0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Review |

Association of Androgen Deprivation Therapy With Cardiovascular Death in Patients With Prostate Cancer:  A Meta-analysis of Randomized Trials FREE

Paul L. Nguyen, MD; Youjin Je, MS; Fabio A. B. Schutz, MD; Karen E. Hoffman, MD, MPH, MHSc; Jim C. Hu, MD, MPH; Arti Parekh, BA; Joshua A. Beckman, MD, MSc; Toni K. Choueiri, MD
[+] Author Affiliations

Author Affiliations: Department of Radiation Oncology (Dr Nguyen) and Lank Center for Genitourinary Oncology (Drs Schutz and Choueiri), Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Harvard School of Public Health, Boston, Massachusetts (Ms Je); Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston (Dr Hoffman); Center for Surgery and Public Health and Divisions of Urology (Dr Hu) and Cardiovascular Medicine (Dr Beckman), Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and Boston University School of Medicine, Boston, Massachusetts (Ms Parekh).


JAMA. 2011;306(21):2359-2366. doi:10.1001/jama.2011.1745.
Text Size: A A A
Published online

Context Whether androgen deprivation therapy (ADT) causes excess cardiovascular deaths in men with prostate cancer is highly controversial and was the subject of a joint statement by multiple medical societies and a US Food and Drug Administration safety warning.

Objective To perform a systematic review and meta-analysis of randomized trials to determine whether ADT is associated with cardiovascular mortality, prostate cancer–specific mortality (PCSM), and all-cause mortality in men with unfavorable-risk, nonmetastatic prostate cancer.

Data Sources A search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials databases for relevant randomized controlled trials in English between January 1, 1966, and April 11, 2011.

Study Selection Inclusion required nonmetastatic disease, intervention group with gonadotropin-releasing hormone agonist–based ADT, control group with no immediate ADT, complete information on cardiovascular deaths, and median follow-up of more than 1 year.

Data Extraction Extraction was by 2 independent reviewers. Summary incidence, relative risk (RR), and CIs were calculated using random-effects or fixed-effects models.

Results Among 4141 patients from 8 randomized trials, cardiovascular death in patients receiving ADT vs control was not significantly different (255/2200 vs 252/1941 events; incidence, 11.0%; 95% CI, 8.3%-14.5%; vs 11.2%; 95% CI, 8.3%-15.0%; RR, 0.93; 95% CI, 0.79-1.10; P = .41). ADT was not associated with excess cardiovascular death in trials of at least 3 years (long duration) of ADT (11.5%; 95% CI, 8.1%-16.0%; vs 11.5%; 95% CI, 7.5%-17.3%; RR, 0.91; 95% CI, 0.75-1.10; P = .34) or in trials of 6 months or less (short duration) of ADT (10.5%; 95% CI, 6.3%-17.0%; vs 10.3%; 95% CI, 8.2%-13.0%; RR, 1.00; 95% CI, 0.73-1.37; P = .99). Among 4805 patients from 11 trials with overall death data, ADT was associated with lower PCSM (443/2527 vs 552/2278 events; 13.5%; 95% CI, 8.8%-20.3%; vs 22.1%; 95% CI, 15.1%-31.1%; RR, 0.69; 95% CI, 0.56-0.84; P < .001) and lower all-cause mortality (1140/2527 vs 1213/2278 events; 37.7%; 95% CI, 27.3%-49.4%; vs 44.4%; 95% CI, 32.5%-57.0%; RR, 0.86; 95% CI, 0.80-0.93; P < .001).

Conclusion In a pooled analysis of randomized trials in unfavorable-risk prostate cancer, ADT use was not associated with an increased risk of cardiovascular death but was associated with a lower risk of PCSM and all-cause mortality.

Figures in this Article

Androgen deprivation therapy (ADT) in the form of a gonadotropin-releasing hormone (GnRH) agonist is a mainstay of prostate cancer treatment, but several studies have suggested that ADT may increase a patient's risk of dying from cardiovascular causes.

In 2006, Keating et al1 found that GnRH agonist use was associated with a 44% increased risk of incident diabetes, 16% increase in coronary heart disease, 11% increase in myocardial infarction (MI), and 16% increase in sudden cardiac death in the national Surveillance, Epidemiology, and End Results–Medicare database. In 2007, Tsai et al2 found that ADT was associated with a 2.6-times increase in cardiovascular death among men receiving radical prostatectomy in the CAPSURE database. In addition, D’Amico et al3 reanalyzed data from 2 randomized trials and found that ADT use was associated with a shorter time to fatal MI in a subgroup of men older than 65 years. On the basis of these and other studies,4 the American Heart Association, the American Cancer Society, the American Urological Association, and the American Society for Radiation Oncology issued a joint scientific report to raise awareness of the potential linkage between ADT and cardiovascular events and stated “at this point, it is reasonable, on the basis of the above data, to state that there may be a relation between ADT and cardiovascular events and death.”5 Similarly, the US Food and Drug Administration issued a safety warning on October 20, 2010, requiring labeling on GnRH agonists warning about an “increased risk of diabetes and certain cardiovascular diseases (heart attack, sudden cardiac death, stroke) in men receiving these medications for the treatment of prostate cancer.”6

However, other studies have not confirmed these findings79 and, due to the significant controversy and clinical concern over this issue, we performed an up-to-date meta-analysis of randomized controlled trials to determine whether ADT is associated with cardiovascular mortality, prostate cancer–specific mortality (PCSM), and all-cause mortality in men with unfavorable-risk, nonmetastatic prostate cancer.

