Metastasis and Mortality in Men With Low- and Intermediate-Risk Prostate Cancer on Active Surveillance.

BACKGROUND: Active surveillance (AS) is a safe treatment option for men with low-risk, localized prostate cancer. However, the safety of AS for patients with intermediate-risk prostate cancer remains unclear. PATIENTS AND METHODS: We identified men with NCCN-classified low-risk and favorable and unfavorable intermediate-risk prostate cancer diagnosed between 2001 and 2015 and initially managed with AS in the Veterans Health Administration. We analyzed progression to definitive treatment, metastasis, prostate cancer-specific mortality (PCSM), and all-cause mortality using cumulative incidences and multivariable competing-risks regression. RESULTS: The cohort included 9,733 men, of whom 1,007 (10.3%) had intermediate-risk disease (773 [76.8%] favorable, 234 [23.2%] unfavorable), followed for a median of 7.6 years. The 10-year cumulative incidence of metastasis was significantly higher for patients with favorable (9.6%; 95% CI, 7.1%-12.5%; P<.001) and unfavorable intermediate-risk disease (19.2%; 95% CI, 13.4%-25.9%; P<.001) than for those with low-risk disease (1.5%; 95% CI, 1.2%-1.9%). The 10-year cumulative incidence of PCSM was also significantly higher for patients with favorable (3.7%; 95% CI, 2.3%-5.7%; P<.001) and unfavorable intermediate-risk disease (11.8%; 95% CI, 6.8%-18.4%; P<.001) than for those with low-risk disease (1.1%; 95% CI, 0.8%-1.4%). In multivariable competing-risks regression, favorable and unfavorable intermediate-risk patients had significantly increased risks of metastasis and PCSM compared with low-risk patients (all P<.001). CONCLUSIONS: Compared with low-risk patients, those with favorable and unfavorable intermediate-risk prostate cancer managed with AS are at increased risk of metastasis and PCSM. AS may be an appropriate option for carefully selected patients with favorable intermediate-risk prostate cancer, though identification of appropriate candidates and AS protocols should be tested in future prospective studies.

Validation of an oncology-specific opioid risk calculator in cancer survivors.

BACKGROUND: Clinical guidelines recommend that providers risk-stratify patients with cancer before prescribing opioids. Prior research has demonstrated that a simple cancer opioid risk score might help identify to patients with cancer at the time of diagnosis with a high likelihood of long-term posttreatment opioid use. This current project validates this cancer opioid risk score in a generalizable, population-based cohort of elderly cancer survivors. METHODS: This study identified 44,932 Medicare beneficiaries with cancer who had received local therapy. Longitudinal opioid use was ascertained from Medicare Part D data. A risk score was calculated for each patient, and patients were categorized into low-, moderate-, and high-risk groups on the basis of the predicted probability of persistent opioid use. Model discrimination was assessed with receiver operating characteristic curves. RESULTS: In the study cohort, 5.2% of the patients were chronic opioid users 1 to 2 years after the initiation of cancer treatment. The majority of the patients (64%) were at low risk and had a 1.2% probability of long-term opioid use. Moderate-risk patients (33% of the cohort) had a 5.6% probability of long-term opioid use. High-risk patients (3.5% of the cohort) had a 75% probability of long-term opioid use. The opioid risk score had an area under the receiver operating characteristic curve of 0.869. CONCLUSIONS: This study found that a cancer opioid risk score could accurately identify individuals with a high likelihood of long-term opioid use in a large, generalizable cohort of cancer survivors. Future research should focus on the implementation of these scores into clinical practice and how this could affect prescriber behavior and patient outcomes. LAY SUMMARY: A novel 5-question clinical decision tool allows physicians treating patients with cancer to accurately predict which patients will persistently be using opioid medications after completing therapy.

Active surveillance for intermediate-risk prostate cancer in African American and non-Hispanic White men.

