Androgen Deprivation Therapy, Hypogonadism and Cardiovascular Toxicity in Men with Advanced Prostate Cancer
Abstract
:1. Introduction
2. Cardiovascular Effects of Testosterone
2.1. Favourable Effects
2.2. Deleterious Effects
2.3. Controversial Effects
3. Clinical Cardiovascular Effects of Hypogonadism
3.1. Hypogonadism and Cardiovascular Risk Factors
3.2. Hypogonadism and QTc Interval on ECG
3.3. Hypogonadism and Cardiovascular Mortality
4. Cardiovascular Effects of ADT
4.1. Mechanisms of Cardiovascular Effects of ADT
4.2. Clinical Studies
4.2.1. Studies Showing an Additional Cardiovascular Risk in Patients on ADT
4.2.2. Studies Showing No Additional Cardiovascular Risk in Patients on ADT
4.2.3. Studies Comparing the Cardiovascular Risk of Various ADT
5. Therapeutic Consequences
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Class of Drugs | Examples |
---|---|
GnRH agonist a | Leuprolide, Buserelin, Goserelin, Triptorelin |
GnRH antagonist b | Degarelix, Relugorix |
Cytochrome P450-17 A1 inhibitor | Abiraterone |
Nonsteroidal androgen receptor antagonists | Bicalutamide, Flutamide, Nilutamide, Enzalutamide, Apalutamide, Darolutamide |
5α-reductase inhibitors | Finasteride, Dutasteride |
Population | Adult Men with Prostate Cancer |
---|---|
Intervention | Androgen deprivation therapy |
Comparisons | Placebo, no therapy, radiotherapy, orchiectomy, watchful waiting/active surveillance, local therapy |
Outcomes | Hypertension, myocardial infarction, stroke, arrhythmia, heart failure, venous thromboembolism, QT interval prolongation, sudden cardiac death, cardiovascular mortality |
First Author [Reference] | Year | Study Type | Pts Enrolled | Type of ADT/No pts | Treatment in the Control Group/No pts | Median Age | Follow-Up | Results |
---|---|---|---|---|---|---|---|---|
Studies Showing an Additional Cardio-Vascular Risk in Patients on ADT | ||||||||
Keating [53] | 2006 | Observational SEER program 11 population-based cancer registries | 73,193 | GnRH agonists 25,570 | No therapy/orchiectomy 47,623 | 74.2 ± 5.8 | 4.5 years | Increased risk of DM, CAD, MI, SCD, in the GnRH agonist group versus non therapy group Increased risk of DM in orchiectomy group versus non therapy group |
D’Amico [54] | 2007 | Randomized study | 1372 | GnRH agonist + flutamide + RT | RT | 70.88 | 3–8 months | Fatal MI occurs earlier in men older than 65 years who received 6 months of ADT than in those without ADT and in men younger than 65 years. No significant difference (p = 0.97) was observed in the time to fatal MIs in men age 65 years or older who received 6 to 8 months of ADT compared with 3 months of ADT |
Tsai [55] | 2007 | Observational study | 4881 | 3262 pts on radical prostatectomy + ADT in 1051 pts | RT 1630 pts | 63 | 3.8 years | The use of ADT appears to be associated with an increased risk of death from cardiovascular causes in patients undergoing radical prostatectomy for localized prostate cancer |
O’Farrell [52] | 2015 | Retrospective study | 229,147 | 41,362 pts on GnRH agonist ± non steroidian antiandrogen | 187,785 cancer free pts | 75 | 6 years | CVD risk was highest during the first 6 months of ADT in men who experienced two or more cardiovascular events before therapy |
Alibhai [56] | 2009 | Cohort study | 116769 | 46,995 on ADT | No ADT 69,774 | 75 ± 6.3 | 6.47 years | ADT use for at least 6 months in older men is associated with an increased risk of diabetes and fragility fracture but not MI or sudden cardiac death. |
Studies Showing No Additional Cardio-Vascular Risk in Patients on ADT | ||||||||
Nanda [57] | 2009 | Retrospective study | 5077 | 1521 pts on GnRH agonist+ non steroidian antiandrogen | 3556 RT | 69.5 | 2 years | ADT is significantly associated with an increased risk of all-cause mortality among men with a history of CAD-induced HF or MI but not among men with no comorbidity or a single CAD risk factor. |
