Weekly paclitaxel plus estramustine combination therapy in hormone-refractory prostate cancer: A pilot study

BACKGROUND: Paclitaxel used in combination with estramustine has been shown to exert synergistic cytotoxicity in patients with hormone-refractory prostate cancer (HRPC). There have been few reports of this therapy in an Asian male population. METHODS: Nine patients with progressive metastatic HRPC completed at least one cycle of combination therapy employing weekly paclitaxel plus estramustine. Paclitaxel was given weekly for 3 weeks as a 2-h intravenous infusion at a dose of 100 mg/infusion. The cycle was repeated every 4 weeks. A dose of 280 mg of oral estramustine was administrated twice daily for 21 days from the first day of each cycle. Both efficacy and toxicity were recorded. RESULTS: Grade 1 sensory neuropathy was seen in three patients (33%) and grade 4 thrombopenia/anemia was seen in one patient (11%). Performance status improved in three of seven patients (43%), while six patients (67%) showed a 50% or greater decline in prostate-specific antigen levels. Two of these patients experienced significant improvement in bone pain. One patient died of cardiac infarction during this trial and another died of disseminated intravascular coagulopathy subsequent to gastrointestinal bleeding. An additional patient suffered non-fatal pulmonary infarction. The one-year median survival rate was 22.2% and the overall survival period was 36 weeks. CONCLUSION: Although weekly paclitaxel plus estramustine may pose a significant risk, this combination may have a beneficial effect on the quality of life HRPC patients. A well-designed phase I-II trial in an Asian male population is highly recommended.     

药物去势联合雄激素受体阻断剂治疗晚期前列腺癌(附5年临床观察)

目的 观察药物去势联合雄激素受体阻断剂(氟硝丁酰胺，Flutamide)治疗晚期前列腺癌的疗效及药物去势的稳定性。方法 回顾性分析35例药物去势加雄激素阻断剂治疗晚期前列腺癌的I临床资料。结果 所有病人应用LHRH-A 1个月后血睾酮降至去势水平，持续给药可维持稳定的去势水平。34例有治疗效果，有效率97．1％。经平均38．4月随访，复发率为11．8％。7例出现肝功能异常，15例出现食欲减退，35例出现性欲减退和勃起障碍，2例出现血像异常，16例出现潮热、盗汗。结论 药物去势联合雄激素阻断剂治疗初发的晚期前列腺癌疗效肯定，去势稳定。     

Immunological monitoring during combination of patient-oriented peptide vaccination and estramustine phosphate in patients with metastatic hormone refractory prostate cancer

BACKGROUND: Additive antitumor effects could be achieved by combination of immunotherapy and cytotoxic agents with no or minimum suppression. METHODS: Thirteen patients positive for human leukocyte antigen (HLA)-A24 or -A2 with metastatic hormone refractory prostate cancer (HRPC) who had failed to respond to the prior-peptide vaccination were entered in the combined peptide vaccination and estramustine phosphate. Conducted immune monitoring on those 13 patients were mainly peptide-specific cytotoxic T lymphocyte (CTL) precursor analysis by IFN-gamma productions and peptide-reactive IgG by an enzyme-linked immunosorbent assay (ELISA). RESULTS: Grade 3 arrhythmia or cerebral infarction was observed in two cases, and Grade 1 or 2 dermatologic reaction at the vaccination sites was observed in all 13 cases. Eleven patients who received more than one cycle of treatment were eligible for immunological and clinical evaluation. There was no significant immunosuppression in most cases when the peptide and a half dose (280 mg/day) of estramustine were administrated, whereas severe immunosuppression was observed in the first two patients who received both the peptide and a full dose (560 mg/day) estramustine. Augmentation of peptide-specific CTL precursors or peptide-specific IgG was observed in 6 of 11 or 10 of 11 cases, respectively. Ten of 11 patients showed serum prostate-specific antigen (PSA) level decrease from the baseline including 8 patients with a serum PSA level decrease of > or =50%. CONCLUSIONS: These results encouraged the further evaluation of the combination of peptide vaccination and low-dose estramustine phosphate for metastatic HRPC patients.     

