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Will artificial intelligence make us better doctors?
Given the amount of time physicians spend entering data, clicking through screens, navigating pages, and logging in to computers, one would have hoped that substantial near-term payback for such efforts would have materialized.
Many of us believed this would take the form of health information exchange – the ability to easily access clinical information from hospitals or clinics other than our own, creating a more complete picture of the patient before us. To our disappointment, true information exchange has yet to materialize. (We won’t debate here whether politics or technology is culpable.) We are left to look elsewhere for the benefits of the digitization of the medical records and other sources of health care knowledge.
Lately, there has been a lot of talk about the promise of machine learning and artificial intelligence (AI) in health care. Much of the resurgence of interest in AI can be traced to IBM Watson’s appearance as a contestant on Jeopardy in 2011. Watson, a natural language supercomputer with enough power to process the equivalent of a million books per second, had access to 200 million pages of content, including the full text of Wikipedia, for Jeopardy.1 Watson handily outperformed its human opponents – two Jeopardy savants who were also the most successful contestants in game show history – taking the $1 million first prize but struggling in categories with clues containing only a few words.
MD Anderson and Watson: Dashed hopes follow initial promise
As a result of growing recognition of AI’s potential in health care, IBM began collaborations with a number of health care organizations to deploy Watson.
In 2013, MD Anderson Cancer Center and IBM began a pilot to develop an oncology clinical decision support technology tool powered by Watson to aid MD Anderson “in its mission to eradicate cancer.” Recently, it was announced that the project – which cost the cancer center $62 million – has been put on hold, and MD Anderson is looking for other contractors to replace IBM.
While administrative problems are at least partly responsible for the project’s challenges, the undertaking has raised issues with the quality and quantity of data in health care that call into question the ability of AI to work as well in health care as it did on Jeopardy, at least in the short term.
Health care: Not as data rich as you might think
“We are not ‘Big Data’ in health care, yet.” – Dale Sanders, Health Catalyst.2
In its quest for Jeopardy victory, Watson accessed a massive data storehouse subsuming a vast array of knowledge assembled over the course of human history. Conversely, for health care, Watson is limited to a few decades of scientific journals (that may not contribute to diagnosis and treatment as much as one might think), claims data geared to billing without much clinical information like outcomes, and clinical data from progress notes (plagued by inaccuracies, serial “copy and paste,” and nonstandardized language and numeric representations), and variable-format reports from lab, radiology, pathology, and other disciplines.
To articulate how data-poor health care is, Dale Sanders, executive vice president for software at Health Catalyst, notes that a Boeing 787 generates 500GB of data in a six hour flight while one patient may generate just 100MB of data in an entire year.2 He pointed out that, in the near term, AI platforms like Watson simply do not have enough data substrate to impact health care as many hoped it would. Over the longer term, he says, if health care can develop a coherent, standard approach to data content, AI may fulfill its promise. 
What can AI and related technologies achieve in the near-term?
“AI seems to have replaced Uber as the most overused word or phrase in digital health.” – Reporter Stephanie Baum, paraphrasing from an interview with Bob Kocher, Venrock Partners.3
My observations tell me that we have already made some progress and are likely to make more strides in the coming years, thanks to AI, machine learning, and natural language processing. A few areas of potential gain are:
Clinical documentation
Technology that can derive meaning from words or groups of words can help with more accurate clinical documentation. For example, if a patient has a documented UTI but also has in the record an 11 on the Glasgow Coma Scale, a systolic BP of 90, and a respiratory rate of 24, technology can alert the physician to document sepsis.
Quality measurement and reporting
Similarly, if technology can recognize words and numbers, it may be able to extract and report quality measures (for example, an ejection fraction of 35% in a heart failure patient) from progress notes without having a nurse-abstractor manually enter such data into structured fields for reporting, as is currently the case.
Predicting readmissions, mortality, other events
While machine learning has had mixed results in predicting future clinical events, this is likely to change as data integrity and algorithms improve. Best-of-breed technology will probably use both clinical and machine learning tools for predictive purposes in the future.
In 2015, I had the privilege of meeting Vinod Khosla, cofounder of SUN Microsystems and venture capitalist, who predicts that computers will largely supplant physicians in the future, at least in domains relying on access to data. As he puts it, “the core functions necessary for complex diagnoses, treatments, and monitoring will be driven by machine judgment instead of human judgment.”4
While the benefits of technology, especially in health care, are often oversold, I believe AI and related technologies will some day play a large role alongside physicians in the care of patients. However, for AI to deliver, we must first figure out how to collect and organize health care data so that computers are able to ingest, digest and use it in a purposeful way.
Note: Dr. Whitcomb is founder and advisor to Zato Health, which uses natural language processing and discovery technology in health care.
He is chief medical officer at Remedy Partners in Darien, Conn., and a cofounder and past president of SHM.
References
1. Zimmer, Ben. Is It Time to Welcome Our New Computer Overlords?. The Atlantic. https://www.theatlantic.com/technology/archive/2011/02/is-it-time-to-welcome-our-new-computer-overlords/71388/. Accessed 23 Apr 2017.
2. Sanders, Dale. The MD Anderson / IBM Watson Announcement: What does it mean for machine learning in healthcare? Webinar. https://www.slideshare.net/healthcatalyst1/the-md-anderson-ibm-watson-announcement-what-does-it-mean-for-machine-learning-in-healthcare. Accessed 23 Apr 2017.
3. Baum, Stephanie. Venrock survey predicts a flight to quality for digital health investments. MedCity News. 12 Apr 2017. http://medcitynews.com/2017/04/venrock-survey-predicts-flight-quality-digital-health-investment/. Accessed 22 Apr 2017.
4. Khosla, Vinod. The Reinvention Of Medicine: Dr. Algorithm V0-7 And Beyond. TechCrunch. 22 Sept 2014. https://techcrunch.com/2014/09/22/the-reinvention-of-medicine-dr-algorithm-version-0-7-and-beyond/. Accessed 22 Apr 2017.
Given the amount of time physicians spend entering data, clicking through screens, navigating pages, and logging in to computers, one would have hoped that substantial near-term payback for such efforts would have materialized.
Many of us believed this would take the form of health information exchange – the ability to easily access clinical information from hospitals or clinics other than our own, creating a more complete picture of the patient before us. To our disappointment, true information exchange has yet to materialize. (We won’t debate here whether politics or technology is culpable.) We are left to look elsewhere for the benefits of the digitization of the medical records and other sources of health care knowledge.
Lately, there has been a lot of talk about the promise of machine learning and artificial intelligence (AI) in health care. Much of the resurgence of interest in AI can be traced to IBM Watson’s appearance as a contestant on Jeopardy in 2011. Watson, a natural language supercomputer with enough power to process the equivalent of a million books per second, had access to 200 million pages of content, including the full text of Wikipedia, for Jeopardy.1 Watson handily outperformed its human opponents – two Jeopardy savants who were also the most successful contestants in game show history – taking the $1 million first prize but struggling in categories with clues containing only a few words.
MD Anderson and Watson: Dashed hopes follow initial promise
As a result of growing recognition of AI’s potential in health care, IBM began collaborations with a number of health care organizations to deploy Watson.
In 2013, MD Anderson Cancer Center and IBM began a pilot to develop an oncology clinical decision support technology tool powered by Watson to aid MD Anderson “in its mission to eradicate cancer.” Recently, it was announced that the project – which cost the cancer center $62 million – has been put on hold, and MD Anderson is looking for other contractors to replace IBM.
While administrative problems are at least partly responsible for the project’s challenges, the undertaking has raised issues with the quality and quantity of data in health care that call into question the ability of AI to work as well in health care as it did on Jeopardy, at least in the short term.
Health care: Not as data rich as you might think
“We are not ‘Big Data’ in health care, yet.” – Dale Sanders, Health Catalyst.2
In its quest for Jeopardy victory, Watson accessed a massive data storehouse subsuming a vast array of knowledge assembled over the course of human history. Conversely, for health care, Watson is limited to a few decades of scientific journals (that may not contribute to diagnosis and treatment as much as one might think), claims data geared to billing without much clinical information like outcomes, and clinical data from progress notes (plagued by inaccuracies, serial “copy and paste,” and nonstandardized language and numeric representations), and variable-format reports from lab, radiology, pathology, and other disciplines.
To articulate how data-poor health care is, Dale Sanders, executive vice president for software at Health Catalyst, notes that a Boeing 787 generates 500GB of data in a six hour flight while one patient may generate just 100MB of data in an entire year.2 He pointed out that, in the near term, AI platforms like Watson simply do not have enough data substrate to impact health care as many hoped it would. Over the longer term, he says, if health care can develop a coherent, standard approach to data content, AI may fulfill its promise.
What can AI and related technologies achieve in the near-term?
“AI seems to have replaced Uber as the most overused word or phrase in digital health.” – Reporter Stephanie Baum, paraphrasing from an interview with Bob Kocher, Venrock Partners.3
My observations tell me that we have already made some progress and are likely to make more strides in the coming years, thanks to AI, machine learning, and natural language processing. A few areas of potential gain are:
Clinical documentation
Technology that can derive meaning from words or groups of words can help with more accurate clinical documentation. For example, if a patient has a documented UTI but also has in the record an 11 on the Glasgow Coma Scale, a systolic BP of 90, and a respiratory rate of 24, technology can alert the physician to document sepsis.
Quality measurement and reporting
Similarly, if technology can recognize words and numbers, it may be able to extract and report quality measures (for example, an ejection fraction of 35% in a heart failure patient) from progress notes without having a nurse-abstractor manually enter such data into structured fields for reporting, as is currently the case.
Predicting readmissions, mortality, other events
While machine learning has had mixed results in predicting future clinical events, this is likely to change as data integrity and algorithms improve. Best-of-breed technology will probably use both clinical and machine learning tools for predictive purposes in the future.
In 2015, I had the privilege of meeting Vinod Khosla, cofounder of SUN Microsystems and venture capitalist, who predicts that computers will largely supplant physicians in the future, at least in domains relying on access to data. As he puts it, “the core functions necessary for complex diagnoses, treatments, and monitoring will be driven by machine judgment instead of human judgment.”4
While the benefits of technology, especially in health care, are often oversold, I believe AI and related technologies will some day play a large role alongside physicians in the care of patients. However, for AI to deliver, we must first figure out how to collect and organize health care data so that computers are able to ingest, digest and use it in a purposeful way.
Note: Dr. Whitcomb is founder and advisor to Zato Health, which uses natural language processing and discovery technology in health care.
He is chief medical officer at Remedy Partners in Darien, Conn., and a cofounder and past president of SHM.
References
1. Zimmer, Ben. Is It Time to Welcome Our New Computer Overlords?. The Atlantic. https://www.theatlantic.com/technology/archive/2011/02/is-it-time-to-welcome-our-new-computer-overlords/71388/. Accessed 23 Apr 2017.
2. Sanders, Dale. The MD Anderson / IBM Watson Announcement: What does it mean for machine learning in healthcare? Webinar. https://www.slideshare.net/healthcatalyst1/the-md-anderson-ibm-watson-announcement-what-does-it-mean-for-machine-learning-in-healthcare. Accessed 23 Apr 2017.
3. Baum, Stephanie. Venrock survey predicts a flight to quality for digital health investments. MedCity News. 12 Apr 2017. http://medcitynews.com/2017/04/venrock-survey-predicts-flight-quality-digital-health-investment/. Accessed 22 Apr 2017.
4. Khosla, Vinod. The Reinvention Of Medicine: Dr. Algorithm V0-7 And Beyond. TechCrunch. 22 Sept 2014. https://techcrunch.com/2014/09/22/the-reinvention-of-medicine-dr-algorithm-version-0-7-and-beyond/. Accessed 22 Apr 2017.
Given the amount of time physicians spend entering data, clicking through screens, navigating pages, and logging in to computers, one would have hoped that substantial near-term payback for such efforts would have materialized.
Many of us believed this would take the form of health information exchange – the ability to easily access clinical information from hospitals or clinics other than our own, creating a more complete picture of the patient before us. To our disappointment, true information exchange has yet to materialize. (We won’t debate here whether politics or technology is culpable.) We are left to look elsewhere for the benefits of the digitization of the medical records and other sources of health care knowledge.
Lately, there has been a lot of talk about the promise of machine learning and artificial intelligence (AI) in health care. Much of the resurgence of interest in AI can be traced to IBM Watson’s appearance as a contestant on Jeopardy in 2011. Watson, a natural language supercomputer with enough power to process the equivalent of a million books per second, had access to 200 million pages of content, including the full text of Wikipedia, for Jeopardy.1 Watson handily outperformed its human opponents – two Jeopardy savants who were also the most successful contestants in game show history – taking the $1 million first prize but struggling in categories with clues containing only a few words.
MD Anderson and Watson: Dashed hopes follow initial promise
As a result of growing recognition of AI’s potential in health care, IBM began collaborations with a number of health care organizations to deploy Watson.
In 2013, MD Anderson Cancer Center and IBM began a pilot to develop an oncology clinical decision support technology tool powered by Watson to aid MD Anderson “in its mission to eradicate cancer.” Recently, it was announced that the project – which cost the cancer center $62 million – has been put on hold, and MD Anderson is looking for other contractors to replace IBM.
While administrative problems are at least partly responsible for the project’s challenges, the undertaking has raised issues with the quality and quantity of data in health care that call into question the ability of AI to work as well in health care as it did on Jeopardy, at least in the short term.
Health care: Not as data rich as you might think
“We are not ‘Big Data’ in health care, yet.” – Dale Sanders, Health Catalyst.2
In its quest for Jeopardy victory, Watson accessed a massive data storehouse subsuming a vast array of knowledge assembled over the course of human history. Conversely, for health care, Watson is limited to a few decades of scientific journals (that may not contribute to diagnosis and treatment as much as one might think), claims data geared to billing without much clinical information like outcomes, and clinical data from progress notes (plagued by inaccuracies, serial “copy and paste,” and nonstandardized language and numeric representations), and variable-format reports from lab, radiology, pathology, and other disciplines.
To articulate how data-poor health care is, Dale Sanders, executive vice president for software at Health Catalyst, notes that a Boeing 787 generates 500GB of data in a six hour flight while one patient may generate just 100MB of data in an entire year.2 He pointed out that, in the near term, AI platforms like Watson simply do not have enough data substrate to impact health care as many hoped it would. Over the longer term, he says, if health care can develop a coherent, standard approach to data content, AI may fulfill its promise.
What can AI and related technologies achieve in the near-term?
“AI seems to have replaced Uber as the most overused word or phrase in digital health.” – Reporter Stephanie Baum, paraphrasing from an interview with Bob Kocher, Venrock Partners.3
My observations tell me that we have already made some progress and are likely to make more strides in the coming years, thanks to AI, machine learning, and natural language processing. A few areas of potential gain are:
Clinical documentation
Technology that can derive meaning from words or groups of words can help with more accurate clinical documentation. For example, if a patient has a documented UTI but also has in the record an 11 on the Glasgow Coma Scale, a systolic BP of 90, and a respiratory rate of 24, technology can alert the physician to document sepsis.
Quality measurement and reporting
Similarly, if technology can recognize words and numbers, it may be able to extract and report quality measures (for example, an ejection fraction of 35% in a heart failure patient) from progress notes without having a nurse-abstractor manually enter such data into structured fields for reporting, as is currently the case.
Predicting readmissions, mortality, other events
While machine learning has had mixed results in predicting future clinical events, this is likely to change as data integrity and algorithms improve. Best-of-breed technology will probably use both clinical and machine learning tools for predictive purposes in the future.
In 2015, I had the privilege of meeting Vinod Khosla, cofounder of SUN Microsystems and venture capitalist, who predicts that computers will largely supplant physicians in the future, at least in domains relying on access to data. As he puts it, “the core functions necessary for complex diagnoses, treatments, and monitoring will be driven by machine judgment instead of human judgment.”4
While the benefits of technology, especially in health care, are often oversold, I believe AI and related technologies will some day play a large role alongside physicians in the care of patients. However, for AI to deliver, we must first figure out how to collect and organize health care data so that computers are able to ingest, digest and use it in a purposeful way.
Note: Dr. Whitcomb is founder and advisor to Zato Health, which uses natural language processing and discovery technology in health care.
He is chief medical officer at Remedy Partners in Darien, Conn., and a cofounder and past president of SHM.
References
1. Zimmer, Ben. Is It Time to Welcome Our New Computer Overlords?. The Atlantic. https://www.theatlantic.com/technology/archive/2011/02/is-it-time-to-welcome-our-new-computer-overlords/71388/. Accessed 23 Apr 2017.
2. Sanders, Dale. The MD Anderson / IBM Watson Announcement: What does it mean for machine learning in healthcare? Webinar. https://www.slideshare.net/healthcatalyst1/the-md-anderson-ibm-watson-announcement-what-does-it-mean-for-machine-learning-in-healthcare. Accessed 23 Apr 2017.
3. Baum, Stephanie. Venrock survey predicts a flight to quality for digital health investments. MedCity News. 12 Apr 2017. http://medcitynews.com/2017/04/venrock-survey-predicts-flight-quality-digital-health-investment/. Accessed 22 Apr 2017.
4. Khosla, Vinod. The Reinvention Of Medicine: Dr. Algorithm V0-7 And Beyond. TechCrunch. 22 Sept 2014. https://techcrunch.com/2014/09/22/the-reinvention-of-medicine-dr-algorithm-version-0-7-and-beyond/. Accessed 22 Apr 2017.
Health inequities take a societal toll
Arguably one of the most important public health issues in our nation is the gap between high-quality care and the people who need it most. The passage of the Affordable Care Act was meant, in part, to reduce this gap and increase health equity in terms of both eligibility for, and access to, care. However, lower-income residents, especially those from minority groups, are more likely to be hospitalized for asthma, hypertension, heart disease, and diabetes, and to experience infertility, preterm birth, and fetal death.
Health disparities, or inequities, translate not only into greater suffering for certain segments of the population, but also to significantly greater health care costs for everyone. Racial health disparities are associated with an estimated $35 billion annually in excess expenditures, $10 billion in lost productivity, and nearly $200 billion in premature deaths, according to an article in the Harvard Business Review. A 2013 study estimated that reducing racial disparities in adverse pregnancy outcomes – preeclampsia, preterm birth, gestational diabetes mellitus, and fetal death/stillbirth – could generate health care cost savings of up to $214 million per year (Matern Child Health J. 2013 Oct;17[8]:1518-25).
