Nancy L. Keating

Diabetes and Cardiovascular Disease During Androgen Deprivation Therapy for Prostate Cancer

PURPOSE Androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) agonist is associated with increased fat mass and insulin resistance in men with prostate cancer, but the risk of obesity-related disease during treatment has not been well studied. We assessed whether androgen deprivation therapy is associated with an increased incidence of diabetes and cardiovascular disease. PATIENTS AND METHODS Observational study of a population-based cohort of 73,196 fee-for-service Medicare enrollees age 66 years or older who were diagnosed with locoregional prostate cancer during 1992 to 1999 and observed through 2001. We used Cox proportional hazards models to assess whether treatment with GnRH agonists or orchiectomy was associated with diabetes, coronary heart disease, myocardial infarction, and sudden cardiac death. RESULTS More than one third of men received a GnRH agonist during follow-up. GnRH agonist use was associated with increased risk of incident diabetes (adjusted hazard ratio [HR], 1.44; P < .001), coronary heart disease (adjusted HR, 1.16; P < .001), myocardial infarction (adjusted HR, 1.11; P = .03), and sudden cardiac death (adjusted HR, 1.16; P = .004). Men treated with orchiectomy were more likely to develop diabetes (adjusted HR, 1.34; P < .001) but not coronary heart disease, myocardial infarction, or sudden cardiac death (all P > .20). CONCLUSION GnRH agonist treatment for men with locoregional prostate cancer may be associated with an increased risk of incident diabetes and cardiovascular disease. The benefits of GnRH agonist treatment should be weighed against these potential risks. Additional research is needed to identify populations of men at highest risk of treatment-related complications and to develop strategies to prevent treatment-related diabetes and cardiovascular disease.

Comparative Effectiveness of Minimally Invasive vs Open Radical Prostatectomy

CONTEXT Minimally invasive radical prostatectomy (MIRP) has diffused rapidly despite limited data on outcomes and greater costs compared with open retropubic radical prostatectomy (RRP). OBJECTIVE To determine the comparative effectiveness of MIRP vs RRP. DESIGN, SETTING, AND PATIENTS Population-based observational cohort study using US Surveillance, Epidemiology, and End Results Medicare linked data from 2003 through 2007. We identified men with prostate cancer who underwent MIRP (n = 1938) vs RRP (n = 6899). MAIN OUTCOME MEASURES We compared postoperative 30-day complications, anastomotic stricture 31 to 365 days postoperatively, long-term incontinence and erectile dysfunction more than 18 months postoperatively, and postoperative use of additional cancer therapies, a surrogate for cancer control. RESULTS Among men undergoing prostatectomy, use of MIRP increased from 9.2% (95% confidence interval [CI], 8.1%-10.5%) in 2003 to 43.2% (95% CI, 39.6%-46.9%) in 2006-2007. Men undergoing MIRP vs RRP were more likely to be recorded as Asian (6.1% vs 3.2%), less likely to be recorded as black (6.2% vs 7.8%) or Hispanic (5.6% vs 7.9%), and more likely to live in areas with at least 90% high school graduation rates (50.2% vs 41.0%) and with median incomes of at least

Diabetes and Cardiovascular Disease During Androgen Deprivation Therapy: Observational Study of Veterans With Prostate Cancer

60,000 (35.8% vs 21.5%) (all P < .001). In propensity score-adjusted analyses, MIRP vs RRP was associated with shorter length of stay (median, 2.0 vs 3.0 days; P<.001) and lower rates of blood transfusions (2.7% vs 20.8%; P < .001), postoperative respiratory complications (4.3% vs 6.6%; P = .004), miscellaneous surgical complications (4.3% vs 5.6%; P = .03), and anastomotic stricture (5.8% vs 14.0%; P < .001). However, MIRP vs RRP was associated with an increased risk of genitourinary complications (4.7% vs 2.1%; P = .001) and diagnoses of incontinence (15.9 vs 12.2 per 100 person-years; P = .02) and erectile dysfunction (26.8 vs 19.2 per 100 person-years; P = .009). Rates of use of additional cancer therapies did not differ by surgical procedure (8.2 vs 6.9 per 100 person-years; P = .35). CONCLUSION Men undergoing MIRP vs RRP experienced shorter length of stay, fewer respiratory and miscellaneous surgical complications and strictures, and similar postoperative use of additional cancer therapies but experienced more genitourinary complications, incontinence, and erectile dysfunction.

