Success and failure of single-modality treatment for early prostate cancer

Many men who undergo radical prostatectomy or radiotherapy for early prostate cancer have an excellent outcome; however, a significant proportion subsequently experience disease recurrence and/or cancer-related death. Adjuvant hormonal therapy after treatment of curative intent is given with the aim of eradicating undetected cancer cells outside the surgical margins or radiation field and/or micrometastatic disease. In the analogous setting of early breast cancer, adjuvant hormonal therapy is already established as standard care. Efficacy and tolerability data from the ongoing bicalutamide ('Casodex') Early Prostate Cancer program are expected to determine the role of adjuvant hormonal therapy with antiandrogens in early prostate cancer.     

Immediate Treatment with Bicalutamide, 150 mg/d, Following Radiotherapy in Localized or Locally Advanced Prostate Cancer

Previous studies and meta-analyses have made it clear that some subgroups of prostate cancer patients who have received radiotherapy should benefit from immediate adjuvant hormonal therapy. A cohort totaling 1370 patients who received radiotherapy for early nonmetastatic prostate cancer is currently enrolled in three ongoing, randomized, double-blind, placebo-controlled trials investigating the role of bicalutamide ('Casodex') 150 mg/d as adjuvant to standard care (the bicalutamide Early Prostate Cancer program). At preliminary analysis, conducted after a median follow-up of 3 years, adjuvant therapy with bicalutamide 150 mg/d significantly reduced the risk of objective progression by 37% compared with radiotherapy alone (HR 0.63, 95% CI, 0.46-0.85, P = .0024). Initial results demonstrate that bicalutamide 150 mg/d given as immediate adjuvant therapy following radiotherapy in men with early nonmetastatic prostate cancer has benefits over radiotherapy alone.     

Management of clinically localized prostate cancer

Critics of screening have stated that early detection of prostate cancer does not necessarily reflect a diminishing death rate from the disease. However, several recent reports have demonstrated that the death rate from prostate cancer is decreasing, representing the most compelling validation for aggressive screening. Prostate cancer can be halted only if there is no evidence of systemic or regional metastases and the disease is confined to the surgical field or the radiation template. Surgeons and radiation oncologists must make a concerted effort to exclude men with regional and systemic metastases who are unlikely to benefit from treatment. With the widespread acceptance of prostate-specific antigen screening, a greater proportion of men are being diagnosed with clinically localized prostate cancer. Both radical prostatectomy and radiation therapy are able to halt disease spread in this significant subset of men, but survival outcomes indicate that radical prostatectomy is a more reliable treatment than radiation therapy for clinically localized prostate cancer. Overall, the immediate treatment-related morbidity of radical prostatectomy and radiation therapy in the modern era is quite low. Radical prostatectomy and radiation therapy appear to have a similar impact on continence and erectile function. There is a need for neoadjuvant and adjuvant therapies that can be utilized in those cases where radical prostatectomy and radiation are less likely to completely eradicate or destroy the cancer.     

Emerging pharmacologic therapies for prostate cancer

The last decade has seen explosive growth in the therapy of prostate cancer. Three areas of therapeutics are emerging: 1) new compounds with novel uses; 2) available compounds with new applications; and 3) new compounds applied to established indications. The novel compounds target specific receptor sites of cancer pathways and attack cancer cells with less effect on normal tissue. Earlyphase trials with compounds targeting the endothelin-A and EGF receptors have shown encouraging results in hormone-refractory prostate cancer. In addition, the Early Prostate Cancer Trial of over 8000 men is currently underway to determine the benefit of adjuvant androgen ablation with bicalutamide in men with localized prostate cancer. Early results show a significant 42% reduction in the progression of the disease in the bicalutamide treatment arm. Further, in large, phase 3 clinical trials in patients needing androgen ablation, the GnRH antagonist abarelix caused no testosterone surge and demonstrated a significantly more rapid decline in serum testosterone to the castrate level than did an LHRH agonist analogue. Abarelix should thus have application as a monotherapy in patients who need a rapid onset of action or are at high risk of complications from the clinical flare seen with LHRH agonists. Abarelix also uniquely caused a sustained decline in serum FSH levels, which have been shown in vitro to stimulate prostate cancer cell growth. If these favorable effects can be duplicated in patients, abarelix might also offer a survival benefit.     