Several years ago, the State of Maryland took a unique approach to reducing health disparities by passing the Maryland Health Improvement and Disparities Reduction Act. One of the major components of this legislation was the creation of Health Enterprise Zones (HEZs), distinct geographical areas across the state dedicated to addressing health disparities and improving access to high-quality care. This incentive-based program provides state-funded resources to primary care providers and community-based health organizations specifically to help the neighborhoods they serve. I was deeply honored to serve as chairman of the task force that recommended the establishment of the HEZs.
For this Master Class, I have invited Melissa A. Simon, MD, the George H. Gardner, MD, Professor of Clinical Gynecology and professor of obstetrics and gynecology at Northwestern University, Chicago, to provide some practical advice on how to create greater health equity.
Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].
Arguably one of the most important public health issues in our nation is the gap between high-quality care and the people who need it most. The passage of the Affordable Care Act was meant, in part, to reduce this gap and increase health equity in terms of both eligibility for, and access to, care. However, lower-income residents, especially those from minority groups, are more likely to be hospitalized for asthma, hypertension, heart disease, and diabetes, and to experience infertility, preterm birth, and fetal death.
Health disparities, or inequities, translate not only into greater suffering for certain segments of the population, but also to significantly greater health care costs for everyone. Racial health disparities are associated with an estimated $35 billion annually in excess expenditures, $10 billion in lost productivity, and nearly $200 billion in premature deaths, according to an article in the Harvard Business Review. A 2013 study estimated that reducing racial disparities in adverse pregnancy outcomes – preeclampsia, preterm birth, gestational diabetes mellitus, and fetal death/stillbirth – could generate health care cost savings of up to $214 million per year (Matern Child Health J. 2013 Oct;17[8]:1518-25).
Several years ago, the State of Maryland took a unique approach to reducing health disparities by passing the Maryland Health Improvement and Disparities Reduction Act. One of the major components of this legislation was the creation of Health Enterprise Zones (HEZs), distinct geographical areas across the state dedicated to addressing health disparities and improving access to high-quality care. This incentive-based program provides state-funded resources to primary care providers and community-based health organizations specifically to help the neighborhoods they serve. I was deeply honored to serve as chairman of the task force that recommended the establishment of the HEZs.
For this Master Class, I have invited Melissa A. Simon, MD, the George H. Gardner, MD, Professor of Clinical Gynecology and professor of obstetrics and gynecology at Northwestern University, Chicago, to provide some practical advice on how to create greater health equity.
Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].
Arguably one of the most important public health issues in our nation is the gap between high-quality care and the people who need it most. The passage of the Affordable Care Act was meant, in part, to reduce this gap and increase health equity in terms of both eligibility for, and access to, care. However, lower-income residents, especially those from minority groups, are more likely to be hospitalized for asthma, hypertension, heart disease, and diabetes, and to experience infertility, preterm birth, and fetal death.
Health disparities, or inequities, translate not only into greater suffering for certain segments of the population, but also to significantly greater health care costs for everyone. Racial health disparities are associated with an estimated $35 billion annually in excess expenditures, $10 billion in lost productivity, and nearly $200 billion in premature deaths, according to an article in the Harvard Business Review. A 2013 study estimated that reducing racial disparities in adverse pregnancy outcomes – preeclampsia, preterm birth, gestational diabetes mellitus, and fetal death/stillbirth – could generate health care cost savings of up to $214 million per year (Matern Child Health J. 2013 Oct;17[8]:1518-25).
Several years ago, the State of Maryland took a unique approach to reducing health disparities by passing the Maryland Health Improvement and Disparities Reduction Act. One of the major components of this legislation was the creation of Health Enterprise Zones (HEZs), distinct geographical areas across the state dedicated to addressing health disparities and improving access to high-quality care. This incentive-based program provides state-funded resources to primary care providers and community-based health organizations specifically to help the neighborhoods they serve. I was deeply honored to serve as chairman of the task force that recommended the establishment of the HEZs.
For this Master Class, I have invited Melissa A. Simon, MD, the George H. Gardner, MD, Professor of Clinical Gynecology and professor of obstetrics and gynecology at Northwestern University, Chicago, to provide some practical advice on how to create greater health equity.
Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].
Moving toward health equity in practice
Of all the medical professions, obstetrics and gynecology should be the strongest champion for equity in women’s health in this country and globally. The question is, what does this mean in the reality of 2017 and moving forward in the 21st century? What does it mean in the context of our own practices and in the landscape of current policy and politics?
Finding answers to these questions requires both a deep understanding of the meaning of health equity and a willingness to rethink the architecture and engineering of how we currently provide care.
The terms equity and equality are sometimes used interchangeably, but they actually have quite different meanings. Imagine three women of different heights standing underneath the lowest branch of a tall apple tree. None of the three women are tall enough to pick an apple from the branch.
If we think about equality, we would assist each woman by giving her a box to stand on, and all three boxes would be the same size. This means that while the tallest woman will now be able to pick an apple, the medium-height woman may be able to touch but not pick the apple, and the shortest woman still may not be able to reach the apple at all.
However, if we think about equity, we’d acknowledge that each woman needs her own personalized box to be able to pick the apple. For instance, the shortest woman may need a box that is three times the height of the box used by the tallest woman.
Achieving true population health for all women requires that we similarly eliminate inequities by providing each patient with her own personalized care plan to help her reach and maintain her health.
Women from minority groups have higher rates of low birth weight, preterm birth, stillbirth, gestational diabetes and its complications, HIV, breast cancer mortality and cervical cancer incidence and mortality, infertility and response to fertility treatment, and maternal mortality.
Yet inequity runs deeper than racial/ethnic labels; disparities also are created by a host of other factors, from cognitive or physical disabilities to gender or sexual identity or orientation, one’s ZIP code, working environment, language, and health literacy.
More than ever, the art of medicine involves understanding how to meet every patient where she is – given her own context and beliefs and levels of support – so that every woman has the opportunity to stand on the right-sized box and pick the apple and thrive.
Our practices
Provider bias and stereotyping can impact health care and health outcomes, and it is important that we work to prevent this in ourselves and in our staff. This means not making assumptions. It means really listening to our patients in ways that we may not have before.
Women who have experienced health inequity may have unique barriers to success. Therefore, we must listen for cues and inquire about our patients’ environment and circumstances, as well as their partnerships and support – or lack thereof. We should then acknowledge and communicate that certain social and environmental factors may impact our ability to achieve a desired outcome.
How can we impact the diet of a patient with gestational diabetes, for instance, if we have not adequately communicated what medical nutritional therapy means in the context of her own culture and ability to access food? If she lives in a food desert or has food insecurity or lives in a violence-ridden neighborhood that keeps her from going to a grocery store regularly, we must think outside the box. Ob.gyns. and their clinical care teams can work with women who have less access to nutritious foods, or who have certain cultural food staples, to suggest recipes and grocery lists that make sense with respect to the types of stores they shop in or their cultural preferences.
When it comes to cancer prevention and treatment, how can we expect a woman to be compliant with screening if we cannot help her understand that she can get screening services for free with her health insurance? How can we help a woman who has coverage for, or access to, free screening but then no funding or coverage for a diagnostic test or cancer treatment? How can we support a patient with abnormal cancer screening results who hasn’t followed up for months because she is afraid to leave home without her partner’s permission?
Such questions and circumstances often involve what we call “social determinants of health,” and they force us to rethink how we can better deliver and optimize care. Re-engineering our practices for health equity may involve employing a more diverse practice staff, linking patients with community resources, modifying our practice hours to align better with working women’s schedules, or finding creative ways to discern patients’ motivating factors and then piggyback on these factors.
We may also need to modify how we approach the number of return visits that we request of women so that follow-up care aligns better with their ability to leave work or find childcare. Simply put, we should strive to set up our patients for success, not failure.
We can pointedly ask patients about the kinds of information and support they want and need. We might ask, for instance: What do you need, and how can I work with you, so that you can effectively monitor and control your glucose levels? How can I work with you to help you get onto a trajectory to stop smoking? How can I help you better understand what tests and procedures are covered under your insurance plan, or whether you qualify for free services?
Patients with lower health literacy may need teach-back methods to validate understanding, or messaging that is more focused and limited at any one time. Self-efficacy through patient-centered education and support should be our goal.
Practices and clinics may also be able to adapt elements of the National Cancer Institute’s multicenter Patient Navigation Research Program, in which community health workers or other “patient navigators” address women’s personal barriers to the timely follow-up of abnormal breast and cervical cancer screening results. Patient navigation through this program and similar projects, including programs that we’ve adapted for different racial and ethnic communities in and around Chicago, has reduced or eliminated delays in diagnostic resolution of gynecologic cancer (Cancer. 2015 Nov 15;121[22]:4025-34, Breast Cancer Res Treat. 2016 Aug;158[3]:523-34, Am J Public Health. 2015 May;105[5]:e87-94).
The patient navigation model is increasingly being adapted and used in a variety of contexts outside of cancer care as well. In a postpartum patient navigation program that we tested at Northwestern University’s Medicaid-based outpatient clinic, a navigator was hired to communicate with patients and support them between delivery and completion of their postpartum care. Patients were reminded through calls and/or texts of their postpartum visits and of the benefits of breastfeeding, effective contraception, and other postpartum practices.
The demonstration project was impactful: Women who were enrolled in the program were more likely to return for postpartum care, to receive World Health Organization Tier 1 or 2 contraception, and to have postpartum screening and vaccinations, compared with women who received care before the program began (Obstet Gynecol. 2017 May;129[5]:925-33).
Connections to our patients will help us to achieve health equity. This includes connections between the primary care we provide and the specialty care our patients sometimes require, both inside and outside of our field. We may refer a patient to an oncology team, for instance, and in the process, unwittingly transfer her care such that other conditions that we’ve been managing – hypertension, depression, or diabetes – fall by the wayside.
Instead, we have to re-engineer our processes so that we maintain personalized connections back to these patients. For example, the referring ob.gyn. could develop and send to the oncologist or gynecologic-oncologist a care plan that includes the patient’s comorbid conditions and how they could be managed. This would allow for clearer communication.
Our communities
As ob.gyns., we have a common goal of championing health equity and true population health for every woman, regardless of whether she lives in rural, urban, or suburban America and regardless of whether she has conservative or liberal values. To do so, we must extend ourselves beyond our own practices.
In a committee opinion on Racial and Ethnic Disparities in Obstetrics and Gynecology, the American College of Obstetricians and Gynecologists advises that ob.gyns. take a number of actions to increase health equity. These include raising awareness about inequity and its effects on health outcomes, promoting quality improvement projects that target disparities, working with public health leadership, and helping recruit ob.gyns. and other health care providers from racial and ethnic minority groups (Obstet Gynecol 2015;126:e130-4).
In Chicago, where 1 out of 5 people lives in poverty and 1 out of 10 lives in deep poverty, we are still in our infancy in combating health inequities. However, with partnerships between academic institutions, departments of health, and other organizations across various sectors, we are beginning to move the needle on these entrenched health inequities.
For example, in 2007, there was a 60% difference in breast cancer mortality between black and white women in Chicago. This disparity sparked the development of the Metropolitan Chicago Breast Cancer Task Force and a series of on-the-ground patient navigator programs, along with several key policy changes and new state laws.
State actions included requiring quality reporting on mammography and increasing the Medicaid reimbursement rate for mammography to the Medicare rate. Nationally, beneficial changes were made to Medicare’s quality metrics and to the National Breast and Cervical Cancer Early Detection Program. All told, through a combination of studies and initiatives focused on improving knowledge, trust, access to care, and quality of care, we have been able to decrease the breast cancer mortality gap by 20%.
We also have a role to play in nurturing and developing a workforce that better aligns with our evolving demographics. This involves redesigning how we plant seeds of opportunity among high school students, undergraduates, and young medical students, and how we seek job applicants. Moreover, when we help people get to the next step in their careers, we need to make sure there is continuous support to retain them and help propel them to the next level.
We should think creatively to establish programs or launch initiatives that can help level the playing field for all women. For example, I created a Massive Open Online Course called “Career 911: Your Future Job in Medicine and Healthcare” as a free workforce development pipeline program. It is accessible on a global platform (https://www.coursera.org/learn/healthcarejobs) and is one example of how we as ob.gyns. can leverage our skills and resources.
Along the way, we also need to train our students and residents – and ourselves – to be more familiar with, and articulate about, health care policy. We need to understand how policy is made and modified and how we can be good communicators and thought leaders.
Right now, our ability to articulate our patients’ stories to policy makers and to the public seems underdeveloped and undertapped. The onus is on us to write and speak about how all women must have the opportunity to not only access care but to access high-quality care and preventive services that are important for full health. Providing health equity isn’t about giving someone a handout, but about giving her a helping hand to take control of her health.
Achieving health equity will involve changing our approach to research. If medical research on women’s health continues to be dominated by studies in which participants are homogeneous and from mainly white or well-resourced populations, we will never have output that is generalizable. As practicing ob.gyns., we can look for opportunities to advocate for diversity in research. We can also acknowledge that, for some women, there is historically-rooted distrust of the health care system that serves as a barrier both to obtaining care and enrolling in trials.
By meeting women where they are, and by tailoring their individual boxes as best we can – in research, in workforce development, and in clinical care delivery – we can work toward solutions.
Strategies for achieving women’s health equity
• Modify office hours/dates to allow flexibility for women who have challenges scheduling childcare and time off from work.
• Ensure handouts, educational materials, and all communications are at appropriate health literacy levels.
• Acknowledge and understand an individual woman’s barriers to care, including social determinants of health, and create a care plan that is achievable for her.
• Learn about and refer women to local community resources needed to overcome barriers to care, such as childcare, social services support, support services for intimate partner violence, and substance abuse counseling.
• Examine office processes to optimize the number of visits women have to attend for a particular health issue. Are there ways to explain results and next steps in a care plan without having to make her come back for an office visit?
Dr. Simon is the George H. Gardner Professor of Clinical Gynecology at Northwestern University, Chicago, and director of the Chicago Cancer Health Equity Collaborative. She is a member of the U.S. Preventive Services Task Force, but the views expressed in this piece are her own.
Of all the medical professions, obstetrics and gynecology should be the strongest champion for equity in women’s health in this country and globally. The question is, what does this mean in the reality of 2017 and moving forward in the 21st century? What does it mean in the context of our own practices and in the landscape of current policy and politics?
Finding answers to these questions requires both a deep understanding of the meaning of health equity and a willingness to rethink the architecture and engineering of how we currently provide care.
The terms equity and equality are sometimes used interchangeably, but they actually have quite different meanings. Imagine three women of different heights standing underneath the lowest branch of a tall apple tree. None of the three women are tall enough to pick an apple from the branch.
If we think about equality, we would assist each woman by giving her a box to stand on, and all three boxes would be the same size. This means that while the tallest woman will now be able to pick an apple, the medium-height woman may be able to touch but not pick the apple, and the shortest woman still may not be able to reach the apple at all.
However, if we think about equity, we’d acknowledge that each woman needs her own personalized box to be able to pick the apple. For instance, the shortest woman may need a box that is three times the height of the box used by the tallest woman.
Achieving true population health for all women requires that we similarly eliminate inequities by providing each patient with her own personalized care plan to help her reach and maintain her health.
Women from minority groups have higher rates of low birth weight, preterm birth, stillbirth, gestational diabetes and its complications, HIV, breast cancer mortality and cervical cancer incidence and mortality, infertility and response to fertility treatment, and maternal mortality.
Yet inequity runs deeper than racial/ethnic labels; disparities also are created by a host of other factors, from cognitive or physical disabilities to gender or sexual identity or orientation, one’s ZIP code, working environment, language, and health literacy.
More than ever, the art of medicine involves understanding how to meet every patient where she is – given her own context and beliefs and levels of support – so that every woman has the opportunity to stand on the right-sized box and pick the apple and thrive.
Our practices
Provider bias and stereotyping can impact health care and health outcomes, and it is important that we work to prevent this in ourselves and in our staff. This means not making assumptions. It means really listening to our patients in ways that we may not have before.
Women who have experienced health inequity may have unique barriers to success. Therefore, we must listen for cues and inquire about our patients’ environment and circumstances, as well as their partnerships and support – or lack thereof. We should then acknowledge and communicate that certain social and environmental factors may impact our ability to achieve a desired outcome.
How can we impact the diet of a patient with gestational diabetes, for instance, if we have not adequately communicated what medical nutritional therapy means in the context of her own culture and ability to access food? If she lives in a food desert or has food insecurity or lives in a violence-ridden neighborhood that keeps her from going to a grocery store regularly, we must think outside the box. Ob.gyns. and their clinical care teams can work with women who have less access to nutritious foods, or who have certain cultural food staples, to suggest recipes and grocery lists that make sense with respect to the types of stores they shop in or their cultural preferences.
When it comes to cancer prevention and treatment, how can we expect a woman to be compliant with screening if we cannot help her understand that she can get screening services for free with her health insurance? How can we help a woman who has coverage for, or access to, free screening but then no funding or coverage for a diagnostic test or cancer treatment? How can we support a patient with abnormal cancer screening results who hasn’t followed up for months because she is afraid to leave home without her partner’s permission?
Such questions and circumstances often involve what we call “social determinants of health,” and they force us to rethink how we can better deliver and optimize care. Re-engineering our practices for health equity may involve employing a more diverse practice staff, linking patients with community resources, modifying our practice hours to align better with working women’s schedules, or finding creative ways to discern patients’ motivating factors and then piggyback on these factors.
We may also need to modify how we approach the number of return visits that we request of women so that follow-up care aligns better with their ability to leave work or find childcare. Simply put, we should strive to set up our patients for success, not failure.
We can pointedly ask patients about the kinds of information and support they want and need. We might ask, for instance: What do you need, and how can I work with you, so that you can effectively monitor and control your glucose levels? How can I work with you to help you get onto a trajectory to stop smoking? How can I help you better understand what tests and procedures are covered under your insurance plan, or whether you qualify for free services?
Patients with lower health literacy may need teach-back methods to validate understanding, or messaging that is more focused and limited at any one time. Self-efficacy through patient-centered education and support should be our goal.
