trelstar and Bone-Neoplasms

The development of resistance to anticancer therapies is a major hurdle in preventing long-lasting clinical responses to conventional therapies in hormone-refractory prostate cancer. Herein, the molecular evidence documenting that bone metastasis microenvironment survival factors (mainly the paracrine growth hormone-independent, urokinase-type plasminogen activator-mediated increase of IGF-1 and the endocrine production of growth hormone-dependent IGF-1, mainly liver-derived IGF-1 production) produce an epigenetic form of prostate cancer cells that are resistant to proapoptotic therapies is reviewed. Consequently, the authors present the conceptual framework of a novel antibone microenvironment survival factor, mainly an anti-IGF-1 hormonal manipulation for androgen ablation refractory prostate cancer (a combination of conventional androgen ablation therapy [luteinising hormone-releasing hormone agonist-A or orchiectomy]) with dexamethasone plus somatostatin analogue, which yielded durable objective responses and major improvement of bone pain and performance status in stage D3 prostate cancer patients.

Topics: Adenocarcinoma; Androgen Antagonists; Androgens; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bone Neoplasms; Clinical Trials, Phase II as Topic; Combined Modality Therapy; Dexamethasone; Drug Resistance, Neoplasm; Estramustine; Etoposide; Gonadotropin-Releasing Hormone; Growth Substances; Humans; Leuprolide; Male; Neoplasm Proteins; Neoplasms, Hormone-Dependent; Orchiectomy; Osteoblasts; Osteoclasts; Paracrine Communication; Peptides, Cyclic; Prospective Studies; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Receptors, Androgen; Salvage Therapy; Somatostatin; Survival Analysis; Triptorelin Pamoate

Approximately 15% of men with hormone naïve metastatic prostate cancer primarily fail to respond to androgen deprivation treatment (ADT). The reason why the response to ADT differs in this subgroup of men with prostate cancer remains unclear. The aim of this study was to describe the characteristics of these men and to thereby define predictors of early ADT failure in prostate cancer patients with bone metastases. The study was based on 915 men from the prospective randomized multicenter trial (no. 5) conducted by the Scandinavian Prostate Cancer Group comparing parenteral estrogen with total androgen blockade. Early ADT failure was defined as death from metastatic prostate cancer within 12 months after the start of ADT. Multivariate logistic regression models were applied to identify clinical predictors of early ADT failure. Ninety-four (10.3%) men were primarily nonresponders to ADT. Independent predictors of early ADT failure were poor Eastern Cooperative Oncology Group performance status (PS), analgesic consumption, low hemoglobin, and high Soloway score (extent of disease observed on the scan), in where patients with poor PS and/or high analgesic consumption had a threefold risk of early ADT failure. Not significantly factors related to early ADT failure were age, treatment, cardiovascular comorbidity, T category, grade of malignancy, serum estrogen level, and SHBG at enrolment. We analyzed characteristics of a subgroup of patients who primarily failed to respond to ADT. Four independent clinical predictors of early ADT failure could be defined, and men exhibiting these features should be considered for an alternative treatment.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Bone Neoplasms; Flutamide; Humans; Male; Middle Aged; Orchiectomy; Prospective Studies; Prostatic Neoplasms; Regression Analysis; Risk Factors; Treatment Failure; Triptorelin Pamoate

To evaluate prospectively the combination of a luteinizing hormone-releasing hormone analog with a somatostatin analog and dexamethasone in patients with hormone-refractory prostate cancer (HRPC) in a randomized Phase II study. HRPC presents a challenging therapeutic problem. Salvage chemotherapy is the usual approach at this stage of the disease. The combination of a luteinizing hormone-releasing hormone analog with a somatostatin analog and dexamethasone has produced objective clinical responses in HRPC.. Forty patients with HRPC were randomized to receive one of two treatments. Group 1 underwent chemotherapy (estramustine 140 mg three times daily and etoposide 100 mg orally for 21 days) and group 2 the combination of a somatostatin analog (lanreotide 30 mg intramuscularly every 14 days) and dexamethasone (4 mg tapered to 1 mg), in addition to androgen ablation by orchiectomy or a luteinizing hormone-releasing hormone analog (triptorelin 3.75 mg intramuscularly every 28 days). The clinical and prostate-specific antigen (PSA) response, overall survival, time to progression, and toxicity were compared between the two groups.. The data of 20 patients in group 1 and 18 in group 2 were analyzed. The demographic and clinical data were similar in the two groups at study entry. A PSA response (decrease of greater than 50%) was observed in 45% of group 1 and 44% of group 2. The difference was not statistically significant. A partial clinical response was observed in 29% and 30% of groups 1 and 2, respectively. Again, the difference was not statistically significant. Changes in performance status and pain score during treatment were not significantly different in the two groups. Hematologic toxicity was more frequent in group 1 (80% of patients), and mild diabetes was more frequent in group 2 (22% of patients). The overall survival was 18.8 months in group 1 and 18 months in group 2 (not statistically significant). The time to progression was 6 versus 4 months and, in the PSA responder subgroup, it was 8 versus 7.7 months in groups 1 and 2, respectively (neither difference was statistically significant).. The results of our randomized Phase II study indicated that the new combination treatment (luteinizing hormone-releasing hormone analog, somatostatin analog, and dexamethasone) may be equally effective as salvage chemotherapy in patients with HRPC in terms of the clinical and PSA response, overall survival, and time to progression. A larger prospective Phase III trial is required to confirm our observations.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Combined Modality Therapy; Dexamethasone; Diabetes Mellitus; Disease-Free Survival; Estramustine; Etoposide; Gastrointestinal Diseases; Gonadotropin-Releasing Hormone; Hematologic Diseases; Humans; Life Tables; Male; Middle Aged; Orchiectomy; Peptides, Cyclic; Prostatic Neoplasms; Somatostatin; Survival Analysis; Treatment Outcome; Triptorelin Pamoate