Selection of Studies

We reviewed MEDLINE and EMBASE citations between January 1, 1966, and April 11, 2011, and the Cochrane Central Register of Controlled Trials database through April 11, 2011. The search terms used were prostate cancer and (androgen deprivation or androgen suppression or hormone or gonadotropin), with the results limited to randomized controlled trials in the English language. We included only trials focused on patients with nonmetastatic and non−hormone-refractory disease and that had an intervention group with immediate ADT and a control group of patients receiving no immediate ADT. For inclusion in our study, the trial had to predominantly use a GnRH agonist, have adequate information on cardiovascular deaths, and have a median follow-up of at least 1 year. We required a GnRH agonist because the large observational study by Keating et al1 found an excess risk of coronary heart disease, MI, and sudden cardiac death among men who received GnRH agonists but not those who received orchiectomy, and because orchiectomy is much less commonly used in modern practice. When more than 1 publication was identified from the same clinical trial, we used the most recent or complete report of that trial. Quality of the trials was assessed using the Jadad/Oxford quality scoring system.10 For analysis of PCSM and all-cause mortality, we required trials to report those 2 end points but did not require that they report cardiovascular mortality.

Data Extraction and Clinical End Points

Data abstraction was conducted independently by 2 investigators (P.L.N. and A.P.) according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement11 and any discrepancies between reviewers were resolved by consensus. For each study, we extracted the following information: first author's name, year of publication, median age of patients, number of enrolled patients, inclusion criteria, treatment groups, type of ADT, duration of ADT, number of cardiovascular deaths in ADT and control groups, definition of cardiovascular death, median follow-up, number of PCSM deaths, and number of overall deaths. The definition of cardiovascular death was accepted as defined by the study authors. If it was not specifically defined in the study, then we included events broadly related to cardiac disease and vascular disease. Definitions of cardiovascular disease for each included study are shown in the Table, alongside the study information.3,8,9,1219

Table Graphic Jump LocationTable. Baseline Characteristics and Number of CV Deaths for the Selected Trials of ADT in Nonmetastatic Prostate Cancer
Statistical Analysis

For the calculation of incidence, the number of patients with cardiovascular death and the number of patients who were treated with ADT or placebo were extracted from the individual selected clinical trials. The proportion of patients with those adverse outcomes and 95% CIs were derived from each trial. We also calculated relative risks (RRs) and 95% CIs of cardiovascular death in patients assigned to ADT vs controls in the same trial. To calculate 95% CIs, the variance of a log-transformed study-specific RR was derived using the δ method. For studies reporting zero events in a treatment or control group, we applied a classic half-integer continuity correction to calculate RR and variance. We then repeated this for the end points of PCSM and all-cause mortality.

Statistical heterogeneity among trials included in the meta-analysis was assessed by using the Cochran Q statistic, and inconsistency was quantified with the I2 statistic [100% × (Q − df)/Q], which estimates the percentage of total variation across studies due to heterogeneity rather than chance.20 The assumption of homogeneity was considered invalid for P < .10. Summary incidence and RRs were calculated using random-effects or fixed-effects models depending on the heterogeneity of included studies. When substantial heterogeneity was not observed, the summary estimate calculated on the basis of the fixed-effects model was reported by using the inverse variance method. When substantial heterogeneity was observed, the summary estimate calculated on the basis of the random-effects model was reported by using the DerSimonian and Laird method that considers both within-study and between-study variations.21 For studies with separate treatment groups evaluating varying durations of ADT, we combined the 2 ADT groups for the overall analysis.

To determine the RR of cardiovascular death due to ADT within particular groups, we performed subgroup analyses on trials of short course (ADT for ≤6 months) or long course (ADT for ≥3 years), trials with median age of younger than 70 years or 70 years or older, and trials in which radiation was used. To further test for variation in the RR of cardiovascular death due to ADT by duration of ADT or median age of patients, we conducted a meta-regression analysis by modeling a log-transformed study-specific RR as a dependent variable and duration of ADT (≤6 months or ≥3 years) or median age (<70 or ≥70 years) as an independent variable. In addition, publication bias was evaluated through funnel plots (ie, plots of study results against precision) and with the Begg and Egger tests. Two-tailed P < .05 was considered statistically significant. All statistical analyses were performed by using Stata/SE version 12.0 software (Stata Corp).

Selection of Trials

Our initial search yielded 1041 studies (268 from MEDLINE, 211 from EMBASE, and 562 from the Cochrane Central Register of Controlled Trials). After removing 386 duplicate studies, we evaluated the abstracts of 655 studies. After evaluating the abstract of each study, 637 studies were excluded because they did not meet inclusion criteria. Subsequently, we carefully read the full text of each of the remaining 18 trials and excluded 1 trial for having a follow-up of less than 1 year (n = 167 patients)22 and 6 trials (n = 1105 patients)2228 for no mention of mortality outcomes, which resulted in 11 trials with 4805 patients for PCSM and all-cause mortality end points.3,8,9,1219 Three of these trials (n = 664 patients)1719 had no information on cardiovascular deaths; therefore, the remaining 8 trials (n = 4141 patients) were ultimately selected for inclusion in the cardiovascular death meta-analysis.3,8,9,1216 Median follow-up in these 8 included trials ranged between 7.6 and 13.2 years. A detailed selection process is shown in Figure 1.

