Weekly administration of docetaxel and epirubicin as first-line treatment for hormone-refractory prostate carcinoma.

Androgen-independent prostate carcinoma (AICP) is one of the tumors that continue to respond poorly to chemotherapy. Recently, protocols based on the use of docetaxel have significantly improved survival for patients in this disease. In other types of neoplastic disease, combined therapy with taxanes and anthracycline derivatives has been shown to produce additive effects in terms of growth inhibition, and superior tolerability when associated with weekly administration schedules. These findings prompted us to examine the tolerability and efficacy of weekly treatment of AICP with docetaxel (DOX) plus epirubicin (EPI). We enrolled 35 chemotherapy-naive men with AICP (mean age 72 years, range 68-77) and normal hepatic, renal, and cardiac function. The chemotherapy protocol provided for the IV administration of DOX (30 mg/m2) and EPI (30 mg/m2) on days 1, 8, and 15 every 28 days. Treatment was continued for 6 months or until disease progression and/or unacceptable toxicity was observed. Serum levels of prostate-specific antigen (PSA) were monitored in all patients, and reductions from baseline values of >50% were considered indicative of positive responses to treatment. Thirty-four patients were included in the analysis of toxicity, and objective responses to treatment were assessed in the 28 patients with measurable lesions. Nineteen patients (56%) experienced PSA reductions of >50% that persisted for more than 4 weeks. The response to therapy was classified as complete in 1 of the 28 patients (4%) with measurable disease (at the lymph node level). Thirteen others (13/28, 46%) had partial responses, in nine (32%) the disease remained unchanged, and progression was observed in the remaining five (18%); overall response rate was 50% (CR + PR). Of the 27 patients with pain at the time of enrollment, 16 (59%) experienced pain reduction during treatment. The median time to disease progression was 11.7 months (95% CI: 7.7-15.7) while the median survival time was 18.7 months (95% CI: 12.3-25.1). During the study, four patients developed grade 3 anemia and leukopenia, which was reversible in all cases. Lower grades of asthenia, nausea, vomiting, diarrhea, and peripheral edema were also observed. There were no cases of cardiotoxic effects. Alopecia was frequent but reversible in all cases. The results of this preliminary study indicate that the combined administration of DOX and EPI for treatment of AIPC is effective and well tolerated. The weekly administration of the drug combination appears to be a promising approach to the treatment of these tumors.

Weekly paclitaxel and epirubicin in the treatment of symptomatic hormone-refractory advanced prostate carcinoma: report of a phase II trial.

The efficacy of weekly paclitaxel in androgen-independent prostate cancer and its addictive cytotoxicity with anthracycline derivatives led us to determine the safety and efficacy of a weekly schedule of paclitaxel and epirubicin. Between October 2000 and November 2002, 32 patients were enrolled in this study. Patients characteristics included a median age of 72 years (range 68-77), adequate hepatic, cardiac, renal and bone marrow functions, ECOG performance status of 1-2, and no prior chemotherapy. All patients had received hormonal manipulation and seven patients (22%) had received prior palliative radiation therapy. The regimen consisted of paclitaxel 70 mg/m2 i.v. infusion for 2 h and epirubicin 30 mg/m2 in bolus every week. Treatment was continued for 3 months or until disease progression or unacceptable toxicity were observed. During the study, prostate-specific antigen (PSA) was monitored and response was defined as a 50% reduction in PSA levels, to be confirmed 4 weeks later. Thirty-one patients were evaluable for toxicity and 21 for objective response. Seventeen patients (57%) had a decline above 50% in PSA level that lasted more than 4 weeks with a median time to PSA progression and a median duration of PSA response of approximately 5.5 months. Ten of the 21 patients with measurable disease (47%) had a confirmed objective response (one complete response and 20 partial responses). Thirteen of 25 symptomatic patients (56 %) had improvement in pain. The median time to disease progression was 7.6 months and the median survival was 12.9. The most prominent grade 3 toxicities were reversible myelosuppression and fatigue. Nausea, vomiting, diarrhea and peripheral edema were minimal. No evidence of cardiac toxicity was recorded. Alopecia was frequent, but reversible, in all patients. We conclude that despite the small sample size, this study demonstrates that the combination of weekly paclitaxel and epirubicin is a well-tolerated regimen for androgen-independent prostate cancer. The results imply that a combination of these agents in a weekly schedule may have clinical potential in prostate cancer treatment.

