Antiandrogen withdrawal syndrome with cyproterone acetate

Objectives. To determine whether the antiandrogen withdrawal syndrome occurs with the steroidal antiandrogen cyproterone acetate.Methods. Cyproterone acetate was withheld in 12 patients with progressing androgen-independent metastatic prostate cancer. Eight patients had been receiving cyproterone acetate concomitant with androgen ablation, and in 4 patients it was prescribed after failure of androgen suppression. Time to response and to disease progression were defined by serum prostate-specific antigen (PSA) levels and imaging studies.Results. PSA levels decreased in 5 of the 12 patients; in 4 of them (33%), the decrease exceeded 50%. The decline lasted a median of 24 weeks (range 9 to 37.8). All 5 patients had received initial concomitant exposure to androgen ablation and cyproterone acetate.Conclusions. We recommend that the steroidal antiandrogen cyproterone acetate be added to the list of agents capable of inducing antiandrogen withdrawal syndrome.     

An implant releasing the gonadotropin hormone-releasing hormone agonist histrelin maintains medical castration for up to 30 months in metastatic prostate cancer

PURPOSE: The administration of gonadotropin hormone-releasing hormone agonists is well established for treating metastatic prostate cancer. In an ongoing study we evaluated the effect of a long acting implant that releases the gonadotropin hormone-releasing hormone agonist histrelin ([ImBzl]D-His6,Pro9-Net) in 15 patients with disseminated prostate cancer. MATERIALS AND METHODS: The 2.6 cm. implant releasing 60 microg. histrelin daily is inserted subcutaneously into the upper arm using local anesthesia. Of the patients 8 received 1 and the remainder received 2 implants. Treatment with the antiandrogen flutamide or cyproterone acetate began 2 weeks before implant insertion and continued for up to 12 weeks. Testosterone, luteinizing hormone (LH) and prostate specific antigen were determined monthly, and a metastatic evaluation was performed every 6 months. RESULTS: LH and testosterone increased after flutamide administration and decreased after implant insertion. By day 28 LH and testosterone were completely suppressed. LH and testosterone decreased immediately after cyproterone acetate administration. Prostate specific antigen began to decrease during antiandrogen therapy and decreased further after implant insertion. One patient requested implant removal after 1 year for personal reasons and 1 died of an unrelated cause 18 months after insertion. Escape was demonstrated in 4 cases at 5, 10, 12 and 19 months, although LH and testosterone remained suppressed. Duration of treatment in the remaining 9 patients was between 21 and 30 months. LH and testosterone remained completely suppressed and prostate specific antigen levels were in the normal range. The clinical and biochemical response was identical in those who received 1 or 2 implants. At 12 months 8 patients were challenged at intermittent intervals for up to 24 months with a bolus of 100 microg. gonadotropin hormone-releasing hormone followed by 2 weeks of flutamide. The response was compared with that in untreated controls recently diagnosed with prostate cancer. Unlike controls there was complete LH suppression in the 8 challenged patients. CONCLUSIONS: A histrelin implant suppresses LH and testosterone in prostate cancer for up to 30 months. This finding represents a significant improvement over existing preparations, which must be administered at 1 to 3-month intervals.     

Neoadjuvant hormonal therapy before radical prostatectomy and risk of prostate specific antigen failure

