In this Update, I report on the latest US Preventive Services Task Force (USPSTF) cervical cancer screening recommendations. In addition, I describe the results of 2 studies, a large prospective multicenter study of the accuracy of sentinel lymph node (SLN) biopsy in endometrial cancer, and a proof-of-concept review of use of checkpoint blockade to increase immune response and of its possible role in endometrial cancer.

hrHPV testing used alone as primary screening for cervical cancer: USPSTF recommendations

US Preventive Services Task Force. Draft recommendation statement: cervical cancer: screening. https://www.uspreventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/cervical-cancer-screening2. Published October 2017. Accessed February 5, 2018.

‌

Despite our rapid advances in understanding the molecular underpinnings of cancer, gynecologic malignancies are still a major cause of morbidity and mortality among women. Cervical cancer stands as an example of how a cancer screening test can be implemented to reduce mortality. In this section, I report on the USPSTF cervical cancer screening recommendations, which were updated in October 2017.

Even with the widespread implementation of screening programs for cervical cancer in the United States, 13,240 women will be diagnosed with the disease in 2018, and 4,170 will die from cervical cancer.¹ Most often, cervical cancer occurs in women who have not been adequately screened. It is now recognized that the human papillomavirus (HPV) is the cause of cervical cancer.²

While cervical cytology has long been used as a screening test for cervical cancer, testing for high-risk HPV subtypes (hrHPV testing) also has been used as a screening modality. Traditionally, hrHPV testing is used in combination with cervical cytology, so called cotesting. There is convincing evidence that cervical cytology, as well as strategies that use hrHPV testing, can detect high-grade cervical precancers and cancers and thereby reduce mortality. However, cervical cancer screening is also associated with frequent follow-ups, invasive procedures performed to assess abnormal results, psychological distress, and adverse pregnancy outcomes of treatment for precancerous lesions.

The USPSTF based its new cervical cancer screening recommendations on clinical trial data and decision modeling of various screening strategies, and weighed the benefits and harms of each strategy.

Recommendations from the USPSTF

hrHPV screening for cervical cancer.  TheUSPSTF recommends screening with cervical cytology every 3 years for women 21 to 29 years of age. For women 30 to 65 years of age, screening with cytology every 3 years, or hrHPV testing alone used every 5 years, is recommended.

Data from large randomized trials suggest cytologic screening is slightly less sensitive than hrHPV testing in detecting high-grade (grade 2 or 3) cervical intraepithelial neoplasia (CIN). However, hrHPV testing results in more follow-up tests and colposcopies. In a decision model, the USPSTF found that cotesting increased the number of follow-up tests but did not increase detection of grade 3 CIN or invasive cancer. This is the first clinical guideline to recommend hrHPV testing used alone for screening. The American College of Obstetricians and Gynecologists (ACOG) continues to recommend cotesting (cytology in combination with hrHPV) as a primary screening modality in this population.³

Exceptions. According to the USPSTF, 3 populations should not be screened: women over 65 years of age with adequate prior screening who are not otherwise at high risk for cervical cancer; women under  21 years of age; and women who have had a hysterectomy and do not have a history of grade 2 or 3 CIN or cancer.

Summary. The USPSTF recommendations are intended for the general population and are not applicable to women with a history of high-grade CIN or cervical cancer, women with in utero exposure to diethylstilbestrol, and women who are immunocompromised. The remaining USPSTF recommendations are largely in line with guidelines published by ACOG and other groups.^3,4

Read about SLN biopsy to stage endometrial cancer

SLN biopsy for staging endometrial cancer

Rossi EC, Kowalski LD, Scalici J, et al. A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): a multicentre, prospective, cohort study. Lancet Oncol. 2017;18(3):384-392.

‌

Surgery is the cornerstone of treatment for most gynecologic cancers. The widespread use of minimally invasive surgical techniques and the introduction of less radical procedures for gynecologic cancers have helped reduce surgical morbidity.

For endometrial cancer, the role of lymphadenectomy is controversial. Data from prospective trials of this procedure suggest an association with increased morbidity and long-term sequelae, such as lymphedema, and no association with improved survival.^5,6

SLN biopsy is an important advance and a potential alternative nodal evaluation method that may be associated with decreased morbidity. In this more limited assessment technique, the first nodal drainage basins of a tumor are identified and removed for pathologic evaluation.

Accuracy of SLN biopsy in endometrial cancer was the subject of Rossi and colleagues' recent large prospective multicenter study, the Fluorescence Imaging for Robotic Endometrial Sentinel lymph node biopsy (FIRES) trial.

Details of the study

Rossi and colleagues conducted the FIRES trial to estimate the sensitivity of SLN biopsy in detecting nodal metastases in women with stage I endometrial cancer. Patients (N = 385) from 10 US sites were enrolled in the study. SLN evaluation was performed after cervical injection of indocyanine green followed by robotic-assisted hysterectomy. After identification of the SLN, participants underwent pelvic lymphadenectomy. Performance of para-aortic lymphadenectomy was optional.

Mapping of the SLN was feasible in 86% of patients, including bilateral mapping in 52%. Twelve percent of the participants had nodal metastases. SLN biopsy had a sensitivity of 97% in women who had identification of the SLNs. Similarly, the negative predictive value was high, 99.6%. The procedure was associated with acceptable short-term toxicity with adverse events in 9% of study participants. Common complications included neurologic complications, respiratory distress, nausea and vomiting, and, in 3 patients, bowel injury.

Accurate detection of nodal metastases. Results of the study suggest SLN biopsy is accurate in detecting nodal metastases in women with endometrial cancer. Although long-term toxicity was not examined, other work suggests the lymphedema rates associated with SLN biopsy may be lower than those of lymphadenectomy. While the study described impressive performance characteristics, there remain technical challenges. Even among skilled surgeons trained for the protocol, there was no nodal mapping in nearly half of the women with endometrial cancer. Women without node mapping require full lymphadenectomy thus negating the possible benefits of the procedure.

Read about immunotherapy for gynecologic cancers

Immunotherapy for gynecologic cancers

Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413.

‌

In oncology, precision medicine is rapidly becoming a standard treatment approach. Therapies are being used to target specific genetic alterations in tumors. In cancer immunotherapy, the immune system is being used to facilitate clearance of cancer cells.

The most common mechanism of action of clinically used immunotherapeutic agents is blockade of programmed cell death protein 1 (PD-1), a lymphocyte receptor that prevents the immune system from targeting the body's own cells.⁷ Cancers that have mutations in the DNA mismatch repair (MMR) proteins display microsatellite instability (MSI) and produce high levels of abnormal proteins.⁸ These abnormal proteins serve as tumor antigens that can be targeted by the body's normal immune system. 

In May 2017, the US Food and Drug Administration (FDA) granted accelerated approval of the PD-1 blocking antibody pembrolizumab for the treatment of unresectable or metastatic MSI-high (MSI-H) or MMR-deficient solid tumors.9 The approval was based on data from 149 patients treated in 5 studies that demonstrated a response rate of 39.6%, including responses that lasted at least 6 months in 78% of participants. This was the first ever cancer drug that received FDA approval based on a tumor's biomarker profile without regard to the site of origin. I describe the results of a study by Le and colleagues that examines the possible role of immunotherapy in a variety of solid tumors in this section.

Details of the study

This study examined the clinical efficacy of PD-1 blockade in 86 patients with advanced, MMR-deficient tumors from 12 different sites. Endometrial cancer was the second most frequent primary tumor site in 17% of patients. Within the cohort, the overall objective response rate was 53%, which included 21% of patients with complete radiographic response (no imaging evidence of cancer). Disease control, either complete or partial response or stable disease, was achieved in 77% of patients. After a median follow-up of 12.5 months, neither the median progression-free survival (PFS) nor median overall survival had been reached. The authors estimated that 2-year overall survival was 64%, substantially higher than expected for patients with advanced solid tumors.

Le and colleagues also performed several in vivo laboratory experiments to explore the mechanisms by which patients responded. In addition, they used sequencing to determine the prevalence of MMR deficiency in 12,019 cancer samples that included 32 distinct tumor types (FIGURE). Endometrial cancer had the highest frequency of MMR deficiency (17%). Four percent of cervical cancers and less than 2% of ovarian cancers were MMR-deficient.

The promise of immunotherapy for endometrial cancer. This study's data and other emerging data have important implications for women with gynecologic cancer, particularly endometrial cancer. First, given the frequency of MMR mutations among women with endometrial cancer, MMR testing should be strongly considered for these patients. Many institutions have protocols for reflex testing with immunohistochemistry for women with endometrial cancer. For women with positive test results, germline sequencing can be performed to determine if they have an inherited MMR deficiency, Lynch syndrome. Presence of an MMR deficiency is an important factor in cancer screening and potential treatment.

Second, the impressive results of PD-1 blockade in patients with MMR-deficient tumors suggest that this treatment strategy may be important for women with recurrent or metastatic endometrial cancer. The ideal timing of immunotherapy for women with endometrial cancer is an area of active ongoing study.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In this Update, I report on the latest US Preventive Services Task Force (USPSTF) cervical cancer screening recommendations. In addition, I describe the results of 2 studies, a large prospective multicenter study of the accuracy of sentinel lymph node (SLN) biopsy in endometrial cancer, and a proof-of-concept review of use of checkpoint blockade to increase immune response and of its possible role in endometrial cancer.

hrHPV testing used alone as primary screening for cervical cancer: USPSTF recommendations

US Preventive Services Task Force. Draft recommendation statement: cervical cancer: screening. https://www.uspreventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/cervical-cancer-screening2. Published October 2017. Accessed February 5, 2018.

‌

Despite our rapid advances in understanding the molecular underpinnings of cancer, gynecologic malignancies are still a major cause of morbidity and mortality among women. Cervical cancer stands as an example of how a cancer screening test can be implemented to reduce mortality. In this section, I report on the USPSTF cervical cancer screening recommendations, which were updated in October 2017.

Even with the widespread implementation of screening programs for cervical cancer in the United States, 13,240 women will be diagnosed with the disease in 2018, and 4,170 will die from cervical cancer.¹ Most often, cervical cancer occurs in women who have not been adequately screened. It is now recognized that the human papillomavirus (HPV) is the cause of cervical cancer.²

While cervical cytology has long been used as a screening test for cervical cancer, testing for high-risk HPV subtypes (hrHPV testing) also has been used as a screening modality. Traditionally, hrHPV testing is used in combination with cervical cytology, so called cotesting. There is convincing evidence that cervical cytology, as well as strategies that use hrHPV testing, can detect high-grade cervical precancers and cancers and thereby reduce mortality. However, cervical cancer screening is also associated with frequent follow-ups, invasive procedures performed to assess abnormal results, psychological distress, and adverse pregnancy outcomes of treatment for precancerous lesions.

The USPSTF based its new cervical cancer screening recommendations on clinical trial data and decision modeling of various screening strategies, and weighed the benefits and harms of each strategy.

Recommendations from the USPSTF

hrHPV screening for cervical cancer.  TheUSPSTF recommends screening with cervical cytology every 3 years for women 21 to 29 years of age. For women 30 to 65 years of age, screening with cytology every 3 years, or hrHPV testing alone used every 5 years, is recommended.

Data from large randomized trials suggest cytologic screening is slightly less sensitive than hrHPV testing in detecting high-grade (grade 2 or 3) cervical intraepithelial neoplasia (CIN). However, hrHPV testing results in more follow-up tests and colposcopies. In a decision model, the USPSTF found that cotesting increased the number of follow-up tests but did not increase detection of grade 3 CIN or invasive cancer. This is the first clinical guideline to recommend hrHPV testing used alone for screening. The American College of Obstetricians and Gynecologists (ACOG) continues to recommend cotesting (cytology in combination with hrHPV) as a primary screening modality in this population.³

Exceptions. According to the USPSTF, 3 populations should not be screened: women over 65 years of age with adequate prior screening who are not otherwise at high risk for cervical cancer; women under  21 years of age; and women who have had a hysterectomy and do not have a history of grade 2 or 3 CIN or cancer.

Summary. The USPSTF recommendations are intended for the general population and are not applicable to women with a history of high-grade CIN or cervical cancer, women with in utero exposure to diethylstilbestrol, and women who are immunocompromised. The remaining USPSTF recommendations are largely in line with guidelines published by ACOG and other groups.^3,4

Read about SLN biopsy to stage endometrial cancer

SLN biopsy for staging endometrial cancer

Rossi EC, Kowalski LD, Scalici J, et al. A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): a multicentre, prospective, cohort study. Lancet Oncol. 2017;18(3):384-392.

‌

Surgery is the cornerstone of treatment for most gynecologic cancers. The widespread use of minimally invasive surgical techniques and the introduction of less radical procedures for gynecologic cancers have helped reduce surgical morbidity.

For endometrial cancer, the role of lymphadenectomy is controversial. Data from prospective trials of this procedure suggest an association with increased morbidity and long-term sequelae, such as lymphedema, and no association with improved survival.^5,6

SLN biopsy is an important advance and a potential alternative nodal evaluation method that may be associated with decreased morbidity. In this more limited assessment technique, the first nodal drainage basins of a tumor are identified and removed for pathologic evaluation.

Accuracy of SLN biopsy in endometrial cancer was the subject of Rossi and colleagues' recent large prospective multicenter study, the Fluorescence Imaging for Robotic Endometrial Sentinel lymph node biopsy (FIRES) trial.

Details of the study

Rossi and colleagues conducted the FIRES trial to estimate the sensitivity of SLN biopsy in detecting nodal metastases in women with stage I endometrial cancer. Patients (N = 385) from 10 US sites were enrolled in the study. SLN evaluation was performed after cervical injection of indocyanine green followed by robotic-assisted hysterectomy. After identification of the SLN, participants underwent pelvic lymphadenectomy. Performance of para-aortic lymphadenectomy was optional.

