联合多西紫杉醇治疗非激素依赖性前列腺癌临床进展

非激素依赖性前列腺癌(HIPC)是PCa发展的终末阶段,它的中位生存时间短,约9~18个月。两个大的Ⅲ期临床实验证实多西紫杉醇化疗能延长HIPC患者的生存期。新的联合治疗策略已经发展,结果很有前景,目前大多数研究均集中在联合多西紫杉醇和化疗药物(骨钙三醇)、抗血管生成药、疫苗、生物制剂等上。本文对联合多西紫杉醇治疗HIPC的新进展作一综述。     

A retrospective study of the time to clinical endpoints for advanced prostate cancer

OBJECTIVE: To determine the natural history of patients with prostate cancer who start initial androgen-deprivation therapy (ADT) for biochemical failure with no radiographic evidence of disease (D0) or with radiographic metastatic disease (D2), as the history is either not well-defined or is changing, and such data are critical for guiding therapy after prostate cancer recurrence. PATIENTS AND METHODS: We retrospectively assessed the time to androgen-independence (AI), defined as the first sustained rise in prostate-specific antigen (PSA) level on ADT, time to metastatic disease and overall survival for 80 patients with metastatic prostate cancer in clinical trials at the National Cancer Institute. RESULTS: ADT was initiated after metastatic disease in 37 patients and before metastatic disease in 43 patients; in these 43 patients, the median time to developing metastatic disease on ADT was 37.8 months. The median time to AI from the initiation of ADT was 19.3 and 13.1 months in D0 and D2 patients, respectively. The median overall survival from the start of ADT was 89.0 and 63.0 months, and the median overall survival from the time of AI was 63.1 and 44.2 months in D0 and D2 patients, respectively. These 80 patients, which included 43 who had no metastatic disease when starting ADT, had a median survival of 54.8 months after AI prostate cancer. CONCLUSIONS: We describe the natural history of AI prostate cancer in D0 patients who eventually developed metastasis, and in D2 patients. The results suggest a longer than expected survival with AI prostate cancer, and to our knowledge this is the first study to report the time to metastatic disease for D0 patients from ADT and from AI. These results can be used to help design clinical trials in patients with D0 prostate cancer.     

Neoadjuvant therapy and prostate cancer: what a urologist should know

PURPOSE OF REVIEW: Prostate cancer is curable only when treated at an early stage, when the tumor is still localized to the prostate gland. However, even in apparent cases of clinically localized disease, unsuspected extracapsular disease may significantly increase the risk of primary treatment failure. This risk is especially high if the patient has one or more of the following risk factors: a serum prostate-specific antigen level >20 ng/ml, a Gleason score >7, locally advanced disease (clinical stage T3/T4), and extensive disease on prostate biopsy. RECENT FINDINGS: Various regimens of neoadjuvant hormonal therapy and/or chemotherapy have produced mixed results and generally have not influenced the rate of disease relapse (defined by prostate-specific antigen level) in high-risk patients with localized prostate cancer. In addition, antiangiogenic agents, gene therapy, molecular targeting agents, and other promising new therapies have been investigated in a neoadjuvant setting with limited results. SUMMARY: Despite considerable advances, high-risk localized prostate cancer remains an extremely refractory disease. In patients with high-risk prostate cancer, single-modality treatment in the form of surgery offers a 5-year biochemical disease-free survival rate of no better than 50%. To further elucidate optimal treatment regimens for these patients we must actively enrol patients in clinical trials.     

Secondary hormonal manipulation of prostate cancer

Prostate cancer is the second leading cause of cancer mortality among men in Western countries. The initial treatment of advanced prostate cancer is suppression of testicular androgen production by medical or surgical castration, but nearly all men with metastases develop disease progression. Patients with hormone-resistant prostate cancer (HRPC) have a median survival of approximately 18 months, and no therapy has yet demonstrated a definitive survival advantage. However, in the past several years, a number of promising new treatment strategies have emerged. One of the most important new treatment strategies involves secondary hormonal manipulation after the failure of primary androgen deprivation. This approach is predicated on the recognition that HRPC is a heterogeneous disease, and some patients may respond to alternative hormonal interventions despite the presence of castrate levels of testosterone.     