PURPOSE: To date there is little information on the long-term effect of neoadjuvant hormonal therapy on prostate cancer progression. We performed a prospective study to determine whether patients with prostate cancer receiving neoadjuvant hormonal therapy before radical prostatectomy (hormonal therapy group) have a lower risk of prostate specific antigen (PSA) failure than those treated with radical prostatectomy alone (prostatectomy group). We also evaluated whether type of neoadjuvant hormonal therapy and duration were associated with the risk of PSA failure. MATERIALS AND METHODS: We followed 680 men initially treated for prostate cancer with radical prostatectomy between January 1988 and December 1997 at our university hospital. Of the patients 292 received neoadjuvant hormonal therapy. Median followup was 38 months. Cox regression analysis was used to assess the association between neoadjuvant hormonal therapy and PSA failure (greater than 0.3 ng./ml.) controlling for age, clinical stage, grade, initial PSA and adjuvant therapies. RESULTS: Surgical margins were positive less often in the hormonal therapy (25%) than the prostatectomy (47%) group (p = 0.0001). PSA failure was observed in 163 patients and the 5-year failure rate was 33%. No difference in risk of PSA failure was observed overall between the hormonal therapy and prostatectomy groups (hazards ratio 0.94, 95% confidence interval 0.68 to 1.30). Treatments with antiandrogen alone for any duration, and those combining antiandrogen and luteinizing hormone-releasing hormone analogue for 3 months or less were not associated with improved survival. However, patients receiving combined therapy for more than 3 months had a significantly lower risk of PSA failure than those treated with radical prostatectomy alone (hazards ratio 0.52, 95% confidence interval 0.29 to 0.93). CONCLUSIONS: Prolonged neoadjuvant hormonal therapy combining antiandrogen and luteinizing hormone-releasing hormone analogue may improve disease-free survival after radical prostatectomy.     

Oxidative DNA damage in patients with prostate cancer and its response to treatment

PURPOSE: We evaluated the significance of oxidative DNA damage in patients with prostate cancer based on the measurement of urinary 8-OHdG (8-hydroxy-2'-deoxyguanosine) and analyzed changes in urinary 8-OHdG before and after initial treatment. MATERIALS AND METHODS: A total of 82 patients with prostate cancer were included in this study. Of these 82 patients 42 underwent radical prostatectomy and the remaining 40 received hormonal therapy as initial treatment. Urinary 8-OHdG and creatinine (Cr), and serum prostate specific antigen (PSA) in these 82 patients were assessed before and 2 months after the initiation of treatment. RESULTS: The ratio of urinary 8-OHdG-to-Cr (8-OHdG/Cr) in patients with prostate cancer was significantly higher than in age matched healthy controls. Only age was significantly associated with 8-OHdG/Cr in prostate cancer cases among several clinicopathological factors, including serum PSA clinical T stage, metastasis and Gleason score. There was no significant difference in urinary 8-OHdG/Cr in 42 patients before and after radical prostatectomy, while urinary 8-OHdG/Cr in 40 patients after hormonal therapy was significantly lower than before hormonal therapy. In addition, changes in PSA after initial treatment were not related to changes in urinary 8-OHdG/Cr in either treatment group. CONCLUSIONS: These findings suggest that oxidative stress may be involved in an early event in prostate cancer development and androgen suppression is capable of decreasing oxidative stress. Accordingly androgen withdrawal therapy combined with antioxidative agents may inhibit the progression of prostate cancer.     

Antiandrogen, vaccine and combination therapy in patients with nonmetastatic hormone refractory prostate cancer

PURPOSE: There is no current standard treatment for patients with prostate cancer who have received hormonal therapy but have an increasing prostate specific antigen (PSA) without radiographic evidence of metastasis. This trial was designed to analyze toxicity, immunogenicity and time to treatment failure using vaccine, antiandrogen therapy or their sequential use. MATERIALS AND METHODS: A total of 42 patients were randomized to receive vaccine vs antiandrogen therapy with nilutamide. The vaccine consisted of recombinant vaccinia viruses containing the PSA and B7.1 costimulatory genes as prime vaccinations, and avipox-PSA as boosters. After 6 months patients with an increasing PSA and no metastasis may receive a combination of both treatments. RESULTS: Three patients on nilutamide were removed from study secondary to grade 3 toxicities but no grade 3 toxicities were attributed to vaccine. In the vaccine arm median time to treatment failure was 9.9 months with 13 of 21 decreases in PSA velocity vs 7.6 months with 16 of 21 decreases in PSA velocity in the nilutamide arm (p =0.28). Of the patients in the nilutamide arm 8 had vaccine added at the time of PSA progression. Median time to treatment failure with combined therapy was 5.2 months, with a median duration from study entry of 15.9 months. Of the patients in the vaccine arm 12 had nilutamide added at the time of PSA progression. Median time to treatment failure with combined therapy was 13.9 months and a median of 25.9 months from initiation of therapy. CONCLUSIONS: Further studies are merited to investigate the role of combining vaccine with antiandrogen therapy or vaccine followed by vaccine plus antiandrogen therapy in this patient population.     