Mapping of the SLN was feasible in 86% of patients, including bilateral mapping in 52%. Twelve percent of the participants had nodal metastases. SLN biopsy had a sensitivity of 97% in women who had identification of the SLNs. Similarly, the negative predictive value was high, 99.6%. The procedure was associated with acceptable short-term toxicity with adverse events in 9% of study participants. Common complications included neurologic complications, respiratory distress, nausea and vomiting, and, in 3 patients, bowel injury.

Accurate detection of nodal metastases. Results of the study suggest SLN biopsy is accurate in detecting nodal metastases in women with endometrial cancer. Although long-term toxicity was not examined, other work suggests the lymphedema rates associated with SLN biopsy may be lower than those of lymphadenectomy. While the study described impressive performance characteristics, there remain technical challenges. Even among skilled surgeons trained for the protocol, there was no nodal mapping in nearly half of the women with endometrial cancer. Women without node mapping require full lymphadenectomy thus negating the possible benefits of the procedure.

Read about immunotherapy for gynecologic cancers

Immunotherapy for gynecologic cancers

Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413.

‌

In oncology, precision medicine is rapidly becoming a standard treatment approach. Therapies are being used to target specific genetic alterations in tumors. In cancer immunotherapy, the immune system is being used to facilitate clearance of cancer cells.

The most common mechanism of action of clinically used immunotherapeutic agents is blockade of programmed cell death protein 1 (PD-1), a lymphocyte receptor that prevents the immune system from targeting the body's own cells.⁷ Cancers that have mutations in the DNA mismatch repair (MMR) proteins display microsatellite instability (MSI) and produce high levels of abnormal proteins.⁸ These abnormal proteins serve as tumor antigens that can be targeted by the body's normal immune system. 

In May 2017, the US Food and Drug Administration (FDA) granted accelerated approval of the PD-1 blocking antibody pembrolizumab for the treatment of unresectable or metastatic MSI-high (MSI-H) or MMR-deficient solid tumors.9 The approval was based on data from 149 patients treated in 5 studies that demonstrated a response rate of 39.6%, including responses that lasted at least 6 months in 78% of participants. This was the first ever cancer drug that received FDA approval based on a tumor's biomarker profile without regard to the site of origin. I describe the results of a study by Le and colleagues that examines the possible role of immunotherapy in a variety of solid tumors in this section.

Details of the study

This study examined the clinical efficacy of PD-1 blockade in 86 patients with advanced, MMR-deficient tumors from 12 different sites. Endometrial cancer was the second most frequent primary tumor site in 17% of patients. Within the cohort, the overall objective response rate was 53%, which included 21% of patients with complete radiographic response (no imaging evidence of cancer). Disease control, either complete or partial response or stable disease, was achieved in 77% of patients. After a median follow-up of 12.5 months, neither the median progression-free survival (PFS) nor median overall survival had been reached. The authors estimated that 2-year overall survival was 64%, substantially higher than expected for patients with advanced solid tumors.

Le and colleagues also performed several in vivo laboratory experiments to explore the mechanisms by which patients responded. In addition, they used sequencing to determine the prevalence of MMR deficiency in 12,019 cancer samples that included 32 distinct tumor types (FIGURE). Endometrial cancer had the highest frequency of MMR deficiency (17%). Four percent of cervical cancers and less than 2% of ovarian cancers were MMR-deficient.

The promise of immunotherapy for endometrial cancer. This study's data and other emerging data have important implications for women with gynecologic cancer, particularly endometrial cancer. First, given the frequency of MMR mutations among women with endometrial cancer, MMR testing should be strongly considered for these patients. Many institutions have protocols for reflex testing with immunohistochemistry for women with endometrial cancer. For women with positive test results, germline sequencing can be performed to determine if they have an inherited MMR deficiency, Lynch syndrome. Presence of an MMR deficiency is an important factor in cancer screening and potential treatment.

Second, the impressive results of PD-1 blockade in patients with MMR-deficient tumors suggest that this treatment strategy may be important for women with recurrent or metastatic endometrial cancer. The ideal timing of immunotherapy for women with endometrial cancer is an area of active ongoing study.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In this Update, I report on the latest US Preventive Services Task Force (USPSTF) cervical cancer screening recommendations. In addition, I describe the results of 2 studies, a large prospective multicenter study of the accuracy of sentinel lymph node (SLN) biopsy in endometrial cancer, and a proof-of-concept review of use of checkpoint blockade to increase immune response and of its possible role in endometrial cancer.

hrHPV testing used alone as primary screening for cervical cancer: USPSTF recommendations

US Preventive Services Task Force. Draft recommendation statement: cervical cancer: screening. https://www.uspreventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/cervical-cancer-screening2. Published October 2017. Accessed February 5, 2018.

‌

Despite our rapid advances in understanding the molecular underpinnings of cancer, gynecologic malignancies are still a major cause of morbidity and mortality among women. Cervical cancer stands as an example of how a cancer screening test can be implemented to reduce mortality. In this section, I report on the USPSTF cervical cancer screening recommendations, which were updated in October 2017.

Even with the widespread implementation of screening programs for cervical cancer in the United States, 13,240 women will be diagnosed with the disease in 2018, and 4,170 will die from cervical cancer.¹ Most often, cervical cancer occurs in women who have not been adequately screened. It is now recognized that the human papillomavirus (HPV) is the cause of cervical cancer.²

While cervical cytology has long been used as a screening test for cervical cancer, testing for high-risk HPV subtypes (hrHPV testing) also has been used as a screening modality. Traditionally, hrHPV testing is used in combination with cervical cytology, so called cotesting. There is convincing evidence that cervical cytology, as well as strategies that use hrHPV testing, can detect high-grade cervical precancers and cancers and thereby reduce mortality. However, cervical cancer screening is also associated with frequent follow-ups, invasive procedures performed to assess abnormal results, psychological distress, and adverse pregnancy outcomes of treatment for precancerous lesions.

The USPSTF based its new cervical cancer screening recommendations on clinical trial data and decision modeling of various screening strategies, and weighed the benefits and harms of each strategy.

Recommendations from the USPSTF

hrHPV screening for cervical cancer.  TheUSPSTF recommends screening with cervical cytology every 3 years for women 21 to 29 years of age. For women 30 to 65 years of age, screening with cytology every 3 years, or hrHPV testing alone used every 5 years, is recommended.

Data from large randomized trials suggest cytologic screening is slightly less sensitive than hrHPV testing in detecting high-grade (grade 2 or 3) cervical intraepithelial neoplasia (CIN). However, hrHPV testing results in more follow-up tests and colposcopies. In a decision model, the USPSTF found that cotesting increased the number of follow-up tests but did not increase detection of grade 3 CIN or invasive cancer. This is the first clinical guideline to recommend hrHPV testing used alone for screening. The American College of Obstetricians and Gynecologists (ACOG) continues to recommend cotesting (cytology in combination with hrHPV) as a primary screening modality in this population.³

Exceptions. According to the USPSTF, 3 populations should not be screened: women over 65 years of age with adequate prior screening who are not otherwise at high risk for cervical cancer; women under  21 years of age; and women who have had a hysterectomy and do not have a history of grade 2 or 3 CIN or cancer.

Summary. The USPSTF recommendations are intended for the general population and are not applicable to women with a history of high-grade CIN or cervical cancer, women with in utero exposure to diethylstilbestrol, and women who are immunocompromised. The remaining USPSTF recommendations are largely in line with guidelines published by ACOG and other groups.^3,4

Read about SLN biopsy to stage endometrial cancer

SLN biopsy for staging endometrial cancer

Rossi EC, Kowalski LD, Scalici J, et al. A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): a multicentre, prospective, cohort study. Lancet Oncol. 2017;18(3):384-392.

‌

Surgery is the cornerstone of treatment for most gynecologic cancers. The widespread use of minimally invasive surgical techniques and the introduction of less radical procedures for gynecologic cancers have helped reduce surgical morbidity.

For endometrial cancer, the role of lymphadenectomy is controversial. Data from prospective trials of this procedure suggest an association with increased morbidity and long-term sequelae, such as lymphedema, and no association with improved survival.^5,6

SLN biopsy is an important advance and a potential alternative nodal evaluation method that may be associated with decreased morbidity. In this more limited assessment technique, the first nodal drainage basins of a tumor are identified and removed for pathologic evaluation.

Accuracy of SLN biopsy in endometrial cancer was the subject of Rossi and colleagues' recent large prospective multicenter study, the Fluorescence Imaging for Robotic Endometrial Sentinel lymph node biopsy (FIRES) trial.

Details of the study

Rossi and colleagues conducted the FIRES trial to estimate the sensitivity of SLN biopsy in detecting nodal metastases in women with stage I endometrial cancer. Patients (N = 385) from 10 US sites were enrolled in the study. SLN evaluation was performed after cervical injection of indocyanine green followed by robotic-assisted hysterectomy. After identification of the SLN, participants underwent pelvic lymphadenectomy. Performance of para-aortic lymphadenectomy was optional.

Mapping of the SLN was feasible in 86% of patients, including bilateral mapping in 52%. Twelve percent of the participants had nodal metastases. SLN biopsy had a sensitivity of 97% in women who had identification of the SLNs. Similarly, the negative predictive value was high, 99.6%. The procedure was associated with acceptable short-term toxicity with adverse events in 9% of study participants. Common complications included neurologic complications, respiratory distress, nausea and vomiting, and, in 3 patients, bowel injury.

Accurate detection of nodal metastases. Results of the study suggest SLN biopsy is accurate in detecting nodal metastases in women with endometrial cancer. Although long-term toxicity was not examined, other work suggests the lymphedema rates associated with SLN biopsy may be lower than those of lymphadenectomy. While the study described impressive performance characteristics, there remain technical challenges. Even among skilled surgeons trained for the protocol, there was no nodal mapping in nearly half of the women with endometrial cancer. Women without node mapping require full lymphadenectomy thus negating the possible benefits of the procedure.

Read about immunotherapy for gynecologic cancers

Immunotherapy for gynecologic cancers

Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413.

‌

In oncology, precision medicine is rapidly becoming a standard treatment approach. Therapies are being used to target specific genetic alterations in tumors. In cancer immunotherapy, the immune system is being used to facilitate clearance of cancer cells.

The most common mechanism of action of clinically used immunotherapeutic agents is blockade of programmed cell death protein 1 (PD-1), a lymphocyte receptor that prevents the immune system from targeting the body's own cells.⁷ Cancers that have mutations in the DNA mismatch repair (MMR) proteins display microsatellite instability (MSI) and produce high levels of abnormal proteins.⁸ These abnormal proteins serve as tumor antigens that can be targeted by the body's normal immune system. 

In May 2017, the US Food and Drug Administration (FDA) granted accelerated approval of the PD-1 blocking antibody pembrolizumab for the treatment of unresectable or metastatic MSI-high (MSI-H) or MMR-deficient solid tumors.9 The approval was based on data from 149 patients treated in 5 studies that demonstrated a response rate of 39.6%, including responses that lasted at least 6 months in 78% of participants. This was the first ever cancer drug that received FDA approval based on a tumor's biomarker profile without regard to the site of origin. I describe the results of a study by Le and colleagues that examines the possible role of immunotherapy in a variety of solid tumors in this section.

Details of the study

This study examined the clinical efficacy of PD-1 blockade in 86 patients with advanced, MMR-deficient tumors from 12 different sites. Endometrial cancer was the second most frequent primary tumor site in 17% of patients. Within the cohort, the overall objective response rate was 53%, which included 21% of patients with complete radiographic response (no imaging evidence of cancer). Disease control, either complete or partial response or stable disease, was achieved in 77% of patients. After a median follow-up of 12.5 months, neither the median progression-free survival (PFS) nor median overall survival had been reached. The authors estimated that 2-year overall survival was 64%, substantially higher than expected for patients with advanced solid tumors.

Le and colleagues also performed several in vivo laboratory experiments to explore the mechanisms by which patients responded. In addition, they used sequencing to determine the prevalence of MMR deficiency in 12,019 cancer samples that included 32 distinct tumor types (FIGURE). Endometrial cancer had the highest frequency of MMR deficiency (17%). Four percent of cervical cancers and less than 2% of ovarian cancers were MMR-deficient.

The promise of immunotherapy for endometrial cancer. This study's data and other emerging data have important implications for women with gynecologic cancer, particularly endometrial cancer. First, given the frequency of MMR mutations among women with endometrial cancer, MMR testing should be strongly considered for these patients. Many institutions have protocols for reflex testing with immunohistochemistry for women with endometrial cancer. For women with positive test results, germline sequencing can be performed to determine if they have an inherited MMR deficiency, Lynch syndrome. Presence of an MMR deficiency is an important factor in cancer screening and potential treatment.

Second, the impressive results of PD-1 blockade in patients with MMR-deficient tumors suggest that this treatment strategy may be important for women with recurrent or metastatic endometrial cancer. The ideal timing of immunotherapy for women with endometrial cancer is an area of active ongoing study.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In its landmark publication, “Crossing the quality chasm: A new health system for the 21st century,” the Institute of Medicine (now the National Academy of Medicine) called for an emphasis on patient-centered care that it defined as “Providing care that is respectful of and responsive to individual patient preferences, needs, and values and ensuring that patient values guide all clinical decisions.”¹ Studies suggest that the patient’s view of health care delivery determines outcome and satisfaction.² Therefore, we need to expend more effort to understand what patients need or want from their treatment or interaction with the health care system.