BACKGROUND: The safety of active surveillance (AS) for African American men compared with non-Hispanic White (White) men with intermediate-risk prostate cancer is unclear. METHODS: The authors identified patients with modified National Comprehensive Cancer Network favorable ("low-intermediate") and unfavorable ("high-intermediate") intermediate-risk prostate cancer diagnosed between 2001 and 2015 and initially managed with AS in the Veterans Health Administration database. They analyzed definitive treatment, disease progression, metastases, prostate cancer-specific mortality (PCSM), and all-cause mortality by using cumulative incidences and multivariable competing-risks (disease progression, metastasis, and PCSM) or Cox (all-cause mortality) regression. RESULTS: The cohort included 1007 men (African Americans, 330 [32.8%]; Whites, 677 [67.2%]) followed for a median of 7.7 years; 773 (76.8%) had low-intermediate-risk disease, and 234 (23.2%) had high-intermediate-risk disease. The 10-year cumulative incidences of definitive treatment were not significantly different (African Americans, 83.5%; 95% confidence interval [CI], 78.5%-88.7%; Whites, 80.6%; 95% CI, 76.6%-84.4%; P = .17). Among those with low-intermediate-risk disease, there were no significant differences in the 10-year cumulative incidences of disease progression (African Americans, 46.8%; 95% CI, 40.0%-53.3%; Whites, 46.9%; 95% CI, 42.1%-51.5%; P = .91), metastasis (African Americans, 7.1%; 95% CI, 3.7%-11.8%; Whites, 10.8%; 95% CI, 7.6%-14.6%; P = .17), or PCSM (African Americans, 3.8%; 95% CI, 1.6%-7.5%; Whites, 3.8%; 95% CI, 2.0%-6.3%; P = .69). In a multivariable regression including the entire cohort, African American race was not associated with increased risks of definitive treatment, disease progression, metastasis, PCSM, or all-cause mortality (all P > .30). CONCLUSIONS: Outcomes in the Veterans Affairs Health System were similar for African American and White men treated for low-intermediate-risk prostate cancer with AS.

BRCA testing and outcomes in women with breast cancer.

MAIN PURPOSE: Germline BRCA mutations (BRCAm) strongly influence the risk of developing breast cancer. This study aimed to understand the role of BRCAm testing in affected individuals and to assess its impact on the outcome of BRCAm carriers compared to non-carriers (BRCAwt) with breast cancer. RESEARCH QUESTION: The research question is "Does standard of care testing for BRCAm improve survival outcomes of breast cancer patients?" METHODS: In a single institution observational cohort study, demographic and clinical characteristics were compared between breast cancer patients with and without BRCAm. Frequency of BRCA testing was assessed. Survival outcomes were assessed by initial treatment setting stratified by BRCA status. RESULTS: Of 5712 identified women with breast cancer, 14.6% (n = 835) were tested for a BRCA mutation and had a documented result. The total number and proportion of women tested for a BRCAm increased between 2000 and 2014, resulting in an increased number of BRCAm carriers identified. However, the proportion of women who underwent testing and had a BRCAm decreased during the study period from 27.5% in 2000-2004 to 13.3% in 2010-2014. Disease-free survival was similar in the adjuvant and neoadjuvant treatment settings between BRCAm and BRCAwt patients. Progression-free survival on first line treatment and overall survival for patients with metastatic disease was also similar between BRCAm and BRCAwt patients. CONCLUSIONS: The proportion of women tested and the number of BRCAm identified increased during the study period despite a decreasing proportion of positive results among women tested.

Estimation of healthcare-related charges in women with BRCA mutations and breast cancer.

BACKGROUND: Breast cancer costs were estimated at $16.5 billion in 2010 and were higher than other cancer costs. There are limited studies on breast cancer charges and costs by BRCA mutations and receptor status. We examined overall health care and breast cancer-related charges by BRCA status (BRCAm vs. BRCAwt), receptor status (HER2+ vs. HER2-), and treatment setting (neoadjuvant vs. adjuvant). METHODS: Retrospective cohort study of charge data from 1995-2014 in an academic medical center. Facilities, physician, pharmacy, and diagnosis-related charges were presented as mean and median charges with standard deviation (SD) and interquartile ranges (25%-75%). Wilcoxon rank-sum test was used to assess statistically significant differences in charges between comparators. RESULTS: Total median breast-cancer related charges were $65,414 for BRCAm and $54,635 for BRCAwt (p=0.19); however all-cause charges were higher for BRCAm patients ($145,066 vs. $119,119, p<0.001). HER2+ status was associated with higher median breast cancer charges ($152,159 vs. $44,087, p<0.0001) that was driven by the charges for biological agents. Patients initially seen in the neoadjuvant setting had higher mean breast cancer charges than in the adjuvant setting ($117,922 vs. $80,061, p<0.0001). CONCLUSION: BRCA mutation status was not associated with higher breast cancer charges but HER2+ status had significantly higher charges, due to charges for biological agents. Patients who initially received neoadjuvant treatment had significantly higher overall treatment charges than adjuvant therapy patients. With the advent of novel therapies for BRCAm, the economic impact of these treatments will be important to consider relative to their survival benefits.

Survival of African American and non-Hispanic white men with prostate cancer in an equal-access health care system.