Practices and clinics may also be able to adapt elements of the National Cancer Institute’s multicenter Patient Navigation Research Program, in which community health workers or other “patient navigators” address women’s personal barriers to the timely follow-up of abnormal breast and cervical cancer screening results. Patient navigation through this program and similar projects, including programs that we’ve adapted for different racial and ethnic communities in and around Chicago, has reduced or eliminated delays in diagnostic resolution of gynecologic cancer (Cancer. 2015 Nov 15;121[22]:4025-34, Breast Cancer Res Treat. 2016 Aug;158[3]:523-34, Am J Public Health. 2015 May;105[5]:e87-94).
The patient navigation model is increasingly being adapted and used in a variety of contexts outside of cancer care as well. In a postpartum patient navigation program that we tested at Northwestern University’s Medicaid-based outpatient clinic, a navigator was hired to communicate with patients and support them between delivery and completion of their postpartum care. Patients were reminded through calls and/or texts of their postpartum visits and of the benefits of breastfeeding, effective contraception, and other postpartum practices.
The demonstration project was impactful: Women who were enrolled in the program were more likely to return for postpartum care, to receive World Health Organization Tier 1 or 2 contraception, and to have postpartum screening and vaccinations, compared with women who received care before the program began (Obstet Gynecol. 2017 May;129[5]:925-33).
Connections to our patients will help us to achieve health equity. This includes connections between the primary care we provide and the specialty care our patients sometimes require, both inside and outside of our field. We may refer a patient to an oncology team, for instance, and in the process, unwittingly transfer her care such that other conditions that we’ve been managing – hypertension, depression, or diabetes – fall by the wayside.
Instead, we have to re-engineer our processes so that we maintain personalized connections back to these patients. For example, the referring ob.gyn. could develop and send to the oncologist or gynecologic-oncologist a care plan that includes the patient’s comorbid conditions and how they could be managed. This would allow for clearer communication.
Our communities
As ob.gyns., we have a common goal of championing health equity and true population health for every woman, regardless of whether she lives in rural, urban, or suburban America and regardless of whether she has conservative or liberal values. To do so, we must extend ourselves beyond our own practices.
In a committee opinion on Racial and Ethnic Disparities in Obstetrics and Gynecology, the American College of Obstetricians and Gynecologists advises that ob.gyns. take a number of actions to increase health equity. These include raising awareness about inequity and its effects on health outcomes, promoting quality improvement projects that target disparities, working with public health leadership, and helping recruit ob.gyns. and other health care providers from racial and ethnic minority groups (Obstet Gynecol 2015;126:e130-4).
In Chicago, where 1 out of 5 people lives in poverty and 1 out of 10 lives in deep poverty, we are still in our infancy in combating health inequities. However, with partnerships between academic institutions, departments of health, and other organizations across various sectors, we are beginning to move the needle on these entrenched health inequities.
For example, in 2007, there was a 60% difference in breast cancer mortality between black and white women in Chicago. This disparity sparked the development of the Metropolitan Chicago Breast Cancer Task Force and a series of on-the-ground patient navigator programs, along with several key policy changes and new state laws.
State actions included requiring quality reporting on mammography and increasing the Medicaid reimbursement rate for mammography to the Medicare rate. Nationally, beneficial changes were made to Medicare’s quality metrics and to the National Breast and Cervical Cancer Early Detection Program. All told, through a combination of studies and initiatives focused on improving knowledge, trust, access to care, and quality of care, we have been able to decrease the breast cancer mortality gap by 20%.
We also have a role to play in nurturing and developing a workforce that better aligns with our evolving demographics. This involves redesigning how we plant seeds of opportunity among high school students, undergraduates, and young medical students, and how we seek job applicants. Moreover, when we help people get to the next step in their careers, we need to make sure there is continuous support to retain them and help propel them to the next level.
We should think creatively to establish programs or launch initiatives that can help level the playing field for all women. For example, I created a Massive Open Online Course called “Career 911: Your Future Job in Medicine and Healthcare” as a free workforce development pipeline program. It is accessible on a global platform (https://www.coursera.org/learn/healthcarejobs) and is one example of how we as ob.gyns. can leverage our skills and resources.
Along the way, we also need to train our students and residents – and ourselves – to be more familiar with, and articulate about, health care policy. We need to understand how policy is made and modified and how we can be good communicators and thought leaders.
Right now, our ability to articulate our patients’ stories to policy makers and to the public seems underdeveloped and undertapped. The onus is on us to write and speak about how all women must have the opportunity to not only access care but to access high-quality care and preventive services that are important for full health. Providing health equity isn’t about giving someone a handout, but about giving her a helping hand to take control of her health.
Achieving health equity will involve changing our approach to research. If medical research on women’s health continues to be dominated by studies in which participants are homogeneous and from mainly white or well-resourced populations, we will never have output that is generalizable. As practicing ob.gyns., we can look for opportunities to advocate for diversity in research. We can also acknowledge that, for some women, there is historically-rooted distrust of the health care system that serves as a barrier both to obtaining care and enrolling in trials.
By meeting women where they are, and by tailoring their individual boxes as best we can – in research, in workforce development, and in clinical care delivery – we can work toward solutions.
Strategies for achieving women’s health equity
• Modify office hours/dates to allow flexibility for women who have challenges scheduling childcare and time off from work.
• Ensure handouts, educational materials, and all communications are at appropriate health literacy levels.
• Acknowledge and understand an individual woman’s barriers to care, including social determinants of health, and create a care plan that is achievable for her.
• Learn about and refer women to local community resources needed to overcome barriers to care, such as childcare, social services support, support services for intimate partner violence, and substance abuse counseling.
• Examine office processes to optimize the number of visits women have to attend for a particular health issue. Are there ways to explain results and next steps in a care plan without having to make her come back for an office visit?
Dr. Simon is the George H. Gardner Professor of Clinical Gynecology at Northwestern University, Chicago, and director of the Chicago Cancer Health Equity Collaborative. She is a member of the U.S. Preventive Services Task Force, but the views expressed in this piece are her own.
Of all the medical professions, obstetrics and gynecology should be the strongest champion for equity in women’s health in this country and globally. The question is, what does this mean in the reality of 2017 and moving forward in the 21st century? What does it mean in the context of our own practices and in the landscape of current policy and politics?
Finding answers to these questions requires both a deep understanding of the meaning of health equity and a willingness to rethink the architecture and engineering of how we currently provide care.
The terms equity and equality are sometimes used interchangeably, but they actually have quite different meanings. Imagine three women of different heights standing underneath the lowest branch of a tall apple tree. None of the three women are tall enough to pick an apple from the branch.
If we think about equality, we would assist each woman by giving her a box to stand on, and all three boxes would be the same size. This means that while the tallest woman will now be able to pick an apple, the medium-height woman may be able to touch but not pick the apple, and the shortest woman still may not be able to reach the apple at all.
However, if we think about equity, we’d acknowledge that each woman needs her own personalized box to be able to pick the apple. For instance, the shortest woman may need a box that is three times the height of the box used by the tallest woman.
Achieving true population health for all women requires that we similarly eliminate inequities by providing each patient with her own personalized care plan to help her reach and maintain her health.
Women from minority groups have higher rates of low birth weight, preterm birth, stillbirth, gestational diabetes and its complications, HIV, breast cancer mortality and cervical cancer incidence and mortality, infertility and response to fertility treatment, and maternal mortality.
Yet inequity runs deeper than racial/ethnic labels; disparities also are created by a host of other factors, from cognitive or physical disabilities to gender or sexual identity or orientation, one’s ZIP code, working environment, language, and health literacy.
More than ever, the art of medicine involves understanding how to meet every patient where she is – given her own context and beliefs and levels of support – so that every woman has the opportunity to stand on the right-sized box and pick the apple and thrive.
Our practices
Provider bias and stereotyping can impact health care and health outcomes, and it is important that we work to prevent this in ourselves and in our staff. This means not making assumptions. It means really listening to our patients in ways that we may not have before.
Women who have experienced health inequity may have unique barriers to success. Therefore, we must listen for cues and inquire about our patients’ environment and circumstances, as well as their partnerships and support – or lack thereof. We should then acknowledge and communicate that certain social and environmental factors may impact our ability to achieve a desired outcome.
How can we impact the diet of a patient with gestational diabetes, for instance, if we have not adequately communicated what medical nutritional therapy means in the context of her own culture and ability to access food? If she lives in a food desert or has food insecurity or lives in a violence-ridden neighborhood that keeps her from going to a grocery store regularly, we must think outside the box. Ob.gyns. and their clinical care teams can work with women who have less access to nutritious foods, or who have certain cultural food staples, to suggest recipes and grocery lists that make sense with respect to the types of stores they shop in or their cultural preferences.
When it comes to cancer prevention and treatment, how can we expect a woman to be compliant with screening if we cannot help her understand that she can get screening services for free with her health insurance? How can we help a woman who has coverage for, or access to, free screening but then no funding or coverage for a diagnostic test or cancer treatment? How can we support a patient with abnormal cancer screening results who hasn’t followed up for months because she is afraid to leave home without her partner’s permission?
Such questions and circumstances often involve what we call “social determinants of health,” and they force us to rethink how we can better deliver and optimize care. Re-engineering our practices for health equity may involve employing a more diverse practice staff, linking patients with community resources, modifying our practice hours to align better with working women’s schedules, or finding creative ways to discern patients’ motivating factors and then piggyback on these factors.
We may also need to modify how we approach the number of return visits that we request of women so that follow-up care aligns better with their ability to leave work or find childcare. Simply put, we should strive to set up our patients for success, not failure.
We can pointedly ask patients about the kinds of information and support they want and need. We might ask, for instance: What do you need, and how can I work with you, so that you can effectively monitor and control your glucose levels? How can I work with you to help you get onto a trajectory to stop smoking? How can I help you better understand what tests and procedures are covered under your insurance plan, or whether you qualify for free services?
Patients with lower health literacy may need teach-back methods to validate understanding, or messaging that is more focused and limited at any one time. Self-efficacy through patient-centered education and support should be our goal.
Practices and clinics may also be able to adapt elements of the National Cancer Institute’s multicenter Patient Navigation Research Program, in which community health workers or other “patient navigators” address women’s personal barriers to the timely follow-up of abnormal breast and cervical cancer screening results. Patient navigation through this program and similar projects, including programs that we’ve adapted for different racial and ethnic communities in and around Chicago, has reduced or eliminated delays in diagnostic resolution of gynecologic cancer (Cancer. 2015 Nov 15;121[22]:4025-34, Breast Cancer Res Treat. 2016 Aug;158[3]:523-34, Am J Public Health. 2015 May;105[5]:e87-94).
The patient navigation model is increasingly being adapted and used in a variety of contexts outside of cancer care as well. In a postpartum patient navigation program that we tested at Northwestern University’s Medicaid-based outpatient clinic, a navigator was hired to communicate with patients and support them between delivery and completion of their postpartum care. Patients were reminded through calls and/or texts of their postpartum visits and of the benefits of breastfeeding, effective contraception, and other postpartum practices.
The demonstration project was impactful: Women who were enrolled in the program were more likely to return for postpartum care, to receive World Health Organization Tier 1 or 2 contraception, and to have postpartum screening and vaccinations, compared with women who received care before the program began (Obstet Gynecol. 2017 May;129[5]:925-33).
Connections to our patients will help us to achieve health equity. This includes connections between the primary care we provide and the specialty care our patients sometimes require, both inside and outside of our field. We may refer a patient to an oncology team, for instance, and in the process, unwittingly transfer her care such that other conditions that we’ve been managing – hypertension, depression, or diabetes – fall by the wayside.
Instead, we have to re-engineer our processes so that we maintain personalized connections back to these patients. For example, the referring ob.gyn. could develop and send to the oncologist or gynecologic-oncologist a care plan that includes the patient’s comorbid conditions and how they could be managed. This would allow for clearer communication.
Our communities
As ob.gyns., we have a common goal of championing health equity and true population health for every woman, regardless of whether she lives in rural, urban, or suburban America and regardless of whether she has conservative or liberal values. To do so, we must extend ourselves beyond our own practices.
In a committee opinion on Racial and Ethnic Disparities in Obstetrics and Gynecology, the American College of Obstetricians and Gynecologists advises that ob.gyns. take a number of actions to increase health equity. These include raising awareness about inequity and its effects on health outcomes, promoting quality improvement projects that target disparities, working with public health leadership, and helping recruit ob.gyns. and other health care providers from racial and ethnic minority groups (Obstet Gynecol 2015;126:e130-4).
In Chicago, where 1 out of 5 people lives in poverty and 1 out of 10 lives in deep poverty, we are still in our infancy in combating health inequities. However, with partnerships between academic institutions, departments of health, and other organizations across various sectors, we are beginning to move the needle on these entrenched health inequities.
For example, in 2007, there was a 60% difference in breast cancer mortality between black and white women in Chicago. This disparity sparked the development of the Metropolitan Chicago Breast Cancer Task Force and a series of on-the-ground patient navigator programs, along with several key policy changes and new state laws.
State actions included requiring quality reporting on mammography and increasing the Medicaid reimbursement rate for mammography to the Medicare rate. Nationally, beneficial changes were made to Medicare’s quality metrics and to the National Breast and Cervical Cancer Early Detection Program. All told, through a combination of studies and initiatives focused on improving knowledge, trust, access to care, and quality of care, we have been able to decrease the breast cancer mortality gap by 20%.
We also have a role to play in nurturing and developing a workforce that better aligns with our evolving demographics. This involves redesigning how we plant seeds of opportunity among high school students, undergraduates, and young medical students, and how we seek job applicants. Moreover, when we help people get to the next step in their careers, we need to make sure there is continuous support to retain them and help propel them to the next level.
We should think creatively to establish programs or launch initiatives that can help level the playing field for all women. For example, I created a Massive Open Online Course called “Career 911: Your Future Job in Medicine and Healthcare” as a free workforce development pipeline program. It is accessible on a global platform (https://www.coursera.org/learn/healthcarejobs) and is one example of how we as ob.gyns. can leverage our skills and resources.
Along the way, we also need to train our students and residents – and ourselves – to be more familiar with, and articulate about, health care policy. We need to understand how policy is made and modified and how we can be good communicators and thought leaders.
Right now, our ability to articulate our patients’ stories to policy makers and to the public seems underdeveloped and undertapped. The onus is on us to write and speak about how all women must have the opportunity to not only access care but to access high-quality care and preventive services that are important for full health. Providing health equity isn’t about giving someone a handout, but about giving her a helping hand to take control of her health.
Achieving health equity will involve changing our approach to research. If medical research on women’s health continues to be dominated by studies in which participants are homogeneous and from mainly white or well-resourced populations, we will never have output that is generalizable. As practicing ob.gyns., we can look for opportunities to advocate for diversity in research. We can also acknowledge that, for some women, there is historically-rooted distrust of the health care system that serves as a barrier both to obtaining care and enrolling in trials.
By meeting women where they are, and by tailoring their individual boxes as best we can – in research, in workforce development, and in clinical care delivery – we can work toward solutions.
Strategies for achieving women’s health equity
• Modify office hours/dates to allow flexibility for women who have challenges scheduling childcare and time off from work.
• Ensure handouts, educational materials, and all communications are at appropriate health literacy levels.
• Acknowledge and understand an individual woman’s barriers to care, including social determinants of health, and create a care plan that is achievable for her.
• Learn about and refer women to local community resources needed to overcome barriers to care, such as childcare, social services support, support services for intimate partner violence, and substance abuse counseling.
• Examine office processes to optimize the number of visits women have to attend for a particular health issue. Are there ways to explain results and next steps in a care plan without having to make her come back for an office visit?
Dr. Simon is the George H. Gardner Professor of Clinical Gynecology at Northwestern University, Chicago, and director of the Chicago Cancer Health Equity Collaborative. She is a member of the U.S. Preventive Services Task Force, but the views expressed in this piece are her own.
Consider neurodevelopmental impacts of hyperemesis gravidarum
Hyperemesis gravidarum (HG) affects just 1%-2% of pregnant women, but it’s clinical consequences are significant, with excess vomiting and dehydration, hospitalization, and the need for intravenous fluids being common in that group. In extreme cases, repeated vomiting has led to tears in the esophagus and severe dehydration has caused acute renal failure. All of that leaves aside the obvious suffering and distress it causes for women with the condition.
While studies continue to support the long-held theory that mild-to-moderate nausea and vomiting has a protective effect in pregnancy, that does not appear to be true for HG. Rather, the medical literature shows that HG is associated with small-for-gestational-age neonates, low birth weight, higher rates of preterm birth, and lower Apgar scores at 5 minutes.
I was one of the investigators on a study that prospectively followed more than 200 women with nausea and vomiting in pregnancy from 2006 to 2012. We found that children whose mothers were hospitalized for their symptoms – 22 in all – had significantly lower IQ scores at 3.5 years to 7 years, compared with children whose mothers were not hospitalized. Verbal IQ scores were 107.2 points vs. 112.7 (P = .04), performance IQ scores were 105.6 vs. 112.3 (P = .03), and full scale IQ was 108.7 vs. 114.2 (P = .05).
The study cohort included three groups: women treated with more than four tablets per day of doxylamine/pyridoxine (Diclegis); women treated with up to four tablets per day of the drug; and women who did not receive pharmacotherapy (Obstet Gynecol. 2015. doi: 10.1097/01.AOG.0000463229.81803.1a).
Hospitalized women in the study received antiemetics about a week later, experienced more severe symptoms, and were more likely to report depression. Overall, we found that duration of hospitalization, maternal depression, and maternal IQ all were significant predictors for these outcomes. However, daily antiemetic therapy was not associated with adverse outcomes.
Another study, published the same year, found that children exposed to HG had a more than three times increased risk for a neurodevelopmental diagnosis, including attention disorders, speech and language delays, and sensory disorders. The changes were more prevalent when women experienced symptoms early in pregnancy – prior to 5 weeks of gestation (Eur J Obstet Gynecol Reprod Biol. 2015 Jun;189:79-84).
The study compared neurodevelopmental outcomes for 312 children from 203 women with HG, with 169 children from 89 unaffected mothers. The findings are similar to those of our study, despite the differences in methodologies. Both studies found that the antiemetics were not associated with adverse outcomes, but the symptoms of HG appear to be the culprit.
While more research is needed to confirm these findings, it makes sense that the nutritional deficiencies created by excess vomiting and inability to eat are having an impact on the fetus.