Place holder to copy figure label and caption
Figure 1. Article Selection
Graphic Jump Location

ADT indicates androgen deprivation therapy; GnRH, gonadotropin-releasing hormone.

The baseline characteristics of each trial are shown in the Table. All selected trials included patients with nonmetastatic disease who were treated with immediate predominantly GnRH-agonist–based ADT vs no immediate ADT. Local therapy consisted of external beam radiation (5 trials), surgery (4 trials), or no local therapy (2 trials). Three trials included a substantial proportion of patients with lymph node involvement. The duration of ADT varied from 3 months to lifelong.

Quality of the Studies and Publication Bias

All trials included in the meta-analysis were randomized, multicenter, phase 3 trials. All of the trials were open label and have all been published in full manuscript form. The Jadad/Oxford quality scales require a double-blinded placebo for 2 of the 5 points. Because this would have required sham injections, none of the 11 trials included a double-blinded placebo; therefore, their maximum score was 3 out of 5 points (7 trials), and 4 trials scored 2 out of 5 points.10 No evidence of publication bias was detected for RR of cardiovascular death by either Begg test (P = .54) or Egger test (P = .11), or for the RR of PCSM (Begg test, P = .53; Egger test, P = .24), or for the RR of all-cause mortality (Begg test, P = .76; Egger test, P = .72).

Incidence and RR of Cardiovascular Death

Among the 2200 patients who were treated with ADT, there were 255 cardiovascular deaths. The overall incidence of cardiovascular death was 11.0% (95% CI, 8.3%-14.5%) in the ADT group (heterogeneity test: Q = 33.58; P < .001; I2 = 79.2%). For the control group, there were 1941 patients and 252 cardiovascular deaths, for an overall incidence of 11.2% (95% CI, 8.3%-15.0%; heterogeneity test: Q = 33.81; P < .001; I2 = 79.3%). The corresponding RR of cardiovascular death for ADT vs control was not significant (RR, 0.93; 95% CI, 0.79-1.10; P = .41). No significant heterogeneity was observed in the RR analysis of cardiovascular death (heterogeneity test: Q = 5.12; P = .64; I2 = 0%). Results of individual trials are shown in Figure 2.

Place holder to copy figure label and caption
Figure 2. Relative Risk of Cardiovascular Deaths Associated With ADT Among Patients With Prostate Cancer
Graphic Jump Location

ADT indicates androgen deprivation therapy. The summary relative risk of cardiovascular deaths was calculated using a fixed-effects model. The size of the squares indicates the weight of the study, which is the inverse variance of the effect estimate. The diamond indicates the summary relative risk.

Variation of Association by Duration of ADT

Three trials (DFCI 95-096,3 TROG 96.01,16 and RTOG 86-109) with 1464 patients used ADT for 6 months or less (range, 3-6 months), and 5 trials (EORTC 22863,13 RTOG 85-31,8 EORTC 30891,15 EORTC 30846,14 and ECOG/EST 388612) with 2667 patients used ADT for at least 3 years (range, 3 years to lifelong). Among patients in short-course ADT trials, the incidence of fatal cardiovascular events for ADT vs control was 10.5% (95% CI, 6.3%-17.0%) vs 10.3% (95% CI, 8.2%-13.0%), respectively, and the RR of cardiovascular death was 1.00 (95% CI, 0.73-1.37; P = .99). Among patients in long-course ADT trials, the incidence of fatal cardiovascular events for ADT vs control was 11.5% (95% CI, 8.1%-16.0%) vs 11.5% (95% CI, 7.5%-17.3%), respectively, and the RR of cardiovascular death was 0.91 (95% CI, 0.75-1.10; P = .34). When comparing the RRs of cardiovascular death due to ADT among long-course trials with short-course trials, we did not observe a statistically significant difference (P = .63).

Variation of Association by Median Age in Study

Among the 5 trials with a median age of 70 years or older (DFCI 95-096,3 RTOG 85-31,8 RTOG 86-10,9 EORTC 22863,13 and EORTC 3089115), there was no association between ADT and cardiovascular death (13.3%; 95% CI, 10.4%-16.7%; vs 13.1%; 95% CI, 9.6%-17.6%; RR for ADT vs no ADT, 0.95; 95% CI, 0.79-1.13; P = .53; test for heterogeneity: Q = 3.49; P = .48; I2 = 0%). Among the 3 trials with a median age of younger than 70 years (TROG 96.01,16 ECOG/EST 3886,12 and EORTC 3084614), there was also no evidence of an association between ADT and cardiovascular death (7.1%; 95% CI, 5.4%-9.2%; vs 8.2%; 95% CI, 5.9%-11.3%; RR, 0.88; 95% CI, 0.58-1.34; P = .55; test for heterogeneity: Q = 1.53; P = .46; I2 = 0%). When comparing the RRs of cardiovascular death due to ADT among trials with median age of younger than 70 years vs 70 years or older, we did not observe a statistically significant difference (P = .77).