Measuring patient-reported outcomes (PROs) is an attempt to recognize and address patient concerns. Although currently PROs are focused primarily in the arena of clinical research, their use has the potential to transform daily clinical patient encounters and improve the cost and quality of health care.³

In this article, we provide a brief overview of PROs and describe how they can be used to improve individual patient care, clinical research, and health care quality. We also offer examples of how PROs can be used in specific women’s health conditions.

Illustration: Paul Zwolak for OBG Management

What exactly are PROs?

PROs are reports of the status of a patient’s health condition, health behavior, or experience with health care; they come directly from the patient, without anyone else (such as a clinician or caregiver) interpreting the patient’s response.⁴ PROs usually pertain to general health, quality of life, functional status, or preferences associated with health care or treatment.⁵ Usually PROs are elicited via a self-administered survey and provide the patient’s perspective on treatment benefits, side effects, change in symptoms, general perceptions of feelings or well-being, or satisfaction with care. Often they represent the outcomes that are most important to patients.⁶ The survey usually consists of several questions or items. It can be general or condition specific, and it may represent one or more health care dimensions.

The term patient-reported outcome measure (PROM) refers to the survey instrument used to collect PROs. Patient-reported experience measures (PREMs), such as satisfaction surveys, are considered a subset of PROMs.⁷

Standardized PROs developed out of clinical trials

The use of PROs evolved from clinical trials. The proliferation of PROs resulted in an inability to compare outcomes across trials or different conditions. This led to a need to standardize and possibly harmonize measures and to reach consensus about properties required for a “good” measure and requirements needed for “adequate” reporting. Many investigators and several national and international organizations have provided iterative guidance, including the US Food and Drug Administration (FDA), European Medicines Agency, National Institutes of Health (NIH) Patient-Reported Outcomes Measurement Information System (PROMIS), International Consortium for Health Outcomes Measurement (ICHOM), University of Oxford Patient Reported Outcomes Measurement Group, Cochrane Systematic Reviews, Consolidated Standards of Reporting Trials–Patient Reported Outcomes (CONSORT-PRO) extension (how to report PROs with the CONSORT checklist), and the International Society for Pharmacoeconomics and Outcomes Research (ISPOR).^4,5,8–18

In the United States, the RAND Medical Outcomes Study led to the development of the 12- and 36-item short form surveys, which are widely recognized and commonly used PROMs for health-related quality of life.¹⁹ The study generated multiple additional survey instruments that evaluate other domains and dimensions of health. These surveys have been translated into numerous languages, and the RAND website lists over 100 publications.¹⁹

In 2002, the NIH sponsored PROMIS, a cooperative program designed to develop, validate, and standardize item banks to measure PROs that were relevant across multiple, common medical conditions. Based on literature review, feedback from both healthy and sick patients, and clinical expert opinion, the PROMIS investigators developed a consensus-based framework for self-reported health that included the following domains: pain, fatigue, emotional distress, physical functioning, and social role participation; these domains were evaluated on paper or with computer-assisted technology.^11–14 PROMIS is now a web-based resource with approximately 70 domains pertinent to children and adults in the general population and in those with chronic disease. Measures have been translated into more than 40 languages, and PROMIS-related work has resulted in more than 400 publications.¹⁴

In 2006, the FDA issued a draft document regarding the PRO standards that should be included in clinical trials for consideration of drug and device applications (TABLE 1). These recommendations, updated in 2009, were largely drawn from work published by PROMIS and University of Oxford investigators.^4,14,16

ICHOM specified 2 goals: 1) the core sets should be used in routine clinical practice, and 2) the core sets should be used as end points in clinical studies.¹⁵

As of May 2015, 12 standard sets of outcomes have been developed, representing 35% of the global burden of disease. ICHOM currently is creating networks of hospitals around the world to begin measuring, benchmarking, and performing outcome comparisons that can ultimately be used to inform global health system learning and clinical care improvement.¹⁵

Read about the evolving use of PROs

Use of PROs is evolving

Historically, PROMs have been used primarily in clinical trials to document the relative benefits of an intervention. With today’s focus on patient-centered care, however, there is a growing mandate to integrate PROMs into clinical care, quality improvement, and ultimately reimbursement. Recently, Basch and colleagues eloquently described the benefit of routine collection of PROs for cancer patients and the opportunity for improved care across the health system.²⁰

PROs can be applied on various levels. For example, if a patient reports a symptom (X), or a change in symptom X, the following options are possible:

• Clinician level: Symptom management with altered dose or change in medication. This is associated with improved self-efficacy for the patient, a shift toward goal-oriented care, improved communication with the provider, and improved patient satisfaction.
• Researcher level: PROs should be used as a primary end point, in addition to traditional outcomes (mortality, survival, physiologic markers), to allow for comparative effectiveness studies or patient-centered outcomes research studies that evaluate what matters most to patients relative to the specific health condition, intervention, and symptom management.
• Health system level: Quality assurance, quality improvement activities. How effective is the health system in the management of symptom X? Are all clinicians using the same medication or the same dose? Is there a best practice for managing symptom X?
• Population level: Provides evidence for other clinicians and patients to make decisions about what to expect with treatment for symptom X.

From a reimbursement level, clinicians and providers are paid based on performance—the more satisfied patients are about X, the higher the reimbursement. This has been pertinent particularly in high-volume orthopedic conditions in which anatomic correction of hip or knee joints has not consistently demonstrated improvement in quality of life as measured by the following PROs: perception of pain, mobility, physical functioning, social functioning, and emotional distress. Because of concerns about high volume, high cost, and inconsistent outcomes, the US Department of Health and Human Services has specified that 50% of Medicare and 90% of Medicaid reimbursements will be based on outcomes or value-based purchasing options.²¹

Studies have shown that it is possible to collect PRO data for cancer patients—despite age or severity of illness—and integrate it into clinical care delivery. These data can provide useful, actionable information, resulting in decreased emergency department visits, longer toleration of chemotherapy, and improved survival.²² Similar results have been demonstrated in other medical conditions, although challenges exist when transitioning from research settings to routine care. Challenges include privacy concerns, patient recruitment and tracking, encouraging patients to complete the PRO surveys (nonresponse leads to biased data), real and perceived administrative burden to staff, obtaining clinician buy in, and costs related to surveys and data analysis.²³

Read about the benefits of PROs to patients and clients

Using PROs in women’s health care: Benefits for patients and clinicians

According to a study by Frosch, patients want to know if a prescribed therapy actually improves outcomes, not whether it changes an isolated biomarker that does not translate into subjective improvement.²⁴ They want to know if the trade-off (adverse effects or higher cost) associated with a new drug or therapy is worth the improved mobility or time spent pain free.

Intuitively, all clinicians have similar opportunities for discussions with regard to the risks, benefits, and alternatives of medical treatment, surgical treatment, or expectant management. We routinely document this discussion daily. However, in this era of patient-centered care, when a patient asks, “What should I do, doctor?” we no longer can respond with a default recommendation. We must engage the patient and ask, “What do you want to do? What is most important to you?”

ObGyns are well suited to benefit from standardized efforts to collect PROs, as we frequently discuss with our patients trade-offs regarding treatment risks and benefits and their personal values and preferences. Examples include contraception options, hormone treatment for menopause, medication use during pregnancy, decisions at the limits of viability, preterm delivery for severe preeclampsia, induction/augmentation versus spontaneous labor, epidural versus physiologic labor, repeat cesarean versus vaginal birth after cesarean, and even elective primary cesarean versus vaginal birth.

Validated PROMs exist for benign gynecology, such as abnormal uterine bleeding, fibroids, polycystic ovary syndrome (PCOS), infertility, pelvic organ prolapse and/or urinary incontinence, and surgery for benign gynecology symptoms, as well as for cancer (breast, ovarian, cervical).^25–39

From the PCOS literature we can glean a poignant example of the importance of PROs. Martin and colleagues compared patient and clinician interviews regarding important PROs from the patient perspective.²⁹ Patients identified pain, cramping, heavy bleeding, and bloating as important, whereas clinicians did not consider these symptoms important to patients with PCOS. Clinicians thought “issues with menstruation,” characterized as irregular or no periods, were important, whereas patients were more concerned with heavy bleeding or bleeding of long duration. The authors concluded that concepts frequently expressed by patients and considered important from their perspective did not register with clinicians as being relevant and are not captured on current PRO instruments, emphasizing our knowledge gap and the need to pay attention to what patients want.²⁹

Surprisingly, although pregnancy and childbirth is the number one cause for hospital admissions, a highly preference-driven condition, and a leading cause of morbidity, mortality, and costs, there are few published PROs in the field. In a systematic review of more than 1,700 articles describing PROs published in English through 2014, Martin found that fewer than 1% included PROs specific to pregnancy and childbirth.⁴⁰

ICHOM has created a standard set of outcomes for pregnancy and childbirth based on consensus recommendations from physicians, measurement experts, and patients.⁴¹ The consortium describes 4 domains and 14 subdomains (TABLE 2) and provides suggestions for a validated PROM if known or where appropriate.

Similar domains and subdomains have been corroborated by our research team (the Maternal Quality Indicator [MQI] Work Group), the Childbirth Connection, and Gartner and colleagues.^42–44 The MQI Work Group recently conducted a national survey of what women want and what they think is important for their childbirth experience. We identified 19 domains, consistent with those of other investigators.⁴² Gartner and colleagues advocate for a composite outcome measure that combines the core domains into one preference-based utility measure that is weighted.⁴⁴ The rationale for this recommendation is that the levels of the domains might contribute differently to the overall birth experience. For example, communication might contribute more to an overall measure than pain management.⁴⁴ The development of a childbirth-specific survey to evaluate patient-reported outcomes and patient-reported experiences with care is needed if we are to provide value-based care in this arena.⁴⁵

Looking forward

PROs, PROMs, and PREMs are here to stay. They no longer are limited to clinical research, but increasingly will be incorporated into clinical care, providing us with opportunities to improve the quality of health care delivery, efficiency of patient/clinician interactions, and patients’ ratings of their health care experience.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In its landmark publication, “Crossing the quality chasm: A new health system for the 21st century,” the Institute of Medicine (now the National Academy of Medicine) called for an emphasis on patient-centered care that it defined as “Providing care that is respectful of and responsive to individual patient preferences, needs, and values and ensuring that patient values guide all clinical decisions.”¹ Studies suggest that the patient’s view of health care delivery determines outcome and satisfaction.² Therefore, we need to expend more effort to understand what patients need or want from their treatment or interaction with the health care system.

Measuring patient-reported outcomes (PROs) is an attempt to recognize and address patient concerns. Although currently PROs are focused primarily in the arena of clinical research, their use has the potential to transform daily clinical patient encounters and improve the cost and quality of health care.³

In this article, we provide a brief overview of PROs and describe how they can be used to improve individual patient care, clinical research, and health care quality. We also offer examples of how PROs can be used in specific women’s health conditions.

Illustration: Paul Zwolak for OBG Management

What exactly are PROs?

PROs are reports of the status of a patient’s health condition, health behavior, or experience with health care; they come directly from the patient, without anyone else (such as a clinician or caregiver) interpreting the patient’s response.⁴ PROs usually pertain to general health, quality of life, functional status, or preferences associated with health care or treatment.⁵ Usually PROs are elicited via a self-administered survey and provide the patient’s perspective on treatment benefits, side effects, change in symptoms, general perceptions of feelings or well-being, or satisfaction with care. Often they represent the outcomes that are most important to patients.⁶ The survey usually consists of several questions or items. It can be general or condition specific, and it may represent one or more health care dimensions.

The term patient-reported outcome measure (PROM) refers to the survey instrument used to collect PROs. Patient-reported experience measures (PREMs), such as satisfaction surveys, are considered a subset of PROMs.⁷

Standardized PROs developed out of clinical trials

The use of PROs evolved from clinical trials. The proliferation of PROs resulted in an inability to compare outcomes across trials or different conditions. This led to a need to standardize and possibly harmonize measures and to reach consensus about properties required for a “good” measure and requirements needed for “adequate” reporting. Many investigators and several national and international organizations have provided iterative guidance, including the US Food and Drug Administration (FDA), European Medicines Agency, National Institutes of Health (NIH) Patient-Reported Outcomes Measurement Information System (PROMIS), International Consortium for Health Outcomes Measurement (ICHOM), University of Oxford Patient Reported Outcomes Measurement Group, Cochrane Systematic Reviews, Consolidated Standards of Reporting Trials–Patient Reported Outcomes (CONSORT-PRO) extension (how to report PROs with the CONSORT checklist), and the International Society for Pharmacoeconomics and Outcomes Research (ISPOR).^4,5,8–18

In the United States, the RAND Medical Outcomes Study led to the development of the 12- and 36-item short form surveys, which are widely recognized and commonly used PROMs for health-related quality of life.¹⁹ The study generated multiple additional survey instruments that evaluate other domains and dimensions of health. These surveys have been translated into numerous languages, and the RAND website lists over 100 publications.¹⁹

In 2002, the NIH sponsored PROMIS, a cooperative program designed to develop, validate, and standardize item banks to measure PROs that were relevant across multiple, common medical conditions. Based on literature review, feedback from both healthy and sick patients, and clinical expert opinion, the PROMIS investigators developed a consensus-based framework for self-reported health that included the following domains: pain, fatigue, emotional distress, physical functioning, and social role participation; these domains were evaluated on paper or with computer-assisted technology.^11–14 PROMIS is now a web-based resource with approximately 70 domains pertinent to children and adults in the general population and in those with chronic disease. Measures have been translated into more than 40 languages, and PROMIS-related work has resulted in more than 400 publications.¹⁴

In 2006, the FDA issued a draft document regarding the PRO standards that should be included in clinical trials for consideration of drug and device applications (TABLE 1). These recommendations, updated in 2009, were largely drawn from work published by PROMIS and University of Oxford investigators.^4,14,16

ICHOM specified 2 goals: 1) the core sets should be used in routine clinical practice, and 2) the core sets should be used as end points in clinical studies.¹⁵

As of May 2015, 12 standard sets of outcomes have been developed, representing 35% of the global burden of disease. ICHOM currently is creating networks of hospitals around the world to begin measuring, benchmarking, and performing outcome comparisons that can ultimately be used to inform global health system learning and clinical care improvement.¹⁵

Read about the evolving use of PROs

Use of PROs is evolving

Historically, PROMs have been used primarily in clinical trials to document the relative benefits of an intervention. With today’s focus on patient-centered care, however, there is a growing mandate to integrate PROMs into clinical care, quality improvement, and ultimately reimbursement. Recently, Basch and colleagues eloquently described the benefit of routine collection of PROs for cancer patients and the opportunity for improved care across the health system.²⁰

PROs can be applied on various levels. For example, if a patient reports a symptom (X), or a change in symptom X, the following options are possible:

• Clinician level: Symptom management with altered dose or change in medication. This is associated with improved self-efficacy for the patient, a shift toward goal-oriented care, improved communication with the provider, and improved patient satisfaction.
• Researcher level: PROs should be used as a primary end point, in addition to traditional outcomes (mortality, survival, physiologic markers), to allow for comparative effectiveness studies or patient-centered outcomes research studies that evaluate what matters most to patients relative to the specific health condition, intervention, and symptom management.
• Health system level: Quality assurance, quality improvement activities. How effective is the health system in the management of symptom X? Are all clinicians using the same medication or the same dose? Is there a best practice for managing symptom X?
• Population level: Provides evidence for other clinicians and patients to make decisions about what to expect with treatment for symptom X.

