Intermittent androgen deprivation therapy in patients with prostate cancer: Connecting the dots

Intermittent androgen deprivation therapy(IADT)is now being increasingly opted by the treating physicians and patients with prostate cancer.The most common reason driving this is the availability of an off-treatment period to the patients that provides some relief from treatment-related side-effects,and reduced treatment costs.IADT may also delay the progression to castration-resistant prostate cancer.However,the use of IADT in the setting of prostate cancer has not been strongly substantiated by data from clinical trials.Multiple factors seem to contribute towards this inadequacy of supportive data for the use of IADT in patients with prostate cancer,e.g.,population characteristics(both demographic and clinical),study design,treatment regimen,on-and off-treatment criteria,duration of active treatment,endpoints,and analysis.The present review article focuses on seven clinical trials that evaluated the efficacy of IADT vs.continuous androgen deprivation therapy for the treatment of prostate cancer.The results from these clinical trials have been discussed in light of the factors that may impact the treatment outcomes,especially the disease(tumor)burden.Based on evidence,potential candidate population for IADT has been suggested along with recommendations for the use of IADT in patients with prostate cancer.

Muscle function, physical performance and body composition changes in men with prostate cancer undergoing androgen deprivation therapy

Prostate cancer （PCa） is the most common visceral malignancy in men with androgen deprivation therapy （ADT） the preferred therapy to suppress testosterone production and hence tumor growth. Despite its effectiveness in lowering testosterone, ADT is associated with side effects including loss of muscle mass, diminished muscle strength, decrements in physical performance, earlier fatigue and declining quality of life. This review reports a survey of the literature with a focus on changes in muscle strength, physical function and body composition, due to short-term and long-term ADT. Studies in these areas are sparse, especially well-controlled, prospective randomized trials. Cross-sectional and longitudinal data （up to 2 years） for men with PCa treated with ADT as well as patients with PCa not receiving ADT and age-matched healthy men are presented when available. Based on limited longitudinal data, the adverse effects of ADT on muscle function, physical performance and body composition occur shortly after the onset of ADT and tend to persist and worsen over time. Exercise training is a safe and effective intervention for mitigating these changes and initial guidelines for exercise program design for men with PCa have been published by the American College of Sports Medicine. Disparities in study duration, types of studies and other patient-specific variables such as time since diagnosis, cancer stage and comorbidities may all affect an understanding of the influence of ADT on health, physical performance and mortality.

Use of androgen deprivation therapy in prostate cancer： indications and prevalence

Androgens play a prominent role in the development, maintenance and progression of prostate cancer. The introduction of androgen deprivation therapies into the treatment paradigm for prostate cancer patients has resulted in a wide variety of benefits ranging from a survival advantage for those with clinically localized or locally advanced disease, to improvements in symptom control for patients with advanced disease. Controversies remain, however, surrounding the optimal timing, duration and schedule of these hormonal approaches. Newer hormonal manipulations such as abiraterone acetate have also been investigated and will broaden treatment options for men with prostate cancer, This review highlights the various androgen-directed treatment options available to men with prostate cancer, their specific indications and the evidence supporting each approach, as well as patterns of use of hormonal therapies.

Hematological changes during androgen deprivation therapy

Androgen deprivation therapy （ADT） has been associated with a plethora of adverse effects, consistent with the androgen dependency of multiple reproductive and somatic tissues. One such tissue is the hemopoietic system, and one of the most predictable consequences of ADT is the development of anemia. Although anemia caused by ADT is rarely severe, ADT is often given to frail, elderly men with increased susceptibility to anemia due to multiple other causes. ADT-associated anemia may contribute to fatigue and reduced quality of life （QoL） in such men, although this requires further study. While anemia is an independent risk factor of mortality in men with prostate cancer, it is not known whether treatment of ADT-associated anemia alters clinically important outcomes, or whether treatment affects mortality. Awareness of the phenomenon of ADT-induced anemia should avoid unnecessary work-up in mild cases of normocytic normochromic anemia. However, assessment and treatment of more severe anemia may be required. This should be determined on an individual basis. In contrast to the weli-descrihed actions of ADT on erythropoiesis, its effect on other hemopoietic lineages has been less well elucidated. While preclinical studies have found roles for androgens in maturation and differentiated function of neutrophils, lymphocytes and platelets, the implications of these findings for men with prostate cancer receiving ADT require further studies.