Selecting treatment for high-risk, localized prostate cancer: the case for radiation therapy

Prostate cancers that clinically appear to be localized may nonetheless respond poorly to curative treatment. Pretreatment prostate-specific antigen (PSA) level, biopsy Gleason score, and percentage of positive biopsies are all at least as important as clinical stage in predicting treatment outcome. A patient with a nonpalpable tumor, stage T1c disease, serum PSA of 12 ng/mL, and a Gleason score of 8 to 10 in 2 of 12 biopsy cores has a relatively poor prognosis. In a high-risk patient such as this one, the recommended treatment strategy involves a combination of brachytherapy and conformal external beam radiotherapy. In studies comparing treatments in patients stratified according to a variety of risk measures, this combination has shown biochemical disease-free survival rates superior to those seen following radical prostatectomy. The role of androgen suppression remains unclear.     

New techniques and management options for localized prostate cancer

Prostate cancer is diagnosed in younger men who want treatment that does not compromise their quality of life, take time away from work, or cause worrisome side effects. Laparoscopic radical prostatectomy, robot-assisted laparoscopic radical prostatectomy, and third-generation cryotherapy are modifications of previously used techniques in the treatment of prostate cancer and are presented in this article. Although some or all of the outcomes might be expected to change in the future, the urologic surgeon is left to select an approach, presumably on the basis of the experience, level of training, and care pathways at his or her institution.     

AT‐101 (R‐(−)‐gossypol acetic acid) enhances the effectiveness of androgen deprivation therapy in the VCaP prostate cancer model

Prostate cancer remains a leading cause of cancer death in American men. Androgen deprivation therapy (ADT) is the most common treatment for advanced prostate cancer patients; however, ADT fails in nearly all cases resulting in castration resistant or androgen‐insensitive (AI) disease. In many cases, this progression results from dysregulation of the pro‐survival Bcl‐2 family proteins. Inhibition of pro‐survival Bcl‐2 family proteins, therefore, may be an effective strategy to delay the onset of AI disease. Gossypol, a small molecule inhibitor of pro‐survival Bcl‐2 family proteins, has been demonstrated to inhibit AI prostate cancer growth. The apoptotic effect of gossypol, however, has been demonstrated to be attenuated by the presence of androgen in a prostate cancer xenograft mouse model (Vertebral Cancer of Prostate [VCaP]) treated with AT‐101 (R‐(?)‐gossypol acetic acid). This study was undertaken to better understand the in vitro effects of androgen receptor (AR) on AT‐101‐induced apoptosis. VCaP cells treated with AT‐101 demonstrated an increase in apoptosis and downregulation of Bcl‐2 pro‐survival proteins. Upon AR activation in combination with AT‐101 treatment, apoptosis is reduced, cell survival increases, and caspase activation is attenuated. Akt and X inhibitor of apoptosis (XIAP) are downregulated in the presence of AT‐101, and AR stimulation rescues protein expression. Combination treatment of bicalutamide and AT‐101 increases apoptosis by reducing the expression of these pro‐survival proteins. These data suggest that combination therapy of AT‐101 and ADT may further delay the onset of AI disease, resulting in prolonged progression‐free survival of prostate cancer patients. J. Cell. Biochem. 110: 1187–1194, 2010. Published 2010 Wiley‐Liss, Inc.     

