients with relapsed and refractory MM who have progressed while on a current treatment regimen containing daratumumab
• MEDI4736-NHL-001: A phase 1/2 study to assess the safety and tolerability of durvalumab as monotherapy and in combination therapy in patients with lymphomas, including chronic lymphocytic leukemia. The only arm in this trial for which enrollment is suspended is the arm with the durvalumab, lenalidomide, and rituximab combination.
• MEDI4736-DLBCL-001: A phase 2 study to evaluate the safety and clinical activity of durvalumab in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or with lenalidomide plus R-CHOP in patients with previously untreated, high-risk diffuse large B-cell lymphoma.

The trials that will continue to enroll are:

• MEDI4736-MDS-001: A phase 2 study evaluating the efficacy and safety of subcutaneous azacitidine in combination with durvalumab in previously untreated patients with higher-risk myelodysplastic syndromes or in elderly (≥65 years) acute myeloid leukemia patients not eligible for hematopoietic stem cell transplant
• CC-486-MDS-006: A phase 2 study to evaluate the efficacy and safety of CC-486 alone or in combination with durvalumab in patients with myelodysplastic syndromes who fail to achieve an objective response to treatment with azacitidine for injection or decitabine.

Durvalumab is being developed by Celgene Corporation and MedImmune, the global biologics research and development arm of AstraZeneca.

The use of durvalumab in combination with other agents for the treatment of patients with hematologic malignancies is not approved by the FDA, and the safety and efficacy of those combinations has not been established.

Durvalumab has accelerated approval from the FDA to treat patients with locally advanced or metastatic urothelial carcinoma.

Photo from AstraZeneca

The US Food and Drug Administration (FDA) has placed a partial clinical hold on 5 trials and a full clinical hold on 1 trial of the anti-PD-L1 antibody durvalumab (Imfinzi™).

In these trials, researchers are testing durvalumab in combination with immunomodulatory and chemotherapy agents in patients with multiple myeloma (MM) and lymphomas.

At present, no new patients can be enrolled in any of the 6 trials.

Patients enrolled in the trials on partial clinical hold can remain on treatment if they are receiving clinical benefit.

Patients enrolled in the trial on full clinical hold will discontinue the study treatment.

The FDA’s decision to place these trials on hold is related to risks identified in trials studying another anti-PD-1 agent, pembrolizumab, in MM patients.

Data from the pembrolizumab trials indicate the risks outweigh the benefits when PD-1/PD-L1 treatment is given to MM patients in combination with dexamethasone and pomalidomide or lenalidomide.

In addition, there may be an unfavorable risk-benefit ratio for MM patients receiving PD-1/PD-L1 treatments alone or in other combinations.

With this in mind, the FDA placed the MEDI4736-MM-002 trial on full clinical hold.

MEDI4736-MM-002 is a phase 1b study designed to determine the recommended dose and regimen of durvalumab in combination with lenalidomide, with and without low-dose dexamethasone, in patients with newly diagnosed MM.

The FDA also placed the following trials on partial clinical hold:

• MEDI4736-MM-001: A phase 1b study to determine the recommended dose and regimen of durvalumab either as monotherapy or in combination with pomalidomide, with or without low-dose dexamethasone, in patients with relapsed and refractory MM
• MEDI4736-MM-003: A phase 2 study to determine the safety and efficacy of the combination of durvalumab and daratumumab in patients with relapsed and refractory MM
• MEDI4736-MM-005: A phase 2 study to determine the efficacy of the combination of durvalumab plus daratumumab in patients with relapsed and refractory MM who have progressed while on a current treatment regimen containing daratumumab
• MEDI4736-NHL-001: A phase 1/2 study to assess the safety and tolerability of durvalumab as monotherapy and in combination therapy in patients with lymphomas, including chronic lymphocytic leukemia. The only arm in this trial for which enrollment is suspended is the arm with the durvalumab, lenalidomide, and rituximab combination.
• MEDI4736-DLBCL-001: A phase 2 study to evaluate the safety and clinical activity of durvalumab in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or with lenalidomide plus R-CHOP in patients with previously untreated, high-risk diffuse large B-cell lymphoma.

The trials that will continue to enroll are:

• MEDI4736-MDS-001: A phase 2 study evaluating the efficacy and safety of subcutaneous azacitidine in combination with durvalumab in previously untreated patients with higher-risk myelodysplastic syndromes or in elderly (≥65 years) acute myeloid leukemia patients not eligible for hematopoietic stem cell transplant
• CC-486-MDS-006: A phase 2 study to evaluate the efficacy and safety of CC-486 alone or in combination with durvalumab in patients with myelodysplastic syndromes who fail to achieve an objective response to treatment with azacitidine for injection or decitabine.

Durvalumab is being developed by Celgene Corporation and MedImmune, the global biologics research and development arm of AstraZeneca.

The use of durvalumab in combination with other agents for the treatment of patients with hematologic malignancies is not approved by the FDA, and the safety and efficacy of those combinations has not been established.

Durvalumab has accelerated approval from the FDA to treat patients with locally advanced or metastatic urothelial carcinoma.

Photo from AstraZeneca

The US Food and Drug Administration (FDA) has placed a partial clinical hold on 5 trials and a full clinical hold on 1 trial of the anti-PD-L1 antibody durvalumab (Imfinzi™).

In these trials, researchers are testing durvalumab in combination with immunomodulatory and chemotherapy agents in patients with multiple myeloma (MM) and lymphomas.

At present, no new patients can be enrolled in any of the 6 trials.

Patients enrolled in the trials on partial clinical hold can remain on treatment if they are receiving clinical benefit.

Patients enrolled in the trial on full clinical hold will discontinue the study treatment.

The FDA’s decision to place these trials on hold is related to risks identified in trials studying another anti-PD-1 agent, pembrolizumab, in MM patients.

Data from the pembrolizumab trials indicate the risks outweigh the benefits when PD-1/PD-L1 treatment is given to MM patients in combination with dexamethasone and pomalidomide or lenalidomide.

In addition, there may be an unfavorable risk-benefit ratio for MM patients receiving PD-1/PD-L1 treatments alone or in other combinations.

With this in mind, the FDA placed the MEDI4736-MM-002 trial on full clinical hold.

MEDI4736-MM-002 is a phase 1b study designed to determine the recommended dose and regimen of durvalumab in combination with lenalidomide, with and without low-dose dexamethasone, in patients with newly diagnosed MM.

The FDA also placed the following trials on partial clinical hold:

• MEDI4736-MM-001: A phase 1b study to determine the recommended dose and regimen of durvalumab either as monotherapy or in combination with pomalidomide, with or without low-dose dexamethasone, in patients with relapsed and refractory MM
• MEDI4736-MM-003: A phase 2 study to determine the safety and efficacy of the combination of durvalumab and daratumumab in patients with relapsed and refractory MM
• MEDI4736-MM-005: A phase 2 study to determine the efficacy of the combination of durvalumab plus daratumumab in patients with relapsed and refractory MM who have progressed while on a current treatment regimen containing daratumumab
• MEDI4736-NHL-001: A phase 1/2 study to assess the safety and tolerability of durvalumab as monotherapy and in combination therapy in patients with lymphomas, including chronic lymphocytic leukemia. The only arm in this trial for which enrollment is suspended is the arm with the durvalumab, lenalidomide, and rituximab combination.
• MEDI4736-DLBCL-001: A phase 2 study to evaluate the safety and clinical activity of durvalumab in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or with lenalidomide plus R-CHOP in patients with previously untreated, high-risk diffuse large B-cell lymphoma.