Findings in Patients Who Received Radiation Therapy

When analysis was limited to the 5 trials in which definitive radiation was used (DFCI 95-096,3 TROG 96.01,16 RTOG 85-31,8 RTOG 86-10,9 and EORTC 2286313), there was also no evidence of excess cardiovascular death due to ADT (10.5%; 95% CI, 8.1%-13.6%; vs 11.5%; 95% CI, 9.8%-13.3%; RR, 0.94; 95% CI, 0.76-1.17; P = .57; test for heterogeneity: Q = 3.87; P = .42; I2 = 0%).

Association of ADT With PCSM

There were 443 PCSM deaths among 2527 patients in the ADT group and 552 PCSM deaths among 2278 patients in the control group. The incidence of PCSM among men receiving ADT vs control was 13.5% (95% CI, 8.8%-20.3%) vs 22.1% (95% CI, 15.1%-31.1%). The RR was 0.69 (95% CI, 0.56-0.84; P < .001; heterogeneity test: Q = 24.57; P = .006; I2 = 59.3%), favoring ADT use (Figure 3).

Place holder to copy figure label and caption
Figure 3. Relative Risk of Prostate Cancer–Specific Mortality Associated With ADT Among Patients With Prostate Cancer
Graphic Jump Location

ADT indicates androgen deprivation therapy. The summary relative risk of prostate cancer–specific mortality was calculated using a random-effects model. The size of the squares indicates the weight of the study, which is the inverse variance of the effect estimate. The diamond indicates the summary relative risk.

Association of ADT With Overall Survival

There were 1140 total deaths among 2527 patients in the ADT group and 1213 total deaths among 2278 patients in the control group. The incidence of all-cause mortality among men receiving ADT vs control was 37.7% (95% CI, 27.3%-49.4%) vs 44.4% (95% CI, 32.5%-57.0%). The RR of death was 0.86 (95% CI, 0.80-0.93; P < .001; heterogeneity test: Q = 16.86; P = .08; I2 = 40.7%) (Figure 4).

Place holder to copy figure label and caption
Figure 4. Relative Risk of All-Cause Mortality Associated With ADT Among Patients With Prostate Cancer
Graphic Jump Location

ADT indicates androgen deprivation therapy. The summary relative risk of all-cause mortality was calculated using a random-effects model. The size of the squares indicates the weight of the study, which is the inverse variance of the effect estimate. The diamond indicates the summary relative risk.

Whether ADT causes excess cardiovascular mortality in men with prostate cancer has been highly controversial for the last 5 years and recently led to a joint statement by the American Heart Association, the American Cancer Society, the American Urological Association, and the American Society for Radiation Oncology that there may be a relationship between ADT and cardiovascular events and death, and a safety warning by the Food and Drug Administration requiring GnRH agonist manufacturers to warn about an increased risk of diabetes, heart attack, sudden cardiac death, and stroke.5,6 Because most of the data raising concern about the effect of ADT on cardiovascular events and cardiovascular death has been retrospective, we performed a meta-analysis of prospective randomized trials comparing immediate GnRH-agonist–based ADT vs no ADT or deferred ADT for men with nonmetastatic, unfavorable-risk prostate cancer. In our study of 4141 patients in 8 randomized trials with median follow-up of 7.6 to 13.2 years, we could not find any evidence that ADT causes excess cardiovascular mortality. Our study suggests that for the population as a whole, there is either no adverse effect of ADT on cardiovascular mortality or the magnitude of this effect is likely rather small.

In our analysis, we could not find a subgroup in which ADT was associated with excess cardiovascular mortality. Specifically, we did not see an excess risk of cardiovascular mortality due to ADT among men receiving short-course ADT (≤6 months), men receiving long-course ADT (≥3 years), men receiving radiation, or in trials in which the median age of enrollment was 70 years or older. As shown in some of the individual trials, our meta-analysis found that the use of ADT in men with unfavorable-risk prostate cancer is associated with improved prostate cancer–specific survival and overall survival. Of note, these improved survival findings only apply to men with unfavorable-risk prostate cancer, because the trials analyzed generally did not contain men with low-risk disease, a group for whom there is no compelling evidence that ADT improves survival.

Overall, the results of our study should be generally reassuring to most men with unfavorable-risk prostate cancer considering ADT, because it was associated with improved survival without a measurable excess in cardiovascular mortality, but a few important points need to be raised. First, none of the trials were stratified by preexisting cardiovascular comorbidity; therefore, our study cannot exclude the possibility that a small subgroup of men with underlying cardiac disease (even if controlled) could experience excess cardiovascular mortality due to ADT.29 For example, a post hoc reanalysis of one of the trials included in our meta-analysis (DFCI 95-0963) found that men with moderate to severe comorbidity (mainly cardiac) appeared to have poorer overall survival when treated with ADT and radiation vs radiation alone, although this difference was not statistically significant (P = .08).3 In addition, a retrospective review of a large data set of men who were treated with brachytherapy-based radiation found that although 95% of the men were not harmed by ADT, the 5% of men with a prior history of MI or congestive heart failure (CHF) appeared to have a higher incidence of all-cause mortality when treated with ADT plus radiation compared with radiation alone (25/95 vs 18/161 events; 26.3% vs 11.2% at 5 years; adjusted hazard ratio [HR], 1.96; P = .04).

