血管生成抑制剂在去势抵抗性前列腺癌治疗中的新发现

近年来,去势抵抗性前列腺癌的治疗方法已由传统的抗雄激素及化疗提升到新的雄激素受体信号抑制剂、新一代紫杉醇及免疫疗法阶段。卡巴他赛、恩杂鲁胺、阿比特龙,放射性同位素镭223和sipuleucel-T随机临床试验显示能延长去势抵抗性前列腺癌患者生存期。然而,最终出现肿瘤抵抗也是难免的,去势抵抗性前列腺癌仍是一种主要临床负担,迫切需求新的治疗方法进一步改善CRPC患者生存期及生活质量。新生血管在前列腺癌的形成和进程中发挥至关重要的作用。部分临床试验显示,对失去手术和内分泌治疗时机的去势抵抗性前列腺癌,抗新生血管形成的靶向治疗是一种有效的补充疗法。本文将综述血管生成抑制剂在去势抵抗性前列腺癌治疗中的新发现。     

New drugs for prostate cancer

What's known on the subject? and What does the study add? Recent studies have demonstrated the efficacy of various new treatments. These have been in diverse areas of therapeutics research, including immunology and targeted biological therapy, as well as in new ways of approaching hormone refractory disease. The present paper seeks to review all of the key advances that have been reported in late‐stage clinical studies and place them into the context of managing patients with advanced prostate cancer.

OBJECTIVE

• ? To describe some of the most exciting late stage clinical developments in the field of new therapies for advanced prostate cancer.

METHODS

• ? Pubmed was searched for articles pertaining to prostate cancer therapeutics clinical trials in the last 3 years.

RESULTS

• ? Key positive trials in the areas of androgen resistance, tumour immunology, molecularly targeted agents and cytotoxics were reviewed and discussed in the context of metastatic prostate cancer.

CONCLUSION

• ? Treatments emerging from these areas of scientific endeavour are progressing into clinical trials and are both good cause for hope in patients, and excellent examples of mechanism based drug discovery.

     

Immunotherapy and therapeutic vaccines in prostate cancer： an update on current strategies and clinical implications

In recent years, immunotherapy has emerged as a viable and attractive strategy for the treatment of prostate cancer. While there are multiple ways to target the immune system, therapeutic cancer vaccines and immune checkpoint inhibitors have been most successful in late-stage clinical trials. The landmark Food and Drug Administration approval of sipuleuceI-T for asymptomatic or minimally symptomatic metastatic prostate cancer set the stage for ongoing phase III trials with the cancer vaccine PSA-TRICOM and the immune checkpoint inhibitor ipilimumab. A common feature of these immune-based therapies is the appearance of improved overall survival without short-term changes in disease progression. This class effect appears to be due to modulation of tumor growth rate kinetics, in which the activated immune system exerts constant immunologic pressure that slows net tumor growth. Emerging data suggest that the ideal population for clinical trials of cancer vaccines is patients with lower tumor volume and less aggressive disease. Combination strategies that combine immunotherapy with standard therapies have been shown to augment both immune response and clinical benefit.     

What is the molecular pathology of low-risk prostate cancer?

Objectives  Low-risk prostate cancer is defined as a clinical T1c or T2a tumor with a Gleason score of ≤6 and PSA <10 ng/ml. This is a pretreatment diagnosis and the patient can turn out to have either significant or insignificant disease. With methods currently available in practice it may not be possible to differentiate between these groups. Numerous molecular pathological changes have been described in prostate carcinoma. This review was to evaluate which of these changes may be useful to distinguish the group of patients likely to have significant carcinoma within the low risk category. Materials and methods  The literature on molecular pathology of prostate cancer was reviewed using MEDLINE and reference lists of relevant publications focusing on early and late molecular events and available molecular biomarkers in prostate cancer. Results  There are a variety of molecular markers with the potential to be clinically utilized for assessment of low risk prostate cancer. One of the most promising is TMPRSS2: ETS fusion, which is a homogeneous event occurring early in prostate carcinogenesis. Other promising markers include p27, EZH2 and c-MYC. Conclusions  FISH analysis or RT-PCR based assays to detect TMPRSS2: ETS fusion and immunohistochemical assessment of p27, EZH2 and c-MYC may become useful ancillary tests in patients with low risk prostate cancer. Some serum biomarkers have promise for future use. Large prospective studies followed by clinical trials are necessary before these molecular markers could be integrated into clinical practice.     

