A prospective and randomized study of primary hormonal therapy for patients with localized or locally advanced prostate cancer unsuitable for radical prostatectomy: results of the 5-year follow-up

OBJECTIVE: To evaluate the effect of primary hormonal therapy for patients with localized and locally advanced prostate cancer. PATIENTS AND METHODS: Patients with stage T1b-T3 prostate cancer who were not scheduled for radical prostatectomy were allocated into two groups: group 1 (73 men) received luteinizing hormone-releasing hormone (LHRH) agonist monotherapy and group 2 (78 men) received LHRH agonist and chlormadinone acetate. Patients were followed using serum prostate specific antigen levels, prostate size and the detection of distant metastasis for 5 years. RESULTS: The median (range) follow-up was 78 (63-87) months. The 5-year progression-free survival rate was significantly higher in group 2 (68%) than in group 1 (47%). However, the overall and cause-specific survival rate at 5 years were similar in both groups, at 72% and 93% in group 1, and 64% and 89% in group 2, respectively. CONCLUSION: The overall survival rates of the both groups were no different from that of the normal Japanese population of the same age group. Although this study did not include an untreated group, i.e. watchful waiting, these results might indicate the usefulness of primary hormonal therapy in controlling localized and locally advanced prostate cancer. The 5-year observation period is still short and the study is continuing to determine the 10-year survival.     

新辅助治疗的优势:机器人辅助腹腔镜下前列腺癌根治术治疗局部进展期前列腺癌

目的探讨术前新辅助内分泌治疗(NHT)是否能使接受机器人辅助腹腔镜前列腺癌根治术(RLRP)治疗的局部进展期前列腺癌患者临床获益。方法回顾性研究中国医科大学附属第一医院泌尿外科自2018年5月至2019年8月根治术前通过穿刺活检及MRI诊断为局部进展期前列腺癌患者31例。其中术前行新辅助内分泌治疗12例,年龄(65.67±5.123)岁,未经内分泌治疗19例,年龄(66.58±8.520)岁。比较两组患者手术时间、术中出血量、术后住院时间、术后切缘阳性率、淋巴结阳性率、术后吻合口漏尿等情况。结果 31例手术均无中转开放及二次手术。新辅助治疗组手术时间[(176.84±54.875)min vs.(66.58±8.520)min,P=0.032]和术后住院时间[(9.50±2.505)min vs.(13.87±5.987)min,P=0.048]缩短,术中失血量[(165.68±79.746)mL vs.(13.87±5.987)mL,P=0.013]减少。治疗组肿瘤切缘阳性率(8.33%vs.26.32%,P=0.001)和清扫淋巴结阳性率(17.14%vs.38.18%,P=0.037)也明显低于对照组。术前辅助内分泌治疗并不能降低术后Gleason评分和临床分期(P>0.05)。结论术前新辅助内分泌治疗在RLRP治疗局部进展期前列腺癌患者中可能在一定程度上降低手术难度并且减少术中出血,使患者受益。     

Efficacy of primary hormone therapy for localized or locally advanced prostate cancer: results of a 10-year follow-up

OBJECTIVE: To evaluate the efficacy of primary hormone therapy for localized or locally advanced prostate cancer, by analysing the 10-year survival rates for men with localized or locally advanced prostate cancer treated with primary hormone therapy or prostatectomy. PATIENTS AND METHODS: Between February 1993 and March 1995, men with T1b, T1c or T2-3 N0M0 prostate cancer were enrolled. In all, 176 men who had a prostatectomy were assigned to Study 1 and were given adjuvant luteinizing hormone-releasing hormone (LHRH) agonist; 151 men who did not have a prostatectomy were assigned to Study 2 and had LHRH agonist monotherapy or combined androgen blockade. They were followed until death, loss to follow-up, or until the end of the observation period (31 March 2004). We analysed all cases in each study as a single population, and compared Study 1 with Study 2. RESULTS: The mean patient ages were 67.2 years in Study 1 and 75.7 years in Study 2. During a median of 10.4 years of follow-up, 20 men in Study 1 and 17 in Study 2 died from prostate cancer, and 21 men in Study 1 and 50 in Study 2 died from other causes. In Study 1, the 10-year overall survival rate was 73% and the 10-year cause-specific survival rate was 86%, vs 41% and 78% in Study 2. Overall survival curves were similar to expected survival curves in both studies. There was no significant difference between studies in cause-specific survival. CONCLUSIONS: The progression of prostate cancer was retarded by primary hormone therapy in men with localized or locally advanced prostate cancer. With primary hormone therapy or prostatectomy, the men had a life-expectancy similar to that of the normal population.     

