Liposomal doxorubicin for the treatment of hormone-refractory prostate cancer

There is a pressing need for new agents to treat hormone-refractory prostate cancer (HRPC). Doxorubicin has shown modest activity in this setting, but its use is limited by its toxicities. Liposomal encapsulation of doxorubicin appears to promote enhanced tumor accumulation in some tumor types, and toxicity appears to be reduced. A phase II trial of liposomal doxorubicin was therefore conducted in patients with HRPC. Fourteen patients with progressive HRPC were treated. For the first dose only, patients were randomized to receive either doxorubicin 50 mg/m2 or liposomal doxorubicin 50 mg/m2 in order to evaluate exploratory pharmacokinetics. For all subsequent cycles, all patients received liposomal doxorubicin 50 mg/m2. Response to therapy was assessed with serial measurements of serum prostate-specific antigen (PSA) and sequential imaging studies. All 14 patients were evaluable for response and toxicity. Two patients (14%) had declines in serum PSA of > or = 50%. The first patient had a baseline PSA of 34.7 ng/mL and a nadir of 17.0 ng/mL. The second patient had a baseline PSA of 5580.0 ng/mL and a nadir of 200.7 ng/mL. The latter of these 2 patients had an unambiguous improvement in bone scan and a reduction in pain. Treatment was well tolerated overall. One patient was removed from treatment after the development of a grade 3 infusion reaction with the first cycle of liposomal doxorubicin. Neutropenia was the most common toxicity; in only 1 case was it grade 3, and no cases of grade 4 were seen. Doxorubicin plasma concentrations were best fit by a linear, two-compartment model. Liposomal doxorubicin plasma concentrations were best fit by a linear, one-compartment model. Treatment with liposomal doxorubicin was well tolerated overall. While monotherapy with liposomal doxorubicin has only modest activity in the treatment of HRPC, it may be of interest to study this agent as part of combination chemotherapy.     

State-of-the-art treatment of metastatic hormone-refractory prostate cancer

Initial therapy for advanced prostate cancer includes androgen ablation by surgical or medical castration. Still, nearly all men with metastases will progress to hormone-refractory prostate cancer (HRPC). Current U.S. Food and Drug Administration-approved agents for the treatment of HRPC include mitoxantrone and estramustine, although the vinca alkaloids and the taxanes have shown promising activity in single-agent phase II trials. Combinations of these agents induce a biochemical response in greater than 50% of patients, but the median duration of response is approximately 6 months. Overall survival of patients treated with these combinations is approximately 18-24 months. Studies are ongoing to develop novel therapies that target specific molecular pathways or mechanisms of chemotherapy resistance. Novel agents under development include growth factor receptor inhibitors, antisense oligonucleotides, bisphosphonates, and cell differentiating agents. Evaluation and incorporation of these agents into existing treatment regimens will guide us in the development of more active regimens in the treatment of HRPC.     

激素抗拒性前列腺癌的化疗和新药物治疗

对于雄激素撤除治疗后进展的前列腺癌尚无有效的治疗方法,二线内分泌治疗效果亦不明显。两个大型随机临床试验表明:以多西紫杉醇为基础的化疗能够延长患者的生存期,延缓疾病进展,这为多西紫杉醇联合一些新的生物制剂,巩固长期疗效提供了动力。随着肿瘤疫苗、单克隆抗体、骨靶向药物、反义寡核苷酸、抗血管生成药物和小分子酪氨酸激酶受体抑制剂等的出现,前列腺癌的治疗前景令人振奋。     

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.     

（125）I放射粒子永久性植入治疗激素难治性前列腺癌

目的探讨125I放射粒子永久性植入治疗激素难治性前列腺癌的临床疗效及其价值。方法直肠B超引导下,经会阴穿刺前列腺125I放射粒子植入治疗激素难治性前列腺癌22例,其中3例合并骨转移。结果 22例手术顺利,平均植入125I放射粒子42粒,平均手术时间60分钟,平均住院时间5天,术后随访8-28月,术后3月前列腺缩小,术后短期IPSS评分上升,但3月后开始好转。完全反应16例,部分反应3例,病情稳定3例,PSA无进展生存率100.0%,未发生严重并发症。结论 125I放射粒子植入治疗激素难治性前列腺癌安全、微创、并发症发生率低,疗效肯定、患者生活质量高。     

Androgen-response elements in hormone-refractory prostate cancer: implications for treatment development

Many attempts have been made to derive genetic signatures for progressive prostate cancer for both prognostic and therapeutic purposes. These investigations have resulted in the discovery of many pathways, but the signatures exhibit heterogeneity and restricted reproducibility. A thorough and disciplined analysis of genes with androgen-response elements that are expressed in progressive, castration-resistant prostate cancer is an integral step towards the development of new therapeutic or diagnostic targets. We discuss the effects of bona-fide downstream targets of the androgen receptor on cellular proliferation, evasion of apoptosis, and angiogenesis, and consider the clinical potential of these targets.     

