Endocrine therapy for prostate cancer (Pca) has a history of more than 60 years, and has been widely used in clinical practice since it was first reported by Canadian physicians Huggins and Hodges in 1941 [1]. Currently, endocrine therapy is still the main treatment for advanced Pca, which aims to reduce or eliminate the growth-promoting effect of androgens on prostate cancer cells. It mainly includes depot therapy, anti-androgen drug therapy, maximal androgen blockade, intermittent androgen blockade and treatment of androgen non-dependent prostate cancer. In this article, we review the latest views of current research in this field.
1.Desmotherapy
The aim of desmotherapy is to reduce serum testosterone (testosterone, T) concentration to desmothered levels. It is generally believed that T is reduced to less than 5%-10% of the pre-treatment baseline value to determine the level of destructive. However, some scholars believe that the level of depot should be lower than 50ng/dl, or even lower than 20ng/dl [2]. There are two types of debulking: surgical debulking and pharmacological debulking.
1.1 Surgical debulking The use of bilateral orchiectomy is still the gold standard of advanced Pca debulking treatment at home and abroad, which can remove 90%-95% of T in the body and significantly reduce the pain caused by Pca bone metastases. After bilateral orchiectomy or bilateral testicular seminiferous tubule debridement, serum T and free testosterone (FT) can be decreased by 92.27% and 92.26%, respectively, and dihydrotestosterone (DHT) can be decreased by only 58.36% in Pca patients [3], which This is because DHT produced in the adrenal reticular zone will not be eliminated with the debulking surgery, so additional drugs must be used after debulking to achieve maximum androgen blockade or total androgen blockade.
1.2 Pharmacological denervation refers to the use of estrogenic drugs and luteinizing hormone releasing hormone (LHRH) analogues to block androgen production without removing the testes, so that the T concentration reaches the denuded level.
1.2.1 Estrogen therapy Estrogen can inhibit the release of pituitary luteinizing hormone (LH), which can lower blood T and play a role in the treatment of Pca. The most commonly used estrogen is diaethylstilbestrol (DES), which is inexpensive, has good efficacy, and is a good choice for patients with limited financial resources. the dose of DES is reduced to 1 mg/d and aspirin 75 mg is added to reduce cardiovascular toxicity.
DES was once a classic depot drug, but its widespread clinical use has been limited by the potential for significant cardiovascular disease (including myocardial infarction, cerebral thrombosis, and pulmonary infarction). Because LHRH analogs have similar efficacy to estrogen and no cardiovascular complications, they have been phased out with the use of LHRH analogs, and currently, haloestrol is no longer used as a first-line choice for pharmacological depot.
1.2.2 LHRH analogues include LHRH agonists (LHRH-a) and LHRH antagonists. goserelin (goserelin), trade name: zoladex, 3.6mg; leuprolide (leuprolide), trade name: enantone, 3.75mg, are commonly used for LHRH-a; In addition, triptorelin, trade name: depherelin, 3.75 mg, is administered subcutaneously once every 4 weeks.
LHRH-a is the most widely used deprenyl drug. It binds to the receptors on pituitary gonadotropin-producing cells and causes a transient gonadotropin release and a rise in serum T at the beginning of treatment. This is the main side effect of these drugs, so the first 2 weeks of the first dose should be accompanied by anti-androgen therapy. After about 1 week of LHRH-a treatment, the LHRH receptors are reduced and the pituitary response to LHRH gradually decreases, and the depot effect is achieved after 3-4 weeks. In China, LHRH-a is used only when the patient refuses to undergo surgical decompensation and it is financially acceptable. In addition, about 10% of patients cannot reach the level of depot after LHRH-a injection, and this group of patients may need to be treated by surgical depot [4].
The mechanism of action of LHRH antagonists is similar to that of agonists, but due to their special molecular structure, they do not lead to a transient increase in T and an increase in clinical symptoms after use. The commonly used drug is abarelix (trade name: Plenaxis), a pure LHRH blocker developed by Praecis Pharmaceuticals, Inc. and approved by the US FDA in 2003 and marketed in the US the following year [5]. Abarelix is a drug used to treat advanced prostate cancer when there are no other alternative therapies available to the patient. The drug is labeled for: symptomatic treatment of advanced prostate cancer that cannot be treated with other hormonal therapies and for those who refuse surgical debulking. Degarelix, developed by Ferring, began a phase III clinical trial in February 2006. Degarelix, given continuously for one year, provides rapid and sustained suppression of T levels, while also being effective in maintaining a durable reduction in prostate specific antigen (PSA). The main adverse effects such as fatigue are caused by the reduction of T levels, and no serious toxic side effects and local or systemic allergies have been found. It has not been found to have the same effect of causing histamine release as other LHRH blockers [6].
2. Anti-androgen drug therapy
Anti-androgen drugs (i.e. androgen receptor blockers) are widely used in clinical practice because of their advantages of ease of use, low adverse effects, and avoidance of psychological abnormalities in patients after orchiectomy [5]. They can bind to androgen receptors in the nucleus of prostate cancer cells, thus reducing the growth-promoting effects of T and DHT on cancer cells, and are classified into steroidal and non-steroidal according to their chemical structures.
2.1 Steroidal anti-androgen drugs Cyproterone acetate (CPA) is the representative, in addition to megestrol acetate and medroxyprogesterone acetate, but the overall efficacy is lower than that of CPA. Since CPA decreases serum T, it has side effects such as decreased sexual interest and erectile dysfunction, and a few patients have experienced breast pain, cardiovascular toxicity and liver damage.
2.2 Non-steroidal anti-androgens Commonly used are flutamide, bicalutamide and nilutamide. These drugs have a single action and only bind to androgen receptors, so they are also called pure anti-androgens. The biggest advantage is to maintain the patient’s sexual function, and they have no cardiovascular side effects and do not cause thrombosis.