The trials that will continue to enroll are:

• MEDI4736-MDS-001: A phase 2 study evaluating the efficacy and safety of subcutaneous azacitidine in combination with durvalumab in previously untreated patients with higher-risk myelodysplastic syndromes or in elderly (≥65 years) acute myeloid leukemia patients not eligible for hematopoietic stem cell transplant
• CC-486-MDS-006: A phase 2 study to evaluate the efficacy and safety of CC-486 alone or in combination with durvalumab in patients with myelodysplastic syndromes who fail to achieve an objective response to treatment with azacitidine for injection or decitabine.

Durvalumab is being developed by Celgene Corporation and MedImmune, the global biologics research and development arm of AstraZeneca.

The use of durvalumab in combination with other agents for the treatment of patients with hematologic malignancies is not approved by the FDA, and the safety and efficacy of those combinations has not been established.

Durvalumab has accelerated approval from the FDA to treat patients with locally advanced or metastatic urothelial carcinoma.

Structure of RNA

Alnylam Pharmaceuticals, Inc. has announced suspension of dosing in all trials of fitusiran, an RNAi therapeutic being developed to treat patients with hemophilia A and B, with and without inhibitors.

Alnylam reported a fatal thrombotic event in a patient with hemophilia A without inhibitors in the phase 2 open-label extension study of fitusiran.

As a result, the company has suspended dosing in all ongoing fitusiran studies pending further review of the event and development of a risk mitigation strategy.

Fitusiran trials include the trial in which the death was reported—a phase 2 open-label extension study of hemophilia A and B patients with and without inhibitors—and the ATLAS phase 3 program, in which patient dosing has not yet begun.

Based on an overall consideration of fitusiran’s benefit-risk profile, Alnylam said it aims to resume or begin dosing in these trials as soon as possible, upon agreement with global regulatory authorities and with appropriate protocol amendments in place for enhanced patient safety monitoring.

“We are deeply saddened to learn of this patient’s death, and we extend our sympathies to his family,” said Akshay Vaishnaw, MD, PhD, executive vice president of research and development at Alnylam.

“We believe that fitusiran holds great promise as a potential treatment option for patients with hemophilia, and we remain fully committed to its ongoing development. Following further investigation of this safety finding, implementation of a risk mitigation strategy, and alignment with global regulatory authorities, we expect to resume fitusiran dosing in our clinical studies as soon as possible, potentially as early as late 2017, with a goal of advancing this innovative investigational medicine to hemophilia patients in need.”

About the patient

Alnylam recently became aware of a fatal serious adverse event in a patient with hemophilia A who was receiving fitusiran in the phase 2 open-label extension study.

Approximately 9 days prior to hospital admission, the patient developed exercise-induced right hip pain that was treated with a total of 3 doses of factor VIII concentrate (31-46 IU/kg) on 3 separate days.

Four days prior to admission, when the patient received his third dose of factor, he developed a severe headache.

While he was initially suspected of having viral meningitis, the patient was diagnosed with subarachnoid hemorrhage on the basis of CT imaging, and he was treated with factor VIII concentrate administered 2 to 3 times daily.

Over a 14-day hospitalization, his medical condition worsened, and the patient died from subsequent cerebral edema.

The initial diagnosis of subarachnoid hemorrhage was reported by the investigator as not related to fitusiran.

For a more complete understanding, Alnylam initiated further investigation of the event, including review of the patient’s CT scans by 3 independent neuro-radiologists.

All 3 neuro-radiologists confirmed that the initiating event was a cerebral venous sinus thrombosis and not a subarachnoid hemorrhage.

As a result of this new information, Alnylam suspended dosing in fitusiran studies in order to further investigate the safety event, now considered to be possibly related to fitusiran, and to develop a risk mitigation plan.

The company also notified study investigators and global regulatory authorities.

About fitusiran

Fitusiran is an investigational, once-monthly, subcutaneously administered RNAi therapeutic targeting antithrombin for the treatment of hemophilia A and B, with and without inhibitors. Fitusiran also has the potential to be used for rare bleeding disorders.

Fitusiran is designed to lower levels of antithrombin with the goal of promoting sufficient thrombin generation to restore hemostasis and prevent bleeding.

The safety and efficacy of fitusiran have not been evaluated by the FDA or any other health authority.

Structure of RNA

Alnylam Pharmaceuticals, Inc. has announced suspension of dosing in all trials of fitusiran, an RNAi therapeutic being developed to treat patients with hemophilia A and B, with and without inhibitors.

Alnylam reported a fatal thrombotic event in a patient with hemophilia A without inhibitors in the phase 2 open-label extension study of fitusiran.

As a result, the company has suspended dosing in all ongoing fitusiran studies pending further review of the event and development of a risk mitigation strategy.

Fitusiran trials include the trial in which the death was reported—a phase 2 open-label extension study of hemophilia A and B patients with and without inhibitors—and the ATLAS phase 3 program, in which patient dosing has not yet begun.

Based on an overall consideration of fitusiran’s benefit-risk profile, Alnylam said it aims to resume or begin dosing in these trials as soon as possible, upon agreement with global regulatory authorities and with appropriate protocol amendments in place for enhanced patient safety monitoring.

“We are deeply saddened to learn of this patient’s death, and we extend our sympathies to his family,” said Akshay Vaishnaw, MD, PhD, executive vice president of research and development at Alnylam.

“We believe that fitusiran holds great promise as a potential treatment option for patients with hemophilia, and we remain fully committed to its ongoing development. Following further investigation of this safety finding, implementation of a risk mitigation strategy, and alignment with global regulatory authorities, we expect to resume fitusiran dosing in our clinical studies as soon as possible, potentially as early as late 2017, with a goal of advancing this innovative investigational medicine to hemophilia patients in need.”

About the patient

Alnylam recently became aware of a fatal serious adverse event in a patient with hemophilia A who was receiving fitusiran in the phase 2 open-label extension study.

Approximately 9 days prior to hospital admission, the patient developed exercise-induced right hip pain that was treated with a total of 3 doses of factor VIII concentrate (31-46 IU/kg) on 3 separate days.

Four days prior to admission, when the patient received his third dose of factor, he developed a severe headache.

While he was initially suspected of having viral meningitis, the patient was diagnosed with subarachnoid hemorrhage on the basis of CT imaging, and he was treated with factor VIII concentrate administered 2 to 3 times daily.

Over a 14-day hospitalization, his medical condition worsened, and the patient died from subsequent cerebral edema.

The initial diagnosis of subarachnoid hemorrhage was reported by the investigator as not related to fitusiran.

For a more complete understanding, Alnylam initiated further investigation of the event, including review of the patient’s CT scans by 3 independent neuro-radiologists.

All 3 neuro-radiologists confirmed that the initiating event was a cerebral venous sinus thrombosis and not a subarachnoid hemorrhage.

As a result of this new information, Alnylam suspended dosing in fitusiran studies in order to further investigate the safety event, now considered to be possibly related to fitusiran, and to develop a risk mitigation plan.

