Novel approaches to treating the asymptomatic hormone-refractory prostate cancer patient

For >50 years, the standard treatment for advanced prostate cancer has been hormonal therapy. However, all such treated patients eventually develop disease refractory to androgen suppression as manifested by increasing prostate-specific antigen (PSA) levels, progressive disease on radiographic imaging, and ultimately, symptomatic deterioration. Historical perceptions that treatment of hormone-refractory prostate cancer was a largely futile venture have faded over the past decade with the advances in new therapeutic strategies. With the use of PSA values to follow the progress of patients after definitive therapy, physicians are seeing more patients who have failed hormonal therapy yet have no symptoms from their disease. There are standard therapies available for patients who require palliation for symptoms, but there is no consensus on treatment for asymptomatic patients. To date, there has been no definitive increase in survival with any therapy in this group of patients. In addition, several novel drugs have advanced through preclinical testing into early clinical trials. It is these drugs--alone or in combination--that are designed to target strategic tumor pathways in these patients. This article will review a selection of agents that may be potentially useful in this population.     

Hormonal prevention of prostate cancer

Prostate cancer is disease in which the mortality rate is highly variable among populations. An increasing risk with migratory changes suggests that some environmental factor or factors influence prostate cancer risk. It is well established that the prostate is hormonally influenced. Carcinogenesis is a process of malignant transformation evolving over time, involving cellular growth and division. There is evidence suggesting that androgenic influences over a period time encourages the process of prostate carcinogenesis. Studies of prostate biology support the concept that dihydrotestosterone is the principal androgen responsible for both normal and hyperplastic growth of the prostate gland. It may be that androgen causes prostate carcinogenesis. Suppression of dihydrotestosterone synthesis may inhibit carcinogenic transformation. Some preclinical and clinical observations support this hypothesis. A placebo controlled randomized trial using finasteride, an inhibitor of 5-alpha-reductase, the enzyme that converts testosterone to dihydrotestosterone, is ongoing. The endpoint of this trial is reduction of prostate cancer incidence.     

前列腺癌内分泌治疗的合理选择

自从1941年首次报道以来，前列腺癌的内分泌治疗即在临床上得到广泛应用。经过长期的观察和研究，目前其适用范围已不仅仅局限于对晚期患者的缓解治疗，还包括对早期患者根治术前的新辅助治疗、术后的辅助治疗以及对治愈性治疗后生化复发患者的治疗等。内分泌治疗本身并无治愈效果，甚至其能否延长患者寿命也没有定论，因此对前列腺癌患者选择内分泌治疗时，必须权衡不同治疗方式的利弊，以及对患者生活质量可能造成的影响，方可作出合理决策。     

Hormonal predictors of prostate cancer

INTRODUCTION: Androgens are necessary for the development and functioning of the prostate gland. The association of serum testosterone and pituitary hormone levels with prostate cancer development is not completely understood. In this clinical study, we evaluated the role of serum testosterone, free testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in predicting prostate cancer risk in patients who had transrectal ultrasonography-guided prostate biopsy with the suspicion of prostate cancer. MATERIAL AND METHODS: A total of 211 patients who were selected to undergo prostatic biopsy due to abnormal digital rectal examination and/or a serum prostate-specific antigen (PSA) level >2.5 ng/ml were included in the study. The patient characteristics of total PSA, free/total PSA ratio, serum total testosterone, free testosterone, free/total testosterone ratio, FSH and LH levels were compared according to the pathological diagnosis. RESULTS: The mean age was 63.91 years (range 44-83) and the mean PSA level was 9.23 ng/ml (range 0.13-50.41) in the whole group. Of 211 patients, 69 (32.7%) were positive for prostate cancer. The patients who were positive for prostate cancer had statistically lower levels of serum total testosterone compared with the patients who were diagnosed as having benign prostatic hyperplasia (BPH; 405 vs. 450.5 ng/dl, respectively; p = 0.013). The serum FSH level was significantly higher in men with prostatic cancer than in men with BPH (7.56 vs. 6.06 mIU/ml, respectively; p = 0.029). No significant differences between men with prostatic cancer and those with BPH were found for serum LH levels. When normal ranges for serum free and total testosterone levels were defined as 9 pg/ml and 300 ng/dl, respectively, patients who had low free testosterone and total testosterone levels had significantly higher cancer detection rates than patients with high serum androgen levels: 40.8% (40/98) versus 25.6% (29/113) (p = 0.021), and 48.6% (18/37) versus 29.3% (51/174), respectively (p = 0.023). After logistic regression analysis, none of the hormones showed a significant difference in predicting the risk of prostate cancer in patients undergoing prostate biopsy with suspicion of the disease. CONCLUSION: Our data suggest that patients diagnosed with prostate cancer have low levels of serum testosterone and high levels of serum FSH compared with the patients with BPH. No support was found for the theory that high levels of testosterone increase prostate cancer risk. Further studies are needed to clarify the relationship between hormones and prostate cancer etiology.     