The role of microRNA in castration-resistant prostate cancer

IntroductionCastration-resistant prostate cancer (CRPC) has a historically low median survival rate, but recent advances and discoveries in microRNAs (miRNAs) have opened the potential for new prognostication modalities to enhance therapeutic success. As new chemotherapies and immunotherapies are developed, there is an increasing need for precision and stratification of CRPC to allow for optimization and personalization of therapy.MethodsA systematic literature review was conducted via electronic database resulting in the selection of 42 articles based on title, abstract, study format, and content by a consensus of all participating authors. Most selected articles were published between 2002 and 2013. In this review, we discuss the robustness of miRNAs as a biomarker platform, miRNAs associated with prostate cancer, and recent discoveries of miRNA associations with CRPC.ResultsThe associations discovered have been of interest owing to the ability to differentiate between CRPC and localized prostate cancer. With the evaluation of multiple miRNAs, it is possible to provide a profile regarding tumor characteristics. Furthermore, actions of miRNAs on CRPC tumor cells have the ability to suppress metastatic phenotypes.ConclusionmiRNAs may have a growing role in CRPC prognostication and may potentially transform into a therapeutic potential.     

Anti-angiogenic and cytotoxic targeted systemic therapy for high-risk prostate cancer

In the United States, prostate cancer is the most common noncutaneous cancer diagnosed in men. Although localized disease has a high chance for cure, metastatic disease eventually leads to incurable androgen refractory prostate cancer. There has been an increased focus on anti-angiogenic targeting therapies for high-risk disease. Docetaxol, thalidomide, bevacizumab, angiostatin, and anti-androgen ablation all have proven anti-angiogenic properties in clinical and/or preclinical prostate cancer treatment. This article summarizes the recent clinical and translational research advances in this field. It appears that anti-angiogenic agents may be used to treat high-risk prostate cancer, when used in combination with conventional cytotoxic agents.     

Pancreatic cancer

Pancreatic cancer accounts for 3% of all cancers in the UK; 7000 new cases are diagnosed annually and a similar number die from the disease each year. It has an insidious onset and, as a result, presentation is usually late, with only about 10–20% of patients having disease amenable to surgical resection. Following resection, the median survival is 11–20 months and the 5-year survival is 7–25%. Patients with unresectable locally advanced disease have a median survival of 6–11 months, and those with metastatic disease have a median survival of 2–6 months. Accurate staging has a vital role in the management of pancreatic tumours now that non-surgical palliative options are available. Computed tomography is currently the imaging modality of choice for diagnosis and staging of pancreatic cancer. With recent advances in magnetic resonance imaging and endoscopic ultrasonography, it is now possible to improve the accuracy of preoperative staging, particularly with respect to local invasion and regional node involvement. Resection is the only treatment that offers the potential of cure; ideally, an R0 resection should be aimed for. Chemotherapy renders a survival advantage in the adjuvant setting, even in patients undergoing R1 resections. Palliative chemotherapy can improve survival by 10–15% and other palliative therapies are aimed at relieving jaundice, controlling pain, treating malabsorption and reversing cancer cachexia.     

Pancreatic cancer

Pancreatic cancer accounts for 3% of all cancers in the UK; 7000 new cases are diagnosed annually and a similar number die from the disease each year. It has an insidious onset and as a result presentation is usually late, with only about 10–20% of patients having disease amenable to surgical resection. Following resection, the median survival is 11–20 months and the 5-year survival is 7–25%. Patients with unresectable locally advanced disease have a median survival of 6–11 months, and those with metastatic disease have a median survival of 2–6 months. Accurate staging has a vital role in the management of pancreatic tumours now that non-surgical palliative options are available. Computed tomography is the imaging modality of choice for diagnosis and staging of pancreatic cancer. With recent advances in magnetic resonance imaging and endoscopic ultrasonography, it is now possible to improve the accuracy of preoperative staging, particularly with respect to local invasion and regional node involvement. Resection is the only treatment that offers the potential of cure; ideally, an R0 resection should be aimed for. Chemotherapy renders a survival advantage in the adjuvant setting, even in patients undergoing R1 resections. Palliative chemotherapy with gemcitabine can improve survival by 10–15% and other palliative therapies are aimed at relieving jaundice, controlling pain, treating malabsorption and reversing cancer cachexia.     