Effect of androgen deprivation therapy on bone mineral density in prostate cancer patients

Aim: To evaluate the effect of androgen deprivation therapy (ADT) on bone mineral density (BMD) in prostate cancer patients. Methods: Forty-nine prostate cancer patients with their BMD determined were divided into two groups: the non-treated group included 21 patients before the commencement of ADT and the treated group, 28 patients, who had received ADT for more than 1 year. BMD was measured by dual energy X-ray absorptiometry (DEXA) in the lumbar spine (L2-4) and femoral neck. Results: Thirteen (62 %) non-treated and 23 (82 %) treated patients fulfilled the BMD criteria for osteopenia or osteoporosis. Z scores for age-matched control in lumbar spine and femoral neck were -0.9 ± 0.7 and -0.6 ± 0.5, respectively, in the treated group, and -1.8 ± 1.1 and-1.6 ± 1.0 , respectively, in the non-treated group, the differences between the two groups were highly significant (P<0.01). Conclusion: Prostate cancer patients who received ADT for more than 1 year had a significantly lower BMD in the lumbar spine and femoral neck than those before the beginning of ADT.

Androgen deprivation therapy through bilateral orchiectomy, increased metabolic risks

Prostate cancer is one of the most common malignancies in men. Previous research has determined that androgen deprivation therapy （ADT） may be accompanied by an unfavourable metabolic profile. In this prospective study, 133 men were recruited, including 46 prostate cancer patients who had undergone bilateral orchiectomy and been on flutamide （the ADT group）, 37 men with prostate cancer who had undergone radical prostatectomy （the non-ADT group） and 50 normal control subjects （the control group）. All subjects were followed for at least 12 months. From baseline to 3 months, men in the ADT group had increased levels of fasting serum insulin and low-density lipoprotein compared to the other two groups （P〈0.05）. No obvious changes were found in the other parameters （P〉0.05）. After 12 months, men in the ADT group had increased levels of waist circumference, fasting serum insulin and glucose, total cholesterol, high-density lipoprotein and low-density lipoprotein compared to the other two groups （P〈0.05）. Additionally, the morbidity rate of metabolic syndrome in the ADT group was higher （P〈0.05） compared to the other two groups. ADT through surgical castration for men with prostate cancer may be associated with unfavourable metabolic changes. The benefits of the therapy should be balanced prudently against these risks.

Combination therapy with androgen deprivation for hormone sensitive prostate cancer: A new frontier

Androgen deprivation therapy(ADT)has been the standard of care for the last 75 years in metastatic hormone sensitive prostate cancer(PCa).However,this approach is rarely curative.Recent clinical trials have demonstrated that ADT combined with other agents,notably docetaxel and abiraterone,lead to improved survival.The mechanisms surrounding this improved cancer outcomes are incompletely defined.The response of cancer cells to ADT includes apoptosis and cell death,but a significant fraction remains viable.Our laboratory has demonstrated both in vitro and in vivo that cellular senescence occurs in a subset of these cells.Cellular senescence is a phenotype characterized by cell cycle arrest,senescenceassociated b-galactosidase(SA-b-gal),and a hypermetabolic state.Positive features of cellular senescence include growth arrest and immune stimulation,although persistence may release cytokines and growth factors that are detrimental.Senescent tumor cells generate a catabolic state with increased glycolysis,protein turnover and other metabolic changes that represent targets for drugs,like metformin,to be applied in a synthetic lethal approach.This review examines the response to ADT and the putative role of cellular senescence as a biomarker and therapeutic target in this context.

