Suramin treatment in hormone- and chemotherapy-refractory prostate cancer

OBJECTIVES: Suramin, a polysulfonated naphtylurea with anti-growth factor activity, was used in the treatment of metastatic, hormone- and chemotherapy-refractory prostate cancer. Recent studies have proved the effect of suramin on prostate cancer. METHODS: Between March 1990 and January 1994, 27 patients with metastatic prostate cancer were enrolled in this study. Treatment regimen consisted of a loading phase, allowing patients to reach suramin serum levels between 180 and 250 microg/mL using a suramin dose of 1.4 g/m2 at 3-day intervals. Constant suramin serum levels were maintained by a 0.5 to 1-g/m2 dose every 7 to 10 days. Because previous studies showed suramin to have serious toxicity, compromised organ status was excluded by repeated examinations. RESULTS: Six patients did not complete the suramin loading phase because of side effects and were removed from the study. With an average cumulative suramin dose of 14.2 g, 33% of the assessable patients (7 of 21) experienced a more than 50% reduction of prostate-specific antigen (PSA) and/or alkaline phosphatase (AP) serum levels. Mean survival in these suramin-responsive patients was 495 days. Two of these patients experienced a remarkable reduction of metastases in bone scan examinations. Another 48% of the patients (10 of 21) had essentially unchanged AP and PSA serum levels during suramin treatment, indicating stable disease. Mean survival of these patients was 341 days. In 4 patients undergoing suramin treatment, continuous clinical progression of the disease was observed (mean survival 79 days). Toxicity was less or comparable to prior reported studies; the most common side effects were polyneuropathy, allergic skin rash, and vortex keratopathy. CONCLUSIONS: Suramin has limited, but significant, efficacy even in chemotherapy- and hormone-refractory prostate cancer, without serious toxicity.     

Suramin inhibits DNA damage in human prostate cancer cells treated with topoisomerase inhibitors in vitro

Suramin, a highly sulfonated drug, has been reported to be effective against several human malignancies in vitro and in vivo, and currently is undergoing clinical trials against prostate tumors. The biochemical and molecular mechanisms for suramin's antiproliferative activity are not clear. In order to define the biochemical basis for its antitumor activity and to enhance suramin's chemotherapeutic potential while decreasing its toxicity, we have examined interactions of suramin with topoisomerase I and 11 and several clinically active anticancer drugs against the human prostate (PC3 and LNCaP) cancer cell line. While etoposide, m-AMSA, camptothecin, and SN-38 (the active metabolite of CPT-11) were active in killing prostate cells as single agents, combinations of suramin and these agents were antagonistic against these cells. We found that suramin inhibited activities of purified topoisomerase I and II in vitro as measured by relaxation and cleavage assays. Further studies indicated that suramin also inhibited the drug-induced DNA damage in vitro and in isolated nuclei. These findings indicate that combinations of suramin with topoisomerase inhibitors, for example, VP-16, m-AMSA, or CPT, may not be beneficial to patients receiving suramin-containing chemotherapy. © 1993 Wiley-Liss, Inc.

1 This article is a US Government work and, as such, is in the public domain in the United States of America

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Current treatment strategies for advanced prostate cancer

During the past decade, treatment strategies for patients with advanced prostate cancer involving stage IV (T4N0M0, N1M0 or M1) hormone‐sensitive prostate cancer and recurrent prostate cancer after treatment with curative intent, as well as castration‐resistant prostate cancer, have extensively evolved with the introduction and approval of several new agents including sipuleucel‐T, radium‐223, abiraterone, enzalutamide and cabazitaxel, all of which have shown significant improvement on overall survival. The appropriate use of these agents and the proper sequencing of these agents are still not optimized. The results of several recently reported randomized controlled trials and retrospective studies could assist in developing a treatment strategy for advanced prostate cancer. In addition, prospective studies and molecular characterization of tumors to address these issues are ongoing.     

