title: Risk of disease flare with LHRH agonist therapy in men with prostate cancer: myth or fact?
abstract: OBJECTIVE
  The traditional assumption of a linear relationship between serum testosterone and prostate cancer growth has been seriously challenged, as overwhelming evidence contradicts its basic principles. Luteinizing hormone-releasing hormone (LHRH) agonists are known to cause a peak in serum testosterone level in the initial weeks of treatment, and prevention of the clinical sequelae of testosterone flare by concomitant use of antiandrogens is recommended. Along the present biological concept that there appears to be a limit to the ability of androgens to stimulate prostate cancer growth, termed the saturation model, the use of antiandrogens to prevent this disease flare is questioned. The purpose of this review is to gain historical and modern evidence to provide an objective and up-to-date basis for clinical decision making.
  
  
  METHODS
  We performed a comprehensive research of the electronic databases PubMed and Embase until April 1, 2014. Studies with the subject of disease flare in men with prostate cancer on LHRH agonist therapy were included, as were studies that assessed the efficacy of antiandrogens to prevent this flare. Case reports were included as well.
  
  
  RESULTS
  Overall, 25 studies considering disease flare were included: 9 randomized clinical trials with an LHRH agonist and an LHRH agonist/antiandrogen arm, 14 observational studies evaluating LHRH agonists only, and 2 case reports. The incidence of disease flare was reported between 0% and 83% owing to a wide set of clinical, biochemical, and radiological factors evaluated. In some of the randomized clinical trials, a statistically significant reduction of the incidence of disease flare by concomitant use of antiandrogens was reported. Most of these historical studies report on subjective worsening of disease symptoms as outcome measure. More objective outcome measures such as the prostate-specific antigen level did not seem to increase to higher than the baseline values.
  
  
  CONCLUSIONS
  At present, there is a lack of compelling data showing definite disease progression during the short period of testosterone flare after initiation of LHRH agonist therapy. Based on the saturation model, presence of disease flare and the need to prevent this flare by concomitant use of antiandrogens might well be a misconception.
authors.affiliation: Department of Urology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: a.vis@vumc.nl.
authors.forename: André N
authors.initials: AN
authors.lastname: Vis
authors.affiliation: Department of Urology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Tim M
authors.initials: TM
authors.lastname: van der Sluis
authors.affiliation: Department of Urology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Hoda H M
authors.initials: HHM
authors.lastname: Al-Itejawi
authors.affiliation: Department of Urology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: R Jeroen A
authors.initials: RJA
authors.lastname: van Moorselaar
authors.affiliation: Department of Urology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Eric J H
authors.initials: EJH
authors.lastname: Meuleman
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D012307:Risk Factors; D013739:Testosterone / Q000097:blood
chemical_list: D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone
keywords: Antiandrogen; Bicalutamide; Flare; Flutamide; LHRH agonist; Nilutamide; Prostate cancer