Combination therapy with the antiandrogen flutamide and the luteinizing hormone-releasing hormone (LHRH) agonist [D-Trp6, des-Gly-NH2(10)] LHRH ethylamide or orchiectomy was administered to 268 patients with previously untreated metastatic stage D2 prostate cancer for an average of 1,191 d (3.26 y). Only 17 of the 268 evaluable patients (6.5%) showed no objective positive response to the combination therapy assessed according to the National Prostatic Cancer Project objective criteria of response. The median duration of the disease-free response was 2.23 y and median overall survival was 3.58 y. The median survival for patients with only 1-5 bone metastases was not yet reached at 8 y, but for patients with 6-10 bone lesions, 11-40 bone lesions, and multiple bone metastases (superscan), median survival was markedly reduced to 3.56, 2.36, and 1.76 y, respectively. Analysis of patients according to general symptomatology, pain, and performance status showed median survivals of 5.47, 2.71, and 2.1 y for minimal, moderate, and severe symptoms, respectively. The present data demonstrate that administration of combination therapy to stage D2 prostate cancer patients having 1-5 bone metastases adds a minimum of 4.4 y of good quality life compared with patients whose disease is slightly more advanced. Our findings clearly demonstrate the major importance of starting combination therapy as soon as possible after diagnosis of metastatic prostatic cancer.

Topics: Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Combined Modality Therapy; Flutamide; Gonadotropin-Releasing Hormone; Humans; Male; Orchiectomy; Prostatic Neoplasms; Survival Analysis; Triptorelin Pamoate

Ninety-five patients with stage C (C1 + C2) or D (D1 + D2) prostatic carcinoma were treated with the long-acting formulation of D-TRP-6 LH-RH (Decapeptyl) for up to 39 months. Of 88 patients evaluable for response, about one-half showed an objective response. In most cases, subjective improvement with relief of bone pain and/or urinary symptoms was obtained. Five patients claimed a mild increase in bone pain and one patient a slight worsening of dysuria following the first injection. Median progression-free survival was 13.1 and 16.4 months in patients with stage D2 and D1, respectively. Median survival in stage D2 patients was 27.6 months. These results indicate that the depot formulation of D-TRP-6 LH-RH offers an effective therapeutic alternative for patients with advanced prostatic cancer.

Topics: Aged; Antineoplastic Agents; Bone Neoplasms; Delayed-Action Preparations; Gonadotropin-Releasing Hormone; Humans; Injections, Intramuscular; Italy; Male; Multicenter Studies as Topic; Neoplasms, Hormone-Dependent; Prognosis; Prostatic Neoplasms; Remission Induction; Triptorelin Pamoate

Topics: Adult; Aged; Bone Neoplasms; Clinical Trials as Topic; Delayed-Action Preparations; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Male; Middle Aged; Prostatic Neoplasms; Triptorelin Pamoate

Chronic administration of a depot form of D-Trp6 luteinizing hormone-releasing hormone (LH-RH), an LH-RH analogue (3 mg i.m. every 28 days for a mean period of 9.1 months), to 14 patients with locally extended or metastatic cancer of the prostate provided a good degree of disease control. After a slight and transient increase in gonadotropin secretion, the peptide induced a sharp and long-lasting inhibition of both gonadotropin and testosterone secretion, contemporaneously with clinical improvement and without any important side effects. These results are comparable to those recorded by others after daily administration of LH-RH analogues.