Bolla [58] | 2009 | Randomized study | 970 | 487 pts on RT + 2.5 years GnRH agonists | 483 pts on RT + 6 months GnRH agonists | 69 | 6.4 | There was no significant difference in the cumulative incidence of fatal cardiac events at 5 years: 4.0% in the short-term group and 3.0% in the long-term group |
Punnen [59] | 2011 | Retrospective study of CaPSURE registry | 7248 | ADT (1086 pts) ADT + local therapy (485 pts) | Local therapy (5170 pts), watchful waiting/active surveillance (506 pts) | >65 | 47.6–57 months | A propensity-matching algorithm in a subset of 1391 patients was unable to find a significant difference in cardiovascular mortality between those who did or did not receive ADT. |
Efstathiou [60] | 1987–1992 | randomized | 945 | RT + goserelin (477) | RT (468) | 70 | 9 years | GnRH agonists do not seem to increase cardiovascular mortality in men with locally advanced prostate cancer |
Studies That Compared Different Type of ADT Regarding Their Cardiotoxicity | ||||||||
Liang [61] | 2009–2017 | Meta analysis | 5 studies | ADT 63,258 | Non ADT 209,403 | 69–75 | Abiraterone and enzalutamide increased risk of AMI, CAD, in contrast, this association is not detected in SCD. | |
Shore [62] | 2017–2018 | Randomized phase III trial (HERO) | 930 pts | 622 pts relugolix | 308 pts leuprolide | 71 | 1 year | Relugolix achieved rapid, sustained suppression of testosterone levels that was superior to that with leuprolide, with a 54% lower risk of major adverse cardiovascular events |
Moreira [63] | 2011–2014 | Meta-analysis | 4 studies/5183 pts | Abiraterone-prednisone/prednisone 1333/936 | Enzalutamid/placebo 1672/1244 | 46–95 | 5 years | Abiraterone was associated with cardiovascular adverse effects; enzalutamide was associated with fatigue |
Margel [64] | 2019 | Phase II randomized study included patients with pre-existing cardio-vascular disease; primary endpoint endothelial dysfunction | 80 pts | GnRH antagonist/41 pts | Gn agonist/39 pts | 71–72 | 1 year | 20% randomized to GnRH agonist experienced a major cardiovascular and cerebrovascular event compared to 3% of those on GnRH antagonist |
Zhang [65] | 2000–2020 | Analysis of FDA Adverse Event Reporting System (FAERS} | 6231 hormone monotherapy | 1793 combined therapy | ≥18 years | 20 years | GnRH antagonists were associated with fewer cardiovascular adverse events than GnRH agonists as monotherapy and combination therapy, especially in men ≥ 60 years |
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Gheorghe, G.S.; Hodorogea, A.S.; Ciobanu, A.; Nanea, I.T.; Gheorghe, A.C.D. Androgen Deprivation Therapy, Hypogonadism and Cardiovascular Toxicity in Men with Advanced Prostate Cancer. Curr. Oncol. 2021, 28, 3331-3346. https://doi.org/10.3390/curroncol28050289
Gheorghe GS, Hodorogea AS, Ciobanu A, Nanea IT, Gheorghe ACD. Androgen Deprivation Therapy, Hypogonadism and Cardiovascular Toxicity in Men with Advanced Prostate Cancer. Current Oncology. 2021; 28(5):3331-3346. https://doi.org/10.3390/curroncol28050289
Chicago/Turabian StyleGheorghe, Gabriela Silvia, Andreea Simona Hodorogea, Ana Ciobanu, Ioan Tiberiu Nanea, and Andrei Cristian Dan Gheorghe. 2021. "Androgen Deprivation Therapy, Hypogonadism and Cardiovascular Toxicity in Men with Advanced Prostate Cancer" Current Oncology 28, no. 5: 3331-3346. https://doi.org/10.3390/curroncol28050289
APA StyleGheorghe, G. S., Hodorogea, A. S., Ciobanu, A., Nanea, I. T., & Gheorghe, A. C. D. (2021). Androgen Deprivation Therapy, Hypogonadism and Cardiovascular Toxicity in Men with Advanced Prostate Cancer. Current Oncology, 28(5), 3331-3346. https://doi.org/10.3390/curroncol28050289