From a reimbursement level, clinicians and providers are paid based on performance—the more satisfied patients are about X, the higher the reimbursement. This has been pertinent particularly in high-volume orthopedic conditions in which anatomic correction of hip or knee joints has not consistently demonstrated improvement in quality of life as measured by the following PROs: perception of pain, mobility, physical functioning, social functioning, and emotional distress. Because of concerns about high volume, high cost, and inconsistent outcomes, the US Department of Health and Human Services has specified that 50% of Medicare and 90% of Medicaid reimbursements will be based on outcomes or value-based purchasing options.²¹

Studies have shown that it is possible to collect PRO data for cancer patients—despite age or severity of illness—and integrate it into clinical care delivery. These data can provide useful, actionable information, resulting in decreased emergency department visits, longer toleration of chemotherapy, and improved survival.²² Similar results have been demonstrated in other medical conditions, although challenges exist when transitioning from research settings to routine care. Challenges include privacy concerns, patient recruitment and tracking, encouraging patients to complete the PRO surveys (nonresponse leads to biased data), real and perceived administrative burden to staff, obtaining clinician buy in, and costs related to surveys and data analysis.²³

Read about the benefits of PROs to patients and clients

Using PROs in women’s health care: Benefits for patients and clinicians

According to a study by Frosch, patients want to know if a prescribed therapy actually improves outcomes, not whether it changes an isolated biomarker that does not translate into subjective improvement.²⁴ They want to know if the trade-off (adverse effects or higher cost) associated with a new drug or therapy is worth the improved mobility or time spent pain free.

Intuitively, all clinicians have similar opportunities for discussions with regard to the risks, benefits, and alternatives of medical treatment, surgical treatment, or expectant management. We routinely document this discussion daily. However, in this era of patient-centered care, when a patient asks, “What should I do, doctor?” we no longer can respond with a default recommendation. We must engage the patient and ask, “What do you want to do? What is most important to you?”

ObGyns are well suited to benefit from standardized efforts to collect PROs, as we frequently discuss with our patients trade-offs regarding treatment risks and benefits and their personal values and preferences. Examples include contraception options, hormone treatment for menopause, medication use during pregnancy, decisions at the limits of viability, preterm delivery for severe preeclampsia, induction/augmentation versus spontaneous labor, epidural versus physiologic labor, repeat cesarean versus vaginal birth after cesarean, and even elective primary cesarean versus vaginal birth.

Validated PROMs exist for benign gynecology, such as abnormal uterine bleeding, fibroids, polycystic ovary syndrome (PCOS), infertility, pelvic organ prolapse and/or urinary incontinence, and surgery for benign gynecology symptoms, as well as for cancer (breast, ovarian, cervical).^25–39

From the PCOS literature we can glean a poignant example of the importance of PROs. Martin and colleagues compared patient and clinician interviews regarding important PROs from the patient perspective.²⁹ Patients identified pain, cramping, heavy bleeding, and bloating as important, whereas clinicians did not consider these symptoms important to patients with PCOS. Clinicians thought “issues with menstruation,” characterized as irregular or no periods, were important, whereas patients were more concerned with heavy bleeding or bleeding of long duration. The authors concluded that concepts frequently expressed by patients and considered important from their perspective did not register with clinicians as being relevant and are not captured on current PRO instruments, emphasizing our knowledge gap and the need to pay attention to what patients want.²⁹

Surprisingly, although pregnancy and childbirth is the number one cause for hospital admissions, a highly preference-driven condition, and a leading cause of morbidity, mortality, and costs, there are few published PROs in the field. In a systematic review of more than 1,700 articles describing PROs published in English through 2014, Martin found that fewer than 1% included PROs specific to pregnancy and childbirth.⁴⁰

ICHOM has created a standard set of outcomes for pregnancy and childbirth based on consensus recommendations from physicians, measurement experts, and patients.⁴¹ The consortium describes 4 domains and 14 subdomains (TABLE 2) and provides suggestions for a validated PROM if known or where appropriate.

Similar domains and subdomains have been corroborated by our research team (the Maternal Quality Indicator [MQI] Work Group), the Childbirth Connection, and Gartner and colleagues.^42–44 The MQI Work Group recently conducted a national survey of what women want and what they think is important for their childbirth experience. We identified 19 domains, consistent with those of other investigators.⁴² Gartner and colleagues advocate for a composite outcome measure that combines the core domains into one preference-based utility measure that is weighted.⁴⁴ The rationale for this recommendation is that the levels of the domains might contribute differently to the overall birth experience. For example, communication might contribute more to an overall measure than pain management.⁴⁴ The development of a childbirth-specific survey to evaluate patient-reported outcomes and patient-reported experiences with care is needed if we are to provide value-based care in this arena.⁴⁵

Looking forward

PROs, PROMs, and PREMs are here to stay. They no longer are limited to clinical research, but increasingly will be incorporated into clinical care, providing us with opportunities to improve the quality of health care delivery, efficiency of patient/clinician interactions, and patients’ ratings of their health care experience.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In its landmark publication, “Crossing the quality chasm: A new health system for the 21st century,” the Institute of Medicine (now the National Academy of Medicine) called for an emphasis on patient-centered care that it defined as “Providing care that is respectful of and responsive to individual patient preferences, needs, and values and ensuring that patient values guide all clinical decisions.”¹ Studies suggest that the patient’s view of health care delivery determines outcome and satisfaction.² Therefore, we need to expend more effort to understand what patients need or want from their treatment or interaction with the health care system.

Measuring patient-reported outcomes (PROs) is an attempt to recognize and address patient concerns. Although currently PROs are focused primarily in the arena of clinical research, their use has the potential to transform daily clinical patient encounters and improve the cost and quality of health care.³

In this article, we provide a brief overview of PROs and describe how they can be used to improve individual patient care, clinical research, and health care quality. We also offer examples of how PROs can be used in specific women’s health conditions.

Illustration: Paul Zwolak for OBG Management

What exactly are PROs?

PROs are reports of the status of a patient’s health condition, health behavior, or experience with health care; they come directly from the patient, without anyone else (such as a clinician or caregiver) interpreting the patient’s response.⁴ PROs usually pertain to general health, quality of life, functional status, or preferences associated with health care or treatment.⁵ Usually PROs are elicited via a self-administered survey and provide the patient’s perspective on treatment benefits, side effects, change in symptoms, general perceptions of feelings or well-being, or satisfaction with care. Often they represent the outcomes that are most important to patients.⁶ The survey usually consists of several questions or items. It can be general or condition specific, and it may represent one or more health care dimensions.

The term patient-reported outcome measure (PROM) refers to the survey instrument used to collect PROs. Patient-reported experience measures (PREMs), such as satisfaction surveys, are considered a subset of PROMs.⁷

Standardized PROs developed out of clinical trials

The use of PROs evolved from clinical trials. The proliferation of PROs resulted in an inability to compare outcomes across trials or different conditions. This led to a need to standardize and possibly harmonize measures and to reach consensus about properties required for a “good” measure and requirements needed for “adequate” reporting. Many investigators and several national and international organizations have provided iterative guidance, including the US Food and Drug Administration (FDA), European Medicines Agency, National Institutes of Health (NIH) Patient-Reported Outcomes Measurement Information System (PROMIS), International Consortium for Health Outcomes Measurement (ICHOM), University of Oxford Patient Reported Outcomes Measurement Group, Cochrane Systematic Reviews, Consolidated Standards of Reporting Trials–Patient Reported Outcomes (CONSORT-PRO) extension (how to report PROs with the CONSORT checklist), and the International Society for Pharmacoeconomics and Outcomes Research (ISPOR).^4,5,8–18

In the United States, the RAND Medical Outcomes Study led to the development of the 12- and 36-item short form surveys, which are widely recognized and commonly used PROMs for health-related quality of life.¹⁹ The study generated multiple additional survey instruments that evaluate other domains and dimensions of health. These surveys have been translated into numerous languages, and the RAND website lists over 100 publications.¹⁹

In 2002, the NIH sponsored PROMIS, a cooperative program designed to develop, validate, and standardize item banks to measure PROs that were relevant across multiple, common medical conditions. Based on literature review, feedback from both healthy and sick patients, and clinical expert opinion, the PROMIS investigators developed a consensus-based framework for self-reported health that included the following domains: pain, fatigue, emotional distress, physical functioning, and social role participation; these domains were evaluated on paper or with computer-assisted technology.^11–14 PROMIS is now a web-based resource with approximately 70 domains pertinent to children and adults in the general population and in those with chronic disease. Measures have been translated into more than 40 languages, and PROMIS-related work has resulted in more than 400 publications.¹⁴

In 2006, the FDA issued a draft document regarding the PRO standards that should be included in clinical trials for consideration of drug and device applications (TABLE 1). These recommendations, updated in 2009, were largely drawn from work published by PROMIS and University of Oxford investigators.^4,14,16

ICHOM specified 2 goals: 1) the core sets should be used in routine clinical practice, and 2) the core sets should be used as end points in clinical studies.¹⁵

As of May 2015, 12 standard sets of outcomes have been developed, representing 35% of the global burden of disease. ICHOM currently is creating networks of hospitals around the world to begin measuring, benchmarking, and performing outcome comparisons that can ultimately be used to inform global health system learning and clinical care improvement.¹⁵

Read about the evolving use of PROs

Use of PROs is evolving

Historically, PROMs have been used primarily in clinical trials to document the relative benefits of an intervention. With today’s focus on patient-centered care, however, there is a growing mandate to integrate PROMs into clinical care, quality improvement, and ultimately reimbursement. Recently, Basch and colleagues eloquently described the benefit of routine collection of PROs for cancer patients and the opportunity for improved care across the health system.²⁰

PROs can be applied on various levels. For example, if a patient reports a symptom (X), or a change in symptom X, the following options are possible:

• Clinician level: Symptom management with altered dose or change in medication. This is associated with improved self-efficacy for the patient, a shift toward goal-oriented care, improved communication with the provider, and improved patient satisfaction.
• Researcher level: PROs should be used as a primary end point, in addition to traditional outcomes (mortality, survival, physiologic markers), to allow for comparative effectiveness studies or patient-centered outcomes research studies that evaluate what matters most to patients relative to the specific health condition, intervention, and symptom management.
• Health system level: Quality assurance, quality improvement activities. How effective is the health system in the management of symptom X? Are all clinicians using the same medication or the same dose? Is there a best practice for managing symptom X?
• Population level: Provides evidence for other clinicians and patients to make decisions about what to expect with treatment for symptom X.

From a reimbursement level, clinicians and providers are paid based on performance—the more satisfied patients are about X, the higher the reimbursement. This has been pertinent particularly in high-volume orthopedic conditions in which anatomic correction of hip or knee joints has not consistently demonstrated improvement in quality of life as measured by the following PROs: perception of pain, mobility, physical functioning, social functioning, and emotional distress. Because of concerns about high volume, high cost, and inconsistent outcomes, the US Department of Health and Human Services has specified that 50% of Medicare and 90% of Medicaid reimbursements will be based on outcomes or value-based purchasing options.²¹

Studies have shown that it is possible to collect PRO data for cancer patients—despite age or severity of illness—and integrate it into clinical care delivery. These data can provide useful, actionable information, resulting in decreased emergency department visits, longer toleration of chemotherapy, and improved survival.²² Similar results have been demonstrated in other medical conditions, although challenges exist when transitioning from research settings to routine care. Challenges include privacy concerns, patient recruitment and tracking, encouraging patients to complete the PRO surveys (nonresponse leads to biased data), real and perceived administrative burden to staff, obtaining clinician buy in, and costs related to surveys and data analysis.²³

Read about the benefits of PROs to patients and clients

Using PROs in women’s health care: Benefits for patients and clinicians

According to a study by Frosch, patients want to know if a prescribed therapy actually improves outcomes, not whether it changes an isolated biomarker that does not translate into subjective improvement.²⁴ They want to know if the trade-off (adverse effects or higher cost) associated with a new drug or therapy is worth the improved mobility or time spent pain free.