BACKGROUND: African American (AA) men in the general US population are more than twice as likely to die of prostate cancer (PC) compared with non-Hispanic white (NHW) men. The authors hypothesized that receiving care through the Veterans Affairs (VA) health system, an equal-access medical system, would attenuate this disparity. METHODS: A longitudinal, centralized database of >20 million veterans was used to assemble a cohort of 60,035 men (18,201 AA men [30.3%] and 41,834 NHW men [69.7%]) who were diagnosed with PC between 2000 and 2015. RESULTS: AA men were more likely to live in regions with a lower median income ($40,871 for AA men vs $48,125 for NHW men; P < .001) and lower high school graduation rates (83% for AA men vs 88% for NHW men; P < .001). At the time of diagnosis, AA men were younger (median age, 63.0 years vs 66.0 years; P < .001) and had a higher prostate-specific antigen level (median, 6.7 ng/mL vs 6.2 ng/mL; P < .001), but were less likely to have Gleason score 8 to 10 disease (18.8% among AA men vs 19.7% among NHW men; P < .001), a clinical T classification ≥3 (2.2% vs 2.9%; P < .001), or distant metastatic disease (2.7% vs 3.1%; P = 0.01). The 10-year PC-specific mortality rate was slightly lower for AA men (4.4% vs 5.1%; P = .005), which was confirmed in multivariable competing-risk analysis (subdistribution hazard ratio, 0.85; 95% CI, 0.78-0.93; P < .001). CONCLUSIONS: AA men diagnosed with PC in the VA health system do not appear to present with more advanced disease or experience worse outcomes compared with NHW men, in contrast to national trends, suggesting that access to care is an important determinant of racial equity.

Association Between African American Race and Clinical Outcomes in Men Treated for Low-Risk Prostate Cancer With Active Surveillance.

Importance: There is concern that African American men with low-risk prostate cancer may harbor more aggressive disease than non-Hispanic White men. Therefore, it is unclear whether active surveillance is a safe option for African American men. Objective: To compare clinical outcomes of African American and non-Hispanic White men with low-risk prostate cancer managed with active surveillance. Design, Setting, and Participants: Retrospective cohort study in the US Veterans Health Administration Health Care System of African American and non-Hispanic White men diagnosed with low-risk prostate cancer between January 1, 2001, and December 31, 2015, and managed with active surveillance. The date of final follow-up was March 31, 2020. Exposures: Active surveillance was defined as no definitive treatment within the first year of diagnosis and at least 1 additional surveillance biopsy. Main Outcomes and Measures: Progression to at least intermediate-risk, definitive treatment, metastasis, prostate cancer-specific mortality, and all-cause mortality. Results: The cohort included 8726 men, including 2280 African American men (26.1%) (median age, 63.2 years) and 6446 non-Hispanic White men (73.9%) (median age, 65.5 years), and the median follow-up was 7.6 years (interquartile range, 5.7-9.9; range, 0.2-19.2). Among African American men and non-Hispanic White men, respectively, the 10-year cumulative incidence of disease progression was 59.9% vs 48.3% (difference, 11.6% [95% CI, 9.2% to 13.9%); P < .001); of receipt of definitive treatment, 54.8% vs 41.4% (difference, 13.4% [95% CI, 11.0% to 15.7%]; P < .001); of metastasis, 1.5% vs 1.4% (difference, 0.1% [95% CI, -0.4% to 0.6%]; P = .49); of prostate cancer-specific mortality, 1.1% vs 1.0% (difference, 0.1% [95% CI, -0.4% to 0.6%]; P = .82); and of all-cause mortality, 22.4% vs 23.5% (difference, 1.1% [95% CI, -0.9% to 3.1%]; P = 0.09). Conclusions and Relevance: In this retrospective cohort study of men with low-risk prostate cancer followed up for a median of 7.6 years, African American men, compared with non-Hispanic White men, had a statistically significant increased 10-year cumulative incidence of disease progression and definitive treatment, but not metastasis or prostate cancer-specific mortality. Longer-term follow-up is needed to better assess the mortality risk.

Androgen deprivation therapy and depression in men with prostate cancer treated with definitive radiation therapy.

BACKGROUND: There is no consensus on the association between the use of androgen deprivation therapy (ADT) and the risk of developing depression. This study investigated the association between ADT use and the development of depression, outpatient psychiatric services, inpatient psychiatric services, and suicide in a homogeneous group of men with prostate cancer (PC) treated with definitive radiation therapy (RT) after controlling for multiple sources of selection bias. METHODS: This was a retrospective, observational cohort study of 39,965 veterans with PC who were treated with definitive RT and were diagnosed by the US Department of Veterans Affairs health care system between January 1, 2001, and October 31, 2015. Exposure was ADT initiation within 1 year of the PC diagnosis. The primary outcome was new development of depression. Secondary outcomes were outpatient psychiatric use, inpatient psychiatric use, and suicide. RESULTS: During follow-up, 934 patients were newly diagnosed with depression, 7825 patients used outpatient psychiatric services, 358 patients used inpatient psychiatric services, and 54 patients committed suicide. In the multivariable competing risks regression model, ADT was associated with the development of depression (subdistribution hazard ratio [SHR], 1.50; 95% confidence interval [CI], 1.32-1.71; P < .001). ADT was also associated with outpatient psychiatric utilization (SHR, 1.21; 95% CI, 1.16-1.27; P < .001). Finally, ADT was not associated with inpatient psychiatric utilization or suicide. CONCLUSIONS: An increase in the risk of depression and the use of outpatient psychiatric services was observed in a large cohort of men with PC who received ADT with definitive RT. These results may provide further evidence for the long-term risks of ADT for psychiatric health in the treatment of PC.