The company also notified study investigators and global regulatory authorities.

About fitusiran

Fitusiran is an investigational, once-monthly, subcutaneously administered RNAi therapeutic targeting antithrombin for the treatment of hemophilia A and B, with and without inhibitors. Fitusiran also has the potential to be used for rare bleeding disorders.

Fitusiran is designed to lower levels of antithrombin with the goal of promoting sufficient thrombin generation to restore hemostasis and prevent bleeding.

The safety and efficacy of fitusiran have not been evaluated by the FDA or any other health authority.

Structure of RNA

Alnylam Pharmaceuticals, Inc. has announced suspension of dosing in all trials of fitusiran, an RNAi therapeutic being developed to treat patients with hemophilia A and B, with and without inhibitors.

Alnylam reported a fatal thrombotic event in a patient with hemophilia A without inhibitors in the phase 2 open-label extension study of fitusiran.

As a result, the company has suspended dosing in all ongoing fitusiran studies pending further review of the event and development of a risk mitigation strategy.

Fitusiran trials include the trial in which the death was reported—a phase 2 open-label extension study of hemophilia A and B patients with and without inhibitors—and the ATLAS phase 3 program, in which patient dosing has not yet begun.

Based on an overall consideration of fitusiran’s benefit-risk profile, Alnylam said it aims to resume or begin dosing in these trials as soon as possible, upon agreement with global regulatory authorities and with appropriate protocol amendments in place for enhanced patient safety monitoring.

“We are deeply saddened to learn of this patient’s death, and we extend our sympathies to his family,” said Akshay Vaishnaw, MD, PhD, executive vice president of research and development at Alnylam.

“We believe that fitusiran holds great promise as a potential treatment option for patients with hemophilia, and we remain fully committed to its ongoing development. Following further investigation of this safety finding, implementation of a risk mitigation strategy, and alignment with global regulatory authorities, we expect to resume fitusiran dosing in our clinical studies as soon as possible, potentially as early as late 2017, with a goal of advancing this innovative investigational medicine to hemophilia patients in need.”

About the patient

Alnylam recently became aware of a fatal serious adverse event in a patient with hemophilia A who was receiving fitusiran in the phase 2 open-label extension study.

Approximately 9 days prior to hospital admission, the patient developed exercise-induced right hip pain that was treated with a total of 3 doses of factor VIII concentrate (31-46 IU/kg) on 3 separate days.

Four days prior to admission, when the patient received his third dose of factor, he developed a severe headache.

While he was initially suspected of having viral meningitis, the patient was diagnosed with subarachnoid hemorrhage on the basis of CT imaging, and he was treated with factor VIII concentrate administered 2 to 3 times daily.

Over a 14-day hospitalization, his medical condition worsened, and the patient died from subsequent cerebral edema.

The initial diagnosis of subarachnoid hemorrhage was reported by the investigator as not related to fitusiran.

For a more complete understanding, Alnylam initiated further investigation of the event, including review of the patient’s CT scans by 3 independent neuro-radiologists.

All 3 neuro-radiologists confirmed that the initiating event was a cerebral venous sinus thrombosis and not a subarachnoid hemorrhage.

As a result of this new information, Alnylam suspended dosing in fitusiran studies in order to further investigate the safety event, now considered to be possibly related to fitusiran, and to develop a risk mitigation plan.

The company also notified study investigators and global regulatory authorities.

About fitusiran

Fitusiran is an investigational, once-monthly, subcutaneously administered RNAi therapeutic targeting antithrombin for the treatment of hemophilia A and B, with and without inhibitors. Fitusiran also has the potential to be used for rare bleeding disorders.

Fitusiran is designed to lower levels of antithrombin with the goal of promoting sufficient thrombin generation to restore hemostasis and prevent bleeding.

The safety and efficacy of fitusiran have not been evaluated by the FDA or any other health authority.

Photo from Business Wire

The US Food and Drug Administration (FDA) has placed a partial clinical hold on 3 trials of the PD-1 immune checkpoint inhibitor nivolumab (Opdivo).

The trials were designed to investigate nivolumab-based combination regimens in patients with relapsed or refractory multiple myeloma (MM).

The partial clinical hold means patients currently enrolled in these 3 trials can continue treatment if they are experiencing clinical benefit. However, no new patients can be enrolled at this time.

The partial clinical hold is related to risks identified in trials studying another anti-PD-1 agent, pembrolizumab, in MM patients.

Data from the pembrolizumab trials indicate the risks outweigh the benefits when PD-1/PD-L1 treatment is given to MM patients in combination with dexamethasone and pomalidomide or lenalidomide.

In addition, there may be an unfavorable risk-benefit ratio for MM patients receiving PD-1/PD-L1 treatments alone or in other combinations.

With this in mind, the FDA placed the partial hold on the following nivolumab trials:

• CheckMate-602: A randomized, phase 3 trial of combinations of nivolumab, elotuzumab, pomalidomide, and dexamethasone in relapsed and refractory MM
• CheckMate-039: A phase 1 study intended to establish the tolerability of nivolumab and the combination of nivolumab and daratumumab, with or without pomalidomide and dexamethasone, in patients with relapsed or refractory MM
• CA204142: A phase 2 study of elotuzumab in combination with pomalidomide and low-dose dexamethasone, and in combination with nivolumab, in patients with MM who relapsed after or were refractory to prior treatment with lenalidomide.

Other studies of nivolumab will continue as planned.

Bristol-Myers Squibb, the company developing and marketing nivolumab, said it remains steadfast in its commitment to improve outcomes for MM patients and will work closely with the FDA to address concerns.

Nivolumab is currently FDA-approved to treat:

• Adults with classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplant and brentuximab vedotin or after 3 or more lines of therapy, including autologous transplant
• Patients with previously treated metastatic non-small cell lung cancer
• Metastatic melanoma patients
• Advanced renal cell carcinoma patients who received prior anti-angiogenic therapy
• Patients with recurrent or metastatic squamous cell carcinoma of the head and neck on or after platinum-based therapy
• Patients with previously treated locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-based chemotherapy
• Patients (≥12 years) with microsatellite instability high or mismatch repair-deficient metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
  

Photo from Business Wire

The US Food and Drug Administration (FDA) has placed a partial clinical hold on 3 trials of the PD-1 immune checkpoint inhibitor nivolumab (Opdivo).

The trials were designed to investigate nivolumab-based combination regimens in patients with relapsed or refractory multiple myeloma (MM).

The partial clinical hold means patients currently enrolled in these 3 trials can continue treatment if they are experiencing clinical benefit. However, no new patients can be enrolled at this time.

The partial clinical hold is related to risks identified in trials studying another anti-PD-1 agent, pembrolizumab, in MM patients.

Data from the pembrolizumab trials indicate the risks outweigh the benefits when PD-1/PD-L1 treatment is given to MM patients in combination with dexamethasone and pomalidomide or lenalidomide.

In addition, there may be an unfavorable risk-benefit ratio for MM patients receiving PD-1/PD-L1 treatments alone or in other combinations.