Chemotherapy for metastatic castration‐sensitive prostate cancer

Incorporation of docetaxel into metastatic castration‐sensitive prostate cancer treatment has added a new treatment option to a disease state that had previously not seen change for decades. Early attempts of a chemo‐hormonal approach for castration‐sensitive prostate cancer were not successful. With the demonstration of survival benefits using docetaxel in patients with metastatic castration‐resistant prostate cancer, this encouraged continued research with docetaxel given earlier in the disease course. Three randomized phase III trials have defined the benefits of docetaxel in the metastatic castration‐sensitive prostate cancer setting; however, there remain questions and controversies on the appropriate and optimal patient selection.     

The role of docetaxel based therapy for prostate cancer in the era of targeted medicine

Docetaxel based chemotherapy has been shown to modestly extend life, relieve pain and improve the quality of life in patients with metastatic castration‐resistant prostate cancer. Current trials are attempting to build on the backbone of docetaxel by combining it with novel biological agents. Trials are also investigating the role of docetaxel for earlier stages of prostate cancer. No standard second‐line systemic therapy exists and such patients are candidates for clinical trials. The increased understanding of the mechanisms of progressive castration‐resistant prostate cancer is being translated into an increasing pipeline of novel therapies.     

Contemporary outcomes following robotic prostatectomy for locally advanced and metastatic prostate cancer

While radical prostatectomy (RP) plays a prominent role in the management of localized prostate cancer, its role in high risk or metastatic disease is less clear. Due to changes in prostate cancer screening patterns, particularly those made by the United States Preventive Services Task Force, data is suggesting increasing incidences of high risk and metastatic disease, underlying the importance of continued research in this area. While past approaches to management may have discouraged surgical intervention, more contemporary approaches have attempted to evaluate its effectiveness and utility. The purpose of this review is an updated discussion of the current literature regarding surgical approaches to high risk prostate cancer. The PubMed and Medline databases were queried for English language articles related to the surgical management of high-risk prostate adenocarcinoma. In this review, we examine the utility of surgery as a single or multimodal approach to management with patients with high risk, locally advanced, and metastatic prostate cancer. Outcomes measures are reviewed including data on survival and recurrence rates. Functional outcomes are an important consideration in prostate cancer management and while data is more limited, this review examines some of the key findings. Finally, a discussion regarding surgical complication rates and ongoing clinical trials is addressed. While surgery appears to be promising in this patient cohort, there remains significant heterogeneity in the data that ongoing trials may be able to address. At its current level of understanding, surgery should be considered as a potential tool in patient management, but may play a more prominent role in a multi-modality setting for optimal outcomes.     

Conference report and review: current status of biomarkers potentially associated with prostate cancer outcomes

PURPOSE: The use of prostate specific antigen screening to diagnose and monitor prostate cancer is associated with well-known shortcomings. A 2-day Prostate Cancer Biomarker Conference was convened to identify promising areas of research and focus efforts on the most critical needs. MATERIALS AND METHODS: The conference provided a forum for the presentation and discussion of ongoing prostate cancer biomarker research. This meeting also sought to identify a range of critical issues in the development and validation of biomarkers, foster research collaboration between groups representing government, academic and industry initiatives, and coordinate efforts with planned and ongoing clinical trials. RESULTS: Taken collectively the conference presentations offered various new technologies for biomarker discovery and pathological assessment of clinical disease as well as the promise of biomarkers for improving prostate cancer diagnosis and treatment decisions. However, research efforts focused on biomarker validation and implementation clearly lag behind those directed toward initial biomarker discovery. It is apparent that guidelines are desperately needed to ensure the consistency of sample collection across institutions. CONCLUSIONS: Several ongoing and planned adjuvant prostate cancer trials will provide a tremendous opportunity for biological sample collection along with the potential to validate many biomarkers. Practicing urologists have an opportunity to have a critical role in the successful accrual of patients into these trials.     

