6. Treatment modalities for PCa

PCa treatment is variable, and it is chosen according to the staging of the cancer and, mainly, according to the patient's own preference. Since this type of cancer has slow growth, the presence of low-risk groups, where tumor is diagnosed still in situ, is indicative of an active surveillance treatment in which the patient only accompanies the tumor through regular PSA testing, and digital touch every 3–6 months [90]. During this follow-up period, if the existence of a tumor progression is observed, radiotherapy or surgery is indicated by total removal of the prostate gland (radical prostatectomy).

Radical prostatectomy may be the first choice of the patient who opts for complete removal of the gland, by caution of future metastasis. It is an effective procedure, however, just like any surgical procedure, there may be complications and compromise the patient's quality of life. For this procedure, the most common complications are the urinary incontinence, erectile dysfunction, and inguinal hernia; anyhow, the prognosis tends to be positive and long-lasting [91]. Nonetheless, some tumors may recur over time even after radical prostatectomy. In such cases, it is important to evaluate whether the recurrence was local or occurred at a distance (lymph nodes or other organs, such as liver, bone, or lung).

Hormone therapy is usually used in patients with lymph node involvement or distant metastasis. It consists of reducing androgen concentrations to the level of castration. This can be done by surgical method through bilateral orchiectomy, or through drugs that act on the androgen receptor (AR) pathways; the latter being more commonly used nowadays. At first, hormone deprivation therapy has great effects on the control of advanced PCa. However, it is known that part of the cases evolves to the state of CRPC. The mechanisms responsible for progression of tumor growth, despite hormonal blockade, have not been fully elucidated yet. Current studies have shown that molecular changes in the androgen receptor (AR) are related to such progression. Among these changes, it is relevant to mention the overexpression of AR, mutations in the AR gene that allow its activation by other endogenous steroids, increased production of growth factors activating AR even in the absence of androgen, changes in co-regulatory proteins and upregulation of enzymes related to androgen synthesis [92].

There are two drug lines for hormone therapy; the first line accounts for the central blockers that constitute the agonists of gonadotrophin-releasing hormone (GnRH agonists), and the peripheral androgen receptor blockers. Usually they are used in a comminuted way, since the central blockers, for example, Leuprolide (Lupron) and Gosserelin Acetate (Zoladex), acts through the interruption of the pituitary feedback mechanism, inhibiting LH realizing by the pituitary gland, and leading to a decreased testoterone production [63]. However, because these drugs initially boosted testosterone production, the combination with peripheral androgen receptor blockers, such as Bicalutamide (Casodex), Flutamide (Flutamide) and Androcur (Androcur), shall be indicated due to their binding capacity to the ARs in a way that inhibits androgenic stimulation, deactivating their genetic expression [93].

The second line of therapy is most commonly used when PCa is resistant to the first-line hormonal therapies stage. Abiraterone Acetate (Zytiga) is a drug that primarily acts on the adrenal gland through the inhibition of the 17α-hydroxylase/C17, 20-lyase (CYP17) enzyme, essential for androgen biosynthesis in tissues [94, 95]. Enzalutamide (Xtandi) is another drug of this therapeutic line that works by inhibiting androgen receptors, their signaling pathways, and is able to act on anti-androgen-resistant tumor cells.

It is important to emphasize that hormonal therapy is a palliative treatment, in that it acts to contain the progression of advanced PCa, and not its elimination. In this context, given the scarcity of effective treatments for these types of tumors, it is promising to still search for new biomarkers capable of not only diagnosing PCa early, but also being able to evaluate its aggressiveness and prognosis.