Prostate specific antigen only progression of prostate cancer

PURPOSE: Introduction of the prostate specific antigen (PSA) serum marker for prostate cancer and the subsequent PSA era from 1988 to the present have dramatically altered the diagnosis of the disease. The early to mid 1990s diagnosis boom resulted in a huge increase in clinically localized and early stage disease treatments. Radical prostatectomy rates increased from 17.4 to 54.6/100,000 between 1988 and 1992, and age adjusted rates increased 2 to 4-fold for men in the fifth and sixth decades of life. Since the late 1990s clinicians have been seeing the effects of this diagnosis and localized treatment boom, in that many men each year are experiencing PSA only disease recurrence. Given that the majority are relatively young and otherwise healthy, treatment of PSA only recurrence requires approaches that not only improve survival, but also preserve quality of life. A comprehensive overview of the definition of PSA only recurrence, staging controversies and the wide variety of treatments to be considered is provided. MATERIALS AND METHODS: A literature review and overview of the topic of PSA only recurrence after prior clinically localized prostate cancer treatment were performed. RESULTS: For radical prostatectomy cases PSA only recurrence is broadly defined as any elevation of PSA postoperatively. For radiation treated patients the 1997 American Society for Therapeutic Radiology and Oncology guidelines specify 3 consecutive elevations of PSA after posttreatment PSA nadir is achieved. As localized treatment series in the PSA era have matured, and database and statistical support have improved, a number of useful models to predict PSA only recurrence have emerged. These models are based on traditional prognostic markers, such as pretreatment PSA, and grade and stage of disease as well as emerging molecular and cellular biomarkers. Although bone scans and pelvic computerized tomography are commonly used for re-staging at PSA only recurrence, recent study suggests that their value is limited unless PSA recurrence exceeds 30 to 40 ng./ml. 111Indium capromab pendetide radionuclide scan, which has been approved for radical prostatectomy PSA only recurrence, may be helpful to determine cases best suited for salvage radiotherapy versus systemic hormonal therapy, although more study is needed. Treatment of PSA only recurrence is divided into 2 main categories of salvage local treatments and systemic therapy. The principal dilemma is the inability to determine definitively whether PSA only recurrence is solely due to local progression or distant micrometastases. External beam radiation is the main local salvage treatment for radical prostatectomy recurrence, and cryotherapy, salvage prostatectomy and salvage brachytherapy are options for radiation recurrence. Proper patient selection is critical to the success of all salvage local treatments. Traditional hormonal therapy is the mainstay of systemic treatment for PSA only recurrence, although nontraditional approaches, such as intermittent and low dose hormonal therapy, are under study. Emerging chemopreventive agents, such as vitamins, minerals and other supplements, may have a future role in treatment. CONCLUSIONS: PSA only recurrence after prior local prostate cancer treatment remains a common problem facing clinicians.     

经尿道电切治疗晚期前列腺癌伴膀胱出口梗阻

目的 总结经尿道前列腺电切治疗晚期前列腺癌伴膀胱出口梗阻的手术经验.方法 本组36例患者,年龄68～89岁,平均76.5岁.术前IPSS评分为(18.3±3.1)分;总PSA分别为(60.1±35.4)ng/ml;最大尿流率为(9.4±2.8)ml/s.穿刺病理确诊为前列腺癌,Gleasn评分为(7.3±1.8)分.Whitmore临床分期C期10例,D期26例.36例患者行经尿道前列腺电切术同时行双睾丸切除术,术后加用(氟他胺250mgtid或者比卡鲁胺50mgqd),行全雄激素阻断.结果 36例均顺利完成手术,无围手术期死亡病例.6例(16.7%)术后出现尿失禁,经保守治疗后治愈.1例术后大出血,二次手术止血后恢复顺利,1例术后4个月再次出现排尿困难,再次行TURP后,患者排尿通畅.随访24～55个月,死亡13例,其中死于前列腺癌10例,平均生存32个月,死于其他疾病3例.术后患者排尿症状明显改善,术后3个月尿流率(17.5±3.5)ml/s,术后IPSS评分(8.1±3.4)分.结论 经尿道前列腺电切是治疗晚期前列腺癌伴膀胱出口梗阻的有效方法,可以快速改善患者的排尿症状,提高尿流率.     

