Current Status and Progression of Endocrinotherapy for Prostate Cancer in the View of Translational Medicine
QIAN Li-ya1, MA Hai-ling2, CHEN Xiao-feng2, XIE Jun2,*
1. Department of Endocrinology, Zhangjiagang Hospital of Traditional Chinese Medicine, Zhangjiagang, Jiangsu, 215600, China
2. Department of Pharmacy, Zhangjiagang Hospital of Traditional Chinese Medicine, Zhangjiagang, Jiangsu, 215600, China
*Corresponding Author: XIE Jun, E-mail: 26229220@qq.com
Abstract

Prostate cancer is a common malignant tumor in urological system. It is also the second leading cause of high morbidity and mortality among men in Western countries. The occurrence and development of prostate cancer is a multi-factor and multi-step process involving changes of numerous genes from the aspect of molecular genetics. In the last decades, translational medicine has discovered that numerous basic research specific to the prevention, diagnosis and treatment of prostate cancer has broaden the application prospect, especially endocrinotherapy, which is of great importance in the treatment of prostate cancer. This study mainly reviewed the mechanism, indications and therapeutic protocols of endocrinotherapy, including castration treatment, anti-androgen treatment, maximal androgen blockade (MAB), intermittent hormonal therapy (IHT), neoadjuvant hormonal therapy (NHT) and adjuvant hormonal therapy (AHT), aiming to provide references for the clinical treatment of prostate cancer.

Key words: Prostate cancer; Castration treatment; Anti-androgen treatment Maximal androgen blockade Intermittent hormonal therapy Neoadjuvant hormonal therapy; Adjuvant hormonal therapy Translational medicine
Introduction

Prostate cancer is a common malignant tumor in urological system. It is also the second leading cause of high morbidity and mortality among men in Western countries. It ranks the second in male cancers, and mainly occurs in patients> 50 years old [1, 2]. Prostate cancer is an androgen-dependent cancer, so endocrinotherapy, as an important therapy, has received extensive attention from global experts. In recent years, lots of studies have showed the advances of endocrinotherapy in the treatment of prostate cancer [3, 4]. Situmorang et al. [5] has proved that hormonal therapy plays a well-defined role and is also the primary method in the treatment of patients with metastatic prostate cancer, and it has been extensively used in patients with advanced prostate cancer, especially in elderly patients.

The occurrence and development of prostate cancer is a multi-factor and multi-step process involving changes of numerous genes from the aspect of molecular genetics [6]. Translational medicine is the bridge and rapid passage between basic research and clinical practice, which can transform the basic research results into theories, techniques, methods and drugs in clinical practice. Meanwhile, it can find and propose issues from clinical practice which will be fed back into laboratory. It goes upwards spirally and develops continuously [7]. In the last decades, translational medicine has discovered that numerous basic research specific to the prevention, diagnosis and treatment of prostate cancer has broaden the application prospect, especially endocrinotherapy, which is of great significance in the clinical treatment of prostate cancer.

Endocrinotherapy Mechanisms

As early as in the 1940s, Gilbert [8]found that surgical castration combined with estrogen could effectively postpone the progression of prostate cancer, and prostate cancer cells would undergo apoptosis if they lost the persistent stimulation from androgen, which first proved the hyperresponsiveness of prostate cancer to androgenic deletion, and opened new endocrinotherapy for tumors. Androgen includes testosterone, dehydroepiandrosterone and androstenedione, in which testosterone is the strongest in activity. About 90%-95% testosterone in human plasma is from testis, and little from adrenal gland. Hypothalamus and hypophysis receive negative feedback regulation to hormones. Estrogen and testosterone will inhibit hypothalamus and adenohypophysis to release luteinizing hormone (LH) and luteinizing hormone-releasing hormone (LHRH) when their levels increase, which can evidently reduce the level of androgen. And endocrinotherapy can effectively reduce the function of androgen on prostate cancer cells and normal prostate tissues by enhancing the negative feedback regulation and blocking the production and action pathways of androgen, so as to achieve the expected therapeutic target. Tomida et al. [9] discovered that applying neoadjuvant androgen deprivation (NAD) could result in decrease in prostate volume in patients with prostate cancer, and the decrease dependeded on the therapeutic duration of NAD.