Use of Hormone Replacement Therapy by Postmenopausal Women in the United States

BACKGROUND Previous studies indicate that androgen deprivation therapy for prostate cancer is associated with diabetes and cardiovascular disease among older men. We evaluated the relationship between androgen deprivation therapy and incident diabetes and cardiovascular disease in men of all ages with prostate cancer. METHODS We conducted an observational study of 37,443 population-based men who were diagnosed with local or regional prostate cancer in the Veterans Healthcare Administration from January 1, 2001, through December 31, 2004, with follow-up through December 31, 2005. Cox proportional hazards models were used to assess whether androgen deprivation therapy with gonadotropin-releasing hormone (GnRH) agonists, oral antiandrogens, the combination of the two (ie, combined androgen blockade), or orchiectomy was associated with diabetes, coronary heart disease, myocardial infarction, sudden cardiac death, or stroke, after adjustment for patient and tumor characteristics. All statistical tests were two-sided. RESULTS Overall, 14,597 (39%) of the 37,443 patients were treated with androgen deprivation therapy. Treatment with GnRH agonists was associated with statistically significantly increased risks of incident diabetes (for GnRH agonist therapy, 159.4 events per 1000 person-years vs 87.5 events for no androgen deprivation therapy, difference = 71.9, 95% confidence interval [CI] = 71.6 to 72.2; adjusted hazard ratio [aHR] = 1.28, 95% CI = 1.19 to 1.38), incident coronary heart disease (aHR = 1.19, 95% CI = 1.10 to 1.28), myocardial infarction (12.8 events per 1000 person-years for GnRH agonist therapy vs 7.3 for no androgen deprivation therapy, difference = 5.5, 95% CI = 5.4 to 5.6; aHR = 1.28, 95% CI = 1.08 to 1.52), sudden cardiac death (aHR = 1.35, 95% CI = 1.18 to 1.54), and stroke (aHR = 1.22, 95% CI = 1.10 to 1.36). Combined androgen blockade was statistically significantly associated with an increased risk of incident coronary heart disease (aHR = 1.27, 95% CI = 1.05 to 1.53), and orchiectomy was associated with coronary heart disease (aHR = 1.40, 95% CI = 1.04 to 1.87) and myocardial infarction (aHR = 2.11, 95% CI = 1.27 to 3.50). Oral antiandrogen monotherapy was not associated with any outcome studied. CONCLUSION Androgen deprivation therapy with GnRH agonists was associated with an increased risk of diabetes and cardiovascular disease.

Associations Between End-of-Life Discussion Characteristics and Care Received Near Death: A Prospective Cohort Study

