Lung cancer can sometimes be detected with a low-dose screening CT (computed tomography) scan. During the scan, you will lie down in a donut-like structure while x-rays are passed through your body. Computers then use these x-rays to produce images of the inside of your body. The scan does not hurt and takes only a few seconds to complete.

Benefits of screening

Screening for lung cancer with a chest CT scan has been shown to lower your chance of dying from lung cancer by 20%. That means that for every 5 people who would have died from lung cancer without screening, 1 of these 5 will not.

Downside of screening

False alarms. Screening for lung cancer with a chest CT has been shown to find a small spot or spots (called lung nodules) in the lungs of at least one-quarter of everyone who gets the CT scan. Only 3 or 4 out of 100 of the lung nodules found are cancer, while the rest are small scars that will never affect your health.

For many of the small lung nodules found, there is no way to tell without additional tests if they are a small scar or a lung cancer. These tests usually include CT scans done over time to see if the lung nodule grows. If the lung nodule is large enough, a biopsy may also be required. Therefore, many people who have a lung cancer screening CT scan and do not have lung cancer will have additional tests performed.

The physician who ordered the screening test will be able to advise you about how the lung nodule should be evaluated. He or she may choose to have you visit a lung nodule clinic for advice as well.

Cost. Most insurance programs do not currently cover the cost of a lung cancer screening chest CT, but they usually do cover the evaluation of any abnormal findings.

Quit smoking!

If you currently smoke, you can lower your risk of dying from lung cancer by quitting smoking. The amount your risk will be lowered by quitting smoking is greater than the amount your risk will be lowered by being screened with a CT scan. If you smoke, try to quit. Talk to your doctor about the best strategies for quitting.

This information is provided by your physician and the Cleveland Clinic Journal of Medicine. It is not designed to replace a physician’s medical assessment and judgment.

This page may be reproduced noncommercially to share with patients. Any other reproduction is subject to Cleveland Clinic Journal of Medicine approval. Bulk color reprints are available by calling 216-444-2661.

For patient information on hundreds of health topics, see the Patient Education and Health Information web site, www.clevelandclinic.org/health

Lung cancer can sometimes be detected with a low-dose screening CT (computed tomography) scan. During the scan, you will lie down in a donut-like structure while x-rays are passed through your body. Computers then use these x-rays to produce images of the inside of your body. The scan does not hurt and takes only a few seconds to complete.

Benefits of screening

Screening for lung cancer with a chest CT scan has been shown to lower your chance of dying from lung cancer by 20%. That means that for every 5 people who would have died from lung cancer without screening, 1 of these 5 will not.

Downside of screening

False alarms. Screening for lung cancer with a chest CT has been shown to find a small spot or spots (called lung nodules) in the lungs of at least one-quarter of everyone who gets the CT scan. Only 3 or 4 out of 100 of the lung nodules found are cancer, while the rest are small scars that will never affect your health.

For many of the small lung nodules found, there is no way to tell without additional tests if they are a small scar or a lung cancer. These tests usually include CT scans done over time to see if the lung nodule grows. If the lung nodule is large enough, a biopsy may also be required. Therefore, many people who have a lung cancer screening CT scan and do not have lung cancer will have additional tests performed.

The physician who ordered the screening test will be able to advise you about how the lung nodule should be evaluated. He or she may choose to have you visit a lung nodule clinic for advice as well.

Cost. Most insurance programs do not currently cover the cost of a lung cancer screening chest CT, but they usually do cover the evaluation of any abnormal findings.

Quit smoking!

If you currently smoke, you can lower your risk of dying from lung cancer by quitting smoking. The amount your risk will be lowered by quitting smoking is greater than the amount your risk will be lowered by being screened with a CT scan. If you smoke, try to quit. Talk to your doctor about the best strategies for quitting.

This information is provided by your physician and the Cleveland Clinic Journal of Medicine. It is not designed to replace a physician’s medical assessment and judgment.

This page may be reproduced noncommercially to share with patients. Any other reproduction is subject to Cleveland Clinic Journal of Medicine approval. Bulk color reprints are available by calling 216-444-2661.

For patient information on hundreds of health topics, see the Patient Education and Health Information web site, www.clevelandclinic.org/health

Lung cancer can sometimes be detected with a low-dose screening CT (computed tomography) scan. During the scan, you will lie down in a donut-like structure while x-rays are passed through your body. Computers then use these x-rays to produce images of the inside of your body. The scan does not hurt and takes only a few seconds to complete.

Benefits of screening

Screening for lung cancer with a chest CT scan has been shown to lower your chance of dying from lung cancer by 20%. That means that for every 5 people who would have died from lung cancer without screening, 1 of these 5 will not.

Downside of screening

False alarms. Screening for lung cancer with a chest CT has been shown to find a small spot or spots (called lung nodules) in the lungs of at least one-quarter of everyone who gets the CT scan. Only 3 or 4 out of 100 of the lung nodules found are cancer, while the rest are small scars that will never affect your health.

For many of the small lung nodules found, there is no way to tell without additional tests if they are a small scar or a lung cancer. These tests usually include CT scans done over time to see if the lung nodule grows. If the lung nodule is large enough, a biopsy may also be required. Therefore, many people who have a lung cancer screening CT scan and do not have lung cancer will have additional tests performed.

The physician who ordered the screening test will be able to advise you about how the lung nodule should be evaluated. He or she may choose to have you visit a lung nodule clinic for advice as well.

Cost. Most insurance programs do not currently cover the cost of a lung cancer screening chest CT, but they usually do cover the evaluation of any abnormal findings.

Quit smoking!

If you currently smoke, you can lower your risk of dying from lung cancer by quitting smoking. The amount your risk will be lowered by quitting smoking is greater than the amount your risk will be lowered by being screened with a CT scan. If you smoke, try to quit. Talk to your doctor about the best strategies for quitting.

This information is provided by your physician and the Cleveland Clinic Journal of Medicine. It is not designed to replace a physician’s medical assessment and judgment.

This page may be reproduced noncommercially to share with patients. Any other reproduction is subject to Cleveland Clinic Journal of Medicine approval. Bulk color reprints are available by calling 216-444-2661.

For patient information on hundreds of health topics, see the Patient Education and Health Information web site, www.clevelandclinic.org/health

At the dawn of the genomics era, is the family history still relevant? The answer is a resounding yes.^1,2

The family history is clinically useful because it is a proxy for genetic, environmental, and behavioral risks to health. It can be used to inform risk stratification, allowing for judicious use of screening and opening the door to early and even prophylactic treatment.^3–8 As people live longer, we will need to detect common chronic conditions early in their course so that we can continue to improve health outcomes. Family history can help physicians personalize preventive care for conditions such as diabetes, osteoporosis, and cancers of the breast, colon, and prostate.^2,9–15

However, there is ample evidence that the family history is underused. Most practitioners ask about it infrequently and inconsistently.^16,17 Why is this, and how can we encourage the use of this powerful tool to enhance our daily clinical practice and improve care?

We will discuss here some of the challenges that make it difficult for physicians to collect and use the family history in clinical practice, and review strategies for collecting and using the family history in a more consistent manner. We anticipate that this discussion will be helpful to clinicians, as the family history is an essential input to personalized, preventive care plans.

CHALLENGE 1: ARE PATIENTS’ REPORTS RELIABLE?

A question that often arises when discussing the utility of the family history is the reliability of patients’ reports. Can we trust that patients can accurately report their family history? For many conditions, the answer is yes.^18,19

Ziogas and Anton-Culverl²⁰ asked 1,111 cancer patients whether their relatives had ever had cancer and verified their answers. In more than 95% of cases, if the patient said that a first-degree or second-degree relative did not have cancer of any type, that relative truly did not have cancer. Overall, over-reporting of cancer was rare, occurring in 2.4% of cases.

If the patient said that a relative did have cancer, that statement was usually true as well. The reliability of a report of cancer in first-degree relatives was greater than 75% for most types of cancer (female breast, ovarian, esophageal, colorectal, pancreas, lung, melanoma, brain, thyroid, lymphoma, leukemia). For several of these types of cancer (female breast, colorectal, and brain), the reliability was 90% or higher. For second-degree relatives, the reliability of a reported positive history was moderate (50% to 80%) for the same types of cancer, and for third-degree relatives, the reliability dropped further for all types of cancer except female breast, brain, pancreas, and leukemia, for which the reliability of a positive report remained at 70%.

Wideroff et al²¹ had similar findings in a study of more than 1,000 patients and more than 20,000 of their relatives.

Yoon et al,¹⁸ at the US Centers for Disease Control and Prevention, developed a Web-based risk-assessment tool called Family Healthware, currently undergoing validation trials. They found that patients’ reports were highly reliable for coronary heart disease, stroke, diabetes, and breast, ovarian, and colorectal cancers. They also calculated the degree of risk associated with a positive family history and the prevalence of a family history of each of these diseases.

For the primary care physician, these studies support the reliability of patients’ reports and provide guidance for targeting specific conditions when obtaining a family history.

CHALLENGE 2: NO TIME OR REIMBURSEMENT

Perhaps the most obvious barriers to collecting a family history are lack of time and reimbursement.

Acheson et al,¹⁷ in an observational study of 138 primary care physicians and 4,454 patient visits, found that family history was discussed during 51% of new patient visits and 22% of established patient visits. The rate at which the family history was taken varied from 0% (some physicians never asked) to 81% of all patient visits. On average, physicians spent less than 2.5 minutes collecting the family history.

Not surprisingly, the family history was discussed more often at well-care visits than at illness visits, as the former type of visit tends to be longer and, by definition, to be spent partly on preventive care. A difficulty with this strategy is that, given the shortage of primary care physicians, limited access, and patient preference, most preventive-care visits are combined with problem-focused visits, further decreasing the time available to collect and discuss a family history. While some argue that the family history should routinely be obtained and discussed during preventive-care visits regardless of reimbursement and time, the reality is that it may simply drop on the list of priorities for each visit.

Rich et al³ estimated that taking a family history would increase reimbursement for only one new patient evaluation and management code (99202) and one return-visit code (99213) in Current Procedural Terminology. This action would increase reimbursement enough to support about 10 minutes of physician effort for collecting, documenting, and analyzing the family history. While this is certainly better than the average of less than 2.5 minutes observed by Acheson et al,¹⁷ doctors would probably do it more if they were paid more for it.

Electronic solutions

Given that a lack of time is a barrier, what are some ways to minimize the time it takes to collect a family history?

With more physicians using electronic health records and with increasing use of Internet-based tools in the population at large, information-technology systems have been developed to help obtain the family history. One of the most widely used is the US surgeon general’s My Family Health Portrait, available free at https://familyhistory.hhs.gov. It is one of the broadest electronic family-history collection tools and has been validated for use in risk assessment for diabetes and cancer of the colon, breast, and ovaries.²²

However, electronic solutions have their own challenges. Not all patients have access to the Internet, many need help using these programs, and these tools may not work well with existing electronic medical records systems.²³ Ideally, these programs would also provide built-in decision support for the provider, thereby maximizing data use for final patient risk assessment.²³ Furthermore, electronic solutions are not a one-time-only risk assessment— periodic re-review of family history and reassessment of familial risk are required.²⁴

Does taking a family history improve outcomes? Lessons from breast cancer

One of the reasons physicians don’t get reimbursed for collecting a family history is that it has been difficult to measure any improvement in outcomes associated with risk prediction through family history.

The best examples of improvement in outcomes associated with family history-based risk prediction come from studies of breast cancer. From 5% to 10% of cases of breast cancer are part of hereditary cancer syndromes, many of which have a known genetic cause. The most prevalent of these genetic syndromes is the hereditary breast and ovarian cancer (HBOC) syndrome, caused by mutations in the breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) genes. Clinical testing for BRCA mutations has been available since 1998.²⁵ Women with a BRCA mutation have up to a 65% lifetime risk of developing breast cancer and up to a 40% lifetime risk of developing ovarian cancer.²⁶ Men with a BRCA mutation are at 10 to 100 times the risk of the general population (1% to 10% vs 0.1%) for developing breast cancer, and are also at higher risk of prostate and other cancers.²⁷

People who have a relative who developed breast cancer at a young age are more likely to harbor one of these mutations. For example, based on genetic testing in more than 185,000 people, the prevalence of BRCA mutations among people without cancer, not of Ashkenazi Jewish ancestry (a risk factor for breast cancer), and with no family history of early breast cancer or of ovarian cancer in any relative is 1.5%.²⁸ In contrast, people with no personal history of cancer who have a family history of breast cancer before age 50 have a 5.6% prevalence of BRCA mutation, and if they are of Ashkenazi Jewish ancestry, this number is 16.4%.²⁸

Medical and surgical interventions are available to reduce the risk of cancer in people with hereditary cancer syndromes such as HBOC. Options include screening more often, using advanced screening tests,²⁹ giving preventive drugs such as tamoxifen (Nolvadex), and prophylactic surgery.^30–32 What is the evidence that early screening and intervention in these people improve outcomes?

Domcheck et al³³ prospectively followed more than 2,400 women who had BRCA mutations to assess the effect of prophylactic mastectomy or salpingo-oophorectomy on cancer outcomes. Mastectomy was indeed associated with a lower risk of breast cancer: 0 cases of breast cancer were diagnosed in 3 years of prospective follow-up in the 247 women who elected to undergo mastectomy, compared with 98 cases diagnosed in the 1,372 women who did not elect it over a similar period.

Women who elected to undergo salpingo-oophorectomy had a similarly lower rate of ovarian cancer compared with those who did not elect surgery (1% vs 6%). Additionally, fewer women who elected prophylactic salpingo-oophorectomy died of any cause (3% vs 10%), died of breast cancer (2% vs 6%), or died of ovarian cancer (0.4% vs 3%) compared with women who did not elect surgery.

Taking a family history reduces costs

What is the evidence that appropriate use of the family history decreases health care costs? Let us continue with the example of HBOC syndrome due to BRCA mutations.

Given that germline mutations account for 5% to 10% of cases of breast cancer in the United States and that the women who develop cancer associated with such mutations do so at a relatively young age, these mutations account for a disproportionate share of life-years lost due to cancer.³⁴ Through taking a family history, these women at high risk can be identified and referred for genetic testing. Genetic testing, though costly, is more cost-effective than diagnosing and treating cancer.

Anderson et al,³⁴ in 2006, estimated that cost-effective policies on testing and preventive treatment for persons at high risk of breast cancer could save up to $800 million of the more than $8 billion spent each year on breast cancer diagnosis, prevention, and treatment.

Kwon et al,³⁵ in a simulation model (not a study in real patients), compared four different criteria for BRCA testing in women with ovarian cancer to see which strategy would be most cost-effective in preventing breast and ovarian cancers in their first-degree relatives. The best strategy, according to this analysis, is to test women with ovarian cancer for BRCA mutations if they also have a personal history of breast cancer, have a family history of breast or ovarian cancer, or are of Ashkenazi Jewish ancestry. The estimated cost per life-year gained with this strategy was $32,018, much lower than the widely accepted threshold for cost-effectiveness of $50,000 per life-year gained.

Although many professional organizations, including the US Preventive Services Task Force, have endorsed family-history-based eligibility criteria for genetic counseling and BRCA testing, awareness of the value of genetic testing in people who have been prescreened by family history has been relatively slow in seeping out to insurance carriers, especially Medicaid.^12,36 As evidence continues to accumulate showing that this approach can improve outcomes for at-risk family members, reimbursement and time allotted for obtaining and using the family history should be adjusted.

CHALLENGE 3: A KNOWLEDGE GAP IN CLINICIANS

Another challenge often cited as a cause of the underuse of the family history as a predictor of disease risk is that clinicians may not know enough about the topic. Several studies indicated that even when physicians had obtained some components of the family history, they did not document risk appropriately or recognize the significance of the pattern of inheritance observed.^37–39

In a study comparing primary care physicians and gastroenterologists in their use of the family history to predict the risk of hereditary colon cancer, gastroenterologists were more likely to elicit a family history of colorectal cancer and implement appropriate screening strategies, but overall compliance with screening guidelines was suboptimal in both groups.⁴⁰

A 2011 report by an advisory committee to the secretary of the US Department of Health and Human Services concluded that lack of genetics education in medical school limits the integration of genetics into clinical care.⁴¹

How can we close this knowledge gap?

Recognizing a need, the National Coalition for Health Professional Education in Genetics was established in 1996 by the American Medical Association, the American Nurses Association, and the National Human Genome Research Institute (www.nchpeg.org). Its mission is to promote the education of health professionals and access to information about advances in human genetics to improve the health care of the nation. It offers educational materials, including a newly updated “Core Principles in Family History” program, which can be used to educate medical providers and their patients about various concepts related to genetics and family history.

In addition, physicians can use many risk assessment tools based on family history in patient care. Two of the best known are:

• The Gail breast cancer risk assessment model, hosted by the National Cancer Institute (www.cancer.gov/bcrisktool/)
• The FRAX osteoporosis risk assessment model, developed by the World Health Organization (www.shef.ac.uk/FRAX).

As we continue to educate the medical community about the value of the family history in predicting disease, it will be important to increase efforts in medical schools and residency programs and to find new, more interactive ways of teaching these concepts.

A possible strategy is to highlight the use of pedigree drawing to recognize patterns of inheritance.² In a study of physician attitudes toward using patient-generated pedigrees in practice, such as those produced by the US surgeon general’s My Family Health Portrait, 73% of physicians stated that the patient-generated pedigree would improve their ability to assess the risk of disease, and the majority also agreed that it would not extend the time of the assessment.¹⁶

Is this information clinically useful?

Furthermore, knowing they are at risk might empower people and encourage them to engage with the medical system. For example, counseling people at risk of diabetes as reflected in the family history has been shown to increase their understanding of the risk and of preventive behaviors. Further study is needed to determine if such messages can engender lasting changes in behavior across many diseases.^42–46

TOWARD PERSONALIZED CARE

Especially now that caregivers are striving to provide value-based health care with emphasis on preventive care, the family history remains an important tool for detecting risk of disease. The evidence clearly indicates that medical providers have room for improvement in taking a family history and in using it.

We hope that asking patients about family history and recognizing patterns of disease will help us create personalized preventive-care plans, providing greater opportunity to educate and motivate our patients to work with us towards better health. Future solutions need to focus on time-effective ways to collect and analyze family history and on innovative methods of teaching medical providers at all levels to apply the family history to clinical practice.

At the dawn of the genomics era, is the family history still relevant? The answer is a resounding yes.^1,2

The family history is clinically useful because it is a proxy for genetic, environmental, and behavioral risks to health. It can be used to inform risk stratification, allowing for judicious use of screening and opening the door to early and even prophylactic treatment.^3–8 As people live longer, we will need to detect common chronic conditions early in their course so that we can continue to improve health outcomes. Family history can help physicians personalize preventive care for conditions such as diabetes, osteoporosis, and cancers of the breast, colon, and prostate.^2,9–15

However, there is ample evidence that the family history is underused. Most practitioners ask about it infrequently and inconsistently.^16,17 Why is this, and how can we encourage the use of this powerful tool to enhance our daily clinical practice and improve care?

We will discuss here some of the challenges that make it difficult for physicians to collect and use the family history in clinical practice, and review strategies for collecting and using the family history in a more consistent manner. We anticipate that this discussion will be helpful to clinicians, as the family history is an essential input to personalized, preventive care plans.

CHALLENGE 1: ARE PATIENTS’ REPORTS RELIABLE?

A question that often arises when discussing the utility of the family history is the reliability of patients’ reports. Can we trust that patients can accurately report their family history? For many conditions, the answer is yes.^18,19

Ziogas and Anton-Culverl²⁰ asked 1,111 cancer patients whether their relatives had ever had cancer and verified their answers. In more than 95% of cases, if the patient said that a first-degree or second-degree relative did not have cancer of any type, that relative truly did not have cancer. Overall, over-reporting of cancer was rare, occurring in 2.4% of cases.

If the patient said that a relative did have cancer, that statement was usually true as well. The reliability of a report of cancer in first-degree relatives was greater than 75% for most types of cancer (female breast, ovarian, esophageal, colorectal, pancreas, lung, melanoma, brain, thyroid, lymphoma, leukemia). For several of these types of cancer (female breast, colorectal, and brain), the reliability was 90% or higher. For second-degree relatives, the reliability of a reported positive history was moderate (50% to 80%) for the same types of cancer, and for third-degree relatives, the reliability dropped further for all types of cancer except female breast, brain, pancreas, and leukemia, for which the reliability of a positive report remained at 70%.

Wideroff et al²¹ had similar findings in a study of more than 1,000 patients and more than 20,000 of their relatives.

Yoon et al,¹⁸ at the US Centers for Disease Control and Prevention, developed a Web-based risk-assessment tool called Family Healthware, currently undergoing validation trials. They found that patients’ reports were highly reliable for coronary heart disease, stroke, diabetes, and breast, ovarian, and colorectal cancers. They also calculated the degree of risk associated with a positive family history and the prevalence of a family history of each of these diseases.

For the primary care physician, these studies support the reliability of patients’ reports and provide guidance for targeting specific conditions when obtaining a family history.

CHALLENGE 2: NO TIME OR REIMBURSEMENT

Perhaps the most obvious barriers to collecting a family history are lack of time and reimbursement.

Acheson et al,¹⁷ in an observational study of 138 primary care physicians and 4,454 patient visits, found that family history was discussed during 51% of new patient visits and 22% of established patient visits. The rate at which the family history was taken varied from 0% (some physicians never asked) to 81% of all patient visits. On average, physicians spent less than 2.5 minutes collecting the family history.

Not surprisingly, the family history was discussed more often at well-care visits than at illness visits, as the former type of visit tends to be longer and, by definition, to be spent partly on preventive care. A difficulty with this strategy is that, given the shortage of primary care physicians, limited access, and patient preference, most preventive-care visits are combined with problem-focused visits, further decreasing the time available to collect and discuss a family history. While some argue that the family history should routinely be obtained and discussed during preventive-care visits regardless of reimbursement and time, the reality is that it may simply drop on the list of priorities for each visit.

Rich et al³ estimated that taking a family history would increase reimbursement for only one new patient evaluation and management code (99202) and one return-visit code (99213) in Current Procedural Terminology. This action would increase reimbursement enough to support about 10 minutes of physician effort for collecting, documenting, and analyzing the family history. While this is certainly better than the average of less than 2.5 minutes observed by Acheson et al,¹⁷ doctors would probably do it more if they were paid more for it.

Electronic solutions

Given that a lack of time is a barrier, what are some ways to minimize the time it takes to collect a family history?