Histological findings in the rat prostate cancer model during treatment with a luteinizing hormone-releasing hormone agonist and novantrone

Morphological changes produced by the treatment with the D-tryptophan-6 analog of luteinizing hormone-releasing hormone (D-Trp-6-LH-RH) and mitoxantrone (novantrone) were studied in the Dunning R3327H rat prostate cancer model. Microcapsules of D-Trp-6-LH-RH, calculated to release a controlled dose of 25 micrograms/day, were injected intramuscularly once a month. Novantrone (0.25 mg/kg body weight) was injected intravenously once every 3 weeks. The pathology of tumors was studied in two experiments. In the first experiment, the treatment was started 135 days after tumor transplantation, and the therapy was continued for 105 days. In the second experiment, the treatment was initiated 45 days after tumor transplantation, and was carried on for 70 days. The rats were divided into four groups: 1) untreated control, 2) microcapsule-injected, 3) novantrone-injected, and 4) combination of microcapsules and novantrone-injected. In both experiments, similar results were obtained, which included significant reduction in the tumor volume and weight, a very striking decrease in the number of epithelial tumoral cells with atrophy of the glandular epithelium, and an increase in the stromal connective tissue. All these changes were more prominent in the group treated with the combination of microcapsules and novantrone than in the groups treated with microcapsules or novantrone alone. Pathological results support the view that combined therapy may be more efficacious than the treatment with single agents.     

A randomized study of docetaxel and dexamethasone with low- or high-dose estramustine for patients with advanced hormone-refractory prostate cancer

OBJECTIVE: To test the combination of docetaxel with two different doses of estramustine in patients with hormone-refractory prostate cancer (HRPC), to improve response rates and to lower side-effects, as docetaxel-based chemotherapy is an increasing option for men with advanced HRPC, and alone or combined with estramustine, docetaxel improves median survival. PATIENTS AND METHODS: In all, 72 patients with metastatic HRPC were randomly assigned to receive docetaxel (70 mg/m(2) intravenously, on day 2 every 21 days) and estramustine (3 x 280 mg/day oral starting 1 day before docetaxel, for 5 consecutive days) for arm A, or estramustine (3 x 140 mg/day oral starting 1 day before docetaxel, for 3 consecutive days) for arm B. Premedication with oral dexamethasone at a total daily dose of 16 mg, in divided doses twice a day was administered in arm A on day 1-5 and in arm B on day 1-3. Initially, six cycles were administered. Chemotherapy was restarted after a significant increase in prostate-specific antigen (PSA) level. Patients were monitored for any measurable PSA response and toxicity. RESULTS: Between the arms there was no statistically significant difference in time to progression and overall survival. However, treatment B had less treatment-related toxicity than A. Independent prognostic variables were baseline factors like PSA level, haemoglobin level, Eastern Cooperative Oncology Group performance status, and bone pain at presentation. CONCLUSIONS: In this randomized phase II study the combination of docetaxel and estramustine had substantial activity in HRPC, with a significant incidence of severe toxicity, both haematological and not. Nevertheless, treatment-related toxicity was predictable and manageable. There was no better effect with a higher dose of estramustine with docetaxel than for a lower dose. There was a slight tendency to higher toxicity for high-dose estramustine but this was not statistically significant. The present results support the assertion that estramustine is not necessary in docetaxel-based treatment regimens.     

Docetaxel, with or without estramustine phosphate, as first-line chemotherapy for hormone-refractory prostate cancer: results of a multicentre, randomized phase II trial

OBJECTIVE

To report the results of a randomized phase II trial of docetaxel with and without estramustine phosphate (EP) in patients with hormone‐refractory prostate cancer (HRPC).

PATIENTS AND METHODS

Patients with progressive HRPC were randomized to receive docetaxel 70 mg/m² on day 1 (arm A), or docetaxel 70 mg/m² on day 2 plus oral EP three times daily, at a total daily dose of 840 mg, on days 1–5 (arm B). The primary objective of the trial was to evaluate the activity of the treatments in terms of the response in prostate‐specific antigen (PSA) level.