The adverse effect of ADT in men with a history of MI or CHF was confirmed in a second large retrospective study30 that found that even if such men had high-risk prostate cancer (prostate-specific antigen >20 ng/mL or Gleason score of 8-10 or clinical T3), their risk of all-cause mortality appeared to be higher with ADT than without it (adjusted HR, 2.57; P = .02). In that study, the men with a history of MI or CHF constituted only 9% of the total cohort of men being treated with radiation. Because we were not able to stratify our analysis by underlying cardiac comorbidity, it remains possible that the subgroup of men with prostate cancer and a history of CHF or MI could experience excess cardiovascular mortality due to ADT, and for these men it would seem prudent to continue to be mindful of possible metabolic and cardiovascular sequelae when using ADT. It should also be noted that participants in the phase 3 trials may have had fewer comorbidities than the general age-matched population and could have been less susceptible to any adverse effects of ADT. For example, in the RTOG 85-31 trial,8 the median age was 70 years but only 33% had hypertension and only 9% had diabetes. In contrast, the National Health and Nutrition Examination Survey study31 has shown that the prevalence of hypertension in average men older than 60 years is 60% to 70% and the Centers for Disease Control and Prevention estimates 27% of US men older than 65 years have diabetes.31 To answer the question definitively for men with high-risk cardiac features, we recommend that future randomized trials testing the value of ADT stratify by comorbidity/cardiac history. One example of such a trial is the RTOG 08-15 trial, which compares high-dose radiation with or without short-course ADT in men with intermediate-risk disease and stratifies by Adult Comorbidity Evaluation 27 score.

A second issue is that although our study assessed total cardiovascular deaths, it could not exclude the possibility that cardiovascular deaths happen earlier in men receiving ADT. As mentioned, the postrandomization analysis by D’Amico et al combining the DFCI 95-0963 and TROG 96.0116 data suggested that for men older than 65 years, the cumulative incidence of fatal MI by year 8 was the same for those receiving ADT vs no ADT, but the time to fatal MI was significantly shorter for those men who received ADT.3 Also, the retrospective study that established patients with CHF and MI as a vulnerable subgroup found that the excess deaths with ADT seemed to happen in only the first 6 to 24 months after ADT.32 Because our study is based on trials with approximately a 10-year median follow-up, a theoretical effect in which ADT caused an earlier timing of cardiovascular deaths could have been missed by the time events were totaled at year 10. An additional consideration is that cause of death was generally determined by the treating physician or trial investigator, and only 1 trial (EORTC 3089115) required adjudication of cause of death by 2 independent central reviewers, so it is possible that some cardiovascular deaths were underreported or misclassified.

In addition, although we could not detect excess cardiovascular mortality due to ADT, our study does not exonerate ADT from the metabolic sequelae, which it has been demonstrated to cause in men in prospective series. For example, in a prospective study of men without diabetes,33 ADT significantly increased fasting plasma insulin by 26% and decreased insulin sensitivity by 13% after only 12 weeks of therapy.

Our findings are discordant with the studies of Keating et al1 and Tsai et al,2 2 of the first to raise concern about excess cardiovascular deaths due to ADT. Since those studies were both retrospective, it is possible that subtle imbalances in the underlying health status of men being selected for ADT vs no ADT could have contributed to those findings. Such imbalances would be less likely to occur in randomized trials. An alternative explanation for the discrepancy, as mentioned above, may be that the patients in these phase 3 trials could have been healthier and less susceptible to any adverse cardiovascular effects of ADT than the general population.

In conclusion, our meta-analysis of more than 4000 patients could not find any evidence that ADT increases the risk of cardiovascular death among men with unfavorable-risk, nonmetastatic prostate cancer, but did find a significant association between ADT and improved prostate cancer–specific survival and overall survival. For the majority of men considering ADT for aggressive prostate cancer, these results should be reassuring. It remains unknown whether these results are also applicable to the subgroup of men with a prior history of CHF or MI, and therefore stratification of future randomized trials by cardiovascular comorbidity is needed.

Corresponding Author: Paul L. Nguyen, MD, Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115 (pnguyen@LROC.harvard.edu).

Author Contributions: Dr Nguyen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Nguyen, Hoffman, Choueiri.

Acquisition of data: Nguyen, Parekh, Choueiri.

Analysis and interpretation of data: Nguyen, Je, Schutz, Hoffman, Hu, Parekh, Beckman, Choueiri.

Drafting of the manuscript: Nguyen.

Critical revision of the manuscript for important intellectual content: Nguyen, Je, Schutz, Hoffman, Hu, Parekh, Beckman, Choueiri.

Statistical analysis: Je.

Obtained funding: Nguyen.

Administrative, technical, or material support: Nguyen, Schutz, Parekh, Choueiri.

Study supervision: Nguyen, Choueiri.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: This work was supported by a JCRT Foundation grant; a Doris Duke Clinical Research Fellowship; David and Cynthia Chapin; Richard, Nancy, and Karis Cho; and a grant from an anonymous Family Foundation.

