leuprolide and Neoplasm-Metastasis

Our research into the pathophysiology of micrometastatic dissemination and cancer recurrence has resulted in the initiation of a clinical trial for men with clinically localized and locally advanced disease.. We describe the development of this trial, which exploits anti-angiogenesis therapy, and delineate how our understanding of prostate cancer metastasis influenced its design.. Prostate cancer is a heterogeneous disease. Although many men can be cured with local therapy, a large majority with clinically localized disease will experience a relapse usually at a distant site. This result is most likely due to micrometastatic dissemination early in the disease process. Therefore, successful contemporary treatment of many men with prostate cancer should include a combination of local and systemic therapies. Fortunately, cellular, molecular and genetic features that may predict which men are most in need of this therapeutic approach are being identified and characterized. This insight not only supports the rationale for a combination therapeutic approach to prostate cancer management, but will help identify the pathways and agents that provide the most promising targets for intervention.. Despite advances in prevention and early detection, refinements in surgical technique, and improvements in radiation and systemic therapies, the ability to cure all men with prostate cancer remains unattainable. The continuing challenge is the successful eradication of recurrent and metastatic disease.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Cholestanols; Disease Progression; Humans; Leuprolide; Male; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neovascularization, Pathologic; Orchiectomy; Prostatic Neoplasms

In the randomised phase II LEO trial, we investigated the effect of adding everolimus (EVE) to letrozole (LET) in ovarian-suppressed premenopausal women with hormone receptor-positive (HR+), HER2-negative (HER2-) recurrent/metastatic breast cancer.. Patients with progression or prior exposure to tamoxifen with or without gonadotropin-releasing hormone agonists, either sequentially or concurrently, in adjuvant or metastatic setting were randomly assigned (2:1) to the EVE arm (leuprorelin + LET + EVE) or the LET arm (leuprorelin + LET) until disease progression or unacceptable toxicity. The primary end-point was progression-free survival (PFS). Secondary end-points included overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR) and safety.. Between January 2014 and October 2018, 137 patients were enrolled (median age, 44 years [range, 24-56]). Of them, 75% had endocrine-sensitive disease, and 61% had visceral metastasis. With the median follow-up of 32.4 months, the median PFS was 18.1 months in the EVE arm and 13.8 months in the LET arm (HR 0.73, P = 0.137). Among patients with visceral metastases, the median PFS was significantly longer in the EVE arm (16.4 versus 9.5 months, P = 0.048). The median OS was not reached in both arms. The CBR was significantly higher in the EVE arm (83% versus 62%, P = 0.010). The ORR was similar between the two arms. The most common grade 3/4 adverse events in the EVE arm were neutropenia, alanine aminotransferase elevation and anaemia.. EVE plus LET with ovarian-suppression resulted in longer PFS in tamoxifen-exposed HR+, HER2- metastatic breast cancer patients with visceral metastasis.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Everolimus; Female; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Letrozole; Leuprolide; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Premenopause; Primary Ovarian Insufficiency; Prognosis; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Survival Rate; Tamoxifen; Young Adult

There is no standard first-line chemotherapy for recurrent/metastatic (RM) or unresectable locally advanced (LA) salivary gland carcinoma (SGC).. We conducted a single institution, open-label, single arm, phase II trial of combined androgen blockade (CAB) for androgen receptor (AR)-positive SGC. Leuprorelin acetate was administered subcutaneously at a dose of 3.75 mg every 4 weeks. Bicalutamide was administered orally at a daily dose of 80 mg. Patients were treated until progressive disease or unacceptable toxicities.. Thirty-six eligible patients were enrolled. Thirty-three patients had RM disease and three patients had LA disease. The pathological diagnoses were salivary duct carcinoma (34 patients, 94%) and adenocarcinoma, NOS (two patients, 6%). The best overall response rate was 41.7% [n = 15, 95% confidence interval (CI), 25.5%-59.2%], the clinical benefit rate was 75.0% (n = 27, 95% CI, 57.8%-87.9%). The median progression-free survival was 8.8 months (95% CI, 6.3-12.3 months) and the median overall survival was 30.5 months (95% CI, 16.8 months to not reached). Additional analyses between treatment outcomes and clinicopathological factors or biomarkers including AR positivity, human epidermal growth factor receptor 2 status, and its complex downstream signaling pathway gene mutations showed no statistically significant differences. Elevated grade 3 liver transaminases and increased serum creatinine were reported in two patients, respectively. Discontinuation of leuprorelin acetate or bicalutamide due to adverse event occurred in one patient.. This study suggests that CAB has equivalent efficacy and less toxicity for patients with AR-positive RM or unresectable LA SGC compared with conventional chemotherapy, which warrants further study.. UMIN-CTR (http://www.umin.ac.jp/ctr/index-j.htm), identification number: UMIN000005703.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Disease-Free Survival; Female; Humans; Leuprolide; Male; Middle Aged; Neoplasm Metastasis; Nitriles; Prospective Studies; Receptors, Androgen; Salivary Gland Neoplasms; Tosyl Compounds; Treatment Outcome