With more physicians using electronic health records and with increasing use of Internet-based tools in the population at large, information-technology systems have been developed to help obtain the family history. One of the most widely used is the US surgeon general’s My Family Health Portrait, available free at https://familyhistory.hhs.gov. It is one of the broadest electronic family-history collection tools and has been validated for use in risk assessment for diabetes and cancer of the colon, breast, and ovaries.²²

However, electronic solutions have their own challenges. Not all patients have access to the Internet, many need help using these programs, and these tools may not work well with existing electronic medical records systems.²³ Ideally, these programs would also provide built-in decision support for the provider, thereby maximizing data use for final patient risk assessment.²³ Furthermore, electronic solutions are not a one-time-only risk assessment— periodic re-review of family history and reassessment of familial risk are required.²⁴

Does taking a family history improve outcomes? Lessons from breast cancer

One of the reasons physicians don’t get reimbursed for collecting a family history is that it has been difficult to measure any improvement in outcomes associated with risk prediction through family history.

The best examples of improvement in outcomes associated with family history-based risk prediction come from studies of breast cancer. From 5% to 10% of cases of breast cancer are part of hereditary cancer syndromes, many of which have a known genetic cause. The most prevalent of these genetic syndromes is the hereditary breast and ovarian cancer (HBOC) syndrome, caused by mutations in the breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) genes. Clinical testing for BRCA mutations has been available since 1998.²⁵ Women with a BRCA mutation have up to a 65% lifetime risk of developing breast cancer and up to a 40% lifetime risk of developing ovarian cancer.²⁶ Men with a BRCA mutation are at 10 to 100 times the risk of the general population (1% to 10% vs 0.1%) for developing breast cancer, and are also at higher risk of prostate and other cancers.²⁷

People who have a relative who developed breast cancer at a young age are more likely to harbor one of these mutations. For example, based on genetic testing in more than 185,000 people, the prevalence of BRCA mutations among people without cancer, not of Ashkenazi Jewish ancestry (a risk factor for breast cancer), and with no family history of early breast cancer or of ovarian cancer in any relative is 1.5%.²⁸ In contrast, people with no personal history of cancer who have a family history of breast cancer before age 50 have a 5.6% prevalence of BRCA mutation, and if they are of Ashkenazi Jewish ancestry, this number is 16.4%.²⁸

Medical and surgical interventions are available to reduce the risk of cancer in people with hereditary cancer syndromes such as HBOC. Options include screening more often, using advanced screening tests,²⁹ giving preventive drugs such as tamoxifen (Nolvadex), and prophylactic surgery.^30–32 What is the evidence that early screening and intervention in these people improve outcomes?

Domcheck et al³³ prospectively followed more than 2,400 women who had BRCA mutations to assess the effect of prophylactic mastectomy or salpingo-oophorectomy on cancer outcomes. Mastectomy was indeed associated with a lower risk of breast cancer: 0 cases of breast cancer were diagnosed in 3 years of prospective follow-up in the 247 women who elected to undergo mastectomy, compared with 98 cases diagnosed in the 1,372 women who did not elect it over a similar period.

Women who elected to undergo salpingo-oophorectomy had a similarly lower rate of ovarian cancer compared with those who did not elect surgery (1% vs 6%). Additionally, fewer women who elected prophylactic salpingo-oophorectomy died of any cause (3% vs 10%), died of breast cancer (2% vs 6%), or died of ovarian cancer (0.4% vs 3%) compared with women who did not elect surgery.

Taking a family history reduces costs

What is the evidence that appropriate use of the family history decreases health care costs? Let us continue with the example of HBOC syndrome due to BRCA mutations.

Given that germline mutations account for 5% to 10% of cases of breast cancer in the United States and that the women who develop cancer associated with such mutations do so at a relatively young age, these mutations account for a disproportionate share of life-years lost due to cancer.³⁴ Through taking a family history, these women at high risk can be identified and referred for genetic testing. Genetic testing, though costly, is more cost-effective than diagnosing and treating cancer.

Anderson et al,³⁴ in 2006, estimated that cost-effective policies on testing and preventive treatment for persons at high risk of breast cancer could save up to $800 million of the more than $8 billion spent each year on breast cancer diagnosis, prevention, and treatment.

Kwon et al,³⁵ in a simulation model (not a study in real patients), compared four different criteria for BRCA testing in women with ovarian cancer to see which strategy would be most cost-effective in preventing breast and ovarian cancers in their first-degree relatives. The best strategy, according to this analysis, is to test women with ovarian cancer for BRCA mutations if they also have a personal history of breast cancer, have a family history of breast or ovarian cancer, or are of Ashkenazi Jewish ancestry. The estimated cost per life-year gained with this strategy was $32,018, much lower than the widely accepted threshold for cost-effectiveness of $50,000 per life-year gained.

Although many professional organizations, including the US Preventive Services Task Force, have endorsed family-history-based eligibility criteria for genetic counseling and BRCA testing, awareness of the value of genetic testing in people who have been prescreened by family history has been relatively slow in seeping out to insurance carriers, especially Medicaid.^12,36 As evidence continues to accumulate showing that this approach can improve outcomes for at-risk family members, reimbursement and time allotted for obtaining and using the family history should be adjusted.

CHALLENGE 3: A KNOWLEDGE GAP IN CLINICIANS

Another challenge often cited as a cause of the underuse of the family history as a predictor of disease risk is that clinicians may not know enough about the topic. Several studies indicated that even when physicians had obtained some components of the family history, they did not document risk appropriately or recognize the significance of the pattern of inheritance observed.^37–39

In a study comparing primary care physicians and gastroenterologists in their use of the family history to predict the risk of hereditary colon cancer, gastroenterologists were more likely to elicit a family history of colorectal cancer and implement appropriate screening strategies, but overall compliance with screening guidelines was suboptimal in both groups.⁴⁰

A 2011 report by an advisory committee to the secretary of the US Department of Health and Human Services concluded that lack of genetics education in medical school limits the integration of genetics into clinical care.⁴¹

How can we close this knowledge gap?

Recognizing a need, the National Coalition for Health Professional Education in Genetics was established in 1996 by the American Medical Association, the American Nurses Association, and the National Human Genome Research Institute (www.nchpeg.org). Its mission is to promote the education of health professionals and access to information about advances in human genetics to improve the health care of the nation. It offers educational materials, including a newly updated “Core Principles in Family History” program, which can be used to educate medical providers and their patients about various concepts related to genetics and family history.

In addition, physicians can use many risk assessment tools based on family history in patient care. Two of the best known are:

• The Gail breast cancer risk assessment model, hosted by the National Cancer Institute (www.cancer.gov/bcrisktool/)
• The FRAX osteoporosis risk assessment model, developed by the World Health Organization (www.shef.ac.uk/FRAX).

As we continue to educate the medical community about the value of the family history in predicting disease, it will be important to increase efforts in medical schools and residency programs and to find new, more interactive ways of teaching these concepts.

A possible strategy is to highlight the use of pedigree drawing to recognize patterns of inheritance.² In a study of physician attitudes toward using patient-generated pedigrees in practice, such as those produced by the US surgeon general’s My Family Health Portrait, 73% of physicians stated that the patient-generated pedigree would improve their ability to assess the risk of disease, and the majority also agreed that it would not extend the time of the assessment.¹⁶

Is this information clinically useful?

Furthermore, knowing they are at risk might empower people and encourage them to engage with the medical system. For example, counseling people at risk of diabetes as reflected in the family history has been shown to increase their understanding of the risk and of preventive behaviors. Further study is needed to determine if such messages can engender lasting changes in behavior across many diseases.^42–46

TOWARD PERSONALIZED CARE

Especially now that caregivers are striving to provide value-based health care with emphasis on preventive care, the family history remains an important tool for detecting risk of disease. The evidence clearly indicates that medical providers have room for improvement in taking a family history and in using it.

We hope that asking patients about family history and recognizing patterns of disease will help us create personalized preventive-care plans, providing greater opportunity to educate and motivate our patients to work with us towards better health. Future solutions need to focus on time-effective ways to collect and analyze family history and on innovative methods of teaching medical providers at all levels to apply the family history to clinical practice.

At the dawn of the genomics era, is the family history still relevant? The answer is a resounding yes.^1,2

The family history is clinically useful because it is a proxy for genetic, environmental, and behavioral risks to health. It can be used to inform risk stratification, allowing for judicious use of screening and opening the door to early and even prophylactic treatment.^3–8 As people live longer, we will need to detect common chronic conditions early in their course so that we can continue to improve health outcomes. Family history can help physicians personalize preventive care for conditions such as diabetes, osteoporosis, and cancers of the breast, colon, and prostate.^2,9–15

However, there is ample evidence that the family history is underused. Most practitioners ask about it infrequently and inconsistently.^16,17 Why is this, and how can we encourage the use of this powerful tool to enhance our daily clinical practice and improve care?

We will discuss here some of the challenges that make it difficult for physicians to collect and use the family history in clinical practice, and review strategies for collecting and using the family history in a more consistent manner. We anticipate that this discussion will be helpful to clinicians, as the family history is an essential input to personalized, preventive care plans.

CHALLENGE 1: ARE PATIENTS’ REPORTS RELIABLE?

A question that often arises when discussing the utility of the family history is the reliability of patients’ reports. Can we trust that patients can accurately report their family history? For many conditions, the answer is yes.^18,19

Ziogas and Anton-Culverl²⁰ asked 1,111 cancer patients whether their relatives had ever had cancer and verified their answers. In more than 95% of cases, if the patient said that a first-degree or second-degree relative did not have cancer of any type, that relative truly did not have cancer. Overall, over-reporting of cancer was rare, occurring in 2.4% of cases.

If the patient said that a relative did have cancer, that statement was usually true as well. The reliability of a report of cancer in first-degree relatives was greater than 75% for most types of cancer (female breast, ovarian, esophageal, colorectal, pancreas, lung, melanoma, brain, thyroid, lymphoma, leukemia). For several of these types of cancer (female breast, colorectal, and brain), the reliability was 90% or higher. For second-degree relatives, the reliability of a reported positive history was moderate (50% to 80%) for the same types of cancer, and for third-degree relatives, the reliability dropped further for all types of cancer except female breast, brain, pancreas, and leukemia, for which the reliability of a positive report remained at 70%.

Wideroff et al²¹ had similar findings in a study of more than 1,000 patients and more than 20,000 of their relatives.

Yoon et al,¹⁸ at the US Centers for Disease Control and Prevention, developed a Web-based risk-assessment tool called Family Healthware, currently undergoing validation trials. They found that patients’ reports were highly reliable for coronary heart disease, stroke, diabetes, and breast, ovarian, and colorectal cancers. They also calculated the degree of risk associated with a positive family history and the prevalence of a family history of each of these diseases.

For the primary care physician, these studies support the reliability of patients’ reports and provide guidance for targeting specific conditions when obtaining a family history.

CHALLENGE 2: NO TIME OR REIMBURSEMENT

Perhaps the most obvious barriers to collecting a family history are lack of time and reimbursement.

Acheson et al,¹⁷ in an observational study of 138 primary care physicians and 4,454 patient visits, found that family history was discussed during 51% of new patient visits and 22% of established patient visits. The rate at which the family history was taken varied from 0% (some physicians never asked) to 81% of all patient visits. On average, physicians spent less than 2.5 minutes collecting the family history.

Not surprisingly, the family history was discussed more often at well-care visits than at illness visits, as the former type of visit tends to be longer and, by definition, to be spent partly on preventive care. A difficulty with this strategy is that, given the shortage of primary care physicians, limited access, and patient preference, most preventive-care visits are combined with problem-focused visits, further decreasing the time available to collect and discuss a family history. While some argue that the family history should routinely be obtained and discussed during preventive-care visits regardless of reimbursement and time, the reality is that it may simply drop on the list of priorities for each visit.

Rich et al³ estimated that taking a family history would increase reimbursement for only one new patient evaluation and management code (99202) and one return-visit code (99213) in Current Procedural Terminology. This action would increase reimbursement enough to support about 10 minutes of physician effort for collecting, documenting, and analyzing the family history. While this is certainly better than the average of less than 2.5 minutes observed by Acheson et al,¹⁷ doctors would probably do it more if they were paid more for it.

Electronic solutions

Given that a lack of time is a barrier, what are some ways to minimize the time it takes to collect a family history?

With more physicians using electronic health records and with increasing use of Internet-based tools in the population at large, information-technology systems have been developed to help obtain the family history. One of the most widely used is the US surgeon general’s My Family Health Portrait, available free at https://familyhistory.hhs.gov. It is one of the broadest electronic family-history collection tools and has been validated for use in risk assessment for diabetes and cancer of the colon, breast, and ovaries.²²

However, electronic solutions have their own challenges. Not all patients have access to the Internet, many need help using these programs, and these tools may not work well with existing electronic medical records systems.²³ Ideally, these programs would also provide built-in decision support for the provider, thereby maximizing data use for final patient risk assessment.²³ Furthermore, electronic solutions are not a one-time-only risk assessment— periodic re-review of family history and reassessment of familial risk are required.²⁴

Does taking a family history improve outcomes? Lessons from breast cancer

One of the reasons physicians don’t get reimbursed for collecting a family history is that it has been difficult to measure any improvement in outcomes associated with risk prediction through family history.

The best examples of improvement in outcomes associated with family history-based risk prediction come from studies of breast cancer. From 5% to 10% of cases of breast cancer are part of hereditary cancer syndromes, many of which have a known genetic cause. The most prevalent of these genetic syndromes is the hereditary breast and ovarian cancer (HBOC) syndrome, caused by mutations in the breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) genes. Clinical testing for BRCA mutations has been available since 1998.²⁵ Women with a BRCA mutation have up to a 65% lifetime risk of developing breast cancer and up to a 40% lifetime risk of developing ovarian cancer.²⁶ Men with a BRCA mutation are at 10 to 100 times the risk of the general population (1% to 10% vs 0.1%) for developing breast cancer, and are also at higher risk of prostate and other cancers.²⁷

People who have a relative who developed breast cancer at a young age are more likely to harbor one of these mutations. For example, based on genetic testing in more than 185,000 people, the prevalence of BRCA mutations among people without cancer, not of Ashkenazi Jewish ancestry (a risk factor for breast cancer), and with no family history of early breast cancer or of ovarian cancer in any relative is 1.5%.²⁸ In contrast, people with no personal history of cancer who have a family history of breast cancer before age 50 have a 5.6% prevalence of BRCA mutation, and if they are of Ashkenazi Jewish ancestry, this number is 16.4%.²⁸

Medical and surgical interventions are available to reduce the risk of cancer in people with hereditary cancer syndromes such as HBOC. Options include screening more often, using advanced screening tests,²⁹ giving preventive drugs such as tamoxifen (Nolvadex), and prophylactic surgery.^30–32 What is the evidence that early screening and intervention in these people improve outcomes?

Domcheck et al³³ prospectively followed more than 2,400 women who had BRCA mutations to assess the effect of prophylactic mastectomy or salpingo-oophorectomy on cancer outcomes. Mastectomy was indeed associated with a lower risk of breast cancer: 0 cases of breast cancer were diagnosed in 3 years of prospective follow-up in the 247 women who elected to undergo mastectomy, compared with 98 cases diagnosed in the 1,372 women who did not elect it over a similar period.

Women who elected to undergo salpingo-oophorectomy had a similarly lower rate of ovarian cancer compared with those who did not elect surgery (1% vs 6%). Additionally, fewer women who elected prophylactic salpingo-oophorectomy died of any cause (3% vs 10%), died of breast cancer (2% vs 6%), or died of ovarian cancer (0.4% vs 3%) compared with women who did not elect surgery.

Taking a family history reduces costs

What is the evidence that appropriate use of the family history decreases health care costs? Let us continue with the example of HBOC syndrome due to BRCA mutations.

Given that germline mutations account for 5% to 10% of cases of breast cancer in the United States and that the women who develop cancer associated with such mutations do so at a relatively young age, these mutations account for a disproportionate share of life-years lost due to cancer.³⁴ Through taking a family history, these women at high risk can be identified and referred for genetic testing. Genetic testing, though costly, is more cost-effective than diagnosing and treating cancer.

Anderson et al,³⁴ in 2006, estimated that cost-effective policies on testing and preventive treatment for persons at high risk of breast cancer could save up to $800 million of the more than $8 billion spent each year on breast cancer diagnosis, prevention, and treatment.

Kwon et al,³⁵ in a simulation model (not a study in real patients), compared four different criteria for BRCA testing in women with ovarian cancer to see which strategy would be most cost-effective in preventing breast and ovarian cancers in their first-degree relatives. The best strategy, according to this analysis, is to test women with ovarian cancer for BRCA mutations if they also have a personal history of breast cancer, have a family history of breast or ovarian cancer, or are of Ashkenazi Jewish ancestry. The estimated cost per life-year gained with this strategy was $32,018, much lower than the widely accepted threshold for cost-effectiveness of $50,000 per life-year gained.

Although many professional organizations, including the US Preventive Services Task Force, have endorsed family-history-based eligibility criteria for genetic counseling and BRCA testing, awareness of the value of genetic testing in people who have been prescreened by family history has been relatively slow in seeping out to insurance carriers, especially Medicaid.^12,36 As evidence continues to accumulate showing that this approach can improve outcomes for at-risk family members, reimbursement and time allotted for obtaining and using the family history should be adjusted.

CHALLENGE 3: A KNOWLEDGE GAP IN CLINICIANS

Another challenge often cited as a cause of the underuse of the family history as a predictor of disease risk is that clinicians may not know enough about the topic. Several studies indicated that even when physicians had obtained some components of the family history, they did not document risk appropriately or recognize the significance of the pattern of inheritance observed.^37–39

In a study comparing primary care physicians and gastroenterologists in their use of the family history to predict the risk of hereditary colon cancer, gastroenterologists were more likely to elicit a family history of colorectal cancer and implement appropriate screening strategies, but overall compliance with screening guidelines was suboptimal in both groups.⁴⁰

A 2011 report by an advisory committee to the secretary of the US Department of Health and Human Services concluded that lack of genetics education in medical school limits the integration of genetics into clinical care.⁴¹

How can we close this knowledge gap?

Recognizing a need, the National Coalition for Health Professional Education in Genetics was established in 1996 by the American Medical Association, the American Nurses Association, and the National Human Genome Research Institute (www.nchpeg.org). Its mission is to promote the education of health professionals and access to information about advances in human genetics to improve the health care of the nation. It offers educational materials, including a newly updated “Core Principles in Family History” program, which can be used to educate medical providers and their patients about various concepts related to genetics and family history.

In addition, physicians can use many risk assessment tools based on family history in patient care. Two of the best known are:

• The Gail breast cancer risk assessment model, hosted by the National Cancer Institute (www.cancer.gov/bcrisktool/)
• The FRAX osteoporosis risk assessment model, developed by the World Health Organization (www.shef.ac.uk/FRAX).

As we continue to educate the medical community about the value of the family history in predicting disease, it will be important to increase efforts in medical schools and residency programs and to find new, more interactive ways of teaching these concepts.

A possible strategy is to highlight the use of pedigree drawing to recognize patterns of inheritance.² In a study of physician attitudes toward using patient-generated pedigrees in practice, such as those produced by the US surgeon general’s My Family Health Portrait, 73% of physicians stated that the patient-generated pedigree would improve their ability to assess the risk of disease, and the majority also agreed that it would not extend the time of the assessment.¹⁶

Is this information clinically useful?

Furthermore, knowing they are at risk might empower people and encourage them to engage with the medical system. For example, counseling people at risk of diabetes as reflected in the family history has been shown to increase their understanding of the risk and of preventive behaviors. Further study is needed to determine if such messages can engender lasting changes in behavior across many diseases.^42–46

TOWARD PERSONALIZED CARE

Especially now that caregivers are striving to provide value-based health care with emphasis on preventive care, the family history remains an important tool for detecting risk of disease. The evidence clearly indicates that medical providers have room for improvement in taking a family history and in using it.

We hope that asking patients about family history and recognizing patterns of disease will help us create personalized preventive-care plans, providing greater opportunity to educate and motivate our patients to work with us towards better health. Future solutions need to focus on time-effective ways to collect and analyze family history and on innovative methods of teaching medical providers at all levels to apply the family history to clinical practice.

The concept and promise of personalized health care have been anticipated for decades. Yet in its breadth and in the way we would like it practiced, it is in its infancy.

Personalized health care aims to individualize care by integrating a person’s unique clinical, molecular (ie, genetic, genomic), and environmental information. Applied not only when the patient is sick but also when he or she is well, it builds on and enhances our current standards of care.

As Sir William Osler recognized more than a century ago, “Variability is the law of life, and as no two faces are the same, so no two bodies are alike, and no two individuals react alike and behave alike under the abnormal conditions which we know as disease.”¹

PREDICTING THE RISK OF DISEASE

For years, we have attempted to predict and stratify the risk of disease, and the Human Genome Project has given us a new set of tools to help understand the complexity of disease and its variability.

We know and have known for decades—and in some cultures, for centuries—that family history is the most clinically validated tool for predicting the risk of disease.

Nevertheless, evidence suggests that we physicians are not collecting adequate family histories, and because of this, we are missing opportunities to intervene and prevent diseases predicted by the family history. The current standard of care is to use family medical histories to hone genetic differential diagnoses, and based on the differential diagnoses, to target specific genes to test in the setting of genetic counseling. Current genetic testing is used for molecular diagnoses and predictive testing so that gene-specific clinical management can be subsequently tailored.

PREDICTING RESPONSE TO TREATMENT

The use of personalized health care to predict response to treatment is a novel and constantly evolving practice.

ABO blood typing is a form of genetics-based personalization of safe transfusion that dates back to World War II.

A prominent, recent success story is in cancer treatment. For example, the American Society of Clinical Oncology now recommends that tumors from patients with node-negative, estrogen-receptor-positive breast cancer be evaluated with the Oncotype DX assay.² This test measures the expression of 21 genes, and the score obtained identifies patients most likely to benefit from adjuvant chemotherapy. A similar 12-gene expression signature has been developed for colon cancer, and others have been developed for hematologic cancers.^2,3 As with other new but apparently valid tests, the risk scores derived are sensitive at the extremes but ambiguous in the mid-ranges. We anticipate many more developments in this field.

In the field of pharmacogenomics, there is evidence to suggest that prior knowledge of CYP2C9 and VKORC1 genotypes enhances outcomes for patients starting treatment with warfarin. The US Food and Drug Administration revised the label on warfarin in February 2010, suggesting that genotypes be taken into consideration when the drug is prescribed.⁴

However, clinicians have been slow to adopt genotype testing when prescribing warfarin. Some cite the paucity of large, randomized, controlled trials demonstrating clinical utility of genotype-informed prescribing. Others cite concern that warfarin will soon become obsolete with the arrival of newer anticoagulants (such as factor X inhibitors) that do not carry warfarin’s adverse effects, and these genotypes will therefore become moot. Perhaps, as we move forward and new drugs are developed, companion genotype tests could be developed at the same time to be used with them.⁵

IMPROVING CARE, SAVING MONEY, AND EMPOWERING PATIENTS

The goal of personalized health care, by customizing treatments (medication types and dosages) and preventive strategies, is to optimize medical care and improve outcomes for each patient. It could improve the quality of care by targeting interventions and reducing adverse events, topics that are important to all of us in the current environment of health care reform.