Use of cyproterone acetate in prostate cancer

Cyproterone acetate is a progestational antiandrogen with potent antigonadotropic activity that results in rapid suppression of serum testosterone. Used as a single agent, cyproterone acetate yields a total androgen blockade. It may be combined with low-dose diethylstilbestrol, orchiectomy, or LHRH agonists to improve, in theory, the results of such therapy. In clinical testing, cyproterone acetate has proved equivalent to diethylstilbestrol with markedly less toxicity. It is useful in conjunction with LHRH agonists, either transiently to block the flare phenomenon, or continuously to block peripheral androgen receptors; the necessity for this latter action has not yet been proved. Cyproterone acetate may afford transient objective improvement in patients not responding to other forms of hormone deprivation. Experience in this role is limited. The drug may be used to suppress the hot flushes associated with orchiectomy or LHRH agonist therapy. Cyproterone acetate induces local tumor regression; owing to its reversible effects, it is useful as neoadjuvant or adjuvant androgen withdrawal therapy in patients with lower-stage disease undergoing radical surgery or radiotherapy. Adverse effects are mostly those related to hormone withdrawal, namely, impotence, infertility, and lassitude. Gynecomastia and breast tenderness occur in less than 18% and cardiovascular complications in approximately 10% of treated men.     

A morphological study on the effect of cyproterone acetate on human prostatic carcinoma

Sixteen patients with prostatic carcinoma were treated with 200 mg of Cyproterone acetate daily. No other kind of hormonal treatment was given. Transrectal biopsies of the prostate were taken before the treatment was started, and at regular intervals afterwards. The treatment period lasted from 3 to 16 months, with an average of 9 months. A thorough examination of multiple sections from all specimens revealed no convincing signs of cellular involution. The study has demonstrated no specific or significant atrophic changes following Cyproterone acetate therapy. Some possible explanations regarding the effect of Cyproterone acetate on human malignant prostatic tissue are discussed.     

A 10-year clinical experience with intermittent hormonal therapy for prostate cancer

OBJECTIVES: To evaluate, over a 10-year period, the feasibility, efficacy, duration of action and adverse effects of intermittent hormonal therapy (IHT) in patients with advanced prostate cancer or biochemical recurrence after radical treatment. MATERIALS AND METHODS: Two hundred and thirty-three patients with prostate cancer have been included in an IHT protocol since 1992. Fifty-five patients had already been treated by radical prostatectomy (group A), 35 patients had received radiotherapy or a treatment with high-intensity focused ultrasound (HIFU) (group B) and 143 patients had not received any previous treatment (group C). Three-monthly injection of LHRH analogue combined with a non-steroidal antiandrogen was administered during the treatment phase ("on" phase). Treatment was stopped ("off" phase) when the PSA level fell below 4 ng/ml, regardless of the duration of the "on" phase. Criteria for resumption of hormonal therapy were PSA >20 ng/ml, PSA progression slope over the previous three months >5 ng/ml per month or recurrence of pain or urinary symptoms. RESULTS: The median follow-up was 34.9 months (range: 13-151) and the median initial PSA was 28 ng/ml (range: 1-433). Five cycles were performed in the patients with the longest follow-up. The mean duration of cycles was gradually decreased from 19.6 months to 11.8 months. The "on/off" ratio was close to 30% regardless of the cycle or patient group. Ten patients (4%) died from their cancer during the study, with a median survival of 42.2 months. Six patients (2.5%) developed painful symptoms during IHT. CONCLUSIONS: IHT ensures medium-term (three years) control of the disease, using a treatment resumption criteria of PSA >20 ng/ml and was not associated with major complications.     

Prostate specific antigen in hormonally treated stage D2 prostate cancer: is it always an accurate indicator of disease status?