Impact of androgen deprivation therapy on sexua function

Many patients with prostate cancer for whom androgen deprivation therapy （ADT） is indicated are young and desire to remain sexually active. In such patients, the side effects of androgen therapy on sexual function can be a source of serious reduction in overall quality of life. Providing the appropriate treatment options in this patient population is therefore essential. Nevertheless, treating such patients is challenging and an understanding of the underlying mechanisms of sexual physiology and pathophysiology is crucial to optimal patient care. In this paper, we reviewed what was known regarding the effects of ADT on sexual function in animal models and we also provided a detailed review on the effects of ADT on sexual health in humans and its treatment.

Androgen deprivation therapy-associated vasomotor symptoms

Androgen deprivation therapy （ADT） is widely used as standard therapy in the treatment of locally advanced and metastatic prostate cancer. While efficacious, ADT is associated with multiple side effects, including decreased libido, erectile dysfunction, diabetes, loss of muscle tone and altered body composition, osteoporosis, lipid changes, memory loss, gynecomastia and hot flashes. The breadth of literature for the treatment of hot flashes is much smaller in men than that in women. While hormonal therapy of hot flashes has been shown to be effective, multiple non-hormonal medications and treatment methods have also been developed. This article reviews current options for the treatment of hot flashes in patients taking ADT.

Improving intermittent androgen deprivation therapy： lessons learned from basic and translational research

Intermittent androgen deprivation therapy （IADT） is an alternative to continuous androgen deprivation therapy （ADT） in prostate cancer patients with nonmetastatic disease. ADT is associated with numerous side effects such as hot flashes, sexual dysfunction, anemia, fatigue, loss of muscle mass, osteoporosis, metabolic syndrome and premature cardiovascular disease. IADT was developed with the intention of improving the quality of life and to delay progression of prostate cancer to castration resistance. The benefits of slightly improved quality of life by IADT compared to ADT were demonstrated in multiple clinical trials. IADT was noted to be noninferior to ADT in patients with biochemical recurrence of prostate cancer but in studies performed in patients with metastatic prostate cancer, the results were inconclusive. Our recent studies suggested that the administration of 5 alpha-reductase inhibitors during the off-cycle of IADT can significantly prolong the survival of mice bearing androgen-sensitive prostate tumors when off-cycle duration was short. This review discusses the survival benefit of 5 alpha-reductase inhibition in IADT in animal models and the potential translation of this finding into clinic.

Quality of life issues in men undergoing androgen deprivation therapy： a review

Androgen deprivation therapy （ADT） has been an essential treatment option for treating prostate cancer （PCa）. The role for hormonal treatment initially was restricted to men with metastatic and inoperable, locally advanced disease. Now it has been extended to neoadjuvant or adjuvant therapy for surgery and radiotherapy, for biochemical relapse after surgery or radiation, and even as primary therapy for non-metastatic disease. Fifty percent of PCa patients treated will receive ADT at some point. There is growing concern about the adverse effects and costs associated with more widespread ADT use. The adverse effects on quality of life （QoL）, including physical, social and psychological well-being when men are androgen-deprived, may be considerable. This review examines the QoL issues in the following areas： body feminisation, sexual changes, relationship changes, cognitive and affective symptoms, fatigue, sleep disturbance, depression and physical effects. Further suggestions for therapeutic approaches to reduce these alterations are suFuzested.

Adverse effects of androgen deprivation therapy in men with prostate cancer： a focus on metabolic and cardiovascular complications

Prostate cancer （PCa） is the most common malignancy in men. Prostate being an androgen responsive tissue, androgen deprivation therapy （ADT） is used in the management of locally advanced （improves survival） and metastatic （improves pain and quality of life） PCa. Over the past two decades, the use of ADT has significantly increased as it is also being used in patients with localized disease and those experiencing biochemical recurrences, though without any evidence of survival advantage. Hypogonadism resulting from ADT is associated with decreased muscle mass and strength, increased fat mass, sexual dysfunction, vasomotor symptoms, decreased quality of life, anemia and bone loss. Insulin resistance, diabetes and cardiovascular disease have recently been added to the list of these complications. As the majority of men with PCa die of conditions other than their primary malignancy, recognition and management of these adverse effects is paramount. Here we review data evaluating metabolic and cardiovascular complications of ADT.

