Clinical Prostate Cancer

For the last 60 years, hormonal therapy has been the cornerstone of treatment of metastatic prostate cancer. Unfortunately, hormonal therapy is purely palliative and improved systemic therapies are necessary. Monoclonal antibodies (mAbs) have proven valuable in the treatment of several diseases including cancer. mAbs act by focusing an immune response on or by targeting delivery of highly cytotoxic agents to the cancer cells without targeting normal cells. Prostate-specific membrane antigen (PSMA) has been identified as an ideal antigenic target in prostate cancer. PSMA is the most well-established, highly restricted prostate cancer cell surface antigen. It is expressed at high density on the cell membrane of all prostate cancers, and after antibody binding, the PSMA-antibody complex is rapidly internalized along with any payload carried by the antibody. J591 is the first IgG mAb developed to target the extracellular domain of PSMA, and it has been deimmunized (humanized) to allow repeated dosing in patients. Three phase I studies are in progress, two using the β-emitting radiometals yttrium 90 and lutetium 177, and a third using a cytotoxin (DM1) linked to J591. Imaging of patients after they have received radiolabeled J591 demonstrates excellent tumor targeting.

David Lee

Nancy Price

G. Kesava Reddy

Oliver Sartor

Vinay K. Jain

Highlights from the 40th Annual Meeting of the American Society of Clinical Oncology New Orleans, LA June 2004

第40届美国临床肿瘤学会年会亮点 新奥尔良，路易斯安那州 2004年6月

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 x 14 cm (AP/PA fields) and 12 x 14 cm LFs for the EFs and 10 x 10 cm (AP/PA fields) and 10 x 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 disease-free 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.

Brian S. Kim

Ashkan Lashkari

Roy Vongtama

Steve P. Lee

Robert G. Parker

Effect of Pelvic Lymph Node Irradiation in Salvage Therapy for Patients with Prostate Cancer with a Biochemical Relapse Following Radical Prostatectomy

盆腔淋巴结照射对根治性前列腺切除术后生化复发的前列腺癌患者挽救治疗效果的影响

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.

Timothy Gilligan

Judith Manola

Sally P. Weinrich

Judd W. Moul

Philip W. Kantoff

Absence of a Correlation of Androgen Receptor Gene CAG Repeat Length and Prostate Cancer Risk in an African-American Population

非洲裔美国人群体中雄激素受体基因CAG重复长度与前列腺癌风险无相关性

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.

William R. Berry

James W. Hathorn

Shaker R. Dakhil

David M. Loesch

Don V. Jackson

Mary Ann Gregurich

Jennifer K. Newcomb-Fernandez

Lina Asmar

Phase II Randomized Trial of Weekly Paclitaxel with or Without Estramustine Phosphate in Progressive, Metastatic, Hormone-Refractory Prostate Cancer

II期随机试验：在进展性、转移性、激素难治性前列腺癌中，每周紫杉醇联合或不联合雌莫司汀磷酸盐

Epothilones, a new class of cytotoxic agents, have demonstrated activity in non-small-cell lung cancer (NSCLC). This phase II study examined ixabepilone/carboplatin (cohort A) and ixabepilone/carboplatin/bevacizumab (cohort B) as first-line therapy for patients with advanced NSCLC.Patients were enrolled to either cohort A or B at physician discretion and when eligibility met. Eligible patients had newly diagnosed stage III/IV NSCLC, ECOG PS 0–1, adequate organ function, no active CNS metastases, and, in cohort B, bevacizumab treatment criteria. Both cohorts received ixabepilone 30 mg/m2 and carboplatin AUC = 6 IV day 1 every 3-weeks for a maximum of 6 cycles. Patients assigned to cohort B also received bevacizumab 15 mg/kg IV day 1 of each cycle, and could continue single-agent bevacizumab for 6 additional cycles.Eighty-two patients (median age, 63 years; majority stage IV and former smokers) were enrolled from 11/08 to 10/09 (A-42, B-40) and received medians of 4 and 6 cycles, respectively. The ORRs were 29% and 50%. After median follow up of 17.5 months (A) and 15.7 months (B), median progression free survivals were A-5.3 months (95% CI 2.8–8.6) and B-6.7 months (95% CI 5.1–8.4), with median overall survivals of 9.3 months (95% CI 6.4–16.6) 13.2 months (95% CI 8.9-upper limit not reached), respectively. Grade 3/4 toxicity included: anemia (A-10%, B-27%), neutropenia (A-31%, B-48%), thrombocytopenia (A-19%, B-20%), fatigue (A-10%, B-23%), infection (A-5%, B-20%), and hypersensitivity reaction (A-2%, B-5%). There was one treatment-related death, due to hemoptysis in a cohort B patient with squamous histology.Ixabepilone can be safely combined with carboplatin in newly diagnosed patients with advanced NSCLC. The benefits of treatment appear consistent with those achieved with other modern platinum-doublet regimens. The addition of bevacizumab increases toxicities, however, these are largely expected and reversible. The high ORR and OS observed in the bevacizumab-cohort are encouraging, but would require validation in a larger randomized trial of cohort A versus B.