The clinical significance of serum prostate specific antigen (PSA) values in hormonally treated prostate cancer patients and the effect of hormonal therapy on the serum PSA concentration, independent of the response observed from its antitumor activity, are not well defined. To elucidate further the influence of antiandrogen therapy on serum PSA expression, 81 randomly selected patients with stage D2 prostate cancer were evaluated with respect to serum PSA concentration. These patients were divided into 2 groups on the basis of previous hormonal therapy. Group 1 consisted of 43 patients 55 to 89 years old (mean age 71 years) who had received no prior therapy for prostate cancer. Group 2 included 38 men 58 to 84 years old (mean age 72 years) who had received only androgen deprivation therapy with either bilateral orchiectomy or diethylstilbestrol. The mean interval between initiation of antiandrogen therapy and evaluation of these patients was 14 months (range 8 to 31 months). At the time of PSA determination both groups were similar in all respects, including tumor grade, disease symptoms and bone scan findings. The median serum PSA concentration was 96.0 ng./ml. in group 1 and 16.5 ng./ml. in group 2 (p less than 0.001), despite both groups having similar symptoms and widespread metastatic disease on radionuclide bone scan. In group 1 only 1 patient (2%) had a serum PSA level less than 4.0 ng./ml., whereas 13 men (34%) in group 2 had a serum PSA concentration below 4.0 ng./ml. (p less than 0.001). Of the patients in group 1, 2% and of the men in group 2, 45% had a serum PSA concentration less than 10 ng./ml. (p less than 0.001). These findings demonstrate that the serum PSA level in prostate cancer patients treated hormonally may have a significantly different meaning than the same serum PSA value in patients without hormonal therapy. In addition, these observations suggest that PSA expression may be under hormonal regulation and that androgen deprivation therapy may have a direct effect on the serum PSA concentration, independent of the response obtained from any antitumor activity. However, the exact mechanism of this androgenic influence on PSA expression awaits further investigation at the cellular level.     

Comparing prostate specific antigen outcomes after different types of radiotherapy management of clinically localized prostate cancer highlights the importance of controlling for established prognostic factors

PURPOSE: We evaluated the impact that the composition of prognostic factors in a patient cohort may have on prostate specific antigen (PSA) outcome following external beam radiation therapy for clinically localized prostate cancer. MATERIALS AND METHODS: The distribution of PSA, biopsy Gleason score and American Joint Committee on Cancer (AJCC) T stage in men with prostate cancer treated with interstitial plus external beam radiation therapy was used to select a matched cohort who underwent 3-dimensional (D) conformal external beam radiation therapy. We compared PSA outcomes after 3-D conformal external beam radiation therapy in the overall and matched cohorts of 766 and 570 patients, respectively. RESULTS: Men treated with interstitial plus external beam radiation therapy had a significantly lower rate of PSA greater than 10 to 20 (p = 0. 02) and greater than 20 ng./ml. (p <0.0001), biopsy Gleason score 7 (p = 0.02) and 8 to 10 (p <0.0001), and AJCC stage T2c disease (p <0. 0001). Likewise, these men also had a significantly higher rate of PSA greater than 4 to 10 ng./ml. (p <0.0001), biopsy Gleason score 5 to 6 (p = 0.0001) and AJCC stage T1 disease (p <0.0001) than those who underwent 3-D conformal external beam radiation therapy. The 5-year estimate of PSA failure-free survival after 3-D conformal external beam radiation therapy was 45% versus 67% (p = 0.0007) for all 766 consecutively treated patients and the matched cohort of 570, respectively. CONCLUSIONS: The composition of prognostic factors in a patient cohort may impact PSA outcome. Therefore, controlling for established prognostic factors is essential when comparing PSA outcome after different forms of radiotherapy for adenocarcinoma of the prostate.     