With this in mind, the FDA placed the partial hold on the following nivolumab trials:

• CheckMate-602: A randomized, phase 3 trial of combinations of nivolumab, elotuzumab, pomalidomide, and dexamethasone in relapsed and refractory MM
• CheckMate-039: A phase 1 study intended to establish the tolerability of nivolumab and the combination of nivolumab and daratumumab, with or without pomalidomide and dexamethasone, in patients with relapsed or refractory MM
• CA204142: A phase 2 study of elotuzumab in combination with pomalidomide and low-dose dexamethasone, and in combination with nivolumab, in patients with MM who relapsed after or were refractory to prior treatment with lenalidomide.

Other studies of nivolumab will continue as planned.

Bristol-Myers Squibb, the company developing and marketing nivolumab, said it remains steadfast in its commitment to improve outcomes for MM patients and will work closely with the FDA to address concerns.

Nivolumab is currently FDA-approved to treat:

• Adults with classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplant and brentuximab vedotin or after 3 or more lines of therapy, including autologous transplant
• Patients with previously treated metastatic non-small cell lung cancer
• Metastatic melanoma patients
• Advanced renal cell carcinoma patients who received prior anti-angiogenic therapy
• Patients with recurrent or metastatic squamous cell carcinoma of the head and neck on or after platinum-based therapy
• Patients with previously treated locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-based chemotherapy
• Patients (≥12 years) with microsatellite instability high or mismatch repair-deficient metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
  

Photo from Business Wire

The US Food and Drug Administration (FDA) has placed a partial clinical hold on 3 trials of the PD-1 immune checkpoint inhibitor nivolumab (Opdivo).

The trials were designed to investigate nivolumab-based combination regimens in patients with relapsed or refractory multiple myeloma (MM).

The partial clinical hold means patients currently enrolled in these 3 trials can continue treatment if they are experiencing clinical benefit. However, no new patients can be enrolled at this time.

The partial clinical hold is related to risks identified in trials studying another anti-PD-1 agent, pembrolizumab, in MM patients.

Data from the pembrolizumab trials indicate the risks outweigh the benefits when PD-1/PD-L1 treatment is given to MM patients in combination with dexamethasone and pomalidomide or lenalidomide.

In addition, there may be an unfavorable risk-benefit ratio for MM patients receiving PD-1/PD-L1 treatments alone or in other combinations.

With this in mind, the FDA placed the partial hold on the following nivolumab trials:

• CheckMate-602: A randomized, phase 3 trial of combinations of nivolumab, elotuzumab, pomalidomide, and dexamethasone in relapsed and refractory MM
• CheckMate-039: A phase 1 study intended to establish the tolerability of nivolumab and the combination of nivolumab and daratumumab, with or without pomalidomide and dexamethasone, in patients with relapsed or refractory MM
• CA204142: A phase 2 study of elotuzumab in combination with pomalidomide and low-dose dexamethasone, and in combination with nivolumab, in patients with MM who relapsed after or were refractory to prior treatment with lenalidomide.

Other studies of nivolumab will continue as planned.

Bristol-Myers Squibb, the company developing and marketing nivolumab, said it remains steadfast in its commitment to improve outcomes for MM patients and will work closely with the FDA to address concerns.

Nivolumab is currently FDA-approved to treat:

• Adults with classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplant and brentuximab vedotin or after 3 or more lines of therapy, including autologous transplant
• Patients with previously treated metastatic non-small cell lung cancer
• Metastatic melanoma patients
• Advanced renal cell carcinoma patients who received prior anti-angiogenic therapy
• Patients with recurrent or metastatic squamous cell carcinoma of the head and neck on or after platinum-based therapy
• Patients with previously treated locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-based chemotherapy
• Patients (≥12 years) with microsatellite instability high or mismatch repair-deficient metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
  

Q) What is known about the impact of diet on multiple sclerosis? How can I advise my patients with MS?

Multiple sclerosis (MS) is a chronic inflammatory and degenerative central nervous system disease affecting more than 2.5 million people worldwide. Today, if a Google search is performed for “diet and MS,” more than 67 million results are obtained. Many tout specific protocols as beneficial for MS but have no substantial data to support these claims. This can be confusing for patients as well as providers. How should you advise those who ask for advice on dietary modifications to help control symptoms or disease course?

First, it’s important to remember that individuals with MS have a reduced median lifespan (by about seven years), compared to healthy controls. Furthermore, patients with MS commonly have comorbid conditions—such as diabetes, obesity, and ische­mic heart disease—that increase mortality risk.^1,2 Diet and nutrition are significant factors that impact the course of these diseases.

We must also bear in mind that patients with MS experience symptoms that may impede their efforts to prepare meals. In a 2008 study of 123 MS patients (more than 50% of whom were overweight or obese), fatigue was cited as a significant factor that limited cooking and food preparation. Cognitive impairment and depression also may affect dietary intake. Interestingly, the average recorded intake for all food groups was less than that recommended in the Dietary Guidelines for Americans.³

A web-based survey conducted by the German MS Society in 2011 revealed that 42% of the 337 respondents had modified their diet due to MS. These modifications included change in intake of fatty acids; decrease or elimination of meat, sugar, and additives; and introduction of a low-carb or Paleo diet.⁴

Among an international sample of 2,087 MS patients, a significant association was found between a healthy diet and improved quality of life (both physical and mental) and reduced disability. This “healthy consumption” of fruits, vegetables, and dietary fat was also associated with a marginally decreased risk for relapse. Patients who demonstrated increased disease activity were more likely to have poor consumption of fruits, vegetables, and fats and to consume more meat and dairy products.⁵

There has also been research on specific components of dietary intake. Antioxidant-containing foods, for example, may have an anti-inflammatory effect.⁶ Vitamin B₁₂ deficiency plays a role in immunomodulatory effect, as well as formation of the myelin sheath, although its role (and the effect of biotin supplementation) in MS disease progression requires further study.⁷ Also ongoing is research into various calorie-restriction protocols, altering both timing and amount of caloric intake, since some data suggest this strategy reduces leptin, a satiety hormone that increases inflammation and has been shown to promote more aggressive MS in a mouse model.⁸

In the meantime, what can we conclude about diet and MS? A recent review determined that, although there is insufficient data to support one specific diet, there is sufficient evidence to recommend consumption of fish, foods lower in fat, whole grains, vitamin D, and supplemental omega fatty acids.⁵

It is important to discuss diet with our MS patients. In the German survey, 82% of patients felt that diet was important, yet only 10% had asked a provider for nutritional advice.⁴ In another study, patients indicated that food labels were their top source for nutrition information; only 20% sought advice from a nutritionist.³ We need to ask our MS patients if they are following a particular diet and be prepared to discuss potentially beneficial dietary choices with them—and offer referral to a nutritionist to those who require additional direction and support.—SP

Stacey Panasci, MSPAS, PA-C
Springfield Neurology Associates, LLC
Massachusetts

Q) What is known about the impact of diet on multiple sclerosis? How can I advise my patients with MS?

Multiple sclerosis (MS) is a chronic inflammatory and degenerative central nervous system disease affecting more than 2.5 million people worldwide. Today, if a Google search is performed for “diet and MS,” more than 67 million results are obtained. Many tout specific protocols as beneficial for MS but have no substantial data to support these claims. This can be confusing for patients as well as providers. How should you advise those who ask for advice on dietary modifications to help control symptoms or disease course?