A personalized approach might also, in the long run, decrease the cost of health care by driving appropriate utilization of resources.

Lastly, the true value of personalized health care may be in its potential to improve patient satisfaction and to empower our patients to work with us towards better health.

WE LAUNCH A NEW SERIES

To keep physicians up-to-date on progress in personalized health care, the Cleveland Clinic Journal of Medicine will present a series of articles on the topic. The series, to run once a quarter, begins in this issue, on page 331, with an article on the importance of the family history as a piece of genetic information that can help to predict the risk of disease and inform preventive care plans. Future topics will include the role of genetics and genomics in personalized care of patients with breast and colorectal cancers; the genetic counselor as a part of the health care team; pharmacogenomics; and ethical, legal, and societal considerations.

Our goal in this series is to provide practical information to help our readers incorporate personalized approaches into daily practice. In addition, as patients become more interested in and informed about personalized health care, we hope this information will help clinicians to effectively coach them about its potential benefits and risks. We also hope this information will enable our readers to ask the right questions so that patient and health care provider can work together to help the patient grow old gracefully.

As the series unfolds, we ask you to send us feedback and to suggest other topics in personalized health care you would like us to cover in this series.

The concept and promise of personalized health care have been anticipated for decades. Yet in its breadth and in the way we would like it practiced, it is in its infancy.

Personalized health care aims to individualize care by integrating a person’s unique clinical, molecular (ie, genetic, genomic), and environmental information. Applied not only when the patient is sick but also when he or she is well, it builds on and enhances our current standards of care.

As Sir William Osler recognized more than a century ago, “Variability is the law of life, and as no two faces are the same, so no two bodies are alike, and no two individuals react alike and behave alike under the abnormal conditions which we know as disease.”¹

PREDICTING THE RISK OF DISEASE

For years, we have attempted to predict and stratify the risk of disease, and the Human Genome Project has given us a new set of tools to help understand the complexity of disease and its variability.

We know and have known for decades—and in some cultures, for centuries—that family history is the most clinically validated tool for predicting the risk of disease.

Nevertheless, evidence suggests that we physicians are not collecting adequate family histories, and because of this, we are missing opportunities to intervene and prevent diseases predicted by the family history. The current standard of care is to use family medical histories to hone genetic differential diagnoses, and based on the differential diagnoses, to target specific genes to test in the setting of genetic counseling. Current genetic testing is used for molecular diagnoses and predictive testing so that gene-specific clinical management can be subsequently tailored.

PREDICTING RESPONSE TO TREATMENT

The use of personalized health care to predict response to treatment is a novel and constantly evolving practice.

ABO blood typing is a form of genetics-based personalization of safe transfusion that dates back to World War II.

A prominent, recent success story is in cancer treatment. For example, the American Society of Clinical Oncology now recommends that tumors from patients with node-negative, estrogen-receptor-positive breast cancer be evaluated with the Oncotype DX assay.² This test measures the expression of 21 genes, and the score obtained identifies patients most likely to benefit from adjuvant chemotherapy. A similar 12-gene expression signature has been developed for colon cancer, and others have been developed for hematologic cancers.^2,3 As with other new but apparently valid tests, the risk scores derived are sensitive at the extremes but ambiguous in the mid-ranges. We anticipate many more developments in this field.

In the field of pharmacogenomics, there is evidence to suggest that prior knowledge of CYP2C9 and VKORC1 genotypes enhances outcomes for patients starting treatment with warfarin. The US Food and Drug Administration revised the label on warfarin in February 2010, suggesting that genotypes be taken into consideration when the drug is prescribed.⁴

However, clinicians have been slow to adopt genotype testing when prescribing warfarin. Some cite the paucity of large, randomized, controlled trials demonstrating clinical utility of genotype-informed prescribing. Others cite concern that warfarin will soon become obsolete with the arrival of newer anticoagulants (such as factor X inhibitors) that do not carry warfarin’s adverse effects, and these genotypes will therefore become moot. Perhaps, as we move forward and new drugs are developed, companion genotype tests could be developed at the same time to be used with them.⁵

IMPROVING CARE, SAVING MONEY, AND EMPOWERING PATIENTS

The goal of personalized health care, by customizing treatments (medication types and dosages) and preventive strategies, is to optimize medical care and improve outcomes for each patient. It could improve the quality of care by targeting interventions and reducing adverse events, topics that are important to all of us in the current environment of health care reform.

A personalized approach might also, in the long run, decrease the cost of health care by driving appropriate utilization of resources.

Lastly, the true value of personalized health care may be in its potential to improve patient satisfaction and to empower our patients to work with us towards better health.

WE LAUNCH A NEW SERIES

To keep physicians up-to-date on progress in personalized health care, the Cleveland Clinic Journal of Medicine will present a series of articles on the topic. The series, to run once a quarter, begins in this issue, on page 331, with an article on the importance of the family history as a piece of genetic information that can help to predict the risk of disease and inform preventive care plans. Future topics will include the role of genetics and genomics in personalized care of patients with breast and colorectal cancers; the genetic counselor as a part of the health care team; pharmacogenomics; and ethical, legal, and societal considerations.

Our goal in this series is to provide practical information to help our readers incorporate personalized approaches into daily practice. In addition, as patients become more interested in and informed about personalized health care, we hope this information will help clinicians to effectively coach them about its potential benefits and risks. We also hope this information will enable our readers to ask the right questions so that patient and health care provider can work together to help the patient grow old gracefully.

As the series unfolds, we ask you to send us feedback and to suggest other topics in personalized health care you would like us to cover in this series.

The concept and promise of personalized health care have been anticipated for decades. Yet in its breadth and in the way we would like it practiced, it is in its infancy.

Personalized health care aims to individualize care by integrating a person’s unique clinical, molecular (ie, genetic, genomic), and environmental information. Applied not only when the patient is sick but also when he or she is well, it builds on and enhances our current standards of care.

As Sir William Osler recognized more than a century ago, “Variability is the law of life, and as no two faces are the same, so no two bodies are alike, and no two individuals react alike and behave alike under the abnormal conditions which we know as disease.”¹

PREDICTING THE RISK OF DISEASE

For years, we have attempted to predict and stratify the risk of disease, and the Human Genome Project has given us a new set of tools to help understand the complexity of disease and its variability.

We know and have known for decades—and in some cultures, for centuries—that family history is the most clinically validated tool for predicting the risk of disease.

Nevertheless, evidence suggests that we physicians are not collecting adequate family histories, and because of this, we are missing opportunities to intervene and prevent diseases predicted by the family history. The current standard of care is to use family medical histories to hone genetic differential diagnoses, and based on the differential diagnoses, to target specific genes to test in the setting of genetic counseling. Current genetic testing is used for molecular diagnoses and predictive testing so that gene-specific clinical management can be subsequently tailored.

PREDICTING RESPONSE TO TREATMENT

The use of personalized health care to predict response to treatment is a novel and constantly evolving practice.

ABO blood typing is a form of genetics-based personalization of safe transfusion that dates back to World War II.

A prominent, recent success story is in cancer treatment. For example, the American Society of Clinical Oncology now recommends that tumors from patients with node-negative, estrogen-receptor-positive breast cancer be evaluated with the Oncotype DX assay.² This test measures the expression of 21 genes, and the score obtained identifies patients most likely to benefit from adjuvant chemotherapy. A similar 12-gene expression signature has been developed for colon cancer, and others have been developed for hematologic cancers.^2,3 As with other new but apparently valid tests, the risk scores derived are sensitive at the extremes but ambiguous in the mid-ranges. We anticipate many more developments in this field.

In the field of pharmacogenomics, there is evidence to suggest that prior knowledge of CYP2C9 and VKORC1 genotypes enhances outcomes for patients starting treatment with warfarin. The US Food and Drug Administration revised the label on warfarin in February 2010, suggesting that genotypes be taken into consideration when the drug is prescribed.⁴

However, clinicians have been slow to adopt genotype testing when prescribing warfarin. Some cite the paucity of large, randomized, controlled trials demonstrating clinical utility of genotype-informed prescribing. Others cite concern that warfarin will soon become obsolete with the arrival of newer anticoagulants (such as factor X inhibitors) that do not carry warfarin’s adverse effects, and these genotypes will therefore become moot. Perhaps, as we move forward and new drugs are developed, companion genotype tests could be developed at the same time to be used with them.⁵

IMPROVING CARE, SAVING MONEY, AND EMPOWERING PATIENTS

The goal of personalized health care, by customizing treatments (medication types and dosages) and preventive strategies, is to optimize medical care and improve outcomes for each patient. It could improve the quality of care by targeting interventions and reducing adverse events, topics that are important to all of us in the current environment of health care reform.

A personalized approach might also, in the long run, decrease the cost of health care by driving appropriate utilization of resources.

Lastly, the true value of personalized health care may be in its potential to improve patient satisfaction and to empower our patients to work with us towards better health.

WE LAUNCH A NEW SERIES

To keep physicians up-to-date on progress in personalized health care, the Cleveland Clinic Journal of Medicine will present a series of articles on the topic. The series, to run once a quarter, begins in this issue, on page 331, with an article on the importance of the family history as a piece of genetic information that can help to predict the risk of disease and inform preventive care plans. Future topics will include the role of genetics and genomics in personalized care of patients with breast and colorectal cancers; the genetic counselor as a part of the health care team; pharmacogenomics; and ethical, legal, and societal considerations.

Our goal in this series is to provide practical information to help our readers incorporate personalized approaches into daily practice. In addition, as patients become more interested in and informed about personalized health care, we hope this information will help clinicians to effectively coach them about its potential benefits and risks. We also hope this information will enable our readers to ask the right questions so that patient and health care provider can work together to help the patient grow old gracefully.

As the series unfolds, we ask you to send us feedback and to suggest other topics in personalized health care you would like us to cover in this series.

Prostate cancer is the most common cancer affecting American men. In 2010, an estimated 217,730 men were diagnosed with it and 32,050 died of it.¹ African American men are disproportionately affected, with a prostate cancer incidence two-thirds higher than whites and a mortality rate twice as high.¹ Owing to such disparities, the life expectancy of African Americans is several years shorter than that of non-Hispanic whites.²

For the primary care provider, who is often the first access point for health care in the United States, it is important to understand what mechanisms may underlie these differences and what can be done to narrow the gap.³

WHAT IS THE CAUSE OF THESE DIFFERENCES?

Many studies have looked into the causes of the higher incidence of prostate cancer in African American men and their higher mortality rate from it. The disparity may be due to a variety of factors, some socioeconomic and some biologic.

Poorer access to care, or lower-quality care?

A study of US servicemen who had equal access to care showed that African American men had a higher rate of prostate cancer regardless of access to care and socioeconomic status.⁴

However, the 2002 Institute of Medicine report, Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care, found evidence that racial and ethnic minorities tend to receive lower-quality health care than whites, “even when access-related factors, such as patients’ insurance status and income, are controlled.”⁵

Genetic predisposition?

Some have proposed that the disparity may be a function of genetic predisposition.

Evidence of a genetic component to the high incidence and mortality rate in African American men comes from epidemiologic studies of men with similar genetic backgrounds. For example, men in Nigeria and Ghana also have a high incidence of prostate cancer, as do men of African descent in the Caribbean islands and in the United Kingdom.⁶

Chromosome 8q24 variants have been shown in several studies to be associated with prostate cancer risk and are more common in African American men.^7–10 Some studies have also shown a higher rate of variations in cell apoptosis genes such as BCL2¹¹ and tumor-suppression genes such as EphB2 in African American men.¹²

These findings suggest that genetic differences may contribute to the higher prostate cancer incidence and mortality rate seen in African American men.

More-aggressive cancer, or later detection?

Not only do African American men tend to have a higher incidence of prostate cancer, they also tend to have more-aggressive disease (ie, a higher pathologic grade) at the time of diagnosis, which may contribute to the disparity in mortality rates.^13–19

Initially, there was some controversy as to whether this observation is a result of genetic and biologic factors that may predispose African American men to more-aggressive disease, or if it is due to inadequate screening and delayed presentation. However, a body of evidence supports the contention that prostate cancer is more aggressive in African American men.

For example, a study of autopsy data from men who died of prostate cancer at ages 20 to 49 showed that the age of onset of prostate cancer was similar between African American and white men.²⁰ The Surveillance Epidemiology and End Results (SEER) database showed that African American men had a higher incidence of metastatic disease across all age groups.²⁰ A similar study conducted 10 years later confirmed that rates of subclinical prostate cancer in African American and white men do not differ by race at the early ages, but that advanced or metastatic disease occurred nearly four times as frequently in African American men.²¹

Another study examined prostate biopsies from African American men and found that their tumors expressed higher levels of biomarkers, suggesting they had more-aggressive disease.²²

SCREENING FOR PROSTATE CANCER

Serum prostate-specific antigen (PSA) testing has become the method of choice for prostate cancer screening. However, PSA screening in asymptomatic men is under debate, because it can lead to overdetection and subsequent overtreatment of indolent disease.²³

Several recent studies showed differing results from prostate cancer screening.

The US Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial found that the mortality rate was no lower with combined PSA screening and digital rectal examination during a median follow-up of 11 years than in a control group that had a lower rate of screening.²⁴ However, further analysis of these data, with stratifying by comorbidities, showed that PSA screening in young and healthy men reduces the risk of death from prostate cancer, with minimal overtreatment.²⁵

The European Randomized Study of Screening for Prostate Cancer found a statistically significant 20% reduction in deaths from prostate cancer with PSA screening, but that it was necessary to treat 48 men in order to save one life.²⁶

Another study, published in 2010, showed that regular PSA screening reduced the rate of prostate cancer mortality by half over 14 years.²⁷

African American men generally present with disease that is more advanced than in white men.²⁸ This historically has been attributed to the fact that African Americans have been less likely to be screened for prostate cancer, though recent data indicate the gap is lessening.^29–31 A cross-sectional study from the Texas Medical Center showed that 54.4% of African American men had received PSA screening, compared with 63.2% of white men.³²

Another study showed that African Americans were more likely to have had a longer interval between PSA screenings before diagnosis, and that a longer PSA screening interval was associated with greater odds of having advanced disease at diagnosis.³³ However, when the researchers controlled for the PSA screening interval, they found that African Americans had the same odds of being diagnosed with advanced prostate cancer as white patients did. They concluded that more frequent or systematic PSA screening may reduce the racial differences in cancer stage at diagnosis and in deaths.

Many reasons have been proposed to explain why African Americans receive less screening, including poor communication between physicians and minority patients due to lack of cultural competency among physicians, lack of health insurance (and poor access to quality care as a result), and deficiency of knowledge about screening. Though awareness is rising, many African Americans are unaware of early detection methods for prostate cancer (eg, PSA testing), and other barriers such as cost and transportation exist that may prevent African American men from being screened.^34,35

As gatekeepers, primary care physicians are in a position to address these shortcomings in patient education and to enhance the physician-patient relationship.³⁶

Black men have higher PSA levels, with or without cancer

Physicians must also be aware of racial differences in PSA levels and realize that the predictive value of PSA in the diagnosis of prostate cancer may differ between African Americans and whites.

Black men, with or without prostate cancer, have been found to have higher PSA levels. Kyle and colleagues³⁷ found that African American men without prostate cancer had significantly higher mean PSA levels than white men across all age groups. Furthermore, Vijayakumar et al³⁸ found that African Americans with newly diagnosed localized prostate cancer had higher serum PSA levels than whites at diagnosis.

Although PSA cutoff levels have not been officially modified according to race, primary care physicians should have a lower threshold for referring African American men who have a suspiciously high PSA level for further urologic evaluation. Close partnership between the internist, family practitioner, and urologist will aid in the optimal use of PSA testing for the early detection of prostate cancer.

When to start PSA screening? How often to screen?

The age at which African American men should begin to have their PSA levels checked (with or without a digital rectal examination) continues to debated. However, the American Cancer Society³⁹ recommends that African American men who have a father or brother who had prostate cancer before age 65 should begin having discussions with their physician on this topic and, with their informed consent, screening at age 45.

The frequency of PSA screening depends on the individual’s PSA level. The National Comprehensive Cancer Network⁴⁰ recommends that men at high risk be offered a baseline PSA measurement and digital rectal examination at age 40 and, if the PSA level is higher than 1 ng/mL, that they be offered annual follow-ups. If the PSA level is less than 1 ng/mL, they recommend screening again at age 45. Risk factors for prostate cancer include family history as well as African American race.⁴¹

How should PSA levels be interpreted?

Interpreting PSA results is important in detecting prostate cancer at early stages.

At first, we believed the normal range of PSA for all men was 4.0 ng/mL or less. However, the American Urological Association now recognizes that the normal PSA range, in addition to varying along racial lines, also is age-dependent.⁴² The Cleveland Clinic Minority Men's Health Center's suggested normal ranges of PSA in African American men are:

• Age 40–49: ≤ 2.5 ng/mL
• Age 50–59: ≤ 3.0 ng/mL
• Age 60–69: ≤ 3.5 ng/mL
• Age 70–79: ≤ 4.5 ng/mL
• Age > 80: ≤ 5.0 ng/mL.

Remember that an elevated PSA does not necessarily signify prostate cancer, and that these are reference ranges only and may vary in individual men.

SURVIVAL AFTER DIAGNOSIS

African American men with prostate cancer have significantly higher mortality rates than white men. The possible causes of worse outcomes are many, and there have been many studies that attempted to address this disparity. The question of a more biologically aggressive cancer was previously discussed, but additional factors such as socioeconomic factors, comorbidities, and treatment received have also been studied, and data are mixed.^43–45

In a large SEER database review, once confounding variables of socioeconomic status, cancer stage, and treatment received were eliminated, African Americans had similar stage-for-stage survival from prostate cancer.⁴⁶ Another study found, in 2,046 men, that differences in socioeconomic status explained the difference in mortality rates between white and black patients.⁴⁷

However, other studies that adjusted for socioeconomic status as well as patient and tumor characteristics found that African American and Hispanic men were more likely to die of prostate cancer than white men.⁴⁸

Do African American men receive less-aggressive care?

Studies have also determined that there may be differences in treatments offered to patients, which in turn negatively affect survival.^28,49–53 Potentially curative local therapies (including radical surgery or radiation) may be recommended less often to black men because of major comorbidities or socioeconomic considerations.^49–52

Additionally, potential metastatic disease may be identified in a less timely and accurate manner, as African American men are less likely to undergo pelvic lymph node dissection. This was associated with worse survival in men with poorly differentiated prostate cancer.⁵³

However, returning to the possibility that prostate cancer is biologically more aggressive in African American men, some studies have shown that even after adjusting for treatment, African Americans continue to have worse survival rates.^54,55 One study in men with stage T1 to T3 prostate cancer who chose brachytherapy for treatment reported that after adjusting for PSA, clinical stage, socioeconomic status, and comorbidities, African American and Hispanic race were associated with higher all-cause mortality rates.⁵⁵

Equal care, equal outcomes?

In total, these results suggest that factors unrelated to tumor biology may be additional reasons for the poorer survival rates in African American men with prostate cancer. More favorable survival outcomes for African Americans with localized disease may be achieved with uniform assignment of treatment.

Fowler and Terrell⁵⁶ reviewed the outcomes of 148 black and 209 white men with localized prostate cancer treated with surgery or radiation therapy over an 11-year period at a Veterans Administration hospital. Not surprisingly, the black men presented more often with advanced disease. However, survival outcomes were equivalent between whites and blacks when treatment was assigned in a uniform manner without regard to race. After a median follow-up of 96 months, there were no significant differences in all-cause, cause-specific, metastasis-free, clinical disease-free, or PSA recurrence-free survival rates in 109 black and 167 white men with low-stage cancer treated with surgery or radiation therapy or in 39 black and 42 white men with high-stage disease treated with radiotherapy.⁵⁶

Similarly, Tewari et al⁵⁷ studied a cohort of 402 African American and 642 white men, all of whom underwent radical prostatectomy for clinically localized prostate cancer. They were followed for PSA recurrence to determine if race-specific differences in PSA doubling time or histopathologic variables might account for the higher mortality rate in black men. While there were race-specific differences in baseline serum PSA and incidence of high-grade prostatic intraepithelial neoplasia, race was not an independent risk factor for biochemical recurrence. Instead, other variables such as the Gleason pathology score, bilateral cancers, and margin positivity were independently associated with biochemical recurrence.

Furthermore, researchers at Louisiana State University⁵⁸ retrospectively analyzed data from 205 men of different races with early-stage prostate cancer. The African American men had a higher serum PSA level, suggesting more advanced disease or greater tumor burden at presentation, but no statistically significant differences were found among the pretreatment biopsy variables, including prostate volume (measured by ultrasonography), Gleason score, millimeters of cancer within the biopsy specimen, and percentage of cancer within the biopsy specimen. After treatment, there were no significant differences in survival outcomes along racial lines, leading the authors to conclude that early detection and treatment of prostate cancer in African Americans would be the best approach to lowering mortality rates.

Taken together, these data suggest that if localized prostate cancer is treated adequately and appropriately, African American patients may have improved survival rates.

DIETARY AND LIFESTYLE FACTORS

The incidence of prostate cancer is increasing in other countries where Western diets and lifestyles have been adopted,^59,60 suggesting that nutritional factors may also contribute partly to prostate carcinogenesis. Culture- and race-specific differences in diet may play an important role in prostate cancer risk in certain racial minorities. Many aspects of diet and nutrition have been studied for their impact on prostate cancer.

Dietary risk factors

Too much red meat and processed meat? Although some have suggested that diets high in red and processed meats may lead to a higher risk of prostate cancer, a meta-analysis showed no association.^61,62

Too much calcium? The European Prospective Investigation Into Cancer and Nutrition study found that high dietary intake of dairy protein and calcium from dairy products was associated with a higher risk of prostate cancer.⁶³ A cohort study in the United States had similar findings with regard to calcium.⁶⁴ However, the higher risk of prostate cancer was associated with consumption of 2,000 mg or more of calcium per day, which was consumed by only 2% of the study’s cohort and, as the study’s authors reported, fewer than 1% of US men. As such, only a small population of American men seem to be exposing themselves to a higher risk of prostate cancer by high calcium consumption.

High fat intake? Certain fatty acids have been implicated in general tumor genesis, and that risk has been extrapolated to prostate cancer.⁶⁵ For example, high fat intake and obesity are associated with increased levels of insulin-like growth factor 1, which in turn has been shown to correlate with a significantly elevated risk of prostate cancer.^63,65

Obesity has been shown to increase the risk of more-aggressive prostate cancer, but not of less-aggressive tumors.⁶⁶ Moreover, men who lost weight had a lower risk of prostate cancer than those who maintained their weight over 10 years.⁶⁶ Obesity may be particularly risky for African American men, in whom it was found to be associated with shorter biochemical relapse-free survival, whereas it was not an independent risk factor in white men.⁶⁷

Preventive dietary agents have been elusive

Unfortunately, despite attempts to identify preventive dietary agents, none has yet been confirmed.

