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At least 847 records · Page 47Linked to original sources
PubMed2003

Estimating survival benefit in castrate metastatic prostate cancer: decision making in proceeding to a definitive phase III trial.

OBJECTIVES: In designing a Phase II trial, the acceptable clinical activity region for a new therapy is often developed using data from historically treated patients. This region incorrectly ignores the variability of this estimate, because the efficacy of the prior treatment lies somewhere around the estimate. The size of this interval is dependent on the sample size used. This report illustrates the use of a published method that accounts for this uncertainty and aids in the decision to proceed to a definitive trial. METHODS: A historical data set of low-risk patients with progressive castrate metastatic prostate cancer and a group of similar patients treated in a Phase II chemotherapy trial were used. The 1-year Kaplan-Meier estimate of survival was obtained for both. This approach uses the 75% upper confidence bound of the 1-year survival probability from the historical data set to define the lower limit of acceptable clinical activity. Use of this bound makes the approach more conservative, and hence the decision to proceed to a Phase III trial more difficult. RESULTS: In the low-risk historical patients, the 1-year Kaplan-Meier estimate of survival was 66.4% (75% upper confidence bound 71.0%). In the Phase II patients, the 1-year Kaplan-Meier estimate of survival was 89.5% (95% lower confidence bound 78.2%). CONCLUSIONS: A hypothesis test using the 75% upper confidence bound to define the lower limit of acceptable clinical activity demonstrates that the 1-year survival probability on Taxol/estramustine/carboplatin is greater than that of the historical population, and hence should be taken into a definitive trial. The design provides investigators increased confidence in making this decision.

Androgen Antagonists↗
PubMed1998

European Organization for Research and Treatment of Cancer (EORTC) prostate cancer trials, 1976-1996.

The Genito-Urinary Tract Cancer Cooperative Group (GU Group) is one of the 18 European Organization for Research and Treatment of Cancer (EORTC) cooperative groups. It was established as a nonprofit organization in 1976 with the aim of conducting phase II and phase III clinical trials. Its membership includes urologists, oncologists, radiotherapists, and endocrinologists that work in close collaboration with its five data managers and one statistician in the EORTC Data Center. Eight subcommittees meet independently to plan and to monitor urological trials and to design programs on quality of life and quality control. In the past 20 years, 3,500 prostate cancer patients have been recruited in 16 phase III trials in untreated and advanced disease and in seven phase II trials in hormone-refractory, metastatic disease. This vast experience led the EORTC GU Group to be involved in the development of response and progression criteria, as well as the validation of prognostic factors, quality of life questionnaires, and basic expertise on the design and analysis of prostate cancer trials, including the meta-analysis of the trials with maximal androgen blockade. The conclusions drawn out of this large pool of experience show the complexity of the clinical research questions. Global collaboration and megatrials with the development of surrogate endpoints and the emphasis on quality of life may prove to be as important as the sacred overall survival endpoint.

Antibiotics, Antineoplastic↗
PubMed1999

Chemotherapy for hormone refractory prostate cancer.

New combinations have been developed that show significant activity in therapy for hormone refractory prostate cancer. Several of these are designed to address specific cellular targets unique to prostate cancer. To date, the major benefits of these therapies have been palliative in nature, resulting in an improvement in quality of life, particularly with the combination of mitoxantrone and prednisone. None of these agents or regimens have been shown to affect survival significantly, and none can be considered to be standard therapy for this disease. Nonetheless, the success of these regimens in inducing response has challenged the skepticism concerning the appropriateness of chemotherapy for patients with advanced prostate cancer. The ability to slow and even reverse the growth of far advanced disease raises the possibility that the application of these regimens earlier in the course of the disease will have a more significant impact on the morbidity and, in the long run, on the mortality of prostate cancer. It is hoped that the enrollment of patients into properly designed clinical trials of new agents and combinations will result in the development of therapy with proven efficacy in the near future.

Anthracyclines↗
PubMed2001

Paclitaxel and docetaxel in prostate cancer.