Efficacy of nilutamide as secondary hormonal therapy in androgen-independent prostate cancer

OBJECTIVE: To evaluate the activity of nilutamide as secondary hormonal therapy in patients with androgen-independent prostate cancer (AIPC), as treatment options are limited for these patients and secondary hormonal therapy with antiandrogens has advantages, including low toxicity, oral administration and high patient acceptance. PATIENTS AND METHODS: We retrospectively identified 45 patients with AIPC who were treated with nilutamide as secondary hormonal therapy in two institutions. The decrease in prostate-specific antigen (PSA) levels, side-effects of treatment, and the relationship between baseline characteristics, type and duration of previous therapy and response to nilutamide were assessed. Most patients received oral nilutamide at 150 mg/day. RESULTS: Eighteen of 45 evaluable patients (40%) had a PSA level decrease of > or = 50%. Responders (PSA decline > or = 50%) had a median (range) time to progression of 4.4 (0.31-44.7) months. There were responses to nilutamide whether used as the second to fifth line of hormonal therapy. There were no differences in response to nilutamide based on clinical stage, type of local therapy, PSA level at diagnosis or initiation of nilutamide, or type of previous antiandrogen therapy. Responders were more likely to have received monotherapy with luteinizing hormone-releasing hormone analogues or orchidectomy as first-line hormonal treatment (P = 0.02). The most common reversible adverse effects were mild to moderate visual adaptation effects, reported in 20% of patients. CONCLUSIONS: Nilutamide appears to be an effective secondary hormonal therapy in patients with AIPC and is associated with a mild toxicity profile.     

Effectiveness and adverse effects of hormonal therapy for prostate cancer: Japanese experience and perspective

Recently, novel anti-androgens and inhibitors of androgen biosynthesis have been developed through the elucidation of mechanisms of castration resistance of prostate cancer. We believe that these new developments will improve hormonal therapy. On the other hand, there has been an increase in criticism of hormonal therapy, because hormonal therapy is supposed to induce adverse effects such as cardiovascular disease. In this review, we have introduced the Japanese experience of hormonal therapy, because we believe that there may be ethnic differences between Caucasians and Asian people in the efficacy and adverse effects of hormonal therapy. First, we showed that primary hormonal therapy can achieve long-term control of localized prostate cancer in some cases and that quality of life of patients receiving hormonal therapy is rather better than previously thought. Neoadjuvant and adjuvant hormonal therapy in cases undergoing radical prostatectomy or radiotherapy are very useful for high-risk or locally advanced prostate cancer. Further clinical trials are required to confirm the efficacy of neoadjuvant or adjuvant hormonal therapy. We showed that the death from cardiovascular diseases in Japanese patients receiving hormonal therapy was not higher than that in the general population. However, efforts should be made to decrease the adverse effects of hormonal therapy, because life-style change may increase the susceptibility to adverse effects by hormonal therapy even in Japan. Managements of endocrine and metabolic dysfunction, such as diabetes mellitus, are essential. New hormonal compounds such as selective androgen receptor modulators capable of specifically targeting prostate cancer are expected to be developed.     