Phase II trial of weekly intravenous gemcitabine administration with interferon and interleukin-2 immunotherapy for metastatic renal cell cancer.

PURPOSE: Since metastatic renal cell carcinoma has a poor prognosis and treatment strategies, including hormone therapy, chemotherapy and immunotherapy, have little impact on the quality of life and global survival statistics, new interest has recently focused on the combination of immuno-chemotherapy using pyrimidine analogues, such as gemcitabine. MATERIALS AND METHODS: In a phase II study 16 patients with metastatic renal cell carcinoma were treated with 1,000 mg./m. gemcitabine intravenously on days 1, 8, 15 and 28 for 6 months, 3 MU (1 MU = 1 x 10(6) IU) interferon (IFN)-alpha intramuscularly 3 times a week and 4.5 million IU interleukin (IL)-2 subcutaneously daily for 5 days a week for 2 consecutive weeks every month for 6 months. Responding and nonprogressing cases were maintained on immunotherapy consisting of IFN-alpha and IL-2 for further 6 months. RESULTS: In 15 evaluable patients overall response rate (1 complete response plus 3 partial response) was 28% while stable disease was achieved in 7 (47%). Median survival duration was 20 months (range, 9 to 26+) and median time to tumor progression was 14 months (6 to 26+). The complete response lasted 24+ months and partial response lasted 16 months. The regimen was well tolerated with only 1 case of neutropenia (WHO grade 3), while anorexia, fatigue and flu-like symptoms were the most common toxicity problems but were never greater than grade 2. CONCLUSIONS: Despite the small sample size, this study demonstrates that gemcitabine combined with standard doses of IFN-alpha and low doses of IL-2 is effective treatment for metastatic renal cell carcinoma. This biotherapy was well tolerated and resulted in an optimum objective response and relatively long-term survival.

Gemcitabine plus Epi-doxorubicin as first-line chemotherapy for bladder cancer in advanced or metastatic stage: a phase II.

Combination chemotherapy with newer, more active drugs in patients with advanced and/or metastatic bladder cancer might show improved response rate and survival. Gemcitabine (GEM) and Epidoxorubicin (EPI) have demonstrated activity in this disease. In addition, experimental studies in vitro have shown that the two agents have additive-synergistic effects when used in combination. Our prior phase I dose-finding study in previously untreated patients with advanced or metastatic bladder cancer defined recommended doses for further trials of GEM 1000 mg/m2 and EPI 25 mg/m2 on days 1, 8 and 15 every 28 days. A phase II trial at this dose level was initiated in previously untreated patients to assess efficacy and toxicity. Eligible patients had measurable disease; Karnofsky performance status (PS) of > 40; no prior chemotherapy; and adequate bone marrow reserve, cardiac, hepatic and renal function. Thirty- one patients (22 males, 9 females) with median age of 64 (range 44-75) and median PS of 80 were accrued, and all were eligible. Twelve patients had T4N1-2 M0, 8 had lymph node only metastases, while 11 had visceral metastases (liver, bone, lung). A total of 181 cycles was administered (range 3-7 per patient). Major toxicities (WHO grade > or = 3) were: neutropenia in 5 patients, thrombocytopenia in 2 patients, and anemia in 2 patients. Three patients had febrile neutropenic episodes and only 3 patients required dose reduction. Grade 1-2 non-hematological toxicities included nausea/vomiting, stomatitis and alopecia. No cardiac toxicity was observed. Of the 30 response evaluable patients, 17 (57%) demonstrated a major response (3 complete and 14 partial) (95% CI: 39%-75%), 7 had stable disease (23%) and 6 progressed (20%). These preliminary results confirm the phase I observation that the combination of GEM--EPI is highly active in the treatment of advanced and metastatic bladder cancer with a favourable toxicity profile.

Melatonin as biological response modifier in cancer patients.