Experience with 125I brachytherapy as a radical treatment for prostate cancer at the Russian X-ray Radiology Research Center

Prostate cancer is one of the most common malignancies among males. 125I brachytherapy is a current, effective, comparatively safe, and easy-to-reproduce treatment. The Russian X-ray Radiology Research Center has implanted 125I microsources in patients with localized and locally advanced prostate cancer since 2003; 689 125I implantations were performed in the past year. Tumor-specific survival after brachytherapy did not differ greatly from that following radical prostatectomy. Thus, brachytherapy is a current high-tech treatment for prostate cancer. This therapy shows fewer adverse postradiation effects than radiation teletherapy.     

Treatment of localized prostate cancer

This article provides an overview of treatment of localized prostate cancer, which was discussed in detail in the second scientific session of the 16th International Prostate Cancer Update. The role of radical prostatectomy in localized disease was presented by Bob Djavan, MD. Benefits and risks of radical prostatectomy were addressed by Gerald Chodak, MD. Robert E. Donohue, MD, presented the role of radical prostatectomy in Gleason grade 8, 9, and 10 tumors. Impact of positive margins on outcomes after radical prostatectomy was presented by James A. Eastham, MD. E. David Crawford, MD, provided an overview of the role of targeted therapy. Indications and results of brachytherapy were presented by Mack Roach, III, MD. Finally, Michael J. Manyak, MD, described the evolution of radioimmunoscintigraphy and clinical outcomes data.     

Generation of “Virtual” Control Groups for Single Arm Prostate Cancer Adjuvant Trials

It is difficult to construct a control group for trials of adjuvant therapy (Rx) of prostate cancer after radical prostatectomy (RP) due to ethical issues and patient acceptance. We utilized 8 curve-fitting models to estimate the time to 60%, 65%, … 95% chance of progression free survival (PFS) based on the data derived from Kattan post-RP nomogram. The 8 models were systematically applied to a training set of 153 post-RP cases without adjuvant Rx to develop 8 subsets of cases (reference case sets) whose observed PFS times were most accurately predicted by each model. To prepare a virtual control group for a single-arm adjuvant Rx trial, we first select the optimal model for the trial cases based on the minimum weighted Euclidean distance between the trial case set and the reference case set in terms of clinical features, and then compare the virtual PFS times calculated by the optimum model with the observed PFSs of the trial cases by the logrank test. The method was validated using an independent dataset of 155 post-RP patients without adjuvant Rx. We then applied the method to patients on a Phase II trial of adjuvant chemo-hormonal Rx post RP, which indicated that the adjuvant Rx is highly effective in prolonging PFS after RP in patients at high risk for prostate cancer recurrence. The method can accurately generate control groups for single-arm, post-RP adjuvant Rx trials for prostate cancer, facilitating development of new therapeutic strategies.     

The clinical burden of prostate cancer in Canada: forecasts from the Montreal Prostate Cancer Model

OBJECTIVES: The incidence of prostate cancer is increasing, as is the number of diagnostic and therapeutic interventions to manage this disease. We developed a Markov state-transition model--the Montreal Prostate Cancer Model--for improved forecasting of the health care requirements and outcomes associated with prostate cancer. We then validated the model by comparing its forecasted outcomes with published observations for various cohorts of men. METHODS: We combined aggregate data on the age-specific incidence of prostate cancer, the distribution of diagnosed tumours according to patient age, clinical stage and tumour grade, initial treatment, treatment complications, and progression rates to metastatic disease and death. Five treatments were considered: prostatectomy, radiation therapy, hormonal therapies, combination therapies and watchful waiting. The resulting model was used to calculate age-, stage-, grade- and treatment-specific clinical outcomes such as expected age at prostate cancer diagnosis and death, and metastasis-free, disease-specific and overall survival. RESULTS: We compared the model''s forecasts with available cohort data from the Surveillance, Epidemiology and End Results (SEER) Program, based on over 59,000 cases of localized prostate cancer. Among the SEER cases, the 10-year disease-specific survival rates following prostatectomy for tumour grades 1, 2 and 3 were 98%, 91% and 76% respectively, as compared with the model''s estimates of 96%, 92% and 84%. We also compared the model''s forecasts with the grade-specific survival among patients from the Connecticut Tumor Registry (CTR). The 10-year disease-specific survival among the CTR cases for grades 1, 2 and 3 were 91%, 76% and 54%, as compared with the model''s estimates of 91%, 73% and 37%. INTERPRETATION: The Montreal Prostate Cancer Model can be used to support health policy decision-making for the management of prostate cancer. The model can also be used to forecast clinical outcomes for individual men who have prostate cancer or are at risk of the disease.     

