局限高危前列腺癌患者接受全雄激素阻断联合近距离治疗后的PSA变化模式与其生存预后的临床关联分析

目的:探讨前列腺癌(PCa)患者治疗后PSA变化模式对其生存预后的临床影响。方法:回顾性总结近12年来114例接受全雄激素阻断(MAB)联合近距离治疗的PCa患者的临床资料,从PSA变化规律入手,初步分析患者生存预后的影响因素。结果:患者中位生存时间81(15~144)个月,1、3、5年生存率分别为91.23%、78.07%和68.42%。单因素分析显示:基线PSA水平、PSA最低值、PSA下降时间、PSA倍增时间以及PSA缓解幅度均是可能影响生存预后的临床因素。多因素分析显示:PSA最低值、PSA下降时间以及PSA缓解幅度是独立的预后因素,并分别提高了患者远期生存可能1.7、3.3和6.8倍。结论:局限高危PCa患者在接受MAB联合近距离治疗后,其PSA能否降至1μg/L以下、能否在3个月之内降至最低值,以及PSA最大缓解幅度能否达到96%等因素均是影响患者预后的独立风险因素。     

Commentary on maximal androgen blockade in prostate cancer: A theory to put into practice?

The population at risk of prostate cancer is on the increase, and so is public awareness of this disease. There has been an unresolved controversy surrounding the benefits of maximal androgen blockade (MAB) as a valid approach to treatment of non-curative prostate cancer since it was first proposed in 1945. How are we to interpret the data on MAB in order to give each patient the best advice on treatment? Studies of MAB using medical castration (luteinizing hormone-releasing hormone [LHRH] analogue plus antiandrogen) vs. LHRH analogues alone are inconclusive when viewed collectively, although the largest showed objective benefits for MAB. The remaining studies have insufficient power to show the expected effect size. Studies of MAB using surgical castration plus antiandrogen vs. surgical castration alone also gave inconsistent results, although a meta-analysis is in favor of MAB on objective criteria of response. Among trials of MAB using an LHRH analogue vs. surgical castration alone, one is positive and the remaining two are neutral for MAB. No study shows MAB to be worse than either medical or surgical castration alone. An overall meta-analysis shows a trend for benefit with MAB but is not statistically significant. The existing data have strongly suggested that there may be a particular benefit for certain subgroups of patients (including those with minimal disease) but numbers studied have been too small to allow valid conclusions. The INT 0105 trial in progress may permit firmer conclusions to be drawn on this and other questions. In the meantime one of the drawbacks to current MAB regimens is the exchange of modest clinical advantages for the side effects of nilutamide and flutamide. Given that the disease is noncurative, improved quality of life is the main goal of therapy, and excellent tolerability of treatment is fundamental to this. In a comparative trial, bicalutamide (Casodex) was more effective than flutamide (each in combination with an LHRH analogue) in terms of time to treatment failure and produced a significantly lower incidence of diarrhoea. In conclusion, the evidence supports early use of adequate hormonal treatment, and this should mean either medical or surgical castration, ideally augmented by an antiandrogen. Tolerability of the antiandrogen is a key consideration in gaining an improvement in quality of life with MAB. © 1995 Wiley-Liss, Inc.     

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.     

Why phase III trials of maximal androgen blockade versus castration in M1 prostate cancer rarely show statistically significant differences

BACKGROUND: The meta-analysis of maximal androgen blockade (MAB) concluded that there is no survival advantage of MAB over castration alone. However, the results from the largest trials yield conflicting results. METHODS: The design and results of three trials were examined. RESULTS: Most studies were planned to detect an over-optimistic difference in survival and immature data were published. The survival curves show that statistical assumptions are not fulfilled. Excluding from the meta-analysis all trials where a negative impact of disease flare on survival could not be excluded resulted in no difference in survival between MAB and castration. CONCLUSIONS: Trials of MAB should be planned to detect differences of no more than 5-10% in median survival. The analyses should only be carried out on mature data and should take into account the possibility of a negative impact on survival due to disease flare if no anti-androgen has been given initially with an LH-RH agonist.     

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.     