2.2.1 Flutamide (trade name: Fuzil, formerly known as retarded tumor) The recommended dosage is 250mg, tid, which is the most used anti-androgen drug nowadays. Since it needs to be converted into the active drug form hydroxyflutamide in the liver, it has visceral toxicity. Mild liver damage such as transaminases is often self-limiting after stopping the drug (incidence about 10%), but the incidence of fatal liver damage after taking flutamide has been reported to be 3/10,000, which is 10 times higher than that of the general population, so liver function should be checked regularly while taking the drug.
2.2.2 Bicalutamide, trade name: casodex, 50mg, qd, is a selective anti-androgen drug which has been used more often. Its affinity with androgen receptor is 4 times stronger than that of fibramide, and its structure and composition are different from those of fibramide. This suggests that the two drugs have different sites of action at the androgen receptor. Compared with flutamide, bicalutamide has similar effects on the improvement of quality of life, PSA control rate and symptom relief in patients with advanced Pca, but its hepatotoxicity and other side effects are lower than those of flutamide, and bicalutamide is currently considered to have the best safety and tolerability.
2.2.3 nilutamide Induction dose 300mg/d for 4 weeks, maintenance dose 150mg/d. nilutamide is less subject to metabolic changes in chemical structure in vivo and has longer lasting effect on receptors. if combined with surgical or chemical (with LHRH analog) depot, it can make the peripheral anti-androgenic effect more complete, i.e., it can inhibit the effect of androgens still secreted by adrenal cortex after depot. It can suppress the effect of androgens still secreted by the adrenal cortex after depotting, and it can suppress the increase in serum T and the deterioration of Pca that occurs in the first days after the effect of LHRH analogs. Thus, the effect is more complete. It is suitable for metastatic Pca and can be used in combination with surgery or chemical debulking.
3.Maximal androgen blockade (MAB) treatment
MAB, also known as androgen blockade or combined androgen blockade (CAB), aims to block all T secreted by the testes and adrenal glands from acting on androgens. In men, 90%-95% of T is produced by the testes and the remaining 5%-10% by the adrenal glands, and surgical and pharmacological debulking have comparable effects, but both have no effect on T of adrenal origin, which shows that androgen blockade by debulking alone is incomplete, and this partial androgen blockade is thought to have the potential to cause rapid growth of androgen non-dependent tumor cells [9], leading to the failure of endocrine therapy. failure of endocrine therapy. MAB is now becoming the most common endocrine therapy for patients with advanced Pca.
The results of the Janknegt study showed that the combination of orchiectomy with palliative regression was significantly more effective than orchiectomy alone. Currently, MAB is mainly used in advanced and recurrent Pca, neoadjuvant endocrine therapy before radical surgery and adjuvant endocrine therapy with radiotherapy. However, it is still debated whether MAB is more effective than single endocrine therapy. The European and American Prostate Collaborative Clinical Trials Group (PCTCG) [12] has one of the largest meta-analyses to date comparing complete androgen blockade versus single denervation, including 8,275 patients with locally advanced or metastatic Pca from 27 randomized clinical trials, and showed that the 5-year survival rate for patients treated with MAB was 25.4%, slightly higher than for those who received only a single drug or surgery. The difference was not statistically significant. And there are three obvious disadvantages of long-term MAB treatment: high treatment cost, inevitable androgen non-dependence, and deterioration of quality of life.
4. Intermittent androgen blockade (IAB) treatment
IAB treatment refers to the cyclic treatment method in which Pca patients undergo endocrine therapy for a period of time and then the serum T drops to the depressed level and the PSA drops below the normal level, and then the next treatment is restarted for the same period according to the further development of the tumor (e.g., elevated PSA). Currently, IAB is also known as Intermittent androgen deprivation (IAD) or Intermittent androgen suppression (IAS) in the literature.
With MAB treatment, most Pca patients will eventually develop androgen independent prostate cancer (AIPC), which is not dependent on androgens for growth. Recent studies have shown that MAB does not prolong the time for prostate cancer cells to progress to non-androgen dependent, and it also decreases the quality of life of patients, such as low libido, impotence, fatigue, and depression, and is costly. Therefore, intermittent androgen blockade has been proposed to prolong the transition of tumor cells to non-hormone-dependent cells. Recent phase III clinical reports have shown that at 51 months follow-up, survival of locally advanced and metastatic patients undergoing intermittent endocrine therapy was similar to that of those on continuous therapy, and that 82% of survival time for those whose PSA dropped below 2 ng/ml after first treatment did not require treatment. The current study shows that IAB is a practical treatment strategy that prolongs survival and the emergence of drug resistance at low cost to the patient and provides a better quality of life.
The current IAB treatment regimen abroad is a combination of pharmacological depot and androgen receptor blockers applied intermittently to treat Pca patients. The common combination method is mainly LHRH analog enantone or zoladex plus non-steroidal anti-androgen drugs flutamide or Comstock. the duration of each cycle of IAB treatment and the criteria for stopping treatment are reported differently, and the recommended discontinuation criteria in China is to start a new round of treatment when PSA <0.2ng psa="">4ng/ml. the criteria for IAB re-treatment also exist There are great differences, in general, according to the patient’s clinical stage, pre-treatment serum PSA level, to achieve individualization of serum PSA level: patients with low pre-treatment serum PSA level, when the serum PSA value reaches the initial level then resume treatment; patients with high pre-treatment serum PSA level, when serum PSA>20ug/L or so resume treatment; 3 months of treatment serum PSA<4ug psa= "">10ug/L; asymptomatic patients PSA>20ug/L are resumed treatment.