Does PSA Testing Influence the Natural History of Prostate Cancer?

Prostate-specific antigen (PSA) testing advances the diagnosis of prostate cancer, shifting the stage at diagnosis towards localised disease. However, the widespread application of PSA testing is controversial, due to uncertainties over whether earlier diagnosis of prostate cancer improves the mortality associated with the disease. This article discusses the evidence on the relationship between PSA testing and prostate cancer mortality considering 5-year survival rates, data from randomised, controlled trials and epidemiological trends in disease mortality. Reported improvements in 5-year survival rates for prostate cancer are probably due to lead-time bias (screening leading to earlier diagnosis). Randomised studies evaluating PSA screening are ongoing and will not provide mortality results until the latter part of this decade. Epidemiological data reveal a decline in disease mortality in areas where PSA screening is routine, but the cause of this decline is likely to be multifactorial. In conclusion, an effect of PSA testing on the natural history of prostate cancer is not yet fact, as determined by a randomised controlled trial, but it is certainly more than fiction.     

Therapeutic options in androgen-independent prostate cancer: building on docetaxel

Of men with metastatic prostate cancer who undergo androgen ablation, 70-80% respond rapidly to therapy, as manifested by a reduction in prostate cancer-related symptoms and declines in serum prostate-specific antigen (PSA) level. Unfortunately, after a median of 18-24 months, nearly all patients with metastatic prostate cancer will progress to androgen independence. Until recently the standard of care for treating hormone-refractory prostate cancer (HRPCa) was the combination of mitoxantrone and prednisone, which palliated bone pain but did not extend survival. Two randomized trials with > 1700 patients showed for the first time a survival benefit for patients with HRPC treated with chemotherapy; when compared with mitoxantrone-based therapy, docetaxel based-therapy reduced the risk of death by 20-24%. Future trials in HRPC are attempting to improve the efficacy of docetaxel by incorporating new agents targeting angiogenesis, apoptosis, and signal transduction pathways; there is promising activity for these novel combinations in phase I and II studies. Concepts are also being refined about definitions of response and progressive disease, patient eligibility criteria, and the validity of surrogate markers of efficacy and survival, as shown by changes in PSA level.     

自噬与前列腺癌

自噬作用被认为具有高度复杂性及环境依赖性,在有些肿瘤中表现为肿瘤抑制和促进相对立两方面影响,比如乳腺癌和前列腺癌。本文综述了自噬对前列腺癌的发生、发展及治疗的最新研究进展。重点突出自噬调节在雄激素剥夺期间的影响,讨论了雄激素对前列腺癌细胞自噬作用所产生的调节效应。通过对一些研究的报道结果进行评价、分析,我们认为:自噬抑制并结合抗雄激素治疗对于前列腺癌是非常有前景的新型治疗方法。     

Current status of liver transplantation for cholangiocarcinoma

Cholangiocarcinoma (CCA) is the second most common liver cancer with a median survival of 12-24 mo without treatment. It is further classified based on its location into intrahepatic CCA (iCCA), perihilar CCA (pCCA), and distal CCA. Surgical resection is the mainstay of treatment, but up to 70% of these tumors are inoperable at the time of diagnosis. CCA was previously an absolute contraindication for liver transplantation (LT) due to poor outcomes primary due to early recurrent disease. However, improvement in patient selection criteria and neoadjuvant treatment protocols have improved outcomes for inoperable pCCA patients with recent studies reporting LT may improve survival in iCCA. Future advances in the treatment of CCA should include refining patient selection criteria and organ allocation for all subtypes of CCA, determining effective immunotherapies and the evolving role of personalized medicine in patients ineligible for surgical resection or LT. Our article reviews the current status of LT in CCA, along with future directions in managing patients with CCA.     