晚期前列腺癌内分泌治疗后血清PSA、f-PSA含量的变化

目的探讨前列腺癌(PCa)患内分泌治疗后前列腺特异抗原(PSA)、游离前列腺特异抗原与总前列腺特异抗原比值(f／tPSA)变化的临床意义。方珐测定PCa患内分泌治疗前及治疗后1、3、6个月血清PSA、游离前列腺特异抗原(f-PSA)变化。砖杲治疗后1个月与治疗前相比血清PSA下降明显，治疗后6个月较治疗后1个月血清PSA下降亦有显意义；治疗后患血清f-PSA水平明显下降。f／tPSA值的变化无显意义。结论血清PSA、f-PSA可作为判断PCa内分泌治疗效果的标准．如血清PSA、f-PSA复又升高提示肿瘤复发。     

Androgen and prostate cancer: the role of primary androgen deprivation therapy in localized prostate cancer

BackgroundThe basic mechanisms and clinical efficacy of primary androgen deprivation therapy (PADT), especially combined androgen blockade (CAB) for localized or locally advanced prostate cancer (PCa) have been outlined. An important point relates to which patients are suitable candidates for PADT.MethodsA retrospective review of the efficacy of PADT in 628 patients with localized or locally advanced PCa treated with PADT at seven institutions in Japan was carried out.ResultsIt was found that more than 30% of low- or intermediate-risk localized PCa patients could have their disease controlled over the long-term by PADT alone. Short-term or intermittent PADT could not be recommended because of the possibility of character change in the cancer cells as a result of incomplete androgen ablation.ConclusionAlgorithms are proposed for the treatment of localized PCa not only in low- and intermediate-risk groups, but also in the high-risk group. Future research directions are indicated.     

Combined androgen blockade in the management of advanced prostate cancer: A sensible or ostensible approach

BACKGROUND: To compare the efficacy of orchiectomy alone and orchiectomy plus flutamide in treating patients with advanced carcinoma prostate. MATERIALS AND METHODS: The study was initiated on 1 July 1997 and closed after enrolling 100 patients on 30 June 2000. Patients were prospectively randomized to orchiectomy alone (O) and orchiectomy plus flutamide (OF). A complete response (CR) was defined as the normalization of bone scans and serum prostate-specific antigen (PSA) levels returning to normal (< 4 ng/mL). A partial response (PR) was defined as a 50% reduction in metastasis mass compared to the initial study or a decrease in the PSA level of 50% of the initial value. Progressive disease (PD) was defined as the development of any new hot spot on bone scan or any increase in previously existing PSA level by 25%. RESULTS: A total of 100 patients were entered in the study. The maximum percentage change in PSA levels in both groups was found in the first 3 months after orchiectomy, that is, 95% and 97% for the O and OF groups, respectively. In more than 80% of the patients this decrease in PSA was maintained for 3 years. The mean percentage change at 3 years in the O and OF groups was 70% and 75% (P = 0.95), respectively, and the overall response rate (CR + PR) was 88.50% and 86.53% in the two groups, respectively (P = 0.85). The follow-up period ranged between 3 and 5 years (mean, 3.5 years). The mean time to progression was 27 and 29 months in the O and OF groups, respectively. The overall survival rate at 3 and 5 years in two treatment groups was 45.83% and 48.07%, 20.83% and 23.07% in the O and OF groups, respectively (P = 0.75). CONCLUSIONS: Maximum percentage decrease in PSA is seen within the first 3 months of therapy. Orchiectomy alone is as effective as combination therapy in decreasing serum PSA. Overall survival at 3 and 5 years in the orchiectomy only group was as good as that of combination therapy. These data suggest that the routine addition of flutamide to orchiectomy is not advisable.     