Epidemiology of Coccidioidomycosis in the Veterans Health Administration, 2013-2022.

We describe the epidemiology of coccidioidomycosis among a national cohort of Veterans. Using electronic health record data from adults tested for coccidioidomycosis between 1 January 2013 and 31 December 2022, we analyzed differences in baseline demographics (age, sex, race/ethnicity, birth country, comorbidities, residence, and Charlson Comorbidity Index score) between 4204 coccidioidomycosis-test-positive and 63,322 test-negative Veterans. Log-binomial regression models with adjusted risk ratios (aRRs) were used to evaluate risk factors associated with coccidioidomycosis including dissemination, hospitalization, and mortality. Case counts and incidence rates were highest in select counties in Arizona and California where Coccidioides is endemic. Coccidioidomycosis-positive Veterans were younger, more likely to be male, and Philippine-born. The risk factors most highly associated with being coccidioidomycosis-positive included Native Hawaiian/Pacific Islander (aRR 1.068 [95%CI: 1.039-1.098]), Asian (aRR 1.060 [95%CI: 1.037-1.083]), Black (aRR 1.029 [95%CI: 1.022-1.036]), American Indian/Alaska Native (aRR 1.026 [95%CI: 1.004-1.048]) race, and Hispanic/Latino ethnicity (aRR 1.021 [95%CI: 1.013-1.028]). Black race (aRR: 1.058 [95%CI: 1.037-1.081]) and Hispanic/Latino ethnicity (aRR 1.018 [95%CI: 1.0003-1.036]) were also associated with disseminated coccidioidomycosis, strengthening the evidence for the association of coccidioidomycosis, including severe infections, with specific racial and ethnic groups. There were no statistically significant differences in hospitalization within 45 days of testing or 30-day all-cause mortality. Improving our understanding of coccidioidomycosis risk factors is important for targeted prevention strategies and to reduce delays in diagnosis and ineffective treatment.

Androgen deprivation therapy and acute kidney injury in patients with prostate cancer undergoing definitive radiotherapy.

BACKGROUND: Androgen deprivation therapy (ADT) is frequently utilized in conjunction with radiotherapy (RT) in the definitive management of prostate cancer. Prior studies have suggested an association between ADT use and acute kidney injury (AKI), however, these included heterogeneous populations undergoing a variety of treatments and relied on billing codes to ascertain the incidence of AKI. METHODS: We analyzed a cohort of 27,868 veterans undergoing definitive RT + /- ADT for prostate cancer between 2001 and 2015 using the Veterans Affairs Informatics and Computing Infrastructure (VINCI). Exposure was defined as use of ADT within one year of diagnosis. The primary outcome was AKI, defined by an increase in serum creatinine to at least 1.5 times the baseline value. AKIs were classified as mild, moderate, or severe in accordance with international guidelines. A multivariate competing risks model was used to account for demographic and oncologic factors as well as medications and procedures known to influence the risk of AKI. RESULTS: Most (n = 18,754) men received RT alone; 9,114 men received RT + ADT. The incidence of AKI at two years after diagnosis was 10.5% in the RT + ADT group and 7.9% in the RT group (Gray's test p < 0.01). Multivariate analysis confirmed ADT usage was associated with an increased risk for any AKI (SHR = 1.24, 95% CI = 1.14-1.36, p < 0.01). ADT was also associated with an increased risk of mild AKI (SHR = 1.13, 95% CI = 1.01-1.27, p = 0.04) and moderate AKI (SHR = 1.45, 95% CI = 1.20-1.76, p < 0.01), though not severe AKI (SHR = 1.33, 95% CI = 0.93-1.91, p = 0.11). CONCLUSIONS: Our findings confirm that use of ADT is associated with an increased risk of AKI in patients undergoing definitive RT for prostate cancer. Clinicians should be alert to the potential for renal dysfunction in this population.

Polygenic risk of any, metastatic, and fatal prostate cancer in the Million Veteran Program.