Postmenopausal hormone replacement therapy (HRT) is a subject of major interest in the field of womens health. Although HRT has a clear role in the treatment of menopausal symptoms (1), uncertainty exists about its long-term use to prevent disease and prolong life (2). In randomized, controlled trials, HRT has been shown to improve lipid profiles (3) and increase bone density in postmenopausal women (4) but not to decrease the rate of subsequent coronary events in women with established coronary artery disease (5). Observational studies have shown that women who use HRT have a substantially decreased risk for coronary artery disease (6-8), osteoporosis and fractures (8-10), and death (12), but they may also have an increased risk for breast cancer (13). In 1992, guidelines from the American College of Physicians advised that postmenopausal women who have had hysterectomy and women at risk for coronary heart disease are likely to benefit from preventive HRT (14, 15). A more recent decision analysis suggested that almost all postmenopausal women will benefit from HRT, especially those with risk factors for coronary heart disease (16). Despite these recommendations, the benefits and risks of HRT are not fully defined. The decision to use preventive HRT is usually not simple and is probably influenced by the personal characteristics and beliefs of women and their physicians. Previous studies have sought to characterize women who use postmenopausal HRT (17-27), but most of these studies examined local or highly selected cohorts of patients. A recent report on HRT use in a national sample of women in the United States analyzed past and current use together and last collected data in 1992 (26). To our knowledge, only one study has assessed psychological factors that may influence the decision to use HRT (27). Therefore, we examined patterns of HRT use in a national sample of postmenopausal women during 1995 to understand how sociodemographic, clinical, and psychological characteristics were associated with current use of this treatment. We also assessed patterns of use in women at risk for cardiovascular disease who may benefit most from this therapy. Finally, we sought to identify potential selection effects that may be present in observational studies while randomized clinical trials of this therapy are in progress (28). Methods Study Sample In 1995, the John D. and Catherine T. MacArthur Foundation Research Network on Successful Midlife Development conducted a random-digit telephone survey of a probability sample of adults in the United States from 25 to 74 years of age to identify physical, psychological, and social factors that promote good health, psychological well-being, and social responsibility. The study protocol was approved by the human subjects committee of Harvard Medical School. The survey was conducted by using a multistage sampling design. For the first stage, an equal probability sample of telephone numbers, stratified by county in proportion to population, was selected from more than 70 million directory-listed residential numbers. After determining household eligibility, respondents were selected on the basis of age and sex and were offered a stipend for participation. The response rate for this telephone survey was 70%. United States Census data from 1990 for each telephone exchange were used to assess for response bias, and no statistically significant differences were found between eligible households for which the telephone interview was completed and other households by age, education, income, Hispanic ethnicity, other ethnicity, and residence in a Metropolitan Statistical Area. Participants who completed the telephone interview were also mailed a self-administered questionnaire. We limited our cohort to women 50 to 74 years of age; 93% of these women also completed the self-administered questionnaire and were eligible for our sample, yielding an estimated response rate of 65% for the combined telephone survey and questionnaire. Compared with women who responded to the telephone interview only, these women were younger (mean age, 60.1 compared with 62.7 years; P=0.02), more likely to be married (56% compared with 35%; P=0.004), and more likely to have completed at least 12 years of education (84% compared with 61%; P=0.001). From this cohort (n=668), we identified all postmenopausal women with no personal history of breast cancer (n=495). A woman was considered postmenopausal if she reported that her menses had stopped permanently. Because by 50 years of age, most women with a uterus in our sample had undergone natural menopause, women who had undergone hysterectomy were considered postmenopausal whether or not they had undergone bilateral salpingo-oophorectomy. Data Collection Current users of HRT were women who reported use of hormone replacement, such as estrogen, in the past 30 days. Women were also asked about sociodemographic, clinical, and psychological factors that had previously been associated with use of HRT in other studies or that we postulated might influence its use. Sociodemographic variables included age (denoted by indicator variables for 5-year increments), ethnicity (white or nonwhite), education (<12 years, high school graduate or general education diploma, or college graduate), household income (in quartiles), marital status (currently married), children (one or more), employment status (full-time job), rural residence (not living in a Metropolitan Statistical Area), and geographic region (Northeast, Midwest, South, and West) as defined by the U.S. Census. Clinical variables included a history of hysterectomy, having a regular physician, use of supplemental calcium, physical activity (vigorous activity one or more times per week), and a waist-to-hip ratio of 0.85 or less as a measure of body habitus; all of these factors were previously associated with use of HRT. We also examined self-report of diabetes, cigarette smoking (current, former, or never smoker), family history of myocardial infarction, hypertension, high cholesterol level, personal history of myocardial infarction or angina (based on the Rose criteria [29]), sexual activity, alcohol use, multivitamin use, and use of alternative therapies. Psychological variables included perceived risk for heart disease and cancer (above average compared with average or below), self-perceived physical and mental health (excellent, very good, or good compared with fair or poor), depression (based on the Composite International Diagnostic Interview [30]), self-report of depression or anxiety, perceived control over health, and thought and effort put into health. Women were also asked whether they worry about becoming less attractive or developing illness as they age. Measures of six major personality characteristicsagency (self-confident, forceful, assertive, outspoken, and dominant), agreeableness (helpful, warm, caring, softhearted, and sympathetic), openness (creative, imaginative, intelligent, curious, sophisticated, and adventurous), neuroticism (moody, worrying, nervous, and not calm), extroversion (outgoing, friendly, lively, active, and talkative), and conscientiousness (organized, responsible, hardworking, and not careless)were adapted from standard scales (31-34). Finally, we used the Somatic Amplification Scale (35) to assess somatosensory amplification (experiencing somatic sensation as intense, noxious, and disturbing). Statistical Analysis Data were weighted to adjust for differing probabilities of contacting households, sampling persons within each household, and obtaining completed surveys from designated participants (36) and to approximate the U.S. population on the basis of the Current Population Survey (October 1995). First, we adjusted for differing probabilities of successfully contacting households in geographic areas by mapping 1990 U.S. Census data on age, ethnicity, income, education, and urban location to telephone exchanges. Second, we adjusted for the higher probability of sampling persons in smaller households when their household was contacted. Third, we adjusted for differing probabilities of obtaining self-administered questionnaires from persons who completed the telephone interview by using numerous variables from the telephone interview. Finally, we created post-stratification weights so that the sample more closely approximated the U.S. population on the basis of 1995 Current Population Survey data. Thus, the weighted sample resembles the U.S. population by geographic region, ethnicity, age, education, marital status, and residence in a Metropolitan Statistical Area. We used the Pearson chi-square test to compare rates of HRT use by categorical variables and the Mantel-Haenszel chi-square test for the same comparison after stratifying by hysterectomy status (37). We converted values of each continuous psychological variable to ranks and compared users and nonusers of HRT by using two-way analysis of variance to control for hysterectomy status. We conducted multivariable logistic regression analyses in two stages. Because we had large numbers of sociodemographic, clinical, and psychological variables, we first created three separate models for each of these types of variables. Each model included all variables of a particular type with a P value of 0.2 or less in bivariable analyses. Finally, all variables with P values of 0.2 or less in the intermediate models were included in a final composite main-effects model. Because we also wished to ensure that the final model controlled for key demographic and clinical variables that might confound the effect of statistically significant variables, we also forced the following select variables to enter the final model: ethnicity, marital status, waist-to-hip ratio, income, hypertension, high cholesterol, family history of myocardial infarction, smoking, and personal history of coronary artery disease . Only this final composite multivariable logi