Although their ultimate value in prostate cancer therapy remains to be defined in randomized trials, docetaxel and paclitaxel are active agents in HRPC. Combination therapies using either of these taxanes plus oral EMP show reproducible antitumor activity that appears to be greater and more durable than that of single-agent treatment. Although the optimal combination and schedule have not been determined, weekly paclitaxel and EMP and docetaxel given every 3 weeks or by weekly infusion with EMP are useful treatment options for patients with progressive HRPC. The gastrointestinal toxicity of EMP has been reduced by intermittent rather than continuous administration, and other toxicities may be reduced further by use of intravenous EMP. Although there has been progress, the median time to progression of 5 to 6 months for current taxane-based therapies suggests that they will not have major impact on overall survival for patients with HRPC. Greater benefit may be possible earlier in the course of prostate cancer, and the activity of the taxane-EMP combinations is sufficient to justify clinical trials of adjuvant or neoadjuvant chemotherapy for selected groups of patients with locally advanced and poor-prognosis tumors. Armed with many new molecularly targeted agents that may interact favorably with taxanes, it should be possible to build on current antimicrotubule regimens to improve activity in HRPC. Taxane-EMP combinations provide a platform on which to test additional agents that may enhance the apoptotic response or circumvent cellular stress adaptations that confer drug resistance. Further elucidation of signaling pathways that regulate microtubule dynamics and programmed cell death after exposure to microtubule inhibitors would provide a more rational guide for integrating specific inhibitors of signal transduction with current taxane-based therapies. Pharmacokinetic and pharmacodynamic studies will play a key role in the development of future taxane-based therapies for prostate cancer.

Adenocarcinoma↗
PubMedDate not supplied

High-risk localized prostate cancer: primary surgery and adjuvant therapy.

High risk localized prostate cancer includes patients with palpable disease outside the capsule (clinical stage T3) as well as those with apparently localized disease but with adverse prognostic factors such as Gleason 8-10 tumors or very extensive disease on biopsy. The goals of therapy for these patients are to achieve both long-term local control and to remain free of metastatic disease. The ideal treatment to achieve these goals is unknown. We present a review of the outcome of contemporary reported series of such patients treated with primary radical prostatectomy, with or without neoadjuvant or adjuvant therapies. Over 80% of the patients overall achieved a 5-year disease-specific survival, though well under 50% have undetectable prostate specific antigen at that time point. We also review what is known about the choice and timing of adjuvant therapies, and describe current cooperative group studies underway to answer some of these questions.

Adenocarcinoma↗
PubMedDate not supplied

Neoadjuvant therapy before radical prostatectomy in high-risk localized prostate cancer: defining appropriate endpoints.

High-risk localized prostate cancer remains a vexing problem for clinicians. Definitive local treatments such as surgery and radiation therapy cure only a minority of these patients. As a result, efforts are being made to reduce the risk of recurrence by using chemotherapy and new agents before, during or after definitive local therapy. Neoadjuvant androgen deprivation therapy has yielded disappointing results when combined with surgery. Chemotherapy in the management of localized disease is evolving, and preliminary studies are just now being completed. Although these agents have established activity and acceptable toxicity in the hormone-refractory setting, more extensive use of them in patients with androgen-dependent disease will require data from randomized studies to determine overall efficacy. New molecular-targeted therapies are promising and hold the greatest hope that outcomes in early disease may be improved with early use of systemic therapy. The neoadjuvant surgical model also has promise in assessing the activity of new drugs, because it provides a means to determine molecular effects of specific agents, along with standard pathologic and clinical parameters of efficacy.

Adenocarcinoma↗
PubMed1991

Flow cytometric analysis of DNA ploidy and S-phase fraction from prostatic carcinomas: implications for prognosis and response to endocrine therapy.

We analysed ploidy and S-phase fraction (SPF) from 78 paraffin-embedded primary prostatic carcinomas by DNA flow cytometry. DNA aneuploidy and above median (4.2%) SPF were both associated with high tumour grade, large size of prostate and presence of distant metastases. Both aneuploidy and high SPF (greater than 4.2%) indicated short 10-year progression-free (P = 0.01 for ploidy and P = 0.0002 for SPF), overall (P = 0.004 and P less than 0.0001) as well as prostate cancer survival (P = 0.002 and P less than 0.0001). Ten-year overall survival rate was 45% in cases with SPF below 4.2% and 0% in those with higher values, whereas the corresponding prostate cancer-specific survival rates were 80% and 11%, respectively. None of the seven tumours with SPF above 12% showed an objective response to endocrine therapy, whereas 26/49 (52%) of those with lower SPF values responded (P = 0.01). DNA ploidy, tumour grade, T-stage or M-stage did not significantly correlate with endocrine responsiveness. SPF was also the best predictor of progression free survival in patients treated hormonally. In conclusion, detection of high SPF in prostate cancer may indicate lack of hormonal responsiveness and poor prognosis.

Aged↗