No benefit from selenium or vitamin E. The Selenium and Vitamin E Cancer Prevention Trial was discontinued, as there was no evidence that either agent prevented prostate cancer in relatively healthy men.⁶⁸

Vitamin D? It has been suggested that lower levels of vitamin D could contribute to the higher rates of prostate cancer in African Americans, as vitamin D deficiency is more common in African Americans.⁶⁹ However, several meta-analyses have shown no association between vitamin D and prostate cancer.^70–72

Soy? Attempts at correlating the relatively low incidence of prostate cancer in Asians have revealed that high soy intake may be protective. Asians consume more soy than Americans do (100 vs 3 mg/day), and soy isoflavones such as genistein, glycitein, and daidzein lower the incidence of prostate cancer in laboratory mice.⁷³

Other lifestyle factors

Other lifestyle factors have also been analyzed to see if they contribute to prostate cancer.

Pollution. Some studies have suggested that the etiology of prostate cancer may lie in environmental exposures to pesticides,⁷⁴ metal industrial facilities,⁷⁵ and urban living.⁷⁶

Smoking. Watters et al⁷⁷ found that current and former cigarette smokers were actually at a lower risk of being diagnosed with non-advanced prostate cancer, but current smokers were at higher risk of dying from prostate cancer.

Physical activity. A prospective study of lifetime physical activity of more than 45,000 men found that men who were not sedentary during work and who walked or bicycled more than 30 minutes per day during adult life had an approximately 20% lower incidence of prostate cancer.⁷⁸

In sum, primary care providers who are generally promoting healthy lifestyles can point to a reduction in risk for prostate cancer as yet another benefit to a low-fat diet, a healthy body mass index, and daily exercise.

HOW PRIMARY CARE PHYSICIANS CAN HELP CLOSE THE GAP

Primary care physicians serve as the first point of health access for many in the United States today.

The diagnosis of prostate cancer is made more frequently in African American men than in other American men, often at a higher pathological grade, and with a worse mortality rate. Primary care physicians can help improve these statistics. Interventions targeting overall health, such as promotion of a healthy diet, could be established at primary care visits and could also reduce the incidence of prostate cancer in African American men. Patient education regarding prostate cancer screening, the impact of family history, and the rate of PSA screening could be improved.

Primary care physicians serve a vital role in health education and prostate cancer screening, and therefore they begin the process in potentially reducing the impact of prostate cancer in African American men. The racial disparity seen in prostate cancer may begin to be minimized with primary care physicians and specialists working together to ensure that all men receive appropriate treatment.

Prostate cancer is the most common cancer affecting American men. In 2010, an estimated 217,730 men were diagnosed with it and 32,050 died of it.¹ African American men are disproportionately affected, with a prostate cancer incidence two-thirds higher than whites and a mortality rate twice as high.¹ Owing to such disparities, the life expectancy of African Americans is several years shorter than that of non-Hispanic whites.²

For the primary care provider, who is often the first access point for health care in the United States, it is important to understand what mechanisms may underlie these differences and what can be done to narrow the gap.³

WHAT IS THE CAUSE OF THESE DIFFERENCES?

Many studies have looked into the causes of the higher incidence of prostate cancer in African American men and their higher mortality rate from it. The disparity may be due to a variety of factors, some socioeconomic and some biologic.

Poorer access to care, or lower-quality care?

A study of US servicemen who had equal access to care showed that African American men had a higher rate of prostate cancer regardless of access to care and socioeconomic status.⁴

However, the 2002 Institute of Medicine report, Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care, found evidence that racial and ethnic minorities tend to receive lower-quality health care than whites, “even when access-related factors, such as patients’ insurance status and income, are controlled.”⁵

Genetic predisposition?

Some have proposed that the disparity may be a function of genetic predisposition.

Evidence of a genetic component to the high incidence and mortality rate in African American men comes from epidemiologic studies of men with similar genetic backgrounds. For example, men in Nigeria and Ghana also have a high incidence of prostate cancer, as do men of African descent in the Caribbean islands and in the United Kingdom.⁶

Chromosome 8q24 variants have been shown in several studies to be associated with prostate cancer risk and are more common in African American men.^7–10 Some studies have also shown a higher rate of variations in cell apoptosis genes such as BCL2¹¹ and tumor-suppression genes such as EphB2 in African American men.¹²

These findings suggest that genetic differences may contribute to the higher prostate cancer incidence and mortality rate seen in African American men.

More-aggressive cancer, or later detection?

Not only do African American men tend to have a higher incidence of prostate cancer, they also tend to have more-aggressive disease (ie, a higher pathologic grade) at the time of diagnosis, which may contribute to the disparity in mortality rates.^13–19

Initially, there was some controversy as to whether this observation is a result of genetic and biologic factors that may predispose African American men to more-aggressive disease, or if it is due to inadequate screening and delayed presentation. However, a body of evidence supports the contention that prostate cancer is more aggressive in African American men.

For example, a study of autopsy data from men who died of prostate cancer at ages 20 to 49 showed that the age of onset of prostate cancer was similar between African American and white men.²⁰ The Surveillance Epidemiology and End Results (SEER) database showed that African American men had a higher incidence of metastatic disease across all age groups.²⁰ A similar study conducted 10 years later confirmed that rates of subclinical prostate cancer in African American and white men do not differ by race at the early ages, but that advanced or metastatic disease occurred nearly four times as frequently in African American men.²¹

Another study examined prostate biopsies from African American men and found that their tumors expressed higher levels of biomarkers, suggesting they had more-aggressive disease.²²

SCREENING FOR PROSTATE CANCER

Serum prostate-specific antigen (PSA) testing has become the method of choice for prostate cancer screening. However, PSA screening in asymptomatic men is under debate, because it can lead to overdetection and subsequent overtreatment of indolent disease.²³

Several recent studies showed differing results from prostate cancer screening.

The US Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial found that the mortality rate was no lower with combined PSA screening and digital rectal examination during a median follow-up of 11 years than in a control group that had a lower rate of screening.²⁴ However, further analysis of these data, with stratifying by comorbidities, showed that PSA screening in young and healthy men reduces the risk of death from prostate cancer, with minimal overtreatment.²⁵

The European Randomized Study of Screening for Prostate Cancer found a statistically significant 20% reduction in deaths from prostate cancer with PSA screening, but that it was necessary to treat 48 men in order to save one life.²⁶

Another study, published in 2010, showed that regular PSA screening reduced the rate of prostate cancer mortality by half over 14 years.²⁷

African American men generally present with disease that is more advanced than in white men.²⁸ This historically has been attributed to the fact that African Americans have been less likely to be screened for prostate cancer, though recent data indicate the gap is lessening.^29–31 A cross-sectional study from the Texas Medical Center showed that 54.4% of African American men had received PSA screening, compared with 63.2% of white men.³²

Another study showed that African Americans were more likely to have had a longer interval between PSA screenings before diagnosis, and that a longer PSA screening interval was associated with greater odds of having advanced disease at diagnosis.³³ However, when the researchers controlled for the PSA screening interval, they found that African Americans had the same odds of being diagnosed with advanced prostate cancer as white patients did. They concluded that more frequent or systematic PSA screening may reduce the racial differences in cancer stage at diagnosis and in deaths.

Many reasons have been proposed to explain why African Americans receive less screening, including poor communication between physicians and minority patients due to lack of cultural competency among physicians, lack of health insurance (and poor access to quality care as a result), and deficiency of knowledge about screening. Though awareness is rising, many African Americans are unaware of early detection methods for prostate cancer (eg, PSA testing), and other barriers such as cost and transportation exist that may prevent African American men from being screened.^34,35

As gatekeepers, primary care physicians are in a position to address these shortcomings in patient education and to enhance the physician-patient relationship.³⁶

Black men have higher PSA levels, with or without cancer

Physicians must also be aware of racial differences in PSA levels and realize that the predictive value of PSA in the diagnosis of prostate cancer may differ between African Americans and whites.

Black men, with or without prostate cancer, have been found to have higher PSA levels. Kyle and colleagues³⁷ found that African American men without prostate cancer had significantly higher mean PSA levels than white men across all age groups. Furthermore, Vijayakumar et al³⁸ found that African Americans with newly diagnosed localized prostate cancer had higher serum PSA levels than whites at diagnosis.

Although PSA cutoff levels have not been officially modified according to race, primary care physicians should have a lower threshold for referring African American men who have a suspiciously high PSA level for further urologic evaluation. Close partnership between the internist, family practitioner, and urologist will aid in the optimal use of PSA testing for the early detection of prostate cancer.

When to start PSA screening? How often to screen?

The age at which African American men should begin to have their PSA levels checked (with or without a digital rectal examination) continues to debated. However, the American Cancer Society³⁹ recommends that African American men who have a father or brother who had prostate cancer before age 65 should begin having discussions with their physician on this topic and, with their informed consent, screening at age 45.

The frequency of PSA screening depends on the individual’s PSA level. The National Comprehensive Cancer Network⁴⁰ recommends that men at high risk be offered a baseline PSA measurement and digital rectal examination at age 40 and, if the PSA level is higher than 1 ng/mL, that they be offered annual follow-ups. If the PSA level is less than 1 ng/mL, they recommend screening again at age 45. Risk factors for prostate cancer include family history as well as African American race.⁴¹

How should PSA levels be interpreted?

Interpreting PSA results is important in detecting prostate cancer at early stages.

At first, we believed the normal range of PSA for all men was 4.0 ng/mL or less. However, the American Urological Association now recognizes that the normal PSA range, in addition to varying along racial lines, also is age-dependent.⁴² The Cleveland Clinic Minority Men's Health Center's suggested normal ranges of PSA in African American men are:

• Age 40–49: ≤ 2.5 ng/mL
• Age 50–59: ≤ 3.0 ng/mL
• Age 60–69: ≤ 3.5 ng/mL
• Age 70–79: ≤ 4.5 ng/mL
• Age > 80: ≤ 5.0 ng/mL.

Remember that an elevated PSA does not necessarily signify prostate cancer, and that these are reference ranges only and may vary in individual men.

SURVIVAL AFTER DIAGNOSIS

African American men with prostate cancer have significantly higher mortality rates than white men. The possible causes of worse outcomes are many, and there have been many studies that attempted to address this disparity. The question of a more biologically aggressive cancer was previously discussed, but additional factors such as socioeconomic factors, comorbidities, and treatment received have also been studied, and data are mixed.^43–45

In a large SEER database review, once confounding variables of socioeconomic status, cancer stage, and treatment received were eliminated, African Americans had similar stage-for-stage survival from prostate cancer.⁴⁶ Another study found, in 2,046 men, that differences in socioeconomic status explained the difference in mortality rates between white and black patients.⁴⁷

However, other studies that adjusted for socioeconomic status as well as patient and tumor characteristics found that African American and Hispanic men were more likely to die of prostate cancer than white men.⁴⁸

Do African American men receive less-aggressive care?

Studies have also determined that there may be differences in treatments offered to patients, which in turn negatively affect survival.^28,49–53 Potentially curative local therapies (including radical surgery or radiation) may be recommended less often to black men because of major comorbidities or socioeconomic considerations.^49–52

Additionally, potential metastatic disease may be identified in a less timely and accurate manner, as African American men are less likely to undergo pelvic lymph node dissection. This was associated with worse survival in men with poorly differentiated prostate cancer.⁵³

However, returning to the possibility that prostate cancer is biologically more aggressive in African American men, some studies have shown that even after adjusting for treatment, African Americans continue to have worse survival rates.^54,55 One study in men with stage T1 to T3 prostate cancer who chose brachytherapy for treatment reported that after adjusting for PSA, clinical stage, socioeconomic status, and comorbidities, African American and Hispanic race were associated with higher all-cause mortality rates.⁵⁵

Equal care, equal outcomes?

In total, these results suggest that factors unrelated to tumor biology may be additional reasons for the poorer survival rates in African American men with prostate cancer. More favorable survival outcomes for African Americans with localized disease may be achieved with uniform assignment of treatment.

Fowler and Terrell⁵⁶ reviewed the outcomes of 148 black and 209 white men with localized prostate cancer treated with surgery or radiation therapy over an 11-year period at a Veterans Administration hospital. Not surprisingly, the black men presented more often with advanced disease. However, survival outcomes were equivalent between whites and blacks when treatment was assigned in a uniform manner without regard to race. After a median follow-up of 96 months, there were no significant differences in all-cause, cause-specific, metastasis-free, clinical disease-free, or PSA recurrence-free survival rates in 109 black and 167 white men with low-stage cancer treated with surgery or radiation therapy or in 39 black and 42 white men with high-stage disease treated with radiotherapy.⁵⁶

Similarly, Tewari et al⁵⁷ studied a cohort of 402 African American and 642 white men, all of whom underwent radical prostatectomy for clinically localized prostate cancer. They were followed for PSA recurrence to determine if race-specific differences in PSA doubling time or histopathologic variables might account for the higher mortality rate in black men. While there were race-specific differences in baseline serum PSA and incidence of high-grade prostatic intraepithelial neoplasia, race was not an independent risk factor for biochemical recurrence. Instead, other variables such as the Gleason pathology score, bilateral cancers, and margin positivity were independently associated with biochemical recurrence.

Furthermore, researchers at Louisiana State University⁵⁸ retrospectively analyzed data from 205 men of different races with early-stage prostate cancer. The African American men had a higher serum PSA level, suggesting more advanced disease or greater tumor burden at presentation, but no statistically significant differences were found among the pretreatment biopsy variables, including prostate volume (measured by ultrasonography), Gleason score, millimeters of cancer within the biopsy specimen, and percentage of cancer within the biopsy specimen. After treatment, there were no significant differences in survival outcomes along racial lines, leading the authors to conclude that early detection and treatment of prostate cancer in African Americans would be the best approach to lowering mortality rates.

Taken together, these data suggest that if localized prostate cancer is treated adequately and appropriately, African American patients may have improved survival rates.

DIETARY AND LIFESTYLE FACTORS

The incidence of prostate cancer is increasing in other countries where Western diets and lifestyles have been adopted,^59,60 suggesting that nutritional factors may also contribute partly to prostate carcinogenesis. Culture- and race-specific differences in diet may play an important role in prostate cancer risk in certain racial minorities. Many aspects of diet and nutrition have been studied for their impact on prostate cancer.

Dietary risk factors

Too much red meat and processed meat? Although some have suggested that diets high in red and processed meats may lead to a higher risk of prostate cancer, a meta-analysis showed no association.^61,62

Too much calcium? The European Prospective Investigation Into Cancer and Nutrition study found that high dietary intake of dairy protein and calcium from dairy products was associated with a higher risk of prostate cancer.⁶³ A cohort study in the United States had similar findings with regard to calcium.⁶⁴ However, the higher risk of prostate cancer was associated with consumption of 2,000 mg or more of calcium per day, which was consumed by only 2% of the study’s cohort and, as the study’s authors reported, fewer than 1% of US men. As such, only a small population of American men seem to be exposing themselves to a higher risk of prostate cancer by high calcium consumption.

High fat intake? Certain fatty acids have been implicated in general tumor genesis, and that risk has been extrapolated to prostate cancer.⁶⁵ For example, high fat intake and obesity are associated with increased levels of insulin-like growth factor 1, which in turn has been shown to correlate with a significantly elevated risk of prostate cancer.^63,65

Obesity has been shown to increase the risk of more-aggressive prostate cancer, but not of less-aggressive tumors.⁶⁶ Moreover, men who lost weight had a lower risk of prostate cancer than those who maintained their weight over 10 years.⁶⁶ Obesity may be particularly risky for African American men, in whom it was found to be associated with shorter biochemical relapse-free survival, whereas it was not an independent risk factor in white men.⁶⁷

Preventive dietary agents have been elusive

Unfortunately, despite attempts to identify preventive dietary agents, none has yet been confirmed.

No benefit from selenium or vitamin E. The Selenium and Vitamin E Cancer Prevention Trial was discontinued, as there was no evidence that either agent prevented prostate cancer in relatively healthy men.⁶⁸

Vitamin D? It has been suggested that lower levels of vitamin D could contribute to the higher rates of prostate cancer in African Americans, as vitamin D deficiency is more common in African Americans.⁶⁹ However, several meta-analyses have shown no association between vitamin D and prostate cancer.^70–72

Soy? Attempts at correlating the relatively low incidence of prostate cancer in Asians have revealed that high soy intake may be protective. Asians consume more soy than Americans do (100 vs 3 mg/day), and soy isoflavones such as genistein, glycitein, and daidzein lower the incidence of prostate cancer in laboratory mice.⁷³

Other lifestyle factors

Other lifestyle factors have also been analyzed to see if they contribute to prostate cancer.

Pollution. Some studies have suggested that the etiology of prostate cancer may lie in environmental exposures to pesticides,⁷⁴ metal industrial facilities,⁷⁵ and urban living.⁷⁶

Smoking. Watters et al⁷⁷ found that current and former cigarette smokers were actually at a lower risk of being diagnosed with non-advanced prostate cancer, but current smokers were at higher risk of dying from prostate cancer.

Physical activity. A prospective study of lifetime physical activity of more than 45,000 men found that men who were not sedentary during work and who walked or bicycled more than 30 minutes per day during adult life had an approximately 20% lower incidence of prostate cancer.⁷⁸

In sum, primary care providers who are generally promoting healthy lifestyles can point to a reduction in risk for prostate cancer as yet another benefit to a low-fat diet, a healthy body mass index, and daily exercise.

HOW PRIMARY CARE PHYSICIANS CAN HELP CLOSE THE GAP

Primary care physicians serve as the first point of health access for many in the United States today.

The diagnosis of prostate cancer is made more frequently in African American men than in other American men, often at a higher pathological grade, and with a worse mortality rate. Primary care physicians can help improve these statistics. Interventions targeting overall health, such as promotion of a healthy diet, could be established at primary care visits and could also reduce the incidence of prostate cancer in African American men. Patient education regarding prostate cancer screening, the impact of family history, and the rate of PSA screening could be improved.

Primary care physicians serve a vital role in health education and prostate cancer screening, and therefore they begin the process in potentially reducing the impact of prostate cancer in African American men. The racial disparity seen in prostate cancer may begin to be minimized with primary care physicians and specialists working together to ensure that all men receive appropriate treatment.

Prostate cancer is the most common cancer affecting American men. In 2010, an estimated 217,730 men were diagnosed with it and 32,050 died of it.¹ African American men are disproportionately affected, with a prostate cancer incidence two-thirds higher than whites and a mortality rate twice as high.¹ Owing to such disparities, the life expectancy of African Americans is several years shorter than that of non-Hispanic whites.²

For the primary care provider, who is often the first access point for health care in the United States, it is important to understand what mechanisms may underlie these differences and what can be done to narrow the gap.³

WHAT IS THE CAUSE OF THESE DIFFERENCES?

Many studies have looked into the causes of the higher incidence of prostate cancer in African American men and their higher mortality rate from it. The disparity may be due to a variety of factors, some socioeconomic and some biologic.

Poorer access to care, or lower-quality care?

A study of US servicemen who had equal access to care showed that African American men had a higher rate of prostate cancer regardless of access to care and socioeconomic status.⁴

However, the 2002 Institute of Medicine report, Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care, found evidence that racial and ethnic minorities tend to receive lower-quality health care than whites, “even when access-related factors, such as patients’ insurance status and income, are controlled.”⁵

Genetic predisposition?

Some have proposed that the disparity may be a function of genetic predisposition.

Evidence of a genetic component to the high incidence and mortality rate in African American men comes from epidemiologic studies of men with similar genetic backgrounds. For example, men in Nigeria and Ghana also have a high incidence of prostate cancer, as do men of African descent in the Caribbean islands and in the United Kingdom.⁶

Chromosome 8q24 variants have been shown in several studies to be associated with prostate cancer risk and are more common in African American men.^7–10 Some studies have also shown a higher rate of variations in cell apoptosis genes such as BCL2¹¹ and tumor-suppression genes such as EphB2 in African American men.¹²

These findings suggest that genetic differences may contribute to the higher prostate cancer incidence and mortality rate seen in African American men.

More-aggressive cancer, or later detection?

Not only do African American men tend to have a higher incidence of prostate cancer, they also tend to have more-aggressive disease (ie, a higher pathologic grade) at the time of diagnosis, which may contribute to the disparity in mortality rates.^13–19

Initially, there was some controversy as to whether this observation is a result of genetic and biologic factors that may predispose African American men to more-aggressive disease, or if it is due to inadequate screening and delayed presentation. However, a body of evidence supports the contention that prostate cancer is more aggressive in African American men.

For example, a study of autopsy data from men who died of prostate cancer at ages 20 to 49 showed that the age of onset of prostate cancer was similar between African American and white men.²⁰ The Surveillance Epidemiology and End Results (SEER) database showed that African American men had a higher incidence of metastatic disease across all age groups.²⁰ A similar study conducted 10 years later confirmed that rates of subclinical prostate cancer in African American and white men do not differ by race at the early ages, but that advanced or metastatic disease occurred nearly four times as frequently in African American men.²¹

Another study examined prostate biopsies from African American men and found that their tumors expressed higher levels of biomarkers, suggesting they had more-aggressive disease.²²

SCREENING FOR PROSTATE CANCER

Serum prostate-specific antigen (PSA) testing has become the method of choice for prostate cancer screening. However, PSA screening in asymptomatic men is under debate, because it can lead to overdetection and subsequent overtreatment of indolent disease.²³

Several recent studies showed differing results from prostate cancer screening.

The US Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial found that the mortality rate was no lower with combined PSA screening and digital rectal examination during a median follow-up of 11 years than in a control group that had a lower rate of screening.²⁴ However, further analysis of these data, with stratifying by comorbidities, showed that PSA screening in young and healthy men reduces the risk of death from prostate cancer, with minimal overtreatment.²⁵

The European Randomized Study of Screening for Prostate Cancer found a statistically significant 20% reduction in deaths from prostate cancer with PSA screening, but that it was necessary to treat 48 men in order to save one life.²⁶

Another study, published in 2010, showed that regular PSA screening reduced the rate of prostate cancer mortality by half over 14 years.²⁷

African American men generally present with disease that is more advanced than in white men.²⁸ This historically has been attributed to the fact that African Americans have been less likely to be screened for prostate cancer, though recent data indicate the gap is lessening.^29–31 A cross-sectional study from the Texas Medical Center showed that 54.4% of African American men had received PSA screening, compared with 63.2% of white men.³²

Another study showed that African Americans were more likely to have had a longer interval between PSA screenings before diagnosis, and that a longer PSA screening interval was associated with greater odds of having advanced disease at diagnosis.³³ However, when the researchers controlled for the PSA screening interval, they found that African Americans had the same odds of being diagnosed with advanced prostate cancer as white patients did. They concluded that more frequent or systematic PSA screening may reduce the racial differences in cancer stage at diagnosis and in deaths.