Novel agents for castration‐resistant prostate cancer: Early experience and beyond

Androgen deprivation therapy is the initial treatment for men with advanced prostate cancer. Almost all these patients eventually develop progressive castration‐resistant prostate cancer despite an initial favorable response. Docetaxel was the first agent to show a survival benefit in patients with castration‐resistant prostate cancer. After cancer progression on docetaxel, patients with castration‐resistant prostate cancer had few therapeutic options. A better understanding of the mechanisms of resistance to androgen deprivation therapy has led to the development of novel agents with distinct mechanisms of action. Prospective, large‐scale clinical trials have shown overall survival benefits with the hormonal agents abiraterone acetate and enzalutamide, the immunotherapeutic agent sipuleucel T, the chemotherapeutic agent cabazitaxel, and bone‐targeted Ra‐223. Although these agents provided clinical benefit, treatment for castration‐resistant prostate cancer remains a major clinical challenge. We recognize many questions, such as methods to select patients for specific treatments, optimal sequencing and drug combinations, and means to overcome drug resistance. There is an urgent need to answer these questions and to establish better treatment strategies. The development of biomarkers that are predictive of treatment results is also required. The present article reviews new castration‐resistant prostate cancer treatments, and discusses possible resistant mechanisms as well as potential drug combinations and optimal sequencing.     

Other biomarkers for detecting prostate cancer

Prostate‐specific antigen (PSA) has been used for detecting prostate cancer since 1994. Although it is the best cancer biomarker available, PSA is not perfect. It lacks both the sensitivity and specificity to accurately detect the presence of prostate cancer. None of the PSA thresholds currently in use consistently identify patients with prostate cancer and exclude patients without cancer. Novel approaches to improve our ability to detect prostate cancer and predict the course of the disease are needed. Additional methods for detecting prostate cancer have been evaluated. Despite the discovery of many new biomarkers, only a few have shown some clinical value. These markers include human kallikrein 2, urokinase‐type plasminogen activator receptor, prostate‐specific membrane antigen, early prostate cancer antigen, PCA3, α‐methylacyl‐CoA racemase and glutathione S‐transferase π hypermethylation. We review the reports on biomarkers for prostate cancer detection, and their possible role in the clinical practice.     

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.     

Management of Patients with Advanced Prostate Cancer: Report of the Advanced Prostate Cancer Consensus Conference 2019

BackgroundInnovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but there are still many aspects of management that lack high-level evidence to inform clinical practice. The Advanced Prostate Cancer Consensus Conference (APCCC) 2019 addressed some of these topics to supplement guidelines that are based on level 1 evidence.ObjectiveTo present the results from the APCCC 2019.Design, setting, and participantsSimilar to prior conferences, experts identified 10 important areas of controversy regarding the management of advanced prostate cancer: locally advanced disease, biochemical recurrence after local therapy, treating the primary tumour in the metastatic setting, metastatic hormone-sensitive/naïve prostate cancer, nonmetastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, bone health and bone metastases, molecular characterisation of tissue and blood, inter- and intrapatient heterogeneity, and adverse effects of hormonal therapy and their management. A panel of 72 international prostate cancer experts developed the programme and the consensus questions.Outcome measurements and statistical analysisThe panel voted publicly but anonymously on 123 predefined questions, which were developed by both voting and nonvoting panel members prior to the conference following a modified Delphi process.Results and limitationsPanellists voted based on their opinions rather than a standard literature review or formal meta-analysis. The answer options for the consensus questions had varying degrees of support by the panel, as reflected in this article and the detailed voting results reported in the Supplementary material.ConclusionsThese voting results from a panel of prostate cancer experts can help clinicians and patients navigate controversial areas of advanced prostate management for which high-level evidence is sparse. However, diagnostic and treatment decisions should always be individualised based on patient-specific factors, such as disease extent and location, prior lines of therapy, comorbidities, and treatment preferences, together with current and emerging clinical evidence and logistic and economic constraints. Clinical trial enrolment for men with advanced prostate cancer should be strongly encouraged. Importantly, APCCC 2019 once again identified important questions that merit assessment in specifically designed trials.Patient summaryThe Advanced Prostate Cancer Consensus Conference provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference, which has been held three times since 2015, aims to share the knowledge of world experts in prostate cancer management with health care providers worldwide. At the end of the conference, an expert panel discusses and votes on predefined consensus questions that target the most clinically relevant areas of advanced prostate cancer treatment. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients as part of shared and multidisciplinary decision making.     