Hormonal chemotherapy for hormone-refractory prostate cancer

To our knowledge, no standard chemotherapy for patients with hormone-refractory prostate cancer (HRPC) has been established. Since most patients with HRPC are elderly and have bone metastasis, cytotoxic chemotherapy causes them to be at high risk for myelosuppression. Therefore, chemotherapeutic agents with low toxicity and good compliance should be elected. We conducted three regimens for HRPC on an outpatient basis. Eligibility criteria were defined as serial rising PSA values on 3 or more occasions at least 2 weeks apart or radiological new or extensive lesions under hormonal therapy. The first regimen is comprised of cyclophosphamide (CPM), 100 mg/day, UFT, 400 mg/day, and estramustine phosphate (EMP), 560 mg/day in two daily fractions. The second regimen is comprised of an oral administration of dexamethasone (DEX) (0.5-2 mg/day). The third regimen is comprised of DEX, 1 mg/day, cyclophosphamide, 100 mg/day and UFT, 400 mg/day in two daily fractions. Post-therapy prostate-specific antigen (PSA) level in serum, objective response on bone scan or measurable disease, and symptomatic response on bone pain were assessed. All regimens showed clinical efficacy with mild toxicity. Indications and limitations of these regimens are discussed. Further, the combination trials of taxane and EMP in patients with HRPC are reviewed.     

Ductal prostate cancer: contemporary management and outcomes

OBJECTIVES: To evaluate contemporary management and outcomes of ductal prostate cancer (PCA). MATERIALS AND METHODS: We reviewed all patients with ductal PCA and at least 6 months of follow-up seen at UTMB from 1990 to 2005, which comprised 17 patients (mean age: 67.7 years, range 55-87). At time of diagnosis, 11 patients had localized disease (Group 1) and 6 patients had distant metastasis (Group 2). RESULTS: Treatment of Group 1 patients included radiation and endocrine treatment for at least 2 years (n = 7), radiation alone (n = 2), and radical surgery (n = 2). At a mean follow-up of 3.6 years (r = 1-12 years) 8 patients (67.7%) remained free of recurrence, 1 patient had biochemical recurrence alone, 1 patient had recurrence in the anterior urethra, and the other had progression with metastasis to the brain and subsequent death. In addition to metastasis to regional/distant lymph nodes and bone in Group 2, metastatic sites included brain (n = 1), peritoneum (n = 1), and lung (n = 1). Mean follow-up was 2.3 years (r = 8 months to 4 years). All patients received androgen deprivation. One patient had progression of disease despite lack of biochemical recurrence and is alive at 2.5 years. One patient died from other causes while the 4 remaining patients are in remission at last follow-up. CONCLUSIONS: Contemporary management of localized ductal PCA with radiation and endocrine therapy yields adequate disease-free survival. Metastatic sites include brain, lung, peritoneum, and anterior urethra, and most patients respond well to endocrine treatment.     