Inhibition of androgen-independent prostate cancer cell growth is enhanced by combination therapy targeting Hedgehog and ErbB signalling

Background  

Prostate cancer is a leading cause of male cancer specific mortality. When cure by radical prostatectomy is not possible the next line of prostate cancer treatment is androgen deprivation. However prolonged androgen deprivation often results in relapse and androgen-independent prostate cancer that is inevitably fatal despite optimal chemotherapy. The Hedgehog signalling pathway has recently been implicated in prostate cancer development and metastasis. EGFR or ErbB2 expression has been also correlated with androgen independence, shorter survival and metastasis.     

Single Positive Lymph Node Prostate Cancer Can Be Treated Surgically without Recurrence

Purpose/Objectives

To investigate pN1 prostate cancer (PCa) patients treated surgically without immediate adjuvant treatment.

Materials and Methods

We analyzed the database of 2316 patients at our institution who underwent robot-assisted radical prostatectomy (RARP)/radical prostatectomy (RP) between July 2005 and November 2012. 87 patients with pN1 PCa and received no neoadjuvant and immediate adjuvant therapy were included in the study. Included pN1 PCa patients were followed up for median of 60 months. Biochemical recurrence (BCR)-free survival, metastasis-free survival (MFS), cancer specific survival (CSS), and overall survival (OS) rates were determined by using Kaplan-Meier analysis. Cox regression analysis was performed to investigate the impact of prostate-specific antigen (PSA) level, Gleason score, extraprostatic extension, seminal vesicle invasion, perineural invasion, lymphovascular invasion, positive surgical margin, tumor volume, early post-operative PSA(6 weeks), PSA nadir, lymph node yield, and number of pathologically positive lymph nodes on survival.

Results

The 5-year OS rate of patients was 86.1%, while the CSS rate was 89.6%. The metastasis-free and BCR-free survival rates were 71% and 19.1%, respectively, and each was significantly correlated with the number of positive lymph nodes on log rank tests (p = 0.004 and p = 0.039, respectively). The presence of 2 or more pathologically positive LNs (HR:2.20; 95% CI 1.30–3.72; p = 0.003) and a Gleason score ≥8 (HR: 2.40;95% CI: 1.32–4.38; p = 0.04) were significant negative predictors of BCR free survival on multivariable regression analysis. Furthermore, the presence of 2 or more positive lymph nodes (HR: 1.06; 95% CI 1.01–1.11; p = 0.029) were significant negative predictors of metastasis-free survival on multivariable regression analysis. Additionally, in the patients who had no BCR without adjuvant treatment 9 patients out of 10 (90%) had single positive LN and 5 patients out of 10 (50%) had Gleason score 7. Therefore, single positive LN, and Gleason scores ≤7 have significantly low risk of disease progression.

Conclusions

pN1 PCa patients have heterogenous clinical courses. Patients with single positive LN, and Gleason scores ≤7 have low risk of recurrence. Close observation with delayed adjuvant hormone therapy can be considered in these patients.     