BACKGROUND: Genetic scores may provide an objective measure of prostate cancer risk and thus inform screening decisions. We evaluated whether a polygenic hazard score based on 290 genetic variants (PHS290) is associated with prostate cancer risk in a diverse population, including Black men, who have higher average risk of prostate cancer death but are often treated as a homogeneously high-risk group. METHODS: This was a retrospective analysis of the Million Veteran Program, a national, population-based cohort study of US military veterans conducted 2011-2021. Cox proportional hazards analyses tested for association of genetic and other risk factors (including self-reported race and ethnicity and family history) with age at death from prostate cancer, age at diagnosis of metastatic (nodal or distant) prostate cancer, and age at diagnosis of any prostate cancer. RESULTS: A total of 590 750 male participants were included. Median age at last follow-up was 69 years. PHS290 was associated with fatal prostate cancer in the full cohort and for each racial and ethnic group (P < .001). Comparing men in the highest 20% of PHS290 with those in the lowest 20% (based on percentiles from an independent training cohort), the hazard ratio for fatal prostate cancer was 4.42 (95% confidence interval = 3.91 to 5.02). When accounting for guideline-recommended risk factors (family history, race, and ethnicity), PHS290 remained a strong independent predictor of any, metastatic, and fatal prostate cancer. CONCLUSIONS: PHS290 stratified US veterans of diverse ancestry for lifetime risk of prostate cancer, including metastatic and fatal cancer. Predicting genetic risk of lethal prostate cancer with PHS290 might inform individualized decisions about prostate cancer screening.

Incidence of stroke in the first year after diagnosis of cancer-A systematic review and meta-analysis.

Background: Patients newly diagnosed with cancer represent a population at highest risk for stroke. The objective of this systematic review and meta-analysis was to estimate the incidence of stroke in the first year following a new diagnosis of cancer. Methods: We searched MEDLINE and EMBASE from January 1980 to June 2021 for observational studies that enrolled adults with a new diagnosis of all cancers excluding non-melanoma skin cancer, and that reported the incidence of stroke at 1 year. PRISMA guidelines for meta-analyses were followed. Two reviewers independently extracted data and appraised risk of bias. We used the Dersimonian and Laird random effects method to pool cumulative incidences after logit transformation, and reported pooled proportions as percentages. Statistical heterogeneity was assessed using the I 2 statistic. Results: A total of 12,083 studies were screened; 41 studies were included for analysis. Data from 2,552,121 subjects with cancer were analyzed. The cumulative incidence of total stroke at 1 year was 1.4% (95% CI 0.9-2.2%), while the pooled incidence of ischemic stroke was 1.3% (95% CI 1.0-1.8%) and 0.3% (95% CI 0.1-0.9%) for spontaneous intracerebral hemorrhage (ICH), with consistently high statistical heterogeneity (>99% I 2). Conclusion: The estimated incidence of stroke during the first year after a new diagnosis of cancer is 1.4%, with a higher risk for ischemic stroke than ICH. Cancer patients should be educated on the risk of stroke at the time of diagnosis. Future studies should evaluate optimal primary prevention strategies in this high-risk group of patients. Systematic review registration: https://osf.io/ucwy9/.

Association of Prostate-Specific Antigen Velocity With Clinical Progression Among African American and Non-Hispanic White Men Treated for Low-Risk Prostate Cancer With Active Surveillance.

Importance: The association of prostate-specific antigen velocity (PSAV) with clinical progression in patients with localized prostate cancer managed with active surveillance remains unclear and, to our knowledge, has not been studied in African American patients. Objectives: To test the hypothesis that PSAV is associated with clinical progression in patients with low-risk prostate cancer treated with active surveillance and to identify differences between African American and non-Hispanic White patients. Design, Setting, and Participants: This was a retrospective population-based cohort study using patient records from the Veterans Heath Administration Informatics and Computing Infrastructure on 5296 patients with a diagnosis of localized prostate cancer from January 1, 2001, to December 31, 2015, who were managed with active surveillance. Follow-up extended through March 31, 2020. Low-risk prostate cancer was defined as International Society of Urologic Pathology grade group (GG) 1 clinical tumor stage 2A or lower, PSA level of 10 ng/dL or lower, active surveillance, and no definitive treatment within the first year after diagnosis with at least 1 additional staging biopsy after diagnostic biopsy. Exposures: Prostate-specific antigen testing. Main Outcomes and Measures: The primary outcome was GG progression detected after repeated biopsy or prostatectomy, defined as GG2 or higher or GG3 or higher. The secondary outcome was incident metastases. Cumulative incidence functions and multivariable Cox proportional hazards regression models were used to test associations between PSAV and outcomes. Results: The final cohort (n = 5296) included 3919 non-Hispanic White men (74.0%; mean [SD] age, 65.7 [5.8] years) and 1377 African American men (26.0%; mean [SD] age, 62.8 [6.6] years). Compared with African American patients, non-Hispanic White patients were older (mean [SD] age, 65.7 [5.8] years vs 62.8 [6.6] years; P < .001), presented with higher cT stage (stage T2, 608 [15.5%] vs 111 [8.1%]; P < .001), had a higher Charlson Comorbidity Index score (1 and ≥2, 912 [23.3%] vs 273 [19.8%]; P = .002), had higher median income ($60 000 to ≥$100 000, 1223 [31.2%] vs 282 [20.5%]; P < .001), and had a higher median level of education (20% to ≥30% with college degree, 1192 [30.4%] vs 333 [24.2%]; P < .001). Progression to GG2 or higher occurred in 2062 patients (38.9%), with a cumulative incidence of 43.2%, and progression to GG3 or higher occurred in 728 patients (13.7%). Fifty-four patients (1.0%) developed metastases. On multivariable analysis, PSAV was significantly associated with progression to GG2 (hazard ratio, 1.32 [95% CI, 1.26-1.39]), GG3 (hazard ratio, 1.51 [95% CI, 1.41-1.62]), and metastases (hazard ratio, 1.38 [95% CI, 1.10-1.74]). Optimal PSAV thresholds that were associated with progression were significantly lower for African American patients (0.44 ng/mL/y) compared with non-Hispanic White patients (1.18 ng/mL/y). Conclusions and Relevance: This study suggests that PSAV is significantly associated with grade progression among patients with low-risk prostate cancer managed with active surveillance, but at lower values for African American patients compared with non-Hispanic White patients. These data suggest that serial PSA measures may potentially substitute for multiple prostate biopsies and that African American patients may merit increased frequency of PSA testing.

