Symptomatic Hormone-refractory Prostate Cancer Research Articles

External validation of a nomogram predicting survival in men with metastatic hormone-refractory prostate cancer

e16066 Background: Armstrong et al. (Clin Cancer Res. 2007;13:6396–403) recently published a nomogram predicting the probability of survival in patients with hormone-refractory prostate cancer. The initial report showed a predictive accuracy of 0.69. So far, this nomogram was not yet externally validated. We validated this nomogram in a cohort of patients with hormone-refractory prostate cancer participating in five phase II trials. Methods: In our institution, 84 patients received chemotherapy for metastatic symptomatic hormone-refractory prostate cancer from September 1999 to November 2006. Follow-up was stopped in March 2008 and median follow up for all patients was 15.7 month. 75% of patients received docetaxel based chemotherapy. At the time of inclusion, median age was 69.0 years, median PSA was 40ng/ml, 93% had known bone metastases and 19% had visceral metastases. The area under the receiver operating characteristics curve was used to estimate the predictive accuracy of the nomogram and calibration plots were used for comparison between predicted and observed probabilities. Results: Of all patients, median survival was 15.5 month. The nomogram predicted median survival was 19.9 month, overestimating the true survival by roughly 30%. The predictive accuracy of the predictions at 1 year, 2 years and 5 years was 0.76, 0.69 and 0.64, respectively. The calibration plots showed departures from ideal predictions at 1 year (up to 20% of over estimation of true survival) and 5 years ( up to 19% of under estimation of true survival), whereas the predictions at 2 years showed almost perfect calibrations. Conclusions: The Armstrong et al1 nomogram provides accurate survival predictions in patients with hormone-refractory prostate cancer. The current external validation of this nomogram provides evidence that the nomogram might generally be applied to those patients in daily practice. No significant financial relationships to disclose.

Poor result for atrasentan in prostate cancer

Atrasentan, an endothelin-A-receptor antagonist, did not delay in disease progression in men with metastatic hormone-refractory prostate cancer (HRPC), in a phase III randomised trial (Cancer, published online Sept 20, 2007; DOI:10.1002/cncr22996). The European Cancer Conference; Sept 23–27, 2007; Barcelona, SpainThe endothelin-A-receptor antagonist ZD4054 can improve overall survival (OS) in patients with pain-free or mildly symptomatic hormone-refractory prostate cancer (HRPC) who have bone metastases. In a double-blind phase II trial, Nick James (Birmingham, UK) and co-workers randomly assigned 312 patients in a 1:1:1 ratio to two different doses of ZD4054 or to placebo. No significant difference in progression-free survival (PFS) between treatment groups was noted. However, patients assigned ZD4054 has significantly improved OS compared with those assigned placebo (23·5 and 24·5 months vs 17·3 months). Full-Text PDF

The European Cancer Conference; Sept 23–27, 2007; Barcelona, Spain

The endothelin-A-receptor antagonist ZD4054 can improve overall survival (OS) in patients with pain-free or mildly symptomatic hormone-refractory prostate cancer (HRPC) who have bone metastases. In a double-blind phase II trial, Nick James (Birmingham, UK) and co-workers randomly assigned 312 patients in a 1:1:1 ratio to two different doses of ZD4054 or to placebo. No significant difference in progression-free survival (PFS) between treatment groups was noted. However, patients assigned ZD4054 has significantly improved OS compared with those assigned placebo (23·5 and 24·5 months vs 17·3 months). The hazard ratio (HR) versus placebo for patients assigned the higher dose of ZD4054 was 0·65 (95% CI 0·49–0·86; p=0·052) and the corresponding HR for the low-dose group was 0·55 (0·41–0·73; p=0·008). Headaches, peripheral oedema, and nasal congestion occurred in more than 30% of patients assigned ZD4054.

