Endocrine Systemic Therapy
Many prostate cancers use testosterone as a growth signal. The very first endocrine therapy for prostate cancer was castration; by removing the testes, the production of testosterone was reduced dramatically and most prostate cancers shrank (for a time). The irreversibility of this procedure meant that it was supplanted by gonadotrophin-releasing hormone receptor agonists. GnRH antagonists are newer therapies that are not in common use but have a similar effect.
Important note - Gonadotropin releasing hormone (GnRH) is also known as leutenising-hormone-releasing hormone (LHRH). GnRH/LHRH lead to release of leutenising hormone (LH) as well as follicle stimulating hormone (FSH), hence the former term is preferred.
Function of GnRH Agonists
GnRH is the protein product of the GNRH1 gene. It is 10 amino acids in length and is produced by neurons in the anterior hypothalamus, before passing through the pituitary portal system to the anterior pituitary gland. In the anterior hypothalamus GnRH binds to gonadotrophs, endocrine cells that produce LH and FSH. Importantly, pulsed release and binding of GnRH to the GnRH receptor on gonadotrophs is required for continual LH/FSH release. In men, LH binds to Leydig cells in the testis and promotes testosterone production.
GnRH agonists permanently bind to the GnRH receptor in the gonadotrophs. This leads to an initial surge of LH release with corresponding increase in testosterone production. This is followed by downregulation of GnRH receptors and loss of LH production/testosterone production over 1 - 2 weeks.
The testosterone surge is important when instituting therapy for patients with metastatic disease. The testosterone sensitive cells can respond to the high testosterone levels and cause increasing pain or other symptoms.
Use of GnRH Agonists
There are three times where GnRH agonists are used:
- For high risk, localised prostate cancer - there is evidence of improved overall survival when there is several months of androgen deprivation prior to institution of prostate radiotherapy. GnRH agonists should be continued after treatment for 2 - 3 years total therapy
- For biochemical or clinical recurrence of prostate cancer after definitive treatment - GnRH agonists can provide control (for an average of 2 years) of relapsed prostate cancer
- Initial therapy of metastatic prostate cancer - when prostate cancer is metastatic on diagnosis GnRH agonists provide a relatively low toxicity treatment that, in most cases, is highly effective for months to years.
Cytotoxic Systemic Therapy
When prostate cancer becomes resistant to hormonal therapies, the decision whether to pursue further systemic treatments need to be made.
In all cases hormonal agents (LHRH agonists etc) should be continued to continue suppression of tumour clones that utilise hormonal pathways.
First Line
Docetaxel is the currently recommended chemotherapy agent once hormonal therapy has failed.
Second Line
TROPIC:
Cabazitaxel + Prednisolone shown to be superior to Mitoxantrone + Prednisolone
- 28% reduced risk of death with cabazitaxel.
- Longer progression free survival
- Diarrhoea more common
- Nausea/Vomiting more common
- Neutropenia more common with cabazitaxel.
- Higher rates of febrile neutropenia (7.5% vs 1.5%) and death (5% vs 2%)
Third Line
Mitoxantrone + Prednisolone
- Mitoxantrone inhibits the synthesis of androgens in all tissues, including in tumour cells
- This prevents autocrine stimulation of androgen receptors in tumour cells