Promising new treatment options for metastatic androgen-independent prostate cancer

ObjectiveReview the recent advances in the treatment of androgen independent prostate cancer (AIPC)MethodsReview recent abstracts and literature utilizing Medline/PubMed using key words: androgen independent/ hormone refractory prostate cancer, novel treatment options, Phase II, III trials and meeting abstracts/ presentations.ConclusionTwo pivotal trials SWOG (Southwest Oncology Group) study 9916 and Taxotere 327 have shown that survival can be improved in this population by administration of chemotherapy with docetaxel every three weeks intravenously. An overall survival of 19 months could be achieved with docetaxel/prednisone compared to16 months with mitoxantrone/prednisone. Despite this, there is a need to improve on this survival benefit because the relapse free survival among responders is often short (6 months) and patients often would have progression of their cancer leading to death. Satraplatin, a novel platinum analogue had been found to provide an additional 1.5 week progression free survival benefit in this population in the second line setting. There is however, a need to develop less toxic drugs that would improve survival significantly.     

雄激素非依赖性前列腺癌的治疗进展

前列腺癌是男性泌尿生殖系常见的恶性肿瘤之一,在我国发病率虽较低,但近年来随着人口老龄化及生活条件的改善,发病率有明显增加的趋势。几乎所有一开始对内分泌治疗敏感的前列腺癌最终都将发展成雄激素非依赖性前列腺癌(AIPC)。AIPC是指对内分泌治疗无反应或内分泌治疗后反而促进疾病进展,导致不可逆的临床进展恶化,直至患者死亡。有关AIPC的发病机制以及治疗策略仍缺乏统一的认识,现就此作一综述。     

Development of prostate cancer treatment: the good news

Prostate cancer is the most commonly diagnosed cancer in American men representing one-third of all new cancer cases each year. This translates into one out of every six American men being diagnosed with prostate cancer over the course of their lifetimes. Over 31,000 of these men die each year from prostate cancer. Before the 1980's, 50% of men were diagnosed with widespread metastatic disease and there were few therapeutic choices for patients. The good news for patients is that, over the last 30 years there have been significant advances in detection and prognostication as well as major improvements in the surgical, radiation, and medical oncological management of prostate cancer. This review describes the evolution of these therapeutic modalities for prostate cancer. This evolution has been driven by the explosion of knowledge concerning cancer in general and in the specific biology of prostate cancer in particular over the last 30 years. This knowledge has been obtained by concentrating human and financial resources in organ specific studies of the prostate. The end result of this effort is that, today, 85% of new prostate cancer cases are diagnosed at local and regional stages and the 5-year relative prostate cancer survival rate has increased by 20% since 1985. In addition, the therapeutic approach to prostate cancer can now be individualized based on the characteristics of the patient's disease. Finally, recent data suggest that the death rate from prostate cancer is decreasing by approximately 4% per year since 1994. Further good news for patients is that new discoveries about the biology of prostate cancer are rapidly being translated into new therapies, a large number of which are currently being tested in clinical trials. Continued allocation of appropriate human and material resources should yield new, more effective therapies for prostate cancer that will further impact patient quality of life and survival in the 21st century.     

Importance of peripheral biopsies in maximising the detection of early prostate cancer in repeat 12-core biopsy protocols

OBJECTIVE: To assess cancer-detection rates in repeat 12-core biopsy protocols, as extended multicore prostate biopsy protocols have become standard when investigating men with a raised prostate-specific antigen (PSA) level, but repeat prostate biopsy protocols are still developing. PATIENTS AND METHODS: During a 4.5-year period, 241 of 590 patients with persistently high age-specific PSA levels of 2.6-10 ng/mL and an initial benign biopsy were invited for repeat transrectal ultrasonography-guided 12-core prostatic biopsy. The protocol for repeat biopsy was identical to the first biopsy, and included a periprostatic nerve block. The first six biopsies were obtained from the periphery of the gland directed more laterally at the base, mid-zone and apices. The remainder were parasagittal sextant biopsies. Pathological findings were analysed on an individual core basis. RESULTS: The mean age of the 241 men was 63.4 years; cancer was diagnosed in 40 (16.6%) on repeat biopsy. Men with cancer were older and had a higher median PSA level. The median Gleason score was 6, with a median of two cores positive for cancer. Maximum cancer detection rates were from peripheral apices (37.5%), basal biopsies had the lowest detection rates (23.8% and 16.3%), and parasagittal biopsies missed 35% of detected cancers. Patients with cancer also had significantly lower prostate volumes and higher PSA densities (both P < 0.001). CONCLUSION: A low cancer yield from both peripheral basal and parasagittal basal specimens on repeat biopsy indicates adequate sampling at initial biopsy. The maximum cancer yield in the peripheral mid-zones and apical zones suggests the necessity for concentrated sampling of these zones in repeat biopsy protocols.     