It also raises an important question for the ob.gyn. about when to intervene in these women. Often, clinicians take a wait-and-see approach to nausea and vomiting in pregnancy, but the developing research suggests that earlier intervention would lead to better outcomes for mother and baby. One guide to determining that preventive antiemetics are necessary is to consider whether your patient has had HG in a previous pregnancy or if her mother or sister has experienced HG.
Another consideration is treating the nutritional deficiency that develops in women whose HG symptoms persist. These women are not simply in need of fluids and electrolytes but are missing essential vitamins and proteins. This is an area where much more research is needed, but clinicians can take a proactive approach by providing team care that includes consultation with a dietitians or nutritionist.
Finally, we cannot forget that maternal depression also appears to be significant predictor of poor fetal outcomes, so providing appropriate psychiatric treatment is essential.
Dr. Koren is professor of physiology/pharmacology and pediatrics at Western University in Ontario. He is the founder of the Motherisk Program. Dr. Koren was a principal investigator in the U.S. study that resulted in the approval of Diclegis, marketed by Duchesnay USA, and has served as a consultant to Duchesnay.
Hyperemesis gravidarum (HG) affects just 1%-2% of pregnant women, but it’s clinical consequences are significant, with excess vomiting and dehydration, hospitalization, and the need for intravenous fluids being common in that group. In extreme cases, repeated vomiting has led to tears in the esophagus and severe dehydration has caused acute renal failure. All of that leaves aside the obvious suffering and distress it causes for women with the condition.
While studies continue to support the long-held theory that mild-to-moderate nausea and vomiting has a protective effect in pregnancy, that does not appear to be true for HG. Rather, the medical literature shows that HG is associated with small-for-gestational-age neonates, low birth weight, higher rates of preterm birth, and lower Apgar scores at 5 minutes.
I was one of the investigators on a study that prospectively followed more than 200 women with nausea and vomiting in pregnancy from 2006 to 2012. We found that children whose mothers were hospitalized for their symptoms – 22 in all – had significantly lower IQ scores at 3.5 years to 7 years, compared with children whose mothers were not hospitalized. Verbal IQ scores were 107.2 points vs. 112.7 (P = .04), performance IQ scores were 105.6 vs. 112.3 (P = .03), and full scale IQ was 108.7 vs. 114.2 (P = .05).
The study cohort included three groups: women treated with more than four tablets per day of doxylamine/pyridoxine (Diclegis); women treated with up to four tablets per day of the drug; and women who did not receive pharmacotherapy (Obstet Gynecol. 2015. doi: 10.1097/01.AOG.0000463229.81803.1a).
Hospitalized women in the study received antiemetics about a week later, experienced more severe symptoms, and were more likely to report depression. Overall, we found that duration of hospitalization, maternal depression, and maternal IQ all were significant predictors for these outcomes. However, daily antiemetic therapy was not associated with adverse outcomes.
Another study, published the same year, found that children exposed to HG had a more than three times increased risk for a neurodevelopmental diagnosis, including attention disorders, speech and language delays, and sensory disorders. The changes were more prevalent when women experienced symptoms early in pregnancy – prior to 5 weeks of gestation (Eur J Obstet Gynecol Reprod Biol. 2015 Jun;189:79-84).
The study compared neurodevelopmental outcomes for 312 children from 203 women with HG, with 169 children from 89 unaffected mothers. The findings are similar to those of our study, despite the differences in methodologies. Both studies found that the antiemetics were not associated with adverse outcomes, but the symptoms of HG appear to be the culprit.
While more research is needed to confirm these findings, it makes sense that the nutritional deficiencies created by excess vomiting and inability to eat are having an impact on the fetus.
It also raises an important question for the ob.gyn. about when to intervene in these women. Often, clinicians take a wait-and-see approach to nausea and vomiting in pregnancy, but the developing research suggests that earlier intervention would lead to better outcomes for mother and baby. One guide to determining that preventive antiemetics are necessary is to consider whether your patient has had HG in a previous pregnancy or if her mother or sister has experienced HG.
Another consideration is treating the nutritional deficiency that develops in women whose HG symptoms persist. These women are not simply in need of fluids and electrolytes but are missing essential vitamins and proteins. This is an area where much more research is needed, but clinicians can take a proactive approach by providing team care that includes consultation with a dietitians or nutritionist.
Finally, we cannot forget that maternal depression also appears to be significant predictor of poor fetal outcomes, so providing appropriate psychiatric treatment is essential.
Dr. Koren is professor of physiology/pharmacology and pediatrics at Western University in Ontario. He is the founder of the Motherisk Program. Dr. Koren was a principal investigator in the U.S. study that resulted in the approval of Diclegis, marketed by Duchesnay USA, and has served as a consultant to Duchesnay.
Hyperemesis gravidarum (HG) affects just 1%-2% of pregnant women, but it’s clinical consequences are significant, with excess vomiting and dehydration, hospitalization, and the need for intravenous fluids being common in that group. In extreme cases, repeated vomiting has led to tears in the esophagus and severe dehydration has caused acute renal failure. All of that leaves aside the obvious suffering and distress it causes for women with the condition.
While studies continue to support the long-held theory that mild-to-moderate nausea and vomiting has a protective effect in pregnancy, that does not appear to be true for HG. Rather, the medical literature shows that HG is associated with small-for-gestational-age neonates, low birth weight, higher rates of preterm birth, and lower Apgar scores at 5 minutes.
I was one of the investigators on a study that prospectively followed more than 200 women with nausea and vomiting in pregnancy from 2006 to 2012. We found that children whose mothers were hospitalized for their symptoms – 22 in all – had significantly lower IQ scores at 3.5 years to 7 years, compared with children whose mothers were not hospitalized. Verbal IQ scores were 107.2 points vs. 112.7 (P = .04), performance IQ scores were 105.6 vs. 112.3 (P = .03), and full scale IQ was 108.7 vs. 114.2 (P = .05).
The study cohort included three groups: women treated with more than four tablets per day of doxylamine/pyridoxine (Diclegis); women treated with up to four tablets per day of the drug; and women who did not receive pharmacotherapy (Obstet Gynecol. 2015. doi: 10.1097/01.AOG.0000463229.81803.1a).
Hospitalized women in the study received antiemetics about a week later, experienced more severe symptoms, and were more likely to report depression. Overall, we found that duration of hospitalization, maternal depression, and maternal IQ all were significant predictors for these outcomes. However, daily antiemetic therapy was not associated with adverse outcomes.
Another study, published the same year, found that children exposed to HG had a more than three times increased risk for a neurodevelopmental diagnosis, including attention disorders, speech and language delays, and sensory disorders. The changes were more prevalent when women experienced symptoms early in pregnancy – prior to 5 weeks of gestation (Eur J Obstet Gynecol Reprod Biol. 2015 Jun;189:79-84).
The study compared neurodevelopmental outcomes for 312 children from 203 women with HG, with 169 children from 89 unaffected mothers. The findings are similar to those of our study, despite the differences in methodologies. Both studies found that the antiemetics were not associated with adverse outcomes, but the symptoms of HG appear to be the culprit.
While more research is needed to confirm these findings, it makes sense that the nutritional deficiencies created by excess vomiting and inability to eat are having an impact on the fetus.
It also raises an important question for the ob.gyn. about when to intervene in these women. Often, clinicians take a wait-and-see approach to nausea and vomiting in pregnancy, but the developing research suggests that earlier intervention would lead to better outcomes for mother and baby. One guide to determining that preventive antiemetics are necessary is to consider whether your patient has had HG in a previous pregnancy or if her mother or sister has experienced HG.
Another consideration is treating the nutritional deficiency that develops in women whose HG symptoms persist. These women are not simply in need of fluids and electrolytes but are missing essential vitamins and proteins. This is an area where much more research is needed, but clinicians can take a proactive approach by providing team care that includes consultation with a dietitians or nutritionist.
Finally, we cannot forget that maternal depression also appears to be significant predictor of poor fetal outcomes, so providing appropriate psychiatric treatment is essential.
Dr. Koren is professor of physiology/pharmacology and pediatrics at Western University in Ontario. He is the founder of the Motherisk Program. Dr. Koren was a principal investigator in the U.S. study that resulted in the approval of Diclegis, marketed by Duchesnay USA, and has served as a consultant to Duchesnay.
PARP inhibitors: New developments in ovarian cancer treatment
Ovarian cancer remains the leading cause of death from gynecologic cancer worldwide and one of the five leading causes of death from cancer in women in the United States. In addition to surgery, treatment consists of combination platinum and taxane chemotherapy that offers a high response rate; however, a majority of women will develop persistent or recurrent disease.
A clinical practice statement released by the Society of Gynecologic Oncology in October 2014 states that “women diagnosed with epithelial ovarian, tubal, and peritoneal cancers should receive genetic counseling and be offered genetic testing, even in the absence of family history.” Patients should be informed that this genetic testing serves to prognosticate, inform about personal and familial cancer risk, but also aids in choices of novel therapeutic agents, specifically Poly (ADP-ribose) polymerase (PARP) inhibitors.
Genetic involvement of BRCA
A small proportion of ovarian cancers are attributable to genetic mutations, with approximately 10%-15% of cases caused by germline mutations of BRCA1 and BRCA2. BRCA1 deleterious mutations confer an ovarian cancer risk of approximately 39%-46%; and the risk of ovarian cancer is roughly 12%-20% for patients with BRCA2 deleterious mutations. As a tumor suppressor gene, BRCA is involved in the DNA repair process. Specifically, it is involved in homologous recombination (a form of double-stranded DNA repair mechanism). Thus, cells with defective BRCA proteins cannot repair double-stranded breaks (DSB) in DNA.
The homologous recombination pathway is complex and involves a number of genes. Deficiencies in this pathway confer a sensitivity to PARP inhibition. Tumors that share dysfunction in the homologous recombination pathway, but do not contain mutations in the BRCA gene, are classified as tumors with “BRCAness.”
Generally, the inheritance of a defective BRCA1 or BRCA2 allele (a germline mutation) alone is not enough to cause the development of cancer. Instead, once the second, functioning allele becomes nonfunctional, cancer can arise through an accumulation of mutations in the genetic code.
Furthermore, regardless of germline BRCA status, cancers have high rates of genetic mutation. As a result of the mutation rate, tumors can develop noninherited, noninheritable alterations in BRCA1 or BRCA2 genes (a somatic mutation).
Mechanism of PARP inhibitor activity
The PARP family of enzymes hold a vital role in the repair of DNA and the stabilization of the human genome through the repair of single-stranded breaks (SSB) in DNA. PARP inhibitors were originally developed as a chemosensitizing agent for other cytotoxic agents. It was only later discovered that ovarian cancer cells and mouse models that were deficient in BRCA proteins were especially sensitive to PARP inhibition. Eventually, the clinical development strategy became to employ PARP inhibitors in selected patients with BRCA mutations.
As previously mentioned, cells deficient in the tumor suppressor genes (BRCA1 and BRCA2) have an inability to repair DSBs. Inhibiting PARP enzymes will therefore cause an increase in SSB. During cell replication, these SSBs are converted to DSBs. Ultimately, the accumulation of DSBs leads to cell death. The concept that these two deficiencies – which alone are nonlethal – can be combined to induce cell death is described as synthetic lethality.
The exact mechanism through which PARP inhibitors function is not fully understood; however, four models currently exist to explain how PARP inhibitors instigate synthetic lethality. PARP inhibitors may block base excision repair mechanisms, trap PARP enzymes on damaged DNA, reduce the affinity of functioning BRCA enzymes to damaged DNA, and suppress nonhomologous end joining repair mechanisms.1
FDA approval of PARP inhibitors
In recent years, the Food and Drug Administration has approved three PARP inhibitors in the treatment of ovarian cancer in slightly different clinical scenarios.
Olaparib was tested in a trial of 193 patients who harbored a deleterious or suspected deleterious germline BRCA-associated ovarian cancer who had received prior therapies.2 Overall, the response rate in this population was 41% (95% confidence interval, 28-54) with a median duration of response of 8.0 months. These results led to the FDA approval of olaparib for ovarian cancer treatment as fourth-line therapy in patients with BRCA mutations.
Two separate trials using rucaparib showed an overall response rate of 54% and a duration of response of 9.2 months.3,4 These early results allowed the FDA to grant accelerated approval to another PARP inhibitor for use in ovarian cancer.
More recently, a phase III trial of niraparib maintenance therapy versus placebo enrolled 553 women with recurrent epithelial ovarian cancer.5 Women with germline BRCA mutations had recurrence-free intervals of 21 months on niraparib, compared with 5.5 months for those on placebo. Even without germline BRCA mutations, women benefited from a recurrence-free interval of 9.3 months, compared with 3.9 months for placebo.
PARP inhibitors represent a novel targeted therapy for ovarian cancer, particularly those with deleterious germline or somatic BRCA mutations. When combined with genetic testing for BRCA mutations, PARP inhibitors represent an example of a predictive biomarker paired with a tailored therapeutic. Maturing data from ongoing trials will likely expand the opportunity to use PARP inhibitors for the treatment of ovarian cancer.
References
1. Br J Cancer. 2016 Nov 8;115(10):1157-73.
2. J Clin Oncol. 2015 Jan 20;33(3):244-50.
3. Clin Cancer Res. 2017 Mar 6. pii: clincanres.2796.2016. doi: 10.1158/1078-0432.CCR-16-2796.
4. Lancet Oncol. 2017 Jan;18(1):75-87.
5. N Engl J Med 2016; 375:2154-64.
Dr. Tran is a gynecologic oncology fellow in the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill. Dr. Rossi is an assistant professor in the division of gynecologic oncology at UNC-Chapel Hill. They reported having no relevant financial disclosures.
Ovarian cancer remains the leading cause of death from gynecologic cancer worldwide and one of the five leading causes of death from cancer in women in the United States. In addition to surgery, treatment consists of combination platinum and taxane chemotherapy that offers a high response rate; however, a majority of women will develop persistent or recurrent disease.
A clinical practice statement released by the Society of Gynecologic Oncology in October 2014 states that “women diagnosed with epithelial ovarian, tubal, and peritoneal cancers should receive genetic counseling and be offered genetic testing, even in the absence of family history.” Patients should be informed that this genetic testing serves to prognosticate, inform about personal and familial cancer risk, but also aids in choices of novel therapeutic agents, specifically Poly (ADP-ribose) polymerase (PARP) inhibitors.
Genetic involvement of BRCA
A small proportion of ovarian cancers are attributable to genetic mutations, with approximately 10%-15% of cases caused by germline mutations of BRCA1 and BRCA2. BRCA1 deleterious mutations confer an ovarian cancer risk of approximately 39%-46%; and the risk of ovarian cancer is roughly 12%-20% for patients with BRCA2 deleterious mutations. As a tumor suppressor gene, BRCA is involved in the DNA repair process. Specifically, it is involved in homologous recombination (a form of double-stranded DNA repair mechanism). Thus, cells with defective BRCA proteins cannot repair double-stranded breaks (DSB) in DNA.
The homologous recombination pathway is complex and involves a number of genes. Deficiencies in this pathway confer a sensitivity to PARP inhibition. Tumors that share dysfunction in the homologous recombination pathway, but do not contain mutations in the BRCA gene, are classified as tumors with “BRCAness.”
Generally, the inheritance of a defective BRCA1 or BRCA2 allele (a germline mutation) alone is not enough to cause the development of cancer. Instead, once the second, functioning allele becomes nonfunctional, cancer can arise through an accumulation of mutations in the genetic code.
Furthermore, regardless of germline BRCA status, cancers have high rates of genetic mutation. As a result of the mutation rate, tumors can develop noninherited, noninheritable alterations in BRCA1 or BRCA2 genes (a somatic mutation).
Mechanism of PARP inhibitor activity
The PARP family of enzymes hold a vital role in the repair of DNA and the stabilization of the human genome through the repair of single-stranded breaks (SSB) in DNA. PARP inhibitors were originally developed as a chemosensitizing agent for other cytotoxic agents. It was only later discovered that ovarian cancer cells and mouse models that were deficient in BRCA proteins were especially sensitive to PARP inhibition. Eventually, the clinical development strategy became to employ PARP inhibitors in selected patients with BRCA mutations.
As previously mentioned, cells deficient in the tumor suppressor genes (BRCA1 and BRCA2) have an inability to repair DSBs. Inhibiting PARP enzymes will therefore cause an increase in SSB. During cell replication, these SSBs are converted to DSBs. Ultimately, the accumulation of DSBs leads to cell death. The concept that these two deficiencies – which alone are nonlethal – can be combined to induce cell death is described as synthetic lethality.
The exact mechanism through which PARP inhibitors function is not fully understood; however, four models currently exist to explain how PARP inhibitors instigate synthetic lethality. PARP inhibitors may block base excision repair mechanisms, trap PARP enzymes on damaged DNA, reduce the affinity of functioning BRCA enzymes to damaged DNA, and suppress nonhomologous end joining repair mechanisms.1
FDA approval of PARP inhibitors
In recent years, the Food and Drug Administration has approved three PARP inhibitors in the treatment of ovarian cancer in slightly different clinical scenarios.
Olaparib was tested in a trial of 193 patients who harbored a deleterious or suspected deleterious germline BRCA-associated ovarian cancer who had received prior therapies.2 Overall, the response rate in this population was 41% (95% confidence interval, 28-54) with a median duration of response of 8.0 months. These results led to the FDA approval of olaparib for ovarian cancer treatment as fourth-line therapy in patients with BRCA mutations.
Two separate trials using rucaparib showed an overall response rate of 54% and a duration of response of 9.2 months.3,4 These early results allowed the FDA to grant accelerated approval to another PARP inhibitor for use in ovarian cancer.
More recently, a phase III trial of niraparib maintenance therapy versus placebo enrolled 553 women with recurrent epithelial ovarian cancer.5 Women with germline BRCA mutations had recurrence-free intervals of 21 months on niraparib, compared with 5.5 months for those on placebo. Even without germline BRCA mutations, women benefited from a recurrence-free interval of 9.3 months, compared with 3.9 months for placebo.
PARP inhibitors represent a novel targeted therapy for ovarian cancer, particularly those with deleterious germline or somatic BRCA mutations. When combined with genetic testing for BRCA mutations, PARP inhibitors represent an example of a predictive biomarker paired with a tailored therapeutic. Maturing data from ongoing trials will likely expand the opportunity to use PARP inhibitors for the treatment of ovarian cancer.