Prostatectomy or radiation for localized prostate cancer (PC) can fail in up to 15% to 30% of patients. The purpose of this study was to determine feasibility, tolerability, and outcome of docetaxel followed by hormone therapy in men experiencing an increasing prostate-specific antigen (PSA) after their primary local treatments for PC.. Men with increasing serum PSA after prostatectomy or/and radiation were eligible. Serum PSA had to be > or = 4 ng/mL and serum testosterone had to be in the noncastrate range. Treatment included docetaxel 70 mg/m2 every 3 weeks for up to six cycles, followed by total androgen suppression (luteinizing hormone-releasing hormone agonist plus bicalutamide) and peripheral androgen blockade (finasteride plus bicalutamide) for 12 to 20 months.. Thirty-nine men were enrolled; 32 had PSA-only failure, seven also had clinical metastasis. Baseline median PSA was 13.7 ng/mL. Serum PSA decreased > or = 50% in 17 of 35 patients (48.5%) and > or = 75% in seven of 35 patients (20%) with docetaxel. The PSA decreased to a median of 0.1 ng/mL with subsequent hormone therapy. In 28 of 33 patients the PSA increased (median, 0.41 ng/mL) at a median follow-up of 2.3 months after treatment. In contrast, in five of 33 men the PSA remains at 0.1 ng/mL at a median of 18.9 months after therapy; three of these five men had soft tissue metastasis at entry but remain in complete remission. The most common grade 3 to 4 toxicity was neutropenia (61.5%).. Docetaxel followed by hormone therapy of limited duration may provide disease control in subgroups of men experiencing failure after local treatments for PC.

Topics: Aged; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Docetaxel; Goserelin; Humans; Infusions, Intravenous; Injections, Intramuscular; Injections, Subcutaneous; Leuprolide; Male; Middle Aged; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Taxoids; Treatment Outcome

To assess the effects of intermittent maximal androgen blockade (IMAB) on testosterone (T) levels during on- and off-treatment periods.. A total of 51 patients with metastatic prostate cancer underwent a 6-months period of continuous maximal androgen blockade (MAB) consisting of leuprorelin (3.75 mg at monthly intervals) plus flutamide (250 mg t.i.d.) followed by IMAB. During each cycle, the cut-off prostate-specific antigen (PSA) levels to stop and resume treatment were 4 and 10 ng/ml, respectively. IMAB continued until progression under treatment occurred. Monthly PSA and T measurements were performed in central laboratories.. From the 51 patients included (mean age 67.6 years), 27, 16, 12, 8 and 5 underwent a second, third, fourth, fifth and sixth cycle, respectively (mean follow up: 17 months). Before treatment, 4 patients had a T lower than normal laboratory value but these recovered all to a normal T value at the end of the first cycle. During the 6 cycles, only 8 patients did not recover a normal T at least once during the off-treatment periods (OTP). The mean T values at the end of each OTP did not change during these 6 cycles (Anova test, p=0.621) with a mean stable recovery delay of 32-43 days (Anova test, p=0.722).. IMAB protocol with an initial 6-month treatment period can result in an intermittent castration with the recovery of normal T levels in most patients during six consecutive cycles of treatment.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Drug Administration Schedule; Flutamide; Follow-Up Studies; Humans; Leuprolide; Male; Neoplasm Metastasis; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Treatment Outcome

The investigational objectives of this open, noncomparative phase I study were to determine the pharmacokinetic profile of a single dose of 11.25 mg leuprorelin acetate, the effective duration of the chemical castration (serum testosterone < or = 1.73 nmol/l) and safety in patients with locally advanced and/or metastatic carcinoma of the prostate foreseen for chemical castration, in the hope that such a dose of leuprorelin acetate may be suitable as a depot formulation to be administered 3-monthly to these patients.. A total of 24 males up to 85 years old with histologically proven advanced carcinoma of the prostate were enrolled in the study to obtain 18 eligible patients. Each patient was given 11.25 mg of leuprorelin acetate in a depot formulation subcutaneously after reconstitution in 2 ml of a special suspension vehicle. The study period lasted 24 weeks. Patients whose serum testosterone levels reincreased prior to the end of the observation period of 24 weeks were withdrawn from the study and received the monthly depot formulation of 3.75 mg of leuprorelin acetate.. The 3M-depot formulation of leuprorelin acetate ensured continuous and constant drug release and effective suppression of testosterone serum levels to castration range for at least 13 weeks. After an initial rise, 5 alpha-dihydrotestosterone as well as the gonadotropin serum levels of luteinizing hormone and follicular stimulating hormone reflected the testosterone serum pattern.. The results of this study show that the 3M-depot preparation of leuprorelin acetate is effective in suppressing the serum testosterone levels to the castration range for a targeted period of at least 13 weeks.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Carcinoma; Delayed-Action Preparations; Dihydrotestosterone; Evaluation Studies as Topic; Follicle Stimulating Hormone; Humans; Injections, Subcutaneous; Leuprolide; Linear Models; Luteinizing Hormone; Male; Middle Aged; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatic Neoplasms; Severity of Illness Index; Statistics, Nonparametric; Testosterone; Treatment Outcome