Many reasons have been proposed to explain why African Americans receive less screening, including poor communication between physicians and minority patients due to lack of cultural competency among physicians, lack of health insurance (and poor access to quality care as a result), and deficiency of knowledge about screening. Though awareness is rising, many African Americans are unaware of early detection methods for prostate cancer (eg, PSA testing), and other barriers such as cost and transportation exist that may prevent African American men from being screened.^34,35

As gatekeepers, primary care physicians are in a position to address these shortcomings in patient education and to enhance the physician-patient relationship.³⁶

Black men have higher PSA levels, with or without cancer

Physicians must also be aware of racial differences in PSA levels and realize that the predictive value of PSA in the diagnosis of prostate cancer may differ between African Americans and whites.

Black men, with or without prostate cancer, have been found to have higher PSA levels. Kyle and colleagues³⁷ found that African American men without prostate cancer had significantly higher mean PSA levels than white men across all age groups. Furthermore, Vijayakumar et al³⁸ found that African Americans with newly diagnosed localized prostate cancer had higher serum PSA levels than whites at diagnosis.

Although PSA cutoff levels have not been officially modified according to race, primary care physicians should have a lower threshold for referring African American men who have a suspiciously high PSA level for further urologic evaluation. Close partnership between the internist, family practitioner, and urologist will aid in the optimal use of PSA testing for the early detection of prostate cancer.

When to start PSA screening? How often to screen?

The age at which African American men should begin to have their PSA levels checked (with or without a digital rectal examination) continues to debated. However, the American Cancer Society³⁹ recommends that African American men who have a father or brother who had prostate cancer before age 65 should begin having discussions with their physician on this topic and, with their informed consent, screening at age 45.

The frequency of PSA screening depends on the individual’s PSA level. The National Comprehensive Cancer Network⁴⁰ recommends that men at high risk be offered a baseline PSA measurement and digital rectal examination at age 40 and, if the PSA level is higher than 1 ng/mL, that they be offered annual follow-ups. If the PSA level is less than 1 ng/mL, they recommend screening again at age 45. Risk factors for prostate cancer include family history as well as African American race.⁴¹

How should PSA levels be interpreted?

Interpreting PSA results is important in detecting prostate cancer at early stages.

At first, we believed the normal range of PSA for all men was 4.0 ng/mL or less. However, the American Urological Association now recognizes that the normal PSA range, in addition to varying along racial lines, also is age-dependent.⁴² The Cleveland Clinic Minority Men's Health Center's suggested normal ranges of PSA in African American men are:

• Age 40–49: ≤ 2.5 ng/mL
• Age 50–59: ≤ 3.0 ng/mL
• Age 60–69: ≤ 3.5 ng/mL
• Age 70–79: ≤ 4.5 ng/mL
• Age > 80: ≤ 5.0 ng/mL.

Remember that an elevated PSA does not necessarily signify prostate cancer, and that these are reference ranges only and may vary in individual men.

SURVIVAL AFTER DIAGNOSIS

African American men with prostate cancer have significantly higher mortality rates than white men. The possible causes of worse outcomes are many, and there have been many studies that attempted to address this disparity. The question of a more biologically aggressive cancer was previously discussed, but additional factors such as socioeconomic factors, comorbidities, and treatment received have also been studied, and data are mixed.^43–45

In a large SEER database review, once confounding variables of socioeconomic status, cancer stage, and treatment received were eliminated, African Americans had similar stage-for-stage survival from prostate cancer.⁴⁶ Another study found, in 2,046 men, that differences in socioeconomic status explained the difference in mortality rates between white and black patients.⁴⁷

However, other studies that adjusted for socioeconomic status as well as patient and tumor characteristics found that African American and Hispanic men were more likely to die of prostate cancer than white men.⁴⁸

Do African American men receive less-aggressive care?

Studies have also determined that there may be differences in treatments offered to patients, which in turn negatively affect survival.^28,49–53 Potentially curative local therapies (including radical surgery or radiation) may be recommended less often to black men because of major comorbidities or socioeconomic considerations.^49–52

Additionally, potential metastatic disease may be identified in a less timely and accurate manner, as African American men are less likely to undergo pelvic lymph node dissection. This was associated with worse survival in men with poorly differentiated prostate cancer.⁵³

However, returning to the possibility that prostate cancer is biologically more aggressive in African American men, some studies have shown that even after adjusting for treatment, African Americans continue to have worse survival rates.^54,55 One study in men with stage T1 to T3 prostate cancer who chose brachytherapy for treatment reported that after adjusting for PSA, clinical stage, socioeconomic status, and comorbidities, African American and Hispanic race were associated with higher all-cause mortality rates.⁵⁵

Equal care, equal outcomes?

In total, these results suggest that factors unrelated to tumor biology may be additional reasons for the poorer survival rates in African American men with prostate cancer. More favorable survival outcomes for African Americans with localized disease may be achieved with uniform assignment of treatment.

Fowler and Terrell⁵⁶ reviewed the outcomes of 148 black and 209 white men with localized prostate cancer treated with surgery or radiation therapy over an 11-year period at a Veterans Administration hospital. Not surprisingly, the black men presented more often with advanced disease. However, survival outcomes were equivalent between whites and blacks when treatment was assigned in a uniform manner without regard to race. After a median follow-up of 96 months, there were no significant differences in all-cause, cause-specific, metastasis-free, clinical disease-free, or PSA recurrence-free survival rates in 109 black and 167 white men with low-stage cancer treated with surgery or radiation therapy or in 39 black and 42 white men with high-stage disease treated with radiotherapy.⁵⁶

Similarly, Tewari et al⁵⁷ studied a cohort of 402 African American and 642 white men, all of whom underwent radical prostatectomy for clinically localized prostate cancer. They were followed for PSA recurrence to determine if race-specific differences in PSA doubling time or histopathologic variables might account for the higher mortality rate in black men. While there were race-specific differences in baseline serum PSA and incidence of high-grade prostatic intraepithelial neoplasia, race was not an independent risk factor for biochemical recurrence. Instead, other variables such as the Gleason pathology score, bilateral cancers, and margin positivity were independently associated with biochemical recurrence.

Furthermore, researchers at Louisiana State University⁵⁸ retrospectively analyzed data from 205 men of different races with early-stage prostate cancer. The African American men had a higher serum PSA level, suggesting more advanced disease or greater tumor burden at presentation, but no statistically significant differences were found among the pretreatment biopsy variables, including prostate volume (measured by ultrasonography), Gleason score, millimeters of cancer within the biopsy specimen, and percentage of cancer within the biopsy specimen. After treatment, there were no significant differences in survival outcomes along racial lines, leading the authors to conclude that early detection and treatment of prostate cancer in African Americans would be the best approach to lowering mortality rates.

Taken together, these data suggest that if localized prostate cancer is treated adequately and appropriately, African American patients may have improved survival rates.

DIETARY AND LIFESTYLE FACTORS

The incidence of prostate cancer is increasing in other countries where Western diets and lifestyles have been adopted,^59,60 suggesting that nutritional factors may also contribute partly to prostate carcinogenesis. Culture- and race-specific differences in diet may play an important role in prostate cancer risk in certain racial minorities. Many aspects of diet and nutrition have been studied for their impact on prostate cancer.

Dietary risk factors

Too much red meat and processed meat? Although some have suggested that diets high in red and processed meats may lead to a higher risk of prostate cancer, a meta-analysis showed no association.^61,62

Too much calcium? The European Prospective Investigation Into Cancer and Nutrition study found that high dietary intake of dairy protein and calcium from dairy products was associated with a higher risk of prostate cancer.⁶³ A cohort study in the United States had similar findings with regard to calcium.⁶⁴ However, the higher risk of prostate cancer was associated with consumption of 2,000 mg or more of calcium per day, which was consumed by only 2% of the study’s cohort and, as the study’s authors reported, fewer than 1% of US men. As such, only a small population of American men seem to be exposing themselves to a higher risk of prostate cancer by high calcium consumption.

High fat intake? Certain fatty acids have been implicated in general tumor genesis, and that risk has been extrapolated to prostate cancer.⁶⁵ For example, high fat intake and obesity are associated with increased levels of insulin-like growth factor 1, which in turn has been shown to correlate with a significantly elevated risk of prostate cancer.^63,65

Obesity has been shown to increase the risk of more-aggressive prostate cancer, but not of less-aggressive tumors.⁶⁶ Moreover, men who lost weight had a lower risk of prostate cancer than those who maintained their weight over 10 years.⁶⁶ Obesity may be particularly risky for African American men, in whom it was found to be associated with shorter biochemical relapse-free survival, whereas it was not an independent risk factor in white men.⁶⁷

Preventive dietary agents have been elusive

Unfortunately, despite attempts to identify preventive dietary agents, none has yet been confirmed.

No benefit from selenium or vitamin E. The Selenium and Vitamin E Cancer Prevention Trial was discontinued, as there was no evidence that either agent prevented prostate cancer in relatively healthy men.⁶⁸

Vitamin D? It has been suggested that lower levels of vitamin D could contribute to the higher rates of prostate cancer in African Americans, as vitamin D deficiency is more common in African Americans.⁶⁹ However, several meta-analyses have shown no association between vitamin D and prostate cancer.^70–72

Soy? Attempts at correlating the relatively low incidence of prostate cancer in Asians have revealed that high soy intake may be protective. Asians consume more soy than Americans do (100 vs 3 mg/day), and soy isoflavones such as genistein, glycitein, and daidzein lower the incidence of prostate cancer in laboratory mice.⁷³

Other lifestyle factors

Other lifestyle factors have also been analyzed to see if they contribute to prostate cancer.

Pollution. Some studies have suggested that the etiology of prostate cancer may lie in environmental exposures to pesticides,⁷⁴ metal industrial facilities,⁷⁵ and urban living.⁷⁶

Smoking. Watters et al⁷⁷ found that current and former cigarette smokers were actually at a lower risk of being diagnosed with non-advanced prostate cancer, but current smokers were at higher risk of dying from prostate cancer.

Physical activity. A prospective study of lifetime physical activity of more than 45,000 men found that men who were not sedentary during work and who walked or bicycled more than 30 minutes per day during adult life had an approximately 20% lower incidence of prostate cancer.⁷⁸

In sum, primary care providers who are generally promoting healthy lifestyles can point to a reduction in risk for prostate cancer as yet another benefit to a low-fat diet, a healthy body mass index, and daily exercise.

HOW PRIMARY CARE PHYSICIANS CAN HELP CLOSE THE GAP

Primary care physicians serve as the first point of health access for many in the United States today.

The diagnosis of prostate cancer is made more frequently in African American men than in other American men, often at a higher pathological grade, and with a worse mortality rate. Primary care physicians can help improve these statistics. Interventions targeting overall health, such as promotion of a healthy diet, could be established at primary care visits and could also reduce the incidence of prostate cancer in African American men. Patient education regarding prostate cancer screening, the impact of family history, and the rate of PSA screening could be improved.

Primary care physicians serve a vital role in health education and prostate cancer screening, and therefore they begin the process in potentially reducing the impact of prostate cancer in African American men. The racial disparity seen in prostate cancer may begin to be minimized with primary care physicians and specialists working together to ensure that all men receive appropriate treatment.

A 65-year-old man presents with a 2-month history of generalized weakness, dizziness, and blurred vision. His symptoms began gradually and have been progressing over the last few weeks, so that they now affect his ability to perform normal daily activities.

He has lost 20 lb and has become anorectic. He has no fever, night sweats, headache, cough, hemoptysis, or dyspnea. He has no history of abdominal pain, changes in bowel habits, nausea, vomiting, or urinary symptoms. He was admitted 6 weeks ago for the same symptoms; he was treated for hypotension and received intravenous (IV) fluids and electrolyte supplements for dehydration.

He has a history of hypertension, stroke, vascular dementia, and atrial fibrillation. He is taking warfarin (Coumadin), extended-release diltiazem (Cardizem), simvastatin (Zocor), and donepezil (Aricept). He underwent right hemicolectomy 5 years ago for a large tubular adenoma with high-grade dysplasia in the cecum.

Initial laboratory values are as follows:

• White blood cell count 7.4 × 10⁹/L (reference range 4.5–11.0), with a normal differential
• Mild anemia, with a hemoglobin of 116 g/L (140–175)
• Activated partial thromboplastin time 59.9 sec (23.0–32.4)
• Serum sodium 135 mmol/L (136–142)
• Serum potassium 4.6 mmol/L (3.5–5.0)
• Aspartate aminotransferase 58 U/L (10–30)
• Alanine aminotransferase 16 U/L (10–40)
• Alkaline phosphatase 328 U/L (30–120)
• Urea, creatinine, and corrected calcium are normal.

Electrocardiography shows atrial fibrillation with low-voltage QRS complexes. Chest radiography is normal. A stool test is negative for occult blood. A workup for sepsis is negative.

Q: Which is the appropriate test at this point to determine the cause of the hypotension?

• Serum parathyroid-hormone-related protein
• Baseline serum cortisol, plasma adrenocorticotropic hormone (ACTH) levels, and an ACTH stimulation test with cosyntropin (Cortrosyn)
• Serum thyrotropin level
• Aspiration biopsy of subcutaneous fat with Congo red and immunostaining
• Late-night salivary cortisol

A: The correct next step is to measure baseline serum cortisol, to test ACTH levels, and to order an ACTH stimulation test with cosyntropin.

Primary adrenocortical insufficiency should be considered in patients with metastatic malignancy who present with peripheral vascular collapse, particularly when it is associated with cutaneous hyperpigmentation, chronic malaise, fatigue, weakness, anorexia, weight loss, hypoglycemia, and electrolyte disturbances such as hyponatremia and hyperkalemia.

Checking the baseline serum cortisol and ACTH levels and cosyntropin stimulation testing are vital steps in making an early diagnosis of primary adrenocortical insufficiency. Inappropriately low serum cortisol is highly suggestive of primary adrenal insufficiency, especially if accompanied by simultaneous elevation of the plasma ACTH level. The result of the ACTH stimulation test with cosyntropin is often confirmatory.

Measuring the serum parathyroid-hormone-related protein level is not indicated, since the patient has a normal corrected calcium. Patients with ectopic Cushing syndrome may present with weight loss due to underlying malignancy, but the presence of hypotension and a lack of hypokalemia makes such a diagnosis unlikely, and, therefore, measurement of late-night salivary cortisol is not the best answer. Amyloidosis, hypothyroidism, or hyperthyroidism are unlikely to have this patient’s presentation.

RESULTS OF FURTHER EVALUATION

Our patient’s ACTH serum level was elevated, and an ACTH stimulation test with cosyntropin confirmed the diagnosis of primary adrenal insufficiency.

CT of the abdomen failed to demonstrate primary tumors, but both adrenal glands were enlarged, likely from metastasis (Figure 4). His hypotension responded to treatment with hydrocortisone and fludrocortisone, and his symptoms resolved. No further testing or therapy was directed to the primary occult malignancy, as it was considered advanced. The prognosis was discussed with the patient, and he deferred any further management and was discharged to hospice care. He died a few months later.

PRIMARY ADRENOCORTICAL INSUFFICIENCY

Primary adrenocortical insufficiency is an uncommon disorder caused by destruction or dysfunction of the adrenal cortices. It is characterized by chronic deficiency of cortisol, aldosterone, and adrenal androgens. In the United States, nearly 6 million people are considered to have undiagnosed adrenal insufficiency, which is clinically significant only during times of physiologic stress.¹

Primary adrenocortical insufficiency affects men and women equally. However, the idiopathic autoimmune form of adrenal insufficiency (Addison disease) is two to three times more common in women than in men.

If the condition is undiagnosed or ineffectively treated, the risk of significant morbidity and death is high. Symptoms and signs are nonspecific, and the onset is insidious.

Almost all patients with primary adrenal insufficiency have malaise, fatigue, anorexia, and weight loss. Vomiting, abdominal pain, and fever are more common during an adrenal crisis, when a patient with subclinical disease is subjected to major stress. Postural dizziness or syncope is a common result of volume depletion and hypotension.^2–4 It is commonly accompanied by hyponatremia and hyperkalemia.

Hyperpigmentation is the most characteristic physical finding and is caused by an ACTH-mediated increase in melanin content in the skin.^2,4,5 The resulting brown hyperpigmentation is most obvious in areas exposed to sunlight (face, neck, backs of hands), and in areas exposed to chronic friction or pressure, such as the elbows, knees, knuckles, waist, and shoulders (brassiere straps).⁴ Pigmentation is also prominent in the palmar creases, areolae, axillae, perineum, surgical scars, and umbilicus. Other patterns of hyperpigmentation are patchy pigmentation on the inner surface of lips, the buccal mucosa, under the tongue, and on the hard palate.^3,5 The hyperpigmentation begins to fade within several days and largely disappears after a few months of adequate glucocorticoid therapy.⁴

In the United States, 80% of cases of primary adrenocortical insufficiency are caused by autoimmune adrenal destruction. The remainder are caused by infectious diseases (eg, tuberculosis, fungal infection, cytomegalovirus infection, and Mycobacterium aviumintracellulare infection in the context of human immunodeficiency virus infection), by infiltration of the adrenal glands by metastatic cancer, by adrenal hemorrhage, or by drugs such as ketoconazole, fluconazole (Diflucan), metyrapone (Metopirone), mitotane (Lysodren), and etomidate (Amidate).^4,6

Adrenal metastatic disease

Infiltration of the adrenal glands by metastatic cancer is not uncommon, probably because of their rich sinusoidal blood supply, and the adrenals are the fourth most common site of metastasis. Common primary tumors are lung, breast, melanoma, gastric, esophageal, and colorectal cancers, while metastasis due to an undetermined primary tumor is the least common.⁷

Clinically evident adrenal insufficiency produced by metastatic carcinoma is uncommon because most of the adrenal cortex must be destroyed before hypofunction becomes evident.^7–9

Malignancy rarely presents first as adrenal insufficiency caused by metastatic infiltration.¹⁰

Hormonal therapy may significantly improve symptoms and quality of life in patients with metastatic adrenal insufficiency.^8,11

DIAGNOSIS AND MANAGEMENT

Once primary adrenal insufficiency is suspected, prompt diagnosis and treatment are essential. A low plasma cortisol level (< 3 μg/dL) at 8 am is highly suggestive of adrenal insufficiency if exposure to exogenous glucocorticoids has been excluded (including oral, inhaled, and injected),^12,13 especially if accompanied by simultaneous elevation of the plasma ACTH level (usually > 200 pg/mL). An 8 am cortisol concentration above 15 μg/dL makes adrenal insufficiency highly unlikely, but levels between 3 and 15 μg/dL are nondiagnostic and need to be further evaluated by an ACTH stimulation test with cosyntropin.^4,7

Imaging in primary adrenal insufficiency may be considered when the condition is not clearly autoimmune.¹⁴ Abdominal CT is the ideal imaging test for detecting abnormal adrenal glands. CT shows small, noncalcified adrenals in autoimmune Addison disease. It demonstrates enlarged adrenals in about 85% of cases caused by metastatic or granulomatous disease; and calcification is noted in cases of tuberculous adrenal disease.⁴

Management involves treating the underlying cause and starting hormone replacement therapy. Hormonal therapy consists of corticosteroids and mineralocorticoids; hydrocortisone is the drug of choice and is usually given with fludrocortisone acetate, which has a potent sodium-retaining effect. In the presence of a stressor (fever, surgery, severe illness), the dose of hydrocortisone should be doubled (> 50 mg hydrocortisone per day) for at least 3 to 5 days.^2,4

A 65-year-old man presents with a 2-month history of generalized weakness, dizziness, and blurred vision. His symptoms began gradually and have been progressing over the last few weeks, so that they now affect his ability to perform normal daily activities.

He has lost 20 lb and has become anorectic. He has no fever, night sweats, headache, cough, hemoptysis, or dyspnea. He has no history of abdominal pain, changes in bowel habits, nausea, vomiting, or urinary symptoms. He was admitted 6 weeks ago for the same symptoms; he was treated for hypotension and received intravenous (IV) fluids and electrolyte supplements for dehydration.

He has a history of hypertension, stroke, vascular dementia, and atrial fibrillation. He is taking warfarin (Coumadin), extended-release diltiazem (Cardizem), simvastatin (Zocor), and donepezil (Aricept). He underwent right hemicolectomy 5 years ago for a large tubular adenoma with high-grade dysplasia in the cecum.

Initial laboratory values are as follows:

• White blood cell count 7.4 × 10⁹/L (reference range 4.5–11.0), with a normal differential
• Mild anemia, with a hemoglobin of 116 g/L (140–175)
• Activated partial thromboplastin time 59.9 sec (23.0–32.4)
• Serum sodium 135 mmol/L (136–142)
• Serum potassium 4.6 mmol/L (3.5–5.0)
• Aspartate aminotransferase 58 U/L (10–30)
• Alanine aminotransferase 16 U/L (10–40)
• Alkaline phosphatase 328 U/L (30–120)
• Urea, creatinine, and corrected calcium are normal.

Electrocardiography shows atrial fibrillation with low-voltage QRS complexes. Chest radiography is normal. A stool test is negative for occult blood. A workup for sepsis is negative.

Q: Which is the appropriate test at this point to determine the cause of the hypotension?

• Serum parathyroid-hormone-related protein
• Baseline serum cortisol, plasma adrenocorticotropic hormone (ACTH) levels, and an ACTH stimulation test with cosyntropin (Cortrosyn)
• Serum thyrotropin level
• Aspiration biopsy of subcutaneous fat with Congo red and immunostaining
• Late-night salivary cortisol

A: The correct next step is to measure baseline serum cortisol, to test ACTH levels, and to order an ACTH stimulation test with cosyntropin.

Primary adrenocortical insufficiency should be considered in patients with metastatic malignancy who present with peripheral vascular collapse, particularly when it is associated with cutaneous hyperpigmentation, chronic malaise, fatigue, weakness, anorexia, weight loss, hypoglycemia, and electrolyte disturbances such as hyponatremia and hyperkalemia.

Checking the baseline serum cortisol and ACTH levels and cosyntropin stimulation testing are vital steps in making an early diagnosis of primary adrenocortical insufficiency. Inappropriately low serum cortisol is highly suggestive of primary adrenal insufficiency, especially if accompanied by simultaneous elevation of the plasma ACTH level. The result of the ACTH stimulation test with cosyntropin is often confirmatory.

Measuring the serum parathyroid-hormone-related protein level is not indicated, since the patient has a normal corrected calcium. Patients with ectopic Cushing syndrome may present with weight loss due to underlying malignancy, but the presence of hypotension and a lack of hypokalemia makes such a diagnosis unlikely, and, therefore, measurement of late-night salivary cortisol is not the best answer. Amyloidosis, hypothyroidism, or hyperthyroidism are unlikely to have this patient’s presentation.