Metastatic Prostate Cancer under Androgen Deprivation Therapy: Factors Influencing Castration Resistance

Objective: To evaluate the factors predicting the time to progression to castration-resistant in metastatic prostate cancer under Androgen Deprivation Therapy (ADT) in our center. Patients and Methods: This is a retrospective, descriptive, analytical study in a single center over a period of 2 years. It has interest patients followed for metastasized prostate cancer under ADT. The parameters studied were: epidemiological, clinical, paraclinical, prostate specific antigen (PSA) nadir, time to nadir (TTN) and their link with the castration resistance. Results: The frequency of castration resistant prostate cancer was 28 patients per year. The mean age was 70.4 ± 7.9 years. An ECOG score ≥ 3 was more common as was the cT2c stage. The median of the initial total PSA was 489.6 ng/ml (203.3;1653.2). All patients had adenocarcinoma. The International Society of Urological Pathology (ISUP) 1 was more frequent. Bone metastases were more frequent. The medians of nadir, TTN and the castration resistance were 19.3 ng/ml (3.7;102.1), 5.5 months (3;9) and 11 months (6;15.3), respectively. The Eastern Cooperative Oncology Group (ECOG) score, clinical stage, metastatic site, the nadir and its TTN influenced the DSR. Age, lymph node involvement, initial total PSA and Gleason score did not influence the castration resistance. Conclusion: ADT should be initiated as soon as possible before an attack of general and/or clinical stage advanced to delay resistance. A drilling should be associated with this hormone therapy as much as possible because of its gain on resistance.

Sarcomatoid carcinoma of the prostate with bladder invasion shortly after androgen deprivation:Two case reports

BACKGROUND To summarize the imaging,morphological and biological characteristics of sarcomatoid carcinoma(SC)of the prostate with bladder invasion not long after castration.CASE SUMMARY Our two cases were initially diagnosed with adenocarcinoma of the prostate due to dysuria.However,prostate SC was diagnosed after transurethral resection of the prostate(TURP)and castration after only 5 and 10 mo,respectively.Distinctive liver-like tissues appeared in the second TURP procedure in case 1,while a white,fish flesh-like,narrow pedicled soft globe protruded from the prostate to the bladder in case 2.CONCLUSION The sarcomatoid component of SC may arise from one of the specific groups of cancer cells that are resistant to hormonal therapy.Morphological characteristics of SCs can present as“red hepatization”and“fish flesh”.SCs grow rapidly and have a poor prognosis,and thus,extensive TURP plus radiation may be the treatment of choice.

Dissecting the effects of androgen deprivation therapy on cadherin switching in advanced prostate cancer: A molecular perspective

Prostate cancer is one of the most often diagnosed malignancies in males and its prevalence is rising in both developed and developing countries.Androgen deprivation therapy has been used as a standard treatment approach for advanced prostate cancer for more than 80 years.The primary aim of androgen deprivation therapy is to decrease circulatory androgen and block androgen signaling.Although a partly remediation is accomplished at the beginning of treatment,some cell populations become refractory to androgen deprivation therapy and continue to metastasize.Recent evidences suggest that androgen deprivation therapy may cause cadherin switching,from E-cadherin to N-cadherin,which is the hallmark of epithelial-mesenchymal transition.Diverse direct and indirect mechanisms are involved in this switching and consequently,the cadherin pool changes from E-cadherin to N-cadherin in the epithelial cells.Since E-cadherin represses invasive and migrative behaviors of the tumor cells,the loss of E-cadherin disrupts epithelial tissue structure leading to the release of tumor cells into surrounding tissues and circulation.In this study,we review the androgen deprivation therapy-dependent cadherin switching in advanced prostate cancer with emphasis on its molecular basis especially the transcriptional factors regulated through TFG-βpathway.