Hormone Refractory Prostate Cancer (Hrpc): Present and Future Approaches of Therapy

The use of particles from micro to nanoscale provides benefits to diverse scientific fields, but because a large percentage of their atoms lie on the surface, nanomaterials could be highly reactive and pose potential risks to humans. Due to their wide range of application, Cobalt nano-particles are of great interest both in industry and in life-science. To date, there are few studies on Co nano-particle toxicology. In this respect, this study aims at evaluating in vitro the potential interference of Co nano-particles on the production of several cytokines (IL-2, IL-4, IL-6, IL-10, IFNgamma and TNFalpha) by PBMCs, comparing their effects to those of Co micro-particles and Co solution (CoCl2). Cells were cultured in Opticell flasks with escalating concentrations (10-5, 10-6 and 10-7 M), of Co nano and micro-particles and CoCl2 or without metal. Cytokines were quantified in the supernatants using a human Th1/Th2 cytokine cytometric bead array. Co micro-particles showed a greater inhibitory effect compared to other Co forms. Its inhibitory activity was detected at all concentrations and towards all cytokines, whereas Co solutions selectively inhibited IL-2, IL-10 and TNF-alpha at maximal concentration. Co nano-particles induced an increase of TNF-alpha and IFN-gamma release and an inhibition of IL-10 and IL-2: a cytokine pattern similar to that detected in the experimental and clinical autoimmunity. On the basis of the obtained data, immune endpoints should be sought in the next series of studies both in vitro and in vivo in subjects exposed to cobalt nano-particles.

Management Strategies for Hormone-Refractory Prostate Cancer

There are a range of therapeutic options for the management of prostate cancer in patients in whom the disease has progressed despite hormone-deprivation therapy. These include second- and third-line hormone maneuvers, cytotoxic chemotherapy, systemic isotopes, bisphosphonates, biologically targeted agents, and palliative treatments such as external-beam radiotherapy. Optimal care requires clarity of purpose and experienced judgment of potential benefits and risks. The field has grown rapidly, and there is recent evidence of significant benefit from chemotherapy, in terms of both prolongation of life and symptom relief, using a regimen well tolerated in relatively elderly and infirm patients. The combination of docetaxel with prednisone has a clear role in patients with symptomatic hormone-refractory prostate cancer; however, a number of controversies exist, for example, the dose, cycle interval, duration of treatment, whether to combine docetaxel with other cytotoxic or biologically targeted agents, and its role in patients with asymptomatic disease. The overall benefit of bisphosphonate therapy is less clear in prostate cancer than in other malignancies. As our understanding of the biochemical basis of relative androgen-independence grows, development of targeted agents will become more appropriate and efficient. This is an active field of research and currently there are trials addressing both new cytotoxic agents, such as satraplatin and the epothilones, and a range of biological targets, including the vitamin D receptor, the endothelin A receptor, an augmented prostatic acid phosphatase antigen, as well as tumor angiogenesis.

Hormone-refractory prostate cancer: Issues, approaches, and recommendations

This supplement to Urology offers urologists, medical oncologists, and other healthcare professionals a concise update on current and investigational therapies for asymptomatic (ie, biochemical progression only) as well as symptomatic hormone-refractory prostate cancer (HRPC). It is the product of a roundtable meeting held in Chicago, Illinois, on September 18, 2004, which was attended by a small invited group of internationally recognized prostate cancer specialists from the fields of medical oncology, urology, and endocrinology. The purpose of the roundtable discussion, and of the resulting monograph, was to review and analyze the most recent clinical trial findings and to examine their implications for the current management of and for future research in HRPC.

New standards in the chemotherapy of metastatic hormone-refractory prostate cancer

Hormone-refractory prostate cancer (HRPC) is a major issue in Western countries and the second leading cause of cancer death in North American men. In the prostate-specific antigen era, most HRPCs are currently diagnosed in asymptomatic patients based on biochemical failure, with increasing demand for active treatment. Until recently, chemotherapy for HRPC patients was not considered a standard of care due to the absence of clear data evidencing an overall survival benefit. In fact, few Phase III studies conducted in the 1980s and early 1990s had documented a superiority over corticosteroids alone in terms of biochemical response (declines in serum prostate-specific antigen levels) and quality of life, but not survival. Due to their impact on pain control, mitoxantrone and prednisone were long considered the best regimen for symptomatic HRPC patients. In recent years, more chemotherapeutic agents have been tested, among which the microtubule inhibitors (vinca alkaloids and taxanes) have obtained the most promising results in Phase II trials and have entered Phase III testing. Two well-designed randomized trials have changed this scenario. Both compared docetaxel (with or without estramustine) against mitoxantrone and prednisone, and demonstrated a significant advantage not only in terms of response, pain control and quality of life, but also in terms of overall survival. Which patients need to be treated, the regimen of choice and duration of chemotherapy will be the next questions to be answered in the coming years in the field of HRPC, along with the role of new signal transduction inhibitors and other targeted therapies.