RESULTS

Forty‐five of the 49 patients centrally randomized to arm A and 44 of the 46 in arm B were evaluable for activity. The PSA level decreased by ≥50% in 40% of the patients in arm A and in 75% of those in arm B. The median time to PSA progression was 20 weeks in arm A and 30 weeks in arm B. The patients in arm B had an improvement in pain over time.

CONCLUSION

These data support the existence of a possible advantage in combining docetaxel and EP, which should be verified in a specific randomized phase III study.     

The use of flutamide as a single antiandrogen treatment for hormone-refractory prostate cancer

OBJECTIVE: To investigate the efficacy of low-dose flutamide (125 mg twice daily) in the treatment of prostate-specific antigen (PSA) recurrence after definitive treatment with radical retropubic prostatectomy (RRP), external-beam radiation therapy (RT), or cryotherapy. PATIENTS AND METHODS: In this phase II prospective trial, patients who had a PSA recurrence after definitive treatment for prostate cancer were treated with flutamide. Endpoints for assessing treatment efficacy were PSA progression, treatment toxicity and clinical symptoms. Results were stratified into complete response (PSA < 0.2 ng/mL on two consecutive assessments), partial response (PSA decrease of half that at baseline on two consecutive assessments) and progressive disease. Seventeen patients were enrolled in who definitive treatment for primary prostate cancer had failed. RESULTS: Low-dose flutamide was clinically effective (i.e. complete or partial response) in 13 patients. Four had a complete response (mean duration 28 months), nine a partial response (mean duration 19 months), and two progressive disease, but were in the study for a mean of 1 year before progression. Two patients discontinued the study at 3 months, secondary to drug-related toxicity; one had grade 3 toxicity and five grade 1 toxicity. CONCLUSIONS: The administration of low-dose flutamide (125 mg) was clinically effective in treating PSA recurrence after definitive treatments for prostate cancer, and was well tolerated. Further investigation in a phase III trial is warranted.     

Dramatic decline in prostate-specific antigen by withdrawal of estramustine phosphate in hormone refractory prostate cancer

Prostate-specific antigen (PSA) decline after discontinuation of estramustine phosphate (EMP) is extremely rare. We report a case with dramatic PSA decline after withdrawal of EMP. A patient with prostate cancer had been treated with luteinizing hormone-releasing hormone and EMP. After refractory, EMP was withdrawn. After withdrawal of EMP, PSA dramatically decreased from 214 ng/mL to 3.71 ng/mL (98.5% decline) and remained low for more than 17 months. In association with PSA decline, lumbago and metastatic lesions improved. We should be aware of this phenomenon and the discontinuation of EMP is recommended in patients with rising PSA after an initial response to EMP.     

Safety and efficacy of docetaxel,estramustine phosphate and hydrocortisone in hormone‐refractory prostate cancer patients

Objective: To assess the combination of docetaxel (DTX), estramustine phosphate (EMP) and hydrocortisone for patients with hormone‐refractory prostate cancer (HRPC). Methods: A total of 63 patients with HRPC were treated with a chemotherapeutic regimen including DTX, EMP, and hydrocortisone. Clinical and pathological features were correlated to serum prostate‐specific antigen (PSA) recurrence and survival rates. Incidence and degree of toxicities were also retrospectively reviewed. Results: A median of 11 courses of chemotherapy was administered per patient. PSA levels decreased by >50% in 32 (51%) patients and >90% in 18 (29%) patients. Median time to PSA progression was 6 months (range from 1 to 41 months) and median time of overall survival was 14 months (range from 1 to 56 months). In a univariate analysis to predict overall survival, PSA, hemoglobin, alkaliphosphatase, and performance status prior to the chemotherapy were significant factors. Despite grade 3–4 neutropenia in 87% of patients, grade 5 interstitial pneumonia in one patient and grade 4–5 myocardial infarction in two patients were recognized, the regimen seemed to be relatively safe. Conclusions: Combination chemotherapy with DTX, EMP and hydrocortisone provides survival benefits for patients with HRPC with an acceptable toxicity profile. We need to further evaluate who might benefit most from this regimen.     