Gestagens in the management of prostatic carcinoma

Two different hormonal gestagens, cyproterone acetate and norethisterone, were studied in prostatic carcinoma, for the greatest part in advanced cases. Cyproterone acetate was administered to 80, norethisterone to 38 unselected patients. The period of study extended over 2 years or more. The mechanism of action of gestagens and the role of the hormone receptors are discussed. The significance of serial measurements of plasma testosterone by providing a monitor of hormonal therapy is emphasized. The relevant literature is reviewed. The value of gestagens as an alternative to the traditional hormone therapy of prostatic carcinoma is pointed out.     

Nilutamide as second line hormone therapy for prostate cancer after androgen ablation fails

PURPOSE: We investigate the prostate specific antigen (PSA) response rate with nilutamide as a second line hormonal agent in patients with advanced prostate cancer in whom androgen ablation failed. MATERIALS AND METHODS: From 1998 to 2001, 28 patients with hormone resistant prostate cancer were treated with nilutamide as second line hormonal therapy. Average patient age +/- SD was 72.9 +/- 9.1 years. Median time from diagnosis of cancer to hormone failure was 48 months (range 2 to 120). Median followup from initiation of nilutamide therapy was 26 months (range 15 to 44). All patients had previously received at least 1 antiandrogen (flutamide or bicalutamide) in addition to medical or surgical castration, which failed. RESULTS: Upon initiation of nilutamide therapy 18 of the 28 patients (64%) had an initial reduction in PSA and 8 (29%) sustained a PSA response (greater than 50% decrease) beyond 3 months (range 3 to 21). PSA response to nilutamide in patients with a previous antiandrogen withdrawal response versus nonresponse was 100% and 18%, respectively. In 10 of the 28 patients, (36%) PSA continued to increase. Interstitial pneumonitis developed, in 1 patient and 5 had nonspecific complaints (headaches, nausea, dizziness). During followup 6 of the 28 patients died 1 of whom was a nilutamide responder. No patient died while on nilutamide. CONCLUSIONS: Nilutamide can achieve a significant sustained PSA response with a favorable toxicity profile. Patients with a previous antiandrogen withdrawal response have a significantly greater chance of responding to nilutamide.     

Recovery of serum prostate specific antigen value after interruption of antiandrogen therapy with allylestrenol for benign prostatic hyperplasia

Decrease in serum prostate specific antigen (PSA) concentration is inevitably associated with antiandrogen therapy for benign prostatic hyperplasia (BPH), and might mask the presence of prostate cancer or delay its diagnosis. To determine the appropriate timepoint for determination of correct PSA value, we sequentially measured serum PSA and testosterone levels after discontinuation of antiandrogen therapy for BPH. With informed consent, 12 patients (72.8 +/- 12.2* years old) with BPH were treated with allylestrenol 50 mg/day for 4 months. Serum testosterone and PSA concentrations were determined before and just after treatment, as well as every month after treatment up to 3 months. After treatment with allylestrenol for 4 months, mean serum testosterone and PSA levels were significantly decreased from 408 +/- 136* to 87.9 +/- 76.2* ng/dl, and from 2.81 +/- 0.87* to 2.04 +/- 0.82* ng/ml, respectively. The mean serum PSA level recovered to the pretreatment level within 2 months and mean serum testosterone concentration within one month after discontinuation of administration. In conclusion, during treatment of BPH with antiandrogen allylestrenol, a two-month washout is adequate for determination of correct PSA value (*: M +/- SD).     

Clinical efficacy of alternative antiandrogen therapy in Japanese men with relapsed prostate cancer after first-line hormonal therapy

BACKGROUND: To confirm the effectiveness of alternative antiandrogen therapy (AAT) in Japanese patients with prostate cancer relapse after first-line hormonal therapy. METHODS: A total of 80 patients who had successive serum prostate-specific antigen (PSA) progression after first-line hormonal therapy (luteinizing hormone-releasing hormone agonist alone: 21 cases; combined antiandrogen blockade therapy: 59 cases) were enrolled. We evaluated the positive ratio of antiandrogen withdrawal syndrome (AWS), the PSA responses with second- and third-line AAT, and cause-specific survival in terms of the effectiveness of AAT. RESULTS: The overall positive AWS ratio after first-line therapy was 33%, while that after second-line therapy was 7%. There was no correlation between the first-line PSA response and the positive AWS. Of the 10 positive and the 20 negative AWS cases, secondary antiandrogen administration was effective in 50% and 60% of cases, respectively. The positive PSA responders at second- and third-line therapy were 51% and 13%, respectively. For second-line therapy, the effective rates from steroidal to non-steroidal, from non-steroidal to non-steroidal antiandrogen, and from non-steroidal to steroidal were 83%, 43%, and 14%, respectively. The cause-specific survival of the second-line responders was significantly better than that of the non-responders. CONCLUSION: There was a substantial number of patients who found second-line AAT to be modestly effective. Flutamide was effective as an alternative antiandrogen for the patients' relapse treatment with bicalutamide in Japanese men.     