Mechanism of action of mitoxantrone

Mitoxantrone, a synthetic anthracenedione, was developed in the 1980s as a doxorubicin analogue in a program to find a cytotoxic agent with decreased cardiotoxicity compared with doxorubicin. It was approved by the FDA in 1987 for the treatment of adult acute myeloid leukemia and in 1996 for symptomatic hormone-refractory prostate cancer. In 2000, mitoxantrone was approved by the FDA for the treatment of worsening relapsing-remitting multiple sclerosis (MS), secondary progressive MS, and progressive-relapsing MS. Mitoxantrone is taken up rapidly by tissues, from which it is released slowly, and the terminal half-life ranges from 8.9 hours to 9 days. The highest concentrations of the drug are typically found in the thyroid, liver, and heart, and the drug persists in the body for as long as 272 days. Mitoxantrone is effective in reducing disease progression through a variety of different mechanisms of action. For example, it suppresses the proliferation of T cells, B cells, and macrophages. It impairs antigen presentation and decreases the secretion of proinflammatory cytokines. Mitoxantrone enhances T-cell suppressor function and inhibits B-cell function and antibody production. Finally, it inhibits macrophage-mediated myelin degradation. Compared with interferon betas, mitoxantrone has a broad range of actions and has effects on many different types of immune cells.

Is there a role for chemotherapy in prostate cancer?

There is evidence from randomised-controlled trials that patients with symptomatic hormone-refractory prostate cancer may experience palliative benefit from chemotherapy with mitoxantrone and prednisone. This treatment is well tolerated, even by elderly patients, although the cumulative dose of mitoxantrone is limited by cardiotoxicity. Treatment with docetaxel or paclitaxel, with or without estramustine, appears to convey higher rates of prostate-specific antigen response in phase II trials, but is more toxic. Large phase III trials comparing docetaxel with mitoxantrone have completed accrual. There is no role for chemotherapy in earlier stages of disease except in the context of a well-designed clinical trial.

Phase II Study of Repeated Single 24-Hour Infusion of Low-Dose 5-Fluorouracil for Palliation in Symptomatic Hormone-Refractory Prostate Cancer

Background: To assess the efficacy and toxicity of repeated single 24-hour infusion of low-dose 5-fluorouracil for symptomatic hormone-refractory prostate cancer using relevant endpoints of palliation and biological response. Patients and Methods: 25 patients with histologically confirmed prostatic adenocarcinoma and symptomatic progressive disease despite one or several hormonal treatments and chemotherapy were included in the study. Treatment consisted of a single 24-hour infusion of 500 mg/m² 5-fluorouracil (5-FU) to be repeated on day 21. This regimen was continued until either progression or serious toxicity occurred. Response was assessed by serial measurements of serum prostate-specific antigen (PSA) as well as by health-related quality-of-life instruments (EORTC QLQ-C30 and McGill-Melzack Present Pain Intensity Scale) every 3 weeks. In 10 patients with bidimensionally measurable metastases, objective responses were assessed every 3 months. Results: A mean number of four courses of repeated single 24-hour infusion of 5-FU was administered (range 2–6). Toxicity was absent or mild, and no patient had to be withdrawn from therapy. All patients required analgesics prior to treatment and only 3 patients experienced a significant reduction in pain for 9 weeks, the remaining patients experienced no deterioration for a mean duration of 12 weeks (6–18 weeks). Five patients (20%) demonstrated a biological response of a 50% or greater decrease in PSA from baseline, including 2 (12%) with a 75% or greater decline for 10 weeks (range 6–16 weeks). One partial remission was observed among 10 patients with measurable lesions lasting 12 weeks; 4 patients had stable disease with a mean duration of 12 weeks. Mean survival time from the onset of treatment with 5-FU was 7 months (2–12 months). Conclusions: Though less toxic than other 5-FU regimens, repeated single low-dose 24-hour infusion is of no significant benefit in patients with symptomatic hormone-refractory prostate cancer.