Predicting Persistent Opioid Use, Abuse, and Toxicity Among Cancer Survivors.

BACKGROUND: Although opioids play a critical role in the management of cancer pain, the ongoing opioid epidemic has raised concerns regarding their persistent use and abuse. We lack data-driven tools in oncology to understand the risk of adverse opioid-related outcomes. This project seeks to identify clinical risk factors and create a risk score to help identify patients at risk of persistent opioid use and abuse. METHODS: Within a cohort of 106 732 military veteran cancer survivors diagnosed between 2000 and 2015, we determined rates of persistent posttreatment opioid use, diagnoses of opioid abuse or dependence, and admissions for opioid toxicity. A multivariable logistic regression model was used to identify patient, cancer, and treatment risk factors associated with adverse opioid-related outcomes. Predictive risk models were developed and validated using a least absolute shrinkage and selection operator regression technique. RESULTS: The rate of persistent opioid use in cancer survivors was 8.3% (95% CI = 8.1% to 8.4%); the rate of opioid abuse or dependence was 2.9% (95% CI = 2.8% to 3.0%); and the rate of opioid-related admissions was 2.1% (95% CI = 2.0% to 2.2%). On multivariable analysis, several patient, demographic, and cancer and treatment factors were associated with risk of persistent opioid use. Predictive models showed a high level of discrimination when identifying individuals at risk of adverse opioid-related outcomes including persistent opioid use (area under the curve [AUC] = 0.85), future diagnoses of opioid abuse or dependence (AUC = 0.87), and admission for opioid abuse or toxicity (AUC = 0.78). CONCLUSION: This study demonstrates the potential to predict adverse opioid-related outcomes among cancer survivors. With further validation, personalized risk-stratification approaches could guide management when prescribing opioids in cancer patients.

African-American men with low-risk prostate cancer treated with radical prostatectomy in an equal-access health care system: implications for active surveillance.

BACKGROUND: There is concern that African-American men (AA) with low-risk prostate cancer may present with more aggressive disease and thus may not be candidates for active surveillance (AS). However, it is uncertain if poorer outcomes are due to disparities in access to medical care rather than true biological differences. METHODS: Observational cohort study of patients diagnosed with low-risk PC-Gleason score ≤6, clinical tumor stage ≤2A, and prostate specific antigen (PSA) level ≤10-at US Department of Veterans Affairs between January 1, 2001 and October 31, 2015 and treated with radical prostatectomy. Outcomes included upgrading to Gleason Grade Group 2 (GG2), GG ≥ 3, PSA recurrence, pathologic tumor stage ≥3, positive surgical margins, and all-cause mortality. RESULTS: A total of 2857 men (AA: 835 White: 2022) with a median follow-up of 7.1 years. Overall, there was no significant difference between AA and White men in upgrading to GG ≥ 3 (RR = 1.18, p = 0.43), tumor stage ≥3 (RR = 0.95, p = 0.74), positive surgical margins (RR = 1.14, p = 0.20), PSA recurrence (SHR = 1.26, p = 0.06), and all-cause mortality (SHR = 1.26, p = 0.16). However, there was a significant increase in upgrading for AA to GG2 (RR = 1.49, p < 0.01). CONCLUSIONS: There was no significant difference in most adverse pathologic outcomes between AA and White patients. However, GG2 upgrading was more common in AA men. The implication is that AA may need to undergo additional evaluation, such as a biopsy MRI, before initiating AS. Whether the increase in GG2 upgrading will lead to poorer long-term clinical outcomes such as metastasis and PCSM also requires further investigation.