氩氦刀冷冻术联合间歇性内分泌治疗治疗局部晚期前列腺癌的初步研究

目的探讨氩氦刀冷冻术(argon-helium cryoablation,AHC)联合间歇性内分泌治疗(intermittent hormonal therapy,IHT)治疗局部晚期前列腺癌(locally advanced prostate cancer,LAPC)的疗效和安全性。方法回顾性分析经直肠超声引导下经会阴前列腺穿刺AHC联合IHT治疗的21例LAPC患者的临床资料,并与18例单纯行IHT治疗的LAPC患者进行对照。评估的指标包括血清总前列腺特异性抗原(total prostate specific antigen,tPSA)、最大尿流率(Qmax)、国际前列腺症状评分(IPSS)、前列腺体积、前列腺MRI和全身骨扫描,生活质量调查采用欧洲癌症研究与治疗组织的QLQ-C30总量表和QLQ-PR25子量表,并记录不良反应。结果 AHC治疗患者的tPSA提前达到最低值,Qmax和IPSS评分改善明显,前列腺体积明显缩小,第一轮停用内分泌药物的时间也明显延长;躯体功能和性功能的明显下降以及局部的疼痛,对患者的生活质量造成一定的影响。AHC术后主要并发症为阴囊水肿、盆腔疼痛、闭孔神经炎、尿道腐肉和后尿道狭窄,但未出现尿失禁、尿道直肠瘘等严重并发症。结论 AHC联合IHT治疗LAPC是一种可选择的安全、有效的方法。     

Role of hormonal therapy for prostate cancer: perspective from Japanese experiences

Hormonal therapy has been playing an important role in the treatment of prostate cancer. However, it has recently been the subject of criticism that it shows minimal effectiveness, it may reduce patients’ quality of life, and induce adverse effects. On the other hand, next-generation hormonal drugs have provided new strategies for hormonal therapy to overcome advanced prostate cancer. Therefore, it is necessary to accumulate further clinical evidence concerning the efficacy and adverse effects of hormonal therapy. And, what is important for the treatment of prostate cancer is how we use hormonal therapy most effectively. This article presents a review of the possible roles of hormonal therapy for prostate cancer based upon experience in Japan.     

Effectiveness of adjuvant intermittent endocrine therapy following neoadjuvant endocrine therapy and external beam radiation therapy in men with locally advanced prostate cancer

PURPOSE: To clarify the optimal duration and methods for adjuvant endocrine therapy after external beam radiation therapy (EBRT) in patients with locally advanced prostate cancer. MATERIALS AND METHODS: Between 2001 and 2003, 215 patients with locally advanced prostate cancer were enrolled in the study. Patients were registered as primary candidates of the study and were treated with 6 months of LHRH agonist, with short-term of antiandrogen treatment for flare-up prevention. Patients with PSA levels below 10 ng/ml after the 6-month endocrine treatment were randomly divided into two arms. Then, a total dose of 72 Gy was given to the prostate. After 14 months of the protocol treatment, patients were treated with continuous androgen ablation (arm 1) or intermittent androgen ablation (arm 2). RESULTS: A total of 188 cases (87%) remained in the protocol. The median PSA level at entry was 25.3 ng/ml. The Gleason score was 2-6 in 32 cases (16%), 7 in 94 cases (48%), and 8-10 in 68 cases (35%). The median PSA level showed a remarkable decrease to 1.1, 0.2, and 0.1 ng/ml, after 6, 8, and 14 months of the protocol treatment, respectively. Of the 157 cases treated with EBRT, 153 cases (97.5%) had no biochemical failure in the mean follow-up of 17.3 months. CONCLUSIONS: The present study may reveal the possibilities of intermittent endocrine therapy after EBRT. However, the follow-up interval is short and little can be said about the results observed so far, exception of acute tolerance and patient acceptance of the protocol.     

