Cardiovascular Effects of ADT in
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1 Cardiovascular Effects of ADT in Click to edit Prostate Master Cancer /tle style Pa/ents Chris Plummer Freeman Hospital, Newcastle upon Tyne, UK Newcastle University Bri/sh Cardio- Oncology Society
2 Click declara'on to edit Master /tle style Ferring Pharmaceu/cals Ltd. manufacturers of degarelix (GnRH antagonist) advisory board 30/04/2015.
3 Click outline to edit Master /tle style underlying cardiovascular risks in pa/ents with prostate cancer cardiovascular risks associated with prostate cancer treatment management strategy to minimize overall pa/ent risk.
4 Click prostate to edit cancer Master /tle style commonest cancer in men (24,000 pa in Canada) mean age at diagnosis 71y treatments: surgery radiotherapy ADT: orichiectomy/gnrh agonist/gnrh antagonist other chemotherapy or hormonal therapy good prognosis 84% alive at 10y.
5 Click to edit Master /tle style underlying cardiovascular risk
6 Click cardiovascular to edit Master risk /tle style cardiac risk factors in 100 men with localized PC in Bri/sh Columbia. CHD risk at 10y 20% >10% - <20% 20mg atorvasta/n 10% Davis et al. Journal of Oncology 2015;820403
7 Click cardiovascular to edit Master risk /tle style cardiac risk factors in 100 men with localized PC in Bri/sh Columbia. sta/ns: 21 / 25 (84%) 2 preven/on 19 / 74 (26%) 1 preven/on Davis et al. Journal of Oncology 2015;820403
8 Click cardiovascular to edit Master risk /tle style 9596 men >65y, SEER , 5y f/u ADT for metasta/c prostate cancer, 32% CVD between lowest and highest co- morbidity cohorts: no change in CSM (54%) 4 x CVS mortality (16.3%) 2 x other cause mortality (16.2%) median survival: 40 v 20mo. prostate cancer- specific mortality cardiovascular mortality other- cause mortality Gandeglia et al. Clinical Genitourinary Cancer 2015;13:e123
9 Click to edit Master /tle style androgen depriva/on therapy
10 Click androgen to edit depriva'on Master /tle therapy style orchiectomy (1942) (1980s) (2003) immediate testosterone irreversible, compliance spectrum of side- effects ini/al flare suppress LH >> FH similar side- effects to orchiectomy immediate testosterone lower mean [testosterone] than agonists
11 Click ADT efficacy to edit Master (GnRH agonist /tle or orchiectomy) style Messing et al. NEJM 1999;341:1781
12 Click ADT and to edit CVS Master risk /tle style meta- analysis of 11 RCTs of GnRH agonists 4141 pa/ents with non- metasta/c prostate cancer prostate cancer mortality all- cause mortality cardiovascular mortality no stra/fica/on by baseline cardiac co- morbidity low- risk short follow- up. Nguyen et al. JAMA 2011;306:2359
13 Click ADT and to edit CVS Master risk /tle style meta- analysis of 8 observa/onal studies in 414K men GnRH agonists, orchiectomy, an/- androgens fatal and non- fatal events. myocardial infarc/on stroke Bosco et al. European Urology 2014;68:386
14 Click ADT and to edit CVS Master risk /tle style SEER ,156 men 65-79y ct1 or ct2 localized prostate cancer prostatectomy (24%) DXT (76%) ADT (42%) orchiectomy (0.5%). Wallis et al. Urology 2016;in press
15 Click GnRH to agonists edit Master vs antagonists /tle style pooled data from 6 phase 3 RCTs in 2328 men 30% prior CVD event 1 st CVS event or death in the 1 st year: HR 0.60 p=0.008 HR 0.44 p=0.002 absolute risk reduc/on 8.2% NNT = 12 all men pre- exis/ng CVS disease primary driver for reduced overall mortality ( 2% at 1y). Albertsen et al. European Urology 2014;65:565
16 Click ADT and to edit CVS Master risk - mechanisms /tle style 16 consecu/ve PC pa/ents endothelium- dependent and independent vasodila/on lipids, insulin resistance before and aper 3 months GnRH agonist: Nguyen et al. J Am Heart Assoc 2015;4:e001914
17 Click ADT and to edit CVS Master risk - mechanisms /tle style Nguyen et al. J Am Heart Assoc 2015;4:e001914
18 Click to edit Master /tle style other treatments
19 Click new hormonal to edit Master agents /tle style meta- analysis of 6 phase II/III double- blind RCTs 6735 pa/ents with castra/on- resistant prostate cancer CYP- 17 inhibitors abiraterone & orteronel extra- gonadal testosterone produc/on direct inhibi/on of androgen receptor ac/vity enzalutamide reported toxicity: fluid reten/on, hypokalaemia, hypertension, transaminase increases, cardiac events, atrial fibrilla/on, fa/gue, hot flushes. Iacovelli et al. Eur J Cancer 2015;51:1970