RESULTS OF FURTHER EVALUATION

Our patient’s ACTH serum level was elevated, and an ACTH stimulation test with cosyntropin confirmed the diagnosis of primary adrenal insufficiency.

CT of the abdomen failed to demonstrate primary tumors, but both adrenal glands were enlarged, likely from metastasis (Figure 4). His hypotension responded to treatment with hydrocortisone and fludrocortisone, and his symptoms resolved. No further testing or therapy was directed to the primary occult malignancy, as it was considered advanced. The prognosis was discussed with the patient, and he deferred any further management and was discharged to hospice care. He died a few months later.

PRIMARY ADRENOCORTICAL INSUFFICIENCY

Primary adrenocortical insufficiency is an uncommon disorder caused by destruction or dysfunction of the adrenal cortices. It is characterized by chronic deficiency of cortisol, aldosterone, and adrenal androgens. In the United States, nearly 6 million people are considered to have undiagnosed adrenal insufficiency, which is clinically significant only during times of physiologic stress.¹

Primary adrenocortical insufficiency affects men and women equally. However, the idiopathic autoimmune form of adrenal insufficiency (Addison disease) is two to three times more common in women than in men.

If the condition is undiagnosed or ineffectively treated, the risk of significant morbidity and death is high. Symptoms and signs are nonspecific, and the onset is insidious.

Almost all patients with primary adrenal insufficiency have malaise, fatigue, anorexia, and weight loss. Vomiting, abdominal pain, and fever are more common during an adrenal crisis, when a patient with subclinical disease is subjected to major stress. Postural dizziness or syncope is a common result of volume depletion and hypotension.^2–4 It is commonly accompanied by hyponatremia and hyperkalemia.

Hyperpigmentation is the most characteristic physical finding and is caused by an ACTH-mediated increase in melanin content in the skin.^2,4,5 The resulting brown hyperpigmentation is most obvious in areas exposed to sunlight (face, neck, backs of hands), and in areas exposed to chronic friction or pressure, such as the elbows, knees, knuckles, waist, and shoulders (brassiere straps).⁴ Pigmentation is also prominent in the palmar creases, areolae, axillae, perineum, surgical scars, and umbilicus. Other patterns of hyperpigmentation are patchy pigmentation on the inner surface of lips, the buccal mucosa, under the tongue, and on the hard palate.^3,5 The hyperpigmentation begins to fade within several days and largely disappears after a few months of adequate glucocorticoid therapy.⁴

In the United States, 80% of cases of primary adrenocortical insufficiency are caused by autoimmune adrenal destruction. The remainder are caused by infectious diseases (eg, tuberculosis, fungal infection, cytomegalovirus infection, and Mycobacterium aviumintracellulare infection in the context of human immunodeficiency virus infection), by infiltration of the adrenal glands by metastatic cancer, by adrenal hemorrhage, or by drugs such as ketoconazole, fluconazole (Diflucan), metyrapone (Metopirone), mitotane (Lysodren), and etomidate (Amidate).^4,6

Adrenal metastatic disease

Infiltration of the adrenal glands by metastatic cancer is not uncommon, probably because of their rich sinusoidal blood supply, and the adrenals are the fourth most common site of metastasis. Common primary tumors are lung, breast, melanoma, gastric, esophageal, and colorectal cancers, while metastasis due to an undetermined primary tumor is the least common.⁷

Clinically evident adrenal insufficiency produced by metastatic carcinoma is uncommon because most of the adrenal cortex must be destroyed before hypofunction becomes evident.^7–9

Malignancy rarely presents first as adrenal insufficiency caused by metastatic infiltration.¹⁰

Hormonal therapy may significantly improve symptoms and quality of life in patients with metastatic adrenal insufficiency.^8,11

DIAGNOSIS AND MANAGEMENT

Once primary adrenal insufficiency is suspected, prompt diagnosis and treatment are essential. A low plasma cortisol level (< 3 μg/dL) at 8 am is highly suggestive of adrenal insufficiency if exposure to exogenous glucocorticoids has been excluded (including oral, inhaled, and injected),^12,13 especially if accompanied by simultaneous elevation of the plasma ACTH level (usually > 200 pg/mL). An 8 am cortisol concentration above 15 μg/dL makes adrenal insufficiency highly unlikely, but levels between 3 and 15 μg/dL are nondiagnostic and need to be further evaluated by an ACTH stimulation test with cosyntropin.^4,7

Imaging in primary adrenal insufficiency may be considered when the condition is not clearly autoimmune.¹⁴ Abdominal CT is the ideal imaging test for detecting abnormal adrenal glands. CT shows small, noncalcified adrenals in autoimmune Addison disease. It demonstrates enlarged adrenals in about 85% of cases caused by metastatic or granulomatous disease; and calcification is noted in cases of tuberculous adrenal disease.⁴

Management involves treating the underlying cause and starting hormone replacement therapy. Hormonal therapy consists of corticosteroids and mineralocorticoids; hydrocortisone is the drug of choice and is usually given with fludrocortisone acetate, which has a potent sodium-retaining effect. In the presence of a stressor (fever, surgery, severe illness), the dose of hydrocortisone should be doubled (> 50 mg hydrocortisone per day) for at least 3 to 5 days.^2,4

A 65-year-old man presents with a 2-month history of generalized weakness, dizziness, and blurred vision. His symptoms began gradually and have been progressing over the last few weeks, so that they now affect his ability to perform normal daily activities.

He has lost 20 lb and has become anorectic. He has no fever, night sweats, headache, cough, hemoptysis, or dyspnea. He has no history of abdominal pain, changes in bowel habits, nausea, vomiting, or urinary symptoms. He was admitted 6 weeks ago for the same symptoms; he was treated for hypotension and received intravenous (IV) fluids and electrolyte supplements for dehydration.

He has a history of hypertension, stroke, vascular dementia, and atrial fibrillation. He is taking warfarin (Coumadin), extended-release diltiazem (Cardizem), simvastatin (Zocor), and donepezil (Aricept). He underwent right hemicolectomy 5 years ago for a large tubular adenoma with high-grade dysplasia in the cecum.

Initial laboratory values are as follows:

• White blood cell count 7.4 × 10⁹/L (reference range 4.5–11.0), with a normal differential
• Mild anemia, with a hemoglobin of 116 g/L (140–175)
• Activated partial thromboplastin time 59.9 sec (23.0–32.4)
• Serum sodium 135 mmol/L (136–142)
• Serum potassium 4.6 mmol/L (3.5–5.0)
• Aspartate aminotransferase 58 U/L (10–30)
• Alanine aminotransferase 16 U/L (10–40)
• Alkaline phosphatase 328 U/L (30–120)
• Urea, creatinine, and corrected calcium are normal.

Electrocardiography shows atrial fibrillation with low-voltage QRS complexes. Chest radiography is normal. A stool test is negative for occult blood. A workup for sepsis is negative.

Q: Which is the appropriate test at this point to determine the cause of the hypotension?

• Serum parathyroid-hormone-related protein
• Baseline serum cortisol, plasma adrenocorticotropic hormone (ACTH) levels, and an ACTH stimulation test with cosyntropin (Cortrosyn)
• Serum thyrotropin level
• Aspiration biopsy of subcutaneous fat with Congo red and immunostaining
• Late-night salivary cortisol

A: The correct next step is to measure baseline serum cortisol, to test ACTH levels, and to order an ACTH stimulation test with cosyntropin.

Primary adrenocortical insufficiency should be considered in patients with metastatic malignancy who present with peripheral vascular collapse, particularly when it is associated with cutaneous hyperpigmentation, chronic malaise, fatigue, weakness, anorexia, weight loss, hypoglycemia, and electrolyte disturbances such as hyponatremia and hyperkalemia.

Checking the baseline serum cortisol and ACTH levels and cosyntropin stimulation testing are vital steps in making an early diagnosis of primary adrenocortical insufficiency. Inappropriately low serum cortisol is highly suggestive of primary adrenal insufficiency, especially if accompanied by simultaneous elevation of the plasma ACTH level. The result of the ACTH stimulation test with cosyntropin is often confirmatory.

Measuring the serum parathyroid-hormone-related protein level is not indicated, since the patient has a normal corrected calcium. Patients with ectopic Cushing syndrome may present with weight loss due to underlying malignancy, but the presence of hypotension and a lack of hypokalemia makes such a diagnosis unlikely, and, therefore, measurement of late-night salivary cortisol is not the best answer. Amyloidosis, hypothyroidism, or hyperthyroidism are unlikely to have this patient’s presentation.

RESULTS OF FURTHER EVALUATION

Our patient’s ACTH serum level was elevated, and an ACTH stimulation test with cosyntropin confirmed the diagnosis of primary adrenal insufficiency.

CT of the abdomen failed to demonstrate primary tumors, but both adrenal glands were enlarged, likely from metastasis (Figure 4). His hypotension responded to treatment with hydrocortisone and fludrocortisone, and his symptoms resolved. No further testing or therapy was directed to the primary occult malignancy, as it was considered advanced. The prognosis was discussed with the patient, and he deferred any further management and was discharged to hospice care. He died a few months later.

PRIMARY ADRENOCORTICAL INSUFFICIENCY

Primary adrenocortical insufficiency is an uncommon disorder caused by destruction or dysfunction of the adrenal cortices. It is characterized by chronic deficiency of cortisol, aldosterone, and adrenal androgens. In the United States, nearly 6 million people are considered to have undiagnosed adrenal insufficiency, which is clinically significant only during times of physiologic stress.¹

Primary adrenocortical insufficiency affects men and women equally. However, the idiopathic autoimmune form of adrenal insufficiency (Addison disease) is two to three times more common in women than in men.

If the condition is undiagnosed or ineffectively treated, the risk of significant morbidity and death is high. Symptoms and signs are nonspecific, and the onset is insidious.

Almost all patients with primary adrenal insufficiency have malaise, fatigue, anorexia, and weight loss. Vomiting, abdominal pain, and fever are more common during an adrenal crisis, when a patient with subclinical disease is subjected to major stress. Postural dizziness or syncope is a common result of volume depletion and hypotension.^2–4 It is commonly accompanied by hyponatremia and hyperkalemia.

Hyperpigmentation is the most characteristic physical finding and is caused by an ACTH-mediated increase in melanin content in the skin.^2,4,5 The resulting brown hyperpigmentation is most obvious in areas exposed to sunlight (face, neck, backs of hands), and in areas exposed to chronic friction or pressure, such as the elbows, knees, knuckles, waist, and shoulders (brassiere straps).⁴ Pigmentation is also prominent in the palmar creases, areolae, axillae, perineum, surgical scars, and umbilicus. Other patterns of hyperpigmentation are patchy pigmentation on the inner surface of lips, the buccal mucosa, under the tongue, and on the hard palate.^3,5 The hyperpigmentation begins to fade within several days and largely disappears after a few months of adequate glucocorticoid therapy.⁴

In the United States, 80% of cases of primary adrenocortical insufficiency are caused by autoimmune adrenal destruction. The remainder are caused by infectious diseases (eg, tuberculosis, fungal infection, cytomegalovirus infection, and Mycobacterium aviumintracellulare infection in the context of human immunodeficiency virus infection), by infiltration of the adrenal glands by metastatic cancer, by adrenal hemorrhage, or by drugs such as ketoconazole, fluconazole (Diflucan), metyrapone (Metopirone), mitotane (Lysodren), and etomidate (Amidate).^4,6

Adrenal metastatic disease

Infiltration of the adrenal glands by metastatic cancer is not uncommon, probably because of their rich sinusoidal blood supply, and the adrenals are the fourth most common site of metastasis. Common primary tumors are lung, breast, melanoma, gastric, esophageal, and colorectal cancers, while metastasis due to an undetermined primary tumor is the least common.⁷

Clinically evident adrenal insufficiency produced by metastatic carcinoma is uncommon because most of the adrenal cortex must be destroyed before hypofunction becomes evident.^7–9

Malignancy rarely presents first as adrenal insufficiency caused by metastatic infiltration.¹⁰

Hormonal therapy may significantly improve symptoms and quality of life in patients with metastatic adrenal insufficiency.^8,11

DIAGNOSIS AND MANAGEMENT

Once primary adrenal insufficiency is suspected, prompt diagnosis and treatment are essential. A low plasma cortisol level (< 3 μg/dL) at 8 am is highly suggestive of adrenal insufficiency if exposure to exogenous glucocorticoids has been excluded (including oral, inhaled, and injected),^12,13 especially if accompanied by simultaneous elevation of the plasma ACTH level (usually > 200 pg/mL). An 8 am cortisol concentration above 15 μg/dL makes adrenal insufficiency highly unlikely, but levels between 3 and 15 μg/dL are nondiagnostic and need to be further evaluated by an ACTH stimulation test with cosyntropin.^4,7

Imaging in primary adrenal insufficiency may be considered when the condition is not clearly autoimmune.¹⁴ Abdominal CT is the ideal imaging test for detecting abnormal adrenal glands. CT shows small, noncalcified adrenals in autoimmune Addison disease. It demonstrates enlarged adrenals in about 85% of cases caused by metastatic or granulomatous disease; and calcification is noted in cases of tuberculous adrenal disease.⁴

Management involves treating the underlying cause and starting hormone replacement therapy. Hormonal therapy consists of corticosteroids and mineralocorticoids; hydrocortisone is the drug of choice and is usually given with fludrocortisone acetate, which has a potent sodium-retaining effect. In the presence of a stressor (fever, surgery, severe illness), the dose of hydrocortisone should be doubled (> 50 mg hydrocortisone per day) for at least 3 to 5 days.^2,4

Screening seems to be such an easy concept: look for cancer before it is symptomatic, find it at an early stage, and treat it. We should be more able to cure cancer if it is found during screening, or at least to significantly prolong the patient’s survival by slowing the cancer’s growth and metastasis. But exactly which screening strategies save lives (and what level of efficacy is cost-effective and risk-acceptable to society and individuals) has turned out to be difficult to prove in clinical trials.

For screening to be efficacious, the test must be able to detect cancer at a stage at which early treatment makes a difference. Herein lie two challenges. A person with a cancer that grows so slowly that early treatment may not make a survival difference will not benefit from screening, and neither will someone with cancer that is so aggressive that early treatment will not significantly slow its malignant outcome. The first scenario is called “overdiagnosis”—a diagnosis made during screening that may not affect the prognosis but can lead to significant anxiety as well as additional testing and treatments, with associated costs. This has yet to be fully addressed in lung cancer screening using repeated CT imaging, but it has been discussed in breast and prostate screening.

Other challenges include how individual physicians will implement a successful lung screening program, which is more complex than yearly mammography, requiring consecutive yearly CT screening with tracking of specific results and incidental findings. How will screening be limited to appropriate patients, as dictated by trial results? Will CT review be as successful in the community as it was in trial centers of excellence? Since smoking (an act of personal choice) is the major risk factor that warrants screening, who should bear the cost?

Then there are potential unintended consequences. What if lung cancer screening makes current smokers more complacent about continuing to smoke? We must increase our educational efforts on smoking cessation, efforts that I sense are having a disappointingly limited impact on the younger generation.

Screening seems to be such an easy concept: look for cancer before it is symptomatic, find it at an early stage, and treat it. We should be more able to cure cancer if it is found during screening, or at least to significantly prolong the patient’s survival by slowing the cancer’s growth and metastasis. But exactly which screening strategies save lives (and what level of efficacy is cost-effective and risk-acceptable to society and individuals) has turned out to be difficult to prove in clinical trials.

For screening to be efficacious, the test must be able to detect cancer at a stage at which early treatment makes a difference. Herein lie two challenges. A person with a cancer that grows so slowly that early treatment may not make a survival difference will not benefit from screening, and neither will someone with cancer that is so aggressive that early treatment will not significantly slow its malignant outcome. The first scenario is called “overdiagnosis”—a diagnosis made during screening that may not affect the prognosis but can lead to significant anxiety as well as additional testing and treatments, with associated costs. This has yet to be fully addressed in lung cancer screening using repeated CT imaging, but it has been discussed in breast and prostate screening.

Other challenges include how individual physicians will implement a successful lung screening program, which is more complex than yearly mammography, requiring consecutive yearly CT screening with tracking of specific results and incidental findings. How will screening be limited to appropriate patients, as dictated by trial results? Will CT review be as successful in the community as it was in trial centers of excellence? Since smoking (an act of personal choice) is the major risk factor that warrants screening, who should bear the cost?

Then there are potential unintended consequences. What if lung cancer screening makes current smokers more complacent about continuing to smoke? We must increase our educational efforts on smoking cessation, efforts that I sense are having a disappointingly limited impact on the younger generation.

Screening seems to be such an easy concept: look for cancer before it is symptomatic, find it at an early stage, and treat it. We should be more able to cure cancer if it is found during screening, or at least to significantly prolong the patient’s survival by slowing the cancer’s growth and metastasis. But exactly which screening strategies save lives (and what level of efficacy is cost-effective and risk-acceptable to society and individuals) has turned out to be difficult to prove in clinical trials.

For screening to be efficacious, the test must be able to detect cancer at a stage at which early treatment makes a difference. Herein lie two challenges. A person with a cancer that grows so slowly that early treatment may not make a survival difference will not benefit from screening, and neither will someone with cancer that is so aggressive that early treatment will not significantly slow its malignant outcome. The first scenario is called “overdiagnosis”—a diagnosis made during screening that may not affect the prognosis but can lead to significant anxiety as well as additional testing and treatments, with associated costs. This has yet to be fully addressed in lung cancer screening using repeated CT imaging, but it has been discussed in breast and prostate screening.

Other challenges include how individual physicians will implement a successful lung screening program, which is more complex than yearly mammography, requiring consecutive yearly CT screening with tracking of specific results and incidental findings. How will screening be limited to appropriate patients, as dictated by trial results? Will CT review be as successful in the community as it was in trial centers of excellence? Since smoking (an act of personal choice) is the major risk factor that warrants screening, who should bear the cost?

Then there are potential unintended consequences. What if lung cancer screening makes current smokers more complacent about continuing to smoke? We must increase our educational efforts on smoking cessation, efforts that I sense are having a disappointingly limited impact on the younger generation.

A number of new studies and guidelines published over the last few years are changing the way we treat older patients. This article summarizes these recent developments in a variety of areas—from prevention of falls to targets for hypertension therapy—relevant to the treatment of geriatric patients.

A MULTICOMPONENT APPROACH TO PREVENTING FALS

The American Geriatrics Society and British Geriatrics Society’s 2010 Clinical Practice Guideline for Prevention of Falls in Older Persons¹ has added an important new element since the 2001 guideline: in addition to asking older patients about a fall, clinicians should also ask whether a gait or balance problem has developed.

A complete falls evaluation and multicomponent intervention is indicated for patients who in the past year or since the previous visit have had one fall with an injury or more than one fall, or for patients who report or have been diagnosed with a gait or balance problem. A falls risk assessment is not indicated for a patient with no gait or balance problem and who has had only one noninjurious fall in the previous year that did not require medical attention.

The multicomponent evaluation detailed in the guideline is very thorough and comprises more elements than can be done in a follow-up office visit. In addition to the relevant medical history, physical examination, and cognitive and functional assessment, the fall-risk evaluation includes a falls history, medication review, visual acuity testing, gait and balance assessment, postural and heart-rate evaluation, examination of the feet and footwear, and, if appropriate, a referral for home assessment of environmental hazards.

Intervention consists of many aspects

Of the interventions, exercise has the strongest correlation with falls prevention, and a prescription should include exercises for balance, gait, and strength. Tai chi is specifically recommended.

Medications should be reduced or withdrawn. The previous guideline recommended reducing medications for patients taking four or more medications, but the current guideline applies to everyone.

First cataract removal is associated with reducing the risk of falls.

Postural hypotension should be treated if present.

Vitamin D at 800 U per day is recommended for all elderly people at risk. For elderly people in long-term care, giving vitamin D for proven or suspected deficiency is by itself correlated with risk reduction.

Interventions that by themselves are not associated with risk reduction include education (eg, providing a handout on preventing falls) and having vision checked. For adults who are cognitively impaired, there is insufficient evidence that even the multicomponent intervention helps prevent falls.

CALCIUM AND VITAMIN D MAY NOT BE HARMLESS

Calcium supplements: A cause of heart attack?

Questions have arisen in recent studies about the potential risks of calcium supplementation.

A meta-analysis of 11 trials with nearly 12,000 participants found that the risk of myocardial infarction was significantly higher in people taking calcium supplementation (relative risk 1.27; 95% confidence interval [CI] 1.01–1.59, P = .038).² Patients were predominantly postmenopausal women and were followed for a mean of 4 years. The incidence of stroke and death were also higher in people who took calcium, but the differences did not reach statistical significance. The dosages were primarily 1,000 mg per day (range 600 mg to 2 g). Risk was independent of age, sex, and type of supplement.

The authors concluded (somewhat provocatively, because only the risk of myocardial infarction reached statistical significance) that if 1,000 people were treated with calcium supplementation for 5 years, 26 fractures would be prevented but 14 myocardial infarctions, 10 strokes, and 13 deaths would be caused.

Comments. These data suggest that physicians may wish to prescribe calcium to supplement (not replace) dietary calcium to help patients reach but not exceed current guidelines for total calcium intake for age and sex. They may also want to advise the patient to take the calcium supplement separately from medications, as indicated in Table 2.

Benefits of vitamin D may depend on dosing

Studies show that the risk of hip fracture can be reduced with modest daily vitamin D supplementation, up to 800 U daily, regardless of calcium intake.³ Some vitamin D dosing regimens, however, may also entail risk.

Sanders et al⁴ randomized women age 70 and older to receive an annual injection of a high dose of vitamin D (500,000 U) or placebo for 3 to 5 years. Women in the vitamin D group had 15% more falls and 25% more fractures than those in the placebo group. The once-yearly dose of 500,000 U equates to 1,370 U/day, which is not much higher than the recommended daily dosage. The median baseline serum level was 49 nmol/L and reached 120 nmol/L at 30 days in the treatment group, which was not in the toxic range.

Comments. This study cautions physicians against giving large doses of vitamin D at long intervals. Future studies should focus on long-term clinical outcomes of falls and fractures for dosing regimens currently in practice, such as 50,000 units weekly or monthly.

BISPHOSPHONATES AND NONTRAUMATIC THICK BONE FRACTURES

Bisphosphonates have been regarded as the best drugs for preventing hip fracture. But in 2010, the US Food and Drug Administration (FDA) issued a warning that bisphosphonates have been associated with “atypical” femoral fractures. The atypical fracture pattern is a clean break through the thick bone of the shaft that occurs after minimal or no trauma.⁵ This pattern contrasts with the splintering “typical” fracture in the proximal femur in osteoporotic bone, usually after a fall.