Activity of Epothilone B Analogues Ixabepilone and Patupilone in Hormone-Refractory Prostate Cancer

激素难治性前列腺癌中埃坡霉素B类似物伊沙匹隆和帕妥匹隆的活性

We report a case of orbital metastasis from a neuroendocrine dedifferentiated prostate cancer during progression from hormone-sensitive to hormone refractory stage. A patient receiving androgen deprivation for hormone-sensitive prostate cancer presented with sudden-onset rightsided ptosis and an increasing serum prostate-specific antigen level. Imaging studies revealed a mixed blastic and lytic lesion involving the right orbital wall and the right cavernous sinus. Comparison of the metastatic histology with the original pathology confirmed a histologic change to poorly differentiated prostate adenocarcinoma with neuroendocrine features. Local radiation of the lesion and palliative systemic chemotherapy resulted in marked short-term improvement of all presenting symptoms. Because prostate cancer metastasis involves hematogenous and lymphatic routes, we also evaluated expression of the vascular endothelial growth factor (VEGF) and receptors (VEGFR-1, VEGFR-2, and VEGFR-3) in the metastatic deposit by immunohistochemistry. Strong expression of VEGFR-2 and VEGFR-3 restricted to the malignant epithelium was noted. We recommend a second biopsy of atypical prostate metastasis associated with sudden change to aggressive clinical behavior in order to evaluate for dedifferentiation features before planning appropriate treatment interventions especially in patients who are candidates for systemic chemotherapy.

Suneetha Challagundla

Murat Gokden

Sanjaya Viswamitra

Manish Kohli

Orbital Metastasis from Prostate Cancer: An Atypical Case of Neuroendocrine Dedifferentiation During Progression from Hormone-Sensitive to Refractory Stage

前列腺癌的轨道转移：从激素敏感到难治阶段进展中的神经内分泌去分化非典型病例

Hormone-refractory prostate cancer (HRPC) has modest response rates to second-line estrogenic agents such as diethylstilbestrol and the herbal product PC SPES. Estramustine phosphate (EMP) is a microtubule inhibitory agent with estrogenic properties commonly used in patients with metastatic HRPC. To determine whether previous response to second-line estrogen therapy would predict subsequent response to EMP-based chemotherapy, a retrospective study was conducted.Patients with HRPC previously treated with second-line estrogenic therapy who subsequently received EMP-based chemotherapy were enrolled in a retrospective analysis. The progression of disease or response to treatment was determined with use of standard prostate-specific antigen (PSA) criteria and Response Evaluation Criteria in Solid Tumors.Seventy-eight patients were included in the analysis. Twenty-five patients with disease progression after receiving estrogen therapy received subsequent EMP-based chemotherapy. Overall, initial PSA response to any estrogen therapy was 54%. The overall PSA response to EMP-based chemotherapy was 60%, and the objective response was 36%. The PSA response to subsequent EMP-based chemotherapy was independent of patients having a previous response to estrogen therapy (70% vs. 53%; P = 0.68). The median overall survival for patients receiving estrogenic therapy and subsequent EMP-based chemotherapy was 12.7 months.Previous response to second-line hormonal maneuvers with estrogen therapy does not predict subsequent response to EMP-based chemotherapy.