In order to determine the efficacy and toxicity of the gonadotrophin-releasing hormone agonist Leuprolide in the management of patients with recurrent or metastatic endometrial cancer, we performed a phase II study. Patients were included if there was clinical or radiological documentation of bidimensionally measurable recurrent or metastatic endometrial cancer that was deemed incurable. Treatment was 7.5 mg i.m. every 28 days, and was to continue for at least 2 courses until evidence of disease progression, patient requested withdrawal, or unacceptable toxicity. Twenty-five patients received Leuprolide for recurrent or metastatic endometrial cancer. The median age at study entry was 62 years, and the median time from initial diagnosis to first course of Leuprolide was 25 months. Six patients had received no systemic or radiotherapy prior to study entry, and 2 of these had not previously undergone hysterectomy. Fifteen patients received prior pelvic radiotherapy and 3 patients received prior whole abdominal radiotherapy. Nine of the 25 patients had received prior progestational agents, and 2 had received prior systemic chemotherapy. There were no responders, 8 patients had stable disease for a median 5 months (range 1-8), 14 patients progressed on therapy, and 3 patients were not evaluable for response due to receiving only 1 treatment. One patient experienced a grade 3 toxicity that was possibly attributable to Leuprolide (deep venous thrombosis). The median survival from study entry was 6 months. Twelve patients received progesterone after discontinuing this study, and none responded. Leuprolide does not appear to be a clinically active agent in the treatment of recurrent or metastatic endometrial cancer.

Topics: Adult; Aged; Antineoplastic Agents, Hormonal; Endometrial Neoplasms; Female; Follow-Up Studies; Humans; Leuprolide; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging

To establish the pharmacodynamic and safety equivalence between 2 sustained-release forms of leuprorelin 11.25 mg and 3.75 mg, in the treatment of metastatic prostatic carcinoma.. 44 patients received subcutaneous injections of leuprorelin for 9 months (randomization: 2/l): either 11.25 mg every three months (n = 29) or 3.75 mg monthly (n = 15). Main criterion: centralized monthly assay of plasma testosterone (T).. The equivalence of the 2 forms in terms of mean plasma testosterone was demonstrated (p = 0.002): 1 month: T = 0.19 +/- 0.03 ng/ml; 3 months: T = 0.27 +/- 0.04 ng/ml. Exploratory analysis did not reveal any significant difference between the groups for the number of patients castrated at each visit or for the number of patients with all T values < or = 0.5 ng/ml, or for clinical responses or safety.. The 2 forms have a comparable efficacy and safety.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Hormonal; Chemistry, Pharmaceutical; Delayed-Action Preparations; Humans; Leuprolide; Male; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Therapeutic Equivalency; Treatment Outcome

Comparative efficacy and safety of 2 LHRH analogues in metastatic prostatic carcinoma.. 68 patients received monthly injections for 6 months (randomization): either subcutaneous leuprolide 3.75 mg LP (n = 36), or intramuscular triptorelin 3.75 mg LP (n = 32). (Flare-up prevention: nilutamide). Parameters re-evaluated at 1.3 and 6 months: centralized assays of plasma testosterone (T), LH and serum PSA; clinical symptoms. Main criterion: proportion of patients with T < or = 0.5 ng/mL.. The percentages of patients with T < or = 0.50 ng/mL was not significantly different between the two groups and were equal to 100 and 90%, 97 and 100%, and 100 and 96% at the 3 study times, for leuprolide or triptorelin, respectively. The difference was significant at 1 month on complementary analysis at the limit of T < 0.30 ng/mL: 86% with leuprolide versus 60% with triptorelin (p = 0.02) and for mean plasma testosterone: 0.16 +/- 0.10 ng/mL versus 0.33 +/- 0.44 ng/mL, respectively (p = 0.02). The clinical subjective efficacy was not significantly different.. Both treatments were effective, although plasma testosterone fell more rapidly with leuprolide. No conclusion about the possible clinical or survival benefits can be formulated. Overall safety was satisfactory.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Data Interpretation, Statistical; Drug Tolerance; Humans; Imidazoles; Imidazolidines; Injections, Intramuscular; Injections, Subcutaneous; Leuprolide; Male; Middle Aged; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Time Factors; Triptorelin Pamoate

