Surgical Castration for the Late Development of Resistance to Medical Castration with LHRH Agonists and Antagonists in Castrate-Resistant Prostate Cancert

Case Report

Ann Hematol Oncol. 2014;1(2): 1008.

Surgical Castration for the Late Development of Resistance to Medical Castration with LHRH Agonists and Antagonists in Castrate-Resistant Prostate Cancert

Yaser Al-Marrawi1*,Nazia Raja-Khan2, Kevin WuCarol Mallon RN OCN1, Monika Joshi1, Sheldon Holder1Matthew Kaag3,Jeffrey Sivik DPharm3 and Joseph J Drabick1

1Penn State University/Hershey Medical Center, Cancer Institute, Hershey, PA, USA

2Penn State University/Hershey Medical Center, Endocrinology Division, Hershey, PA, USA

3Penn State University/Hershey Medical Center, Urology Division, Hershey, PA, USA

4Penn State University/Hershey Medical Center, Pharmacy, Hershey, PA, USA

*Corresponding author: Yaser Al-Marrawi, Penn State University/Hershey Medical Center, Cancer Institute, Hershey, PA, USA, 500University Drive, Hershey, PA 17033

Received: October 10, 2014; Accepted: October 31, 2014; Published: November 03, 2014


Acquired resistance to GNRH agonists or antagonists used for the induction of medical castration for the treatment of metastatic prostate cancer has been rarely reported. To date, the mechanism(s) behind the development of apparent resistance to these agents has yet to be adequately defined while the impact of this refractoriness may possibly be detrimental even in Castrate-Resistant Prostate Cancer (CRPC). Here we describe two men with CRPC who were compliant with their GNRH agonist and who had documented low testosterone levels for years. They then developed rising testosterone levels despite documented continued receipt of these agents. Switching to the pure LHRH antagonist, degarelix, did not improve the testosterone suppression. Of interest, repeated determinations of luteinizing hormone were undetectable in both men suggesting the apparent resistance was not at the level of the hypothalamicpituitary axis. They did not have elevated Beta-HCG, prolactin or estrogen levels. The testosterone levels also did not respond to abiraterone given for their CRPC nor did them everhave sterile abscesses which have been associated with resistance to LHRH agonists. They therefore underwent surgical castration with bilateral orchiectomy and their testosterone levels returned to appropriate castrate levels againsuggesting that the failure of medical castration was not due to androgen production by the tumor cells but rather by the gonads. Understanding the endocrine mechanism for this failure remains unclear but the response to surgical castration suggests it is at the level of the gonads. These cases and others support the continued checking of testosterone levels while on long term medical castration agent since resistance can occur after many years of good control. Then, surgical castration becomes the treatment of choice.

Keywords: Surgical Castration; LHRH Agonist Resistance; LHRH Antagonist Resistance; Medical Castration Resistance; Resistant Prostate Cancer; Endocrine Therapy Resistance; Prostate Cancer Resistant To Endocrine Therapy


Androgen-Deprivation Therapy (ADT) in the form of castration has been the mainstay of therapy for prostate cancer since the 1940s [1-5]. The goal of ADT is to reduce gonadal androgens to castration levelswhether applied surgically with bilateral orchiectomy or medically via gonadotropin receptor- blockage using either LHRH agonists or antagonist (Figure 1). ADT typically only works for a limited time before prostate cancer cells find a way of surviving despite castration serum levels of testosterone, the prostate cancer cells may survive on low levels of androgens produced by the adrenal glands or may actually produce their own androgens [6-8]. They may also survive by becoming completely independent of androgen stimulation [9-11]. Prostate cancer at that juncture has become castration resistant. Even in CRPC, castration therapy should be continued since many of the clones remain sensitive to castration such that stopping it and allowing testosterone levels to rise can result in flares of disease [12]. It has been demonstrated that incomplete testosterone suppression has been associated with increased biochemical failure rates and metastases with worsesurvival [13]. Previous case reports reported a correlation between LHRH analogues resistance and formation of sterile abscesses or inflammation at sites of LHRH analogue injection which apparently interfere with absorption of the drug from the injection site [14]. However, other reports noted LHRH resistance despite absence of any sterile abscess with goserelin [15], and that resistance developed shortly after initiation of therapy with the second 3-month injection despite the sharp initial response in terms of serum testosterone level and PSA level as well. Many oncologists stop monitoring testosterone levels after levels of testosterone post initiation of medical castration have attained castrate levels. The previous case-reports and our experience suggest that testosterone levels should be monitored regularlyin patients on medical castration with GNRH agonists or antagonists since resistance to these drugs can occur either early or late. The mechanism for this apparent failure of these agents to adequately suppress testosterone after years of control has not been elucidated adequately to date but does respond to surgical castration. Here we present 2 cases of men with advanced prostate cancer who developed rising testosterone levels despite regular receipt of theseagents which had worked previously. Some endocrine testingwere performed trying to uncovera defectresponsible for this breakthrough and in both cases the problem resolved with surgical castration.