Chemotherapy for prostate cancer

Androgen deprivation therapy remains the mainstay of therapy for patients with advanced prostate cancer and for selected patients with localized prostate cancer. Androgen deprivation therapy is the model of target-based therapies in this disease. Although it is clear that other target-based therapies need to be developed, cytotoxic chemotherapy is emerging as an effective form of treatment for men with prostate cancer. The early studies combining mitoxantrone plus a corticosteroid demonstrated that chemotherapy could be given to men with symptomatic hormone-refractory prostate cancer with minimal toxicity, and significant palliation could be provided. Since then, it has been recognized that estramustine, when combined with a variety of microtubular inhibitors, is very active in hormone-refractory prostate cancer. Doublets combining estramustine plus a taxane seem to be the most active. Although it appears that estramustine may add some activity to taxanes, the mechanism of its activity is uncertain, and its overall value is similarly questioned, particularly in light of its significant toxicity. Regimens that omit estramustine are being explored (ie, either taxane alone or taxane plus biologic agents). In addition, triplet therapy (combining estramustine plus a taxane plus a third drug, such as carboplatin or etoposide) is being explored. Finally, the utility of chemotherapy is beginning to be explored in the context of earlier disease in the neoadjuvant, adjuvant, or serologically relapsing group of patients. Data from these studies are just beginning to be gathered.

Calcitriol (1,25-Dihydroxycholecalciferol) Potentiates Activity of Mitoxantrone/Dexamethasone in an Androgen Independent Prostate Cancer Model

Mitoxantrone combined with glucocorticoids is widely used for androgen independent prostate cancer. It is well tolerated, reduces prostate specific antigen, diminishes pain and improves quality of life. Calcitriol (1,25-dihydroxycholecalciferol) inhibits proliferation, modulates cell cycle progression, induces apoptosis and potentiates the cytotoxic effects of a number of agents. Glucocorticoids potentiate the antitumor effects of calcitriol and blunt calcitriol induced hypercalcemia. Therefore, we investigated the effect of calcitriol on the antitumor efficacy of mitoxantrone and dexamethasone or mitoxantrone/dexamethasone in the PC-3 androgen independent prostate cancer model. We treated PC-3 cells in vitro with various concentrations of mitoxantrone/dexamethasone with and without calcitriol, and assessed growth inhibition by crystal violet assays. We similarly treated mice bearing PC-3 xenografts and performed excision clonogenic assays and tumor outgrowth studies to assess antitumor activity. Calcitriol significantly increased mitoxantrone/dexamethasone mediated growth inhibition in PC-3 cells (p <0.05). Median dose effect analysis indicated that calcitriol is synergistic with mitoxantrone. Adding calcitriol to mitoxantrone/dexamethasone significantly reduced the surviving fraction per gm. tumor compared with mitoxantrone/dexamethasone or untreated controls (p <0.03). Calcitriol plus mitoxantrone/dexamethasone also caused significantly greater tumor regression in PC-3 xenografts compared with treatment with mitoxantrone/dexamethasone or untreated controls (p <0.02). These preclinical data demonstrate that calcitriol increases the antitumor activity of mitoxantrone/dexamethasone in the PC-3 model system. This combination may be efficacious for prostate cancer.

A retrospective analysis of the relationship between changes in serum PSA, palliative response and survival following systemic treatment in a Canadian randomized trial for symptomatic hormone-refractory prostate cancer

To investigate the relationship between changes in serum PSA, palliative response and survival following systemic treatment for symptomatic hormone-refractory prostate cancer (HRPC). A retrospective review of 161 patients, treated with mitoxantrone and prednisone (M + P) (n = 80), or prednisone alone (P) (n = 81) from a Canadian randomized phase III clinical trial. PSA response was defined by > or =50% decline compared to baseline. Palliative response was defined by the primary and secondary endpoints of the trial. All responses were required to be maintained on two visits at least three weeks apart. The Cox proportional hazards model and a landmark analysis (at nine weeks) were used to evaluate survival differences between PSA responders and non-responders. Using an intent-to-treat analysis in which patients with missing PSA data are considered non-responders, 34% of M + P and 11% of P patients achieved a PSA response (P = 0.0001). Nineteen of thirty-six (53%) patients with PSA response and twenty-six of ninety (29%) patients without PSA response achieved a palliative response (P = 0.001 Chi-square test, phi coefficient = 0.28). From the landmark analysis. PSA responders had longer survival than non-responders (P = 0.009). In multivariate analysis, better performance status, higher hemoglobin and PSA response (P < 0.001) predicted for survival, but palliative response did not (P = 0.11). There is significant but imperfect statistical association between PSA response and palliative response. PSA response was associated with longer survival. Patients treated with M + P were more likely to achieve a PSA response and a palliative response than those treated with P.