To review the outcome of therapy with maximal androgen blockade and compare the efficacy and safety of bicalutamide and flutamide, each used in combination with luteinizing hormone-releasing hormone analogue (LHRH-A) therapy, in patients with untreated metastatic (Stage D2) prostate cancer.. Randomized, double-blind (for antiandrogen therapy), multicenter study with a 2 x 2 factorial design. A total of 813 patients were allocated 1:1 to bicalutamide (50 mg once daily) or flutamide (250 mg three times daily), plus 2:1 to goserelin acetate (3.6 mg every 28 days) or leuprolide acetate (7.5 mg every 28 days).. At the time of analysis (median follow-up, 49 weeks), bicalutamide plus LHRH-A was associated with a statistically significant improvement in time-to-treatment failure, the primary endpoint, when compared with flutamide plus LHRH-A. The results with longer follow-up (median, 95 weeks) support previous findings of an improved time-to-treatment failure with bicalutamide plus LHRH-A; however, the difference between groups was not statistically significant. A treatment failure endpoint was reached by 68% of patients in the bicalutamide plus LHRH-A group, compared with 72% of patients in the flutamide plus LHRH-A group. The hazard ratio of bicalutamide plus LHRH-A to flutamide plus LHRH-A was 0.87 (95% confidence interval [CI], 0.74-1.03; P = 0.10). The upper one-sided 95% confidence limit for survival was 1.00, meeting the definition for equivalence (< 1.25). With longer follow-up, overall mortality was 34%, with equivalent survival between groups: 32% of patients in the bicalutamide plus LHRH-A group died, compared with 35% in the flutamide plus LHRH-A group. The hazard ratio of bicalutamide plus LHRH-A to flutamide plus LHRH-A was 0.88 (95% CI, 0.69-1.11; P = 0.29). The upper one-sided 95% confidence limit for survival was 1.07, meeting the definition for equivalence (< 1.25). Diarrhea occurred in 24% of patients in the flutamide plus LHRH-A group compared with 10% of patients in the bicalutamide plus LHRH-A group (P < 0.001).. In patients with metastatic prostate cancer, bicalutamide plus LHRH-A is effective and well tolerated. Because of its efficacy and tolerability profile, together with its convenient once-daily dosing formulation, bicalutamide represents a prime candidate for antiandrogen of first choice in combination with LHRH-A therapy in the treatment of men with metastatic prostate cancer.

Topics: Adult; Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Flutamide; Follow-Up Studies; Goserelin; Humans; Leuprolide; Male; Middle Aged; Neoplasm Metastasis; Nitriles; Prostatic Neoplasms; Tosyl Compounds

The results of therapy in 288 men with pathologic Stage C prostate cancer who underwent radical retropubic prostatectomy (RRP) were analyzed to determine the effects of adjuvant therapy.. Twenty-seven of the 288 patients received preoperative neoadjuvant hormonal therapy (leuprolide acetate). Postoperatively, 60 patients received adjuvant radiotherapy (RT) to the prostate bed. Follow-up ranged from 3 to 83 months (median = 32 months). Freedom from failure (FFF) was defined as maintaining a serum PSA level of < or = 0.3 ng/ml.. The FFF was 61% at 3 years and 45% at 5 years for the entire group. The FFF following RRP plus RT was 75% at 3 years and 57% at 5 years as compared to 56% at 3 years and 40% at 5 years for RRP without RT (p=0.049). The FFF following RRP plus neoadjuvant hormonal therapy was 58% at 3 years and 40% at 5 years as compared to 60% at 3 years and 45% at 5 years following RRP without hormonal therapy (p=0.3). In patients without seminal vesicle (SV) invasion, the FFF was 81% at 3 years and 5 years for RRP plus RT as compared to 61% at 3 years and 50% at 5 years for RRP without RT (p=0.01). In patients with SV invasion, the FFF was 61% at 3 years and 36% at 5 years for RRP plus RT as compared to 44% at 3 years and 23% at 5 years for RRP without RT (p=0.23). The projected local control rate was 83% at 5 years for those with RRP alone as compared to 100% for RRP plus RT (p=0.02). Survival at 5 years was projected to be 92% and was not significantly altered by the administration of adjuvant therapies.. Postoperative RT was associated with significantly improved local control and FFF rates, especially in patients with tumors which did not involve the seminal vesicles.

Topics: Aged; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Combined Modality Therapy; Humans; Leuprolide; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Prostatectomy; Prostatic Neoplasms; Radiotherapy, Adjuvant; Treatment Failure

To test the feasibility of using intermittent androgen suppression in the treatment of prostate cancer by taking advantage of the reversible action of medical castration.. Observations were made on a group of 47 patients (clinical Stage D2, 14; D1, 10; C, 19; B2, 2; and A2, 2) with a mean follow-up time of 125 weeks. Treatment was initiated with combined androgen blockade and continued for at least 6 months until a serum prostate-specific antigen (PSA) nadir was observed. Medication was then withheld until the serum PSA increased to a mean value between 10 and 20 ng/mL. This cycle of treatment and no treatment was repeated until the regulation of serum PSA became androgen independent.. The first two treatment cycles lasted 73 and 75 weeks, with a mean time off therapy of 30 and 33 weeks and an overall mean percentage time off therapy of 41% and 45%, respectively. The mean time to achieve a nadir level of serum PSA was 20 weeks in cycle 1 and 18 weeks in cycle 2. Serum testosterone returned to the normal range within 8 weeks (range, 1 to 26) of stopping treatment. The off-treatment period in both cycles was associated with an improvement in sense of well-being and the recovery of libido and potency in the men who reported normal or near-normal sexual function before the start of therapy. In 7 patients with Stage D2 disease, the cancer progressed to an androgen-independent state. The mean and median times to progression were 128 weeks and 108 weeks, respectively. Seven patients have died, 1 from a noncancer-related illness, with mean and median overall survival times of 210 weeks and 166 weeks, respectively.. Prostate cancer is amenable to control by intermittent androgen suppression. This approach affords an improved quality of life when the patient is off therapy. It also results in reduced toxicity and cost of treatment and possibly delays tumor progression. Whether survival is affected in a beneficial or adverse way remains to be studied in a randomized, prospective study.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Cyproterone Acetate; Diethylstilbestrol; Drug Therapy, Combination; Follow-Up Studies; Goserelin; Humans; Leuprolide; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Neoplasms, Hormone-Dependent; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Rate; Time Factors