Oral vinorelbine as first line chemotherapy in unfit elderly patients with hormone-refractory prostate cancer

Hormone-refractory prostate cancer (HRPC) is a rapidly progressive disease which produces considerable morbidity and involves mostly men over 70, often comorbid and with poor tolerance to chemotherapy. Low-toxicity chemotherapy is a reasonable option in this setting. Vinorelbine and a corticosteroid show activity and clinical benefit responses in HRPC. An oral regimen is preferable for elderly patients. This study aimed to evaluate safety, prostate-specific antigen (PSA) response, clinical benefit and progression-free survival in chemonaive elderly HRPC patients. 33 men, median age 78.2, were treated with oral vinorelbine 60 mg/m2 days 1 and 8 every 3 weeks, escalable to 80 mg/m2 after the first cycle, and prednisone 5 mg b.i.d. The main toxicity was hematopoietic (mild at 60 mg/m2 and moderate at 80 mg/m2). Of 27 evaluable patients, 9 (33%) had PSA responses and 9 had clinical benefit, PSA-correlated in 5 cases (56%). Median progression-free survival was 13.4 weeks, median overall survival 45 weeks. Oral vinorelbine plus prednisone is safe and has moderate activity, with biochemical and clinical responses in about one-third of patients and could be an option in unfit elderly HRPC patients.     

Clinical outcome of patients with docetaxel-resistant hormone-refractory prostate cancer treated with second-line cyclophosphamide-based metronomic chemotherapy

For patients with docetaxel-resistant hormone-refractory prostate cancer (HRPC) no standard chemotherapeutic treatment exists. In this study, we evaluate the efficacy of cyclophosphamide (CP)-based metronomic chemotherapy in this patient population. Patients with metastatic HRPC with disease progression under docetaxel-based chemotherapy were eligible. The primary endpoint was prostate-specific antigen (PSA) response. Secondary endpoints were survival and toxicity. Low-dose CP (50 mg/d) and dexamethasone (1 mg/d) were administered orally in a metronomic manner. Treatment was continued until disease progression or intolerable side effects occurred. Seventeen patients were enrolled in this study. The median follow-up was 12 weeks (range: 4–60). Median age was 68 years (range: 42–85). Median PSA at study entry was 134 ng/ml (range: 46.0–6554). Nine patients had a PSA response (median 44.4%), four patients ≥50% and five patients <50%. Eight patients had a PSA progression. Overall survival was 24 months. Five patients reported a decrease in bone pain after 4 weeks' treatment. No grade 3 and 4 toxicities were noted. In this study, low-dose metronomically administered CP demonstrated efficacy as a second-line treatment in patients with docetaxel-resistant HRPC. The treatment was well tolerated and almost without toxicity. Further advantages of low-dose CP were its convenient oral administration, dosing schedule, low cost, and low-toxicity profile. These attributes in combination with immunoregulatory and antiangiogenic potentials make CP also a prime candidate for combination with other treatment regimens.     

冷冻治疗激素难治性前列腺癌

目的探讨经会阴冷冻治疗激素难治性前列腺癌的临床价值。方法回顾分析18例经内分泌治疗后确认进展为激素难治性前列腺癌患者行在直肠超声引导下经会阴冷冻治疗的临床资料,对手术安全性及疗效进行分析总结。结果 18例患者手术均顺利,平均手术时间98min,术中无明显出血。术后平均住院5天。术后随访10～38个月,平均21个月。完全反应(CR)4例,部分反应(PR)8例,病情稳定(SD)3例,病情恶化(PD)3例。总有效率(CR+PR)66.7%,PSA无进展生存率83.3%(15/18)。未发生严重并发症。结论经会阴冷冻治疗激素难治性前列腺癌安全、微创,并发症低,近期     

Phase II trial evaluating a docetaxel-capecitabine combination as treatment for hormone-refractory prostate cancer

BACKGROUND: Docetaxel is a well-recognized drug in patients with hormone-refractory prostate cancer (HRPC), either alone or combined with estramustine. In this indication, a Phase II trial was conducted investigating a docetaxel-capecitabine combination. METHODS: Forty-six patients presenting with documented HRPC were enrolled in the study. The treatment regimen consisted of docetaxel (D) at a dose of 35 mg /m2/week (intravenously, 3 consecutive weeks) plus oral capecitabine (C) at a dose of 625 mg/m2 twice daily (Days 5-18) every 28 days for 4 cycles. The primary endpoint was the biological response defined as a reduction in prostate-specific antigen (PSA) level > or =50%. Secondary endpoints were overall survival, safety, and quality of life. RESULTS: Thirty of 44 assessable patients (68.2%) achieved a biological response, 14 of whom (31.8%) normalized their PSA value. The median overall survival time was 17.7 months (95% confidence interval, 15.8 to not reached). Four treatment cycles were completed by 87% of the patients. Hematologic toxicity was mild. The main Grade 3-4 toxicities were cutaneous toxicity (13.1%) and changes in nails (6.5%). Physical functioning and role scales were higher before treatment (P = .02 and P = .003, respectively), fatigue and diarrhea were more frequent during and after treatment (P = .0003 and P = .03, respectively), and pain was lower during and after treatment. CONCLUSIONS: The results of the current study demonstrated the high efficacy of the DC combination in patients with HRPC, and the associated good tolerability. This combination offers a new alternative to the docetaxel-estramustine combination. Further randomized trials are warranted.