Particle therapy for prostate cancer: The past,present and future

Although prostate cancer control using radiotherapy is dose‐dependent, dose–volume effects on late toxicities in organs at risk, such as the rectum and bladder, have been observed. Both protons and carbon ions offer advantageous physical properties for radiotherapy, and create favorable dose distributions using fewer portals compared with photon‐based radiotherapy. Thus, particle beam therapy using protons and carbon ions theoretically seems suitable for dose escalation and reduced risk of toxicity. However, it is difficult to evaluate the superiority of particle beam radiotherapy over photon beam radiotherapy for prostate cancer, as no clinical trials have directly compared the outcomes between the two types of therapy due to the limited number of facilities using particle beam therapy. The Japanese Society for Radiation Oncology organized a joint effort among research groups to establish standardized treatment policies and indications for particle beam therapy according to disease, and multicenter prospective studies have been planned for several common cancers. Clinical trials of proton beam therapy for intermediate‐risk prostate cancer and carbon‐ion therapy for high‐risk prostate cancer have already begun. As particle beam therapy for prostate cancer is covered by the Japanese national health insurance system as of April 2018, and the number of facilities practicing particle beam therapy has increased recently, the number of prostate cancer patients treated with particle beam therapy in Japan is expected to increase drastically. Here, we review the results from studies of particle beam therapy for prostate cancer and discuss future developments in this field.     

前列腺癌ADT相关骨质疏松症的机制及防治进展

前列腺癌是男性最常见的癌症及主要死因之一。从20世纪40年代开始人们认识到前列腺癌对雄激素具有高度依赖的特点后,雄激素剥夺治疗（androgen deprivation therapy,ADT）现已成为局限性、复发性和转移性前列腺癌治疗的标准治疗方案。但ADT在治疗前列腺癌的同时却会出现骨质疏松等副作用。就骨质疏松而言,大部分前列腺癌患者在接受ADT前已患有骨质疏松症,接受ADT会使其原有骨质疏松症状加剧,在另一方面又增加了患者骨折的风险。因此探讨ADT相关性骨质疏松发病机制及防治进展已成为前列腺癌内分泌治疗及骨质疏松临床诊疗研究的重点。本文总结了前列腺癌ADT相关骨质疏松近几年来一系列研究成果,就其发病机制及防治进展作以下综述,如ADT相关骨质疏松症中雄激素的作用机制、ADT的药物种类及其作用机制和ADT相关骨质疏松症的研究,为医务工作者们了解前列腺癌ADT相关性骨质疏松发病机制及防治进展提供参考。     

Insignificant Prostate Cancer and Active Surveillance: From Definition to Clinical Implications

Context

Due to early detection strategies, prostate cancer is diagnosed early in its natural history. It remains unclear whether all patients diagnosed with prostate cancer warrant radical treatment or may benefit from delayed intervention following active surveillance.

Objective

A systematic review of active surveillance protocols to investigate the inclusion criteria for active surveillance and the outcome of treatment.

Evidence acquisition

Medline was searched using the following terms: prostate cancer, active surveillance and expectant management for dates up to October 2008. Further studies were chosen on the basis of manual searches of reference lists and review papers.

Evidence synthesis

Numerous studies on active surveillance were identified. The recent inclusion criteria of the studies are rather similar. Keeping the short follow-up of all studies in mind, the majority of men stay on active surveillance, and the percentage of patients receiving active treatment is as high as 35% of all patients. Once a patients requires active treatment, most patients still present with curable prostate cancer. Furthermore, only few deaths due to prostate cancer have occurred.

Conclusions

Active surveillance is an alternative option to immediate treatment of men with presumed insignificant prostate cancer. It seems that criteria used to identify men with low-risk prostate cancer are rather similar, and immediate treatment of men meeting these criteria may result in an unnecessary number of treatments in these highly selected patients. Data from randomised trials comparing active surveillance and active treatment will provide additional insight into outcome and follow-up strategies.     

Clinical development of immunotherapy for prostate cancer

Prostate cancer is the most common cancer in men, and the second leading cause of cancer‐related death in Western countries. Prostate cancer‐related death occurs in patients with metastatic castration‐resistant prostate cancer. Although several new drugs for castration‐resistant prostate cancer have been approved, each of these has prolonged survival by just a few months. Consequently, new therapies are sorely needed. Recently, it has been recognized that immunotherapy is an effective treatment for prostate cancer patients. Several strategies, such as cancer vaccines and immune checkpoint inhibitors, have been investigated in clinical studies for prostate cancer patients. In the present review, the results of the most recent clinical studies investigating immunotherapy in prostate cancer patients are reported, and the future clinical development of immunotherapy for prostate cancer is discussed.     