前列腺癌根治术治疗不同分级前列腺癌患者的临床研究

目的:探究前列腺癌根治术在不同危险度前列腺癌患者中治疗的临床效果,为临床前列腺癌患者的治疗提供依据。方法:选择2008年1月~2015年12月期间我院94例前列腺癌患者为研究对象,根据D'Amico评分将其分为高危、中危及低危三组,收集患者基线资料、术后随访资料,并比较三组手术并发症;采用Kaplan-Meier分析法计算三组患者生存率,并采用Log-rank检验比较不同危险组的生存率。结果:高危组患者进行开放性手术人数多于中危组和低危组,且中危组多于低危组,差异具有统计学意义(P0.05);高危组患者术前Gleason评分和PAS水平高于中危组和低危组,且中危组高于低危组,差异具有统计学意义(P0.05);术后5年高危组患者完全控尿率显著低于中危组和低危组(P0.05);三组患者间5年无生化复发率比较无统计学意义(P0.05)。结论:前列腺癌根治术治疗高危前列腺患者较中、低危患者疗效较差,但仍可达到较好的疗效,可在临床推广使用。     

Is it possible to provide a prognosis after radical prostatectomy for prostate cancer by means of a PSA regression model?

BACKGROUND: For over 15 years, studies have been done to evaluate the elimination kinetics of the prostate-specific antigen (PSA) after radical prostatectomy. Even though evaluation of PSA regression in the two-compartment model has become established, no clear data are currently available as to whether a statement can be made with regard to tumor prognosis from a computation of the PSA half-life (PSA-HL). This study focuses on the determination of the PSA-HL in the two-compartment model and on its correlation with the biochemical recurrence-free survival. In addition, a computer program is being developed to simplify the determination of PSA-HL. MATERIAL AND METHODS: Seventy-seven prospective patients were examined who subsequently had a radical prostatectomy at our facility without neoadjuvant or adjuvant hormone deprivation. In addition to preoperative measurement of the PSA value (dO), PSA determinations were carried out postoperatively on days 5, 10 and 60, and at four-monthly intervals thereafter (mean follow-up: 16 months). By means of the computer program developed for this purpose, CTK.TumW, the PSA half-lives for the first (d0-d5, PSA-HL1) and second (d5-d10, PSA-HL2) compartments were subsequently determined and their effect on biochemical recurrence-free survival was assessed. RESULTS: PSA-HL1 and PSA-HL2 were 1.89 (+/- 0.03) and 3.39 (+/- 0.14) days, respectively. Whilst PSA-HL1 did not permit any prognostic statement, the median PSA-HL in the second compartment between patients with and without disease progression differed significantly (4.44 versus 3.12 days; p < 0.001). Discrimination analysis produced a cutoff of 3.8 days for the second compartment; patients with a PSA-HL2 > or = 3.8 days had a significantly worse biochemical recurrence-free survival after 18 months than the other patients (27% versus 93%; p < 0.001). CONCLUSION: The PSA regression kinetics after radical prostatectomy follows a two-compartment model in which the prognostic value of the PSA-HL1 is limited. When a cutoff of 3.8 days is used, evaluation of the PSA-HL in compartment 2 (d5-10) appears to permit a prognostic statement. Due to the limited postsurgical follow-up, the disease process was only assessed as biochemical recurrence-free survival, and a longer follow-up will be necessary to generate data on progression-free survival.     

MANAGEMENT OF EARLY PROSTATIC CARCINOMA

It is important to make a diagnosis of prostatic carcinoma as early as possible, because early treatment gives the best results whether radical prostatectomy is done or endocrine therapy used. Open perineal biopsy is the most accurate method of making a diagnosis. Perineal needle biopsy or the newer approach of transrectal needle biopsy is probably about 75 per cent accurate in making a diagnosis.Ten-year survival with conservative therapy, as determined in a review of a series of cases, was 50 per cent—about the same as that following radical prostatectomy; but the patients with prostatectomy are clinically free of malignant disease whereas the former are not. Radical prostatectomy is indicated in a few selected cases.The results from endocrine therapy begun immediately after diagnosis are significantly better than those from delayed treatment. Orchiectomy and estrogens promise a little longer survival than estrogens alone.     

