Since the 1940s, endocrine therapy (including surgical or pharmacologic debulking, androgen receptor antagonists, and other anti-androgen drugs) has become the first-line treatment option for advanced metastatic prostate cancer. The current stage of endocrine therapy includes.
1.Destruction
(1) Surgical debulking
It has been considered as the gold standard for the treatment of advanced prostate cancer. After debulking surgery, the tumor shrinks rapidly, 80% of patients with bone metastases have reduced pain and improved symptoms of urethral obstruction, 90% of patients with limited prostate cancer have their PSA reduced to normal after surgery, and 70% of patients have undetectable PSA after surgery. However, this procedure is only effective for androgen-dependent prostate cancer and not for androgen-non-dependent prostate cancer. Because the cancer cells are not all apoptotic after orchiectomy, there are still androgen non-dependent cells surviving, so debulking can only provide temporary relief, about 10-20% of patients can survive for 5 years, and patients eventually die of prostate cancer.
(2) Drug depot
Luteinizing hormone-releasing hormone analog (LHRH-a) is a synthetic luteinizing hormone-releasing hormone, and the products that have been marketed are: leuprorelin, goserelin and triptorelin. LHRH-a has become one of the standard treatments for androgen removal.
(3) Estrogen
Estrogen action is mainly to inhibit testicular solid ketones, and the most commonly used ones are hexestrol and estradiol valerate. It has been reported that 3 mg of hexestrol daily can cause an extreme reduction of testosterone in the blood, as in post-orchiectomy levels. However, cardiovascular adverse effects are significantly increased. Despite the application of low doses of hexestrol (e.g., 1 mg/day) and concomitant low-dose warfarin (1 mg/day), or low-dose aspirin (75-100 mg/day) for prophylaxis, cardiovascular adverse effects are still high and should therefore be applied with caution. Estrogen is one of the classical endocrine therapies.
2. Maximal androgen blockade (MAB)
In 1945, Huggins et al. began to introduce the concept of total androgen blockade (TAB) in clinical practice, i.e. bilateral adrenalectomy followed by denervation surgery with a view to complete removal of androgens, but this approach has not been widely adopted due to the high rate of disability and mortality.MAB treatment removes or blocks both testicular- and adrenal-derived androgens. Commonly used clinical approaches include orchiectomy or LHRH analogs plus anti-androgen agents (mainly steroids and non-steroids) to block the effects of peripheral androgens, such as flutamide, nilumet and Comstock. Studies have shown that the androgenic MAB approach with the combination of non-steroidal anti-androgenic agents can prolong overall survival by 3-6 months compared to debulking alone, with an average 5-year survival rate of 2.9%. For limited prostate cancer, the longer the application of MAB therapy, the lower the PSA recurrence rate. The combination of MAB therapy with bicalutamide can reduce the risk of death by 20% relative to debulking alone, and can extend progression-free survival accordingly.
3. Pre-radical neoadjuvant endocrine therapy (NHT)
Pre-radical neoadjuvant endocrine therapy refers to the endocrine treatment of prostate cancer patients for a certain period of time before radical prostatectomy to reduce tumor volume, clinical stage, and positive prostate margin tumor rate, which in turn prolongs survival. It has been reported in the literature that stage T2 is the best indication for neoadjuvant therapy, which can significantly reduce the cutting edge positive rate, while stage T1 and T3 are relative indications with insignificant changes in cutting edge positive rate. The method is mostly MAB with LHRH-a and anti-androgens, or LHRH-a, anti-androgen drugs or estradiol nitrogen mustard alone, but the MAB method is more reliable in efficacy. Duration 3-9 months. Neoadjuvant therapy may reduce clinical staging, may reduce the rate of positive prostate margin tumors, reduce the rate of local recurrence, and may extend survival without PSA recurrence for longer than 3 months, while the effect on overall survival requires longer follow-up. Neoadjuvant therapy does not reduce infiltration of lymph nodes and seminal vesicles.
4. Intermittent endocrine therapy (IHT)
In 1992, Beginning of the clinical trial of intermittent anti-androgen therapy, androgen combination blockade was applied at the beginning of treatment, and after the serum PSA dropped to 4ng/ml, the treatment was stopped for clinical observation, and anti-androgen therapy was applied again when the PSA rebounded to more than 10ng/ml, which had no significant adverse effects on the survival rate and tumor tension, but significantly prolonged the time of tumor dependence on androgens. The treatment has no significant adverse effects on the survival rate and tumor tension, but significantly prolonged the time of tumor dependence on androgens. The domestic recommended discontinuation criteria are after PSA≤0,2ng/ml for 3-6 months, and after PSA rises to 4ng/ml, a new round of treatment is started. Treatment modality: MAB approach is mostly used, but pharmacological depot (LHRH-a) or steroidal cyproterone acetate (CPA) is also available. Studies suggest that intermittent endocrine therapy may maintain the hormone dependence of prostate cancer cells and delay the progression of prostate cancer cells to non-hormone dependence, thus possibly prolonging patient survival. There is also a risk of accelerating the progression from androgen-dependent to non-hormone-dependent.
5. Adjuvant endocrine therapy (AHT)
Adjuvant endocrine therapy targets undetected cancer cells in the pelvic lymph nodes, as well as underlying lesions outside the original treatment area, with the aim of improving overall patient survival and tumor-free survival. Most of the literature reports that AHT treatment can delay the time of disease progression, but there is no consistent conclusion whether it can improve the survival rate of patients. The choice of treatment timing and time limit should take into account the patient’s pathological stage, treatment side effects and cost, etc., which are still inconclusive. Most advocate starting immediately after surgery or radiotherapy. Adjuvant therapy is indicated for the following grades of tumors.
(1) Positive postoperative pathological margins.
(2) Positive postoperative pathological lymph nodes (pN+).
(3) postoperative pathologically confirmed T3 stage (pT3).
(4) ≤T2 with high-risk factors.
Treatment modalities may be MAB, pharmacological depot (LHRH-a) or anti-androgens.