Complete androgen ablation suppresses prostate stem cell antigen (PSCA) mRNA expression in human prostate carcinoma

BACKGROUND: Prostate stem cell antigen (PSCA) is a recently identified glycosylphosphatidylinositol (GPI)-anchored cell surface protein belonging to the Thy-1/Ly-6 family of cell surface antigens. Prior data in prostate cancers indicated that PSCA is directly regulated by androgens and PSCA expression increases with high-tumor grade, advanced stage, extracapsular invasion, and androgen-independent progression. The effect of complete androgen ablation (CAA) on tumor PSCA mRNA expression has not been elucidated. The purpose of the present study was to investigate the variations in the expression levels of PSCA mRNA before and after CAA, and further evaluate the clinically prognostic value of PSCA in human prostate carcinoma. MATERIALS AND METHODS: PSCA in situ hybridization (ISH) was performed on the cancerous pretreatment biopsy or transurethral resection of prostate (TURP) tissue of 42 men with primarily organ-confined prostate cancer before CAA, and on their tumor tissue from radical retropubic prostatectomy after CAA with bicalutamide and goserelin acetate for 3 months prior to undergoing radical prostatectomy. Tumor cytoplasmic staining of PSCA mRNA was evaluated by two independent pathologists and the differences of PSCA mRNA expression levels between the samples before and after CAA were analyzed using the Student's t-test. Thirty-six to forty months follow-up studies after radical retropubic prostatectomy were performed and aimed at assessing the correlation of PSCA mRNA expression level with local recurrences or metastases from the cancer. RESULTS: The percent of cells positive for PSCA mRNA by ISH labeling declined from 67.3% (0-89%)+/-9.4% before CAA to 33.8% (0-92%)+/-7.7% after CAA (P<0.001). Before CAA, 40 of 42 cases (95.2%) were positive for PSCA mRNA labeling, however, after CAA the percentage of positive reactivity of PSCA mRNA was decreased to 27 of 40 cases (67.5%), in which none was found with local recurrences or distant metastases after radical prostatectomy on follow-up. This decline in PSCA mRNA labeling was dependent on the original tumor grade with Gleason score of or=8: 73.4%+/-13.8% (P<0.05, respectively). The rest 13 cases had the increased percentage of cells positive for PSCA mRNA after CAA, in which 3 cases were found with local recurrences and 4 cases with distant metastases from tumor on follow-up. CONCLUSIONS: Our data demonstrate that CAA for prostate cancer can suppress PSCA mRNA expression with a tumor grade dependence and the increased expression of PSCA mRNA after CAA may be a clinically adverse predictor for tumor recurrences or distant metastases.     

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.     

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.     

Pure red cell aplasia in a prostate cancer patient treated with leuprolide acetate and chlormadinone acetate

Abstract  Pure red cell aplasia (PRCA) is characterized by anemia with reticulocytopenia but with normal leukocyte and platelet counts, and a bone marrow with a selective absence of erythroid precursor cells. Drug-induced PRCA is a rare secondary form of PRCA, and is usually acute and fully reversible by the withdrawal of the causative drugs. We report a rare case of PRCA in a prostate cancer patient treated with combined androgen blockade (CAB) consisted of leuprolide acetate as a luteinizing hormone-releasing hormone agonist and chlormadinone acetate as an antiandrogen. This case demonstrated that these drugs could be a cause of PRCA, and suggests that regular close monitoring for anemia is needed in prostate cancer patients treated with these drugs.     

间歇性与持续性雄激素阻断治疗晚期前列腺癌疗效比较

目的 比较间歇性与持续性雄激素阻断治疗晚期前列腺癌的疗效和副反应。方法 晚期前列腺癌患者69例，分2组。A组34例行间歇性联合雄激素阻断治疗，B组35例行手术去势加抗雄激素药物即持续性雄激素阻断治疗。比较2组患者的疾病进展时间和副反应发生率。结果 A组中位随访31．5（10～60）个月，B组32．6（12～63）个月。A组患者共行60个周期治疗，平均治疗周期13．7个月，其中治疗期6．4个月、间歇期7．3个月。A、B组中位疾病进展时间分别为31、28个月，差异无统计学意义（P=0．446）；骨转移患者中A组中位疾病进展时间24个月，B组为18个月，2组比较差异有统计学意义（P=0．04）。2组副反应发生率分别为：潮热症状A组20．6％（7／34），B组62．9％（22／35）（P〈0．01）；骨质疏松A组11．8％（4／34），B组31．4％（11／35）（P〈0．05）；乳房肿痛A组14．7％（5／34），B组37．1％（13／35）（P〈0．05）。结论 对晚期前列腺癌患者行雄激素阻断治疗应首选间歇性联合雄激素阻断治疗。     

经尿道前列腺等离子汽化电切联合间断雄激素阻断治疗晚期前列腺癌

目的:探讨经尿道前列腺电切术联合间断雄激素阻断治疗前列腺癌的临床疗效。方法:回顾分析我院为24例确诊为合并膀胱出口梗阻晚期前列腺癌患者行经尿道前列腺等离子汽化加全间断雄激素阻断术的临床资料。结果:24例手术均获成功,术中出血少,术后随访12个月,术后3个月国际前列腺症状评分(7.12±4.24),生活质量评分(1.8±0.4),残余尿(26.5±12.2)ml,最大尿流率(17.82±2.78)ml/s,血清PSA平均(6.3±2.1)ng/ml。结论:等离子汽化电切加间断雄激素阻断治疗能提高合并膀胱出口梗阻晚期前列腺癌患者的生存质量。     