References
1. Br J Cancer. 2016 Nov 8;115(10):1157-73.
2. J Clin Oncol. 2015 Jan 20;33(3):244-50.
3. Clin Cancer Res. 2017 Mar 6. pii: clincanres.2796.2016. doi: 10.1158/1078-0432.CCR-16-2796.
4. Lancet Oncol. 2017 Jan;18(1):75-87.
5. N Engl J Med 2016; 375:2154-64.
Dr. Tran is a gynecologic oncology fellow in the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill. Dr. Rossi is an assistant professor in the division of gynecologic oncology at UNC-Chapel Hill. They reported having no relevant financial disclosures.
Ovarian cancer remains the leading cause of death from gynecologic cancer worldwide and one of the five leading causes of death from cancer in women in the United States. In addition to surgery, treatment consists of combination platinum and taxane chemotherapy that offers a high response rate; however, a majority of women will develop persistent or recurrent disease.
A clinical practice statement released by the Society of Gynecologic Oncology in October 2014 states that “women diagnosed with epithelial ovarian, tubal, and peritoneal cancers should receive genetic counseling and be offered genetic testing, even in the absence of family history.” Patients should be informed that this genetic testing serves to prognosticate, inform about personal and familial cancer risk, but also aids in choices of novel therapeutic agents, specifically Poly (ADP-ribose) polymerase (PARP) inhibitors.
Genetic involvement of BRCA
A small proportion of ovarian cancers are attributable to genetic mutations, with approximately 10%-15% of cases caused by germline mutations of BRCA1 and BRCA2. BRCA1 deleterious mutations confer an ovarian cancer risk of approximately 39%-46%; and the risk of ovarian cancer is roughly 12%-20% for patients with BRCA2 deleterious mutations. As a tumor suppressor gene, BRCA is involved in the DNA repair process. Specifically, it is involved in homologous recombination (a form of double-stranded DNA repair mechanism). Thus, cells with defective BRCA proteins cannot repair double-stranded breaks (DSB) in DNA.
The homologous recombination pathway is complex and involves a number of genes. Deficiencies in this pathway confer a sensitivity to PARP inhibition. Tumors that share dysfunction in the homologous recombination pathway, but do not contain mutations in the BRCA gene, are classified as tumors with “BRCAness.”
Generally, the inheritance of a defective BRCA1 or BRCA2 allele (a germline mutation) alone is not enough to cause the development of cancer. Instead, once the second, functioning allele becomes nonfunctional, cancer can arise through an accumulation of mutations in the genetic code.
Furthermore, regardless of germline BRCA status, cancers have high rates of genetic mutation. As a result of the mutation rate, tumors can develop noninherited, noninheritable alterations in BRCA1 or BRCA2 genes (a somatic mutation).
Mechanism of PARP inhibitor activity
The PARP family of enzymes hold a vital role in the repair of DNA and the stabilization of the human genome through the repair of single-stranded breaks (SSB) in DNA. PARP inhibitors were originally developed as a chemosensitizing agent for other cytotoxic agents. It was only later discovered that ovarian cancer cells and mouse models that were deficient in BRCA proteins were especially sensitive to PARP inhibition. Eventually, the clinical development strategy became to employ PARP inhibitors in selected patients with BRCA mutations.
As previously mentioned, cells deficient in the tumor suppressor genes (BRCA1 and BRCA2) have an inability to repair DSBs. Inhibiting PARP enzymes will therefore cause an increase in SSB. During cell replication, these SSBs are converted to DSBs. Ultimately, the accumulation of DSBs leads to cell death. The concept that these two deficiencies – which alone are nonlethal – can be combined to induce cell death is described as synthetic lethality.
The exact mechanism through which PARP inhibitors function is not fully understood; however, four models currently exist to explain how PARP inhibitors instigate synthetic lethality. PARP inhibitors may block base excision repair mechanisms, trap PARP enzymes on damaged DNA, reduce the affinity of functioning BRCA enzymes to damaged DNA, and suppress nonhomologous end joining repair mechanisms.1
FDA approval of PARP inhibitors
In recent years, the Food and Drug Administration has approved three PARP inhibitors in the treatment of ovarian cancer in slightly different clinical scenarios.
Olaparib was tested in a trial of 193 patients who harbored a deleterious or suspected deleterious germline BRCA-associated ovarian cancer who had received prior therapies.2 Overall, the response rate in this population was 41% (95% confidence interval, 28-54) with a median duration of response of 8.0 months. These results led to the FDA approval of olaparib for ovarian cancer treatment as fourth-line therapy in patients with BRCA mutations.
Two separate trials using rucaparib showed an overall response rate of 54% and a duration of response of 9.2 months.3,4 These early results allowed the FDA to grant accelerated approval to another PARP inhibitor for use in ovarian cancer.
More recently, a phase III trial of niraparib maintenance therapy versus placebo enrolled 553 women with recurrent epithelial ovarian cancer.5 Women with germline BRCA mutations had recurrence-free intervals of 21 months on niraparib, compared with 5.5 months for those on placebo. Even without germline BRCA mutations, women benefited from a recurrence-free interval of 9.3 months, compared with 3.9 months for placebo.
PARP inhibitors represent a novel targeted therapy for ovarian cancer, particularly those with deleterious germline or somatic BRCA mutations. When combined with genetic testing for BRCA mutations, PARP inhibitors represent an example of a predictive biomarker paired with a tailored therapeutic. Maturing data from ongoing trials will likely expand the opportunity to use PARP inhibitors for the treatment of ovarian cancer.
References
1. Br J Cancer. 2016 Nov 8;115(10):1157-73.
2. J Clin Oncol. 2015 Jan 20;33(3):244-50.
3. Clin Cancer Res. 2017 Mar 6. pii: clincanres.2796.2016. doi: 10.1158/1078-0432.CCR-16-2796.
4. Lancet Oncol. 2017 Jan;18(1):75-87.
5. N Engl J Med 2016; 375:2154-64.
Dr. Tran is a gynecologic oncology fellow in the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill. Dr. Rossi is an assistant professor in the division of gynecologic oncology at UNC-Chapel Hill. They reported having no relevant financial disclosures.
Pelvic organ prolapse: Effective treatments
Editor’s Note: This is the fifth installment of a six-part series that will review key concepts and articles that ob.gyns. can use to prepare for the American Board of Obstetrics and Gynecology Maintenance of Certification examination. The series is adapted from Ob/Gyn Board Master (obgynboardmaster.com), an online board review course created by Erudyte. This month’s edition of the Board Corner focuses on pelvic organ prolapse.
The American College of Obstetricians and Gynecologists’ “Practice Bulletins” are important practice management guidelines for ob.gyn. clinicians. The Practice Bulletins are rich sources of material that is often tested on board exams. Earlier this year, ACOG released a revised Practice Bulletin (#176) updating its advice on the diagnosis and management of pelvic organ prolapse (POP).1 It is a well-written document summarizing most of the landmark articles published in the field of female pelvic medicine and reconstructive surgery. We recommend you read this bulletin and review this topic carefully.
Let’s begin with a possible medical board question: Which of the following procedures is the most effective for a sexually-active patient with advanced prolapse?
A. Sacrospinous ligament suspension (SSLS)
B. Uterosacral ligament suspension (USLS)
C. Sacrocolpopexy (SCP)
D. Colpocleisis
E. Hysteropexy
A randomized trial comparing SSLS and USLS found the two apical procedures with native tissue repair are equally effective with comparable functional and adverse outcomes (answers A and B are incorrect). However, randomized trials comparing SCP to SSLS show that SCP with synthetic mesh has the lowest recurrence rate for prolapse. Colpocleisis is done for patients who are not sexually active (answer D is incorrect). Hysteropexy is performed for patients who desire preservation of the uterus. There is less available evidence on safety and efficacy, compared with hysterectomy at the time of prolapse repair (answer E is incorrect)
Key points
The key points to remember are:
1. SCP is the most effective prolapse repair technique.
2. USLS and SSLS fixation are equally effective when compared with one another.
3. Colpocleisis is a highly successful procedure for POP in patients who are not sexually active.
Literature summary
The lifetime risk for undergoing surgery for POP or stress incontinence is 20%. POP is the descent of one or more aspects of the vagina or uterus, which allows nearby organs to herniate into the vagina. POP should only be treated if it is symptomatic and bothersome for the patient. The pessary is an alternative to surgical treatment of prolapse.
Proven risk factors for POP are increased parity, vaginal delivery, age, obesity, chronic constipation, and certain congenital anomalies. A history should be taken to elucidate symptoms of prolapse, such as bulge, pressure, sexual dysfunction, lower urinary tract dysfunction, or defecatory dysfunction. It is also important to find out how much the POP is affecting her quality of life. A physical exam is best performed with a split speculum, with bladder empty, while the patient performs a Valsalva maneuver. We recommend using the POP-Q system to grade the severity of prolapse. The tone of the pelvic floor muscle should also be evaluated (absent, weak, normal, or strong) during pelvic exam.
The minimum testing necessary for a patient with POP is urinalysis and a postvoid residual. A stress test with a full bladder should also be done with and without reduction of the prolapse. If you’re considering surgery and the patient has advanced prolapse and/or other complicating factors – such as obstructive symptoms or significant neurologic disorder – you should consider performing urodynamic testing as well.
Native tissue, suture-based reconstructive repairs of the vagina include apical procedures, such as SSLS and USLS, in addition to anterior colporrhaphy and posterior repair. At 2-year follow-up, SSLS and USLS along with anterior colporrhaphy and posterior repair are equally effective for treatment of prolapse with comparable functional and adverse outcomes. SCP is more effective than SSLS but the abdominal procedure (not laparoscopic) may be associated with more complications. Currently, there are no published randomized trials comparing minimally-invasive SCP to USLS, but one is underway (clinicaltrials.gov).
Other procedures for POP include obliterative procedures such as colpocleisis, which is highly effective for patients who do not desire future vaginal intercourse and also has low morbidity. Preservation of the uterus by hysteropexy procedures (either transvaginal or transabdominal) are also options for women desiring to preserve their uterus, but these procedures have little safety and efficacy data. Regardless of the procedure performed, routine intraoperative cystoscopy should be done to assure ureteral patency and to rule out injury to the lower urinary tract.
Some type of prophylactic anti-incontinence procedure – retropubic or Burch – may be done at the time of vaginal prolapse repair or abdominal prolapse repair, respectively, in order to reduce the chance of postoperative stress urinary incontinence in a patient without symptoms of stress incontinence. The exception to this is in a patient who has an elevated postvoid residual or someone with a prior anti-incontinence procedure without symptoms of stress urinary incontinence.
Practice tips
Finally, here are some precautions and words of advice about the following POP procedures:
- Neither synthetic nor biologic grafts should be used to augment posterior repairs as these do not improve outcomes.
- Transvaginal repair of rectocele is superior to the transanal repair techniques.
- Synthetic mesh augmentation of the anterior vaginal wall may improve anatomic outcomes, but this comes at a cost (more reoperations and higher rate of complications). Thus, surgeons performing these procedures should have specialized training and the patient should have a unique indication and must undergo proper consent as recommended by ACOG.
Dr. Siddighi is editor-in-chief of the Ob/Gyn Board Master and director of female pelvic medicine and reconstructive surgery and director of grand rounds at Loma Linda University Health in California. Ob.Gyn. News and Ob/Gyn Board Master are owned by the same parent company, Frontline Medical Communications.
Reference
Editor’s Note: This is the fifth installment of a six-part series that will review key concepts and articles that ob.gyns. can use to prepare for the American Board of Obstetrics and Gynecology Maintenance of Certification examination. The series is adapted from Ob/Gyn Board Master (obgynboardmaster.com), an online board review course created by Erudyte. This month’s edition of the Board Corner focuses on pelvic organ prolapse.
The American College of Obstetricians and Gynecologists’ “Practice Bulletins” are important practice management guidelines for ob.gyn. clinicians. The Practice Bulletins are rich sources of material that is often tested on board exams. Earlier this year, ACOG released a revised Practice Bulletin (#176) updating its advice on the diagnosis and management of pelvic organ prolapse (POP).1 It is a well-written document summarizing most of the landmark articles published in the field of female pelvic medicine and reconstructive surgery. We recommend you read this bulletin and review this topic carefully.
Let’s begin with a possible medical board question: Which of the following procedures is the most effective for a sexually-active patient with advanced prolapse?
A. Sacrospinous ligament suspension (SSLS)
B. Uterosacral ligament suspension (USLS)
C. Sacrocolpopexy (SCP)
D. Colpocleisis
E. Hysteropexy
A randomized trial comparing SSLS and USLS found the two apical procedures with native tissue repair are equally effective with comparable functional and adverse outcomes (answers A and B are incorrect). However, randomized trials comparing SCP to SSLS show that SCP with synthetic mesh has the lowest recurrence rate for prolapse. Colpocleisis is done for patients who are not sexually active (answer D is incorrect). Hysteropexy is performed for patients who desire preservation of the uterus. There is less available evidence on safety and efficacy, compared with hysterectomy at the time of prolapse repair (answer E is incorrect)
Key points
The key points to remember are:
1. SCP is the most effective prolapse repair technique.
2. USLS and SSLS fixation are equally effective when compared with one another.
3. Colpocleisis is a highly successful procedure for POP in patients who are not sexually active.
Literature summary
The lifetime risk for undergoing surgery for POP or stress incontinence is 20%. POP is the descent of one or more aspects of the vagina or uterus, which allows nearby organs to herniate into the vagina. POP should only be treated if it is symptomatic and bothersome for the patient. The pessary is an alternative to surgical treatment of prolapse.
Proven risk factors for POP are increased parity, vaginal delivery, age, obesity, chronic constipation, and certain congenital anomalies. A history should be taken to elucidate symptoms of prolapse, such as bulge, pressure, sexual dysfunction, lower urinary tract dysfunction, or defecatory dysfunction. It is also important to find out how much the POP is affecting her quality of life. A physical exam is best performed with a split speculum, with bladder empty, while the patient performs a Valsalva maneuver. We recommend using the POP-Q system to grade the severity of prolapse. The tone of the pelvic floor muscle should also be evaluated (absent, weak, normal, or strong) during pelvic exam.
The minimum testing necessary for a patient with POP is urinalysis and a postvoid residual. A stress test with a full bladder should also be done with and without reduction of the prolapse. If you’re considering surgery and the patient has advanced prolapse and/or other complicating factors – such as obstructive symptoms or significant neurologic disorder – you should consider performing urodynamic testing as well.
Native tissue, suture-based reconstructive repairs of the vagina include apical procedures, such as SSLS and USLS, in addition to anterior colporrhaphy and posterior repair. At 2-year follow-up, SSLS and USLS along with anterior colporrhaphy and posterior repair are equally effective for treatment of prolapse with comparable functional and adverse outcomes. SCP is more effective than SSLS but the abdominal procedure (not laparoscopic) may be associated with more complications. Currently, there are no published randomized trials comparing minimally-invasive SCP to USLS, but one is underway (clinicaltrials.gov).
Other procedures for POP include obliterative procedures such as colpocleisis, which is highly effective for patients who do not desire future vaginal intercourse and also has low morbidity. Preservation of the uterus by hysteropexy procedures (either transvaginal or transabdominal) are also options for women desiring to preserve their uterus, but these procedures have little safety and efficacy data. Regardless of the procedure performed, routine intraoperative cystoscopy should be done to assure ureteral patency and to rule out injury to the lower urinary tract.
Some type of prophylactic anti-incontinence procedure – retropubic or Burch – may be done at the time of vaginal prolapse repair or abdominal prolapse repair, respectively, in order to reduce the chance of postoperative stress urinary incontinence in a patient without symptoms of stress incontinence. The exception to this is in a patient who has an elevated postvoid residual or someone with a prior anti-incontinence procedure without symptoms of stress urinary incontinence.
Practice tips
Finally, here are some precautions and words of advice about the following POP procedures:
- Neither synthetic nor biologic grafts should be used to augment posterior repairs as these do not improve outcomes.
- Transvaginal repair of rectocele is superior to the transanal repair techniques.
- Synthetic mesh augmentation of the anterior vaginal wall may improve anatomic outcomes, but this comes at a cost (more reoperations and higher rate of complications). Thus, surgeons performing these procedures should have specialized training and the patient should have a unique indication and must undergo proper consent as recommended by ACOG.
Dr. Siddighi is editor-in-chief of the Ob/Gyn Board Master and director of female pelvic medicine and reconstructive surgery and director of grand rounds at Loma Linda University Health in California. Ob.Gyn. News and Ob/Gyn Board Master are owned by the same parent company, Frontline Medical Communications.
Reference
Editor’s Note: This is the fifth installment of a six-part series that will review key concepts and articles that ob.gyns. can use to prepare for the American Board of Obstetrics and Gynecology Maintenance of Certification examination. The series is adapted from Ob/Gyn Board Master (obgynboardmaster.com), an online board review course created by Erudyte. This month’s edition of the Board Corner focuses on pelvic organ prolapse.
The American College of Obstetricians and Gynecologists’ “Practice Bulletins” are important practice management guidelines for ob.gyn. clinicians. The Practice Bulletins are rich sources of material that is often tested on board exams. Earlier this year, ACOG released a revised Practice Bulletin (#176) updating its advice on the diagnosis and management of pelvic organ prolapse (POP).1 It is a well-written document summarizing most of the landmark articles published in the field of female pelvic medicine and reconstructive surgery. We recommend you read this bulletin and review this topic carefully.
Let’s begin with a possible medical board question: Which of the following procedures is the most effective for a sexually-active patient with advanced prolapse?
A. Sacrospinous ligament suspension (SSLS)
B. Uterosacral ligament suspension (USLS)
C. Sacrocolpopexy (SCP)
D. Colpocleisis
E. Hysteropexy
A randomized trial comparing SSLS and USLS found the two apical procedures with native tissue repair are equally effective with comparable functional and adverse outcomes (answers A and B are incorrect). However, randomized trials comparing SCP to SSLS show that SCP with synthetic mesh has the lowest recurrence rate for prolapse. Colpocleisis is done for patients who are not sexually active (answer D is incorrect). Hysteropexy is performed for patients who desire preservation of the uterus. There is less available evidence on safety and efficacy, compared with hysterectomy at the time of prolapse repair (answer E is incorrect)
Key points
The key points to remember are:
1. SCP is the most effective prolapse repair technique.
2. USLS and SSLS fixation are equally effective when compared with one another.
3. Colpocleisis is a highly successful procedure for POP in patients who are not sexually active.
Literature summary
The lifetime risk for undergoing surgery for POP or stress incontinence is 20%. POP is the descent of one or more aspects of the vagina or uterus, which allows nearby organs to herniate into the vagina. POP should only be treated if it is symptomatic and bothersome for the patient. The pessary is an alternative to surgical treatment of prolapse.
