A prospective analysis of the time to normalization of serum androgens following 6 months of androgen deprivation therapy in patients on a randomized phase III clinical trial using limited hormonal therapy.

Purpose: Patients with prostate cancer are treated with neoadjuvant, adjuvant and intermittent therapy with gonadotropin-releasing hormone agonists (GnRH-A). While these are largely successful in decreasing testosterone (T) and dihydroxytestosterone (DHT) to castrate levels, discontinuation of such therapy often results in continued suppression of androgens for variable periods of time. We present the largest published series of patients evaluating the timing of T and DHT increase after cessation of GnRH therapy.

Clinical trials in metastatic prostate cancer--has there been real progress in the past decade?

Hormone refractory prostate cancer remains a challenge. While only palliative treatment strategies were available for the past several decades, many promising agents have been investigated over the past decade. Of those the taxanes appeared with significant anti-tumor activity and recently, two large randomized controlled trials demonstrated for the first time, a survival and palliative benefit with docetaxel based chemotherapy.

Chemotherapy for androgen-independent prostate cancer.

The evolution of taxanes as treatment for androgen-independent prostate cancer hes emerged from both the laboratory and clinic. Docetaxel is a potent in vitro inhibitor of Bcl-2, an antiapoptotic gene. Phase I and II studies with docetaxel alone or in combination with estramustine demonstrated promissing median survivals of 14--23 months, higher than what would have been expected for historic controls.

Quality of life impact of three different doses of suramin in patients with metastatic hormone-refractory prostate carcinoma: results of Intergroup O159/Cancer and Leukemia Group B 9480.

Background: Research has suggested that men with hormone-refractory prostate carcinoma have a lower quality of life (QOL) compared with men who have hormone-sensitive prostate carcinoma and that quality of life (QOL) steadily declines over the last year of life for men with prostate carcinoma. The primary purpose of the current study was to evaluate whether there was evidence of palliative effects associated with suramin at any of the three doses administered in the original clinical trial.

Methods: Patients with histologically confirmed advanced hormone-refractory adenocarcinoma of the prostate were randomized to receive suramin at a low dose (n = 129; median age, 69 years), an intermediate dose (n = 129; median age, 71 years), or a high dose (n = 127; median age, 70 years) as part of the Intergroup 0159/Cancer and Leukemia Group B 9480 trial.

Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer.

Background: Mitoxantrone-based chemotherapy palliates pain without extending survival in men with progressive androgen-independent prostate cancer. We compared docetaxel plus estramustine with mitoxantrone plus prednisone in men with metastatic, hormone-independent prostate cancer.

Methods: We randomly assigned 770 men to one of two treatments, each given in 21-day cycles: 280 mg of estramustine three times daily on days 1 through 5, 60 mg of docetaxel per square meter of body-surface area on day 2, and 60 mg of dexamethasone in three divided doses before docetaxel, or 12 mg of mitoxantrone per square meter on day 1 plus 5 mg of prednisone twice daily.

Complications of androgen deprivation therapy in men with prostate cancer.

Androgen deprivation therapy (ADT) is indicated for the treatment of metastatic prostate cancer and locally advanced disease. In addition to sexual side effects, long-term ADT results in several other changes, including hot flashes; gynecomastia; changes in body composition, metabolism, and the cardiovascular system; osteoporosis; anemia; psychiatric and cognitive problems; and fatigue and diminished quality of life. This review discusses these complications of ADT and treatments aimed at reducing them.

Eligibility and outcomes reporting guidelines for clinical trials for patients in the state of a rising prostate-specific antigen: recommendations from the Prostate-Specific Antigen Working Group.

Purpose: To define methodology to show clinical benefit for patients in the state of a rising prostate-specific antigen (PSA).

Hypothesis: A clinical states framework was used to address the hypothesis that definitive phase III trials could not be conducted in this patient population.

Patient Population: The Group focused on men with systemic (nonlocalized) recurrence and a defined risk of developing clinically detectable metastases.

Management of high-risk localized prostate cancer: the integration of local and systemic therapy approaches.

Using a combination of PSA, Gleason score, and clinical stage, it is possible to identify a group of patients with prostate cancer who have a high risk of relapse following initial treatment (e.g., radiotherapy or radical prostatectomy).

Southwest Oncology Group studies in bladder cancer.

Over 50,000 patients are diagnosed annually with bladder cancer, and approximately 10,000 eventually will die of their disease. Thus, the Southwest Oncology Group (SWOG) Genitourinary Cancer Committee is committed to the study of therapeutic interventions in patients with superficial, invasive, and metastatic bladder cancer. In the past 15 years, SWOG has completed six Phase III, randomized trials.

Fas-mediated apoptosis is dependent on wild-type p53 status in human cancer cells expressing a temperature-sensitive p53 mutant alanine-143.

The p53 mutant 143Ala is a human temperature-sensitive mutant with two conformational states. To definitively determine whether the Fas signal transduction pathway and the function of the pathway are dependent on p53 status, we have established stable transfectants of p53 mutant 143Ala in two human cancer cell lines: H1299 (lung cancer line) and PC-3 (prostate cancer line), the native state of which contains null p53 status and can grow at 37 degrees C and 32.5 degrees C.