Therapeutic Indications of Endocrinotherapy

According to the guidelines of American Society of Clinical Oncology (ASCO) [10], the indications of endocrinotherapy for prostate cancer mainly contain: (1) patients with metastatic prostate cancer, including that in stages N1 and M1; (2) patients with locally early or advanced prostate cancer who could not receive radical radiotherapy or prostatectomy due to lack of indications; (3) patients who planned to receive radical radiotherapy or prostatectomy could be given preoperative complementary endocrinotherapy to shrink the tumor size; (4) patients who could receive endocrinotherapy as complementary treatment after radical radiotherapy or prostatectomy; (5) patients who had local recurrence after specific treatment but could not receive local re-treatment based on practical situation.

Endocrinotherapy Protocols
Castration treatment

Castration treatment aims to reduce the in-vivo androgen level through castration therapy so as to achieve the target of inhibiting the growth of prostate cancer cells. Generally, the indexes of serum testosterone are primarily detected based on their pre-castration levels, and the castration is regarded to be successful if the levels are reduced by 5%-10%. Castration treatment includes surgical castration and drug castration. (1) Surgical castration: Bilateral coated orchiectomy and common bilateral orchiectomy are two commonly-used methods in surgical castration, which have similar clinical therapeutic efficacy. However, the former has become one of the standard castration methods because it makes patients subjectively believe that the testis has been maintained after surgery, and it also reduce psychological trauma to some extent and rapidly lower testosterone level in a short time. However, surgical castration has been greatly limited in therapeutic efficacy because it only removes the androgen secreted by testis, but cannot inhibit the androgen secreted by adrenal glands. Surgical castration is an optimal protocol for patients demanding quick decrease of testosterone level. Moreover, it is more popular in developing regions as well as second- and third-tier cities due to its strong operability and low price under local anesthesia. (2) Drug castration: It is defined as the method using some specific drugs to reduce in-vivo androgen level in patients with prostate cancer, so as to inhibit the growth of prostate cancer cells. The commonly used drugs contain LHRH antagonists, LHRH-analogue (LHRH-A), estrogen and its analogues, etc.

LHRH receptor antagonists can directly combine with LHRH receptors of hypophysis, and rapidly lead to the decrease of LH, follicle stimulating hormone (FSH) and testosterone, thus becoming the newest endocrinotherapy drugs. Du et al.[11] evaluated the in-vitro release mechanisms and in-vivo biological performance of poly(D, L-lactideco-glycolide) (PLGA) microspheres, including a highly potent LHRH antagonist (LXT-101) in the treatment of patients with prostate cancer, and the results indicated that the mechanism of LXT-101 PLGA 14 000 microspheres was in close association with the cooperation of polymer degradation and drug diffusion, the appearance of prostates, vesicular seminalis and testis changed markedly, and the weights of sexual organs decreased evidently, showing that some LHRH antagonist microspheres like LXT-101 could be used as a promising drug delivery system candidate for prostate cancer. Rick et al. [12] found that using agonists of LHRH could modernize and improve the therapeutic efficacy of patients with hormone-sensitive advanced prostate cancer, but it still had some shortcomings, such as microsurges in testosterone, exacerbation of clinical symptoms and initial surge in testosterone, whereas the third-generation LHRH antagonist could better control prostate-specific antigen and FSH, and improve testosterone suppression, which prolonged the disease progression and provided excellent efficacy for serum alkaline phosphatase, demonstrating that application of antagonists of LHRH is a better approach in the treatment of advanced prostate cancer.