20 Click new hormonal to edit Master agents /tle style cardiac toxicity any, any grade (no detail available) abiraterone orteronel enzalutamide TOTAL 561 / 3788 = 14.8% 338 / 2947 = 11.5% 3.3% Iacovelli et al. Eur J Cancer 2015;51:1970
21 Click new hormonal to edit Master agents /tle style hypertension any grade: abiraterone orteronel enzalutamide TOTAL 566 / 4520 = 12.5% 249 / 3310 = 7.5% 5.0% Iacovelli et al. Eur J Cancer 2015;51:1970
22 Click finasteride to edit Master /tle style inhibits 5α- reductase required in androgen synthesis symptoma/c benefits reduced prostate size increased urinary flow rate no effect on overall survival Unger et al. JNCI Natl Cancer Inst 2016;108:djw168
23 Click cixutumumab to edit Master v ramucirumab /tle style metasta/c castra/on resistant prostate cancer cixutumumab targets insulin- like growth factor ramucirumab targets VEGF receptor- 2 Hussain et al. Eur J Cancer 2015;51:1714
24 Click to edit Master /tle style cardiovascular risk reduc/on
25 Click primary to edit preven'on Master /tle guidance style
26 Click risk factor edit modifica'on Master /tle style all stop smoking diet/weight (fat/salt/calories/alcohol etc.) physical ac/vity blood pressure target <140/85mmHg secondary preven'on MI, angina, CVA, TIA, PVD, atorvasta/n 80mg nocte, aspirin/β- blockers/acei as indicated primary preven'on QRisk or Framingham Risk score age, sex, ethnicity, post- code, smoking, diabetes, FH x, CKD, AF, BP R x, RhA, lipids, BP, BMI 10% 10y risk atorvasta/n 20mg nocte.
27 Q- RISK Click to edit Master Framingham /tle style Risk
28 Click pa'ent to edit advice Master /tle style Guan et al. Circula>on 2015;132:e218
29 Click sta'n to use edit in Master cancer /tle style 296x10 3 pa/ents with cancer diagnosis in Denmark 1995 to 2007 followed to 31/12/09. Nielsen et al. NEJM 2012:367;1792
30 Click sta'n to use edit in Master prostate /tle cancer style meta- analysis of 34 observa/onal studies all- cause mortality: Raval et al. Prostate Cancer and Prosta>c Disease 2016:19;151
31 Click sta'n to use edit in Master prostate /tle cancer style meta- analysis of 34 observa/onal studies prostate cancer- specific mortality : Raval et al. Prostate Cancer and Prosta>c Disease 2016:19;151
32 Click sta'n to use edit in Master prostate /tle cancer style meta- analysis of observa/onal studies all- cause mortality cancer- specific mortality pre- diagnosis post- diagnosis Zhong et al. Cancer Treatment Reviews 2015:41;554
33 Click mechanism(s) to edit Master /tle style lowering protein prenyla/on Krens et al. PLoS ONE 2014;9:e reduc/on in tumour cell prolifera/on and migra/on Cardwell et al. Epidemiology 2015;26:68 Livingstone et al. Cancer Med 2014;3:1284 inhibi/on of Ras signaling Nam et al. An/cancer Res 2014;34:355 induc/on of apoptosis through phosphoryla/on of Akt and down- regula/on of mtor Kaffenberger et al. Urol Oncol 2014;33:e11. Zhong et al. Cancer Treatment Reviews 2015:41;554
34 Click to edit Master /tle style conclusions
35 Click conclusions to edit Master /tle style high cardiovascular risk popula/on common cause of death in PC risk factor modifica/on 1 > 2 - required sta/n therapy may be highly effec/ve in mortality highly effec/ve treatments for prostate cancer CV risk may be by GnRH agonists in men with CVD ADT and other treatments increase CV risk factors increased vigilance and management of hypertension, hyperlipidemia, insulin resistance, QTc etc.
36 Click challenges to edit for Master the future /tle style educa/on pa/ents, primary care, cardiologists, oncologists evidence based CVS 1 and 2 preven/on RCTs with CVS outcomes orchiectomy vs GnRH agonist vs antagonist sta/ns for prostate cancer and CVS end- points ethical? basic science mechanisms of ADTs, sta/ns etc. opportunity to improve prognosis in prostate cancer pa'ents.
37 Click to edit Master /tle style Thank You.
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Naviga2ng the Adverse Effects of ADT: Improving Pa2ent Outcomes
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