Another characteristic of the atypical fractures is a higher incidence of postoperative complications requiring revision surgery. In more than 14,000 women in secondary analyses of three large randomized bisphosphonate trials, 12 fractures in 10 patients were found that were classified as atypical, averaging to an incidence of 2.3 per 10,000 patient-years.⁶

A population-based, nested case-control study⁷ using Canadian pharmacy records evaluated more than 200,000 women at least 68 years old who received bisphosphonate therapy. Of these, 716 (0.35%) sustained an atypical femoral fracture and 9,723 (4.7%) had a typical osteoporotic femoral fracture. Comparing the duration of bisphosphonate use between the two groups, the authors found that the risk of an atypical fracture increased with years of usage (at 5 years or more, the adjusted odds ratio was 2.74, 95% CI 1.25–6.02), but the risk of a typical fracture decreased (at 5 years or more, the adjusted odds ratio was 0.76, 95% CI 0.63–0.93). The study suggests that for every 100 hip fractures that bisphosphonate therapy prevents, it causes one atypical hip fracture.

Comments. These studies have caused some experts to advocate periodic bisphosphonate “vacations,”⁸ but for how long remains an open question because the risk of a typical fracture will increase. It is possible that a biomarker can help establish the best course, but that has yet to be determined.

DENOSUMAB: A NEW DRUG FOR OSTEOPOROSIS WITH A BIG PRICE TAG

Denosumab (Prolia, Xgeva), a newly available injectable drug, is a monoclonal antibody member of the tumor necrosis factor super-family.⁹ It is FDA-approved for osteoporosis in postmenopausal women at a dosage of 60 mg every 6 months and for skeletal metastases from solid tumors (120 mg every 4 weeks). It is also being used off-label for skeletal protection in women taking aromatase inhibitors and for men with androgen deficiency.

This drug is expensive, costing $850 per 60-mg dose wholesale, and no data are yet available on its long-term effects.

Since the drug is not cleared via renal mechanisms, there is some hope that it can be used to treat osteoporosis in patients with advanced chronic kidney disease, since bisphosphonates are contraindicated in those with an estimated glomerular filtration rate (GFR) less than 30 to 35 mL/min. However, the major study of denosumab to date, the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) study, had no patients with stage 5 chronic kidney disease (GFR < 15 mL/min/1.73 m² or on dialysis), and too few with stage 4 chronic kidney disease (GFR 15–29) to demonstrate either the safety or efficacy of denosumab in patients with advanced chronic kidney disease.¹⁰

HYPERTENSION TREATMENT

A secondary analysis of a recent large hypertension study confirmed the benefits of antihypertensive therapy in very old adults and suggested new targets for systolic and diastolic blood pressures.^11,12

The Systolic Hypertension in the Elderly Program (SHEP) trial,¹³ the Systolic Hypertension in Europe (Syst-Eur) trial,¹⁴ and the Hypertension in the Very Elderly Trial (HYVET)¹⁵ are the major, randomized, placebo-controlled antihypertensive trials in older adults. They all showed a reduction in the risk of stroke and cardiovascular events. The diuretic studies (SHEP and HYVET)^13,15 also showed a lower risk of heart failure and death.

Most recently, secondary analysis of the International Verapamil-Trandolapril (INVEST) study^11,12 showed that adults in the oldest groups (age 70–79 and 80 and older), experienced a greater risk of adverse cardiovascular outcomes if systolic blood pressure was lowered to below about 130 mm Hg. As diastolic blood pressure was lowered to about the 65–70 mm Hg range, all age groups in the study experienced an increased risk of cardiovascular events. These results confirm the findings of a secondary analysis of the SHEP trial,¹⁶ showing an increased risk of cardiovascular events when diastolic pressure was lowered to below approximately 65 mm Hg.

These studies have been incorporated into 75 pages of the 2011 Expert Consensus Document on Hypertension in the Elderly issued by the American College of Cardiology Foundation and the American Heart Association.¹⁷ In a nutshell, the guidelines suggest that older adults less than 80 years of age be treated comparably to middle-aged adults. However, for adults age 80 and older:

• A target for systolic blood pressure of 140 to 145 mm Hg “can be acceptable.”
• Initiating treatment with monotherapy (with a low-dose thiazide, calcium channel blocker, or renin-angiotensin-aldosterone system drug) is reasonable. A second drug may be added if needed.
• Patients should be monitored for “excessive” orthostasis.
• Systolic blood pressure lower than 130 mm Hg and diastolic blood pressure lower than 65 mm Hg should be avoided.

TRANSCATHETER AORTIC VALVE IMPLANTATION APPROVED BY THE FDA

An estimated 2% to 9% of the elderly have aortic stenosis. Aortic valve replacement reduces mortality rates and improves function in all age groups, including octogenarians. Those with asymptomatic aortic stenosis tend to decline very quickly once they develop heart failure, syncope, or angina. Aortic valve replacement has been shown to put people back on the course they were on before they became symptomatic.

Transcatheter self-expanding transaortic valve implantation was approved by the FDA in November 2011. The procedure does not require open surgery and involves angioplasty of the old valve, with the new valve being passed into place through a catheter and expanded. Access is either transfemoral or transapical.

Transaortic valve implantation has been rapidly adopted in Europe since 2002 without any randomized control trials. The Placement of Aortic Transcatheter Valves (PARTNER) trial¹⁸ in 2011 was the first randomized trial of this therapy. It was conducted at 25 centers, with nearly 700 patients with severe aortic stenosis randomized to undergo either transcatheter aortic valve replacement with a balloon-expandable valve (244 via the transfemoral and 104 via the transapical approach) or surgical replacement. The mean age of the patients was 84 years, and the Society of Thoracic Surgeons mean score was 12%, indicating high perioperative risk.

At 30 days after the procedure, the rates of death were 3.4% with transcatheter implantation and 6.5% with surgical replacement (P = .07). At 1 year, the rates were 24.2% and 26.8%, respectively (P = 0.44, and P = .001 for noninferiority). However, the rate of major stroke was higher in the transcatheter implantation group: 3.8% vs 2.1% in the surgical group (P = .20) at 1 month and 5.1% vs 2.4% (P = .07) at 1 year. Vascular complications were significantly more frequent in the transcatheter implantation group, and the new onset of atrial fibrillation and major bleeding were significantly higher in the surgical group.

Patients in the transcatheter implantation group had a significantly shorter length of stay in the intensive care unit and a shorter index hospitalization. At 30 days, the transcatheter group also had a significant improvement in New York Heart Association functional status and a better 6-minute walk performance, although at 1 year, these measures were similar between the two groups and were greatly improved over baseline. Quality of life, measured using the Kansas City Cardiomyopathy Questionnaire, was higher both at 6 months and at 1 year in the transcatheter implantation group compared with those who underwent the open surgical procedure.¹⁹

Comments. The higher risk of stroke with the transcatheter implantation procedure remains a concern. More evaluation is also needed with respect to function and cognition in the very elderly, and of efficacy and safety in higher- and lower-risk patients.

DEPRESSION CAN BE EFFECTIVELY TREATED WITH MEDICATION

Many placebo-controlled trials have demonstrated the effectiveness of treating depression with medications in elderly people who are cognitively intact and living in the community. A Cochrane Review²⁰ found that in placebo-controlled trials, the number needed to treat to produce one recovery with tricyclic antidepressants, selective serotonin reuptake inhibitors, and monoamine oxidase inhibitors was less than 10 for each of the drug classes.

Since the newer drugs appear to be safer and to have fewer adverse effects than the older drugs, more older adults have been treated with antidepressants, including patients with comorbidities such as dementia that were exclusion criteria in early studies. For example, the number of older adults treated with antidepressants has increased 25% since 1992; at the same time the number being referred for cognitive-based therapies has been reduced by 43%.²¹ Similar trends are apparent in elderly people in long-term care. In 1999, about one-third of people in long-term care were diagnosed with depression; in 2007 more than one-half were.²²

Treating depression is less effective when dementia is present

Up to half of adults age 85 and older living in the community may have dementia. In long-term care facilities, most residents likely have some cognitive impairment or are diagnosed with dementia. Many of these are also taking antidepressive agents.

A review of studies in the Medline and Cochrane registries found seven trials that treated 330 patients with antidepressants for combined depression and dementia. Efficacy was not confirmed.²³

After this study was published, Banerjee et al²⁴ treated 218 patients who had depression and dementia in nine centers in the United Kingdom. Patients received sertraline (Zoloft), mirtazapine (Remeron), or placebo. Reductions in depression scores at 13 weeks and at 39 weeks did not differ between the groups, and adverse events were more frequent in the treatment groups than in the placebo groups.

Comments. The poor performance of antidepressants in patients with dementia may be due to misdiagnosis, such as mistaking apathy for depression.²⁵ It is also possible that better criteria than we have now are needed to diagnose depression in patients with dementia, or that current outcome measures are not sensitive for depression when dementia is present.

It may also be unsafe to treat older adults long-term with antidepressive agents. For example, although selective serotonin reuptake inhibitors, the most commonly prescribed antidepressive agents, are considered safe, their side effects are numerous and include sexual dysfunction, bleeding (due to platelet dysfunction), hyponatremia, early weight loss, tremor (mostly with paroxetine [Paxil]), sedation, apathy (especially with high doses), loose stools (with sertraline), urinary incontinence, falls, bone loss, and QTc prolongation.

Citalopram: Maximum dosage in elderly

In August 2011, an FDA Safety Communication was issued for citalopram (Celexa), stating that the daily dose should not exceed 40 mg in the general population and should not exceed 20 mg in patients age 60 and older. The dose should also not exceed 20 mg for a patient at any age who has hepatic impairment, who is known to be a poor metabolizer of CYP 2C19, or who takes cimetidine (Tagamet), since that drug inhibits the metabolism of citalopram at the CYP 2C19 enzyme site.

Although the FDA warning specifically mentions only cimetidine, physicians may have concerns about other drugs that inhibit CYP 2C19, such as proton pump inhibitors (eg, omeprazole [Prilosec]) when taken concomitantly with citalopram. Also, escitalopram (Lexapro) and sertraline are quite similar to citalopram; although they were not mentioned in the FDA Safety Communication, higher doses of these drugs may put patients at similar risk.

ALZHEIMER DISEASE: NEED TO BETTER IDENTIFY PEOPLE AT RISK

The definition of dementia is essentially the presence of a cognitive problem that affects the ability to function. For people with Alzheimer disease, impairment of cognitive performance precedes functional decline. Those with a cognitive deficit who still function well have, by definition, mild cognitive impairment (MCI). Although MCI could be caused by a variety of vascular and other neurologic processes, the most common cause of MCI in the United States is Alzheimer disease.

Unfortunately, the population with MCI currently enrolled in clinical trials to reduce the risk of progression to Alzheimer disease is heterogeneous. Many study participants may never get dementia, and others may have had the pathology present for decades and are progressing rapidly. Imaging and biomarkers are emerging as good indicators that predict progression and could help to better define populations for clinical trials.²⁶

Studies now indicate that people with MCI that is ultimately due to Alzheimer disease are likely to have amyloid beta peptide 42 evident in the cerebrospinal fluid 10 to 20 years before symptoms arise. At the same time, amyloid is also likely to be evident in the brain with amyloid-imaging positron emission tomography (PET). Some time later, abnormalities in metabolism are also evident on fluorodeoxyglucose (FDG) PET, as are changes such as reduced hippocampal volume on magnetic resonance imaging (MRI).

The 1984 criteria for diagnosing MCI due to Alzheimer disease were recently revised to incorporate the evolving availability of biomarkers.^27,28 The diagnosis of MCI itself is still based on clinical ascertainment including history, physical examination, and cognitive testing. It requires diagnosis of a cognitive decline from a prior level but maintenance of activities of daily living with no or minimal assistance. This diagnosis is certainly challenging since it requires ascertainment of a prior level of function and corroboration, when feasible, with an informant. Blood tests and imaging, which are readily available, constitute an important part of the assessment.

Attributing the MCI to Alzheimer disease requires consistency of the disease course—a gradual decline in Alzheimer disease, rather than a stroke, head injury, neurologic disease such as Parkinson disease, or mixed causes.

Knowledge of genetic factors, such as the presence of a mutation in APP, PS1, or PS2, can be predictive with young patients. The presence of one or two 34 alleles in the apolipoprotein E (APOE) gene is the only genetic variant broadly accepted as increasing the risk for late-onset Alzheimer dementia, whereas the 32 allele decreases risk.

Refining the risk attribution to Alzheimer disease requires biomarkers, currently available only in research settings:

• High likelihood—amyloid beta peptide detected by PET or cerebrospinal fluid analysis and evidence of neuronal degeneration or injury (elevated tau in the cerebrospinal fluid, decreased FDG uptake on PET, and atrophy evident by structural MRI)
• Intermediate likelihood—presence of amyloid beta peptide or evidence of neuronal degeneration or injury
• Unlikely—biomarkers tested and negative
• No comment—biomarkers not tested or reporting is indeterminate.

Comments. There is significant potential for misunderstanding the new definition for MCI. Patients who are concerned about their memory may request biomarker testing in an effort to determine if they currently have or will acquire Alzheimer disease. Doctors may be tempted to refer patients for biomarker testing (via imaging or lumbar puncture) to “screen” for MCI or Alzheimer disease.

It should be emphasized that MCI itself is still a clinical diagnosis, with the challenges noted above of determining whether there has been a cognitive decline from a prior level of function but preservation of activities of daily living. The biomarkers are not proposed to diagnose MCI, but only to help identify the subset of MCI patients most likely to progress rapidly to Alzheimer disease.

At present, the best use of biomarker testing is to aid research by identifying high-risk people among those with MCI who enroll in prospective trials for testing interventions to reduce the progression of Alzheimer disease.

A number of new studies and guidelines published over the last few years are changing the way we treat older patients. This article summarizes these recent developments in a variety of areas—from prevention of falls to targets for hypertension therapy—relevant to the treatment of geriatric patients.

A MULTICOMPONENT APPROACH TO PREVENTING FALS

The American Geriatrics Society and British Geriatrics Society’s 2010 Clinical Practice Guideline for Prevention of Falls in Older Persons¹ has added an important new element since the 2001 guideline: in addition to asking older patients about a fall, clinicians should also ask whether a gait or balance problem has developed.

A complete falls evaluation and multicomponent intervention is indicated for patients who in the past year or since the previous visit have had one fall with an injury or more than one fall, or for patients who report or have been diagnosed with a gait or balance problem. A falls risk assessment is not indicated for a patient with no gait or balance problem and who has had only one noninjurious fall in the previous year that did not require medical attention.

The multicomponent evaluation detailed in the guideline is very thorough and comprises more elements than can be done in a follow-up office visit. In addition to the relevant medical history, physical examination, and cognitive and functional assessment, the fall-risk evaluation includes a falls history, medication review, visual acuity testing, gait and balance assessment, postural and heart-rate evaluation, examination of the feet and footwear, and, if appropriate, a referral for home assessment of environmental hazards.

Intervention consists of many aspects

Of the interventions, exercise has the strongest correlation with falls prevention, and a prescription should include exercises for balance, gait, and strength. Tai chi is specifically recommended.

Medications should be reduced or withdrawn. The previous guideline recommended reducing medications for patients taking four or more medications, but the current guideline applies to everyone.

First cataract removal is associated with reducing the risk of falls.

Postural hypotension should be treated if present.

Vitamin D at 800 U per day is recommended for all elderly people at risk. For elderly people in long-term care, giving vitamin D for proven or suspected deficiency is by itself correlated with risk reduction.

Interventions that by themselves are not associated with risk reduction include education (eg, providing a handout on preventing falls) and having vision checked. For adults who are cognitively impaired, there is insufficient evidence that even the multicomponent intervention helps prevent falls.

CALCIUM AND VITAMIN D MAY NOT BE HARMLESS

Calcium supplements: A cause of heart attack?

Questions have arisen in recent studies about the potential risks of calcium supplementation.

A meta-analysis of 11 trials with nearly 12,000 participants found that the risk of myocardial infarction was significantly higher in people taking calcium supplementation (relative risk 1.27; 95% confidence interval [CI] 1.01–1.59, P = .038).² Patients were predominantly postmenopausal women and were followed for a mean of 4 years. The incidence of stroke and death were also higher in people who took calcium, but the differences did not reach statistical significance. The dosages were primarily 1,000 mg per day (range 600 mg to 2 g). Risk was independent of age, sex, and type of supplement.

The authors concluded (somewhat provocatively, because only the risk of myocardial infarction reached statistical significance) that if 1,000 people were treated with calcium supplementation for 5 years, 26 fractures would be prevented but 14 myocardial infarctions, 10 strokes, and 13 deaths would be caused.

Comments. These data suggest that physicians may wish to prescribe calcium to supplement (not replace) dietary calcium to help patients reach but not exceed current guidelines for total calcium intake for age and sex. They may also want to advise the patient to take the calcium supplement separately from medications, as indicated in Table 2.

Benefits of vitamin D may depend on dosing

Studies show that the risk of hip fracture can be reduced with modest daily vitamin D supplementation, up to 800 U daily, regardless of calcium intake.³ Some vitamin D dosing regimens, however, may also entail risk.

Sanders et al⁴ randomized women age 70 and older to receive an annual injection of a high dose of vitamin D (500,000 U) or placebo for 3 to 5 years. Women in the vitamin D group had 15% more falls and 25% more fractures than those in the placebo group. The once-yearly dose of 500,000 U equates to 1,370 U/day, which is not much higher than the recommended daily dosage. The median baseline serum level was 49 nmol/L and reached 120 nmol/L at 30 days in the treatment group, which was not in the toxic range.

Comments. This study cautions physicians against giving large doses of vitamin D at long intervals. Future studies should focus on long-term clinical outcomes of falls and fractures for dosing regimens currently in practice, such as 50,000 units weekly or monthly.

BISPHOSPHONATES AND NONTRAUMATIC THICK BONE FRACTURES

Bisphosphonates have been regarded as the best drugs for preventing hip fracture. But in 2010, the US Food and Drug Administration (FDA) issued a warning that bisphosphonates have been associated with “atypical” femoral fractures. The atypical fracture pattern is a clean break through the thick bone of the shaft that occurs after minimal or no trauma.⁵ This pattern contrasts with the splintering “typical” fracture in the proximal femur in osteoporotic bone, usually after a fall.

Another characteristic of the atypical fractures is a higher incidence of postoperative complications requiring revision surgery. In more than 14,000 women in secondary analyses of three large randomized bisphosphonate trials, 12 fractures in 10 patients were found that were classified as atypical, averaging to an incidence of 2.3 per 10,000 patient-years.⁶

A population-based, nested case-control study⁷ using Canadian pharmacy records evaluated more than 200,000 women at least 68 years old who received bisphosphonate therapy. Of these, 716 (0.35%) sustained an atypical femoral fracture and 9,723 (4.7%) had a typical osteoporotic femoral fracture. Comparing the duration of bisphosphonate use between the two groups, the authors found that the risk of an atypical fracture increased with years of usage (at 5 years or more, the adjusted odds ratio was 2.74, 95% CI 1.25–6.02), but the risk of a typical fracture decreased (at 5 years or more, the adjusted odds ratio was 0.76, 95% CI 0.63–0.93). The study suggests that for every 100 hip fractures that bisphosphonate therapy prevents, it causes one atypical hip fracture.

Comments. These studies have caused some experts to advocate periodic bisphosphonate “vacations,”⁸ but for how long remains an open question because the risk of a typical fracture will increase. It is possible that a biomarker can help establish the best course, but that has yet to be determined.

DENOSUMAB: A NEW DRUG FOR OSTEOPOROSIS WITH A BIG PRICE TAG

Denosumab (Prolia, Xgeva), a newly available injectable drug, is a monoclonal antibody member of the tumor necrosis factor super-family.⁹ It is FDA-approved for osteoporosis in postmenopausal women at a dosage of 60 mg every 6 months and for skeletal metastases from solid tumors (120 mg every 4 weeks). It is also being used off-label for skeletal protection in women taking aromatase inhibitors and for men with androgen deficiency.

This drug is expensive, costing $850 per 60-mg dose wholesale, and no data are yet available on its long-term effects.

Since the drug is not cleared via renal mechanisms, there is some hope that it can be used to treat osteoporosis in patients with advanced chronic kidney disease, since bisphosphonates are contraindicated in those with an estimated glomerular filtration rate (GFR) less than 30 to 35 mL/min. However, the major study of denosumab to date, the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) study, had no patients with stage 5 chronic kidney disease (GFR < 15 mL/min/1.73 m² or on dialysis), and too few with stage 4 chronic kidney disease (GFR 15–29) to demonstrate either the safety or efficacy of denosumab in patients with advanced chronic kidney disease.¹⁰

HYPERTENSION TREATMENT

A secondary analysis of a recent large hypertension study confirmed the benefits of antihypertensive therapy in very old adults and suggested new targets for systolic and diastolic blood pressures.^11,12

The Systolic Hypertension in the Elderly Program (SHEP) trial,¹³ the Systolic Hypertension in Europe (Syst-Eur) trial,¹⁴ and the Hypertension in the Very Elderly Trial (HYVET)¹⁵ are the major, randomized, placebo-controlled antihypertensive trials in older adults. They all showed a reduction in the risk of stroke and cardiovascular events. The diuretic studies (SHEP and HYVET)^13,15 also showed a lower risk of heart failure and death.

Most recently, secondary analysis of the International Verapamil-Trandolapril (INVEST) study^11,12 showed that adults in the oldest groups (age 70–79 and 80 and older), experienced a greater risk of adverse cardiovascular outcomes if systolic blood pressure was lowered to below about 130 mm Hg. As diastolic blood pressure was lowered to about the 65–70 mm Hg range, all age groups in the study experienced an increased risk of cardiovascular events. These results confirm the findings of a secondary analysis of the SHEP trial,¹⁶ showing an increased risk of cardiovascular events when diastolic pressure was lowered to below approximately 65 mm Hg.

These studies have been incorporated into 75 pages of the 2011 Expert Consensus Document on Hypertension in the Elderly issued by the American College of Cardiology Foundation and the American Heart Association.¹⁷ In a nutshell, the guidelines suggest that older adults less than 80 years of age be treated comparably to middle-aged adults. However, for adults age 80 and older:

• A target for systolic blood pressure of 140 to 145 mm Hg “can be acceptable.”
• Initiating treatment with monotherapy (with a low-dose thiazide, calcium channel blocker, or renin-angiotensin-aldosterone system drug) is reasonable. A second drug may be added if needed.
• Patients should be monitored for “excessive” orthostasis.
• Systolic blood pressure lower than 130 mm Hg and diastolic blood pressure lower than 65 mm Hg should be avoided.

TRANSCATHETER AORTIC VALVE IMPLANTATION APPROVED BY THE FDA

An estimated 2% to 9% of the elderly have aortic stenosis. Aortic valve replacement reduces mortality rates and improves function in all age groups, including octogenarians. Those with asymptomatic aortic stenosis tend to decline very quickly once they develop heart failure, syncope, or angina. Aortic valve replacement has been shown to put people back on the course they were on before they became symptomatic.