The effect of brachytherapy, external beam irradiation and hormonal therapy on prostate volume

PURPOSE: We describe the effects of prostate brachytherapy with or without hormonal therapy, or external beam irradiation on gland volume. MATERIALS AND METHODS: A total of 600 men with localized prostate cancer underwent 125I (357), 103Pd (118) or partial 103Pd combined with external beam irradiation (125) brachytherapy. Of the 600 men 299 (49.8%) received 3 to 9 months of hormonal therapy, which was initiated 3 months before implantation. Hormonal therapy consisted of luteinizing hormone-releasing hormone agonist plus antiandrogen in 251, luteinizing hormone-releasing hormone agonist in 41 and flutamide plus finasteride in 7. Prostate volume measurements were made before the initiation of hormonal therapy, at implantation and yearly. Median followup was 5.2 years. Associations were tested by chi-square analysis. Means were compared by 1-way ANOVA and the Student t test. RESULTS: Median initial prostate volume was 38.5 cc (range 9.2 to 151.5). Pre-implantation hormonal therapy resulted in a median prostate volume decrease of 33.1%. The mean reduction for luteinizing hormone-releasing hormone agonist was 27.6%, for luteinizing hormone-releasing hormone agonist plus antiandrogen it was 32.8% and for flutamide plus finasteride it was 10.8% (p=0.003). Prostate volume decreased 36.6% by year 1, 42.4% by year 4, 45.6% by year 6 and 51.2% by year 8 (p<0.0001). There was no difference in prostate volume reduction at year 1 between men receiving hormonal therapy vs implantation alone. Patients treated with 103Pd had a greater prostate volume reduction at 1 year than those who received 125I (p=0.004). Conversely patients treated with hormonal therapy and 125I had a smaller prostate volume reduction than those implanted with 125I alone (p=0.023). After year 1 there were no longer differences between any groups. CONCLUSIONS: Luteinizing hormone-releasing hormone agonist plus antiandrogen is more successful for reducing prostate volume before prostate brachytherapy than luteinizing hormone-releasing hormone agonist or flutamide plus finasteride. Hormonal therapy offered no advantage over implantation alone for post-implantation prostate volume reduction. 103Pd appears to reduce prostate volume more rapidly than 125I but this advantage is lost by year 2. No rebound in prostate volume was noted at longer followup.     

Penile length changes in men treated with androgen suppression plus radiation therapy for local or locally advanced prostate cancer

PURPOSE: We determined penile length alterations in men treated with androgen suppression plus radiation therapy for local or locally advanced prostate cancer. MATERIALS AND METHODS: From November 2000 to November 2005, 47 patients were enrolled in this prospective study. After clinical staging all patients received hormonal therapy (luteinizing hormone releasing agonist, leuprolide acetate or goserelin every 3 months for a total of 3 injections) and at month 7 of hormonal therapy radiation therapy was begun (total 70 Gy) for 7 weeks. Stretched penile length measurements were performed before starting androgen suppression therapy and every 3 months thereafter with a paper ruler. RESULTS: With the initiation of therapy a gradual decrease in stretched penile length was observed. Penile shortening was statistically significant at a mean followup of 18 months (mean 14.2 to 8.6 cm, p <0.001). CONCLUSIONS: Our findings support observations of decreased penile length after neoadjuvant hormonal therapy plus external beam radiation therapy for local or locally advanced prostate cancer. Patients should be counseled before therapy that penile shortening may occur.     