Testosterone therapy does not increase the risks of prostate cancer recurrence or death after definitive treatment for localized disease.

BACKGROUND: The safety of testosterone therapy (TT) after definitive treatment for localized prostate cancer remains undefined. We analyzed the risks of biochemical recurrence and mortality in men receiving TT after treatment for localized prostate cancer. METHODS: Cohort analysis using the national US Veterans Affairs Informatics and Computing Infrastructure. We identified 69,984 patients with localized prostate cancer diagnosed from 2001 to 2015 treated with surgery or radiation. We coded receipt of TT after treatment as a time-dependent covariate; used the National Death Index to identify cause of death; and defined biochemical recurrence as PSA > 0.2 ng/mL after surgery and nadir + 2 ng/mL after radiation. We analyzed recurrence and mortality using cumulative incidence curves, Fine-Gray competing risk regression, and Cox regression. RESULTS: This cohort included 28,651 surgery patients and 41,333 radiation patients, of whom 469 (1.64%) and 543 (1.31%), respectively, received TT with a median follow-up of 6.95 years. Comparing testosterone users to nonusers, there were no between-group differences in biochemical recurrence, prostate cancer-specific mortality, or overall mortality after surgery [hazard ratios (HR): 1.07; HR: 0.72 (p = 0.43); and HR: 1.11 (p = 0.43), respectively] or radiation [HR: 1.07; HR: 1.02 (p = 0.95); and HR: 1.02 (p = 0.86), respectively]. Limitations included lack of detailed data on TT duration and serum testosterone concentrations. CONCLUSIONS: In this multi-ethnic national cohort, TT did not increase the risks of biochemical recurrence or prostate cancer-specific or overall mortality after surgery or radiation. These data suggest that TT is safe in appropriate men after definitive treatment of localized prostate cancer.

Stroke and thromboembolic events in men with prostate cancer treated with definitive radiation therapy with or without androgen deprivation therapy.

BACKGROUND: There is conflicting evidence regarding the association between androgen deprivation therapy (ADT) for prostate cancer (PC) and the risk of developing stroke and thromboembolic events. Our study evaluated the association between ADT use and development of stroke, transient ischemic attack (TIA), deep vein thrombosis (DVT), and pulmonary embolism (PE) in a homogenous group of men with PC treated with definitive radiation therapy (RT) after controlling for multiple sources of confounding. METHODS: Observational cohort study of patients diagnosed with PC at the US Department of Veterans Affairs between 1 January 2001 and October 31, 2015 and treated with definitive RT. Exposure was initiation of ADT within 1 year of PC diagnosis. Primary outcomes were development of stroke, TIA, DVT, or PE. RESULTS: 44,246 men with median follow-up of 6.8 years. The overall cumulative incidences of stroke, TIA, DVT, and PE at 10 years were 6.0, 3.0, 3.4, and 1.9%, respectively. In the multivariable competing risks model, there was a significant association between ADT and stroke (subdistribution hazard ratio (SHR) = 1.19, 95% CI = 1.09-1.30, p < 0.01), TIA (SHR = 1.24, 95% CI = 1.08-1.41, p < 0.01), and DVT (SHR = 1.18, 95% CI = 1.04-1.34, p < 0.01). ADT was only associated with PE in men receiving ADT for > 1 year (SHR = 1.34, 95% CI = 1.06-1.69, p-value = 0.03). CONCLUSION: We observed an increase in the risk of stroke, TIA, and DVT in men receiving ADT and an increased risk of PE in men receiving long-term ADT. These results highlight concerns regarding long-term risks of ADT on stroke and thromboembolic events in the treatment of PC.

Benzodiazepines, Health Care Utilization, and Suicidal Behavior in Veterans With Posttraumatic Stress Disorder.

