title: Cardiovascular outcomes in patients with locally advanced and metastatic prostate cancer treated with luteinising-hormone-releasing-hormone agonists or transdermal oestrogen: the randomised, phase 2 MRC PATCH trial (PR09).
abstract: BACKGROUND
  Luteinising-hormone-releasing-hormone agonists (LHRHa) to treat prostate cancer are associated with long-term toxic effects, including osteoporosis. Use of parenteral oestrogen could avoid the long-term complications associated with LHRHa and the thromboembolic complications associated with oral oestrogen.
  
  
  METHODS
  In this multicentre, open-label, randomised, phase 2 trial, we enrolled men with locally advanced or metastatic prostate cancer scheduled to start indefinite hormone therapy. Randomisation was by minimisation, in a 2:1 ratio, to four self-administered oestrogen patches (100 μg per 24 h) changed twice weekly or LHRHa given according to local practice. After castrate testosterone concentrations were reached (1·7 nmol/L or lower) men received three oestrogen patches changed twice weekly. The primary outcome, cardiovascular morbidity and mortality, was analysed by modified intention to treat and by therapy at the time of the event to account for treatment crossover in cases of disease progression. This study is registered with ClinicalTrials.gov, number NCT00303784.
  
  
  RESULTS
  85 patients were randomly assigned to receive LHRHa and 169 to receive oestrogen patches. All 85 patients started LHRHa, and 168 started oestrogen patches. At 3 months, 70 (93%) of 75 receiving LHRHa and 111 (92%) of 121 receiving oestrogen had achieved castrate testosterone concentrations. After a median follow-up of 19 months (IQR 12-31), 24 cardiovascular events were reported, six events in six (7·1%) men in the LHRHa group (95% CI 2·7-14·9) and 18 events in 17 (10·1%) men in the oestrogen-patch group (6·0-15·6). Nine (50%) of 18 events in the oestrogen group occurred after crossover to LHRHa. Mean 12-month changes in fasting glucose concentrations were 0·33 mmol/L (5·5%) in the LHRHa group and -0·16 mmol/L (-2·4%) in the oestrogen-patch group (p=0·004), and for fasting cholesterol were 0·20 mmol/L (4·1%) and -0·23 mmol/L (-3·3%), respectively (p<0·0001). Other adverse events reported by 6 months included gynaecomastia (15 [19%] of 78 patients in the LHRHa group vs 104 [75%] of 138 in the oestrogen-patch group), hot flushes (44 [56%] vs 35 [25%]), and dermatological problems (10 [13%] vs 58 [42%]).
  
  
  CONCLUSIONS
  Parenteral oestrogen could be a potential alternative to LHRHa in management of prostate cancer if efficacy is confirmed. On the basis of our findings, enrolment in the PATCH trial has been extended, with a primary outcome of progression-free survival.
  
  
  BACKGROUND
  Cancer Research UK, MRC Clinical Trials Unit.
authors: MRC Clinical Trials Unit, London, UK. rel@ctu.mrc.ac.uk
authors: Ruth E
authors: RE
authors: Langley
authors: Fay H
authors: FH
authors: Cafferty
authors: Abdulla A
authors: AA
authors: Alhasso
authors: Stuart D
authors: SD
authors: Rosen
authors: Subramanian Kanaga
authors: SK
authors: Sundaram
authors: Suzanne C
authors: SC
authors: Freeman
authors: Philip
authors: P
authors: Pollock
authors: Rachel C
authors: RC
authors: Jinks
authors: Ian F
authors: IF
authors: Godsland
authors: Roger
authors: R
authors: Kockelbergh
authors: Noel W
authors: NW
authors: Clarke
authors: Howard G
authors: HG
authors: Kynaston
authors: Mahesh Kb
authors: MK
authors: Parmar
authors: Paul D
authors: PD
authors: Abel
mesh_terms: D000368:Aged; D000726:Androgen Antagonists / Q000008:administration & dosage; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000401:mortality / Q000503:physiopathology; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions; D004967:Estrogens / Q000008:administration & dosage*; D019584:Hot Flashes / Q000188:drug therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011966:Receptors, LHRH / Q000008:administration & dosage* / Q000819:agonists
chemical_list: D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D004967:Estrogens; C484844:GNRHR protein, human; D011966:Receptors, LHRH