The use of estramustine phosphate in the modern management of advanced prostate cancer

What’s known on the subject? and What does the study add? Estramustine phosphate has anti‐tumour properties and it improves patient outcomes if combined with other chemotherapy agents such as doeetaxel. The efficacy of estramustine phosphate in selected patients and its safety profile, provided used with any low‐molecular‐weight heparin support its use as a second‐line treatment in hormone‐resistant prostate cancer.

OBJECTIVES

• ? Estramustine phosphate is a nitrogen mustard derivative of estradiol‐17β‐phosphate and has anti‐tumour properties.
• ? Interest in estramustine has been renewed because of the results of clinical studies showing improved patient outcomes if estramustine is combined with other chemotherapy agents such as docetaxel.

PATIENTS AND METHODS

• ? Relevant clinical studies using chemotherapy combinations including estramustine are discussed.
• ? Efficacy and safety outcomes are summarized.

RESULTS

• ? Combination therapy with estramustine and docetaxel can increase PSA response rates, improve quality of life and increase median patient survival compared with chemotherapy regimens that do not include estramustine.
• ? Although the overall tolerability of estramustine is favourable, its use can be associated with an increased risk of thromboembolic events.

CONCLUSIONS

• ? The identification of suitable patient groups and the effective management of the risk of thromboembolism with the adjunct of low‐molecular‐weight heparins support the use of estramustine as an effective second‐line treatment strategy in hormone‐resistant prostate cancer.
• ? These promising findings warrant further investigation in a randomized clinical trial.

     

Necessity of re-evaluation of estramustine phosphate sodium (EMP) as a treatment option for first-line monotherapy in advanced prostate cancer

Estramustine phosphate sodium (EMP) was first introduced in the early 1970s for the treatment of prostate cancer, when EMP was supposed to have the dual effect of estrogenic activity and cytotoxicity. For the following decades, it was used mainly in hormone-refractory cases, with a conventional dosage of 4-9 capsules/day, which showed a 30-35% objective response rate. However, a very limited number of cases have been reported that used EMP as a first-line monotherapy in the conventional dosage. One study showed a response rate of 82%, which is at least as effective as conventional estrogen (diethylstilbestrol; DES) monotherapy. Nevertheless, EMP was almost abandoned for the treatment of prostate cancer because of severe adverse side-effects, especially in the cardiovascular system and gastrointestinal tract. Recently, two facts have become evident. First, EMP interferes with cellular microtubule dynamics but does not show alkylating effects. Second, EMP is able to produce a complex with calcium when dairy products are taken concomitantly with EMP, resulting in a decrease in the absorption rate of EMP from the gut. Many clinical trials have been undertaken without warning against concomitant dairy product intake since the introduction of EMP. This fact will jeopardize almost all the clinical trials performed before 1990. It is considered that response rates have been underestimated and better results could have been obtained because side-effects decrease dose-dependently. Low-dose EMP monotherapy (2 capsules/day) has been performed infrequently in previously untreated advanced prostate cancer. The only large trial by the European Organization for Research and Treatment of Cancer in 1984 was biased in selecting patients. Nevertheless, the response rate of EMP is comparable to that of DES. In this study, the adverse side-effects of EMP were less than that of DES. Recently, a study was conducted at the University of Tokyo of 11 patients with advanced prostate cancer on low-dose EMP as first-line monotherapy. The study found that the mean serum prostate-specific antigen level decreased to within the normal range by day 50; mean serum testosterone, leutinizing hormone and follicle-stimulating hormone reduced to undetectable levels by day 20; and mean serum estradiol increased to a very high level within 1 week. These data implicate that low-dose EMP can suppress quickly and adequately the pituitary-gonadal axis, although the antitumor effect has not as yet been elucidated. For these reasons, it is necessary to re-evaluate low-dose EMP monotherapy in previously untreated advanced prostate cancer.     

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.     