Nonrandomized clinical trials have suggested that preoperative androgen deprivation can decrease the likelihood of positive surgical margins in patients with clinically localized prostate cancer. A multicenter prospective randomized trial compared radical prostatectomy alone to radical prostatectomy after 3 months of leuprolide acetate depot and flutamide in patients with stage cT2bNxM0 prostate cancer and a serum prostate specific antigen level less than 50 ng./ml.. We randomized 149 patients to undergo androgen deprivation and 138 to undergo lymphadenectomy with (137) or without (1) prostatectomy. Of the 154 patients randomized to the surgery alone group 144 underwent pelvic node dissection with (138) or without (6) prostatectomy.. There was no statistically significant difference between the 2 groups in operating time, blood loss, need for transfusion, postoperative morbidity or length of hospital stay. There were 4 rectal and 2 ureteral injuries in the surgery alone group and none in the pretreatment group (p < 0.05). Patients who received androgen deprivation preoperatively had a significantly lower rate of capsule penetration (47% versus 78%, p < 0.001), positive surgical margins (18% versus 48%, p < 0.001) and tumor at the urethral margin (6% versus 17%, p < 0.01).. Long-term followup data will be needed to determine whether there will be a lower incidence of biochemical relapse as determined by prostate specific antigen, local recurrence or metastasis, with an improvement in patient survival.

Topics: Aged; Combined Modality Therapy; Flutamide; Follow-Up Studies; Humans; Leuprolide; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Preoperative Care; Prospective Studies; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms

In a recent intergroup study under the auspices of the National Cancer Institute, 603 eligible patients with newly diagnosed disseminated adenocarcinoma of the prostate were prospectively randomized in a double-blinded clinical trial to receive either a gonadotropin-releasing hormone analogue (leuprolide) and a nonsteroidal antiandrogen (flutamide) or leuprolide and placebo. Of the 603 eligible patients, 300 were in the leuprolide and placebo arm and 303 were in the leuprolide and flutamide arm. At the time of disease progression, the code was broken: Those patients in the placebo arm were given the opportunity to receive flutamide, and the patients in the flutamide arm were treated at their physician's discretion. There was no survival time distribution difference, based on survival measured from the progression data, between the patients who were received flutamide after progression and those who were treated at their physician's discretion after progression. Furthermore, the addition of flutamide to leuprolide at the time of disease progression resulted in a survival-time distribution that is similar to other treatments of hormone-refractory prostate cancer.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Flutamide; Humans; Leuprolide; Male; Neoplasm Metastasis; Prospective Studies; Prostatic Neoplasms; Regression Analysis; Survival Rate

Prostate cancer is the most common cancer in American men today. Unfortunately, at the time of diagnosis, most men will have either regional or distant metastatic disease.. Six hundred three patients with advanced prostate cancer who could be examined were randomized in a double-blind, placebo-controlled trial to receive the luteinizing hormone-releasing hormone (LHRH) agonist leuprolide with either flutamide or placebo.. Patients receiving the combined therapy arm of leuprolide and flutamide had an increased progression-free survival time of 16.9 versus 13.8 months and a survival advantage of 35.1 versus 20.3 months. A more striking difference was found in the subset of patients receiving combination therapy who had good performance and minimal disease.. There appears to be a definite advantage of combination therapy over leuprolide alone, especially in patients with minimal disease and good performance. Another larger intergroup study using orchiectomy and flutamide versus orchiectomy and placebo is currently underway.