Intuitively, all clinicians have similar opportunities for discussions with regard to the risks, benefits, and alternatives of medical treatment, surgical treatment, or expectant management. We routinely document this discussion daily. However, in this era of patient-centered care, when a patient asks, “What should I do, doctor?” we no longer can respond with a default recommendation. We must engage the patient and ask, “What do you want to do? What is most important to you?”

ObGyns are well suited to benefit from standardized efforts to collect PROs, as we frequently discuss with our patients trade-offs regarding treatment risks and benefits and their personal values and preferences. Examples include contraception options, hormone treatment for menopause, medication use during pregnancy, decisions at the limits of viability, preterm delivery for severe preeclampsia, induction/augmentation versus spontaneous labor, epidural versus physiologic labor, repeat cesarean versus vaginal birth after cesarean, and even elective primary cesarean versus vaginal birth.

Validated PROMs exist for benign gynecology, such as abnormal uterine bleeding, fibroids, polycystic ovary syndrome (PCOS), infertility, pelvic organ prolapse and/or urinary incontinence, and surgery for benign gynecology symptoms, as well as for cancer (breast, ovarian, cervical).^25–39

From the PCOS literature we can glean a poignant example of the importance of PROs. Martin and colleagues compared patient and clinician interviews regarding important PROs from the patient perspective.²⁹ Patients identified pain, cramping, heavy bleeding, and bloating as important, whereas clinicians did not consider these symptoms important to patients with PCOS. Clinicians thought “issues with menstruation,” characterized as irregular or no periods, were important, whereas patients were more concerned with heavy bleeding or bleeding of long duration. The authors concluded that concepts frequently expressed by patients and considered important from their perspective did not register with clinicians as being relevant and are not captured on current PRO instruments, emphasizing our knowledge gap and the need to pay attention to what patients want.²⁹

Surprisingly, although pregnancy and childbirth is the number one cause for hospital admissions, a highly preference-driven condition, and a leading cause of morbidity, mortality, and costs, there are few published PROs in the field. In a systematic review of more than 1,700 articles describing PROs published in English through 2014, Martin found that fewer than 1% included PROs specific to pregnancy and childbirth.⁴⁰

ICHOM has created a standard set of outcomes for pregnancy and childbirth based on consensus recommendations from physicians, measurement experts, and patients.⁴¹ The consortium describes 4 domains and 14 subdomains (TABLE 2) and provides suggestions for a validated PROM if known or where appropriate.

Similar domains and subdomains have been corroborated by our research team (the Maternal Quality Indicator [MQI] Work Group), the Childbirth Connection, and Gartner and colleagues.^42–44 The MQI Work Group recently conducted a national survey of what women want and what they think is important for their childbirth experience. We identified 19 domains, consistent with those of other investigators.⁴² Gartner and colleagues advocate for a composite outcome measure that combines the core domains into one preference-based utility measure that is weighted.⁴⁴ The rationale for this recommendation is that the levels of the domains might contribute differently to the overall birth experience. For example, communication might contribute more to an overall measure than pain management.⁴⁴ The development of a childbirth-specific survey to evaluate patient-reported outcomes and patient-reported experiences with care is needed if we are to provide value-based care in this arena.⁴⁵

Looking forward

PROs, PROMs, and PREMs are here to stay. They no longer are limited to clinical research, but increasingly will be incorporated into clinical care, providing us with opportunities to improve the quality of health care delivery, efficiency of patient/clinician interactions, and patients’ ratings of their health care experience.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

SAN DIEGO – Baseline Expanded Disability Status Scale scores and number of relapses during the first year were the most consistent predictors of disability worsening or relapses over the subsequent 3 years in long-term analysis of three phase 3 fingolimod trials.

Those patients identified at higher risk for worse long-term clinical outcomes could benefit from an early review of multiple sclerosis (MS) treatment regimens to help prevent worsening disability, Pavle Repovic, MD, PhD, said in an interview.

Damian McNamara/Frontline Medical News

“The idea for some time now has been to figure out what will tell whether a patient is responding to a therapy early on or not,” Dr. Repovic said at ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

To explore long-term clinical predictors of disability progression and relapse risk, Dr. Repovic and his colleagues analyzed three phase 3 trials assessing fingolimod (Gilenya). They evaluated parameters at baseline and during the first year of the FREEDOMS, FREEDOMS II, and TRANSFORMS studies.

SOURCE: Repovic P et al. Abstract P210.

SAN DIEGO – Baseline Expanded Disability Status Scale scores and number of relapses during the first year were the most consistent predictors of disability worsening or relapses over the subsequent 3 years in long-term analysis of three phase 3 fingolimod trials.

Those patients identified at higher risk for worse long-term clinical outcomes could benefit from an early review of multiple sclerosis (MS) treatment regimens to help prevent worsening disability, Pavle Repovic, MD, PhD, said in an interview.

Damian McNamara/Frontline Medical News

“The idea for some time now has been to figure out what will tell whether a patient is responding to a therapy early on or not,” Dr. Repovic said at ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

To explore long-term clinical predictors of disability progression and relapse risk, Dr. Repovic and his colleagues analyzed three phase 3 trials assessing fingolimod (Gilenya). They evaluated parameters at baseline and during the first year of the FREEDOMS, FREEDOMS II, and TRANSFORMS studies.

SOURCE: Repovic P et al. Abstract P210.

SAN DIEGO – Baseline Expanded Disability Status Scale scores and number of relapses during the first year were the most consistent predictors of disability worsening or relapses over the subsequent 3 years in long-term analysis of three phase 3 fingolimod trials.

Those patients identified at higher risk for worse long-term clinical outcomes could benefit from an early review of multiple sclerosis (MS) treatment regimens to help prevent worsening disability, Pavle Repovic, MD, PhD, said in an interview.

Damian McNamara/Frontline Medical News

“The idea for some time now has been to figure out what will tell whether a patient is responding to a therapy early on or not,” Dr. Repovic said at ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

To explore long-term clinical predictors of disability progression and relapse risk, Dr. Repovic and his colleagues analyzed three phase 3 trials assessing fingolimod (Gilenya). They evaluated parameters at baseline and during the first year of the FREEDOMS, FREEDOMS II, and TRANSFORMS studies.

SOURCE: Repovic P et al. Abstract P210.

EXPERT COMMENTARY

Lower urinary tract infection (UTI) is one of the most common medical complications of pregnancy. Approximately 5% to 10% of all pregnant women have asymptomatic bacteriuria, which usually antedates the pregnancy and is detected at the time of the first prenatal appointment. Another 2% to 3% develop acute cystitis during pregnancy. The dominant organisms that cause lower UTIs in pregnant women are Escherichia coli, Klebsiella pneumoniae, Proteus species, group B streptococci, enterococci, and Staphylococcus saprophyticus.

One goal of treating asymptomatic bacteriuria and acute cystitis is to prevent ascending infection (pyelonephritis), which can be associated with preterm delivery, sepsis, and adult respiratory distress syndrome. Another key goal is to use an antibiotic that eradicates the uropathogen without causing harm to either the mother or fetus.

In 2009, Crider and colleagues reported that 2 of the most commonly used antibiotics for UTIs, sulfonamides and nitrofurantoin, were associated with a disturbing spectrum of birth defects.¹ Following that report, in 2011 the American College of Obstetricians and Gynecologists (ACOG) published a committee opinion that recommended against the use of these 2 agents in the first trimester of pregnancy unless other antibiotics were unlikely to be effective.²

Details of the study

Centers for Disease Control and Prevention investigators recently conducted a study to assess the effect of these ACOG recommendations on clinical practice. Ailes and co-workers used the Truven Health MarketScan Commercial Database to examine antibiotic prescriptions filled by pregnant women with UTIs.

The database included 482,917 pregnancies in 2014 eligible for analysis. A total of 7.2% (n = 34,864) of pregnant women were treated as outpatients for a UTI within the 90-day interval before the last menstrual period or during the pregnancy. Among these women, the most commonly prescribed antibiotics during the first trimester were nitrofurantoin (34.7%), ciprofloxacin (10.5%), cephalexin (10.3%), and trimethoprim-sulfamethoxazole (7.6%).

The authors concluded that 43% of women used an antibiotic (nitrofurantoin or trimethoprim-sulfamethoxazole) in the first trimester that had potential teratogenicity, despite the precautionary statement articulated in the ACOG committee opinion.²

Antibiotic-associated effects

Of all the antibiotics that could be used to treat a lower UTI in pregnancy, nitrofurantoin probably has the greatest appeal. The drug is highly concentrated in the urine and is very active against all the common uropathogens except Proteus species. It is not absorbed significantly outside the lower urinary tract, and thus it does not alter the natural flora of the bowel or vagina (such alteration would predispose the patient to antibiotic-associated diarrhea or vulvovaginal candidiasis). Nitrofurantoin is inexpensive and usually is very well tolerated.

In the National Birth Defects Prevention Study by Crider and colleagues, nitrofurantoin was associated with anophthalmia or microphthalmos (adjusted odds ratio [AOR], 3.7; 95% confidence interval [CI], 1.1–12.2), hypoplastic left heart syndrome (AOR, 4.2; 95% CI, 1.9–9.1), atrial septal defects (AOR, 1.9; 95% CI, 1.1–3.4), and cleft lip with cleft palate (AOR, 2.1; 95% CI, 1.2–3.9).¹ Other investigations, including one published as recently as 2013, have not documented these same associations.³

Similarly, the combination of trimethoprim-sulfamethoxazole also has considerable appeal for treating lower UTIs in pregnancy because it is highly active against most uropathogens, is inexpensive, and usually is very well tolerated. The report by Crider and colleagues, however, was even more worrisome with respect to the possible teratogenicity of this antibiotic.¹ The authors found that use of this antibiotic in the first trimester was associated with anencephaly (AOR, 3.4; 95% CI, 1.3–8.8), coarctation of the aorta (AOR, 2.7; 95% CI, 1.3–5.6), hypoplastic left heart (AOR, 3.2; 95% CI, 1.3–7.6), choanal atresia (AOR, 8.0; 95% CI, 2.7–23.5), transverse limb deficiency (AOR, 2.5; 95% CI, 1.0–5.9), and diaphragmatic hernia (AOR, 2.4; 95% CI, 1.1–5.4). Again, other authors, using different epidemiologic methods, have not found the same associations.³

Study strengths and weaknesses

The National Birth Defects Prevention Study by Crider and colleagues was a large, well-funded, and well-designed epidemiologic study. It included more than 13,000 patients from 10 different states.

Nevertheless, the study had certain limitations.⁴ The findings are subject to recall bias because the investigators questioned patients about antibiotic use after, rather than during, pregnancy. Understandably, the investigators were not able to verify the prescriptions for antibiotics by reviewing each individual medical record. In fact, one-third of study participants were unable to recall the exact name of the antibiotic they received. The authors did not precisely distinguish between single-agent sulfonamides and the combination drug, trimethoprim-sulfamethoxazole, although it seems reasonable to assume that the majority of the prescriptions were for the latter. Finally, given the observational nature of the study, the authors could not be certain that the observed associations were due to the antibiotic, the infection for which the drug was prescribed, or another confounding factor.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Lower urinary tract infection (UTI) is one of the most common medical complications of pregnancy. Approximately 5% to 10% of all pregnant women have asymptomatic bacteriuria, which usually antedates the pregnancy and is detected at the time of the first prenatal appointment. Another 2% to 3% develop acute cystitis during pregnancy. The dominant organisms that cause lower UTIs in pregnant women are Escherichia coli, Klebsiella pneumoniae, Proteus species, group B streptococci, enterococci, and Staphylococcus saprophyticus.

One goal of treating asymptomatic bacteriuria and acute cystitis is to prevent ascending infection (pyelonephritis), which can be associated with preterm delivery, sepsis, and adult respiratory distress syndrome. Another key goal is to use an antibiotic that eradicates the uropathogen without causing harm to either the mother or fetus.

In 2009, Crider and colleagues reported that 2 of the most commonly used antibiotics for UTIs, sulfonamides and nitrofurantoin, were associated with a disturbing spectrum of birth defects.¹ Following that report, in 2011 the American College of Obstetricians and Gynecologists (ACOG) published a committee opinion that recommended against the use of these 2 agents in the first trimester of pregnancy unless other antibiotics were unlikely to be effective.²

Details of the study

Centers for Disease Control and Prevention investigators recently conducted a study to assess the effect of these ACOG recommendations on clinical practice. Ailes and co-workers used the Truven Health MarketScan Commercial Database to examine antibiotic prescriptions filled by pregnant women with UTIs.

The database included 482,917 pregnancies in 2014 eligible for analysis. A total of 7.2% (n = 34,864) of pregnant women were treated as outpatients for a UTI within the 90-day interval before the last menstrual period or during the pregnancy. Among these women, the most commonly prescribed antibiotics during the first trimester were nitrofurantoin (34.7%), ciprofloxacin (10.5%), cephalexin (10.3%), and trimethoprim-sulfamethoxazole (7.6%).

The authors concluded that 43% of women used an antibiotic (nitrofurantoin or trimethoprim-sulfamethoxazole) in the first trimester that had potential teratogenicity, despite the precautionary statement articulated in the ACOG committee opinion.²

Antibiotic-associated effects

Of all the antibiotics that could be used to treat a lower UTI in pregnancy, nitrofurantoin probably has the greatest appeal. The drug is highly concentrated in the urine and is very active against all the common uropathogens except Proteus species. It is not absorbed significantly outside the lower urinary tract, and thus it does not alter the natural flora of the bowel or vagina (such alteration would predispose the patient to antibiotic-associated diarrhea or vulvovaginal candidiasis). Nitrofurantoin is inexpensive and usually is very well tolerated.