The neuroendocrine system modulates the immune response through neuropeptides and neurohormones, findings which point to the existence of a neuro-endocrine-immune system regulatory axis. At the same time, there is growing evidence that the pineal gland has anti-neoplastic properties, which include the action of its principal hormone, melatonin (MLT), on the immune system through the release of cytokines by activated T-cells and monocytes. The present study was carried out on 31 patients (19 males and 12 females, age range 46-73 years) with advanced solid tumors (7 gastric, 9 enteric, 8 renal, 5 bladder, 2 prostate) who either failed to respond to chemotherapy and radiotherapy or showed insignificant responses and were therefore shifted to MLT therapy (10 mg/die orally for 3 months). We obtained blood samples just before the start of MLT administration and after 30 days of therapy. Plasma was collected in EDTA tubes on ice, immediately centrifuged at 4 degrees C and stored frozen at -80 degrees C; samples were measured by immunoradiometric assays (Medgenix-Fleurus, Belgium) for tumor necrosis factor alpha (TNF), interleukin-1, 2 and 6 (IL-1, IL-2, IL-6) and interferon gamma (IFN). We used Student's paired t-test to compare each patient's cytokine circulating levels before and after MLT administration and found a significant differences (p < 0.05). After 3 months of therapy, none of our patients displayed adverse reactions to MLT or had to discontinue treatment. Nineteen patients (61%) showed disease progression. The other 12 (39%), however, achieved disease stabilization with no further growth of either the primary tumor or of secondaries; moreover, they experienced an improvement in their general well-being, in terms of Tchekmedyian's criteria, associated with a significative decrease of IL-6 circulating levels. These findings are consistent with the hypothesis that MLT modulates immune function in cancer patients by activating the cytokine system which exerts growth-inhibitory properties over a wide range of tumor cell types. Furthermore, by stimulating the cytotoxic activity of macrophages and monocytes, MLT plays a critical role in host defence against the progression of neoplasia.

Weekly epidoxorubicin therapy in hormone-refractory metastatic prostate cancer.

In a pilot trial, we treated thirty-three hormone resistant metastatic prostate cancer patients with a combination of androgen blockade plus weekly cytotoxic therapy and determined both response and toxicity in 32 of them. Their median Karnofsky performance status at the time of entry was 65. We administered Epidoxorubicin (EpiDx) intravenously, at a dose of 35 mg/m2, every week for 4 months. Initially, all patients had only hormonal therapy and chemotherapy was added once they progressed. In terms of W.H.O. criteria, 9 patients (28%) had a partial response, the disease was stable in 14 (44%), and progressive in 9 (28%); even in this last group, 6 patients with bone metastases experienced lasting relief from pain. No patients had to interrupt treatment due to leukopenia or cardiotoxicity. Other toxicities, including nausea and vomiting, mucositis and alopecia, were mild. Pretreatment prostate-specific antigen (PSA) levels decreased significantly (p < 0.05) in 26 patients (81%) after treatment. In our view, weekly EpiDx administration serves as an active regimen in hormone-refractory prostate cancer.

Endoluminal instillation of epidoxorubicin as adjuvant treatment for upper urinary tract urothelial tumours.

Intravesical use of chemotherapeutic agents has been documented as effective and beneficial in the treatment and prophylaxis of bladder urothelial cancer. Because of the success achieved with these agents, several investigators have proposed these same drugs as adjuvant treatment after conservative procedures for urothelial tumours of the upper urinary tract. Experiences concerning topical therapy for upper tract urothelial neoplasms are still limited, but suggest a great potential benefit in terms of improved tumour control. Advances in endourologic techniques and increasing interest in the conservative management of upper urinary tract urothelial cancer may lead to more frequent use of topical chemotherapy. Specific guidelines and surveillance protocols, similar to those with superficial bladder cancer, are required to determine the role of this adjuvant therapy in the treatment of urothelial tumours of the upper urinary tract. This report shows our experience gained on endoluminal instillation of epidoxorubicin in a selected group of 9 patients who underwent local excission of ureteral or renal pelvis tumours.

[Urethral parameatal cysts. Report of two cases and review of the literature]. / Cisti uretrali parameatali. Descrizione di due casi e revisione della letteratura.

Two cases of parameatal urethral cysts in the male are reported. These round cysts don't interfere with sexual function but can determinate an alteration of the urinary flow (biforcation of the flow). The aetiology of these cysts is not completely understood, while the treatment is univoque and simple: complete excision but no aspiration or marsupialization.

Modulation of human lymphoblastoid interferon activity by melatonin in metastatic renal cell carcinoma. A phase II study.