Early chemohormonal therapy in prostate cancer: preliminary data and randomized trials.

Chemotherapy was traditionally perceived to be ineffective for prostate cancer and was only administered to patients with symptomatic hormone-refractory disease. Although previous reviews have confirmed this belief, recent studies have demonstrated significant antitumor activity with chemotherapy regimens. This article highlights the preliminary results of recent studies involving chemohormonal therapy.

Preferential induction of necrosis in human breast cancer cells by a p53 peptide derived from the MDM2 binding site.

p53 is the most frequently altered gene in human cancer and therefore represents an ideal target for cancer therapy. Several amino terminal p53-derived synthetic peptides were tested for their antiproliferative effects on breast cancer cell lines MDA-MB-468 (mutant p53), MCF-7 (overexpressed wild-type p53), and MDA-MB-157 (null p53). p53(15)Ant peptide representing the majority of the mouse double minute clone 2 binding site on p53 (amino acids 12-26) fused to the Drosophila carrier protein Antennapedia was the most effective.

A phase II trial of docetaxel and estramustine in patients with refractory metastatic breast carcinoma.

Background: The similarity between the mechanism of action between docetaxel and estramustine generated the hypothesis of synergistic antimicrotubule effects and cytotoxicity when the two agents are combined. In addition, it has been demonstrated that estramustine binds P-glycoprotein in vitro and, thus, may prevent the efflux of taxanes in tumors that over-express P-glycoprotein. To further evaluate the combinations clinical efficacy and safety, a trial was performed in heavily pretreated patients with metastatic breast carcinoma (MBC).

Refractory disease, new horizons and patient-physician relationships.

Understanding the role of chemotherapy for prostate cancer has advanced along two axes, better definition of endpoints, and biologic understanding of disease targets. Use of PSA as a surrogate endpoint makes possible the more rational design of phase III trials which will include survival and disease free intervals as an endpoint. Pain control has emerged as an important treatment endpoint through which more cost-effective care can be envisioned.

The novel antimicrotubule agent cryptophycin 52 (LY355703) induces apoptosis via multiple pathways in human prostate cancer cells.

We assessed the ability of cryptophycin 52 (LY355703), a novel antimicrotubule, to induce growth arrest and apoptosis in prostate cancer cell lines and investigated potential molecular mechanisms of death. LNCaP (androgen-dependent) and DU-145 (androgen-independent) cells accumulated in G(2)-M phase of the cell cycle and progressively acquired sub-G(0)-G(1) DNA content after 48 h of exposure to cryptophycin 52 (1-10 pM). Induction of apoptosis was confirmed by DNA ladder formation and detection of cytoplasmic nucleosomes.

Phase I trial of interferon alpha2b and liposome-encapsulated all-trans retinoic acid in the treatment of patients with advanced renal cell carcinoma.

Background: Studies suggest that retinoic acid (RA) can augment the antitumor effects of interferon-based therapy in patients with advanced renal cell carcinoma (RC); however, this benefit has not been achieved convincingly using oral formulations of 13-cis RA and all-trans RA. Liposome-encapsulated all-trans RA (ATRA-IV) has improved pharmacokinetics with increased and prolonged ATRA serum levels compared with oral retinoids.

Methods: Cohorts of 3-6 patients with progressive metastatic RC received a dose of 3 MU interferon alpha2b per day subcutaneously, which was escalated weekly to 5 MU and then to 10 MU, plus ATRA-IV beginning at a dose of 90 mg/m(2) intravenously three times per week (Monday, Wednesday, and Friday), with a planned escalation to a maximum of 140 mg/m(2).

Chemotherapy for androgen-independent prostate cancer.

While men with metastatic prostate cancer frequently show a good initial response to androgen ablation, few options have been available for progressive hormone-refractory prostate cancer, and survival following chemotherapy has not exceeded 9 to 12 months. The combination of prednisone and mitoxantrone has significant palliative effects on bone pain but does not extend survival. The combination of estramustine phosphate (EMP) with the taxanes paclitaxel or docetaxel produces greater than additive cytotoxicity in vivo, and phase I and II studies of taxane-based therapy demonstrate improved survival in hormone-refractory prostate cancer compared to historical controls.

Randomized study of three different doses of suramin administered with a fixed dosing schedule in patients with advanced prostate cancer: results of intergroup 0159, cancer and leukemia group B 9480.

Purpose: To test the hypothesis that the efficacy and toxicity of suramin in the treatment of patients with hormone-refractory prostate cancer was dose dependent.

Patients And Methods: Patients were randomized with equal probability to receive low-, intermediate-, or high-dose suramin (total doses 3.192, 5.

Cure of undifferentiated small cell carcinoma of the urinary bladder with M-VAC chemotherapy.

Small cell carcinoma (SCC) of the urinary bladder is a rare, aggressive malignancy with approximately 135 cases reported in the literature. Treatments have included chemotherapy, radical surgery, radiotherapy, and combinations of these. We present the apparent cure of a 73-year-old man who presented with clinical stage T2 SCC of the urinary bladder.