In the National Birth Defects Prevention Study by Crider and colleagues, nitrofurantoin was associated with anophthalmia or microphthalmos (adjusted odds ratio [AOR], 3.7; 95% confidence interval [CI], 1.1–12.2), hypoplastic left heart syndrome (AOR, 4.2; 95% CI, 1.9–9.1), atrial septal defects (AOR, 1.9; 95% CI, 1.1–3.4), and cleft lip with cleft palate (AOR, 2.1; 95% CI, 1.2–3.9).¹ Other investigations, including one published as recently as 2013, have not documented these same associations.³

Similarly, the combination of trimethoprim-sulfamethoxazole also has considerable appeal for treating lower UTIs in pregnancy because it is highly active against most uropathogens, is inexpensive, and usually is very well tolerated. The report by Crider and colleagues, however, was even more worrisome with respect to the possible teratogenicity of this antibiotic.¹ The authors found that use of this antibiotic in the first trimester was associated with anencephaly (AOR, 3.4; 95% CI, 1.3–8.8), coarctation of the aorta (AOR, 2.7; 95% CI, 1.3–5.6), hypoplastic left heart (AOR, 3.2; 95% CI, 1.3–7.6), choanal atresia (AOR, 8.0; 95% CI, 2.7–23.5), transverse limb deficiency (AOR, 2.5; 95% CI, 1.0–5.9), and diaphragmatic hernia (AOR, 2.4; 95% CI, 1.1–5.4). Again, other authors, using different epidemiologic methods, have not found the same associations.³

Study strengths and weaknesses

The National Birth Defects Prevention Study by Crider and colleagues was a large, well-funded, and well-designed epidemiologic study. It included more than 13,000 patients from 10 different states.

Nevertheless, the study had certain limitations.⁴ The findings are subject to recall bias because the investigators questioned patients about antibiotic use after, rather than during, pregnancy. Understandably, the investigators were not able to verify the prescriptions for antibiotics by reviewing each individual medical record. In fact, one-third of study participants were unable to recall the exact name of the antibiotic they received. The authors did not precisely distinguish between single-agent sulfonamides and the combination drug, trimethoprim-sulfamethoxazole, although it seems reasonable to assume that the majority of the prescriptions were for the latter. Finally, given the observational nature of the study, the authors could not be certain that the observed associations were due to the antibiotic, the infection for which the drug was prescribed, or another confounding factor.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Lower urinary tract infection (UTI) is one of the most common medical complications of pregnancy. Approximately 5% to 10% of all pregnant women have asymptomatic bacteriuria, which usually antedates the pregnancy and is detected at the time of the first prenatal appointment. Another 2% to 3% develop acute cystitis during pregnancy. The dominant organisms that cause lower UTIs in pregnant women are Escherichia coli, Klebsiella pneumoniae, Proteus species, group B streptococci, enterococci, and Staphylococcus saprophyticus.

One goal of treating asymptomatic bacteriuria and acute cystitis is to prevent ascending infection (pyelonephritis), which can be associated with preterm delivery, sepsis, and adult respiratory distress syndrome. Another key goal is to use an antibiotic that eradicates the uropathogen without causing harm to either the mother or fetus.

In 2009, Crider and colleagues reported that 2 of the most commonly used antibiotics for UTIs, sulfonamides and nitrofurantoin, were associated with a disturbing spectrum of birth defects.¹ Following that report, in 2011 the American College of Obstetricians and Gynecologists (ACOG) published a committee opinion that recommended against the use of these 2 agents in the first trimester of pregnancy unless other antibiotics were unlikely to be effective.²

Details of the study

Centers for Disease Control and Prevention investigators recently conducted a study to assess the effect of these ACOG recommendations on clinical practice. Ailes and co-workers used the Truven Health MarketScan Commercial Database to examine antibiotic prescriptions filled by pregnant women with UTIs.

The database included 482,917 pregnancies in 2014 eligible for analysis. A total of 7.2% (n = 34,864) of pregnant women were treated as outpatients for a UTI within the 90-day interval before the last menstrual period or during the pregnancy. Among these women, the most commonly prescribed antibiotics during the first trimester were nitrofurantoin (34.7%), ciprofloxacin (10.5%), cephalexin (10.3%), and trimethoprim-sulfamethoxazole (7.6%).

The authors concluded that 43% of women used an antibiotic (nitrofurantoin or trimethoprim-sulfamethoxazole) in the first trimester that had potential teratogenicity, despite the precautionary statement articulated in the ACOG committee opinion.²

Antibiotic-associated effects

Of all the antibiotics that could be used to treat a lower UTI in pregnancy, nitrofurantoin probably has the greatest appeal. The drug is highly concentrated in the urine and is very active against all the common uropathogens except Proteus species. It is not absorbed significantly outside the lower urinary tract, and thus it does not alter the natural flora of the bowel or vagina (such alteration would predispose the patient to antibiotic-associated diarrhea or vulvovaginal candidiasis). Nitrofurantoin is inexpensive and usually is very well tolerated.

In the National Birth Defects Prevention Study by Crider and colleagues, nitrofurantoin was associated with anophthalmia or microphthalmos (adjusted odds ratio [AOR], 3.7; 95% confidence interval [CI], 1.1–12.2), hypoplastic left heart syndrome (AOR, 4.2; 95% CI, 1.9–9.1), atrial septal defects (AOR, 1.9; 95% CI, 1.1–3.4), and cleft lip with cleft palate (AOR, 2.1; 95% CI, 1.2–3.9).¹ Other investigations, including one published as recently as 2013, have not documented these same associations.³

Similarly, the combination of trimethoprim-sulfamethoxazole also has considerable appeal for treating lower UTIs in pregnancy because it is highly active against most uropathogens, is inexpensive, and usually is very well tolerated. The report by Crider and colleagues, however, was even more worrisome with respect to the possible teratogenicity of this antibiotic.¹ The authors found that use of this antibiotic in the first trimester was associated with anencephaly (AOR, 3.4; 95% CI, 1.3–8.8), coarctation of the aorta (AOR, 2.7; 95% CI, 1.3–5.6), hypoplastic left heart (AOR, 3.2; 95% CI, 1.3–7.6), choanal atresia (AOR, 8.0; 95% CI, 2.7–23.5), transverse limb deficiency (AOR, 2.5; 95% CI, 1.0–5.9), and diaphragmatic hernia (AOR, 2.4; 95% CI, 1.1–5.4). Again, other authors, using different epidemiologic methods, have not found the same associations.³

Study strengths and weaknesses

The National Birth Defects Prevention Study by Crider and colleagues was a large, well-funded, and well-designed epidemiologic study. It included more than 13,000 patients from 10 different states.

Nevertheless, the study had certain limitations.⁴ The findings are subject to recall bias because the investigators questioned patients about antibiotic use after, rather than during, pregnancy. Understandably, the investigators were not able to verify the prescriptions for antibiotics by reviewing each individual medical record. In fact, one-third of study participants were unable to recall the exact name of the antibiotic they received. The authors did not precisely distinguish between single-agent sulfonamides and the combination drug, trimethoprim-sulfamethoxazole, although it seems reasonable to assume that the majority of the prescriptions were for the latter. Finally, given the observational nature of the study, the authors could not be certain that the observed associations were due to the antibiotic, the infection for which the drug was prescribed, or another confounding factor.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

How real is triptans’ serotonin syndrome risk? Are free testosterone and frailty linked? Breast cancer mortality trends keep moving, and what pioglitazone may offer NASH patients.

Listen to the MDedge Daily News podcast for all the details on today’s top news.

How real is triptans’ serotonin syndrome risk? Are free testosterone and frailty linked? Breast cancer mortality trends keep moving, and what pioglitazone may offer NASH patients.

Listen to the MDedge Daily News podcast for all the details on today’s top news.

How real is triptans’ serotonin syndrome risk? Are free testosterone and frailty linked? Breast cancer mortality trends keep moving, and what pioglitazone may offer NASH patients.

Listen to the MDedge Daily News podcast for all the details on today’s top news.

Healthy foods may be available in grocery stores in rural American Indian communities, but the price can be high. Researchers from University of Washington looked at the availability and cost of 68 food items that comprise the Nutrition Environment Measures Survey in Stores (NEMS-S), which evaluates whether food items adhere to the USDA Thrifty Food Plan (TFP). The TFP “market basket” represents the minimal cost of a healthy diet for a family of 4 for 1 week. The study included 27 stores within a 90-mile radius of the town center of a large American Indian reservation: 13 convenience stores, 10 grocery stores, 3 discount/dollar stores, and 1 discount supermarket. Of the surveyed stores, 10 were on the reservation, including 4 grocery stores.

All NEMS-S foods were available at the discount supermarket, and about 97% of the foods were available at the grocery stores. Convenience and discount/dollar stores were less likely to carry the foods.

The cost of a TFP market basket ranged from 3% lower to 24% higher than the national average. It also varied among the community stores: The TFP cost  > 15% at the discount supermarket than at grocery stores ($152.91 vs $179.52). However, the researchers note that the cost of foods that made up the TFP market basket varied across food groups. For instance, the mean cost of dairy products was 43% lower at the discount supermarket than at the grocery stores, while fresh fruits and vegetables were 6% higher.

Healthy foods may be available in grocery stores in rural American Indian communities, but the price can be high. Researchers from University of Washington looked at the availability and cost of 68 food items that comprise the Nutrition Environment Measures Survey in Stores (NEMS-S), which evaluates whether food items adhere to the USDA Thrifty Food Plan (TFP). The TFP “market basket” represents the minimal cost of a healthy diet for a family of 4 for 1 week. The study included 27 stores within a 90-mile radius of the town center of a large American Indian reservation: 13 convenience stores, 10 grocery stores, 3 discount/dollar stores, and 1 discount supermarket. Of the surveyed stores, 10 were on the reservation, including 4 grocery stores.

All NEMS-S foods were available at the discount supermarket, and about 97% of the foods were available at the grocery stores. Convenience and discount/dollar stores were less likely to carry the foods.

The cost of a TFP market basket ranged from 3% lower to 24% higher than the national average. It also varied among the community stores: The TFP cost  > 15% at the discount supermarket than at grocery stores ($152.91 vs $179.52). However, the researchers note that the cost of foods that made up the TFP market basket varied across food groups. For instance, the mean cost of dairy products was 43% lower at the discount supermarket than at the grocery stores, while fresh fruits and vegetables were 6% higher.

Healthy foods may be available in grocery stores in rural American Indian communities, but the price can be high. Researchers from University of Washington looked at the availability and cost of 68 food items that comprise the Nutrition Environment Measures Survey in Stores (NEMS-S), which evaluates whether food items adhere to the USDA Thrifty Food Plan (TFP). The TFP “market basket” represents the minimal cost of a healthy diet for a family of 4 for 1 week. The study included 27 stores within a 90-mile radius of the town center of a large American Indian reservation: 13 convenience stores, 10 grocery stores, 3 discount/dollar stores, and 1 discount supermarket. Of the surveyed stores, 10 were on the reservation, including 4 grocery stores.

All NEMS-S foods were available at the discount supermarket, and about 97% of the foods were available at the grocery stores. Convenience and discount/dollar stores were less likely to carry the foods.

The cost of a TFP market basket ranged from 3% lower to 24% higher than the national average. It also varied among the community stores: The TFP cost  > 15% at the discount supermarket than at grocery stores ($152.91 vs $179.52). However, the researchers note that the cost of foods that made up the TFP market basket varied across food groups. For instance, the mean cost of dairy products was 43% lower at the discount supermarket than at the grocery stores, while fresh fruits and vegetables were 6% higher.

2018 BMT Tandem Meetings

SALT LAKE CITY—Researchers say they have identified prognostic biomarkers for chronic graft-vs-host disease (cGVHD) in children.

The group found that recent thymic emigrants (RTEs) and regulatory T cells expressing CD31 and CD45RA (Treg RTEs) were significantly lower at day 100 after transplant in patients who developed cGVHD.

Because prior research indicated that RTEs are higher in adults with cGVHD, the researchers concluded that thymic function may play a bigger role in cGVHD development for children than for adults.

Geoff D.E. Cuvelier, MD, of CancerCare Manitoba in Winnipeg, Canada, presented these findings at the 2018 BMT Tandem Meetings (abstract 104).

“Our group became interested in these populations of recent thymic emigrants when 2 adult studies^1,2 . . . showed that higher proportions of recent thymic emigrants at day 100 were prognostic for the development of chronic graft-vs-host disease,” Dr Cuvelier said.

This led his group to evaluate whether RTEs (CD4⁺CD45RA⁺CD31⁺ T cells), as well as Treg RTEs—Tregs (CD4⁺CD25⁺CD127^Low) that co-express naïve and recently emigrated markers (CD45RA⁺CD31⁺)—are prognostic for pediatric cGVHD at day 100 after allogeneic hematopoietic stem cell transplant (allo-HSCT).

The researchers’ study enrolled patients younger than 18 years of age who underwent allo-HSCT to treat malignant and non-malignant diseases. There were 144 patients who had 1 year of follow-up after allo-HSCT.

Thirty-seven of the patients (25.7%) had cGVHD, and 34 (23.6%) had late acute GVHD (post-day 100). The remaining 73 patients (50.7%) had neither cGVHD nor late acute GVHD, so they served as controls.