LHRH-A, an artificial LHRH, can bind to the receptors on gonadotropin (Gn) secretory cells of hypophysis. Its action mechanism can be summarized as: (1) In initial stage of application, LHRH-A can transiently promote the production of LH and testosterone until the exhaust of FSH and LH, consequently reducing the testosterone concentration to pre-castration level; (2) LHRH-A can directly reduce the sensitivity of target cell Gn receptors, but the testosterone concentration increases rapidly immediately after drug administration and decreases after treatment for 3-5 d, which then reaches to the castration level after 3-4 weeks; (3) LHRH-A has stronger affinity with hypophysis, but its long-term administration in large doses is easy to cause exhaust of Gn of hypophysis and reduce LHRH’ s regulatory function, so as to realize the clinical efficacy of hypophysectomy with selective drugs. Commonly used drugs for LHRH-A are composed of triptorelin, goserelin and leuprorelin, which are similar in clinical efficacy without requirement of orchiectomy, so they have replaced surgical castration gradually in European and American countries. Usami et al. [13] conducted the first double-blinded study comparing bicalutamide in combination with LHRH-A versus LHRH-A monotherapy in the treatment of patients with advanced prostate cancer, in which both groups received subcutaneous depot injection of LHRH-A protocol (leuprorelin acetate 3.75 mg or goserelin acetate 3.6 mg), while combined group was added with bicalutamide 80 mg, and the results revealed that time to achieve a prostate-specific antigen (PSA) level of ≤ 4 ng/mL was prominently shorter in combined group than that in control group (8.1 weeks vs. 24.1 weeks, respectively; hazard ratio (HR) 3.96; 95% CI 2.77-5.66; P< 0.001), and time-to-treatment failure and time to disease progression (TTP) were markedly longer in combined group than those in control group, but there was no statistical difference between two groups in drug tolerability, indicating that combination of LHRH-A could provide more benefits for patients with advanced prostate cancer, without increasing adverse reactions or reducing tolerability, deserving to be widely applied in clinic. It should be noted that in initial application of LHRH-A, early increase of testosterone may aggravate the patients’ symptoms, so anti-androgen drugs are recommended 2 weeks before treatment. However, for patients with bone metastasis spinal compression and bladder-neck obstruction, the therapeutic protocols should be regulated and cautiously applied according to patients’ comprehensive conditions. It is still controversial at home and abroad whether LHRH-A can inhibit testis and adrenal glands simultaneously from secreting testosterone, and whether it can be used after surgical castration. Therefore, LHRH-A-associated mechanisms need more basic research to be illustrated.

Estrogen and its analogues mainly regulate the secretion of LHRH and LH through the negative feedback of hypothalamus-pituitary-gonad axis, so as to reduce the production of testosterone. They can also combine with androgen receptors in competition with testosterone to inhibit the influence of testosterone on prostate cancer cells. Fabre et al. [14] conducted a cross sectional study in which the serum levels of PSA, cortisol, bioavailable testosterone, total and free testosterone, estradiol and LH were measured, and the results showed that serum levels of estradiol and leptin were evidently higher in patients with prostate cancer (P< 0.0001; P=0.04, respectively), and Logistic regression analysis showed that serum leptin (OR: 1.248, 95%CI: 1.048-1.487, P=0.013), estradiol (OR: 1.044, 95%CI: 1.008-1.081, P=0.016) and cortisol (OR: 1.110, 95%CI: 1.016-1.213, P=0.022) were the dependent variables that explained the variance, suggesting the coexistence of an altered circulating hormonal profile with increased levels of leptin, estradiol and cortisol in patients with prostate cancer. Moreover, Rahman et al. [15] believed that androgens could not only promote normal prostate maturity, but also impact the progression and development of prostate cancer. Both exogenous and endogenous oestrogens might be equally as relevant as androgens in the growth of prostate cancer, which showed that an understanding of the mechanisms behind enzalutamide [16] and abiraterone resistance [17], and whether this was linked to altered oestrogen and androgen metabolism, would be needed before the performance of next large step towards the development of endocrine therapy for prostate cancer. Additionally, they also have direct toxicity on prostate cancer cells, which may promote the apoptosis of cancer cells. As a typical endocrinotherapy, estrogen and its analogues have been widely used in clinic. However, they have been recommended as the second-line endocrinotherapy protocol because they can greatly increase the risk of cardiovascular diseases during clinical treatment.

Anti-androgen treatment

Anti-androgen treatment is defined as a therapeutic method in which anti-androgen drugs can inhibit testosterone entering into cell nucleus, suppress Gn effect and block the androgen-induced intracellular response by combining with androgen receptors on target organs in competition with endogenous androgen, so as to reduce the androgen level. Moreover, it can also launch tumor cell apoptosis and inhibit cell proliferation.