First, it’s important to remember that individuals with MS have a reduced median lifespan (by about seven years), compared to healthy controls. Furthermore, patients with MS commonly have comorbid conditions—such as diabetes, obesity, and ische­mic heart disease—that increase mortality risk.^1,2 Diet and nutrition are significant factors that impact the course of these diseases.

We must also bear in mind that patients with MS experience symptoms that may impede their efforts to prepare meals. In a 2008 study of 123 MS patients (more than 50% of whom were overweight or obese), fatigue was cited as a significant factor that limited cooking and food preparation. Cognitive impairment and depression also may affect dietary intake. Interestingly, the average recorded intake for all food groups was less than that recommended in the Dietary Guidelines for Americans.³

A web-based survey conducted by the German MS Society in 2011 revealed that 42% of the 337 respondents had modified their diet due to MS. These modifications included change in intake of fatty acids; decrease or elimination of meat, sugar, and additives; and introduction of a low-carb or Paleo diet.⁴

Among an international sample of 2,087 MS patients, a significant association was found between a healthy diet and improved quality of life (both physical and mental) and reduced disability. This “healthy consumption” of fruits, vegetables, and dietary fat was also associated with a marginally decreased risk for relapse. Patients who demonstrated increased disease activity were more likely to have poor consumption of fruits, vegetables, and fats and to consume more meat and dairy products.⁵

There has also been research on specific components of dietary intake. Antioxidant-containing foods, for example, may have an anti-inflammatory effect.⁶ Vitamin B₁₂ deficiency plays a role in immunomodulatory effect, as well as formation of the myelin sheath, although its role (and the effect of biotin supplementation) in MS disease progression requires further study.⁷ Also ongoing is research into various calorie-restriction protocols, altering both timing and amount of caloric intake, since some data suggest this strategy reduces leptin, a satiety hormone that increases inflammation and has been shown to promote more aggressive MS in a mouse model.⁸

In the meantime, what can we conclude about diet and MS? A recent review determined that, although there is insufficient data to support one specific diet, there is sufficient evidence to recommend consumption of fish, foods lower in fat, whole grains, vitamin D, and supplemental omega fatty acids.⁵

It is important to discuss diet with our MS patients. In the German survey, 82% of patients felt that diet was important, yet only 10% had asked a provider for nutritional advice.⁴ In another study, patients indicated that food labels were their top source for nutrition information; only 20% sought advice from a nutritionist.³ We need to ask our MS patients if they are following a particular diet and be prepared to discuss potentially beneficial dietary choices with them—and offer referral to a nutritionist to those who require additional direction and support.—SP

Stacey Panasci, MSPAS, PA-C
Springfield Neurology Associates, LLC
Massachusetts

Q) What is known about the impact of diet on multiple sclerosis? How can I advise my patients with MS?

Multiple sclerosis (MS) is a chronic inflammatory and degenerative central nervous system disease affecting more than 2.5 million people worldwide. Today, if a Google search is performed for “diet and MS,” more than 67 million results are obtained. Many tout specific protocols as beneficial for MS but have no substantial data to support these claims. This can be confusing for patients as well as providers. How should you advise those who ask for advice on dietary modifications to help control symptoms or disease course?

First, it’s important to remember that individuals with MS have a reduced median lifespan (by about seven years), compared to healthy controls. Furthermore, patients with MS commonly have comorbid conditions—such as diabetes, obesity, and ische­mic heart disease—that increase mortality risk.^1,2 Diet and nutrition are significant factors that impact the course of these diseases.

We must also bear in mind that patients with MS experience symptoms that may impede their efforts to prepare meals. In a 2008 study of 123 MS patients (more than 50% of whom were overweight or obese), fatigue was cited as a significant factor that limited cooking and food preparation. Cognitive impairment and depression also may affect dietary intake. Interestingly, the average recorded intake for all food groups was less than that recommended in the Dietary Guidelines for Americans.³

A web-based survey conducted by the German MS Society in 2011 revealed that 42% of the 337 respondents had modified their diet due to MS. These modifications included change in intake of fatty acids; decrease or elimination of meat, sugar, and additives; and introduction of a low-carb or Paleo diet.⁴

Among an international sample of 2,087 MS patients, a significant association was found between a healthy diet and improved quality of life (both physical and mental) and reduced disability. This “healthy consumption” of fruits, vegetables, and dietary fat was also associated with a marginally decreased risk for relapse. Patients who demonstrated increased disease activity were more likely to have poor consumption of fruits, vegetables, and fats and to consume more meat and dairy products.⁵

There has also been research on specific components of dietary intake. Antioxidant-containing foods, for example, may have an anti-inflammatory effect.⁶ Vitamin B₁₂ deficiency plays a role in immunomodulatory effect, as well as formation of the myelin sheath, although its role (and the effect of biotin supplementation) in MS disease progression requires further study.⁷ Also ongoing is research into various calorie-restriction protocols, altering both timing and amount of caloric intake, since some data suggest this strategy reduces leptin, a satiety hormone that increases inflammation and has been shown to promote more aggressive MS in a mouse model.⁸

In the meantime, what can we conclude about diet and MS? A recent review determined that, although there is insufficient data to support one specific diet, there is sufficient evidence to recommend consumption of fish, foods lower in fat, whole grains, vitamin D, and supplemental omega fatty acids.⁵

It is important to discuss diet with our MS patients. In the German survey, 82% of patients felt that diet was important, yet only 10% had asked a provider for nutritional advice.⁴ In another study, patients indicated that food labels were their top source for nutrition information; only 20% sought advice from a nutritionist.³ We need to ask our MS patients if they are following a particular diet and be prepared to discuss potentially beneficial dietary choices with them—and offer referral to a nutritionist to those who require additional direction and support.—SP

Stacey Panasci, MSPAS, PA-C
Springfield Neurology Associates, LLC
Massachusetts

SAN DIEGO – The way Mathew M. Avram, MD, JD, sees it, the best way to avoid complications from using lasers for aesthetic procedures is to trust your own eyes, not the laser device itself.

“Lasers are never perfect,” he said at the annual Masters of Aesthetics Symposium. “The same device made by the same manufacturer may produce highly different outputs at the same setting. Moreover, lasers produce much different energies after they’ve been serviced. So, if you have two devices sitting right next to each other, don’t assume that the energy output on one device is exactly the same as the other device.”

[email protected]

SAN DIEGO – The way Mathew M. Avram, MD, JD, sees it, the best way to avoid complications from using lasers for aesthetic procedures is to trust your own eyes, not the laser device itself.

“Lasers are never perfect,” he said at the annual Masters of Aesthetics Symposium. “The same device made by the same manufacturer may produce highly different outputs at the same setting. Moreover, lasers produce much different energies after they’ve been serviced. So, if you have two devices sitting right next to each other, don’t assume that the energy output on one device is exactly the same as the other device.”

[email protected]

SAN DIEGO – The way Mathew M. Avram, MD, JD, sees it, the best way to avoid complications from using lasers for aesthetic procedures is to trust your own eyes, not the laser device itself.

“Lasers are never perfect,” he said at the annual Masters of Aesthetics Symposium. “The same device made by the same manufacturer may produce highly different outputs at the same setting. Moreover, lasers produce much different energies after they’ve been serviced. So, if you have two devices sitting right next to each other, don’t assume that the energy output on one device is exactly the same as the other device.”