Stable versus partial response in advanced prostate cancer

Stable response to therapy in patients with advanced prostate cancer, as experienced in clinical trials of the National Prostatic Cancer Project (NPCP), has been reexamined. Data from ten complete trials totaling over 1,300 patients have been examined for survival patterns within categories of response to therapy. Survival patterns, both for all patients and for those alive at 12 weeks, were significantly poorer for patients categorized as progressors after 12 weeks on treatment than for those categorized as stable or as partial regressions. Furthermore, comparisons of survival patterns for those patients categorized as stable or partial regression revealed no statistically significant differences between them. The similarity of survival for the stable and partial regression categories indicates that the stable category represents more than a segment of the population with slowly progressing disease and can be taken as an indicator of response to therapy.     

Hormones and prostate cancer: current perspectives and future directions

Prostate cancer is the most commonly diagnosed non-skin cancer in men in most western countries. Despite the high morbidity and mortality from prostate cancer, its etiology remains obscure. Although compelling laboratory data suggest a role for androgens in prostate carcinogenesis, most epidemiologic data on humans are inconclusive. To provide insights and directions for future epidemiologic research on hormones and prostate cancer, this review focuses on current perspectives of serum-based studies and polymorphisms in relevant hormone-related genes. We highlight the importance of methodologic studies and investigations of hormone levels in the prostatic tissue to help clarify the often-contradictory data on serologic studies. We recommend careful analysis and cautious interpretation of studies of genetic markers, including repeats and single nucleotide polymorphisms (SNPs), as false positive and negative results may arise in many current and future studies with limited statistical power and non-representative samples from the population. The review also highlights the reasons to perform functional analyses of SNPs, a critical and often under-appreciated component of molecular epidemiologic investigations.The time is ripe for large-scale multidisciplinary investigations that incorporate molecular genetics, biochemistry, histopathology, and endocrinology into traditional epidemiologic studies. Such collaboration will lead to a deeper understanding of the etiologic pathways of prostate cancer, ultimately yielding better preventive, diagnostic, and therapeutic strategies.     

Pathobiology of autochthonous prostate cancer in a pre-clinical transgenic mouse model

BACKGROUND: Animal models that closely mimic clinical disease can be exploited to hasten the pace of translational research. To this end, we have defined windows of opportunity in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of prostate cancer as a paradigm for designing pre-clinical trials. METHODS: The incidence of cancer, metastasis, and distribution of pathology were examined as a function of time in TRAMP mice. The expression of various markers of differentiation were characterized. RESULTS: The TRAMP model develops progressive, multifocal, and heterogeneous disease. Each lobe of the prostate progressed at a different rate. Cytokeratin 8, E-cadherin, and androgen receptor (AR) were expressed during cancer progression but levels were reduced or absent in late stage disease. A distinct epithelial to neuroendocrine (ENT) shift was observed to be a stochastic event related to prostate cancer progression in TRAMP. CONCLUSIONS: This study will serve as the basis for the rational design of pre-clinical studies with genetically engineered mouse models.     

The results of transperineal versus transrectal prostate biopsy: a systematic review and meta-analysis

This systematic review was performed to compare the efficacy and complications of transperineal (TP) vs. transrectal (TR) prostate biopsy. A systematic research of PUBMED, EMBASE and the Cochrane Library was performed to identify all clinical controlled trials on prostate cancer (PCa) detection rate and complications achieved by TP and TR biopsies. Prostate biopsies included sextant, extensive and saturation biopsy procedures. All patients were assigned to a TR group and a TP group. Subgroup analysis was performed according to prostate-specific antigen (PSA) levels and digital rectal examination (DRE) findings. The Cochrane Collaboration's RevMan 5.1 software was used for the meta-analysis. A total of seven trials, including three randomized controlled trials (RCTs) and four case-control studies (CCS), met our inclusion criteria. There was no significant difference in the cancer detection rate between the sextant TR and TP groups (risk difference (RD), -0.02; 95% confidence interval (CI), -0.08-0.03; P=0.34). Meta-analysis for RCTs combined with CCS showed that there was no difference in the cancer detection rate between the extensive TR and TP group (RD, -0.01; 95% CI, -0.05-0.04; P=0.81). There was no significant difference in PCa detection rate between the saturation TR and TP approaches (31.4% vs. 25.7%, respectively; P=0.3). There were also no significant differences in cancer detection between the TR and TP groups in each subgroup. Although the data on complications were not pooled for the meta-analysis, no significant difference was found when comparing TR and TP studies. TR and TP biopsies were equivalent in terms of efficiency and related complications. TP prostate biopsy should be an available and alternative procedure for use by urologists.