Topics: Acid Phosphatase; Aged; Antineoplastic Agents; Bone Neoplasms; Clinical Trials as Topic; Delayed-Action Preparations; Gonadotropin-Releasing Hormone; Gonadotropins, Pituitary; Humans; Male; Prostate; Prostatic Neoplasms; Testosterone; Triptorelin Pamoate

The relevance of drug treatment for prostate cancer increases with the number of patients who develop castration resistance. Currently, no unified treatment regimen for castration-resistant prostate cancer exists, but the standard treatment for these patients is continuous androgen deprivation therapy. This paper presents the experience of concomitant use of abiraterone acetate and triptorelin in patients with castration-resistant prostate cancer. Ten patients with disease duration of 1.5 to 18 years and established castration resistance are currently being followed up. Nine of ten patients have long-term bone metastases, one patient has visceral metastases. The combination therapy produced a significant PSA decrease in nine patients and regression of bone lesions in two patients.

Topics: Aged; Aged, 80 and over; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Humans; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Triptorelin Pamoate

To report the outcome and course of disease in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with first-line docetaxel followed by abiraterone acetate in a single center.. In this retrospective observational study, we reviewed the course of disease of all applicable patients with mCRPC treated with docetaxel followed by abiraterone at our center. We analyzed progression-free survival (PFS) of docetaxel and abiraterone treatments. We further searched for predictive factors for the duration of treatment response.. Median PFS between initiation of androgen deprivation therapy and the diagnosis of mCRPC was 32 months. Median PFS on docetaxel treatment was 9 months. Median PFS on abiraterone treatment was 11 months. Patients with higher Gleason scores (GS) (8-10) at initial diagnosis had a significantly longer median PFS on docetaxel as compared to patients with GS 6-7, p = 0.01. We demonstrate a significant correlation between the PFS on docetaxel and PFS on abiraterone in the post-docetaxel setting (Kendall tau r = 0.32, p = 0.019) as well as a significant negative correlation between the PSA nadir under abiraterone treatment and the time to progression under abiraterone (Kendall tau r = -0.43, p = 0.007).. High Gleason score appears to be predictive of duration of response to docetaxel. Interestingly, progression-free survival with abiraterone appears to be correlated with the duration of response with docetaxel, whereas PSA decline and low nadir appear to be predictive of response to abiraterone.

Topics: Aged; Androgen Antagonists; Androstenes; Anilides; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Buserelin; Cohort Studies; Disease-Free Survival; Docetaxel; Flutamide; Humans; Leuprolide; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Nitriles; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Tosyl Compounds; Treatment Outcome; Triptorelin Pamoate

Prostate carcinoma is one of the most frecuent cancers in men. Significant numbers of patients have regional lymph node and bone metastases during the course of the disease. Mediastinal lymphadenopathy and cutaneous metastases are uncommon and signify well-advanced disease. We report the case of a patient with prostate cancer who develops mediastinal lymphadenopathy, pulmonary nodules and cutaneous metastases 8 years after the diagnosis.

Topics: Adenocarcinoma; Androgen Antagonists; Androgens; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cyproterone; Diphosphonates; Estramustine; Fatal Outcome; Flutamide; Humans; Imidazoles; Ketoconazole; Lung Neoplasms; Lymphatic Metastasis; Male; Mediastinum; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Radionuclide Imaging; Skin Neoplasms; Triptorelin Pamoate; Zoledronic Acid

Experimental and preliminary clinical studies have suggested that the pineal hormone melatonin (MLT) may stimulate hormone receptor expression on both normal and cancer cells. Moreover, MLT has appeared to inhibit the growth of some cancer cell lines, including prostate cancer, either by exerting a direct cytostatic action, or by decreasing the endogenous production of some tumor growth factors, such as prolactin (PRL) and insulin-like growth factor-1 (IGF-1). On this basis, a study was carried out to evaluate the clinical efficacy of a neuroendocrine combination consisting of the LHRH analogue triptorelin plus MLT in metastatic prostate cancer progressing on triptorelin alone.. The study including 14 consecutive metastatic prostate cancer patients with poor clinical conditions (median age: 70.5 years; median PS: 50%), refractory or resistant to a previous therapy with the LHRH analogue triptorelin alone. Triptorelin was injected i.m. at 3.75 mg every 28 days, and MLT was given orally at 20 mg/day in the evening every day until progression, starting 7 days prior to triptorelin.. A decrease in PSA serum levels greater than 50% was obtained in 8/14 (57%) patients. Moreover, PSA mean concentrations significantly decreased on therapy of triptorelin plus MLT. In addition, a normalization of platelet number was obtained in 3/5 patients with persistent thrombocytopenia prior to study. Mean serum levels of both PRL and IGF-1 significantly decreased on therapy. Finally, a survival longer than 1 year was achieved in 9/14 (64%) patients. This preliminary study would suggest that the concomitant administration of the pineal hormone MLT may overcome the clinical resistance to LHRH analogues and improve the clinical conditions in metastatic prostatic cancer patients.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bone Neoplasms; Drug Resistance; Follow-Up Studies; Humans; Injections, Intramuscular; Insulin-Like Growth Factor I; Lymphatic Metastasis; Male; Melatonin; Middle Aged; Pilot Projects; Pineal Gland; Prolactin; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Outcome; Triptorelin Pamoate