前列腺癌内分泌治疗方法研究及预后分析

目的:探究延长前列腺癌患者进展为激素非依赖性前列腺癌(AIPC)时间的内分泌治疗方法。方法:经直肠活检穿刺证实前列腺癌患者93例,分为3组:22例患者接受双侧睾丸切除加比卡鲁胺联合治疗,行持续性全雄激素阻断(CAD);71例患者行间歇性内分泌治疗方法,其中29例患者行标准间歇性内分泌治疗(IAD),42例患者行改良型间歇性内分泌治疗;两组治疗期用戈舍瑞林或亮丙瑞林联合比卡鲁胺的用药方案,行雄激素最大阻断(MAB),当患者血清PSA下降至<0.2μg/L,维持用药3个月。进入间歇期,IAD组停药,改良型IAD组停用促黄体生成激素释放激素类似物(LHRH-a),但维持使用比卡鲁胺,两组在间歇期内出现PSA持续升高,且大于4μg/L时,则再次启用MAB,直至患者进展为AIPC。比较CAD、IAD及改良型IAD 3组患者疾病随访时间、疾病进展时间及治疗周期。结果:3组患者人口学特征、基线资料及随访时间相似,中位进展时间分别为(26.50±4.15)月、(30.00±7.83)月和(34.93±5.08)月,CAD与标准IAD组比较差异无统计学意义(P=0.143),改良型IAD组与CAD及IAD组比较差异有统计学意义(P=0.001,0.032)。Kaplan-Meier生存分析显示,改良组中位进展时间明显长于标准IAD治疗组(P=0.01)。标准IAD与改良型IAD组平均治疗周期分别为(16.13±3.33)月和(19.58±4.30)月,两组第1治疗周期间歇期分别为(9.6±3.2)月和(14.2±3.7)月,组间比较差异显著(P=0.001)。结论:与CAD和标准IAD比较,改良型IAD可显著延长前列腺癌患者进展为AIPC的时间。     

Innovative approaches in prostate cancer ultrasound

Today, systematic random biopsies have virtually replaced ultrasound as an imaging tool in the early diagnosis and staging of prostate cancer. Transrectal ultrasonography (TRUS) is now utilized almost only to guide the biopsy needle into the correct anatomical or topographical region of the prostate. Nevertheless, a large number of clinically significant carcinomas are not discovered despite of multiple systematic biopsies. This has led to a dramatic increase in the number of biopsy samples taken, with 6, 10, 12 to 143 being taken during one session depending on the site. Newer modalities and innovative techniques are being investigated in order to accurately identify patients with prostate cancer at different stages of the disease. Innovative ultrasonography techniques may improve the diagnosis and staging of current imaging techniques.     

High-risk prostate cancer: from definition to contemporary management

Context

High-risk prostate cancer (PCa) is a potentially lethal disease. It is clinically important to identify patients with high-risk PCa early on because they stand to benefit the most from curative therapy. Because of recent advances in PCa management, a multimodal approach may be advantageous.

Objective

Define high-risk PCa, and identify the best diagnostic and treatment patterns for patients with clinically localized and locally advanced disease. A critical analysis of published results following monomodal and/or multimodal therapy for high-risk PCa patients was also performed.

Evidence acquisition

A review of the literature was performed using the Medline, Embase, Scopus, and Web of Science databases as well as the Cochrane Database of Systematic Reviews.

Evidence synthesis

High-risk PCa accounts for ≤15% of all new diagnoses. Compared with patients with low- and intermediate-risk PCa, patients with high-risk PCa are at increased risk of treatment failure. Unfortunately, no contemporary randomized controlled trials comparing different treatment modalities exist. Evaluation of the results published to date shows that no single treatment can be universally recommended. Most often, a multimodal approach is warranted to optimize patient outcomes.