[email protected]

The available evidence is sufficient to support switching appropriate patients with rheumatologic diseases from a bio-originator agent to an approved biosimilar agent, according to new consensus-based recommendations from an international multidisciplinary task force.

“Treatment with biological agents has dramatically improved the outcome for patients with inflammatory diseases. However, the high cost of these medications has limited access for many patients,” Jonathan Kay, MD, of UMass Memorial Medical Center and the University of Massachusetts, Worcester, and his colleagues wrote on behalf of the Task Force on the Use of Biosimilars to Treat Rheumatological Diseases. Biosimilars of agents no longer protected by patent allow for increased availability at lower costs, they noted. In the European Union, the United States, Japan, and other countries, biosimilars of adalimumab, etanercept, infliximab, and rituximab have been approved, and those for which the bio-originator is no longer protected by patent have been marketed.

Sara Freeman/Frontline Medical News

• Treatment of rheumatic diseases is based on a shared decision-making process between patients and their rheumatologists.
• The contextual aspects of the health care system should be taken into consideration when treatment decisions are made.
• A biosimilar, as approved by authorities in a highly regulated area, is neither better nor worse in efficacy and is not inferior in safety to its bio-originator.
• Patients and health care providers should be informed about the nature of biosimilars, their approval process, and their safety and efficacy.
• Harmonized methods should be established to obtain reliable pharmacovigilance data, including traceability, about both biosimilars and bio-originators.

These principles represent the key issues regarding biosimilars as identified by the task force. As for the specific recommendations, the task force agreed that:

1. The availability of biosimilars must significantly lower the cost of treating an individual patient and increase access to optimal therapy for all patients with rheumatic diseases (level 5, grade D evidence).

2. Approved biosimilars can be used to treat appropriate patients in the same way as their bio-originators (level 1b, grade A evidence, indicating that the recommendation is based on an individual randomized, controlled trial and that the level 1 evidence is consistent).

3. Antidrug antibodies to biosimilars need not be measured in clinical practice as no significant differences have been detected between biosimilars and their bio-originators (level 2b, grade B evidence, indicating that the recommendation is based on an individual cohort study/low-quality randomized, controlled trial and consistent level 2 or 3 evidence).

4. Relevant preclinical and phase 1 data on a biosimilar should be available when phase 3 data are published (level 5, grade D evidence).

5. Confirmation of efficacy and safety in a single indication is sufficient for extrapolation to other diseases for which the bio-originator has been approved because biosimilars are equivalent in physiochemical, functional, and pharmacokinetic properties to the bio-originator (level 5, grade D evidence).

6. Available evidence suggests that a single switch from a bio-originator to one of its biosimilars is safe and effective; there is no reason to expect a different clinical outcome. However, patient perspectives must be considered (level 1b, grade A evidence).

7. Multiple switching between biosimilars and their bio-originators or other biosimilars should be assessed in registries (level 5, grade D evidence).

8. No switch to or among biosimilars should be initiated without the prior awareness of the patient and the treating health care provider (level 5, grade D evidence).

Differing opinions about the use of biosimilars as published by various subspecialty organizations highlight a lack of confidence among many clinicians with respect to appropriate use of the products, but that is changing amid a rapidly growing body of evidence, the task force said. The group achieved a high level of agreement about both the evaluation of biosimilars and their use to treat rheumatologic diseases, reaching 100% consensus for six of the recommendations and 91% and 96% for the other two.

“Data available as of December 2016 support the use of biosimilars by rheumatologists to encourage a fair and competitive market for biologics. Biosimilars now provide an opportunity to expand access to effective but expensive medications, increasing the number of available treatment choices and helping to control rapidly increasing drug expenditures,” they concluded.

The task force’s work was funded by an unrestricted educational grant from Amgen. Dr. Kay and his coauthors reported financial relationships with multiple pharmaceutical companies, many of which are developing biosimilars.

[email protected]

The available evidence is sufficient to support switching appropriate patients with rheumatologic diseases from a bio-originator agent to an approved biosimilar agent, according to new consensus-based recommendations from an international multidisciplinary task force.

“Treatment with biological agents has dramatically improved the outcome for patients with inflammatory diseases. However, the high cost of these medications has limited access for many patients,” Jonathan Kay, MD, of UMass Memorial Medical Center and the University of Massachusetts, Worcester, and his colleagues wrote on behalf of the Task Force on the Use of Biosimilars to Treat Rheumatological Diseases. Biosimilars of agents no longer protected by patent allow for increased availability at lower costs, they noted. In the European Union, the United States, Japan, and other countries, biosimilars of adalimumab, etanercept, infliximab, and rituximab have been approved, and those for which the bio-originator is no longer protected by patent have been marketed.

Sara Freeman/Frontline Medical News

• Treatment of rheumatic diseases is based on a shared decision-making process between patients and their rheumatologists.
• The contextual aspects of the health care system should be taken into consideration when treatment decisions are made.
• A biosimilar, as approved by authorities in a highly regulated area, is neither better nor worse in efficacy and is not inferior in safety to its bio-originator.
• Patients and health care providers should be informed about the nature of biosimilars, their approval process, and their safety and efficacy.
• Harmonized methods should be established to obtain reliable pharmacovigilance data, including traceability, about both biosimilars and bio-originators.

These principles represent the key issues regarding biosimilars as identified by the task force. As for the specific recommendations, the task force agreed that:

1. The availability of biosimilars must significantly lower the cost of treating an individual patient and increase access to optimal therapy for all patients with rheumatic diseases (level 5, grade D evidence).

2. Approved biosimilars can be used to treat appropriate patients in the same way as their bio-originators (level 1b, grade A evidence, indicating that the recommendation is based on an individual randomized, controlled trial and that the level 1 evidence is consistent).

3. Antidrug antibodies to biosimilars need not be measured in clinical practice as no significant differences have been detected between biosimilars and their bio-originators (level 2b, grade B evidence, indicating that the recommendation is based on an individual cohort study/low-quality randomized, controlled trial and consistent level 2 or 3 evidence).

4. Relevant preclinical and phase 1 data on a biosimilar should be available when phase 3 data are published (level 5, grade D evidence).

5. Confirmation of efficacy and safety in a single indication is sufficient for extrapolation to other diseases for which the bio-originator has been approved because biosimilars are equivalent in physiochemical, functional, and pharmacokinetic properties to the bio-originator (level 5, grade D evidence).

6. Available evidence suggests that a single switch from a bio-originator to one of its biosimilars is safe and effective; there is no reason to expect a different clinical outcome. However, patient perspectives must be considered (level 1b, grade A evidence).

7. Multiple switching between biosimilars and their bio-originators or other biosimilars should be assessed in registries (level 5, grade D evidence).

8. No switch to or among biosimilars should be initiated without the prior awareness of the patient and the treating health care provider (level 5, grade D evidence).

Differing opinions about the use of biosimilars as published by various subspecialty organizations highlight a lack of confidence among many clinicians with respect to appropriate use of the products, but that is changing amid a rapidly growing body of evidence, the task force said. The group achieved a high level of agreement about both the evaluation of biosimilars and their use to treat rheumatologic diseases, reaching 100% consensus for six of the recommendations and 91% and 96% for the other two.