Salvage treatments for prostate-specific antigen relapse of cT3N0M0 prostatic adenocarcinoma after radical prostatectomy combined with neoadjuvant androgen deprivation

Objective The aim of the study was to evaluate the efficiency of salvage treatments for prostate specific antigen(PSA)relapse of cT3N0M0 prostatic adenocarcinoma(PCa)after radical prostatectomy(RP)combined with neoadjuvant androgen deprivation(ADT).Methods A total of 332 patients with cT3N0M0 PCa were enrolled in the prospective study and received RP and pelvic lymph node dissection with neoadjuvant ADT for 3 months.All patients with PSA relapse were treated with salvage external beam radiation therapy(RT)and ADT for 6 months.Results The 5-year postoperative PSA relapse rate was 40.96%(136/332).The patients have been divided into the PSA relapse and PSA relapse-free groups in order to compare patient characteristics.The ratio of patients with Gleason score≥8 and positive surgical margin in the PSA relapse group were significantly higher than those of in the PSA relapse-free group(P=0.01).The mean duration between the start of operative treatment and PSA relapse was 31 months.Salvage treatment to all 136 PSA relapse patients led to favorable outcomes.PSA relapse was not observed after salvage treatment by the end of follow-up.The 5-year overall survival rates of the PSA relapse and PSA relapse-free groups were 94.9%and 93.9%,respectively.Conclusion In pursuit of curative treatment,our study showed that RP combined with neoadjuvant ADT is an aggressive multimodality strategy associated with lower PSA relapse and better survival outcomes for stage cT3N0M0 PCa patients.Patients with PSA relapse after RP may benefit from early aggressive salvage RT combined with short-term ADT.

Radiomics based on biparametric MRI for the detection of significant residual prostate cancer after androgen deprivation therapy:using whole-mount histopathology as reference standard

We aimed to study radiomics approach based on biparametric magnetic resonance imaging(MRI)for determining significant residual cancer after androgen deprivation therapy(ADT).Ninety-two post-ADT prostate cancer patients underwent MRI before prostatectomy(62 with significant residual disease and 30 with complete response or minimum residual disease[CR/MRD]).Totally,100 significant residual,52 CR/MRD lesions,and 70 benign tissues were selected according to pathology.First,381 radiomics features were extracted from T2-weighted imaging,diffusion-weighted imaging,and apparent diffusion coefficient(ADC)maps.Optimal features were selected using a support vector machine with a recursive feature elimination algorithm(SVM-RFE).Then,ADC values of significant residual,CR/MRD lesions,and benign tissues were compared by one-way analysis of variance.Logistic regression was used to construct models with SVM features to differentiate between each pair of tissues.Third,the efficiencies of ADC value and radiomics models for differentiating the three tissues were assessed by area under receiver operating characteristic curve(AUC).The ADC value(mean±standard deviation[s.d.])of significant residual lesions([1.10±0.02]×10^(-3)mm^(2)s^(−1))was significantly lower than that of CR/MRD([1.17±0.02]×10^(-3)mm^(2)s^(−1)),which was significantly lower than that of benign tissues([1.30±0.02]×10^(-3)mm^(2)s^(−1);both P<0.05).The SVM feature models were comparable to ADC value in distinguishing CR/MRD from benign tissue(AUC:0.766 vs 0.792)and distinguishing residual from benign tissue(AUC:0.825 vs 0.835)(both P>0.05),but superior to ADC value in differentiating significant residual from CR/MRD(AUC:0.748 vs 0.558;P=0.041).Radiomics approach with biparametric MRI could promote the detection of significant residual prostate cancer after ADT.

Impacts of androgen deprivation therapy on the risks and outcomes of SARS-CoV-2 infection in patients with prostate cancer

Studies have investigated the effects of androgen deprivation therapy(ADT)use on the incidence and clinical outcomes of coronavirus disease 2019(COVID-19);however,the results have been inconsistent.We searched the PubMed,Medline,Cochrane,Scopus,and Web of Science databases from inception to March 2022;13 studies covering 84003 prostate cancer(PCa)patients with or without ADT met the eligibility criteria and were included in the meta-analysis.We calculated the pooled risk ratios(RRs)with 95%confidence intervals(CIs)to explore the association between ADT use and the infection risk of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)and severity of COVID-19.After synthesizing the evidence,the pooled RR in the SARS-CoV-2 positive group was equal to 1.17,and the SARS-CoV-2 positive risk in PCa patients using ADT was not significantly different from that in those not using ADT(P=0.544).Moreover,no significant results concerning the beneficial effect of ADT on the rate of intensive care unit admission(RR=1.04,P=0.872)or death risk(RR=1.23,P=0.53)were found.However,PCa patients with a history of ADT use had a markedly higher COVID-19 hospitalization rate(RR=1.31,P=0.015)than those with no history of ADT use.These findings indicate that ADT use by PCa patients is associated with a high risk of hospitalization during infection with SARS-CoV-2.A large number of high quality studies are needed to confirm these results.