Proven risk factors for POP are increased parity, vaginal delivery, age, obesity, chronic constipation, and certain congenital anomalies. A history should be taken to elucidate symptoms of prolapse, such as bulge, pressure, sexual dysfunction, lower urinary tract dysfunction, or defecatory dysfunction. It is also important to find out how much the POP is affecting her quality of life. A physical exam is best performed with a split speculum, with bladder empty, while the patient performs a Valsalva maneuver. We recommend using the POP-Q system to grade the severity of prolapse. The tone of the pelvic floor muscle should also be evaluated (absent, weak, normal, or strong) during pelvic exam.
The minimum testing necessary for a patient with POP is urinalysis and a postvoid residual. A stress test with a full bladder should also be done with and without reduction of the prolapse. If you’re considering surgery and the patient has advanced prolapse and/or other complicating factors – such as obstructive symptoms or significant neurologic disorder – you should consider performing urodynamic testing as well.
Native tissue, suture-based reconstructive repairs of the vagina include apical procedures, such as SSLS and USLS, in addition to anterior colporrhaphy and posterior repair. At 2-year follow-up, SSLS and USLS along with anterior colporrhaphy and posterior repair are equally effective for treatment of prolapse with comparable functional and adverse outcomes. SCP is more effective than SSLS but the abdominal procedure (not laparoscopic) may be associated with more complications. Currently, there are no published randomized trials comparing minimally-invasive SCP to USLS, but one is underway (clinicaltrials.gov).
Other procedures for POP include obliterative procedures such as colpocleisis, which is highly effective for patients who do not desire future vaginal intercourse and also has low morbidity. Preservation of the uterus by hysteropexy procedures (either transvaginal or transabdominal) are also options for women desiring to preserve their uterus, but these procedures have little safety and efficacy data. Regardless of the procedure performed, routine intraoperative cystoscopy should be done to assure ureteral patency and to rule out injury to the lower urinary tract.
Some type of prophylactic anti-incontinence procedure – retropubic or Burch – may be done at the time of vaginal prolapse repair or abdominal prolapse repair, respectively, in order to reduce the chance of postoperative stress urinary incontinence in a patient without symptoms of stress incontinence. The exception to this is in a patient who has an elevated postvoid residual or someone with a prior anti-incontinence procedure without symptoms of stress urinary incontinence.
Practice tips
Finally, here are some precautions and words of advice about the following POP procedures:
- Neither synthetic nor biologic grafts should be used to augment posterior repairs as these do not improve outcomes.
- Transvaginal repair of rectocele is superior to the transanal repair techniques.
- Synthetic mesh augmentation of the anterior vaginal wall may improve anatomic outcomes, but this comes at a cost (more reoperations and higher rate of complications). Thus, surgeons performing these procedures should have specialized training and the patient should have a unique indication and must undergo proper consent as recommended by ACOG.
Dr. Siddighi is editor-in-chief of the Ob/Gyn Board Master and director of female pelvic medicine and reconstructive surgery and director of grand rounds at Loma Linda University Health in California. Ob.Gyn. News and Ob/Gyn Board Master are owned by the same parent company, Frontline Medical Communications.
Reference
Disease-Modifying Drug Treatment Before, During, and After Pregnancy in Women With MS
Treatment Before, During, and After Pregnancy
To evaluate treatment patterns before, during, and after pregnancy in women with MS and a live birth, Dr. Houtchens and colleagues used a US administrative claims database to conduct a retrospective analysis of women ages 18 to 65 with MS, a claim indicative of a live birth, and one-year continuous eligibility before and after pregnancy in the IMS Health Real World Data Adjudicated Claims US database from January 1, 2006, to June 30, 2015. Disease-modifying drug treatment was evaluated during the year prior to pregnancy (at three-month intervals), the three trimesters of pregnancy, puerperium (six weeks post-pregnancy), and one year post pregnancy (seven to 12 weeks post pregnancy and three to six, six to nine, and nine to 12 months post pregnancy). The researchers evaluated the proportion of women exposed to disease-modifying drug treatment during the 12 time periods. Results were also stratified by the number of relapses women experienced in the year prior to pregnancy.
Of 190,475 women with MS, 2,158 met eligibility criteria. Mean age was 30.26. Most women had commercial health insurance (98%) and were from the Midwest (32%), South (30%), or Northeast (29%) regions of the US.
The proportion of women with MS and a live birth treated with any disease-modifying drug was 20.48% at nine to 12 months pre-pregnancy, 21.46% at six to nine months pre-pregnancy, 20.62% at three to six months pre-pregnancy, and 17.75% at three months pre-pregnancy. During pregnancy, the proportion of women treated with a disease-modifying drug decreased to 12.05% during the first trimester and 1.90% during the second trimester, and then increased slightly to 2.97% during the third trimester. The proportion of women treated with disease-modifying drugs increased to 8.34% during puerperium, 12.93% during seven to 12 weeks post partum, 21.97% during three to six months post partum, 24.47% during six to nine months post partum, and 25.49% during nine to 12 months post partum. The majority of women (81.9%) had received disease-modifying drug treatment by six to nine months post partum. The proportion of women with disease-modifying drug treatment before and after pregnancy increased numerically with the number of relapses experienced before pregnancy.
Treatment After a Live Birth
In a separate analysis using the same cohort, Dr. Houtchens and colleagues looked closer at the time to initiation of disease-modifying drug treatment after a live birth in women with MS. Of the 2,094 women included in this analysis, the proportion with a live birth initiating a disease-modifying drug treatment within one year was 28.46%, and the proportion with no disease-modifying treatment within one year was 71.54%.
For those initiating a disease-modifying treatment within one year, mean time from live birth to first treatment was 118.98 days, and median time to first treatment was 93.50 days. A total of 16.11% received a disease-modifying drug less than 30 days after live birth, approximately half initiated a treatment within 90 days (47.82%), and three-quarters initiated a disease-modifying drug within six months (75.5%). The proportion of patients initiating treatment within one year after live birth increased with higher numbers of pre-pregnancy relapses (zero relapses, n = 441, 24.53%; one relapse, n = 108, 50.94%; two relapses, n = 33, 54.10%; three or more relapses, n = 14, 60.87%). The mean number of days until disease-modifying drug initiation for those receiving treatment within one year who had zero pre-pregnancy relapses was 123.57 (median, 99); one relapse, 107.95 (median, 80); two relapses, 120.76 (median, 98); and three or more relapses, 55.57 (median, 49.5). Patients who received disease-modifying drug treatment one year pre-pregnancy were more likely to receive treatment within one year after delivery, compared with patients without exposure to treatment in the year before pregnancy (72.58% vs 12.44%).
This study was supported by EMD Serono.
Treatment Before, During, and After Pregnancy
To evaluate treatment patterns before, during, and after pregnancy in women with MS and a live birth, Dr. Houtchens and colleagues used a US administrative claims database to conduct a retrospective analysis of women ages 18 to 65 with MS, a claim indicative of a live birth, and one-year continuous eligibility before and after pregnancy in the IMS Health Real World Data Adjudicated Claims US database from January 1, 2006, to June 30, 2015. Disease-modifying drug treatment was evaluated during the year prior to pregnancy (at three-month intervals), the three trimesters of pregnancy, puerperium (six weeks post-pregnancy), and one year post pregnancy (seven to 12 weeks post pregnancy and three to six, six to nine, and nine to 12 months post pregnancy). The researchers evaluated the proportion of women exposed to disease-modifying drug treatment during the 12 time periods. Results were also stratified by the number of relapses women experienced in the year prior to pregnancy.
Of 190,475 women with MS, 2,158 met eligibility criteria. Mean age was 30.26. Most women had commercial health insurance (98%) and were from the Midwest (32%), South (30%), or Northeast (29%) regions of the US.
The proportion of women with MS and a live birth treated with any disease-modifying drug was 20.48% at nine to 12 months pre-pregnancy, 21.46% at six to nine months pre-pregnancy, 20.62% at three to six months pre-pregnancy, and 17.75% at three months pre-pregnancy. During pregnancy, the proportion of women treated with a disease-modifying drug decreased to 12.05% during the first trimester and 1.90% during the second trimester, and then increased slightly to 2.97% during the third trimester. The proportion of women treated with disease-modifying drugs increased to 8.34% during puerperium, 12.93% during seven to 12 weeks post partum, 21.97% during three to six months post partum, 24.47% during six to nine months post partum, and 25.49% during nine to 12 months post partum. The majority of women (81.9%) had received disease-modifying drug treatment by six to nine months post partum. The proportion of women with disease-modifying drug treatment before and after pregnancy increased numerically with the number of relapses experienced before pregnancy.
Treatment After a Live Birth
In a separate analysis using the same cohort, Dr. Houtchens and colleagues looked closer at the time to initiation of disease-modifying drug treatment after a live birth in women with MS. Of the 2,094 women included in this analysis, the proportion with a live birth initiating a disease-modifying drug treatment within one year was 28.46%, and the proportion with no disease-modifying treatment within one year was 71.54%.
For those initiating a disease-modifying treatment within one year, mean time from live birth to first treatment was 118.98 days, and median time to first treatment was 93.50 days. A total of 16.11% received a disease-modifying drug less than 30 days after live birth, approximately half initiated a treatment within 90 days (47.82%), and three-quarters initiated a disease-modifying drug within six months (75.5%). The proportion of patients initiating treatment within one year after live birth increased with higher numbers of pre-pregnancy relapses (zero relapses, n = 441, 24.53%; one relapse, n = 108, 50.94%; two relapses, n = 33, 54.10%; three or more relapses, n = 14, 60.87%). The mean number of days until disease-modifying drug initiation for those receiving treatment within one year who had zero pre-pregnancy relapses was 123.57 (median, 99); one relapse, 107.95 (median, 80); two relapses, 120.76 (median, 98); and three or more relapses, 55.57 (median, 49.5). Patients who received disease-modifying drug treatment one year pre-pregnancy were more likely to receive treatment within one year after delivery, compared with patients without exposure to treatment in the year before pregnancy (72.58% vs 12.44%).
This study was supported by EMD Serono.
Treatment Before, During, and After Pregnancy
To evaluate treatment patterns before, during, and after pregnancy in women with MS and a live birth, Dr. Houtchens and colleagues used a US administrative claims database to conduct a retrospective analysis of women ages 18 to 65 with MS, a claim indicative of a live birth, and one-year continuous eligibility before and after pregnancy in the IMS Health Real World Data Adjudicated Claims US database from January 1, 2006, to June 30, 2015. Disease-modifying drug treatment was evaluated during the year prior to pregnancy (at three-month intervals), the three trimesters of pregnancy, puerperium (six weeks post-pregnancy), and one year post pregnancy (seven to 12 weeks post pregnancy and three to six, six to nine, and nine to 12 months post pregnancy). The researchers evaluated the proportion of women exposed to disease-modifying drug treatment during the 12 time periods. Results were also stratified by the number of relapses women experienced in the year prior to pregnancy.
Of 190,475 women with MS, 2,158 met eligibility criteria. Mean age was 30.26. Most women had commercial health insurance (98%) and were from the Midwest (32%), South (30%), or Northeast (29%) regions of the US.
The proportion of women with MS and a live birth treated with any disease-modifying drug was 20.48% at nine to 12 months pre-pregnancy, 21.46% at six to nine months pre-pregnancy, 20.62% at three to six months pre-pregnancy, and 17.75% at three months pre-pregnancy. During pregnancy, the proportion of women treated with a disease-modifying drug decreased to 12.05% during the first trimester and 1.90% during the second trimester, and then increased slightly to 2.97% during the third trimester. The proportion of women treated with disease-modifying drugs increased to 8.34% during puerperium, 12.93% during seven to 12 weeks post partum, 21.97% during three to six months post partum, 24.47% during six to nine months post partum, and 25.49% during nine to 12 months post partum. The majority of women (81.9%) had received disease-modifying drug treatment by six to nine months post partum. The proportion of women with disease-modifying drug treatment before and after pregnancy increased numerically with the number of relapses experienced before pregnancy.
Treatment After a Live Birth
In a separate analysis using the same cohort, Dr. Houtchens and colleagues looked closer at the time to initiation of disease-modifying drug treatment after a live birth in women with MS. Of the 2,094 women included in this analysis, the proportion with a live birth initiating a disease-modifying drug treatment within one year was 28.46%, and the proportion with no disease-modifying treatment within one year was 71.54%.
For those initiating a disease-modifying treatment within one year, mean time from live birth to first treatment was 118.98 days, and median time to first treatment was 93.50 days. A total of 16.11% received a disease-modifying drug less than 30 days after live birth, approximately half initiated a treatment within 90 days (47.82%), and three-quarters initiated a disease-modifying drug within six months (75.5%). The proportion of patients initiating treatment within one year after live birth increased with higher numbers of pre-pregnancy relapses (zero relapses, n = 441, 24.53%; one relapse, n = 108, 50.94%; two relapses, n = 33, 54.10%; three or more relapses, n = 14, 60.87%). The mean number of days until disease-modifying drug initiation for those receiving treatment within one year who had zero pre-pregnancy relapses was 123.57 (median, 99); one relapse, 107.95 (median, 80); two relapses, 120.76 (median, 98); and three or more relapses, 55.57 (median, 49.5). Patients who received disease-modifying drug treatment one year pre-pregnancy were more likely to receive treatment within one year after delivery, compared with patients without exposure to treatment in the year before pregnancy (72.58% vs 12.44%).
This study was supported by EMD Serono.
CAR T cells elicit durable, potent responses in kids with EM relapse of ALL
CHICAGO—Outcomes for pediatric patients with relapsed acute lymphoblastic leukemia (ALL) are dismal, with the probability of event-free survival ranging from 15% to 70% after a first relapse to 15% to 20% after a second relapse.
“So novel therapies are obviously urgently needed,” Mala Kiran Talekar, MD, of the Children's Hospital of Philadelphia in Pennsylvania, affirmed. “And herein comes the role of CAR T cells as a breakthrough therapy for relapsed/refractory pediatric ALL.”
She presented the outcome of chimeric antigen receptor (CAR) T-cell therapy in pediatric patients with non-CNS extramedullary (EM) relapse at the ASCO 2017 Annual meeting as abstract 10507.
The investigators had drawn the patient population for this analysis from 2 CAR studies, CTL019 and CTL119.
CTL019, which had already been completed, employed a murine CAR, and CTL119 is ongoing and uses a humanized CAR.
Of the 60 patients enrolled in CTL019, 56 (93%) achieved a complete response (CR) at day 28, and 100% had a CNS remission. Their 12-month overall survival (OS) was 79%.
“[K]eep in mind, when the study first started,” Dr Talekar said, “the patient population that had been referred to us was patients who had suffered a second or greater relapse or had been refractory to forms of treatment available to them, and the majority had been refractory to multiple therapies.”
The humanized CAR study, CTL119, is divided into 2 cohorts—one with CAR-naïve patients (n=22) and the other a CAR-retreatment arm (n=15) with patients who had received previous CAR therapy and relapsed.
Dr Talekar explained that the humanized CAR was made with the intention of decreasing rejection or loss of persistence of the T cells related to murine antigenicity.
Nine patients (60%) in the CAR-retreatment arm achieved a CR at day 28, and at 6 months, 78% experienced relapse-free survival (RFS) with a median follow-up of 12 months.
All of the CAR-naïve patients achieved CR at day 28, with 86% achieving RFS at 6 months, with a median follow-up of 10 months.
ALL with EM involvement
The investigators identified 10 pediatric patients treated in the murine (n=6) or humanized (n=4) trials who had received CAR therapy for isolated extramedullary disease or for combined bone marrow extramedullary (BM/EM) relapse of ALL.
They defined EM relapse as involvement of a non-CNS site confirmed by imaging with or without pathology within 12 months of CAR T-cell infusion. After infusion, patients had diagnostic imaging performed at 1, 3, 6, 9, and 12 months.
Of the 10 patients, 5 had active EM involvement at the time of infusion, 2 had isolated EM relapse—1 with parotid and multifocal bony lesions and 1 with testis and sinus lesions—and 5 had multiple sites of EM relapse.
The patients had 2 to 4 prior ALL relapses, 2 had prior local radiation to the EM site, and all 10 had received prior bone marrow transplants.
Three patients had an MLL rearrangement, 1 had hypodiploid ALL, and 1 had trisomy 21.
Nine of the 10 patients achieved MRD-negative CR at day 28.
One patient was not evaluable because his disease progressed within 2 weeks of CAR therapy in both the bone marrow and EM site. He died 6 weeks after the infusion.
Five patients evaluated by serial imaging had objective responses. Two had no evidence of EM disease by day 28, 2 had resolution by 3 months, and 1 had continued decrease in the size of her uterine mass at 3 and 6 months. She underwent hysterectomy at 8 months with no evidence of disease on pathology.
Four patients with a prior history of skin or testicular involvement had no evidence of disease by exam at day 28.
Three of the 9 patients relapsed with CD19+ disease. One had skin/medullary involvement and died at 38 months after CAR T-cell infusion. And 2 had medullary disease: 1 died at 17 months and 1 is alive at 28 months.
The remaining 6 patients are alive and well at a median follow-up of 10 months (range, 3 – 16 months) without recurrence of disease.
The investigators therefore concluded that single agent CAR T-cell immunotherapy can induce potent and durable response in patients with EM relapse of their ALL. 
CHICAGO—Outcomes for pediatric patients with relapsed acute lymphoblastic leukemia (ALL) are dismal, with the probability of event-free survival ranging from 15% to 70% after a first relapse to 15% to 20% after a second relapse.
“So novel therapies are obviously urgently needed,” Mala Kiran Talekar, MD, of the Children's Hospital of Philadelphia in Pennsylvania, affirmed. “And herein comes the role of CAR T cells as a breakthrough therapy for relapsed/refractory pediatric ALL.”