Transcatheter self-expanding transaortic valve implantation was approved by the FDA in November 2011. The procedure does not require open surgery and involves angioplasty of the old valve, with the new valve being passed into place through a catheter and expanded. Access is either transfemoral or transapical.

Transaortic valve implantation has been rapidly adopted in Europe since 2002 without any randomized control trials. The Placement of Aortic Transcatheter Valves (PARTNER) trial¹⁸ in 2011 was the first randomized trial of this therapy. It was conducted at 25 centers, with nearly 700 patients with severe aortic stenosis randomized to undergo either transcatheter aortic valve replacement with a balloon-expandable valve (244 via the transfemoral and 104 via the transapical approach) or surgical replacement. The mean age of the patients was 84 years, and the Society of Thoracic Surgeons mean score was 12%, indicating high perioperative risk.

At 30 days after the procedure, the rates of death were 3.4% with transcatheter implantation and 6.5% with surgical replacement (P = .07). At 1 year, the rates were 24.2% and 26.8%, respectively (P = 0.44, and P = .001 for noninferiority). However, the rate of major stroke was higher in the transcatheter implantation group: 3.8% vs 2.1% in the surgical group (P = .20) at 1 month and 5.1% vs 2.4% (P = .07) at 1 year. Vascular complications were significantly more frequent in the transcatheter implantation group, and the new onset of atrial fibrillation and major bleeding were significantly higher in the surgical group.

Patients in the transcatheter implantation group had a significantly shorter length of stay in the intensive care unit and a shorter index hospitalization. At 30 days, the transcatheter group also had a significant improvement in New York Heart Association functional status and a better 6-minute walk performance, although at 1 year, these measures were similar between the two groups and were greatly improved over baseline. Quality of life, measured using the Kansas City Cardiomyopathy Questionnaire, was higher both at 6 months and at 1 year in the transcatheter implantation group compared with those who underwent the open surgical procedure.¹⁹

Comments. The higher risk of stroke with the transcatheter implantation procedure remains a concern. More evaluation is also needed with respect to function and cognition in the very elderly, and of efficacy and safety in higher- and lower-risk patients.

DEPRESSION CAN BE EFFECTIVELY TREATED WITH MEDICATION

Many placebo-controlled trials have demonstrated the effectiveness of treating depression with medications in elderly people who are cognitively intact and living in the community. A Cochrane Review²⁰ found that in placebo-controlled trials, the number needed to treat to produce one recovery with tricyclic antidepressants, selective serotonin reuptake inhibitors, and monoamine oxidase inhibitors was less than 10 for each of the drug classes.

Since the newer drugs appear to be safer and to have fewer adverse effects than the older drugs, more older adults have been treated with antidepressants, including patients with comorbidities such as dementia that were exclusion criteria in early studies. For example, the number of older adults treated with antidepressants has increased 25% since 1992; at the same time the number being referred for cognitive-based therapies has been reduced by 43%.²¹ Similar trends are apparent in elderly people in long-term care. In 1999, about one-third of people in long-term care were diagnosed with depression; in 2007 more than one-half were.²²

Treating depression is less effective when dementia is present

Up to half of adults age 85 and older living in the community may have dementia. In long-term care facilities, most residents likely have some cognitive impairment or are diagnosed with dementia. Many of these are also taking antidepressive agents.

A review of studies in the Medline and Cochrane registries found seven trials that treated 330 patients with antidepressants for combined depression and dementia. Efficacy was not confirmed.²³

After this study was published, Banerjee et al²⁴ treated 218 patients who had depression and dementia in nine centers in the United Kingdom. Patients received sertraline (Zoloft), mirtazapine (Remeron), or placebo. Reductions in depression scores at 13 weeks and at 39 weeks did not differ between the groups, and adverse events were more frequent in the treatment groups than in the placebo groups.

Comments. The poor performance of antidepressants in patients with dementia may be due to misdiagnosis, such as mistaking apathy for depression.²⁵ It is also possible that better criteria than we have now are needed to diagnose depression in patients with dementia, or that current outcome measures are not sensitive for depression when dementia is present.

It may also be unsafe to treat older adults long-term with antidepressive agents. For example, although selective serotonin reuptake inhibitors, the most commonly prescribed antidepressive agents, are considered safe, their side effects are numerous and include sexual dysfunction, bleeding (due to platelet dysfunction), hyponatremia, early weight loss, tremor (mostly with paroxetine [Paxil]), sedation, apathy (especially with high doses), loose stools (with sertraline), urinary incontinence, falls, bone loss, and QTc prolongation.

Citalopram: Maximum dosage in elderly

In August 2011, an FDA Safety Communication was issued for citalopram (Celexa), stating that the daily dose should not exceed 40 mg in the general population and should not exceed 20 mg in patients age 60 and older. The dose should also not exceed 20 mg for a patient at any age who has hepatic impairment, who is known to be a poor metabolizer of CYP 2C19, or who takes cimetidine (Tagamet), since that drug inhibits the metabolism of citalopram at the CYP 2C19 enzyme site.

Although the FDA warning specifically mentions only cimetidine, physicians may have concerns about other drugs that inhibit CYP 2C19, such as proton pump inhibitors (eg, omeprazole [Prilosec]) when taken concomitantly with citalopram. Also, escitalopram (Lexapro) and sertraline are quite similar to citalopram; although they were not mentioned in the FDA Safety Communication, higher doses of these drugs may put patients at similar risk.

ALZHEIMER DISEASE: NEED TO BETTER IDENTIFY PEOPLE AT RISK

The definition of dementia is essentially the presence of a cognitive problem that affects the ability to function. For people with Alzheimer disease, impairment of cognitive performance precedes functional decline. Those with a cognitive deficit who still function well have, by definition, mild cognitive impairment (MCI). Although MCI could be caused by a variety of vascular and other neurologic processes, the most common cause of MCI in the United States is Alzheimer disease.

Unfortunately, the population with MCI currently enrolled in clinical trials to reduce the risk of progression to Alzheimer disease is heterogeneous. Many study participants may never get dementia, and others may have had the pathology present for decades and are progressing rapidly. Imaging and biomarkers are emerging as good indicators that predict progression and could help to better define populations for clinical trials.²⁶

Studies now indicate that people with MCI that is ultimately due to Alzheimer disease are likely to have amyloid beta peptide 42 evident in the cerebrospinal fluid 10 to 20 years before symptoms arise. At the same time, amyloid is also likely to be evident in the brain with amyloid-imaging positron emission tomography (PET). Some time later, abnormalities in metabolism are also evident on fluorodeoxyglucose (FDG) PET, as are changes such as reduced hippocampal volume on magnetic resonance imaging (MRI).

The 1984 criteria for diagnosing MCI due to Alzheimer disease were recently revised to incorporate the evolving availability of biomarkers.^27,28 The diagnosis of MCI itself is still based on clinical ascertainment including history, physical examination, and cognitive testing. It requires diagnosis of a cognitive decline from a prior level but maintenance of activities of daily living with no or minimal assistance. This diagnosis is certainly challenging since it requires ascertainment of a prior level of function and corroboration, when feasible, with an informant. Blood tests and imaging, which are readily available, constitute an important part of the assessment.

Attributing the MCI to Alzheimer disease requires consistency of the disease course—a gradual decline in Alzheimer disease, rather than a stroke, head injury, neurologic disease such as Parkinson disease, or mixed causes.

Knowledge of genetic factors, such as the presence of a mutation in APP, PS1, or PS2, can be predictive with young patients. The presence of one or two 34 alleles in the apolipoprotein E (APOE) gene is the only genetic variant broadly accepted as increasing the risk for late-onset Alzheimer dementia, whereas the 32 allele decreases risk.

Refining the risk attribution to Alzheimer disease requires biomarkers, currently available only in research settings:

• High likelihood—amyloid beta peptide detected by PET or cerebrospinal fluid analysis and evidence of neuronal degeneration or injury (elevated tau in the cerebrospinal fluid, decreased FDG uptake on PET, and atrophy evident by structural MRI)
• Intermediate likelihood—presence of amyloid beta peptide or evidence of neuronal degeneration or injury
• Unlikely—biomarkers tested and negative
• No comment—biomarkers not tested or reporting is indeterminate.

Comments. There is significant potential for misunderstanding the new definition for MCI. Patients who are concerned about their memory may request biomarker testing in an effort to determine if they currently have or will acquire Alzheimer disease. Doctors may be tempted to refer patients for biomarker testing (via imaging or lumbar puncture) to “screen” for MCI or Alzheimer disease.

It should be emphasized that MCI itself is still a clinical diagnosis, with the challenges noted above of determining whether there has been a cognitive decline from a prior level of function but preservation of activities of daily living. The biomarkers are not proposed to diagnose MCI, but only to help identify the subset of MCI patients most likely to progress rapidly to Alzheimer disease.

At present, the best use of biomarker testing is to aid research by identifying high-risk people among those with MCI who enroll in prospective trials for testing interventions to reduce the progression of Alzheimer disease.

A number of new studies and guidelines published over the last few years are changing the way we treat older patients. This article summarizes these recent developments in a variety of areas—from prevention of falls to targets for hypertension therapy—relevant to the treatment of geriatric patients.

A MULTICOMPONENT APPROACH TO PREVENTING FALS

The American Geriatrics Society and British Geriatrics Society’s 2010 Clinical Practice Guideline for Prevention of Falls in Older Persons¹ has added an important new element since the 2001 guideline: in addition to asking older patients about a fall, clinicians should also ask whether a gait or balance problem has developed.

A complete falls evaluation and multicomponent intervention is indicated for patients who in the past year or since the previous visit have had one fall with an injury or more than one fall, or for patients who report or have been diagnosed with a gait or balance problem. A falls risk assessment is not indicated for a patient with no gait or balance problem and who has had only one noninjurious fall in the previous year that did not require medical attention.

The multicomponent evaluation detailed in the guideline is very thorough and comprises more elements than can be done in a follow-up office visit. In addition to the relevant medical history, physical examination, and cognitive and functional assessment, the fall-risk evaluation includes a falls history, medication review, visual acuity testing, gait and balance assessment, postural and heart-rate evaluation, examination of the feet and footwear, and, if appropriate, a referral for home assessment of environmental hazards.

Intervention consists of many aspects

Of the interventions, exercise has the strongest correlation with falls prevention, and a prescription should include exercises for balance, gait, and strength. Tai chi is specifically recommended.

Medications should be reduced or withdrawn. The previous guideline recommended reducing medications for patients taking four or more medications, but the current guideline applies to everyone.

First cataract removal is associated with reducing the risk of falls.

Postural hypotension should be treated if present.

Vitamin D at 800 U per day is recommended for all elderly people at risk. For elderly people in long-term care, giving vitamin D for proven or suspected deficiency is by itself correlated with risk reduction.

Interventions that by themselves are not associated with risk reduction include education (eg, providing a handout on preventing falls) and having vision checked. For adults who are cognitively impaired, there is insufficient evidence that even the multicomponent intervention helps prevent falls.

CALCIUM AND VITAMIN D MAY NOT BE HARMLESS

Calcium supplements: A cause of heart attack?

Questions have arisen in recent studies about the potential risks of calcium supplementation.

A meta-analysis of 11 trials with nearly 12,000 participants found that the risk of myocardial infarction was significantly higher in people taking calcium supplementation (relative risk 1.27; 95% confidence interval [CI] 1.01–1.59, P = .038).² Patients were predominantly postmenopausal women and were followed for a mean of 4 years. The incidence of stroke and death were also higher in people who took calcium, but the differences did not reach statistical significance. The dosages were primarily 1,000 mg per day (range 600 mg to 2 g). Risk was independent of age, sex, and type of supplement.

The authors concluded (somewhat provocatively, because only the risk of myocardial infarction reached statistical significance) that if 1,000 people were treated with calcium supplementation for 5 years, 26 fractures would be prevented but 14 myocardial infarctions, 10 strokes, and 13 deaths would be caused.

Comments. These data suggest that physicians may wish to prescribe calcium to supplement (not replace) dietary calcium to help patients reach but not exceed current guidelines for total calcium intake for age and sex. They may also want to advise the patient to take the calcium supplement separately from medications, as indicated in Table 2.

Benefits of vitamin D may depend on dosing

Studies show that the risk of hip fracture can be reduced with modest daily vitamin D supplementation, up to 800 U daily, regardless of calcium intake.³ Some vitamin D dosing regimens, however, may also entail risk.

Sanders et al⁴ randomized women age 70 and older to receive an annual injection of a high dose of vitamin D (500,000 U) or placebo for 3 to 5 years. Women in the vitamin D group had 15% more falls and 25% more fractures than those in the placebo group. The once-yearly dose of 500,000 U equates to 1,370 U/day, which is not much higher than the recommended daily dosage. The median baseline serum level was 49 nmol/L and reached 120 nmol/L at 30 days in the treatment group, which was not in the toxic range.

Comments. This study cautions physicians against giving large doses of vitamin D at long intervals. Future studies should focus on long-term clinical outcomes of falls and fractures for dosing regimens currently in practice, such as 50,000 units weekly or monthly.

BISPHOSPHONATES AND NONTRAUMATIC THICK BONE FRACTURES

Bisphosphonates have been regarded as the best drugs for preventing hip fracture. But in 2010, the US Food and Drug Administration (FDA) issued a warning that bisphosphonates have been associated with “atypical” femoral fractures. The atypical fracture pattern is a clean break through the thick bone of the shaft that occurs after minimal or no trauma.⁵ This pattern contrasts with the splintering “typical” fracture in the proximal femur in osteoporotic bone, usually after a fall.

Another characteristic of the atypical fractures is a higher incidence of postoperative complications requiring revision surgery. In more than 14,000 women in secondary analyses of three large randomized bisphosphonate trials, 12 fractures in 10 patients were found that were classified as atypical, averaging to an incidence of 2.3 per 10,000 patient-years.⁶

A population-based, nested case-control study⁷ using Canadian pharmacy records evaluated more than 200,000 women at least 68 years old who received bisphosphonate therapy. Of these, 716 (0.35%) sustained an atypical femoral fracture and 9,723 (4.7%) had a typical osteoporotic femoral fracture. Comparing the duration of bisphosphonate use between the two groups, the authors found that the risk of an atypical fracture increased with years of usage (at 5 years or more, the adjusted odds ratio was 2.74, 95% CI 1.25–6.02), but the risk of a typical fracture decreased (at 5 years or more, the adjusted odds ratio was 0.76, 95% CI 0.63–0.93). The study suggests that for every 100 hip fractures that bisphosphonate therapy prevents, it causes one atypical hip fracture.

Comments. These studies have caused some experts to advocate periodic bisphosphonate “vacations,”⁸ but for how long remains an open question because the risk of a typical fracture will increase. It is possible that a biomarker can help establish the best course, but that has yet to be determined.

DENOSUMAB: A NEW DRUG FOR OSTEOPOROSIS WITH A BIG PRICE TAG

Denosumab (Prolia, Xgeva), a newly available injectable drug, is a monoclonal antibody member of the tumor necrosis factor super-family.⁹ It is FDA-approved for osteoporosis in postmenopausal women at a dosage of 60 mg every 6 months and for skeletal metastases from solid tumors (120 mg every 4 weeks). It is also being used off-label for skeletal protection in women taking aromatase inhibitors and for men with androgen deficiency.

This drug is expensive, costing $850 per 60-mg dose wholesale, and no data are yet available on its long-term effects.

Since the drug is not cleared via renal mechanisms, there is some hope that it can be used to treat osteoporosis in patients with advanced chronic kidney disease, since bisphosphonates are contraindicated in those with an estimated glomerular filtration rate (GFR) less than 30 to 35 mL/min. However, the major study of denosumab to date, the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) study, had no patients with stage 5 chronic kidney disease (GFR < 15 mL/min/1.73 m² or on dialysis), and too few with stage 4 chronic kidney disease (GFR 15–29) to demonstrate either the safety or efficacy of denosumab in patients with advanced chronic kidney disease.¹⁰

HYPERTENSION TREATMENT

A secondary analysis of a recent large hypertension study confirmed the benefits of antihypertensive therapy in very old adults and suggested new targets for systolic and diastolic blood pressures.^11,12

The Systolic Hypertension in the Elderly Program (SHEP) trial,¹³ the Systolic Hypertension in Europe (Syst-Eur) trial,¹⁴ and the Hypertension in the Very Elderly Trial (HYVET)¹⁵ are the major, randomized, placebo-controlled antihypertensive trials in older adults. They all showed a reduction in the risk of stroke and cardiovascular events. The diuretic studies (SHEP and HYVET)^13,15 also showed a lower risk of heart failure and death.

Most recently, secondary analysis of the International Verapamil-Trandolapril (INVEST) study^11,12 showed that adults in the oldest groups (age 70–79 and 80 and older), experienced a greater risk of adverse cardiovascular outcomes if systolic blood pressure was lowered to below about 130 mm Hg. As diastolic blood pressure was lowered to about the 65–70 mm Hg range, all age groups in the study experienced an increased risk of cardiovascular events. These results confirm the findings of a secondary analysis of the SHEP trial,¹⁶ showing an increased risk of cardiovascular events when diastolic pressure was lowered to below approximately 65 mm Hg.

These studies have been incorporated into 75 pages of the 2011 Expert Consensus Document on Hypertension in the Elderly issued by the American College of Cardiology Foundation and the American Heart Association.¹⁷ In a nutshell, the guidelines suggest that older adults less than 80 years of age be treated comparably to middle-aged adults. However, for adults age 80 and older:

• A target for systolic blood pressure of 140 to 145 mm Hg “can be acceptable.”
• Initiating treatment with monotherapy (with a low-dose thiazide, calcium channel blocker, or renin-angiotensin-aldosterone system drug) is reasonable. A second drug may be added if needed.
• Patients should be monitored for “excessive” orthostasis.
• Systolic blood pressure lower than 130 mm Hg and diastolic blood pressure lower than 65 mm Hg should be avoided.

TRANSCATHETER AORTIC VALVE IMPLANTATION APPROVED BY THE FDA

An estimated 2% to 9% of the elderly have aortic stenosis. Aortic valve replacement reduces mortality rates and improves function in all age groups, including octogenarians. Those with asymptomatic aortic stenosis tend to decline very quickly once they develop heart failure, syncope, or angina. Aortic valve replacement has been shown to put people back on the course they were on before they became symptomatic.

Transcatheter self-expanding transaortic valve implantation was approved by the FDA in November 2011. The procedure does not require open surgery and involves angioplasty of the old valve, with the new valve being passed into place through a catheter and expanded. Access is either transfemoral or transapical.

Transaortic valve implantation has been rapidly adopted in Europe since 2002 without any randomized control trials. The Placement of Aortic Transcatheter Valves (PARTNER) trial¹⁸ in 2011 was the first randomized trial of this therapy. It was conducted at 25 centers, with nearly 700 patients with severe aortic stenosis randomized to undergo either transcatheter aortic valve replacement with a balloon-expandable valve (244 via the transfemoral and 104 via the transapical approach) or surgical replacement. The mean age of the patients was 84 years, and the Society of Thoracic Surgeons mean score was 12%, indicating high perioperative risk.

At 30 days after the procedure, the rates of death were 3.4% with transcatheter implantation and 6.5% with surgical replacement (P = .07). At 1 year, the rates were 24.2% and 26.8%, respectively (P = 0.44, and P = .001 for noninferiority). However, the rate of major stroke was higher in the transcatheter implantation group: 3.8% vs 2.1% in the surgical group (P = .20) at 1 month and 5.1% vs 2.4% (P = .07) at 1 year. Vascular complications were significantly more frequent in the transcatheter implantation group, and the new onset of atrial fibrillation and major bleeding were significantly higher in the surgical group.

Patients in the transcatheter implantation group had a significantly shorter length of stay in the intensive care unit and a shorter index hospitalization. At 30 days, the transcatheter group also had a significant improvement in New York Heart Association functional status and a better 6-minute walk performance, although at 1 year, these measures were similar between the two groups and were greatly improved over baseline. Quality of life, measured using the Kansas City Cardiomyopathy Questionnaire, was higher both at 6 months and at 1 year in the transcatheter implantation group compared with those who underwent the open surgical procedure.¹⁹

Comments. The higher risk of stroke with the transcatheter implantation procedure remains a concern. More evaluation is also needed with respect to function and cognition in the very elderly, and of efficacy and safety in higher- and lower-risk patients.

DEPRESSION CAN BE EFFECTIVELY TREATED WITH MEDICATION

Many placebo-controlled trials have demonstrated the effectiveness of treating depression with medications in elderly people who are cognitively intact and living in the community. A Cochrane Review²⁰ found that in placebo-controlled trials, the number needed to treat to produce one recovery with tricyclic antidepressants, selective serotonin reuptake inhibitors, and monoamine oxidase inhibitors was less than 10 for each of the drug classes.

Since the newer drugs appear to be safer and to have fewer adverse effects than the older drugs, more older adults have been treated with antidepressants, including patients with comorbidities such as dementia that were exclusion criteria in early studies. For example, the number of older adults treated with antidepressants has increased 25% since 1992; at the same time the number being referred for cognitive-based therapies has been reduced by 43%.²¹ Similar trends are apparent in elderly people in long-term care. In 1999, about one-third of people in long-term care were diagnosed with depression; in 2007 more than one-half were.²²

Treating depression is less effective when dementia is present

Up to half of adults age 85 and older living in the community may have dementia. In long-term care facilities, most residents likely have some cognitive impairment or are diagnosed with dementia. Many of these are also taking antidepressive agents.

A review of studies in the Medline and Cochrane registries found seven trials that treated 330 patients with antidepressants for combined depression and dementia. Efficacy was not confirmed.²³

After this study was published, Banerjee et al²⁴ treated 218 patients who had depression and dementia in nine centers in the United Kingdom. Patients received sertraline (Zoloft), mirtazapine (Remeron), or placebo. Reductions in depression scores at 13 weeks and at 39 weeks did not differ between the groups, and adverse events were more frequent in the treatment groups than in the placebo groups.

Comments. The poor performance of antidepressants in patients with dementia may be due to misdiagnosis, such as mistaking apathy for depression.²⁵ It is also possible that better criteria than we have now are needed to diagnose depression in patients with dementia, or that current outcome measures are not sensitive for depression when dementia is present.

It may also be unsafe to treat older adults long-term with antidepressive agents. For example, although selective serotonin reuptake inhibitors, the most commonly prescribed antidepressive agents, are considered safe, their side effects are numerous and include sexual dysfunction, bleeding (due to platelet dysfunction), hyponatremia, early weight loss, tremor (mostly with paroxetine [Paxil]), sedation, apathy (especially with high doses), loose stools (with sertraline), urinary incontinence, falls, bone loss, and QTc prolongation.

Citalopram: Maximum dosage in elderly