Clinical prostate cancer最新文献

Since the advent of prostate-specific antigen testing, most prostate cancers are now detected in an early, organ-confined stage. Because of this, local therapies including radical prostatectomy and irradiation have become more common in the treatment of men with prostate cancer. Nonetheless, relapse of disease remains a major problem. In the past decade, many groups have studied the early use of chemotherapy with or without hormonal therapy after radical prostatectomy, specifically, and found it to be safe. In this article, we will summarize the data for neoadjuvant and adjuvant chemotherapy and chemohormonal therapy in conjunction with radical prostatectomy. We will also highlight more recent clinical trial designs, including a multicenter pilot study of adjuvant docetaxel therapy, which has several important distinctions when compared with previous studies, including the active chemotherapeutic agent docetaxel, better risk-adapted patient accrual, and higher statistical power. Although data for this study are not yet mature, these differences in clinical trial design make such studies in adjuvant chemotherapy for patients with high-risk prostate cancer novel and promising.

Prostate cancer is a leading cause of morbidity and mortality among males. Androgen ablation as initial therapy for advanced prostate cancer provides high response rates but does not cure disease, as nearly all men with metastases will eventually progress to hormone-refractory prostate cancer (HRPC). Present chemotherapy regimens for HRPC can provide palliation and have recently demonstrated an increase in overall survival. Over the past 2 decades, these regimens represent clear advances in the treatment of metastatic prostate cancer but also demonstrate that newer therapies are needed. Studies are ongoing to provide viable alternatives among traditional cytotoxic therapies as well as among novel agents targeting specific molecular pathways. This article reviews some of the newer therapies being developed and evaluated, including the epothilone analogues, human epidermal growth factor receptor pathway inhibitors, angiogenesis inhibitors, and endothelin receptor antagonists.

This study was conducted to determine the similarity of response rates and safety produced by weekly paclitaxel with or without oral estramustine in patients with metastatic hormone-refractory prostate cancer. Between December 1998 and December 1999, 163 patients were randomized to receive 28-day cycles of paclitaxel 100 mg/m² on days 2, 9, and 16 plus estramustine 280 mg orally 3 times a day on days 1-3, 8-10, and 15- 17, or to receive paclitaxel 100 mg/m² alone on days 1, 8, and 15. Objective response was defined as a ≥ 50% decrease in prostate-specific antigen (PSA) maintained for 4 weeks with stable or improved performance status. Response rates included 37 partial responses for paclitaxel/estramustine (47%) and 22 partial responses for paclitaxel (27%; P < 0.01). Median duration of response was 15.1 months for paclitaxel/estramustine and 15.5 months for paclitaxel; median survival was 16.1 months and 13.1 months, respectively (P = 0.049). Common toxicities for both treatments included neutropenia, gastrointestinal events, neuropathy, and asthenia. Thromboembolic events were more frequent in the paclitaxel/estramustine arm (no prophylactic anticoagulants). The rate of PSA decline for paclitaxel/estramustine was almost 2 times that of paclitaxel (47% vs. 27%), with acceptable toxicity. Multivariate analysis of prognostic factors affecting survival was not significant for treatment arm (P = 0.08). Although the incidence of thromboembolic events appeared to be increased in the paclitaxel/estramustine arm, the addition of estramustine was responsible for a 20% increase in the rate of PSA decline. Neither treatment arm had significant impact on quality of life as measured by the Functional Assessment of Cancer Therapy–Prostate quality of life questionnaire. This study produced encouraging data; further studies of paclitaxel/estramustine are recommended.

Radiation therapy (RT) as salvage treatment for a biochemical relapse following prostatectomy has been shown to be of benefit measured by serum prostate-specific antigen (PSA) control. However, identifying a target volume for RT has not been well established in this setting. In this study, the results of postoperative RT delivered to extended fields (EFs), prostatic fossa, and pelvic lymph nodes encompassing at least the obturator lymph nodes are compared with treatment of limited fields (LFs), prostatic fossa only, as salvage treatment for patients with a biochemical relapse. Between 1987 and 1999, 68 patients were referred for postprostatectomy RT. Of these patients, 46 were treated for salvage intent by RT alone without adjuvant hormones, 21 patients were treated to EFs and 25 treated to LFs. All patients were treated using 4-field plans. The mean field sizes measured 15 × 14 cm (AP/PA fields) and 12 × 14 cm LFs for the EFs and 10 × 10 cm (AP/PA fields) and 10 × 10 cm (lateral fields) for the LFs. The mean total doses for the EFs and LFs were 6300 and 6200 cGy, respectively, using 180-cGy daily increments. All patients treated to the EFs received boost doses to the prostatic fossa after 4500 cGy total dose to the pelvis. The 10-year actuarial biochemical diseasefree survival (DFS) rates for the EF and LF groups were 52% and 47%, respectively (P = 0.523). The distant metastasis-free survival (DMFS) rates were 77% and 78% (P = 0.925), and overall survival (OS) rates were 88% and 68% (P = 0.615) for the EF and LF group, respectively. A subset analysis of patients with adverse pathologic features (including tumor-involved surgical margins, lymph node involvement, seminal vesicle involvement, extracapsular extension, and/or perineural invasion) showed biochemical DFS rates of 57% and 44% (P = 0.217) for the EF and LF groups, respectively. The DMFS rates were 84% and 72% (P = 0.423), and OS rates 92% and 61% (P = 0.366) for the EF and LF groups, respectively. For patients with increasing PSA levels after a radical prostatectomy, salvage irradiation is a viable option for biochemical control. Our results suggest that EF radiation with coverage of pelvic lymph nodes shows a trend toward better PSA control in those with adverse pathologic features, although statistical significance was not achieved because of the limited number of patients who satisfied the restricted criteria excluding use of adjuvant hormones.