Squamous cell carcinoma of the prostate

Squamous cell carcinoma of the prostate is rare, accounting for 0.5-1% of all prostatic cancers. It is highly aggressive and responds poorly to any mode of therapy. We present a case of squamous cell carcinoma of the prostate that developed in a patient with prostatic adenocarcinoma following radiation therapy.     

Small cell carcinoma of the prostate with hypercalcemia

We present a case of small cell prostate carcinoma with hypercalcemia in a 75-year-old man. He was diagnosed as having stage T3bN1M0 adenocarcinoma of the prostate. His serum prostate-specific antigen level was reduced to below the normal range after a combination treatment of a luteinizing hormone-releasing hormone agonist and flutamide for prostate carcinoma. He subsequently experienced increasing fatigue, poor appetite, short time loss of consciousness and pain in his lower abdomen. His serum calcium level and carcinoembryonic antigen were increased. He died 5 months from the start of treatment. The autopsy revealed small cell carcinoma of the prostate and multiple metastasis of the lung, liver, pancreas, lymph nodes and spine.     

Germline CAG repeat length of the androgen receptor and time to progression in patients with prostate cancer treated with androgen deprivation therapy

Study Type – Prognosis (retrospective cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Germline CAG repeat polymorphisms in the androgen receptor (AR‐CAG) have been shown to influence the activity of the androgen receptor, but there has been conflicting data from small retrospective studies evaluating the effect of CAG repeat polymorphisms on response to ADT. This is the largest published study to date investigating the association of germline AR‐CAG repeat lengths and efficacy of ADT in prostate cancer. Germline AR‐CAG repeat lengths do not predict response to ADT.

OBJECTIVES

? Germline CAG repeat polymorphisms in the androgen receptor (AR‐CAG) have been shown to influence the activity of the AR. ? The purpose of the present study was to determine if AR‐CAG repeat length correlates with time to progression on androgen deprivation therapy (ADT).

PATIENTS AND METHODS

? Germline AR‐CAG repeat lengths were determined in a cohort of 480 patients with recurrent or metastatic prostate cancer treated at a single tertiary care institution and correlated to time to progression (TTP) and overall survival.

RESULTS

? There was no significant correlation between differences in the AR‐CAG repeat lengths and TTP or overall survival in patients with prostate cancer receiving ADT. ? AR‐CAG repeat lengths did not significantly correlate with age, prostate‐specific antigen (PSA), Gleason score or clinical stage at diagnosis. ? In patients with metastatic disease, longer AR‐CAG repeat lengths (>23 vs ≤23) were associated with a longer TTP on ADT, but this finding was of borderline significance (median TTP 18.3 vs 15.5 months, P= 0.09; adjusted HR = 0.76, 95% confidence interval = 0.54–1.09).

CONCLUSIONS

? This is the largest published study to date investigating the association of germline AR‐CAG repeat lengths and efficacy of ADT in prostate cancer. ? Germline AR‐CAG repeat lengths do not predict response to ADT.     

Effects of flutamide as a second-line agent for maximum androgen blockade of hormone refractory prostate cancer

We analyzed clinical effects of flutamide as a second-line agent for maximum androgen blockade (MAB) in patients with relapsing prostate cancer who received bicalutamide as the first-line MAB agent. This study included 13 patients with progressive prostate cancer who had relapsed after first-line MAB, with bicalutamide at 80 mg/day. After checking for antiandrogen withdrawal syndrome, they were given flutamide at 375 mg/day as second-line MAB. The effectiveness of that therapy was evaluated by changes in prostatic specific antigen (PSA) levels, with response defined as a decrease of greater than 50% from the start of therapy. We also compared several factors between responders and non-responders. Nine (69.2%) of the 13 patients showed a decrease in PSA levels, of whom five (38.5%) had a greater than 50% decrease and were defined as responders. The median duration of PSA response was 11.0 months (range 5-20 months). Patients who had a longer duration of response to first-line MAB had a significantly greater response to second-line MAB. For advanced prostate cancer patients who progressed on first-line MAB with bicalutamide, flutamide administration as a second-line antiandrogen was found to be relatively effective, especially for those who showed a longer duration of response to the first-line MAB. Our results confirm previous findings that MAB using flutamide is an effective second-line hormonal therapy.