Combination chemotherapy with weekly docetaxel and estramustine for hormone refractory prostate cancer in Japanese patients

Abstract:   The aim is to evaluate the efficacy and toxicity of weekly docetaxel and estramustine for Japanese men with hormone refractory prostate cancer who were treated at a single institution. Twenty eligible patients had histologically proven adenocarcinoma of the prostate with metastases that were progressing despite complete androgen blockade and antiandrogen withdrawal. All of the patients received docetaxel 30 mg/m² weekly (days 1, 8, 15, 22, 29, and 36). After a two week break, the treatment schedule was repeated. Patients were scheduled to receive daily oral estramustine 560 mg/day throughout the protocol. In the serum prostate specific antigen (PSA) response, three (15%) patients achieved a complete response, and 8 (40%) acheived a partial response. Overall survival and time to progression were 13.4 months and 6.4 months, respectively, however sixty-seven percent of the patients had to discontinue treatment because of toxicity. The high toxicity of this protocol suggests that the regimen and/or the timing should be altered for Japanese patients.     

New treatment paradigm for prostate cancer: abarelix initiation therapy for immediate testosterone suppression followed by a luteinizing hormone-releasing hormone agonist

Study Type – Therapy (prospective cohort) Level of Evidence 2a What's known on the subject? and What does the study add? The sequential administration of a GnRH antagonist followed by an LHRH agonist in the management of prostate cancer patients has not been studied, but such a program would provide a more physiologic method of achieving testosterone suppression and avoid the obligatory testosterone surge and need for concomitant antiandrogens that accompany LHRH agonist therapy. The current study which uses abarelix initiation therapy for 12 weeks followed by either leuprolide or goserelin demonstrates the ability to more rapidly achieve testosterone suppression, avoid the obligatory LHRH induced testosterone surge, avoid the necessity of antiandrogens, all of which were accomplished safely, without inducing either additional or novel safety issues.

OBJECTIVE

• ? To demonstrate the safety and endocrinological and biochemical efficacy of initiating treatment with the gonadotropin‐releasing hormone (GnRH) antagonist, abarelix, followed by administration of an luteinizing hormone‐releasing hormone (LHRH) agonist in patients with advanced and metastatic prostate cancer.

PATIENTS AND METHODS

• ? A multicentre, open‐label design study was conducted at 22 centres in the US involving patients with: localized, locally advanced or metastatic disease; with a rising prostate‐specific antigen (PSA) after definitive local treatment; patients undergoing neoadjuvant hormonal therapy before local therapy (radical prostatectomy, radiation therapy or cryosurgery); and patients in whom intermittent therapy was the planned treatment.
• ? All patients received abarelix for 12 weeks followed by an LHRH agonist (either leuprolide or goserelin) for 8 weeks
• ? The primary efficacy endpoint was achievement and maintenance of castration defined as testosterone <50 ng/dL from day 29 through to day 141 and whether abarelix initiation therapy could eliminate the testosterone surge after two consecutive doses of LHRH agonist therapy.
• ? PSA, LH and follicle‐stimulating hormone (FSH) levels were measured and adverse events were monitored.

RESULTS

• ? A total of 176 patients were enrolled into the present study, the majority of whom had localized prostate cancer (82%) and a PSA level <10 ng/mL (62%).
• ? At the end of the abarelix treatment period (day 85), 93.8% of patients achieved castrate levels; during the first week of switch over to the LHRH agonist therapy (days 85–92) the rate was 86.5% and during the week after the second LHRH agonist injection (days 114–12) it was 93.3%.
• ? A small, transient increase in testosterone occurred during the first injection of the LHRH agonist; mean (standard deviation [sd ]) values increased from 17 (17.8) ng/dL at day 85 to 37.3 (51.07) ng/dL at day 86.
• ? Mean (sd ) PSA levels decreased from 20.5 (56.6) ng/mL at baseline to 3.7 (23.5) ng/mL on day 85 and remained stable throughout the LHRH agonist treatment phase.
• ? Treatment‐related adverse events occurred in 84% of patients overall; a similar incidence was reported during the two treatment phases.

CONCLUSIONS

• ? Abarelix initiation therapy results in the desired effect of achieving rapid testosterone suppression; testosterone surges after subsequent LHRH agonist therapy are greatly abrogated or completely eliminated.
• ? This treatment paradigm (abarelix initiation followed by agonist maintenance) obviates the need for an antiandrogen.
• ? Abarelix was well tolerated and no clinically meaningful or novel adverse events were observed during abarelix treatment or in the transition to LHRH agonist maintenance therapy.