BACKGROUND: Numerous attempts to identify active cytotoxic agents for the treatment of metastatic renal cell carcinoma (RCC) have proved disappointing. However, several recent developments in biologic therapy of neoplastic disease have substantially improved the prospects for the treatment of advanced RCC. Melatonin (MLT), a hormone regulated by the pineal gland, has been shown to act on the immune system by causing the release of cytokines from activated T-cell populations. METHODS: A series of 22 patients with documented progressing RCC entered a trial in which the authors studied the effect of a long term regimen (12 months) with human lymphoblastoid interferon (IFN), 3 mega units (MU) intramuscularly 3 times per week, and MLT, 10 mg orally every day. RESULTS: Twenty-one patients were evaluable for response and toxicity. There were seven remissions (33%): three complete, involving lung and soft tissue and four partial, with a median duration at the time of this writing of 16 months. Nine patients achieved stable disease, and five progressed. General toxicity was mild. Fever, chills, arthralgias, and myalgias occurred rarely. Leukopenia and hepatic enzyme elevation were modest and always reversible. CONCLUSIONS: Response rate and toxic effects observed during this study warrant additional randomized studies to define the role of MLT's concomitant administration in the clinical response to IFN in metastatic RCC.

Cyclophosphamide, epidoxorubicin and Carboplatin as treatment for advanced-carcinoma of the bladder - a phase-ii study.

In advanced carcinoma of the bladder, the M-VAC chemotherapy schedule can yield positive results, but at the cost of very high toxicity. Recent studies have shown epidoxorubicin and to a lesser degree, carboplatin to be active against urothelial tumors, with cardiac, haematological and renal toxicity lower than that observed with CISCA or M-VAC chemotherapy regimens. In this study, we determined the toxicity and efficacy of cyclophosphamide 400 mg/m(2), epidoxorubicin 75 mg/m(2) and carboplatin 300 mg/m(2) in a 28-day course. From February 1990 to December 1991, we enrolled 33 advanced bladder cancer patients (25 males, 8 females), mean age 63 years. 31 patients were evaluable for toxicity and response. The major disease localizations were: locoregional 15 (48%), lymph nodes 6 (20%), liver 5 (16%), lung 3 (10%) and bone 2 (6%). A total of 186 cycles of therapy were administered, with a mean of 5.4 per patient. Six patients (19%) had a complete response (CR): 2 locoregional, 3 lymph node and 1 lung. Eleven patients (36%) had a partial response (PR), for an overall response rate of 55%. The median duration of response was 53 weeks and median survival for the entire group of patients was 40 weeks. No delays or interruptions due to sepsis occurred during therapy; haematological, cardiac and renal toxicity were below WHO grade 3. The efficacy of this chemotherapy regimen proved to be comparable to that of more aggressive schedules, while its toxicity was markedly lower.

Ultrastructural changes of Leydig cells in prepubertal varicocele.

Testicular biopsies from 25 boys, aged 11-17, with left clinically evident varicocele were studied. Electron microscopic observations documented diffuse histological changes of smooth endoplasmic reticulum, Golgi apparatus and mitochondria of Leydig cells. Ultrastructural modifications of these subcellular structures related to steroid hormone synthesis may impede the normal growth and maturation of the testis and impair fertility potential.

Our experience with sacral evoked potentials in impotence.

Pudendal-pudendal and pelvic-pudendal sacral evoked potentials (ESP) were studied in 40 patients complaining of erectile impotence. Electromyographic results allowed us to recognize the organic cause of impotence in 4 men with visceral neuropathies. Sacral evoked responses extend our diagnostic possibilities in evaluating erectile impairment secondary to subclinical neurological abnormalities.

Surgical procedure in congenital curvature of the penis.

The results of 18 cases of surgical correction for congenital curvature of the penis are presented. In 17 out of 18 cases sexual intercourse which were very difficult or impossible before operation were referred as normal or satisfactory after surgery.

Calcium, zinc, magnesium, concentration in seminal plasma of infertile men with prostatitis.

Seminal plasma, Zinc, Magnesium and Calcium concentrations were evaluated in 15 infertile men with chronic prostatitis and in 10 controls. Highly significant difference (p less than 0,01) was observed in Calcium concentration only in the group of bacterial prostatitis with respect to the controls. The possible significance of these data is suggested.