Association of time to prostate-specific antigen nadir and logarithm of prostate-specific antigen velocity after progression in metastatic prostate cancer with prior primary androgen deprivation therapy

We investigated the association of time to prostate-specific antigen nadir （TTPN） and logarithm of prostate-specific antigen velocity after progression Log（PSAVAP） in metastatic prostate cancer with prior primary androgen deprivation therapy （ADT）. All metastatic prostate cancer patients treated with primary ADT from 2000 to 2009 were reviewed. Patients who developed disease progression were included in the subsequent analyses. Patients were categorized into three groups according to their TTPN： TTPN of 〈3 months, 3-17 months, and 〉17 months. We compared the Log（PSAVAP） between the different TTPN groups using Mann-Whitney U-test and Kruskal-Wallis test. Further multiple linear regression analyses on Log（PSAVAP） were performed to adjust for other potential confounding factors. Among 419 patients who were treated with primary ADT, 306 patients developed disease progression with a median follow-up of 28 months, Longer TTPN was associated with lower Log（PSAVAP） （P = 0.008） within all subgroup analyses （TTPN of 〈3 vs 3-17 months, P = 0.020; TTPN of 3-17 vs 〉17 months, P = 0.009; and TTPN of 〈3 vs 〉17 months, P = 0.001）. Upon multiple linear regression analyses, baseline PSA （regression coefficient 0.001, P = 0.045）, PSA nadir （regression coefficient 0.002, P = 0.040）, and TTPN （regression coefficient -0.030, P = 0.001） were the three factors that were significantly associated with Log（PSAVAP）. In conclusion, a longer TTPN was associated with lower Log（PSAVAP） in metastatic prostate cancer patients following primary ADT. TTPN cut-offs at 3 months and 17 months appeared to have prognostic significance in predicting Log（PSAVAP）. TTPN may serve as a good prognostic indicator in deciding the treatment strategy in patients with disease progression.

Serum testosterone level predicts the effective time of androgen deprivation therapy in metastatic prostate cancer patients

Androgen deprivation therapy （ADT） is the standard of care for patients with metastatic prostate cancer. However, whether serum testosterone levels, using a cut-off point of 50 ng d1-1, are related to the effective time of ADT in newly diagnosed prostate cancer patients remains controversial. Moreover, recent studies have shown that some patients may benefit from the addition of upfront docetaxel chemotherapy. To date, no studies have been able to distinguish patients who will benefit from the combination of ADT and docetaxel chemotherapy. This study included 206 patients who were diagnosed with metastatic prostate cancer and showed progression to castrate-resistance prostate cancer （CRPC）. Serum testosterone levels were measured prospectively after ADT for 1, 3, and 6 months. The endpoint was the time to CRPC. In univariate and multivariate analyses, testosterone levels 〈50 ng d1-1 were not associated with the effective time of ADT. Receiver operating characteristic and univariate analysis showed that testosterone levels of 〈25 ng d1-1 after the first month of ADT offered the best overall sensitivity and specificity for prediction of a longer time to CRPC （adjusted hazard ratio [HR], 1.46; 95% confidence interval [95% CI], 1.08-1.96; P = 0.013）. Our results show that serum testosterone level of 25 ng d1-1 plays a prognostic role in prostate cancer patients receiving ADT. A testosterone value of 25 ng dl-~ after the first month of ADT can distinguish patients who benefit from ADT effectiveness for only a short time. These patients may need to receive ADT and concurrent docetaxel chemotherapy.