     

Time course of serum testosterone and luteinizing hormone levels after cessation of long-term luteinizing hormone-releasing hormone agonist treatment in patients with prostate cancer

INTRODUCTION: In order to elucidate the influence of hormone-releasing hormone (LH-RH) agonist therapy cessation on pituitary/testicular function and its clinical implications, we investigated prospectively hormonal (luteinizing hormone: LH; testosterone: T) responses in patients with prostate cancer who received long-term LH-RH 10 agonist therapy. PATIENTS AND METHODS: A consecutive 32 patients who had received LH-RH agonist therapy over 24 months were enrolled. As a baseline, T and LH were measured at the time of LH-RH agonist therapy cessation, monthly for 3 months, and subsequently, every 3 months. RESULTS: The median duration of LH-RH agonist therapy was 30 months (24-87 months) with median follow-up duration of 24 months following cessation. All patients had castrated T levels and suppressed LH levels at baseline. Median duration of castrated T levels following cessation was 6 months. Median time to normalization of T levels was 24 months. LH levels returned to normal within 3 months in all cases. Patients who received androgen deprivation therapy for 30 months or longer required a longer time for recovery of T levels. Patients over 65 years of age showed a statistically significant longer time for recovery of T levels (P=0.0167). CONCLUSIONS: Long-term LH-RH agonist therapy has remarkable effects on serum T level that last for a significant time after cessation, a fact that should be applied to the interpretation of both PSA and serum T levels after cessation of androgen deprivation therapy.     

Interstitial pneumonitis related to flutamide monotherapy for prostate cancer

A 88-year-old man with prostate cancer was receiving non-steroidal anti-androgen therapy (flutamide, 375 mg/day). Three weeks after starting therapy, the patient developed dyspnea and bilateral pulmonary interstitial infiltrates. The withdrawal of flutamide and the initiation of steroid therapy resulted in clinical improvement.     

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.     

Erectile function and nocturnal penile tumescence in patients with prostate cancer undergoing luteinizing hormone-releasing hormone agonist therapy.

BACKGROUND: Luteinizing hormone-releasing hormone (LHRH) agonists have been widely used as effective agents in endocrine therapy for prostate cancer. Continuous administration of the drug results in profound suppression of testicular androgen production. However, the side effects on erectile function have not been fully investigated. METHODS: We studied the influences of testosterone suppression on male sexual function and nocturnal penile tumescence in nine sexually active patients with prostate cancer who were treated with an LHRH agonist. RESULTS: Following reduction of serum testosterone concentrations to a castration level by the administration of the LHRH agonist, sexual desire, sexual interest and sexual intercourse were totally annulled, with significant changes in frequency, magnitude, duration and rigidity of nocturnal erections observed in all patients. CONCLUSIONS: These results demonstrate that the LHRH agonist strongly suppresses erectile function and sexual activity. Taking into account the quality of sexual function for relatively young and sexually active patients and their partners, it is necessary to establish effective modalities that minimize the adverse effects on sexual function for the treatment of patients with prostate cancer.     

Inhibition of prostate cancer growth by estramustine and colchicine

Hormone-refractory prostate cancer continues to be associated with a very poor prognosis. Agents that inhibit microtubule function have been found to be cytotoxic to prostate cancer cells in preclinical and clinical settings. It was the aim of this study to assess the activity of estramustine and colchicine, two microtubule inhibitors, in hormone-refractory prostate cancer. In clinically achievable concentrations, the combination of estramustine and colchicine was cytotoxic to both the Dunning rat prostate adenocarcinoma cell line MAT-LyLu (MLL) and human prostate cancer cells (PC-3). Microtubule function was assessed in vitro to evaluate possible mechanisms of action. In motility and cell cycle analysis assays, estramustine and colchicine inhibited cellular motility but not cell cycle transit. In vivo, these two agents both inhibited the growth of implanted Dunning rat prostate adenocarcinoma MLL cells but did not appear to have additive effects. The use of oral colchicine in the treatment of hormone-refractory prostate cancer requires further investigation.