Conclusions

A significant minority of patients continue to present with high-risk PCa, which remains lethal in some cases. Outcomes following treatment of men with high-risk tumors have not substantially improved over time. However, not all high-risk patients are at the same risk of PCa progression and death. At present, a multimodal approach seems the best way to achieve acceptable outcomes for high-risk PCa patients.     

Salvage surgery for radiorecurrent prostate cancer: contemporary outcomes

PURPOSE: We present a 30-year experience with performing salvage surgery in patients with persistent prostate cancer (PCA) after definitive radiotherapy. MATERIALS AND METHODS: Patients with biopsy proven PCA following definitive radiotherapy who underwent salvage surgery were identified retrospectively (1967 to 2000). Prostate specimens were evaluated by a single pathologist. Progression-free survival (PFS) and cancer specific survival (CSS) estimates were made with multivariate analysis of outcome predictors. Complications were reviewed. RESULTS: Sufficient information was available on 199 patients, including 138 with retropubic prostatectomy (RP) and 61 with cystoprostatectomies (CP). Median followup was 7.0 years. Rectal injury rates (5% for RP and 10% for CP) remained stable, while transfused units of blood decreased. Urinary extravasation (15% of cases) and bladder neck contracture (22%) were the most common complications. Urinary continence (0 pads) improved from 43% to 56% of patients (p = 0.17) with an additional 20% requiring 1 or fewer pad daily. Overall 10-year CSS in all patients undergoing salvage surgery was 65%. Patients undergoing RP fared better than those needing CP (10-year CSS 77% vs 38%, p <0.001 and median PFS 8.7 vs. 4.4 years, p <0.001). Tumor ploidy, percent 4/5 Gleason grade and pathological stage were strong predictors of outcome, while margin status and preoperative prostate specific antigen had minimal predictive strength. CONCLUSIONS: Significant PFS and CSS can be expected following salvage surgery for radioresistant PCA. Several pathological features of the removed prostate are predictive of survival. The surgical risks of salvage surgery are now defined. Morbidity rates, including continence, have moderately improved with time.     

Hormonal sensitivity following endocrine withdrawal in hormone-refractory prostate cancer

BACKGROUND: Prostate cancer is proposed to be classified according to hormonal sensitivity. The purpose of this study is to examine hormonal sensitivity of the patient with refractory prostate cancer subsequent to primary hormonal therapy. METHODS: Sixteen patients with refractory prostate cancer subsequent to primary combination hormonal therapy were enrolled in this study. All 16 patients with progressive disease after elimination of oral hormonal agents or after response following hormonal withdrawal received dexamethasone (DXM) (initially 1.5 or 1.0 mg, then tapered to 0.5 mg) orally not only for the purpose of second-line hormonal therapy but also as an indicator of hormonal sensitivity. RESULTS: Overall, 4 patients showed a prostate-specific antigen (PSA) decrease of >50% from baseline on discontinuation of hormonal agents, while another 7 patients showed a PSA decrease of <50%. Five patients showed PSA level was progressed after the withdrawal. In all patients with PSA values that decline not only >50% but also <50% following oral endocrine withdrawal, the fall in PSA values had been >50% following DXM administration. However, the PSA value in the patients with PSA progression following the oral endocrine withdrawal kept rising after DXM administration. CONCLUSIONS: The findings in this study would just suggest a possible relationship between DXM sensitivity and the response to endocrine withdrawal. The patients whose PSA values decline following oral endocrine withdrawal may maintain hormonal sensitivity.     

Estrogen therapy in patients with prostate cancer: a contemporary systematic review

Purpose

To evaluate the effectiveness and harms of DES in treating prostate cancer compared to other forms of androgen deprivation therapy (orchiectomy, LHRH agonists, and anti-androgens).

Methods

We included clinical trials comparing DES with other forms of ADT (bicalutamide, flutamide, LHRH agonists, or orchiectomy) in PCa treatment. The primary outcomes were overall survival, cancer-specific survival, and progression-free survival, and secondary outcomes were cardiovascular effects. We searched in MEDLINE, EMBASE, Central, and Lilacs from inception to nowadays and saturated information for unpublished data in other sources. We performed a qualitative analysis of all included studies. It was not possible to perform meta-analysis due to low-quality trials and high heterogeneity.