即刻辅助内分泌治疗在高危局限期或局部晚期前列腺癌根治性手术后的应用价值

目的:以术后2年PSA复发率评价高危局限期或局部晚期前列腺癌根治性手术后即刻辅助内分泌治疗(AHT)的疗效。方法:回顾性总结在2010年9月至2012年3月在我院泌尿外科确诊为高危局限期或者局部晚期的62例前列腺癌患者。所有患者在术前(腹腔镜或耻骨后前列腺癌根治术)均行MRI、ECT(全身骨显像检查),均未发现有区域盆腔淋巴结及骨转移。其中32例患者(A组)在手术后2周至1个月内给予辅助内分泌治疗(AHT),包括口服及注射药物;30例患者(B组)术后未采取任何处理措施。所有患者在术后每3个月复查1次PSA,每6个月行1次ECT检查,每3个月随访1次(包括患者的药物不良反应、用药持续时间及剂量、生存质量),共计2年。结果:A组中有7例患者生化复发,其2年的总体无生化复发率为78.13%。B组中有14例生化复发,其2年的总体无生化复发率为53.33%(P0.05)。结论:高危局限期或局部晚期前列腺癌根治性手术后即刻AHT可以提高患者无生化复发生存率,对控制该疾病的进一步发展甚至术后的转移有重要意义。     

Deferred combined androgen blockade therapy using bicalutamide in patients with hormone-refractory prostate cancer during androgen deprivation monotherapy

OBJECTIVE: To assess the effect of adding bicalutamide on serum prostate-specific antigen (PSA) levels in patients with hormone-refractory prostate cancer (HRPC) during androgen deprivation monotherapy (ADMT). PATIENTS AND METHODS: Forty-four patients with HRPC were treated with deferred combined androgen blockade (CAB) therapy, administering bicalutamide 80 mg once daily. HRPC was defined biochemically as three consecutive rises in PSA level during ADMT. The treatment response was defined as a > or = 50% decline in PSA levels. Prognostic values of various pretreatment variables for responsiveness to deferred CAB were determined statistically. When the disease relapsed during deferred CAB, bicalutamide was discontinued and the patients were evaluated for the antiandrogen withdrawal syndrome (AWS). RESULTS: Of the 44 patients, 29 (66%) had a PSA response; the median PSA failure-free survival was 9.2+ months. Biopsy Gleason score was the only pretreatment variable predictive of a PSA response (mean Gleason score 7.9 in responders and 8.7 in nonresponders). The PSA doubling time (PSA-DT) was the only statistically significant variable of PSA failure-free survival in a multivariate analysis. The 1- and 2-year PSA failure-free survival rates were 43% and 31% in patients with a PSA-DT of >4 months, while it was 21% and none, respectively, in those with a PSA-DT of <4 months. Responders to deferred CAB had a statistically longer cancer-specific survival than nonresponders. None of 20 patients who were evaluated for AWS had the condition. CONCLUSIONS: Deferred CAB therapy using bicalutamide is effective in patients with progression during ADMT, particularly in those with lower Gleason score tumours or a longer PSA-DT. AWS after deferred CAB is uncommon.     

Combined external radiotherapy and hormonal therapy for localized carcinoma of the prostate

Forty-nine patients with localized carcinoma of the prostate were treated by external radiotherapy together with hormonal manipulation and were followed up to six years. Hormonal manipulation included bilateral orchiectomy and diethylstilbestrol, 3 mg/day. The cumulative five-year survival for the 49 patients was 87.6%, with 11 % progression rate to stage D during that period. In 40 patients (81.6%), a decrease in the size of the prostate was noted. In none of the patients was there local recurrence of the tumor during the period of follow-up. Transient gastrointestinal and/or urinary symptoms occurred following radiotherapy in 11 patients (22.4%), and in four patients severe cystitis or proctitis appeared. Complications related to hormonal therapy occurred in 11 patients (22.4%). The high survival rates reported herein, together with the low progression rate to stage D during six years of follow-up, may justify the early institution of radiotherapy in combination with hormonal manipulation for patients with localized carcinoma of the prostate. A randomized study with an extended number of patients is underway to further evaluate this mode of therapy.     

A re-assessment of the role of combined androgen blockade for advanced prostate cancer

Combined androgen blockade is a controversial topic, which has arguments both for and against. It is revisited by the authors of this mini‐review, with a full discussion on the benefits and cautions with this approach. A wide range of other issues is also addressed in this section: bilateral testicular cancer, male‐factor infertility, and buccal mucosa urethroplasty. All of these are of interest to general urologists, as well as to those with a more specific area of interest.     