Topics: Double-Blind Method; Drug Therapy, Combination; Flutamide; Humans; Leuprolide; Male; Neoplasm Metastasis; Prostatic Neoplasms; Survival Rate; United States

Topics: Anilides; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Flutamide; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Neoplasm Metastasis; Prostatic Neoplasms

Leuprolide is a new, potent analogue of gonadotropin-releasing hormone which, after an initial transient stimulation, causes a profound suppression of serum gonadotropins and testosterone. One hundred eighteen patients with advanced carcinoma of the prostate have undergone treatment with leuprolide in a multi-institutional trial. Minimal evidence of objective response was seen in patients who had failed prior endocrine therapy with orchiectomy or estrogens. In patients without previous hormonal treatment, leuprolide induced an objective disease response (72%) comparable to alternative primary endocrine therapy. Considering the lack of significant side effects seen with long-term GnRH agonists, compounds such as leuprolide may prove to be the preferred initial endocrine therapy for selected patients with metastatic carcinoma of the prostate.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Castration; Clinical Trials as Topic; Diethylstilbestrol; Dihydrotestosterone; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms; Testosterone

We compared the efficacy and safety of the gonadotropin-releasing hormone analogue, leuprolide (1 mg subcutaneously daily), with diethylstilbestrol (DES, 3 mg by mouth daily) in patients with prostate cancer and distant metastases (Stage D2) who had not previously received systemic treatment. Initial therapy (leuprolide or DES) was continued for as long as an objective response was noted; cross-over to the alternative arm occurred at the time of disease progression or intolerable adverse reactions. Ninety-eight patients were randomly assigned to leuprolide, and 101 to DES. Suppression of testosterone and dihydrotestosterone and decreases in acid phosphatase were comparable in the two groups. Patients receiving DES experienced more frequent painful gynecomastia (P less than 0.00001), nausea and vomiting (P = 0.02), edema (P = 0.008), and thromboembolism (P = 0.065) than those receiving leuprolide. The leuprolide group reported more "hot flashes" (P = 0.00001). Overall, 86 per cent of the leuprolide group had an objective response (complete response, 1 per cent; partial response, 37 per cent; stable disease, 48 per cent), as compared with 85 per cent of the DES group (complete, 2 per cent; partial, 44 per cent; stable, 39 per cent). Actual survival rates at one year were 87 per cent for the leuprolide group and 78 per cent for the DES group (P = 0.17). We conclude that leuprolide offers an important alternative treatment that is therapeutically equivalent to and causes fewer side effects than DES for the initial systemic management of metastatic prostate cancer.

Topics: Acid Phosphatase; Adult; Aged; Antineoplastic Agents; Diethylstilbestrol; Drug Evaluation; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms; Random Allocation

Topics: Adenocarcinoma; Administration, Topical; Aged; Antineoplastic Agents, Hormonal; Carcinoma; Collagen Diseases; Glycation End Products, Advanced; Humans; Japan; Leuprolide; Male; Neoplasm Metastasis; Prostatic Neoplasms; Skin Diseases, Genetic; Steroids; Treatment Outcome; Ultraviolet Therapy

The mechanisms of metastatic progression from hormonal therapy (HT) are largely unknown in luminal breast cancer. Here we demonstrate the enrichment of CD133(hi)/ER(lo) cancer cells in clinical specimens following neoadjuvant endocrine therapy and in HT refractory metastatic disease. We develop experimental models of metastatic luminal breast cancer and demonstrate that HT can promote the generation of HT-resistant, self-renewing CD133(hi)/ER(lo)/IL6(hi) cancer stem cells (CSCs). HT initially abrogates oxidative phosphorylation (OXPHOS) generating self-renewal-deficient cancer cells, CD133(hi)/ER(lo)/OXPHOS(lo). These cells exit metabolic dormancy via an IL6-driven feed-forward ER(lo)-IL6(hi)-Notch(hi) loop, activating OXPHOS, in the absence of ER activity. The inhibition of IL6R/IL6-Notch pathways switches the self-renewal of CD133(hi) CSCs, from an IL6/Notch-dependent one to an ER-dependent one, through the re-expression of ER. Thus, HT induces an OXPHOS metabolic editing of luminal breast cancers, paradoxically establishing HT-driven self-renewal of dormant CD133(hi)/ER(lo) cells mediating metastatic progression, which is sensitive to dual targeted therapy.

Topics: AC133 Antigen; Anastrozole; Androstadienes; Animals; Antigens, CD; Antineoplastic Agents, Hormonal; Bone Neoplasms; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Cell Line, Tumor; Cell Self Renewal; Drug Resistance, Neoplasm; Estradiol; Female; Flow Cytometry; Fulvestrant; Gene Expression Regulation, Neoplastic; Glycoproteins; Humans; In Vitro Techniques; Interleukin-6; Letrozole; Leuprolide; MCF-7 Cells; Mice, Inbred NOD; Mice, SCID; Neoplasm Metastasis; Neoplasm Transplantation; Neoplastic Stem Cells; Nitriles; Oxidative Phosphorylation; Peptides; Real-Time Polymerase Chain Reaction; Receptor, Notch3; Receptors, Estrogen; Receptors, Notch; Signal Transduction; Tamoxifen; Triazoles

Topics: Androgen Antagonists; Androgens; Anilides; Drug-Related Side Effects and Adverse Reactions; Flutamide; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Libido; Male; Medicare; Neoplasm Metastasis; Nitriles; Penis; Prostatic Neoplasms; Tosyl Compounds; United States