Novel therapeutics for the management of castration-resistant prostate cancer (CRPC)

Androgen-deprivation therapy is the initial treatment for metastatic prostate cancer. Although highly effective, all men who live long enough will eventually experience disease progression and develop castration resistance. Patients who have castration-resistant prostate cancer (CRPC) have a median survival of ≈1-3 years. When evaluating novel therapies for CRPC, one must consider the endpoints measured for determination of response. We will discuss PSA, circulating tumour cells, progression-free survival, overall survival, and other endpoints used in clinical trials. Docetaxel and sipuleucel-T are currently the preferred first-line treatment options for patients with CRPC; cabazitaxel is a new option for patients after docetaxel failure. Patients with CRPC historically have very poor survival, underscoring the unmet need for novel therapeutics. Although many agents appear promising, well-designed randomized phase III trials are necessary to establish their impact on survival and health-related quality of life. Promising new therapies include hormonal agents, such as abiraterone and MDV3100, as well as other novel immunotherapeutics and anti-prostate-specific membrane antigen therapies. In the future, we anticipate therapies tailored to individual patients' malignancies using various molecular analyses.     

Accuracy of life tables in predicting overall survival in patients after radical prostatectomy

OBJECTIVE

To test the accuracy of life tables (LT), the standard tool for predicting life‐expectancy (LE), but the accuracy of which is unknown in patients with prostate cancer, where the 10‐year LE is a widely accepted threshold for the delivery of definitive therapy.

PATIENTS AND METHODS

We tested the accuracy of predictions of LE from LT in 9678 men treated with radical prostatectomy (RP) for prostate cancer. The predictions of LE from LT at 10 years after RP were compared to Kaplan Meier‐derived 10‐year survival values. Moreover, the accuracy of LT predictions was quantified in a Cox‐regression using Harrell’s concordance index. To control for the effect of prostate cancer mortality, analyses were repeated in a subset of 5955 patients with no evidence of disease recurrence. Additional stratification schemes were applied to control for age and comorbidity.

RESULTS

At RP, the median age was 64 years, the median Charlson Comorbidity Index (CCI) was 1 and the median LT‐derived LE was 16 years. The median actuarial survival was not reached (mean 12.4 years). In the whole group the LT‐predicted 10‐year survival was 96.8%, vs an observed of 75.3%. In men with no disease recurrence the LT‐predicted survival was 97.3%, vs 81.1% observed. After age and CCI stratification, LT overestimated the 10‐year survival the most in those aged 65–69 years and in patients with CCI scores of >2.

CONCLUSION

The overestimation of LE can lead to overtreatment of prostate cancer, especially in those men who die early from other causes.     

Future opportunities for the diagnosis and treatment of prostate cancer

Despite recent advances, current diagnostic tests and treatment of prostate cancer have limitations. In the last few years, numerous biomolecules have been investigated with the aim of improving diagnosis, including kallikrein-like proteases, growth factors and neuroendocrine markers. Analysis of susceptibility genes has also been a focus of attention. Extensive research into new therapeutic approaches is also underway, including targeting angiogenesis, immune regulation and stromal-epithelial interactions. Gene therapy, gene chip technology and proteomics have emerged as promising innovations. The host of novel diagnostic markers and therapies require appropriate validation, both phenotypical and functional. A further consideration is the need to re-evaluate clinical trial design and end points to facilitate progression of promising targets through the clinical trial process. Overall, the outlook for the treatment of prostate cancer looks promising, with any advances likely to require both a multimodal and multidisciplinary approach.