Hormone therapy for locally advanced prostate cancer

PURPOSE: We assessed cause specific and all cause survival in men with locally advanced prostate cancer after hormone therapy. MATERIALS AND METHODS: Between February 1991 and November 2000, 208 men with locally advanced prostate cancer were treated with gonadal androgen ablation or gonadal androgen ablation and an antiandrogen at a single medical center. Median PSA was 46 ng./ml. (range 2 to 748). Median potential followup was 78 months (range 4 to 122) and the median observation period was 46 months (range 3 to 122). RESULTS: Of the patients 14 (7%) died of causes related to cancer and 71 (34%) died of competing co-morbid disease. Actuarial cause specific survival at 5 and 8 years was 92% and 80%, respectively. The only demographic or tumor related variable that influenced cause specific survival was Gleason score less than 8 versus 8 or greater (p = 0.02). Actuarial all cause survival at 5 and 8 years was 59% and 41%, respectively. The only variable that influenced all cause survival was a Charlson weighted co-morbidity score of less than 2 versus 2 or greater (p <0.0001). Major morbidity from the primary tumor, including bothersome obstructive voiding symptoms requiring transurethral prostate resection, ureteral obstruction or persistent hematuria, developed in 13 patients (6%), while major treatment related morbidity, including flutamide hepatotoxicity and hip fracture, developed in 4. CONCLUSIONS: Hormone therapy for locally advanced prostate cancer is associated with minimal morbidity from the primary tumor and from treatment. All cause survival parallels that reported for integrated hormone and radiation therapy.     

Clinical outcome of maximum androgen blockade using flutamide as second-line hormonal therapy for hormone-refractory prostate cancer

OBJECTIVES: To investigate the efficacy of maximum androgen blockade (MAB) using flutamide as second-line hormonal therapy for advanced hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS: The study included 55 patients with HRPC who were treated with MAB using flutamide (375 mg daily) as second-line hormonal therapy. All patients had previously received bicalutamide combined with either surgical or medical castration as first-line hormonal therapy, which failed. The effect of the second-line therapy was evaluated by serum prostate-specific antigen (PSA) level alone, and the response defined as a decrease of >50% from the baseline PSA at the start of second-line therapy. RESULTS: On initiating second-line hormonal therapy there was a reduction in the PSA level in 25 of the 55 patients (45%), among whom 12 (22%) were regarded as responders, while the PSA level continued to increase in the remaining 30 (55%). The median (range) duration of the PSA response was 6 (1-13) months. During the observation period there were no severe side-effects from the second-line MAB therapy. Patients without bone metastases or whose disease progressed >1 year after first-line therapy had a significantly higher incidence of PSA response to second-line therapy, despite no significant effect of other factors examined on the PSA response to second-line therapy. Furthermore, the cause-specific survival in responders to second-line therapy was significantly better than that in nonresponders; however, multivariate analysis showed that no factors, including response to second-line therapy, could be used as independent predictors of cause-specific survival. CONCLUSIONS: MAB using flutamide as second-line hormonal therapy can give a comparatively favourable PSA response with no severe side-effects; therefore, this therapy may be suitable for patients with HRPC after primary MAB using bicalutamide has failed, particularly in those with no bone metastases or whose disease has progressed for >1 year after first-line therapy.     

Susceptibility of the prostate cancer cell to different physical, hormonal, and chemical agents: present status and theoretical prospects for improved prostate cancer therapy

The benefits and limitations of present modes of treatment of prostatic cancer with physical, hormonal, and chemical agents are briefly reviewed. The theoretical possibility that the heterogeneous clones that comprise prostatic cancer might be killed or controlled by selective targeting of cytotoxic agents (actual or potential) to malignant cells is discussed in terms of two types of delivery vehicles to provide for cell selectivity: (1) monoclonal antibodies against specific cell surface markers on cancer cells and (2) steroid ligands for receptors present in clones of malignant cells. The problems and prospects of these selective delivery systems as potential therapeutic modalities for prostatic cancer are considered.