Utilization and Outcomes of Minimally Invasive Radical Prostatectomy

PURPOSE National guidelines recommend that discussions about end-of-life (EOL) care planning happen early for patients with incurable cancer. We do not know whether earlier EOL discussions lead to less aggressive care near death. We sought to evaluate the extent to which EOL discussion characteristics, such as timing, involved providers, and location, are associated with the aggressiveness of care received near death. PATIENTS AND METHODS We studied 1,231 patients with stage IV lung or colorectal cancer in the Cancer Care Outcomes Research and Surveillance Consortium, a population- and health system-based prospective cohort study, who died during the 15-month study period but survived at least 1 month. Our main outcome measure was the aggressiveness of EOL care received. RESULTS Nearly half of patients received at least one marker of aggressive EOL care, including chemotherapy in the last 14 days of life (16%), intensive care unit care in the last 30 days of life (9%), and acute hospital-based care in the last 30 days of life (40%). Patients who had EOL discussions with their physicians before the last 30 days of life were less likely to receive aggressive measures at EOL, including chemotherapy (P = .003), acute care (P < .001), or any aggressive care (P < .001). Such patients were also more likely to receive hospice care (P < .001) and to have hospice initiated earlier (P < .001). CONCLUSION Early EOL discussions are prospectively associated with less aggressive care and greater use of hospice at EOL.

Adverse Effects of Androgen Deprivation Therapy and Strategies to Mitigate Them

PURPOSE Demand for minimally invasive radical prostatectomy (MIRP) to treat prostate cancer is increasing; however, outcomes remain unclear. We assessed utilization, complications, lengths of stay, and salvage therapy rates for MIRP versus open radical prostatectomy assessed whether MIRP surgeon volume is associated with better outcomes. METHODS We identified 2,702 men undergoing MIRP and open radical prostatectomy during 2003 to 2005 from a national 5% sample of Medicare beneficiaries. We assessed the association between surgical approach and outcomes, adjusting for surgeon volume, age, race, comorbidity, and geographic region. RESULTS MIRP utilization increased from 12.2% in 2003 to 31.4% in 2005. Men undergoing MIRP versus open radical prostatectomy had fewer perioperative complications (29.8% v 36.4%; P = .002) and shorter lengths of stay (1.4 v 4.4 days; P < .001); however, they were more likely to receive salvage therapy (27.8% v 9.1%, P < .001). In adjusted analyses, MIRP versus open radical prostatectomy was associated with fewer perioperative complications (odds ratio [OR], 0.73; 95% CI, 0.60 to 0.90), shorter lengths of stay (parameter estimate, -2.99; 95% CI, -3.45 to -2.53) but more anastomotic strictures (OR, 1.40; 95% CI, 1.04 to 1.87) and higher rates of salvage therapy (OR, 3.67; 95% CI, 2.81 to 4.81). Patients of high-volume MIRP experienced fewer anastomotic strictures (OR, 0.93; 95% CI, 0.87 to 0.99) and less salvage therapy (OR, 0.92; 95% CI, 0.88 to 0.98). CONCLUSION Men undergoing MIRP versus open radical prostatectomy have lower risk for perioperative complications and shorter lengths of stay, but are at higher risk for salvage therapy and anastomotic strictures. However, risk for these unfavorable outcomes decreases with increasing MIRP surgical volume.