Twenty cases of cGVHD were severe, 12 were moderate, and 5 were mild. cGVHD was initially diagnosed at a mean of 192 days post-transplant. The median number of organ systems involved was 3 (range, 1-6). Seventeen patients (46%) had overlap syndrome.

The researchers found that RTEs as a percentage of CD4 T cells were significantly lower at day 100 in patients with cGVHD than in controls—7.8% and 13.5%, respectively (P=0.007). The difference between controls and patients with late acute GVHD was not significant—13.5% and 9.4%, respectively (P=0.08).

Treg RTEs as a percentage of all Tregs were also significantly lower at day 100 in patients with cGVHD than in controls—6.4% and 13.2%, respectively (P=0.002). Again, the difference between controls and patients with late acute GVHD was not significant—13.2% and 9.1%, respectively (P=0.06).

However, further analysis revealed that percentages of RTEs and Treg RTEs were significantly lower at day 100 in patients who developed any type of GVHD after day 100.

The percentage of RTEs was 13.5% in controls and 8.5% in patients with any GVHD after day 100 (P=0.009). The percentage of Treg RTEs was 13.2% and 7.6%, respectively (P=0.004).

“Both recent thymic emigrants and Treg RTEs at day 100 are prognostic biomarkers for chronic graft-vs-host disease in children in this large, multi-institutional, prospective trial,” Dr Cuvelier said in closing.

“Unlike adults, in children, RTEs are proportionally lower, not higher, in patients that later develop chronic GVHD compared to no chronic GVHD. This may suggest that thymic dysfunction and thymic output may play a greater role in chronic GVHD development in children compared to adults.”

To expand upon this research, Dr Cuvelier and his colleagues are planning to begin model building using prognostic cellular and plasma biomarkers at day 100 to determine high-risk profiles for cGVHD.

1. Greinix HT et al; CD19+CD21low B Cells and CD4+CD45RA+CD31+ T Cells Correlate with First Diagnosis of Chronic Graft-versus-Host Disease. BBMT 2015; 21(2):250-258.

2. Li AM et al. An Early Naïve T Cell Population Lacking PD1 Expression at Day 100 As A Prognostic Biomarker of Chronic GVHD. TSS 2017; 210.6.

2018 BMT Tandem Meetings

SALT LAKE CITY—Researchers say they have identified prognostic biomarkers for chronic graft-vs-host disease (cGVHD) in children.

The group found that recent thymic emigrants (RTEs) and regulatory T cells expressing CD31 and CD45RA (Treg RTEs) were significantly lower at day 100 after transplant in patients who developed cGVHD.

Because prior research indicated that RTEs are higher in adults with cGVHD, the researchers concluded that thymic function may play a bigger role in cGVHD development for children than for adults.

Geoff D.E. Cuvelier, MD, of CancerCare Manitoba in Winnipeg, Canada, presented these findings at the 2018 BMT Tandem Meetings (abstract 104).

“Our group became interested in these populations of recent thymic emigrants when 2 adult studies^1,2 . . . showed that higher proportions of recent thymic emigrants at day 100 were prognostic for the development of chronic graft-vs-host disease,” Dr Cuvelier said.

This led his group to evaluate whether RTEs (CD4⁺CD45RA⁺CD31⁺ T cells), as well as Treg RTEs—Tregs (CD4⁺CD25⁺CD127^Low) that co-express naïve and recently emigrated markers (CD45RA⁺CD31⁺)—are prognostic for pediatric cGVHD at day 100 after allogeneic hematopoietic stem cell transplant (allo-HSCT).

The researchers’ study enrolled patients younger than 18 years of age who underwent allo-HSCT to treat malignant and non-malignant diseases. There were 144 patients who had 1 year of follow-up after allo-HSCT.

Thirty-seven of the patients (25.7%) had cGVHD, and 34 (23.6%) had late acute GVHD (post-day 100). The remaining 73 patients (50.7%) had neither cGVHD nor late acute GVHD, so they served as controls.

Twenty cases of cGVHD were severe, 12 were moderate, and 5 were mild. cGVHD was initially diagnosed at a mean of 192 days post-transplant. The median number of organ systems involved was 3 (range, 1-6). Seventeen patients (46%) had overlap syndrome.

The researchers found that RTEs as a percentage of CD4 T cells were significantly lower at day 100 in patients with cGVHD than in controls—7.8% and 13.5%, respectively (P=0.007). The difference between controls and patients with late acute GVHD was not significant—13.5% and 9.4%, respectively (P=0.08).

Treg RTEs as a percentage of all Tregs were also significantly lower at day 100 in patients with cGVHD than in controls—6.4% and 13.2%, respectively (P=0.002). Again, the difference between controls and patients with late acute GVHD was not significant—13.2% and 9.1%, respectively (P=0.06).

However, further analysis revealed that percentages of RTEs and Treg RTEs were significantly lower at day 100 in patients who developed any type of GVHD after day 100.

The percentage of RTEs was 13.5% in controls and 8.5% in patients with any GVHD after day 100 (P=0.009). The percentage of Treg RTEs was 13.2% and 7.6%, respectively (P=0.004).

“Both recent thymic emigrants and Treg RTEs at day 100 are prognostic biomarkers for chronic graft-vs-host disease in children in this large, multi-institutional, prospective trial,” Dr Cuvelier said in closing.

“Unlike adults, in children, RTEs are proportionally lower, not higher, in patients that later develop chronic GVHD compared to no chronic GVHD. This may suggest that thymic dysfunction and thymic output may play a greater role in chronic GVHD development in children compared to adults.”

To expand upon this research, Dr Cuvelier and his colleagues are planning to begin model building using prognostic cellular and plasma biomarkers at day 100 to determine high-risk profiles for cGVHD.

1. Greinix HT et al; CD19+CD21low B Cells and CD4+CD45RA+CD31+ T Cells Correlate with First Diagnosis of Chronic Graft-versus-Host Disease. BBMT 2015; 21(2):250-258.

2. Li AM et al. An Early Naïve T Cell Population Lacking PD1 Expression at Day 100 As A Prognostic Biomarker of Chronic GVHD. TSS 2017; 210.6.

2018 BMT Tandem Meetings

SALT LAKE CITY—Researchers say they have identified prognostic biomarkers for chronic graft-vs-host disease (cGVHD) in children.

The group found that recent thymic emigrants (RTEs) and regulatory T cells expressing CD31 and CD45RA (Treg RTEs) were significantly lower at day 100 after transplant in patients who developed cGVHD.

Because prior research indicated that RTEs are higher in adults with cGVHD, the researchers concluded that thymic function may play a bigger role in cGVHD development for children than for adults.

Geoff D.E. Cuvelier, MD, of CancerCare Manitoba in Winnipeg, Canada, presented these findings at the 2018 BMT Tandem Meetings (abstract 104).

“Our group became interested in these populations of recent thymic emigrants when 2 adult studies^1,2 . . . showed that higher proportions of recent thymic emigrants at day 100 were prognostic for the development of chronic graft-vs-host disease,” Dr Cuvelier said.

This led his group to evaluate whether RTEs (CD4⁺CD45RA⁺CD31⁺ T cells), as well as Treg RTEs—Tregs (CD4⁺CD25⁺CD127^Low) that co-express naïve and recently emigrated markers (CD45RA⁺CD31⁺)—are prognostic for pediatric cGVHD at day 100 after allogeneic hematopoietic stem cell transplant (allo-HSCT).

The researchers’ study enrolled patients younger than 18 years of age who underwent allo-HSCT to treat malignant and non-malignant diseases. There were 144 patients who had 1 year of follow-up after allo-HSCT.

Thirty-seven of the patients (25.7%) had cGVHD, and 34 (23.6%) had late acute GVHD (post-day 100). The remaining 73 patients (50.7%) had neither cGVHD nor late acute GVHD, so they served as controls.

Twenty cases of cGVHD were severe, 12 were moderate, and 5 were mild. cGVHD was initially diagnosed at a mean of 192 days post-transplant. The median number of organ systems involved was 3 (range, 1-6). Seventeen patients (46%) had overlap syndrome.

The researchers found that RTEs as a percentage of CD4 T cells were significantly lower at day 100 in patients with cGVHD than in controls—7.8% and 13.5%, respectively (P=0.007). The difference between controls and patients with late acute GVHD was not significant—13.5% and 9.4%, respectively (P=0.08).

Treg RTEs as a percentage of all Tregs were also significantly lower at day 100 in patients with cGVHD than in controls—6.4% and 13.2%, respectively (P=0.002). Again, the difference between controls and patients with late acute GVHD was not significant—13.2% and 9.1%, respectively (P=0.06).

However, further analysis revealed that percentages of RTEs and Treg RTEs were significantly lower at day 100 in patients who developed any type of GVHD after day 100.

The percentage of RTEs was 13.5% in controls and 8.5% in patients with any GVHD after day 100 (P=0.009). The percentage of Treg RTEs was 13.2% and 7.6%, respectively (P=0.004).

“Both recent thymic emigrants and Treg RTEs at day 100 are prognostic biomarkers for chronic graft-vs-host disease in children in this large, multi-institutional, prospective trial,” Dr Cuvelier said in closing.

“Unlike adults, in children, RTEs are proportionally lower, not higher, in patients that later develop chronic GVHD compared to no chronic GVHD. This may suggest that thymic dysfunction and thymic output may play a greater role in chronic GVHD development in children compared to adults.”

To expand upon this research, Dr Cuvelier and his colleagues are planning to begin model building using prognostic cellular and plasma biomarkers at day 100 to determine high-risk profiles for cGVHD.

1. Greinix HT et al; CD19+CD21low B Cells and CD4+CD45RA+CD31+ T Cells Correlate with First Diagnosis of Chronic Graft-versus-Host Disease. BBMT 2015; 21(2):250-258.

2. Li AM et al. An Early Naïve T Cell Population Lacking PD1 Expression at Day 100 As A Prognostic Biomarker of Chronic GVHD. TSS 2017; 210.6.

Image by Difu Wu

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the approved use of bosutinib (BOSULIF) to include treatment of patients with newly diagnosed, chronic phase, Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML).

Bosutinib is currently approved in Europe to treat patients with Ph+ CML in chronic, accelerated, or blast phase who have received one or more tyrosine kinase inhibitors and for whom imatinib, nilotinib, and dasatinib are not considered appropriate treatment options.

The CHMP’s opinion on bosutinib will be reviewed by the European Commission (EC). If the EC agrees with the CHMP, the commission will grant a centralized marketing authorization that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.

The EC typically makes a decision within 67 days of the CHMP’s recommendation.

The CHMP’s recommendation for bosutinib is based on results from the BFORE trial, which were recently published in the Journal of Clinical Oncology.

The publication included data on 536 patients newly diagnosed with chronic phase CML. They were randomized 1:1 to receive bosutinib (n=268) or imatinib (n=268).

The modified intent-to-treat population included Ph+ patients with e13a2/e14a2 transcripts who had at least 12 months of follow-up. In this group, there were 246 patients in the bosutinib arm and 241 in the imatinib arm.

In the modified intent-to-treat population, the rate of major molecular response at 12 months was 47.2% in the bosutinib arm and 36.9% in the imatinib arm (P=0.02). The rate of complete cytogenetic response was 77.2% and 66.4%, respectively (P<0.008).

In the entire study population, 22.0% of patients receiving bosutinib and 26.8% of those receiving imatinib discontinued treatment—12.7% and 8.7%, respectively, due to drug-related toxicity.

Adverse events that were more common in the bosutinib arm than the imatinib arm included grade 3 or higher diarrhea (7.8% vs 0.8%), increased alanine levels (19% vs 1.5%), increased aspartate levels (9.7% vs 1.9%), cardiovascular events (3% vs 0.4%), and peripheral vascular events (1.5% vs 1.1%).

Cerebrovascular events were more common with imatinib than bosutinib (0.4% and 0%, respectively).

Image by Difu Wu

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the approved use of bosutinib (BOSULIF) to include treatment of patients with newly diagnosed, chronic phase, Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML).

Bosutinib is currently approved in Europe to treat patients with Ph+ CML in chronic, accelerated, or blast phase who have received one or more tyrosine kinase inhibitors and for whom imatinib, nilotinib, and dasatinib are not considered appropriate treatment options.

The CHMP’s opinion on bosutinib will be reviewed by the European Commission (EC). If the EC agrees with the CHMP, the commission will grant a centralized marketing authorization that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.

The EC typically makes a decision within 67 days of the CHMP’s recommendation.

The CHMP’s recommendation for bosutinib is based on results from the BFORE trial, which were recently published in the Journal of Clinical Oncology.

The publication included data on 536 patients newly diagnosed with chronic phase CML. They were randomized 1:1 to receive bosutinib (n=268) or imatinib (n=268).

The modified intent-to-treat population included Ph+ patients with e13a2/e14a2 transcripts who had at least 12 months of follow-up. In this group, there were 246 patients in the bosutinib arm and 241 in the imatinib arm.

In the modified intent-to-treat population, the rate of major molecular response at 12 months was 47.2% in the bosutinib arm and 36.9% in the imatinib arm (P=0.02). The rate of complete cytogenetic response was 77.2% and 66.4%, respectively (P<0.008).

In the entire study population, 22.0% of patients receiving bosutinib and 26.8% of those receiving imatinib discontinued treatment—12.7% and 8.7%, respectively, due to drug-related toxicity.

Adverse events that were more common in the bosutinib arm than the imatinib arm included grade 3 or higher diarrhea (7.8% vs 0.8%), increased alanine levels (19% vs 1.5%), increased aspartate levels (9.7% vs 1.9%), cardiovascular events (3% vs 0.4%), and peripheral vascular events (1.5% vs 1.1%).