Polymorphism of gonadotropin action： clinical implications

It has recently became apparent that the structural heterogeneity of gonadotropin molecules can contribute to variations of their action in different physiological and pathophysiological conditions. One reason for the structural variations of circulating gonadotropin molecules is the rnicroheterogeneity caused by the variability of glycosylation of individual gonadotropin molecules. The carbohydrate moieties of gonadotropins are important for their intrinsic bioactivity, as reflected by measurement of their bioactivity to immunoreactivity (B/I) ratios. We have reassessed this phenomenon by improved in vitro bioassay and immunoassay methods, and it appears that the intrinsic bioactivity of gonadotropins, in particular of LH, is more constant than previously assumed. Many of the previously documented differences, some even considered diagnostic for certain clinical conditions, have turned out to be methodological artifacts. The first part of this review summarizes our recent findings on the B/I ratios of LH, with special reference to the male. The second part of this review describes a common polymorphism that was recently discovered in the gene of the LH β-subtmit. The variant LHβ allele contains two point mutations, which introduce to LH two amino acid changes and an extra glycosylation site. The LH variant is common world-wide, with carrier frequency varying from 0 to 52% in various ethnic groups. The LH variant differs functionally from wild-type LH, and it seems to predispose its carriers,both men and women, to mild aberrations of reproductive function. It is important for the clinician to be aware of this variant LH form, not detected by all immunoassays, because it may explain some aberrant results of LH measurements in patient samples. (Asian J Androl 2000 Dec;2:241-246)     

Neuroendocrine differentiation in prostate cancer: implications for new treatment modalities

OBJECTIVES: This review aims to provide practising clinicians with the most recent knowledge of the biological nature of prostate cancer (PC) to facilitate investigation of new treatment modalities for patients with PC, especially the hormone-refractory state of the disease. METHODS: Review of the literature using PubMed search and scientific journal publications. RESULTS: Much progress has been made towards an understanding of the development and progression of PC, and the factors which drive the development of androgen independence. Neuroendocrine (NE) cells may provide an intriguing link between NE cell differentiation and tumour progression in PC with the genetically supported formation of androgen-independent clones which regulate the proliferation of neighbouring non-NE-phenotype cancer cells in a paracrine manner by secretion of NE products. Various NE peptides stimulate proliferation of androgen-independent PC through transactivation of the androgen receptors (AR). Therefore, cancerous epithelial cells that increase their responsiveness to NE factors or induce NE cells to release trophic factors may have a survival advantage over their siblings. CONCLUSION: This review shows the need to improve our understanding of the biological nature of PC, especially cancer cells of the NE phenotype and their regulatory products to develop new therapeutic protocols and trials based on NE hormones and their agonists/antagonists.     

Low-dose diethylstilbestrol for the treatment of advanced prostate cancer

ObjectivesThe purpose of this study was to assess the efficacy and safety of low-dose (1 mg) daily diethylstilbestrol (DES) for the treatment of castrate-resistant prostate cancer (CRPC).Materials and methodsA retrospective chart review was performed on patients treated with low-dose DES who had CRPC despite anti-androgen withdrawal. The study population consists of 63 patients treated in the pre- and post-chemotherapy settings based on a database review; 58 had sufficient data for efficacy, all were analyzed for safety.ResultsA PSA decrease of ≥50% was observed in 19 of 49 pre-chemotherapy patients (39%) with a median time to progression (TTP) of 30 weeks (95% CI, 21.9, 68.7). A PSA decrease of <50% was seen in another 16 patients (33%) with a median TTP of 16.4 weeks (95% CI, 13.0, 37.6). Fourteen patients (29%) had progressive disease by PSA testing; their median TTP was 6.9 weeks (95% CI, 5.6, 12.9). Thromboembolic events included 2 patients with DVTs and 1 patient who developed primary fibrinolysis syndrome. Additional adverse events included gynecomastia in 37 of 63 patients (59%). Secondary observations included PSA responses in 3 of 9 patients treated with DES after chemotherapy progression and a high rate of PSA responses in patients re-treated with DES after a drug holiday.ConclusionsLow-dose DES is safe and effective in a modern cohort of men with CRPC despite anti-androgen treatment. Its potential role in the post-chemotherapy setting and the suggestion of efficacy on re-challenge merits additional consideration.     