Role of the Sponsors: The funding organizations or sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer.  J Clin Oncol. 2006;24(27):4448-4456
PubMed   |  Link to Article
Tsai HK, D’Amico AV, Sadetsky N, Chen MH, Carroll PR. Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality.  J Natl Cancer Inst. 2007;99(20):1516-1524
PubMed   |  Link to Article
D’Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial.  JAMA. 2008;299(3):289-295
PubMed   |  Link to Article
Saigal CS, Gore JL, Krupski TL,  et al.  Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer.  Cancer. 2007;110(7):1493-1500
PubMed   |  Link to Article
Levine GN, D’Amico AV, Berger P,  et al.  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.  Circulation. 2010;121(6):833-840
PubMed   |  Link to Article
US Food and Drug Administration.  FDA Drug Safety Communication: Update to Ongoing Safety Review of GnRH Agonists and Notification to Manufacturers of GnRH Agonists to Add New Safety Information to Labeling Regarding Increased Risk of Diabetes and Certain Cardiovascular Diseases. http://www.fda.gov/Drugs/DrugSafety/ucm229986.htm. Accessed October 28, 2011
Alibhai SM, Duong-Hua M, Sutradhar R,  et al.  Impact of androgen deprivation therapy on cardiovascular disease and diabetes.  J Clin Oncol. 2009;27(21):3452-3458
PubMed   |  Link to Article
Efstathiou JA, Bae K, Shipley WU,  et al.  Cardiovascular mortality after androgen deprivation therapy for locally advanced prostate cancer: RTOG 85-31.  J Clin Oncol. 2009;27(1):92-99
PubMed   |  Link to Article
Roach M III, Bae K, Speight J,  et al.  Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610.  J Clin Oncol. 2008;26(4):585-591
PubMed   |  Link to Article
Jadad AR, Moore RA, Carroll D,  et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary?  Control Clin Trials. 1996;17(1):1-12
PubMed   |  Link to Article
Moher D, Liberati A, Tetzlaff J, Altman DG.PRISMA Group.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.  BMJ. 2009;339:b2535
PubMed   |  Link to Article
Messing EM, Manola J, Yao J,  et al.  Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy.  Lancet Oncol. 2006;7(6):472-479
PubMed   |  Link to Article
Bolla M, Van Tienhoven G, Warde P,  et al.  External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study.  Lancet Oncol. 2010;11(11):1066-1073
PubMed   |  Link to Article
Schröder FH, Kurth K-H, Fossa SD,  et al.  Early versus delayed endocrine treatment of T2-T3 pN1-3 M0 prostate cancer without local treatment of the primary tumour: final results of European Organisation for the Research and Treatment of Cancer protocol 30846 after 13 years of follow-up (a randomised controlled trial).  Eur Urol. 2009;55(1):14-22
PubMed   |  Link to Article
Studer UE, Whelan P, Albrecht W,  et al.  Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment of Cancer (EORTC) trial 30891.  J Clin Oncol. 2006;24(12):1868-1876
PubMed   |  Link to Article
Denham JW, Steigler A, Lamb DS,  et al.  Short-term neoadjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised trial.  Lancet Oncol. 2011;12(5):451-459
PubMed   |  Link to Article
Aus G, Abrahamsson PA, Ahlgren G,  et al.  Three-month neoadjuvant hormonal therapy before radical prostatectomy: a 7-year follow-up of a randomized controlled trial.  BJU Int. 2002;90(6):561-566
PubMed   |  Link to Article
Schulman CC, Debruyne FM, Forster G,  et al.  4-Year follow-up results of a European prospective randomized study on neoadjuvant hormonal therapy prior to radical prostatectomy in T2-3N0M0 prostate cancer.  Eur Urol. 2000;38(6):706-713
PubMed   |  Link to Article
Yee DS, Lowrance WT, Eastham JA, Maschino AC, Cronin AM, Rabbani F. Long-term follow-up of 3-month neoadjuvant hormone therapy before radical prostatectomy in a randomized trial.  BJU Int. 2010;105(2):185-190
PubMed   |  Link to Article
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses.  BMJ. 2003;327(7414):557-560
PubMed   |  Link to Article
DerSimonian R, Laird N. Meta-analysis in clinical trials.  Control Clin Trials. 1986;7(3):177-188
PubMed   |  Link to Article
Prezioso D, Lotti T, Polito M, Montironi R. Neoadjuvant hormone treatment with leuprolide acetate depot 3.75 mg and cyproterone acetate, before radical prostatectomy: a randomized study.  Urol Int. 2004;72(3):189-195
PubMed   |  Link to Article
Dalkin BL, Ahmann FR, Nagle R, Johnson CS. Randomized study of neoadjuvant testicular androgen ablation therapy before radical prostatectomy in men with clinically localized prostate cancer.  J Urol. 1996;155(4):1357-1360
PubMed   |  Link to Article
Green HJ, Pakenham KI, Headley BC,  et al.  Quality of life compared during pharmacological treatments and clinical monitoring for non-localized prostate cancer: a randomized controlled trial.  BJU Int. 2004;93(7):975-979
PubMed   |  Link to Article
Laverdière J, Nabid A, De Bedoya LD,  et al.  The efficacy and sequencing of a short course of androgen suppression on freedom from biochemical failure when administered with radiation therapy for T2-T3 prostate cancer.  J Urol. 2004;171(3):1137-1140
PubMed   |  Link to Article
Soloway MS, Pareek K, Sharifi R,  et al.  Neoadjuvant androgen ablation before radical prostatectomy in cT2bNxMo prostate cancer: 5-year results.  J Urol. 2002;167(1):112-116
PubMed   |  Link to Article
Labrie F, Cusan L, Gomez JL,  et al.  Neoadjuvant hormonal therapy: the Canadian experience.  Urology. 1997;49(3A):(suppl)  56-64
PubMed   |  Link to Article
Black PC, Basen-Engquist K, Wang X,  et al.  A randomized prospective trial evaluating testosterone, haemoglobin kinetics and quality of life, during and after 12 months of androgen deprivation after prostatectomy: results from the Postoperative Adjuvant Androgen Deprivation trial.  BJU Int. 2007;100(1):63-69
PubMed   |  Link to Article
Nguyen PL, Chen MH, Goldhaber SZ,  et al.  Coronary revascularization and mortality in men with congestive heart failure or prior myocardial infarction who receive androgen deprivation.  Cancer. 2011;117(2):406-413
PubMed   |  Link to Article
Nguyen PL, Chen MH, Beckman JA,  et al.  Influence of androgen deprivation therapy on all-cause mortality in men with high-risk prostate cancer and a history of congestive heart failure or myocardial infarction.  Int J Radiat Oncol Biol PhysLink to Article
PubMed
Centers for Disease Control and Prevention.  National Diabetes Fact Sheet: National Estimates and General Information on Diabetes and Prediabetes in the United States, 2011. Atlanta, GA: US Dept of Health and Human Services; 2011
Nanda A, Chen MH, Braccioforte MH, Moran BJ, D’Amico AV. Hormonal therapy use for prostate cancer and mortality in men with coronary artery disease−induced congestive heart failure or myocardial infarction.  JAMA. 2009;302(8):866-873
PubMed   |  Link to Article
Smith MR, Lee H, Nathan DM. Insulin sensitivity during combined androgen blockade for prostate cancer.  J Clin Endocrinol Metab. 2006;91(4):1305-1308
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1. Article Selection
Graphic Jump Location