She presented the outcome of chimeric antigen receptor (CAR) T-cell therapy in pediatric patients with non-CNS extramedullary (EM) relapse at the ASCO 2017 Annual meeting as abstract 10507.
The investigators had drawn the patient population for this analysis from 2 CAR studies, CTL019 and CTL119.
CTL019, which had already been completed, employed a murine CAR, and CTL119 is ongoing and uses a humanized CAR.
Of the 60 patients enrolled in CTL019, 56 (93%) achieved a complete response (CR) at day 28, and 100% had a CNS remission. Their 12-month overall survival (OS) was 79%.
“[K]eep in mind, when the study first started,” Dr Talekar said, “the patient population that had been referred to us was patients who had suffered a second or greater relapse or had been refractory to forms of treatment available to them, and the majority had been refractory to multiple therapies.”
The humanized CAR study, CTL119, is divided into 2 cohorts—one with CAR-naïve patients (n=22) and the other a CAR-retreatment arm (n=15) with patients who had received previous CAR therapy and relapsed.
Dr Talekar explained that the humanized CAR was made with the intention of decreasing rejection or loss of persistence of the T cells related to murine antigenicity.
Nine patients (60%) in the CAR-retreatment arm achieved a CR at day 28, and at 6 months, 78% experienced relapse-free survival (RFS) with a median follow-up of 12 months.
All of the CAR-naïve patients achieved CR at day 28, with 86% achieving RFS at 6 months, with a median follow-up of 10 months.
ALL with EM involvement
The investigators identified 10 pediatric patients treated in the murine (n=6) or humanized (n=4) trials who had received CAR therapy for isolated extramedullary disease or for combined bone marrow extramedullary (BM/EM) relapse of ALL.
They defined EM relapse as involvement of a non-CNS site confirmed by imaging with or without pathology within 12 months of CAR T-cell infusion. After infusion, patients had diagnostic imaging performed at 1, 3, 6, 9, and 12 months.
Of the 10 patients, 5 had active EM involvement at the time of infusion, 2 had isolated EM relapse—1 with parotid and multifocal bony lesions and 1 with testis and sinus lesions—and 5 had multiple sites of EM relapse.
The patients had 2 to 4 prior ALL relapses, 2 had prior local radiation to the EM site, and all 10 had received prior bone marrow transplants.
Three patients had an MLL rearrangement, 1 had hypodiploid ALL, and 1 had trisomy 21.
Nine of the 10 patients achieved MRD-negative CR at day 28.
One patient was not evaluable because his disease progressed within 2 weeks of CAR therapy in both the bone marrow and EM site. He died 6 weeks after the infusion.
Five patients evaluated by serial imaging had objective responses. Two had no evidence of EM disease by day 28, 2 had resolution by 3 months, and 1 had continued decrease in the size of her uterine mass at 3 and 6 months. She underwent hysterectomy at 8 months with no evidence of disease on pathology.
Four patients with a prior history of skin or testicular involvement had no evidence of disease by exam at day 28.
Three of the 9 patients relapsed with CD19+ disease. One had skin/medullary involvement and died at 38 months after CAR T-cell infusion. And 2 had medullary disease: 1 died at 17 months and 1 is alive at 28 months.
The remaining 6 patients are alive and well at a median follow-up of 10 months (range, 3 – 16 months) without recurrence of disease.
The investigators therefore concluded that single agent CAR T-cell immunotherapy can induce potent and durable response in patients with EM relapse of their ALL.
CHICAGO—Outcomes for pediatric patients with relapsed acute lymphoblastic leukemia (ALL) are dismal, with the probability of event-free survival ranging from 15% to 70% after a first relapse to 15% to 20% after a second relapse.
“So novel therapies are obviously urgently needed,” Mala Kiran Talekar, MD, of the Children's Hospital of Philadelphia in Pennsylvania, affirmed. “And herein comes the role of CAR T cells as a breakthrough therapy for relapsed/refractory pediatric ALL.”
She presented the outcome of chimeric antigen receptor (CAR) T-cell therapy in pediatric patients with non-CNS extramedullary (EM) relapse at the ASCO 2017 Annual meeting as abstract 10507.
The investigators had drawn the patient population for this analysis from 2 CAR studies, CTL019 and CTL119.
CTL019, which had already been completed, employed a murine CAR, and CTL119 is ongoing and uses a humanized CAR.
Of the 60 patients enrolled in CTL019, 56 (93%) achieved a complete response (CR) at day 28, and 100% had a CNS remission. Their 12-month overall survival (OS) was 79%.
“[K]eep in mind, when the study first started,” Dr Talekar said, “the patient population that had been referred to us was patients who had suffered a second or greater relapse or had been refractory to forms of treatment available to them, and the majority had been refractory to multiple therapies.”
The humanized CAR study, CTL119, is divided into 2 cohorts—one with CAR-naïve patients (n=22) and the other a CAR-retreatment arm (n=15) with patients who had received previous CAR therapy and relapsed.
Dr Talekar explained that the humanized CAR was made with the intention of decreasing rejection or loss of persistence of the T cells related to murine antigenicity.
Nine patients (60%) in the CAR-retreatment arm achieved a CR at day 28, and at 6 months, 78% experienced relapse-free survival (RFS) with a median follow-up of 12 months.
All of the CAR-naïve patients achieved CR at day 28, with 86% achieving RFS at 6 months, with a median follow-up of 10 months.
ALL with EM involvement
The investigators identified 10 pediatric patients treated in the murine (n=6) or humanized (n=4) trials who had received CAR therapy for isolated extramedullary disease or for combined bone marrow extramedullary (BM/EM) relapse of ALL.
They defined EM relapse as involvement of a non-CNS site confirmed by imaging with or without pathology within 12 months of CAR T-cell infusion. After infusion, patients had diagnostic imaging performed at 1, 3, 6, 9, and 12 months.
Of the 10 patients, 5 had active EM involvement at the time of infusion, 2 had isolated EM relapse—1 with parotid and multifocal bony lesions and 1 with testis and sinus lesions—and 5 had multiple sites of EM relapse.
The patients had 2 to 4 prior ALL relapses, 2 had prior local radiation to the EM site, and all 10 had received prior bone marrow transplants.
Three patients had an MLL rearrangement, 1 had hypodiploid ALL, and 1 had trisomy 21.
Nine of the 10 patients achieved MRD-negative CR at day 28.
One patient was not evaluable because his disease progressed within 2 weeks of CAR therapy in both the bone marrow and EM site. He died 6 weeks after the infusion.
Five patients evaluated by serial imaging had objective responses. Two had no evidence of EM disease by day 28, 2 had resolution by 3 months, and 1 had continued decrease in the size of her uterine mass at 3 and 6 months. She underwent hysterectomy at 8 months with no evidence of disease on pathology.
Four patients with a prior history of skin or testicular involvement had no evidence of disease by exam at day 28.
Three of the 9 patients relapsed with CD19+ disease. One had skin/medullary involvement and died at 38 months after CAR T-cell infusion. And 2 had medullary disease: 1 died at 17 months and 1 is alive at 28 months.
The remaining 6 patients are alive and well at a median follow-up of 10 months (range, 3 – 16 months) without recurrence of disease.
The investigators therefore concluded that single agent CAR T-cell immunotherapy can induce potent and durable response in patients with EM relapse of their ALL.
Azacitidine alone comparable to AZA combos for most MDS patients
A 3-arm phase 2 study of azacitidine alone or in combination with lenalidomide or vorinostat in patients with higher-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) has shown the combination therapies to have similar overall response rates (ORR) to azacitidine monotherapy. Based on these findings, investigators did not choose either combination arm for phase 3 testing of overall survival.
However, patients with CMML treated with the azacitidine-lenalidomide combination had twice the ORR compared with azacitidine monotherapy, they reported.
And patients with certain mutations, such as DNMT3A, BCOR, and NRAS, had higher overall response rates, although only those with the DNMT3A mutation were significant.
Mikkael A. Sekeres, MD, of the Cleveland Clinic in Cleveland, Ohio, and colleagues reported these findings in the Journal of Clinical Oncology on behalf of the North American Intergroup Study SWOG S117.
Doses of azacitidine were the same for monotherapy and combination arms: 75 mg/m2/day intravenously or subcutaneously on days 1 to 7 of a 28-day cycle.
Patients in the lenalidomide arm received 10 mg/day orally of that drug on days 1 to 21, and patients in the vorinostat arm received 300 mg twice daily orally on days 3 to 9.
Patient characteristics
Patients had MDS of IPSS Intermediate-2 or higher or bone marrow blasts 5% or greater. Patients with CMML had fewer than 20% blasts.
The investigators randomized 277 patients to receive either azacitidine alone (n=92), azacitidine plus lenalidomide (n=93), or azacitidine plus vorinostat (n=92).
Patients were a median age of 70 years (range, 28 to 93). Eighty-five patients (31%) were female, 53 (19%) had CMML, and 18 (6%) had treatment-related MDS. More than half the patients were transfusion-dependent at baseline.
Baseline characteristics were similar across the 3 arms. The investigators noted that the baseline characteristics were also similar across the 90 centers participating in the study, whether they were an MDS Center of Excellence or a high-volume center.
Adverse events
For the most part, therapy-related adverse events were similar across the arms.
Rates of grade 3 or higher febrile neutropenia and infection and infestations were similar for all 3 cohorts: 89% for azaciditine monotherapy, 91% for the lenalidomide combination, and 91% for the vorinostat combination.
However, the vorinostat arm had more grade 3 or higher gastrointestinal toxicities (14 patients, 15%) compared with the monotherapy arm (4 patients, 4%), P=0.02.
And patients receiving lenalidomide experienced more grade 3 or higher rash (14 patients, 16%) compared with patients receiving monotherapy (3 patients, 3%), P=0.005.
Patients in the combination arms stopped therapy at significantly higher rates than the monotherapy arm. Eight percent of patients receiving monotherapy stopped treatment compared with 20% in the lenalidomide arm and 21% in the vorinostat arm.
Patients in the combination arms also had more dose modifications not specified in the protocol than those in the monotherapy arm. Twenty-four percent receiving azacitidine monotherapy had non-protocol defined dose modifications, compared with 43% in the lenalidomide arm and 42% in the vorinostat arm.
Responses
The ORR for the entire study population was 38%.
Patients in the monotherapy arm had an ORR of 38%, those in the lenalidomide arm, 49%, and those in the vorinostate arm, 27%. Neither arm achieved significance compared with the monotherapy arm.
Patients who were treatment-naïve in the lenalidomide arm had a somewhat improved ORR compared with monotherapy, P=0.08.
The median duration of response for all cohorts was 15 months: 10 months for monotherapy, 14 months for lenalidomide, and 18 months for vorinostat.
Patients who were able to remain on therapy for 6 months or more in the lenalidomide arm achieved a higher ORR of 87% compared with monotherapy (62%, P=0.01). However, there was no difference in response duration with longer therapy.
The median overall survival (OS) was 17 months for all patients, 15 months for patients in the monotherapy group, 19 months for those in the lenalidomide arm, and 17 months for those in the vorinostat group.
CMML patients had similar OS across treatment arms, with the median not yet reached for patients in the monotherapy arm.
Subgroup responses
Patients with CMML in the lenalidomide arm had a significantly higher ORR than CMML patients in the monotherapy arm, 68% and 28%, respectively (P=0.02).
Median duration of response for CMML patients was 19 months, with no differences between the arms.
The investigators observed no differences in ORR for therapy-related MDS, IPSS subgroups, transfusion-dependent patients, or allogeneic transplant rates.
However, they noted ORR was better for patients with chromosome 5 abnormality regardless of treatment arm than for those without the abnormality (odds ratio, 2.17, P=0.008).
One hundred thirteen patients had mutational data available. They had a median number of 2 mutations (range, 0 to 7), with the most common being ASXL1 (n = 31), TET2 (n = 26), SRSF2 (n = 23), TP53 (n = 22), RUNX1 (n = 21), and U2AF1 (n = 19).
Patients with DNMT3A mutation had a significantly higher ORR than for patients without mutations, 67% and 34%, respectively P=0.025).
Patients with BCOR and NRAS mutations had numerically higher, but non-significant, ORR than non-mutated patients. Patients with BCOR mutation had a 57% ORR compared with 34% for non-mutated patients (P=0.23). Patients with NRAS mutation had a 60% ORR compared with 36% for non-mutated patients (P=0.28).
Patients with mutations in TET2 (P = .046) and TP53 (P = .003) had a worse response duration than those without mutations.
Response duration was significantly better with fewer mutations. For 2 or more mutations, the hazard ration was 6.86 versus no mutations (P=0.01).
The investigators believed under-dosing may have compromised response and survival in the combination arms. They suggested that studies focused on the subgroups that seemed to benefit from the combinations should be conducted.
A 3-arm phase 2 study of azacitidine alone or in combination with lenalidomide or vorinostat in patients with higher-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) has shown the combination therapies to have similar overall response rates (ORR) to azacitidine monotherapy. Based on these findings, investigators did not choose either combination arm for phase 3 testing of overall survival.
However, patients with CMML treated with the azacitidine-lenalidomide combination had twice the ORR compared with azacitidine monotherapy, they reported.
And patients with certain mutations, such as DNMT3A, BCOR, and NRAS, had higher overall response rates, although only those with the DNMT3A mutation were significant.
Mikkael A. Sekeres, MD, of the Cleveland Clinic in Cleveland, Ohio, and colleagues reported these findings in the Journal of Clinical Oncology on behalf of the North American Intergroup Study SWOG S117.
Doses of azacitidine were the same for monotherapy and combination arms: 75 mg/m2/day intravenously or subcutaneously on days 1 to 7 of a 28-day cycle.
Patients in the lenalidomide arm received 10 mg/day orally of that drug on days 1 to 21, and patients in the vorinostat arm received 300 mg twice daily orally on days 3 to 9.
Patient characteristics
Patients had MDS of IPSS Intermediate-2 or higher or bone marrow blasts 5% or greater. Patients with CMML had fewer than 20% blasts.
The investigators randomized 277 patients to receive either azacitidine alone (n=92), azacitidine plus lenalidomide (n=93), or azacitidine plus vorinostat (n=92).
Patients were a median age of 70 years (range, 28 to 93). Eighty-five patients (31%) were female, 53 (19%) had CMML, and 18 (6%) had treatment-related MDS. More than half the patients were transfusion-dependent at baseline.
Baseline characteristics were similar across the 3 arms. The investigators noted that the baseline characteristics were also similar across the 90 centers participating in the study, whether they were an MDS Center of Excellence or a high-volume center.
Adverse events
For the most part, therapy-related adverse events were similar across the arms.
Rates of grade 3 or higher febrile neutropenia and infection and infestations were similar for all 3 cohorts: 89% for azaciditine monotherapy, 91% for the lenalidomide combination, and 91% for the vorinostat combination.
However, the vorinostat arm had more grade 3 or higher gastrointestinal toxicities (14 patients, 15%) compared with the monotherapy arm (4 patients, 4%), P=0.02.
And patients receiving lenalidomide experienced more grade 3 or higher rash (14 patients, 16%) compared with patients receiving monotherapy (3 patients, 3%), P=0.005.
Patients in the combination arms stopped therapy at significantly higher rates than the monotherapy arm. Eight percent of patients receiving monotherapy stopped treatment compared with 20% in the lenalidomide arm and 21% in the vorinostat arm.
Patients in the combination arms also had more dose modifications not specified in the protocol than those in the monotherapy arm. Twenty-four percent receiving azacitidine monotherapy had non-protocol defined dose modifications, compared with 43% in the lenalidomide arm and 42% in the vorinostat arm.
Responses
The ORR for the entire study population was 38%.
Patients in the monotherapy arm had an ORR of 38%, those in the lenalidomide arm, 49%, and those in the vorinostate arm, 27%. Neither arm achieved significance compared with the monotherapy arm.
Patients who were treatment-naïve in the lenalidomide arm had a somewhat improved ORR compared with monotherapy, P=0.08.
The median duration of response for all cohorts was 15 months: 10 months for monotherapy, 14 months for lenalidomide, and 18 months for vorinostat.
Patients who were able to remain on therapy for 6 months or more in the lenalidomide arm achieved a higher ORR of 87% compared with monotherapy (62%, P=0.01). However, there was no difference in response duration with longer therapy.
The median overall survival (OS) was 17 months for all patients, 15 months for patients in the monotherapy group, 19 months for those in the lenalidomide arm, and 17 months for those in the vorinostat group.
CMML patients had similar OS across treatment arms, with the median not yet reached for patients in the monotherapy arm.
Subgroup responses
Patients with CMML in the lenalidomide arm had a significantly higher ORR than CMML patients in the monotherapy arm, 68% and 28%, respectively (P=0.02).
Median duration of response for CMML patients was 19 months, with no differences between the arms.
The investigators observed no differences in ORR for therapy-related MDS, IPSS subgroups, transfusion-dependent patients, or allogeneic transplant rates.
However, they noted ORR was better for patients with chromosome 5 abnormality regardless of treatment arm than for those without the abnormality (odds ratio, 2.17, P=0.008).
One hundred thirteen patients had mutational data available. They had a median number of 2 mutations (range, 0 to 7), with the most common being ASXL1 (n = 31), TET2 (n = 26), SRSF2 (n = 23), TP53 (n = 22), RUNX1 (n = 21), and U2AF1 (n = 19).
Patients with DNMT3A mutation had a significantly higher ORR than for patients without mutations, 67% and 34%, respectively P=0.025).
Patients with BCOR and NRAS mutations had numerically higher, but non-significant, ORR than non-mutated patients. Patients with BCOR mutation had a 57% ORR compared with 34% for non-mutated patients (P=0.23). Patients with NRAS mutation had a 60% ORR compared with 36% for non-mutated patients (P=0.28).
Patients with mutations in TET2 (P = .046) and TP53 (P = .003) had a worse response duration than those without mutations.
Response duration was significantly better with fewer mutations. For 2 or more mutations, the hazard ration was 6.86 versus no mutations (P=0.01).
The investigators believed under-dosing may have compromised response and survival in the combination arms. They suggested that studies focused on the subgroups that seemed to benefit from the combinations should be conducted.
A 3-arm phase 2 study of azacitidine alone or in combination with lenalidomide or vorinostat in patients with higher-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) has shown the combination therapies to have similar overall response rates (ORR) to azacitidine monotherapy. Based on these findings, investigators did not choose either combination arm for phase 3 testing of overall survival.