Haemoglobin levels often decline into the anaemic range with androgen deprivation therapy (ADT). We conducted a chart review of patients receiving ADT for metastatic prostate cancer to assess anaemia-related symptoms.. 135 stage IV prostate cancer cases were reviewed for treatment type; haemoglobin values before and after treatment; and symptoms of anaemia. Mean haemoglobin levels before and after for all treatment forms, for leuprolide alone, and for combination leuprolide/bicalutamide were calculated and evaluated for significant differences. The numbers of patients developing symptoms were recorded and the effects of specific therapies evaluated.. For all ADT treated patients, mean haemoglobin declined by -1.11 g/dL (p<.0001). Leuprolide-alone treated patients had a mean decline of -1.66 g/dL (p<0.0001). Leuprolide and bicalutamide combination treatment caused a mean decline of -0.78 g/dL (p=0.0426). 16 of 43 patients had anemia symptoms. Contingency analysis with Fisher's exact test shows patients receiving leuprolide therapy alone versus other forms of ADT were significantly less likely to have symptoms (chi(2)=0.0190).. The present study confirms that ADT results in a significant drop in haemoglobin levels into the anaemic range. A number of patients become symptomatic from this change. Practitioners should monitor haemoglobin levels, and treat symptomatic patients.

Topics: Aged; Androgen Antagonists; Anemia; Anilides; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Goserelin; Hemoglobins; Humans; Leuprolide; Linear Models; Male; Neoplasm Metastasis; Nitriles; Prostatic Neoplasms; Retrospective Studies; Tosyl Compounds

The changes in serum prostate specific antigen (PSA) concentrations can be used as a prognostic factor in patients undergoing maximum androgen blockade for metastatic prostate cancer.. A total of 149 patients followed up in our department were classified into 4 groups on the basis of PSA changes: group 1; those with normalisation of PSA levels within the first 3 months, group 2; those with normalisation PSA between months 3 and 6, group 3; those with a decrease in PSA but not reaching normal range, group 4; those with no decrease. The gleason scores and the number of bone metastases were also compared between the groups.. The time to progression was significantly delayed in group 1 (mean: 23.3 months) compared to those with group 2 (mean: 16.9 months) (P<0.02). The time to progression in group 3 (mean: 8.45 months) was significantly shorter compared to the first two groups (P<0.001). Also, in patients with gleason scores 5-7 (grades 2) and gleason scores over 7 (grade 3) and group 1, the time to progression (mean: 21.2 months) was significantly delayed compared to those with the same gleason scores but with group 2 (mean: 13.4 months) (P<0.001).. The decrease in PSA level is more important than gleason scores in determining the time to progression. Early normalisation of PSA delays the time to progression, and when combined with gleason scores, PSA is an important prognostic factor in predicting the success of the therapy.

Topics: Aged; Antineoplastic Agents, Hormonal; Goserelin; Humans; Leuprolide; Male; Middle Aged; Monitoring, Physiologic; Neoplasm Metastasis; Orchiectomy; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies

The cost of luteinizing hormone releasing hormone analogue and antiandrogen for prostate cancer is being scrutinized by the Health Care Finance Administration and other insurers. We compared the discounted present value cost of medical hormonal therapy to that of orchiectomy as well as the value created by these treatments from the insurer and patient perspectives.. We performed a telephone survey of 42 patients receiving hormonal therapy to estimate the value created by medical versus surgical castration from the patient perspective. The cost of medical hormonal therapy was discounted back to the present value and compared with the cost of bilateral orchiectomy.. The total cost of bilateral orchiectomy was $2,022, while the discounted present value cost using the average wholesale price for 30 months of medical hormonal therapy was $13,620. Therefore, medical hormonal therapy costs $11,598 more than orchiectomy ($13,620 - $2,022). A discounted payment of $386 per month for 30 months is necessary to recoup the $11,598 difference. All surveyed patients on medical hormonal therapy stated that avoiding orchiectomy was worth $386 per month and it was an appropriate insurer expense. If patients paid $386 per month out-of-pocket, 22 of the 42 (52%) would pay the additional monthly expense, while 20 (48%) indicated that they could not afford the additional expense.. These results indicate that medical hormonal therapy costs significantly more than bilateral orchiectomy but creates positive value for men with prostate cancer by enabling them to avoid orchiectomy.

Topics: Algorithms; Androgen Antagonists; Antineoplastic Agents, Hormonal; Attitude to Health; Centers for Medicare and Medicaid Services, U.S.; Cost of Illness; Financing, Personal; Gonadotropin-Releasing Hormone; Health Care Costs; Hospital Charges; Humans; Insurance Carriers; Leuprolide; Male; Maryland; Neoplasm Metastasis; Orchiectomy; Patient Satisfaction; Prostatic Neoplasms; Relative Value Scales; United States

