Side Effects and Management of ADT for Prostate Cancer

Abstract

Androgen deprivation therapy (ADT) is the main treatment for advanced prostate cancer and is increasingly used in combination with radiotherapy in patients with earlier stages of prostate cancer. For many years, gonadotropin-releasing hormone (GnRH) agonists have been the ADT standard of treatment. There are, however, several drawbacks related to the mechanism of action of GnRH agonists. In particular, the initial testosterone surge associated with these agents delays the achievement of castration levels of testosterone and can produce a flare in clinical symptoms in patients with advanced disease [1, 2]. Furthermore, microsurges in testosterone levels occur with repeated agonist administration [3]. In this context, it is interesting to note that increases in testosterone above 1.1 nmol/L (32 ng/dL) during agonist treatment were associated with a significantly shorter survival free of androgen-independent progression than patients who had increases <32 ng/dL [4]. Despite the proven success of hormonal therapy, most patients showing an initial response will eventually experience disease progression [5]. Cancer that relapses after initial ADT is termed androgen-independent or castration-resistant prostate cancer (CRPC) [6]. The precise definition of CPRC is, however, controversial. Recent European Association of Urology guidelines define CRPC as castration levels of testosterone (<1.7 nmol/L [50 ng/dL]) and three consecutive rises of PSA, 1 week apart, resulting in two 50% increases over the nadir, with a PSA > 2 ng/mL, despite consecutive hormonal manipulations [7]. However, other definitions of progression have been used. Sharifi et al., for example, defined androgen independence as the first sustained increase in PSA level from the PSA nadir after starting ADT [8]. Based on this definition, they found that the median time to androgen independence was 13–19 months after starting ADT, depending on the disease stage at initiation. In patients with metastatic disease, it is estimated that >90% will progress to androgen independence within 18–24 months [9]. As CRPC carries a much poorer prognosis [10] and might signal the need for chemotherapy [11], any delay in the onset of castration resistance is clearly desirable. GnRH antagonists represent an alternative form of ADT, with a direct and immediate action that allows castration without an initial testosterone surge or subsequent microsurges.