However, patients with CMML treated with the azacitidine-lenalidomide combination had twice the ORR compared with azacitidine monotherapy, they reported.
And patients with certain mutations, such as DNMT3A, BCOR, and NRAS, had higher overall response rates, although only those with the DNMT3A mutation were significant.
Mikkael A. Sekeres, MD, of the Cleveland Clinic in Cleveland, Ohio, and colleagues reported these findings in the Journal of Clinical Oncology on behalf of the North American Intergroup Study SWOG S117.
Doses of azacitidine were the same for monotherapy and combination arms: 75 mg/m2/day intravenously or subcutaneously on days 1 to 7 of a 28-day cycle.
Patients in the lenalidomide arm received 10 mg/day orally of that drug on days 1 to 21, and patients in the vorinostat arm received 300 mg twice daily orally on days 3 to 9.
Patient characteristics
Patients had MDS of IPSS Intermediate-2 or higher or bone marrow blasts 5% or greater. Patients with CMML had fewer than 20% blasts.
The investigators randomized 277 patients to receive either azacitidine alone (n=92), azacitidine plus lenalidomide (n=93), or azacitidine plus vorinostat (n=92).
Patients were a median age of 70 years (range, 28 to 93). Eighty-five patients (31%) were female, 53 (19%) had CMML, and 18 (6%) had treatment-related MDS. More than half the patients were transfusion-dependent at baseline.
Baseline characteristics were similar across the 3 arms. The investigators noted that the baseline characteristics were also similar across the 90 centers participating in the study, whether they were an MDS Center of Excellence or a high-volume center.
Adverse events
For the most part, therapy-related adverse events were similar across the arms.
Rates of grade 3 or higher febrile neutropenia and infection and infestations were similar for all 3 cohorts: 89% for azaciditine monotherapy, 91% for the lenalidomide combination, and 91% for the vorinostat combination.
However, the vorinostat arm had more grade 3 or higher gastrointestinal toxicities (14 patients, 15%) compared with the monotherapy arm (4 patients, 4%), P=0.02.
And patients receiving lenalidomide experienced more grade 3 or higher rash (14 patients, 16%) compared with patients receiving monotherapy (3 patients, 3%), P=0.005.
Patients in the combination arms stopped therapy at significantly higher rates than the monotherapy arm. Eight percent of patients receiving monotherapy stopped treatment compared with 20% in the lenalidomide arm and 21% in the vorinostat arm.
Patients in the combination arms also had more dose modifications not specified in the protocol than those in the monotherapy arm. Twenty-four percent receiving azacitidine monotherapy had non-protocol defined dose modifications, compared with 43% in the lenalidomide arm and 42% in the vorinostat arm.
Responses
The ORR for the entire study population was 38%.
Patients in the monotherapy arm had an ORR of 38%, those in the lenalidomide arm, 49%, and those in the vorinostate arm, 27%. Neither arm achieved significance compared with the monotherapy arm.
Patients who were treatment-naïve in the lenalidomide arm had a somewhat improved ORR compared with monotherapy, P=0.08.
The median duration of response for all cohorts was 15 months: 10 months for monotherapy, 14 months for lenalidomide, and 18 months for vorinostat.
Patients who were able to remain on therapy for 6 months or more in the lenalidomide arm achieved a higher ORR of 87% compared with monotherapy (62%, P=0.01). However, there was no difference in response duration with longer therapy.
The median overall survival (OS) was 17 months for all patients, 15 months for patients in the monotherapy group, 19 months for those in the lenalidomide arm, and 17 months for those in the vorinostat group.
CMML patients had similar OS across treatment arms, with the median not yet reached for patients in the monotherapy arm.
Subgroup responses
Patients with CMML in the lenalidomide arm had a significantly higher ORR than CMML patients in the monotherapy arm, 68% and 28%, respectively (P=0.02).
Median duration of response for CMML patients was 19 months, with no differences between the arms.
The investigators observed no differences in ORR for therapy-related MDS, IPSS subgroups, transfusion-dependent patients, or allogeneic transplant rates.
However, they noted ORR was better for patients with chromosome 5 abnormality regardless of treatment arm than for those without the abnormality (odds ratio, 2.17, P=0.008).
One hundred thirteen patients had mutational data available. They had a median number of 2 mutations (range, 0 to 7), with the most common being ASXL1 (n = 31), TET2 (n = 26), SRSF2 (n = 23), TP53 (n = 22), RUNX1 (n = 21), and U2AF1 (n = 19).
Patients with DNMT3A mutation had a significantly higher ORR than for patients without mutations, 67% and 34%, respectively P=0.025).
Patients with BCOR and NRAS mutations had numerically higher, but non-significant, ORR than non-mutated patients. Patients with BCOR mutation had a 57% ORR compared with 34% for non-mutated patients (P=0.23). Patients with NRAS mutation had a 60% ORR compared with 36% for non-mutated patients (P=0.28).
Patients with mutations in TET2 (P = .046) and TP53 (P = .003) had a worse response duration than those without mutations.
Response duration was significantly better with fewer mutations. For 2 or more mutations, the hazard ration was 6.86 versus no mutations (P=0.01).
The investigators believed under-dosing may have compromised response and survival in the combination arms. They suggested that studies focused on the subgroups that seemed to benefit from the combinations should be conducted.
Study contradicts AAP recommendations on infant room-sharing
Infants who slept in their own rooms by age 9 months slept significantly longer and better than those who continued sharing a room with their parents as recommended by the American Academy of Pediatrics, the authors of a prospective study of 279 mother-infant dyads reported June 5.
The findings “raise questions about the well-intended AAP recommendation that room-sharing should ideally occur for all infants until their first birthday,” wrote Ian M. Paul, MD, of Penn State University, Hershey, and his associates (Pediatrics. 2017 Jun 5. doi: 10.1542/peds.2017-0122). “Perhaps our most troubling finding was that room-sharing was associated with overnight transitions to bed-sharing, which is strongly discouraged by the AAP.”
Insufficient sleep leads to excess weight gain during infancy and sleep problems later in childhood and has negative implications for parents. “The desire to optimize infant sleep duration and consolidation, however, must be balanced with safe infant sleep,” the researchers emphasized. About 3,500 infants die annually of SIDS and other sleep-related deaths, about 90% of which occur before age 6 months. Currently, however, the AAP’s updated 2016 recommendations advise that infants sleep on a separate surface in their parents’ room for at least the first 6 months and ideally for 1 year (Pediatrics. 2016; 138:e20162938).
To examine relationships among where, how well, and how long infants slept, the researchers analyzed Brief Infant Sleep Questionnaires collected from first-time mothers of term singletons as part of the prospective, single-center Intervention Nurses Start Infants Growing on Healthy Trajectories (INSIGHT) study.
For 4-month-olds, average reported sleep duration was similar whether they slept alone or in the parental bedroom. Solo sleepers, however, had better sleep consolidation, averaging 46 more minutes of sleep at the longest stretch, compared with room sharers (P = .02). By age 9 months, infants who had slept alone by age 4 months averaged 40 more minutes of nightly sleep than room-sharers and 26 more minutes than infants who began sleeping alone after 4 months of age (P = .008). Furthermore, the average longest sleep span of early solo sleepers was 100 minutes more than that of room-sharers and 45 minutes more than that of infants who began sleeping alone between ages 4 and 9 months (P = .01).
At age 30 months, infants who had slept alone by age 9 months averaged 45 more minutes of nightly sleep than those who had shared a room (P = .004). Room-sharing at 4 months also was tied to a two-fold greater odds of having pillows, blankets, or other unsafe objects on the sleep surface, the researchers said. Together, the findings support revising the AAP recommendation until evidence conclusively supports it, they concluded.
The study’s funders included Penn State University, Hershey; Penn State Children’s Hospital; the U.S. Department of Agriculture; the Penn State Clinical and Translational Science Institute, and the National Institutes of Health/National Center for Advancing Translational Sciences. The investigators reported having no conflicts of interest.
The study by Dr. Paul and his associates is an important contribution to the literature, wrote Rachel Y. Moon, MD, and Fern R. Hauck, MD, in an accompanying editorial (Pediatrics. 2017 Jun 5. doi: 10.1542/peds.2017-1323). However, they said, more research is needed.
For example, it is unclear whether sleep consolidation in young infants is preferable from a physiologic perspective. “The ability to arouse is critical physiologically, and a leading hypothesis is that failure to arouse makes an infant vulnerable to SIDS,” they wrote.
Dr. Moon and Dr. Hauck also noted that the AAP’s recommendation on room-sharing without bed-sharing is based on studies conducted in England, New Zealand, and Scotland showing that room-sharing lowers the risk of SIDS, compared with solitary sleeping.
“More recent, unpublished data from the New Zealand Sudden and Unexplained Death in Infancy study show similar protection from room-sharing, with an adjusted odds ratio of 0.36 (95% confidence interval, 0.19-0.71) for room-sharing infants compared with solitary-sleeping infants (E. Mitchell, MBBS, personal communication, 2016),” they wrote. “Because none of these studies stratified the risk by infant age in months, it is difficult to determine the optimal endpoint for room-sharing.
“We strongly support more research, both about the physiology of infant sleep and arousal for room-sharing infants and about the consequences of room-sharing on parental and child sleep.”
Dr. Moon and Dr. Hauck are with the University of Virginia, Charlottesville. They had no relevant disclosures.
The study by Dr. Paul and his associates is an important contribution to the literature, wrote Rachel Y. Moon, MD, and Fern R. Hauck, MD, in an accompanying editorial (Pediatrics. 2017 Jun 5. doi: 10.1542/peds.2017-1323). However, they said, more research is needed.
For example, it is unclear whether sleep consolidation in young infants is preferable from a physiologic perspective. “The ability to arouse is critical physiologically, and a leading hypothesis is that failure to arouse makes an infant vulnerable to SIDS,” they wrote.
Dr. Moon and Dr. Hauck also noted that the AAP’s recommendation on room-sharing without bed-sharing is based on studies conducted in England, New Zealand, and Scotland showing that room-sharing lowers the risk of SIDS, compared with solitary sleeping.
“More recent, unpublished data from the New Zealand Sudden and Unexplained Death in Infancy study show similar protection from room-sharing, with an adjusted odds ratio of 0.36 (95% confidence interval, 0.19-0.71) for room-sharing infants compared with solitary-sleeping infants (E. Mitchell, MBBS, personal communication, 2016),” they wrote. “Because none of these studies stratified the risk by infant age in months, it is difficult to determine the optimal endpoint for room-sharing.
“We strongly support more research, both about the physiology of infant sleep and arousal for room-sharing infants and about the consequences of room-sharing on parental and child sleep.”
Dr. Moon and Dr. Hauck are with the University of Virginia, Charlottesville. They had no relevant disclosures.
The study by Dr. Paul and his associates is an important contribution to the literature, wrote Rachel Y. Moon, MD, and Fern R. Hauck, MD, in an accompanying editorial (Pediatrics. 2017 Jun 5. doi: 10.1542/peds.2017-1323). However, they said, more research is needed.
For example, it is unclear whether sleep consolidation in young infants is preferable from a physiologic perspective. “The ability to arouse is critical physiologically, and a leading hypothesis is that failure to arouse makes an infant vulnerable to SIDS,” they wrote.
Dr. Moon and Dr. Hauck also noted that the AAP’s recommendation on room-sharing without bed-sharing is based on studies conducted in England, New Zealand, and Scotland showing that room-sharing lowers the risk of SIDS, compared with solitary sleeping.
“More recent, unpublished data from the New Zealand Sudden and Unexplained Death in Infancy study show similar protection from room-sharing, with an adjusted odds ratio of 0.36 (95% confidence interval, 0.19-0.71) for room-sharing infants compared with solitary-sleeping infants (E. Mitchell, MBBS, personal communication, 2016),” they wrote. “Because none of these studies stratified the risk by infant age in months, it is difficult to determine the optimal endpoint for room-sharing.
“We strongly support more research, both about the physiology of infant sleep and arousal for room-sharing infants and about the consequences of room-sharing on parental and child sleep.”
Dr. Moon and Dr. Hauck are with the University of Virginia, Charlottesville. They had no relevant disclosures.
Infants who slept in their own rooms by age 9 months slept significantly longer and better than those who continued sharing a room with their parents as recommended by the American Academy of Pediatrics, the authors of a prospective study of 279 mother-infant dyads reported June 5.
The findings “raise questions about the well-intended AAP recommendation that room-sharing should ideally occur for all infants until their first birthday,” wrote Ian M. Paul, MD, of Penn State University, Hershey, and his associates (Pediatrics. 2017 Jun 5. doi: 10.1542/peds.2017-0122). “Perhaps our most troubling finding was that room-sharing was associated with overnight transitions to bed-sharing, which is strongly discouraged by the AAP.”
Insufficient sleep leads to excess weight gain during infancy and sleep problems later in childhood and has negative implications for parents. “The desire to optimize infant sleep duration and consolidation, however, must be balanced with safe infant sleep,” the researchers emphasized. About 3,500 infants die annually of SIDS and other sleep-related deaths, about 90% of which occur before age 6 months. Currently, however, the AAP’s updated 2016 recommendations advise that infants sleep on a separate surface in their parents’ room for at least the first 6 months and ideally for 1 year (Pediatrics. 2016; 138:e20162938).
To examine relationships among where, how well, and how long infants slept, the researchers analyzed Brief Infant Sleep Questionnaires collected from first-time mothers of term singletons as part of the prospective, single-center Intervention Nurses Start Infants Growing on Healthy Trajectories (INSIGHT) study.
For 4-month-olds, average reported sleep duration was similar whether they slept alone or in the parental bedroom. Solo sleepers, however, had better sleep consolidation, averaging 46 more minutes of sleep at the longest stretch, compared with room sharers (P = .02). By age 9 months, infants who had slept alone by age 4 months averaged 40 more minutes of nightly sleep than room-sharers and 26 more minutes than infants who began sleeping alone after 4 months of age (P = .008). Furthermore, the average longest sleep span of early solo sleepers was 100 minutes more than that of room-sharers and 45 minutes more than that of infants who began sleeping alone between ages 4 and 9 months (P = .01).
At age 30 months, infants who had slept alone by age 9 months averaged 45 more minutes of nightly sleep than those who had shared a room (P = .004). Room-sharing at 4 months also was tied to a two-fold greater odds of having pillows, blankets, or other unsafe objects on the sleep surface, the researchers said. Together, the findings support revising the AAP recommendation until evidence conclusively supports it, they concluded.
The study’s funders included Penn State University, Hershey; Penn State Children’s Hospital; the U.S. Department of Agriculture; the Penn State Clinical and Translational Science Institute, and the National Institutes of Health/National Center for Advancing Translational Sciences. The investigators reported having no conflicts of interest.
Infants who slept in their own rooms by age 9 months slept significantly longer and better than those who continued sharing a room with their parents as recommended by the American Academy of Pediatrics, the authors of a prospective study of 279 mother-infant dyads reported June 5.
The findings “raise questions about the well-intended AAP recommendation that room-sharing should ideally occur for all infants until their first birthday,” wrote Ian M. Paul, MD, of Penn State University, Hershey, and his associates (Pediatrics. 2017 Jun 5. doi: 10.1542/peds.2017-0122). “Perhaps our most troubling finding was that room-sharing was associated with overnight transitions to bed-sharing, which is strongly discouraged by the AAP.”
Insufficient sleep leads to excess weight gain during infancy and sleep problems later in childhood and has negative implications for parents. “The desire to optimize infant sleep duration and consolidation, however, must be balanced with safe infant sleep,” the researchers emphasized. About 3,500 infants die annually of SIDS and other sleep-related deaths, about 90% of which occur before age 6 months. Currently, however, the AAP’s updated 2016 recommendations advise that infants sleep on a separate surface in their parents’ room for at least the first 6 months and ideally for 1 year (Pediatrics. 2016; 138:e20162938).
To examine relationships among where, how well, and how long infants slept, the researchers analyzed Brief Infant Sleep Questionnaires collected from first-time mothers of term singletons as part of the prospective, single-center Intervention Nurses Start Infants Growing on Healthy Trajectories (INSIGHT) study.
For 4-month-olds, average reported sleep duration was similar whether they slept alone or in the parental bedroom. Solo sleepers, however, had better sleep consolidation, averaging 46 more minutes of sleep at the longest stretch, compared with room sharers (P = .02). By age 9 months, infants who had slept alone by age 4 months averaged 40 more minutes of nightly sleep than room-sharers and 26 more minutes than infants who began sleeping alone after 4 months of age (P = .008). Furthermore, the average longest sleep span of early solo sleepers was 100 minutes more than that of room-sharers and 45 minutes more than that of infants who began sleeping alone between ages 4 and 9 months (P = .01).
At age 30 months, infants who had slept alone by age 9 months averaged 45 more minutes of nightly sleep than those who had shared a room (P = .004). Room-sharing at 4 months also was tied to a two-fold greater odds of having pillows, blankets, or other unsafe objects on the sleep surface, the researchers said. Together, the findings support revising the AAP recommendation until evidence conclusively supports it, they concluded.
The study’s funders included Penn State University, Hershey; Penn State Children’s Hospital; the U.S. Department of Agriculture; the Penn State Clinical and Translational Science Institute, and the National Institutes of Health/National Center for Advancing Translational Sciences. The investigators reported having no conflicts of interest.
FROM PEDIATRICS
Key clinical point: Infants who slept in their own room by age 4 months slept significantly longer and better than those who continued sharing a room with their parents as recommended by the American Academy of Pediatrics.
Major finding: By age 9 months, infants who had slept alone by age 4 months averaged 40 more minutes of nightly sleep than room sharers and 26 more minutes than infants who began sleeping alone after 4 months of age (P = .008). Furthermore, the average longest sleep span of early solo sleepers was 100 minutes more than that of room-sharers and 45 minutes more than that of infants who began sleeping alone between ages 4 and 9 months (P = .01).
Data source: Secondary analyses of 279 mother-infant dyads from the single-center, prospective Intervention Nurses Start Infants Growing on Healthy Trajectories (INSIGHT) study.
Disclosures: The study funders included Penn State University, Hershey; Penn State Children’s Hospital; the U.S. Department of Agriculture; the Penn State Clinical and Translational Science Institute, and the National Institutes of Health/National Center for Advancing Translational Sciences. The investigators reported having no conflicts of interest.