Jorge A. Garcia

Vivian Weinberg

Eric J. Small

Prior Estrogen Therapy as a Predictor of Response to Subsequent Estramustine-Based Chemotherapy in Patients with Androgen-Independent Prostate Cancer

既往雌激素治疗作为激素非依赖性前列腺癌患者对后续雌莫司汀化疗反应的预测因子

Prostate-specific membrane antigen (PSMA) is a relatively omnipresent molecule with a multiplicity of functions and has been shown to be a reasonable target for immunologic approaches such as vaccines or more directed therapy with radioactively labeled monoclonal antibodies against PSMA. Given the abundance of various glycoprotein and carbohydrate antigens expressed on the surface of prostate cancer cells and cell lines, PSMA stands out as another self-antigen that is not only expressed on cancer cells but also on neovasculature. Although vaccines are varied in their design and target goal, recent technology has afforded researchers the opportunity to induce recruitment of multiple effector cell populations, cytokines, and factors that can elicit cellular and humoral responses. This review serves to present unique approaches in vaccine development that can induce immunologic responsiveness to PSMA with potential impact on disease progression.

Susan F. Slovin

Prostate-Specific Membrane Antigen Vaccines: Naked DNA and Protein Approaches

前列腺特异性膜抗原疫苗：裸DNA与蛋白质方法

Differences in diet have been proposed to be at least partially responsible for the low rate of prostate cancer in Asian populations compared with men in Western countries. One of the compounds that occurs in a greater quantity in the Eastern diet is genistein, an isoflavonoid found in high concentrations in serum after ingestion of soy-rich foods. Extensive molecular studies have been performed to determine its potential health benefits. The mechanism of action of genistein is complex and includes several cellular pathways. In addition to its estrogenic and/or antiestrogenic activities, genistein has been reported to inhibit steroidogenesis and block several protein tyrosine kinases, including epidermal growth factor receptor and src tyrosine kinases. Moreover, it arrests the cell cycle, induces apoptosis, and has antiangiogenic and antimetastatic properties and antioxidant activity. Herein, we review the current literature on the molecular mechanisms of genistein in relation to its effects on prostate cancer cells.

Jasmin Bektic

Roman Guggenberger

Iris E. Eder

Alexandre E. Pelzer

Andreas P. Berger

Georg Bartsch

Helmut Klocker

Molecular Effects of the Isoflavonoid Genistein in Prostate Cancer

异黄酮染料木素在前列腺癌中的分子效应

Structural studies of topoisomerase-fluoroquinolone-DNA ternary complexes revealed a cavity between the quinolone N-1 position and the active site tyrosine. Fluoroquinolone derivatives having positively charged or aromatic moieties extended from the N-1 position were designed to probe for binding contacts with the phosphotyrosine residue in ternary complex. While alkylamine, alkylphthalimide, and alkylphenyl groups introduced at the N-1 position afforded derivatives that maintained modest inhibition of the supercoiling activity of DNA gyrase, none retained ability to poison DNA gyrase. Thus, the addition of a large and/or long moiety at the N-1 position disrupts ternary complex formation, and retained ability to inhibit supercoiling is likely through interference with the strand breakage reaction. Two derivatives were found to possess inhibitory effects on the decatenation activity of human topoisomerase II.

Preeta Tyagi

Eric Nadler

Arif Hussain

Potential Role of Inhibiting the Vascular Endothelial Growth Factor Pathway in Advanced Prostate Cancer

抑制血管内皮生长因子通路在晚期前列腺癌中的潜在作用

Publication Information	Publisher: Cancer Information Group, LP，Publishing cycle: ，Journal Type: journal，Open Access Journals: No
Basic data	Year of publication: 2002，Proportion of original research papers: ，Self Citation Rate:， Gold OA Rate:

Clinical Prostate Cancer

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