First-line hormonal manipulation: Surgical and medical castration with LHRH agonists and antagonists, steroids, and pure antiandrogens

Abstract

Over the past years, many different approaches to the treatment of advanced, metastatic carcinoma of the prostate have been introduced, and with impressive speed. Today, endocrine therapy, in the form of androgen deprivation (ADT), as first suggested by Charles Huggins, is still the standard treatment and is always the first step in any systemic therapy for metastatic, hormone-sensitive carcinoma of the prostate [1]. Charles Huggins and Clarence V Hodges were awarded the Nobel Prize for Physiology and Medicine in 1966 for their research in 1941 into the effects of androgens on prostate carcinoma cells [2]. Andrew V Schally developed the LHRH agonists and, together with Roger Guillemin, received the Nobel Prize in 1977 for their research on peptide hormone production in the brain. In 1971, Schally et al. were the first to isolate and elucidate the structure and synthesis of the hypothalamic “luteinizing hormone releasing hormone” (LHRH) [3-5]. Recognizing the importance of the hypothalamic-pituitary-gonadal axis in the growth of prostate carcinoma cells and the elucidation of gonadotropin releasing hormone (GnRH) resulted in the gradual development of hormone therapy for carcinoma of the prostate in the last century. Numerous agonistic and antagonistic therapeutic substances that intervene in the testosterone synthesis feedback loop have been established in clinical practice. Despite decades of clinical use, much controversy still reigns over the best approach to ADT (surgical vs. medical), the best time to start treatment (immediate or delayed), the type of ADT (simple vs. total), and the modality and duration of treatment (intermittent or continuous) [6]. Moreover, the gold standard of ADT alone as first-line therapy may well be modified soon thanks to study findings published in 2015 that so far show - at least for patients with metastatic carcinoma of the prostate - statistically significant and clinically relevant advantages of first-line therapy of ADT combined with chemotherapy rather than ADT alone [7-9]. Curative treatment of metastatic disease is still not yet possible. This applies to both carcinoma of the prostate, which is metastatic at the time of diagnosis, and to recurrences of disease after initial treatment with curative intent (including salvage therapy).