Results

Overall, 1700 references were scanned and 14 prospective randomized trials with a total of 3986 patients were included in the final analysis. Although trials showed DES as similarly effective to another forms of ADT, evidences about cardiovascular toxicity in out of date high doses have discouraged its use. In doses of 1 mg, DES has been used as secondary line PCa treatment with safety.

Conclusions

DES might be similarly effective to other forms of ADT on advanced PCa patients, with potential important roles. Intriguingly, the burden of severe cardiovascular toxicity is mainly related to old-fashioned doses of 5.0 and 3.0 mg. Modern PCa hormonal knowledge warrants stout high-quality prospective randomized trials in the low-dose 1 mg DES scenario.

     

Novel targets and approaches in advanced prostate cancer

PURPOSE OF REVIEW: The development of therapeutic resistance is the underlying cause for most cancer deaths. By understanding the molecular basis of resistance to androgen withdrawal and chemotherapy in prostate cancer, the rational design of targeted therapeutics is possible. We review new treatment options for men with advanced prostate cancer. RECENT FINDINGS: Although the taxanes currently represent the most active chemotherapeutic agents and standard of care for first-line treatment of metastatic hormone-refractory prostate cancer, most patients eventually progress because of intrinsic or acquired drug resistance. In recent years, increased knowledge of cancer progression and therapeutic resistance has identified many gene targets that regulate apoptosis, proliferation, and cell signalling. To date, numerous novel compounds have entered clinical trials as either single agents or in combination with cytotoxic chemotherapy. SUMMARY: Even though hormone-refractory prostate cancer is still incurable, it is not untreatable. As cancer cells are proficient at adapting to therapeutic stressors, a combination regimen with drugs that target crucial cellular networks like the apoptotic rheostat may be more promising than treatment with highly selective single-target agents. Recent findings are very hopeful, but challenges remain to demonstrate effective antitumour activity in phase III trials with survival as the principal endpoint.     

Immunology and immunotherapy approaches for prostate cancer

Several mechanisms that impair the immune response to promote tumour progression are reported. These mechanisms aim to reduce the ability of antigen-presenting cells to present antigen and activate na?ve T cells to support an active immune response or to create a suppressive environment that induce non-functional tumour-associated antigen-specific T cells. Prostate cancer (PC) alone accounts for 33% of incident cancer cases and about 9% of all cancer-related deaths among men in the USA during 2006. Whereas androgen deprivation has remained the first line of therapy for advanced PC, other therapies are still required due to progression to an androgen-resistant state and eventually loss of control in patients receiving hormonal therapy. Immunotherapy seems to be a promising approach to enhance tumour-specific T-cell responses in different cancers including prostate. More importantly, clinical trials in advanced PC patients have shown that immunotherapy may generate significant clinical responses. Immunology and immunotherapy aspects of PC with focus on prostate-specific antigen will be presented.     

Rationale for chemotherapeutic approaches to prostate cancer

The problems of curing tumors with a low growth fraction with cytotoxic chemotherapeutic agents include 1) the fact that such agents attack biochemical pathways common and vital to all cells, 2) the existence in a tumor of cells with both temporary and permanent resistance to specific agents, and 3) the exponential nature of cell kill, which necessitates a much more intensive treatment to effect cure than to effect remission. The possible bases for selectivity of anticancer drugs include those factors that affect the concentration of the active form of the drug at the active site, those that affect the drug receptor interaction and those that determine whether this interaction will lead to cell death. Possible ways of overcoming resistance include combination chemotherapy, more intensive chemotherapy, adjuvant chemotherapy, and maneuvers leading to recruitment of cells into cycle. Because of tumor cell heterogeneity a different approach may be needed to effect cure from that required to induce complete remission.