The plasma levels of pituitary hormones (LH, FSH and prolactin) as well as testosterone were determined in 62 patients treated with combined therapy using the LHRH agonist [D-Trp6, des-Gly-NH2(10)]LHRH ethylamide and the antiandrogen Flutamide. Plasma radioimmunoassayable LH and FSH levels increased to 534% (p less than 0.01) and 150% (p less than 0.01) of control, respectively, during the first 5 days of treatment, while, afterwards, a marked inhibition was observed which remained constant at approximately 30-50% of control values during the whole period of treatment. All patients showed a decrease of plasma testosterone concentration to approximately 10% of control levels. Detailed determinations of plasma testicular and adrenal steroid levels were then performed in 15 patients. Our data indicate that, except for the blockade of testicular 17-hydroxyprogesterone secretion, the combined therapy has no effect on plasma C-21 steroid levels. However, adrenal C-19 steroids, namely dehydroepiandrosterone and its sulfate, androst-5-ene-3 beta, 17 beta-diol and androstenedione were decreased to approximately 50% of control values (p less than or equal to 0.01). The main testicular steroids, testosterone and dihydrotestosterone, which were increased during the first 10 days of combined administration, rapidly decreased and reached approximately 10% of control values at later time intervals. The present study extends our previous observations indicating that the combined antihormonal treatment affects both testicular and adrenal steroidogenesis. Moreover, we have demonstrated that, up to at least 2 years, this treatment, in addition to decreasing the serum levels of testicular androgens, causes an inhibition of the plasma levels of C-19 steroids from adrenal origin.

Topics: Adenocarcinoma; Adrenal Cortex Hormones; Androgens; Androstane-3,17-diol; Androstenediol; Androstenedione; Androsterone; Anilides; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Dehydroepiandrosterone; Flutamide; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Hydrocortisone; Kinetics; Luteinizing Hormone; Male; Pregnenolone; Progesterone; Prolactin; Prostatic Neoplasms; Testosterone; Triptorelin Pamoate

D-Trp-6-LH-RH, a long acting LH-RH agonist was given in a phase II trial to 85 patients aged 52 to 88 (mean 69) with advanced prostatic carcinoma, stage B (8 pts), C (9 pts) and D (68 pts). Twenty-five patients were previously untreated, 40 had received previous hormonal therapy but none was considered has having hormone resistant tumor; 20 patients had received surgery or radiotherapy or both. D-Trp-6-LH-RH was given s.c. at a daily dose of 500 micrograms during the first seven days, followed by 100 micrograms daily. Antitumor activity was assessed after 90 days and treatment was continued in responders. The results were the following: plasmatic levels of LH were sharply decreased and those of testosterone were in all cases under 1 ng/ml by the 90th day of treatment; urinary symptoms and bone pain disappeared or were greatly improved in almost all patients; the volume of the prostate measured by ultrasonography and/or computerized tomography regressed by more than 50% of initial volume in 44% of the 34 patients for which this parameter was evaluable; bone scintiscans were improved in 18% of evaluable patients; plasmatic levels of prostatic acid phosphatases determined by radio immuno-assay were elevated in 28 patients, 61% of which presented a decrease superior to 50% or normalisation of this parameter. No disease flare up was observed on initiation of therapy. Impotence was constant but reversible on discontinuation of therapy. No other side effect could be attributed to therapy.

Topics: Acid Phosphatase; Aged; Aged, 80 and over; Bone Neoplasms; Gonadotropin-Releasing Hormone; Humans; Male; Middle Aged; Prostatic Hyperplasia; Prostatic Neoplasms; Triptorelin Pamoate; Urination Disorders

Serum concentrations of luteinising hormone and testosterone were measured by radioimmunoassay one, two, four, seven, and 24 hours after the subcutaneous administration of 500 micrograms of the luteinising hormone releasing hormone agonist [D-Trp6, des-Gly-NH2(10)] LHRH ethylamide or [D-Ser(TBU)6, des-Gly-NH2(10)]LHRH ethylamide in patients who had previously received daily treatment with these peptides for 0, 1, 6, 12, 18, and 24 months. No increase in the serum concentrations of luteinising hormone or testosterone were detected at any time between one and 24 months' treatment. The data show that daily subcutaneous administration of the two luteinising hormone releasing hormone agonists used at the appropriate dose can maintain concentrations of serum androgens equivalent to those after castration during long term treatment.

Topics: Bone Neoplasms; Buserelin; Flutamide; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Male; Prostatic Neoplasms; Radioimmunoassay; Testosterone; Time Factors; Triptorelin Pamoate