“Data available as of December 2016 support the use of biosimilars by rheumatologists to encourage a fair and competitive market for biologics. Biosimilars now provide an opportunity to expand access to effective but expensive medications, increasing the number of available treatment choices and helping to control rapidly increasing drug expenditures,” they concluded.

The task force’s work was funded by an unrestricted educational grant from Amgen. Dr. Kay and his coauthors reported financial relationships with multiple pharmaceutical companies, many of which are developing biosimilars.

[email protected]

The available evidence is sufficient to support switching appropriate patients with rheumatologic diseases from a bio-originator agent to an approved biosimilar agent, according to new consensus-based recommendations from an international multidisciplinary task force.

“Treatment with biological agents has dramatically improved the outcome for patients with inflammatory diseases. However, the high cost of these medications has limited access for many patients,” Jonathan Kay, MD, of UMass Memorial Medical Center and the University of Massachusetts, Worcester, and his colleagues wrote on behalf of the Task Force on the Use of Biosimilars to Treat Rheumatological Diseases. Biosimilars of agents no longer protected by patent allow for increased availability at lower costs, they noted. In the European Union, the United States, Japan, and other countries, biosimilars of adalimumab, etanercept, infliximab, and rituximab have been approved, and those for which the bio-originator is no longer protected by patent have been marketed.

Sara Freeman/Frontline Medical News

• Treatment of rheumatic diseases is based on a shared decision-making process between patients and their rheumatologists.
• The contextual aspects of the health care system should be taken into consideration when treatment decisions are made.
• A biosimilar, as approved by authorities in a highly regulated area, is neither better nor worse in efficacy and is not inferior in safety to its bio-originator.
• Patients and health care providers should be informed about the nature of biosimilars, their approval process, and their safety and efficacy.
• Harmonized methods should be established to obtain reliable pharmacovigilance data, including traceability, about both biosimilars and bio-originators.

These principles represent the key issues regarding biosimilars as identified by the task force. As for the specific recommendations, the task force agreed that:

1. The availability of biosimilars must significantly lower the cost of treating an individual patient and increase access to optimal therapy for all patients with rheumatic diseases (level 5, grade D evidence).

2. Approved biosimilars can be used to treat appropriate patients in the same way as their bio-originators (level 1b, grade A evidence, indicating that the recommendation is based on an individual randomized, controlled trial and that the level 1 evidence is consistent).

3. Antidrug antibodies to biosimilars need not be measured in clinical practice as no significant differences have been detected between biosimilars and their bio-originators (level 2b, grade B evidence, indicating that the recommendation is based on an individual cohort study/low-quality randomized, controlled trial and consistent level 2 or 3 evidence).

4. Relevant preclinical and phase 1 data on a biosimilar should be available when phase 3 data are published (level 5, grade D evidence).

5. Confirmation of efficacy and safety in a single indication is sufficient for extrapolation to other diseases for which the bio-originator has been approved because biosimilars are equivalent in physiochemical, functional, and pharmacokinetic properties to the bio-originator (level 5, grade D evidence).

6. Available evidence suggests that a single switch from a bio-originator to one of its biosimilars is safe and effective; there is no reason to expect a different clinical outcome. However, patient perspectives must be considered (level 1b, grade A evidence).

7. Multiple switching between biosimilars and their bio-originators or other biosimilars should be assessed in registries (level 5, grade D evidence).

8. No switch to or among biosimilars should be initiated without the prior awareness of the patient and the treating health care provider (level 5, grade D evidence).

Differing opinions about the use of biosimilars as published by various subspecialty organizations highlight a lack of confidence among many clinicians with respect to appropriate use of the products, but that is changing amid a rapidly growing body of evidence, the task force said. The group achieved a high level of agreement about both the evaluation of biosimilars and their use to treat rheumatologic diseases, reaching 100% consensus for six of the recommendations and 91% and 96% for the other two.

“Data available as of December 2016 support the use of biosimilars by rheumatologists to encourage a fair and competitive market for biologics. Biosimilars now provide an opportunity to expand access to effective but expensive medications, increasing the number of available treatment choices and helping to control rapidly increasing drug expenditures,” they concluded.

The task force’s work was funded by an unrestricted educational grant from Amgen. Dr. Kay and his coauthors reported financial relationships with multiple pharmaceutical companies, many of which are developing biosimilars.

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The Diagnosis: Rosai-Dorfman Disease

Rosai-Dorfman disease is a rare histiocytic proliferative disorder of unknown etiology. It has 2 forms: limited cutaneous and systemic. The systemic form, also known as sinus histiocytosis with massive lym­phadenopathy, affects the lymph nodes and other organs at times. The disease is characterized by a proliferation of histiocytes in the lymph nodes, most commonly in the cervical basin¹; however, the inguinal, axillary, mediastinal, or para-aortic nodes also may be affected.^1,2 The skin is the most common site of extranodal disease, seen in approximately 10% of cases.¹ Cutaneous involvement often is in the facial area but also can be found on the trunk, ears, neck, arms, legs, and genitals. Clinically, skin lesions appear as papules, plaques, and/or nodules.²

Histopathologic examination of Rosai-Dorfman disease generally shows a dense sheetlike dermal infiltrate of large polygonal histiocytes (Figure 1). Histiocytes may display pale pink or clear cytoplasm. The pathognomonic finding is emperipolesis, which consists of histiocytes with engulfed lymphocytes, erythrocytes, plasma cells, and/or granulocytes surrounded by a clear halo. Immunohistochemical staining also is characteristic, with lesional histiocytes showing expression of S-100 protein (Figure 1, inset) and CD68. The associated inflammatory infiltrate is mixed, containing primarily plasma cells but also lymphocytes, neutrophils, and eosinophils.

Blastomycosis (Figure 2) is a systemic infection due to inhalation of Blastomyces dermatitidis conidia. Primary infection occurs in the lungs, and with dissemination the skin is the most common subsequently involved organ.³ Cutaneous blastomycosis shows pseudoepitheliomatous hyperplasia with neutrophilic microabscesses and a dense dermal infiltrate containing suppurative granulomatous inflammation. The nonpigmented yeast phase typically is 8 to 15 µm in length with a refractile cell wall and characteristic single, broad-based budding.³

Granuloma faciale (Figure 3) is a rare disease with unknown etiology characterized by reddish brown plaques or nodules most commonly occurring on the face.^4,5 Histology shows a dense nodular dermal infiltrate with a grenz zone. The infiltrate is mixed, containing mostly neutrophils with leukocytoclasis and eosinophils. Leukocytoclastic vasculitis is present with associated extravasated erythrocytes. In chronic fibrosing granuloma faciale, lesions can demonstrate fibrosis and hemosiderin deposition, similar to erythema elevatum diutinum.

Juvenile xanthogranuloma (Figure 4) is a common histiocytic disease of early childhood, though adult cases have been reported.⁶ Tumors are found on the head and trunk and are typically firm, reddish yellow papules or nodules.^6,7 Histologic examination shows a nodular infiltrate of foamy histiocytes in the superficial dermis. Touton-type multinucleated giant cells with a peripheral rim of xanthomatized foamy cytoplasm and a wreathlike arrangement of nuclei are characteristic. Associated eosinophils are seen. No emperipolesis is present.