Optimal treatment of locally advanced prostate cancer

The treatment of clinically locally advanced prostate cancer (cT3–4) is subject to controversies. Patients with lymph node metastases as well as patients with overstaged localized and thus curable disease fall into this category. Radical prostatectomy, external beam radiotherapy and early or deferred hormonal therapy are possible treatment options. Multimodal treatment (i.e., a combination of these options) is frequently used. After radical prostatectomy, Gleason score-adjusted disease-specific survival does not differ meaningfully between the tumor stages pT2 and pT3–4. In the case of lymph node metastases after radical prostatectomy, but not in node-negative disease, adjuvant hormonal treatment seems to improve survival. Adjuvant radiotherapy may improve biochemical and local control in locally advanced prostate cancer, a survival benefit has, however, not yet been proven. External beam radiotherapy alone provides unfavourable survival rates in locally advanced prostate cancer. Adjuvant hormonal treatment may improve outcome in this setting. When no curative treatment is chosen, early hormonal treatment seems to provide modest benefit compared with deferred therapy.     

EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer

ObjectivesOur aim is to present a summary of the 2010 version of the European Association of Urology (EAU) guidelines on the treatment of advanced, relapsing, and castration-resistant prostate cancer (CRPC).MethodsThe working panel performed a literature review of the new data emerging from 2007 to 2010. The guidelines were updated, and the levels of evidence (LEs) and/or grades of recommendation (GR) were added to the text based on a systematic review of the literature, which included a search of online databases and bibliographic reviews.ResultsLuteinising hormone-releasing hormone (LHRH) agonists are the standard of care in metastatic prostate cancer (PCa). Although LHRH antagonists decrease testosterone without any testosterone surge, their clinical benefit remains to be determined. Complete androgen blockade has a small survival benefit of about 5%. Intermittent androgen deprivation (IAD) results in equivalent oncologic efficacy when compared with continuous androgen-deprivation therapy (ADT) in well-selected populations. In locally advanced and metastatic PCa, early ADT does not result in a significant survival advantage when compared with delayed ADT. Relapse after local therapy is defined by prostate-specific antigen (PSA) values > 0.2 ng/ml following radical prostatectomy (RP) and > 2 ng/ml above the nadir after radiation therapy (RT). Therapy for PSA relapse after RP includes salvage RT at PSA levels < 0.5 ng/ml and salvage RP or cryosurgical ablation of the prostate in radiation failures. Endorectal magnetic resonance imaging and 11C-choline positron emission tomography/computed tomography (CT) are of limited importance if the PSA is < 2.5 ng/ml; bone scans and CT can be omitted unless PSA is >20 ng/ml. Follow-up after ADT should include screening for the metabolic syndrome and an analysis of PSA and testosterone levels. Treatment of castration-resistant prostate cancer (CRPC) includes second-line hormonal therapy, novel agents, and chemotherapy with docetaxel at 75 mg/m² every 3 wk. Cabazitaxel as a second-line therapy for relapse after docetaxel might become a future option. Zoledronic acid and denusomab can be used in men with CRPC and osseous metastases to prevent skeletal-related complications.ConclusionThe knowledge in the field of advanced, metastatic, and CRPC is rapidly changing. These EAU guidelines on PCa summarise the most recent findings and put them into clinical practice. A full version is available at the EAU office or online at www.uroweb.org.     

局部进展期前列腺癌的治疗进展

局部进展期前列腺癌是介于局限型和进展型病变之间的高危前列腺癌,以易发生局部、远处转移及术后复发为特点.通常认为单一治疗手段对该期病变难以奏效,以放疗辅助内分泌治疗为代表的综合治疗被认为是标准治疗方案.目前针对局部进展期前列腺癌的各项临床试验已经展开,新治疗方案也不断问世.本文对各种治疗方法作一总结和比较.     

MRC study: when to commence treatment in advanced prostate cancer

No abstract     

Danazol treatment of advanced prostate cancer: clinical and hormonal effects

Danazol was administered to 19 patients with advanced prostate cancer. These patients were treated for periods ranging from 3 days to 18 weeks. There were no objective remissions, but three patients (15.8%) had objectively stable disease (N.P.C.P. criteria) with complete pain control for periods ranging 15-18 weeks. Seven patients experienced tumor flare reactions, one requiring withdrawal of treatment and one resulting in rapid clinical deterioration and death. Four other patients died within 3 weeks and, although they were already in the terminal phase of disease when treatment commenced, it is possible that the deaths were treatment related. This study indicates that danazol has only limited activity in the treatment of advanced prostate cancer and is associated with a high incidence of tumor flare reactions with the risk of rapid clinical deterioration.     