Cerebrovascular events were more common with imatinib than bosutinib (0.4% and 0%, respectively).

Image by Difu Wu

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the approved use of bosutinib (BOSULIF) to include treatment of patients with newly diagnosed, chronic phase, Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML).

Bosutinib is currently approved in Europe to treat patients with Ph+ CML in chronic, accelerated, or blast phase who have received one or more tyrosine kinase inhibitors and for whom imatinib, nilotinib, and dasatinib are not considered appropriate treatment options.

The CHMP’s opinion on bosutinib will be reviewed by the European Commission (EC). If the EC agrees with the CHMP, the commission will grant a centralized marketing authorization that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.

The EC typically makes a decision within 67 days of the CHMP’s recommendation.

The CHMP’s recommendation for bosutinib is based on results from the BFORE trial, which were recently published in the Journal of Clinical Oncology.

The publication included data on 536 patients newly diagnosed with chronic phase CML. They were randomized 1:1 to receive bosutinib (n=268) or imatinib (n=268).

The modified intent-to-treat population included Ph+ patients with e13a2/e14a2 transcripts who had at least 12 months of follow-up. In this group, there were 246 patients in the bosutinib arm and 241 in the imatinib arm.

In the modified intent-to-treat population, the rate of major molecular response at 12 months was 47.2% in the bosutinib arm and 36.9% in the imatinib arm (P=0.02). The rate of complete cytogenetic response was 77.2% and 66.4%, respectively (P<0.008).

In the entire study population, 22.0% of patients receiving bosutinib and 26.8% of those receiving imatinib discontinued treatment—12.7% and 8.7%, respectively, due to drug-related toxicity.

Adverse events that were more common in the bosutinib arm than the imatinib arm included grade 3 or higher diarrhea (7.8% vs 0.8%), increased alanine levels (19% vs 1.5%), increased aspartate levels (9.7% vs 1.9%), cardiovascular events (3% vs 0.4%), and peripheral vascular events (1.5% vs 1.1%).

Cerebrovascular events were more common with imatinib than bosutinib (0.4% and 0%, respectively).

Photo by Bill Branson

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the current indication for denosumab (XGEVA®).

The CHMP said the drug should be approved for use in preventing skeletal related events (SREs) in adults with advanced malignancies involving bone, which includes multiple myeloma (MM).

Denosumab is currently approved in Europe to prevent SREs—defined as radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression—in adults with bone metastases from solid tumors.

The drug is also approved for the treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity.

The CHMP’s opinion on expanding the indication for denosumab will be reviewed by the European Commission (EC).

If the EC agrees with the CHMP, the commission will grant a centralized marketing authorization that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.

The EC typically makes a decision within 67 days of the CHMP’s recommendation.

The CHMP’s recommendation for denosumab is based on data from the ’482 study, which were recently published in The Lancet Oncology.

In this phase 3 trial, denosumab proved non-inferior to zoledronic acid for delaying SREs in patients with newly diagnosed MM and bone disease.

Researchers randomized 1718 patients to receive subcutaneous denosumab at 120 mg and intravenous placebo every 4 weeks (n=859) or intravenous zoledronic acid at 4 mg (adjusted for renal function at baseline) and subcutaneous placebo every 4 weeks (n=859). All patients also received investigators’ choice of first-line MM therapy.

The median time to first on-study SRE was 22.8 months for patients in the denosumab arm and 24 months for those in the zoledronic acid arm (hazard ratio=0.98; 95% confidence interval: 0.85-1.14; P non-inferiority=0.010).

There were fewer renal treatment-emergent adverse events in the denosumab arm than the zoledronic acid arm—10% and 17%, respectively.

But there were more hypocalcemia adverse events in the denosumab arm than the zoledronic acid arm—17% and 12%, respectively.

Photo by Bill Branson

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the current indication for denosumab (XGEVA®).

The CHMP said the drug should be approved for use in preventing skeletal related events (SREs) in adults with advanced malignancies involving bone, which includes multiple myeloma (MM).

Denosumab is currently approved in Europe to prevent SREs—defined as radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression—in adults with bone metastases from solid tumors.

The drug is also approved for the treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity.

The CHMP’s opinion on expanding the indication for denosumab will be reviewed by the European Commission (EC).

If the EC agrees with the CHMP, the commission will grant a centralized marketing authorization that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.

The EC typically makes a decision within 67 days of the CHMP’s recommendation.

The CHMP’s recommendation for denosumab is based on data from the ’482 study, which were recently published in The Lancet Oncology.

In this phase 3 trial, denosumab proved non-inferior to zoledronic acid for delaying SREs in patients with newly diagnosed MM and bone disease.

Researchers randomized 1718 patients to receive subcutaneous denosumab at 120 mg and intravenous placebo every 4 weeks (n=859) or intravenous zoledronic acid at 4 mg (adjusted for renal function at baseline) and subcutaneous placebo every 4 weeks (n=859). All patients also received investigators’ choice of first-line MM therapy.

The median time to first on-study SRE was 22.8 months for patients in the denosumab arm and 24 months for those in the zoledronic acid arm (hazard ratio=0.98; 95% confidence interval: 0.85-1.14; P non-inferiority=0.010).

There were fewer renal treatment-emergent adverse events in the denosumab arm than the zoledronic acid arm—10% and 17%, respectively.

But there were more hypocalcemia adverse events in the denosumab arm than the zoledronic acid arm—17% and 12%, respectively.

Photo by Bill Branson

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the current indication for denosumab (XGEVA®).

The CHMP said the drug should be approved for use in preventing skeletal related events (SREs) in adults with advanced malignancies involving bone, which includes multiple myeloma (MM).

Denosumab is currently approved in Europe to prevent SREs—defined as radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression—in adults with bone metastases from solid tumors.

The drug is also approved for the treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity.

The CHMP’s opinion on expanding the indication for denosumab will be reviewed by the European Commission (EC).

If the EC agrees with the CHMP, the commission will grant a centralized marketing authorization that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.

The EC typically makes a decision within 67 days of the CHMP’s recommendation.

The CHMP’s recommendation for denosumab is based on data from the ’482 study, which were recently published in The Lancet Oncology.

In this phase 3 trial, denosumab proved non-inferior to zoledronic acid for delaying SREs in patients with newly diagnosed MM and bone disease.

Researchers randomized 1718 patients to receive subcutaneous denosumab at 120 mg and intravenous placebo every 4 weeks (n=859) or intravenous zoledronic acid at 4 mg (adjusted for renal function at baseline) and subcutaneous placebo every 4 weeks (n=859). All patients also received investigators’ choice of first-line MM therapy.

The median time to first on-study SRE was 22.8 months for patients in the denosumab arm and 24 months for those in the zoledronic acid arm (hazard ratio=0.98; 95% confidence interval: 0.85-1.14; P non-inferiority=0.010).

There were fewer renal treatment-emergent adverse events in the denosumab arm than the zoledronic acid arm—10% and 17%, respectively.

But there were more hypocalcemia adverse events in the denosumab arm than the zoledronic acid arm—17% and 12%, respectively.

TriHealth of Cincinnati is testing the waters of value-based payment for maternity care.

The impetus came from a Cincinnati-based employer that contracts with TriHealth under its self-insured health care plan, according to Jennifer Pavelka, project lead for the health system’s Maternity Bundling Care Select Program.

“Employers are looking at the value proposition and are having keen interest in the achievement of the triple aim of optimal outcomes, optimal experience, both with a mindfulness on value, Ms. Pavelka said in an interview. “An employer that had extensive experience with other episodes of care [payments], particularly in the space of knee and hip replacements in the orthopedic world, wanted to dip their toe into a value-based program for maternity.”

TriHealth, Mike Mattingly

“Many forays into value-based payments are very much code driven, saying this code, this service is included in the bundle and this is not,” Ms. Pavelka said. “Part of what makes our work really challenging and exciting is the fact that we have taken in the realm of the methodology and philosophy of bundles, we are implementing a prospective bundled payment model.”

• Finding opportunities to improve outcomes and patient experience.
• Developing better quality metrics.
• Reducing waste in the system.
• Creating stronger health care teams.

Value-based payments can “actually bring together hospitals and health care providers onto the same team and the way they do that is by tying the payment together,” Dr. Nijagal said.

The biggest challenge, according to Dr. Nijagal, is that the conversion takes time and the patience to realize that benefits will likely not be fully realized until the system is able to get to a prospective payment model, in which the real innovation can take place (Am J Obstet Gynecol. 2018 Jan 12. doi. org/10.1016/j.ajog.2018.01.014).

“We are having to prioritize just getting providers to agree to doing them and because of that, we are not actually seeing the improvements in quality and cost that we would expect,” Dr. Nijagal said. “For example, a number of the programs that have been rolled out have been the upside risk only, which is superimportant because that is the way you are going to get people to feel more comfortable. It’s a stepping-stone, but you are not going to see the benefits.” And if you can’t prove benefit, it will be harder to get people to move to a two-sided risk model where the real innovation can take place.

To that end, TriHealth provides full transparency with the program so physicians can see how patients in the bundle are doing compared to the overall TriHealth patient population.

“We provide those to them in a dashboard on a monthly basis with transparency so they can see how the other providers in other practices are doing within the system,” Dr, Marcotte said.

[email protected]

TriHealth of Cincinnati is testing the waters of value-based payment for maternity care.

The impetus came from a Cincinnati-based employer that contracts with TriHealth under its self-insured health care plan, according to Jennifer Pavelka, project lead for the health system’s Maternity Bundling Care Select Program.

“Employers are looking at the value proposition and are having keen interest in the achievement of the triple aim of optimal outcomes, optimal experience, both with a mindfulness on value, Ms. Pavelka said in an interview. “An employer that had extensive experience with other episodes of care [payments], particularly in the space of knee and hip replacements in the orthopedic world, wanted to dip their toe into a value-based program for maternity.”

TriHealth, Mike Mattingly

“Many forays into value-based payments are very much code driven, saying this code, this service is included in the bundle and this is not,” Ms. Pavelka said. “Part of what makes our work really challenging and exciting is the fact that we have taken in the realm of the methodology and philosophy of bundles, we are implementing a prospective bundled payment model.”

• Finding opportunities to improve outcomes and patient experience.
• Developing better quality metrics.
• Reducing waste in the system.
• Creating stronger health care teams.

Value-based payments can “actually bring together hospitals and health care providers onto the same team and the way they do that is by tying the payment together,” Dr. Nijagal said.

The biggest challenge, according to Dr. Nijagal, is that the conversion takes time and the patience to realize that benefits will likely not be fully realized until the system is able to get to a prospective payment model, in which the real innovation can take place (Am J Obstet Gynecol. 2018 Jan 12. doi. org/10.1016/j.ajog.2018.01.014).

“We are having to prioritize just getting providers to agree to doing them and because of that, we are not actually seeing the improvements in quality and cost that we would expect,” Dr. Nijagal said. “For example, a number of the programs that have been rolled out have been the upside risk only, which is superimportant because that is the way you are going to get people to feel more comfortable. It’s a stepping-stone, but you are not going to see the benefits.” And if you can’t prove benefit, it will be harder to get people to move to a two-sided risk model where the real innovation can take place.

To that end, TriHealth provides full transparency with the program so physicians can see how patients in the bundle are doing compared to the overall TriHealth patient population.

“We provide those to them in a dashboard on a monthly basis with transparency so they can see how the other providers in other practices are doing within the system,” Dr, Marcotte said.

[email protected]

TriHealth of Cincinnati is testing the waters of value-based payment for maternity care.

The impetus came from a Cincinnati-based employer that contracts with TriHealth under its self-insured health care plan, according to Jennifer Pavelka, project lead for the health system’s Maternity Bundling Care Select Program.

“Employers are looking at the value proposition and are having keen interest in the achievement of the triple aim of optimal outcomes, optimal experience, both with a mindfulness on value, Ms. Pavelka said in an interview. “An employer that had extensive experience with other episodes of care [payments], particularly in the space of knee and hip replacements in the orthopedic world, wanted to dip their toe into a value-based program for maternity.”

TriHealth, Mike Mattingly

“Many forays into value-based payments are very much code driven, saying this code, this service is included in the bundle and this is not,” Ms. Pavelka said. “Part of what makes our work really challenging and exciting is the fact that we have taken in the realm of the methodology and philosophy of bundles, we are implementing a prospective bundled payment model.”

• Finding opportunities to improve outcomes and patient experience.
• Developing better quality metrics.
• Reducing waste in the system.
• Creating stronger health care teams.

Value-based payments can “actually bring together hospitals and health care providers onto the same team and the way they do that is by tying the payment together,” Dr. Nijagal said.

The biggest challenge, according to Dr. Nijagal, is that the conversion takes time and the patience to realize that benefits will likely not be fully realized until the system is able to get to a prospective payment model, in which the real innovation can take place (Am J Obstet Gynecol. 2018 Jan 12. doi. org/10.1016/j.ajog.2018.01.014).

“We are having to prioritize just getting providers to agree to doing them and because of that, we are not actually seeing the improvements in quality and cost that we would expect,” Dr. Nijagal said. “For example, a number of the programs that have been rolled out have been the upside risk only, which is superimportant because that is the way you are going to get people to feel more comfortable. It’s a stepping-stone, but you are not going to see the benefits.” And if you can’t prove benefit, it will be harder to get people to move to a two-sided risk model where the real innovation can take place.

To that end, TriHealth provides full transparency with the program so physicians can see how patients in the bundle are doing compared to the overall TriHealth patient population.

“We provide those to them in a dashboard on a monthly basis with transparency so they can see how the other providers in other practices are doing within the system,” Dr, Marcotte said.

[email protected]