THE USE OF BISPHOSPHONATE FOR THE PALLIATIVE TREATMENT OF PAINFUL BONE METASTASIS DUE TO HORMONE REFRACTORY PROSTATE CANCER

Hormone refractory prostate cancer is dominated by osseous metastases leading to bone pain and pathological fractures. We assessed the clinical efficacy of bisphosphonate in the management of symptomatic skeletal metastases due to prostate cancer. A total of 85 patients with painful osseous metastases due to hormone refractory prostate cancer were treated with clodronate in an open prospective nonrandomized clinical study. Clodronate was started as an intravenous phase for 8 days at a dose of 300 mg. daily followed by an oral maintenance phase of 1,600 mg. daily. The primary study end point was decreased pain without an increase in analgesic medication for at least 2 consecutive measurements. Secondary end points were decreased analgesics, an improved Karnofsky index and mobility as well as the duration of bisphosphonate action. Decreased pain was documented by a 10-point visual analog scale and consumption of analgesics was documented in a diary. A palliative response with a significant decrease in mean pain score from 7.9 (range 6 to 10) to 2.5 (range 0 to 4) (p <0.001) was achieved in 64 of the 85 patients (75%), 19 (22%) were completely pain-free without further need of analgesics and 45 significantly decreased the daily consumption of analgesics. The mean duration of bisphosphonate action was 9 weeks (range 4 to 22) and mean survival was 12 weeks (range 6 to 22). Improvement in bone pain was paralleled by an improvement in the mean Karnofsky index of 45% (range 30% to 60%) to 70% (range 50% to 80%) at the end of the treatment period. Bisphosphonate treatment of painful osseous metastases due to hormone refractory prostate cancer results in a significant pain decrease and a significant decrease in the daily consumption of analgesics in 75% of patients. Each characteristic is paralleled by an increase in the Karnofsky index, mainly due to better mobility. Bisphosphonate should have a definite role in the palliative management of symptomatic hormone refractory prostate cancer.

PROSTATE SPECIFIC ANTIGEN RESPONSE TO MITOXANTRONE AND PREDNISONE IN PATIENTS WITH REFRACTORY PROSTATE CANCER: PROGNOSTIC FACTORS AND GENERALIZABILITY OF A MULTICENTER TRIAL TO CLINICAL PRACTICE

We determine prostate specific antigen (PSA) response and durability, and prognostic factors associated with response and survival in patients with symptomatic hormone refractory prostate cancer treated with mitoxantrone and prednisone at a single institution. We then compare the results with those of a randomized phase III clinical trial. A retrospective review of all 133 patients treated with mitoxantrone and prednisone at Princess Margaret Hospital since 1994 was performed. PSA response and duration, and overall survival were determined as well as the influence of baseline factors on these outcome parameters. Results were compared to those for patients randomized to receive mitoxantrone and prednisone in the Canadian clinical trial which demonstrated palliative benefit of this regimen. Patients treated after trial closure had shorter survival (p = 0.003) but represented a poorer prognosis cohort. PSA response of the trial and post-trial cases was 34% and 28%, respectively (p = 0.36), and median duration of response was 118 and 175 days or greater, respectively. Factors predictive of PSA response in the non-trial cohort were longer time from diagnosis of prostate cancer (p = 0. 027) and higher baseline PSA (p = 0.013). Factors predictive of increased survival in both groups were younger age (p <0.04), better baseline Eastern Cooperative Oncology Group performance status (p <0. 02), and higher hemoglobin (p </=0.05) and PSA response (p <0.0001). Gleason score was not predictive of response or survival. Although patients treated outside of the trial had poorer prognostic features, rates of PSA response to mitoxantrone and prednisone were comparable. Factors predictive of survival were similar in the 2 cohorts. Results of the randomized trial are generalizable to clinical practice.

Analysis of survival by palliative response in patients with symptomatic hormone refractory prostate cancer

Analysis of survival by palliative response in patients with symptomatic hormone refractory prostate cancer