Bicalutamide vs cyproterone acetate in preventing flare with LHRH analogue therapy for prostate cancer--a pilot study

OBJECTIVE: To evaluate the efficacy of bicalutamide vs cyproterone acetate in preventing PSA flare (as a surrogate for tumour flare) for patients requiring luteinizing hormone-releasing hormone (LHRH) analogue therapy for prostate cancer. PATIENTS AND METHODS: In this pilot study, 40 men were randomized 1 : 1 to bicalutamide 50 mg o.d. or cyproterone acetate 100 mg t.i.d. 5 days prior to goserelin acetate and continued for 21 days thereafter. PSA, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone were obtained before treatment and on days 6, 8, 10, 16, 21 and 28. Primary end point was PSA. Hormone profile and clinical features including urinary symptoms and bone pain were secondary end points. RESULTS: Both groups were equally matched apart from serum creatinine and ALP. The speed and magnitude of the percentage change in median PSA from baseline was increased for the CPA group but there was no statistically significant difference in the two groups. Although those receiving bicalutamide all showed a testosterone peak, this remained within the normal range. No difference in the frequency of drug-specific adverse events was found. None of the patients died or developed cord compression during the study period. CONCLUSION: Bicalutamide is able to suppress the initial PSA surge as effectively as cyproterone acetate albeit slightly delayed. A statement whether bicalutamide is equally good at preventing clinical flare cannot be made and should be assessed in an appropriately powered study.     

Similar rates of exponential decrease in serum concentrations of free prostate-specific antigen (PSA), PSA complexed to alpha-1-antichymotrypsin, and human glandular kallikrein 2 (hK2) in prostate cancer patients treated with GnRH-analogues

BACKGROUND: Our recently reported finding of rapid bi-exponential elimination of free prostate-specific antigen (PSA) after radical retropubic prostatectomy in patients with moderately elevated PSA levels, which contrasted a very slow, linear elimination of PSA complexed to alpha-1-antichymotrypsin (ACT), prompted us to study whether these elimination rates were applicable for patients selected for castration treatment with very high pretreatment concentrations of PSA in serum. In addition, serum concentrations of hK2, the activator of proPSA, were measured. METHODS: Pretreatment serum was obtained from 21 previously untreated prostate cancer patients due for hormonal treatment with a GnRH-analog. Samples were also collected during treatment up to a minimum of 24 weeks at 2-week intervals and analyzed with immunofluorometric assays for free PSA (PSA-F), PSA complexed to alpha-1-antichymotrypsin (PSA-ACT), total PSA (PSA-T), and human kallikrein 2 (hK2). For pharmaco-kinetic analysis the serum concentrations of hK2 and PSA forms for each patient were plotted against time both before and after logarithmic transformation and the half-lives were calculated as ln2/k. RESULTS: Median pretreatment serum concentrations were 322 ng/ml (range, 1.9-2210) for PSA-T, 27.8 ng/ml (range, 1.14-259) for PSA-F, and 207 ng/ml (range, 0.8-2080) for PSA-ACT. All patients had castrate levels of serum testosterone (< 2.5 nmol/l) in less than 21 days after initiation of GnRH-analog treatment. It was possible to evaluate data from 19/21 patients which showed an exponential decrease of all PSA concentrations in serum, with mean half-lives of 12.9 days (range, 7.3-30) for PSA-T, 15.5 days (range, 7.7-37.5) for PSA-F, and 12.3 days (range, 6.6-30) for PSA-ACT. Median pretreatment percent free PSA (PSA-F/PSA-T) was 12% compared to 18% at nadir. The median pretreatment level of hK2 was 3.5 ng/ml (range, 0.29-30.3). There was an exponential decrease in hK2 concentrations in serum after initiation of hormonal treatment with a mean half-life of 18.7 days (range, 7.5-37.5). CONCLUSIONS: For the majority of patients with hormonally treated prostate cancer the serum concentrations of PSA-T, PSA-F, PSA-ACT, and hK2 decreased slowly in parallel and mono-exponentially after initiation of treatment. Mean half-lives were between 12 and 19 days.