ADT indicates androgen deprivation therapy; GnRH, gonadotropin-releasing hormone.

Place holder to copy figure label and caption
Figure 2. Relative Risk of Cardiovascular Deaths Associated With ADT Among Patients With Prostate Cancer
Graphic Jump Location

ADT indicates androgen deprivation therapy. The summary relative risk of cardiovascular deaths was calculated using a fixed-effects model. The size of the squares indicates the weight of the study, which is the inverse variance of the effect estimate. The diamond indicates the summary relative risk.

Place holder to copy figure label and caption
Figure 3. Relative Risk of Prostate Cancer–Specific Mortality Associated With ADT Among Patients With Prostate Cancer
Graphic Jump Location

ADT indicates androgen deprivation therapy. The summary relative risk of prostate cancer–specific mortality was calculated using a random-effects model. The size of the squares indicates the weight of the study, which is the inverse variance of the effect estimate. The diamond indicates the summary relative risk.

Place holder to copy figure label and caption
Figure 4. Relative Risk of All-Cause Mortality Associated With ADT Among Patients With Prostate Cancer
Graphic Jump Location

ADT indicates androgen deprivation therapy. The summary relative risk of all-cause mortality was calculated using a random-effects model. The size of the squares indicates the weight of the study, which is the inverse variance of the effect estimate. The diamond indicates the summary relative risk.

Tables

Table Graphic Jump LocationTable. Baseline Characteristics and Number of CV Deaths for the Selected Trials of ADT in Nonmetastatic Prostate Cancer