Shorter androgen receptor gene CAG repeat length has been associated with an increased risk of prostate cancer, an earlier age of onset, and more advanced stage of disease. Studies comparing the distribution of CAG repeat lengths within different populations have reported that racial groups with higher prostate cancer incidence also have shorter CAG repeat lengths. We evaluated CAG repeat length in 685 black men in Louisiana, South Carolina, and the District of Columbia who were participating in prostate cancer screening, comparing the 118 who were diagnosed with prostate cancer with 567 who had normal serum prostate-specific antigen levels and no evidence of cancer on digital rectal examination. The median CAG repeat length was 21 among cases and 19 among controls (P = 0.11). Cases were significantly older than controls, with a median age of 68 years compared with 54 years (P < 0.0001). After adjusting for age, we found no association between prostate cancer risk and CAG repeat length (odds ratio, 1.05; 95% CI, 0.98-1.13; P = 0.16). Dividing CAG repeat lengths into septiles and calculating the odds ratio for each revealed no specific repeat-length range with a significantly elevated or depressed risk of prostate cancer, but a trend test showed a significant association between longer CAG repeat lengths and an elevated risk of prostate cancer (P = 0.02). Neither grade nor stage was associated with CAG repeat length. This study confirms earlier reports that black men have shorter CAG repeat lengths than reported white and Asian populations. We did not find an increased risk of prostate cancer among black men with fewer CAG repeats.

The bispecific antibody (BiAb) anti-CD3 × anti-Her2/neu (Her2Bi), combines Her2/neu targeting with nonmajor histocompatibility complex–restricted cytotoxicity mediated by activated T cells (ATCs). To evaluate this adaptive immunotherapeutic strategy for augmenting antitumor immune response toward hormone-refractory prostate cancer (HRPC), normal donor or patient T cells were activated with anti- CD3, expanded ex vivo in interleukin-2, and then armed with Her2Bi (5-500 ng per million ATCs). In vitro, arming ATCs with Her2Bi increased the percent specific cytotoxicity toward PC-3 prostate adenocarcinoma cells 2-3 fold and increased the secretion of Th₁ cytokines granulocyte-macrophage colony-stimulating factor, tumor necrosis factor–α, and interferon-γ when compared with unarmed ATCs or ATCs armed with an irrelevant BiAb. Her2Bi-armed ATCs administered with PC-3 (Winn Assay) or injected intratumorally prevented development or induced remissions, respectively, of PC-3 tumors in severe combined immunodeficient beige mice. Intravenously administered Her2Bi-armed ATCs localized to PC-3 xenografts mediated cytotoxicity toward tumor cells and produced significant tumor growth delay of PC-3 tumors, but not Her2/neu–negative LS174T colon adenocarcinoma xenografts. By flow cytometry analyses, Her2Biarmed ATCs had a proliferative advantage over unarmed ATCs and persisted in the circulation and tumor tissues longer than unarmed ATCs. These findings suggest that Her2Bi-armed ATC therapy may be an effective, nontoxic, tumor-specific treatment for Her2-positive HRPC.

A number of studies report a high frequency of double primary cancers of the bladder and prostate. The coincidence was as high as 70% for prostate cancers in patients with bladder cancer, and 3.4% for bladder cancers in patients with prostate cancer. Two studies reviewing medical records reported a significant risk of bladder cancer after prostate cancer and of prostate cancer after bladder cancer. Only 1 of 3 cancer registry studies reported a significantly increased risk of prostate cancer after bladder cancer, and 3 of 11 studies reported a significantly increased risk in bladder cancer after prostate cancer. There was an association between DNA repair and N-acetyltransferase polymorphisms and risk of prostate and bladder cancer. These data suggest that these cancers may share a common carcinogenic process or that these patients are particularly susceptible to both cancers. Because of the association between these cancers, patients who are diagnosed with prostate or bladder cancer should be followed closely for the detection of the second urologic malignancy.