Anti-androgen drugs can be divided into sterides and non-sterides according to their different chemical structures. Cyproterone acetate (CPA), as the representative of sterides, can not only block androgen receptors, but also have the activities of glucocorticoids and progestin, and can inhibit adrenal glands to secret androgen and hypophysis to secret Gn. Additionally, high-concentration CPA has direct cytotoxic effect on prostate cancer cells. Verhagen et al. [18] conducted an open-label, multicenter randomized trial by comparing the clinical efficacy of continuous treatment (CT) versus intermittent treatment (IT) using cyproterone acetate (CPA) in the treatment of patients with bone metastatic prostate cancer, and the results showed an average of 1.7 episodes on CPA in patients on IT before start of LHRH analogues, and there were significant differences in 3 of the 5 functional scales of EORTC QLQ C 30 between IT and CT, but no difference was observed in time to cancer-specific and overall survival, time to PSA and/or clinical progression on LHRH analogues, and time to PSA progression on CPA, illustrating that IT by CPA is in close association with modest advantages and less symptoms in QOL domains, but no significant difference was recorded in clinical progression or survival as well as time to PSA. Nonsteroidal antiandrogen (NSAA) can only block androgen receptors, but has no in-vivo hormonal activity. The commonly used drugs contain bicalutamide and flutamide, etc. NSAA cannot reduce testosterone level, so it will not change patients’ physical agility and sexual ability during drug administration, and is relatively low in the prevalence of cardiovascular diseases and osteoporosis [19], with primary adverse reactions being gynecomastia and tidal fever, etc. Yokomizo et al.[20] determined whether immediate antiandrogen switching from bicalutamide to flutamide would decrease PSA in patients with advanced prostate cancer after administration of CAB, and the results indicated that PSA decreased to at least 50% after drug administration, and patients responded well to CAB, with median OS in responders prominently longer than that in non-responders. These findings suggest that an immediate switch from bicalutamide to flutamide is effective for advanced prostate cancer after first-line CAB using bicalutamide. Single anti-androgen treatment is rarely used clinically because it cannot completely block in-vivo androgen, whereas its combination with castration treatment is commonly seen. Therefore, the single anti-androgen treatment is not recommended by Chinese Urological Association (CUA). In recent years, with continuous development of endocrinotherapy for prostate cancer, some new anti-androgen drugs have been gradually applied in clinic, such as enzalutamide and Abiraterone Acetate (ZYTIGA), etc., but their clinical efficacy should be further verified.

Maximal androgen blockade (MAB)

MAB, also termed as CAB, is defined as a therapeutic method that can simultaneously block the androgen from adrenal glands and testis, and antagonize the androgen receptors. This protocol was initially proposed by Labrie in 1983, and had been commonly used in clinic using drug castration combined with anti-androgen treatment, such as bicalutamide combined with goserelin. Moul et al. [21]found that compared with single castration treatment, MAB could slightly increase the survival time of patients with prostate cancer, but it also increased the medical cost and incidence of adverse reactions, and had poor influence on patients’ quality of life (QOL). In addition, Qian et al.[22] conducted a study to evaluate the clinical efficacy and drug tolerability of bicalutamide 150 mg in the treatment of patients with castration-resistant prostate cancer, and the results displayed that bicalutamide 150 mg as secondary hormonal therapy was effective and safety and could be well tolerated by patients with castration-resistant prostate cancer, especially those using flutamide as first-line nonsteroidal antiandrogen, and those with lower serum PSA level and Gleason score. Therefore, it has been recommended as an alternative protocol by European Association of Urology (EAU) guidelines on condition that patients’ serum testosterone level is not significantly reduced after castration treatment [23].

Intermittent hormonal therapy (IHT)