OBJECTIVE: To evaluate the relationships between benzodiazepine use and (1) health care utilization and (2) suicide risk in veterans diagnosed with posttraumatic stress disorder (PTSD). METHODS: This propensity-matched retrospective cohort study included veterans diagnosed with 1 ICD-9 code for PTSD who were active users of the Veterans Affairs health care system between January 1, 2001, and December 31, 2014. Exposure included at least 1 thirty-day prescription of a benzodiazepine within 1 year following PTSD diagnosis among patients with no recent history of benzodiazepine use. The primary outcomes were health care utilization and suicidal behavior. RESULTS: A total of 242,493 of 1,134,201 eligible veterans were included in the propensity-matched cohort, 80,831 (7.13%) of whom were prescribed benzodiazepines. Veterans with PTSD who received benzodiazepines had significantly more hospitalizations (incident rate ratio [IRR] = 1.27; 95% CI, 1.10-1.47) and emergency department (IRR = 1.16; 95% CI, 1.13-1.20), general outpatient (IRR = 1.19; 95% CI, 1.16-1.21), outpatient mental health (IRR = 1.49; 95% CI, 1.41-1.57), and total mental health (IRR = 1.37; 95% CI, 1.34-1.40) visits. Benzodiazepine users had a significantly greater risk of death due to suicide (hazard ratio [HR] = 2.74; 95% CI, 2.40-3.13) and were significantly more likely to have medically documented suicide attempts (HR = 1.85; 95% CI, 1.65-2.08) and suicidal ideation (HR = 1.57; 95% CI, 1.48-1.67). CONCLUSIONS: Benzodiazepine users had higher rates of health care utilization and were more likely to attempt and complete suicide than patients without benzodiazepine exposure. This study strengthens the empirical evidence against the use of benzodiazepines in veterans with PTSD. Prescribers should weigh the benefits and risks-especially the almost 3-fold increase in suicide risk-when prescribing benzodiazepines in these patients.

Outcomes When Using Adjunct Dexmedetomidine with Propofol Sedation in Mechanically Ventilated Surgical Intensive Care Patients.

Objective: Compare the duration of mechanical ventilation between patients receiving sedation with continuous infusions of propofol alone or combination with the use of dexmedetomidine and propofol. Design: Retrospective, propensity matched (1:1) cohort study, employing eight variables chosen a priori for matching. Timing of exposure to dexmedetomidine initiation was incorporated into a matching algorithm. Setting: Level 1, university-based, 32-bed, adult, mixed trauma and surgical intensive care unit (SICU). Continuous sedation was delivered according to a protocol methodology with daily sedation vacation and spontaneous breathing trials. Choice of sedation agent was physician directed. Patients: Between 2010 and 2014, 149 SICU patients receiving mechanical ventilation for >24 h received dexmedetomidine with propofol. Propensity matching resulted in 143 pair cohorts. Interventions: Dexmedetomidine with propofol or propofol alone. Measurements and Main Results: There was no statistical difference in SICU length of stay (LOS), with a median absolute difference of 5.3 h for propofol alone group (p = 0.43). The SICU mortality was not statistically different (RR = 1.002, p = 0.88). Examining a 14-day period post-treatment with dexmedetomidine, on any given day (excluding days 1 and 14), dexmedetomidine with propofol-treated patients had a 0.5% to 22.5% greater likelihood of being delirious (CAM-ICU positive). In addition, dexmedetomidine with propofol-treated patients had a 4.5% to 18.8% higher likelihood of being above the target sedation score (more agitated) compared to propofol-alone patients. Conclusions: In this propensity matched cohort study, adjunct use of dexmedetomidine to propofol did not show a statistically significant reduction with respect to mechanical ventilation (MV) duration, SICU LOS, or SICU mortality, despite a trend toward receiving fewer hours of propofol. There was no evidence that dexmedetomidine with propofol improved sedation scores or reduced delirium.

Pharmacokinetics of Continuous Infusion Beta-lactams in the Treatment of Acute Pulmonary Exacerbations in Adult Patients With Cystic Fibrosis.

BACKGROUND: Several clinical trials have shown the efficacy of continuous infusion beta-lactam (BL) antibiotics in patients with cystic fibrosis (CF); however, little is known about pharmacokinetic changes during the treatment of an acute pulmonary exacerbation (APE). Identifying and understanding these changes may assist in optimizing antibiotic dosing during APE treatment. METHODS: This study was a retrospective cohort study of 162 adult patients with CF admitted to the University of Utah Hospital between January 1, 2008, and May 15, 2014, for treatment of an APE with both a continuous infusion BL and IV tobramycin. We extracted the administered doses of continuous infusion BLs and tobramycin along with serum drug concentrations and calculated medication clearance rates. The primary outcome was change in clearance rates of continuous infusion BLs between day 2 and day 7 of APE treatment. RESULTS: The BL clearance rate increased 20.7% (95% CI, 11.42 to 32.49; P < .001), whereas the tobramycin clearance rate decreased 6.3% (95% CI, -12.29 to -4.45; P < .001). The mean percent predicted FEV1 increased between admission and discharge by 12.2% (95% CI, -13.81 to -10.55; P < .001). CONCLUSIONS: Clinicians should monitor BL levels along with aminoglycoside levels and make dose adjustments to maximize the chance of optimal antibiotic treatment. Continuous infusion BL and tobramycin clearance can change dramatically during the treatment of an APE, which may necessitate significant changes in dosing to achieve optimal antibiotic levels. Clearance rates of these antibiotics may change in opposite directions, requiring specific monitoring of each medication.