间歇性雄激素阻断治疗晚期前列腺癌效果观察

目的 评价间歇性雄激素阻断治疗晚期前列腺癌的可行性及优点.方法 选取晚期前列腺癌患者59例,随机分为2组.给予间歇性雄激素阻断治疗30例(A组),给予持续雄激素阻断治疗29例(B组),观察两组患者的疾病进展及治疗期间副反应的发生情况,比较两种方法的治疗效果.结果 A组患者平均随访26个月,B组患者平均随访27个月,两组患者疾病进展情况未见明显差异.A组患者副反应低于B组患者且能在治疗间歇期得到缓解.结论 间歇性雄激素阻断治疗方法可行,能够减少患者治疗的副反应,提高患者生活质量.     

Locally advanced prostate cancer: a population-based study of treatment patterns

Study Type – Therapy (practice patterns) Level of Evidence 2b What's known on the subject? and What does the study add? The treatment of locally advanced prostate cancer varies widely even though there is level one evidence supporting the use of multimodality therapy as compared with monotherapy. This study defines treatment patterns of locally advanced prostate cancer within the United States and identifies predicators of who receives multimodality therapy rather than monotherapy.

OBJECTIVE

• ? To identify treatment patterns and predictors of receiving multimodality therapy in patients with locally advanced prostate cancer (LAPC).

PATIENTS AND METHODS

• ? The cohort comprised patients ≥66 years with clinical stage T3 or T4 non‐metastatic prostate cancer diagnosed between 1998 and 2005 identified from the Surveillance, Epidemiology and End Results (SEER) cancer registry records linked with Medicare claims.
• ? Treatments were classified as radical prostatectomy (RP), radiation therapy (RT) and androgen deprivation therapy (ADT) received within 6 and 24 months of diagnosis.
• ? We assessed trends over time and used multivariable logistic regression to identify predictors of multimodality treatment.

RESULTS

• ? Within the first 6 months of diagnosis, 1060 of 3095 patients (34%) were treated with a combination of RT and ADT, 1486 (48%) received monotherapy (RT alone, ADT alone or RP alone), and 461 (15%) received no active treatment.
• ? The proportion of patients who received RP increased, exceeding 10% in 2005.
• ? Use of combined RT and ADT and use of ADT alone fluctuated throughout the study period.
• ? In all 6% of patients received RT alone in 2005.
• ? Multimodality therapy was less common in patients who were older, African American, unmarried, who lived in the south, and who had co‐morbidities or stage T4 disease.

CONCLUSIONS

• ? Treatment of LAPC varies widely, and treatment patterns shifted during the study period.
• ? The slightly increased use of multimodality therapy since 2003 is encouraging, but further work is needed to increase combination therapy in appropriate patients and to define the role of RP.

     

Brachytherapy for advanced prostate cancer bleeding

Advanced prostate cancer patients frequently deal with intractable prostatic bleeding which is a difficult problem to manage. Intraurethral high-dose rate (HDR) brachytherapy may palliate this condition. Advanced prostate cancer patients with intractable prostatic bleeding were offered brachytherapy with Iridium-192 using a Micro-selectron HDR machine. During a 5-year period, analysis was performed in 23 patients with a median age and Gleason score of 78 years and 9, respectively. Following brachytherapy, haematuria resolved in 19 of the 23 patients and was recurrence free at 6 months. Intraurethral HDR brachytherapy is a potentially effective modality for treating haematuria in patients with advanced prostate cancer.     

Current treatment in high risk and locally advanced prostate cancer

Treatment of locally advanced prostate cancer remains controversial. Treatment options include radical prostatectomy (PR), radiotherapy (RT) and hormonotherapy (HT). A Medline database search with key words "prostate cancer", "locally advanced", "high risk" and "treatment" in articles published during the last 15 years was done. Fifty one out of 329 papers were selected and reviewed. Selection criteria were a minimum of scientific evidence level of IIa, except for some specific level IV reference. Numerous randomized studies show that patients may benefit of a combined therapy with RT and HT. RP has shown its usefulness in selected cases of locally advanced prostate cancer. Results of long follow-up series are similar to those obtained with RT and HT. Furthermore, the possibility of clinical over staging is an argument in favour of RP. We perform an updated revision of every possible choice available in the treatment of these tumours.