Metastatic involvement of the pituitary gland is a very unusual presentation of prostatic cancer. We report a favorable response to medical treatment in such a patient.. A 77-year-old man presented with blindness, ophthalmoplegia in his left eye, and mild impairment of memory and mental status. Neuroradiological studies showed a huge intra- and suprasellar lesion that destroyed the sellar floor and extended into the sphenoid sinus. Transsphenoidal biopsy of the lesion demonstrated a prostatic adenocarcinoma. Postoperative studies revealed an enlarged prostate gland and multiple lytic bone lesions. The patient was treated with a combination of leuprolide acetate plus flutamide. Four months later, the patient exhibited a marked improvement in his neurologic status and regained vision in the right eye (visual acuity 6/20). Repeat magnetic resonance imaging of the sellar region confirmed a striking shrinkage of the prostatic metastasis. The clinical status remained stable for 22 months, after which time the disease progressed and the patient died 25 months after beginning treatment.. A favorable response to combined androgen blockade suggests that medical therapy should be considered the therapy of first choice when surgical removal of the metastatic lesion in the pituitary is impossible or too risky.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Bone Neoplasms; Diagnosis, Differential; Flutamide; Humans; Leuprolide; Magnetic Resonance Imaging; Male; Neoplasm Metastasis; Pituitary Neoplasms; Prostatic Neoplasms; Time Factors

Eighteen previously untreated patients with metastatic carcinoma of the prostate were treated with LHRH analogue. They were divided into 3 groups according to the degree of glandular differentiation. In all groups, a transient rise of PAP and PSA was observed after the LH and testosterone surge. However, relative values of LH, testosterone, PAP and PSA did not differ significantly among the 3 groups. These facts suggest that a transient rise of PAP and PSA is caused by testosterone surge independently from the degree of glandular differentiation after LHRH analogue administration in patients with advanced prostatic cancer.

Topics: Acid Phosphatase; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Humans; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Prognosis; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

Luteinizing hormone releasing hormone agonists have been shown to reduce the levels of androgens in the peripheral circulation and to reduce prostate volume. The objective of this study was to quantify testicular function in patients with metastatic carcinoma of the prostate treated with a luteinizing hormone releasing hormone agonist, leuprolide, by analysis of spermatic vein blood for testosterone and androstenedione, and by determination of the maximum velocity of the 17 beta-hydroxysteroid oxidoreductase enzyme in testicular tissue in vitro. A chemical analysis of the spermatic vein blood of 19 patients with a median age of 78 years revealed the presence of significantly high levels of testosterone and androstenedione, 20.7 +/- 1.9 micrograms % and 6.7 +/- 0.7 micrograms %, respectively. These androgens could not be detected in patients treated with leuprolide before orchiectomy. Patients treated with leuprolide for several months followed by a period of no treatment before orchiectomy secreted testosterone and androstenedione levels comparable to the control group. The maximum velocity of the 17 beta-hydroxysteroid oxidoreductase enzyme in vitro in the testes of the leuprolide treated patients was significantly inhibited. Enzyme activity returned to normal levels when leuprolide treatment was followed by a recovery period of no treatment before orchiectomy.

Topics: 17-Hydroxysteroid Dehydrogenases; Aged; Aged, 80 and over; Androgens; Androstenedione; Humans; Leuprolide; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms; Testis; Testosterone

Topics: Follicle Stimulating Hormone; Humans; Kinetics; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms

Current management techniques for metastatic prostatic cancer have given rise to controversies regarding the optimal timing, form, and degree of androgen deprivation. Low-dose diethylstilbestrol (DES) or orchiectomy decrease serum testosterone levels while posing less cardiovascular risk than high-dose DES. LH-RH analogues, such as leuprolide or buserelin, also inhibit testosterone production. Some studies suggest that some tumor cells may be relatively, rather than absolutely, androgen dependent. This has been the rationale for the combined use of a pure antiandrogen and an LH-RH agonist. Unfortunately, while this combination has been found effective in previously untreated patients, it has not been equally effective in those who have undergone prior therapy and demonstrated disease progression.

Topics: Adenocarcinoma; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Buserelin; Castration; Cyclophosphamide; Diethylstilbestrol; Estramustine; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Male; Neoplasm Metastasis; Prostatic Neoplasms

Leuprolide (Lupron, TAP Pharmaceuticals, North Chicago), a gonadotropin-releasing hormone analogue, was administered to 26 premenopausal women with metastatic breast cancer. Of 25 evaluable patients, 11 (44%) had a partial response with a median duration of 39 weeks and five (20%) remained stable. Six patients showed early rapid progression of their disease. Toxicity was mild and included hot flashes, nausea, vomiting, and headache. Leuprolide induced amenorrhea in all patients who received treatment for ten weeks or longer. We conclude that this GnRH analogue provides a safe and effective means of producing medical castration in premenopausal patients with metastatic breast carcinoma.

Topics: Adult; Antineoplastic Agents; Breast Neoplasms; Combined Modality Therapy; Drug Evaluation; Female; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Mastectomy; Menstruation; Middle Aged; Neoplasm Metastasis; Ovary; Receptors, Estrogen

Topics: Antineoplastic Agents; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Neoplasm Metastasis; Prostatic Neoplasms