References

Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer.  J Clin Oncol. 2006;24(27):4448-4456
PubMed   |  Link to Article
Tsai HK, D’Amico AV, Sadetsky N, Chen MH, Carroll PR. Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality.  J Natl Cancer Inst. 2007;99(20):1516-1524
PubMed   |  Link to Article
D’Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial.  JAMA. 2008;299(3):289-295
PubMed   |  Link to Article
Saigal CS, Gore JL, Krupski TL,  et al.  Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer.  Cancer. 2007;110(7):1493-1500
PubMed   |  Link to Article
Levine GN, D’Amico AV, Berger P,  et al.  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.  Circulation. 2010;121(6):833-840
PubMed   |  Link to Article
US Food and Drug Administration.  FDA Drug Safety Communication: Update to Ongoing Safety Review of GnRH Agonists and Notification to Manufacturers of GnRH Agonists to Add New Safety Information to Labeling Regarding Increased Risk of Diabetes and Certain Cardiovascular Diseases. http://www.fda.gov/Drugs/DrugSafety/ucm229986.htm. Accessed October 28, 2011
Alibhai SM, Duong-Hua M, Sutradhar R,  et al.  Impact of androgen deprivation therapy on cardiovascular disease and diabetes.  J Clin Oncol. 2009;27(21):3452-3458
PubMed   |  Link to Article
Efstathiou JA, Bae K, Shipley WU,  et al.  Cardiovascular mortality after androgen deprivation therapy for locally advanced prostate cancer: RTOG 85-31.  J Clin Oncol. 2009;27(1):92-99
PubMed   |  Link to Article
Roach M III, Bae K, Speight J,  et al.  Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610.  J Clin Oncol. 2008;26(4):585-591
PubMed   |  Link to Article
Jadad AR, Moore RA, Carroll D,  et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary?  Control Clin Trials. 1996;17(1):1-12
PubMed   |  Link to Article
Moher D, Liberati A, Tetzlaff J, Altman DG.PRISMA Group.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.  BMJ. 2009;339:b2535
PubMed   |  Link to Article
Messing EM, Manola J, Yao J,  et al.  Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy.  Lancet Oncol. 2006;7(6):472-479
PubMed   |  Link to Article
Bolla M, Van Tienhoven G, Warde P,  et al.  External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study.  Lancet Oncol. 2010;11(11):1066-1073
PubMed   |  Link to Article
Schröder FH, Kurth K-H, Fossa SD,  et al.  Early versus delayed endocrine treatment of T2-T3 pN1-3 M0 prostate cancer without local treatment of the primary tumour: final results of European Organisation for the Research and Treatment of Cancer protocol 30846 after 13 years of follow-up (a randomised controlled trial).  Eur Urol. 2009;55(1):14-22
PubMed   |  Link to Article
Studer UE, Whelan P, Albrecht W,  et al.  Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment of Cancer (EORTC) trial 30891.  J Clin Oncol. 2006;24(12):1868-1876
PubMed   |  Link to Article
Denham JW, Steigler A, Lamb DS,  et al.  Short-term neoadjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised trial.  Lancet Oncol. 2011;12(5):451-459
PubMed   |  Link to Article
Aus G, Abrahamsson PA, Ahlgren G,  et al.  Three-month neoadjuvant hormonal therapy before radical prostatectomy: a 7-year follow-up of a randomized controlled trial.  BJU Int. 2002;90(6):561-566
PubMed   |  Link to Article
Schulman CC, Debruyne FM, Forster G,  et al.  4-Year follow-up results of a European prospective randomized study on neoadjuvant hormonal therapy prior to radical prostatectomy in T2-3N0M0 prostate cancer.  Eur Urol. 2000;38(6):706-713
PubMed   |  Link to Article
Yee DS, Lowrance WT, Eastham JA, Maschino AC, Cronin AM, Rabbani F. Long-term follow-up of 3-month neoadjuvant hormone therapy before radical prostatectomy in a randomized trial.  BJU Int. 2010;105(2):185-190
PubMed   |  Link to Article
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses.  BMJ. 2003;327(7414):557-560
PubMed   |  Link to Article
DerSimonian R, Laird N. Meta-analysis in clinical trials.  Control Clin Trials. 1986;7(3):177-188
PubMed   |  Link to Article
Prezioso D, Lotti T, Polito M, Montironi R. Neoadjuvant hormone treatment with leuprolide acetate depot 3.75 mg and cyproterone acetate, before radical prostatectomy: a randomized study.  Urol Int. 2004;72(3):189-195
PubMed   |  Link to Article
Dalkin BL, Ahmann FR, Nagle R, Johnson CS. Randomized study of neoadjuvant testicular androgen ablation therapy before radical prostatectomy in men with clinically localized prostate cancer.  J Urol. 1996;155(4):1357-1360
PubMed   |  Link to Article
Green HJ, Pakenham KI, Headley BC,  et al.  Quality of life compared during pharmacological treatments and clinical monitoring for non-localized prostate cancer: a randomized controlled trial.  BJU Int. 2004;93(7):975-979
PubMed   |  Link to Article
Laverdière J, Nabid A, De Bedoya LD,  et al.  The efficacy and sequencing of a short course of androgen suppression on freedom from biochemical failure when administered with radiation therapy for T2-T3 prostate cancer.  J Urol. 2004;171(3):1137-1140
PubMed   |  Link to Article
Soloway MS, Pareek K, Sharifi R,  et al.  Neoadjuvant androgen ablation before radical prostatectomy in cT2bNxMo prostate cancer: 5-year results.  J Urol. 2002;167(1):112-116
PubMed   |  Link to Article
Labrie F, Cusan L, Gomez JL,  et al.  Neoadjuvant hormonal therapy: the Canadian experience.  Urology. 1997;49(3A):(suppl)  56-64
PubMed   |  Link to Article
Black PC, Basen-Engquist K, Wang X,  et al.  A randomized prospective trial evaluating testosterone, haemoglobin kinetics and quality of life, during and after 12 months of androgen deprivation after prostatectomy: results from the Postoperative Adjuvant Androgen Deprivation trial.  BJU Int. 2007;100(1):63-69
PubMed   |  Link to Article
Nguyen PL, Chen MH, Goldhaber SZ,  et al.  Coronary revascularization and mortality in men with congestive heart failure or prior myocardial infarction who receive androgen deprivation.  Cancer. 2011;117(2):406-413
PubMed   |  Link to Article
Nguyen PL, Chen MH, Beckman JA,  et al.  Influence of androgen deprivation therapy on all-cause mortality in men with high-risk prostate cancer and a history of congestive heart failure or myocardial infarction.  Int J Radiat Oncol Biol PhysLink to Article
PubMed
Centers for Disease Control and Prevention.  National Diabetes Fact Sheet: National Estimates and General Information on Diabetes and Prediabetes in the United States, 2011. Atlanta, GA: US Dept of Health and Human Services; 2011
Nanda A, Chen MH, Braccioforte MH, Moran BJ, D’Amico AV. Hormonal therapy use for prostate cancer and mortality in men with coronary artery disease−induced congestive heart failure or myocardial infarction.  JAMA. 2009;302(8):866-873
PubMed   |  Link to Article
Smith MR, Lee H, Nathan DM. Insulin sensitivity during combined androgen blockade for prostate cancer.  J Clin Endocrinol Metab. 2006;91(4):1305-1308
PubMed   |  Link to Article

Letters

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 75

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
Related Collections
PubMed Articles