IHT is defined as a therapeutic method in which endocrinotherapy is persistently used for patients with prostate cancer until the testosterone level decreases to castration level, and the level will maintained for several months before withdrawal. The endocrinotherapy should be repeated according to tumor growth in a cycle of treatment period-treatment interval-treatment period. The therapeutic mechanism of IHT is that under the condition of low in-vivo androgen level, prostate cancer cells can grow continuously by supplemented androgen to obtain anti-apoptotic potential, so as to prolong the time of prostate cancer to enter into hormone-independent stage. IHT can effectively improve the patients’ QOL, reduce medical cost, prolong the time of prostate cancer from androgen-dependent stage to independent stage, and has certain survival benefits when compared with conventional treatment. Magnan et al.[24] conducted a systematic review and meta-analysis to compare the efficacy and tolerability of IHT verse continuous hormonal therapy (CHT) in patients with prostate cancer, and it was found that there was no significant difference between IHT and CHT in progression-free survival (HR, 0.94; 95%CI: 0.84-1.05; 4 trials, 1 774 patients), cancer-specific survival (HR, 1.02; 95%CI: 0.87-1.19; 5 trials, 3 613 patients), and OS (HR, 1.02; 95%CI: 0.93-1.11; 8 trials, 5 352 patients), and the difference in QOL was minimal, which pointed out that though IHT was not superior to CHT in OS, it had significant improvement in QOL, so it could be used as an alternative option for patients with recurrent or metastatic prostate cancer. There is great controversy in the withdrawal criteria and start time of IHT, which are determined according to experience and ongoing clinical trials at home and abroad, with observational indexes being pre-treatment PSA level, clinical stage, presence of metastasis and tolerability of endocrinotherapy, etc. Shaw et al.[25]discovered that drug withdrawal was safe and effective when PSA≤ 1 μ g/L, and the therapeutic time could be less than 3 months to patients with local prostate cancer and more than 9 months in those with metastases. The therapeutic modes of IHT contain MAB and drug castration treatment without surgical castration. IHT has been extensively used in clinic, but still lacks of large-scale and long-term clinical controlled trials.

Neoadjuvant hormonal therapy (NHT)

Pre-radical NHT is defined as the endocrinotherapy conducted before radical prostatectomy, which can prolong patients’ survival time by diminishing tumor size and reducing the clinical staging, local recurrence rates as well as positive rates of incisal edge of prostate cancer. It is advisable for patients with prostate cancer in classes T2 and T3. NHT often adopts MAB and LHRH-A protocols, or single anti-androgen drugs or LHRH-A in clinic, in which MAB is extremely significant in clinical efficacy lasting for 3-9 months. Smith et al.[26]pointed that NHT could reduce the positive rate of surgical edge, lymph node infiltration rate and clinical stages of tumors, but it could not significantly prolong the postoperative OS and PFS. Joung et al.[27] discovered that 6 out of 111 patients achieved complete response (CR) after NHT, which demonstrated the prevalence of pT0 disease and its outcomes in patients with high-risk prostate cancer after NHT. Mizowaki et al. [28] proved that high-dose intensity-modulated radiation therapy (IMRT) combined with NHT could not only effectively control PSA level, but also achieve excellent survival outcomes with acceptable morbidities in the treatment of Japanese patients with intermediate- and high-risk T1c-T2N0M0 prostate cancer.

Adjuvant hormonal therapy (AHT)

AHT is defined as the therapeutic method in which endocrinotherapy is used as complementary method after radical prostatectomy or radiotherapy. It is mainly used for mini-metastatic nidi, residual positive lymph nodes and residual tumor nidi on edge, so as to prolong patients’ survival time. AHT indications: (1) pathological incisal edge of prostate cancer was positive (+) after radical prostatectomy; (2) postoperative pathological lymph node metastasis was positive (+); (3) postoperative pathological pattern was T3 or high-risk T2; (4) AHT was available after radical radiotherapy in patients with locally high-risk prostate cancer; (5) AHT was available after radiotherapy in patients with locally advanced prostate cancer. This method is recommended to be conducted immediately after operation or radiotherapy, and its protocols include castration treatment, anti-androgen drugs, and MAB. Solberg et al. [29]found that radical radiotherapy combined with endocrinotherapy still had excellent therapeutic efficacy in the treatment of local prostate cancer. Moreover, Cuppone et al.[30] proposed that long-term application of endocrinotherapy (like ARH) after radiotherapy could effectively reduce the biochemical recurrence, local recurrence and distant metastasis in patients with prostate cancer. In addition, Wong et al.[31] also proved that application of adjuvant radiation therapy (aRT) combined with AHT could significantly increase the OS of patients with pN+ prostate cancer than single aRT/AHT.

Conclusion

At present, endocrinotherapy has become a primary therapeutic method for patients with middle and advanced prostate cancer. However, there are still multiple controversies in efficacy and protocol selection of endocrinotherapy, and there are no standard therapeutic protocols. Endocrinotherapy for prostate cancer has been developed for over 70 years, and 3 scholars have received Nobel Prize in Medicine. It is firmly believed that more standard endocrinotherapy protocols for prostate cancer will be perfected along with the extensive development of clinical trials following the deep exploration and study conducted by medical scientists and clinical physicians.

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