Reticulohistiocytoma (Figure 5) is a benign dermal lesion that presents as solitary or less commonly multiple red-brown papules or nodules.⁸ Lesions consist of well-delineated nodular aggregates of histiocytes containing a finely granular eosinophilic ground glass cytoplasm. Few, if any, eosinophils are found. The lack of Touton multinucleated giant cells or emperipolesis and lack of expression of S-100 protein helps to distinguish reticulohistiocytoma from other entities in the differential diagnosis.

The Diagnosis: Rosai-Dorfman Disease

Rosai-Dorfman disease is a rare histiocytic proliferative disorder of unknown etiology. It has 2 forms: limited cutaneous and systemic. The systemic form, also known as sinus histiocytosis with massive lym­phadenopathy, affects the lymph nodes and other organs at times. The disease is characterized by a proliferation of histiocytes in the lymph nodes, most commonly in the cervical basin¹; however, the inguinal, axillary, mediastinal, or para-aortic nodes also may be affected.^1,2 The skin is the most common site of extranodal disease, seen in approximately 10% of cases.¹ Cutaneous involvement often is in the facial area but also can be found on the trunk, ears, neck, arms, legs, and genitals. Clinically, skin lesions appear as papules, plaques, and/or nodules.²

Histopathologic examination of Rosai-Dorfman disease generally shows a dense sheetlike dermal infiltrate of large polygonal histiocytes (Figure 1). Histiocytes may display pale pink or clear cytoplasm. The pathognomonic finding is emperipolesis, which consists of histiocytes with engulfed lymphocytes, erythrocytes, plasma cells, and/or granulocytes surrounded by a clear halo. Immunohistochemical staining also is characteristic, with lesional histiocytes showing expression of S-100 protein (Figure 1, inset) and CD68. The associated inflammatory infiltrate is mixed, containing primarily plasma cells but also lymphocytes, neutrophils, and eosinophils.

Blastomycosis (Figure 2) is a systemic infection due to inhalation of Blastomyces dermatitidis conidia. Primary infection occurs in the lungs, and with dissemination the skin is the most common subsequently involved organ.³ Cutaneous blastomycosis shows pseudoepitheliomatous hyperplasia with neutrophilic microabscesses and a dense dermal infiltrate containing suppurative granulomatous inflammation. The nonpigmented yeast phase typically is 8 to 15 µm in length with a refractile cell wall and characteristic single, broad-based budding.³

Granuloma faciale (Figure 3) is a rare disease with unknown etiology characterized by reddish brown plaques or nodules most commonly occurring on the face.^4,5 Histology shows a dense nodular dermal infiltrate with a grenz zone. The infiltrate is mixed, containing mostly neutrophils with leukocytoclasis and eosinophils. Leukocytoclastic vasculitis is present with associated extravasated erythrocytes. In chronic fibrosing granuloma faciale, lesions can demonstrate fibrosis and hemosiderin deposition, similar to erythema elevatum diutinum.

Juvenile xanthogranuloma (Figure 4) is a common histiocytic disease of early childhood, though adult cases have been reported.⁶ Tumors are found on the head and trunk and are typically firm, reddish yellow papules or nodules.^6,7 Histologic examination shows a nodular infiltrate of foamy histiocytes in the superficial dermis. Touton-type multinucleated giant cells with a peripheral rim of xanthomatized foamy cytoplasm and a wreathlike arrangement of nuclei are characteristic. Associated eosinophils are seen. No emperipolesis is present.

Reticulohistiocytoma (Figure 5) is a benign dermal lesion that presents as solitary or less commonly multiple red-brown papules or nodules.⁸ Lesions consist of well-delineated nodular aggregates of histiocytes containing a finely granular eosinophilic ground glass cytoplasm. Few, if any, eosinophils are found. The lack of Touton multinucleated giant cells or emperipolesis and lack of expression of S-100 protein helps to distinguish reticulohistiocytoma from other entities in the differential diagnosis.

The Diagnosis: Rosai-Dorfman Disease

Rosai-Dorfman disease is a rare histiocytic proliferative disorder of unknown etiology. It has 2 forms: limited cutaneous and systemic. The systemic form, also known as sinus histiocytosis with massive lym­phadenopathy, affects the lymph nodes and other organs at times. The disease is characterized by a proliferation of histiocytes in the lymph nodes, most commonly in the cervical basin¹; however, the inguinal, axillary, mediastinal, or para-aortic nodes also may be affected.^1,2 The skin is the most common site of extranodal disease, seen in approximately 10% of cases.¹ Cutaneous involvement often is in the facial area but also can be found on the trunk, ears, neck, arms, legs, and genitals. Clinically, skin lesions appear as papules, plaques, and/or nodules.²

Histopathologic examination of Rosai-Dorfman disease generally shows a dense sheetlike dermal infiltrate of large polygonal histiocytes (Figure 1). Histiocytes may display pale pink or clear cytoplasm. The pathognomonic finding is emperipolesis, which consists of histiocytes with engulfed lymphocytes, erythrocytes, plasma cells, and/or granulocytes surrounded by a clear halo. Immunohistochemical staining also is characteristic, with lesional histiocytes showing expression of S-100 protein (Figure 1, inset) and CD68. The associated inflammatory infiltrate is mixed, containing primarily plasma cells but also lymphocytes, neutrophils, and eosinophils.

Blastomycosis (Figure 2) is a systemic infection due to inhalation of Blastomyces dermatitidis conidia. Primary infection occurs in the lungs, and with dissemination the skin is the most common subsequently involved organ.³ Cutaneous blastomycosis shows pseudoepitheliomatous hyperplasia with neutrophilic microabscesses and a dense dermal infiltrate containing suppurative granulomatous inflammation. The nonpigmented yeast phase typically is 8 to 15 µm in length with a refractile cell wall and characteristic single, broad-based budding.³

Granuloma faciale (Figure 3) is a rare disease with unknown etiology characterized by reddish brown plaques or nodules most commonly occurring on the face.^4,5 Histology shows a dense nodular dermal infiltrate with a grenz zone. The infiltrate is mixed, containing mostly neutrophils with leukocytoclasis and eosinophils. Leukocytoclastic vasculitis is present with associated extravasated erythrocytes. In chronic fibrosing granuloma faciale, lesions can demonstrate fibrosis and hemosiderin deposition, similar to erythema elevatum diutinum.

Juvenile xanthogranuloma (Figure 4) is a common histiocytic disease of early childhood, though adult cases have been reported.⁶ Tumors are found on the head and trunk and are typically firm, reddish yellow papules or nodules.^6,7 Histologic examination shows a nodular infiltrate of foamy histiocytes in the superficial dermis. Touton-type multinucleated giant cells with a peripheral rim of xanthomatized foamy cytoplasm and a wreathlike arrangement of nuclei are characteristic. Associated eosinophils are seen. No emperipolesis is present.

Reticulohistiocytoma (Figure 5) is a benign dermal lesion that presents as solitary or less commonly multiple red-brown papules or nodules.⁸ Lesions consist of well-delineated nodular aggregates of histiocytes containing a finely granular eosinophilic ground glass cytoplasm. Few, if any, eosinophils are found. The lack of Touton multinucleated giant cells or emperipolesis and lack of expression of S-100 protein helps to distinguish reticulohistiocytoma from other entities in the differential diagnosis.