Androgen-Deprivation Therapy in Prostate Cancer and Cardiovascular Risk: A Science Advisory From the American Heart Association, American Cancer Society, and American Urological Association Endorsed by the American Society for Radiation Oncology

CONTEXT Androgen-deprivation therapy (ADT) is a key component of treatment for aggressive and advanced prostate cancer, but it has also been associated with adverse effects on bone, metabolic, cardiovascular, sexual, and cognitive health as well as body composition. OBJECTIVE To review the current literature on the adverse effects of ADT and strategies for ameliorating harm from ADT. EVIDENCE ACQUISITION The Medline database (through PubMed) was searched from inception to August 1, 2013, for studies documenting the side effects of ADT and for randomized and prospective trials of interventions to mitigate those side effects. EVIDENCE SYNTHESIS Adverse effects of ADT include decreases in bone mineral density; metabolic changes such as weight gain, decreased muscle mass, and increased insulin resistance; decreased libido and sexual dysfunction; hot flashes; gynecomastia; reduced testicle size; anemia; and fatigue. Several observational studies suggest an increased risk of diabetes and cardiovascular events, although most published studies report that ADT is not linked to greater cardiovascular mortality. Randomized trials have found value in treatments for some adverse effects including bone loss (bisphosphonates, denosumab, selective estrogen receptor modulators), markers of metabolic syndrome (exercise, diet, metformin), gynecomastia (tamoxifen, prophylactic radiation), muscle loss (resistance and aerobic exercise), and hot flashes (venlafaxine, medroxyprogesterone, cyproterone acetate, gabapentin). CONCLUSIONS ADT is often a necessary component of the treatment of aggressive prostate cancer, yet it has known harms that can impair health and quality of life. Clinicians should be aware of interventions that can help mitigate these adverse effects. PATIENT SUMMARY Androgen deprivation therapy is a critical component of the management of aggressive and advanced prostate cancer, but it causes adverse effects including bone loss, metabolic changes, gynecomastia, muscle loss, hot flashes, and possibly increased cardiovascular events. Clinicians should be aware of interventions that can help mitigate these adverse effects.

Physician factors associated with discussions about end-of-life care.

Androgen-deprivation therapy (ADT) is a widely used treatment for prostate cancer. Recently, several studies have reported an association between ADT and an increased risk of cardiovascular events, including myocardial infarction and cardiovascular mortality.1-5 These reports have led to increased interest and discussion regarding the metabolic effects of ADT and its possible association with increased cardiovascular risk. In addition, likely as a result of these reports, internists, endocrinologists, and cardiologists are now being consulted regarding the evaluation and management of patients in whom ADT is being initiated. Most of these physicians are not aware of the possible effects of ADT on cardiovascular risk factors or the issues regarding ADT and cardiovascular disease. Therefore, this multidisciplinary writing group has been commissioned to review and summarize the metabolic effects of ADT, to evaluate the data regarding a possible relation between ADT and cardiovascular events in patients with prostate cancer, and to generate suggestions regarding the evaluation and management of patients, both with and without known cardiac disease, in whom ADT is being initiated (Table 1). TABLE 1 Prospective Studies of the Effects of ADT on Cardiac Risk Factors ADT was first used in prostate cancer for patients with overt metastatic disease,7 and it remains the mainstay of therapy for this group. ADT combined with external-beam radiation therapy is a standard of care in the treatment of men with high-risk prostate cancer, on the basis of evidence that shows a survival benefit in multiple randomized controlled trials.8-13 However, ADT is also often used for other prostate cancer states (eg, for prostate volume reduction in men planning to undergo definitive local therapy with brachytherapy, or in the case of rising prostate-specific antigen after definitive local treatment),14,15 and in these cases, its role in prolonging survival is less certain.

How Are Patients' Specific Ambulatory Care Experiences Related to Trust, Satisfaction, and Considering Changing Physicians?

Guidelines recommend advanced care planning for terminally ill patients with <1 year to live. Few data are available regarding when physicians and their terminally ill patients typically discuss end‐of‐life issues.