Radiation Therapy after Radical Prostatectomy for Prostate Cancer: Evaluation of Complications and Influence of Radiation Timing on Outcomes in a Large,Population-Based Cohort

PurposeTo evaluate the influence of timing of salvage and adjuvant radiation therapy on outcomes after prostatectomy for prostate cancer.MethodsUsing the Surveillance, Epidemiology, and End Results-Medicare linked database, we identified prostate cancer patients diagnosed during 1995–2007 who had one or more adverse pathological features after prostatectomy. The final cohort of 6,137 eligible patients included men who received prostatectomy alone (n = 4,509) or with adjuvant (n = 894) or salvage (n = 734) radiation therapy. Primary outcomes were genitourinary, gastrointestinal, and erectile dysfunction events and survival after treatment(s).ResultsRadiation therapy after prostatectomy was associated with higher rates of gastrointestinal and genitourinary events, but not erectile dysfunction. In adjusted models, earlier treatment with adjuvant radiation therapy was not associated with increased rates of genitourinary or erectile dysfunction events compared to delayed salvage radiation therapy. Early adjuvant radiation therapy was associated with lower rates of gastrointestinal events that salvage radiation therapy, with hazard ratios of 0.80 (95% CI, 0.67–0.95) for procedure-defined and 0.70 (95% CI, 0.59, 0.83) for diagnosis-defined events. There was no significant difference between ART and non-ART groups (SRT or RP alone) for overall survival (HR = 1.13 95% CI = (0.96, 1.34) p = 0.148).ConclusionsRadiation therapy after prostatectomy is associated with increased rates of gastrointestinal and genitourinary events. However, earlier radiation therapy is not associated with higher rates of gastrointestinal, genitourinary or sexual events. These findings oppose the conventional belief that delaying radiation therapy reduces the risk of radiation-related complications.     

Prognostic values of morphological and clinical parameters in pT2-pT3 prostate cancer in elderly people

Prostate cancer is a disease of elderly men, the incidence of which increases in an age dependent manner. This study presents the correlation of clinical and morphological parameters in locally confined (pT2) and locally advanced (pT3) prostate cancer. We analyzed a group of elderly men treated with radical prostatectomy in the period 1999-2008 in the University Hospital Rijeka. We found no statistical association between pT stage and age categories, preoperative prostate-specific antigen, digitorectal examination and biopsy Gleason score. There was a significant correlation of higher Gleason score in prostate specimens after radical prostatectomy and a higher frequency of a positive surgical margin in tumors with pT3 than in pT2 stage (p = 0.003; p = 0.011 respectively). Recurrence-free survival was shorter in patients with tumors with positive surgical margins as well as in patients with pT3 stage (p = 0.030; p = 0.001 respectively). We conclude that higher tumor grade and positive surgical margins are indicators of a worse prognosis in our patients.     

Influence of bicalutamide with or without tamoxifen or anastrozole on insulin-like growth factor 1 and binding proteins in prostate cancer patients

BACKGROUND: There is growing evidence that IGF-1 and binding proteins may be involved in prostate cancer promotion and progression. PATIENTS AND METHODS: IGF-1 and binding proteins (IGFBP-1 and 3) serum levels were measured at baseline and after 3 and 6 months of treatment in a selected group of patients with prostate cancer who were randomly assigned to treatment with bicalutamide, bicalutamide plus anastrozole or bicalutamide plus tamoxifen in a comparative study investigating the role of pharmacological medication in the development of bicalutamide-induced gynecomastia. RESULTS: Bicalutamide monotherapy does not appear to alter the IGF-1/IGFBP system. In fact, the increase in IGF-1 levels induced by this treatment was paralleled by comparable increases in binding protein (IGFBP-3). No major changes from baseline up to month 6 either in IGF-1 or in IGFBP-1 and 3 were observed in the bicalutamide plus anastrozole arm. The addition of tamoxifen to bicalutamide produced a sharp decrease in IGF-1 levels (p<0.001) coupled with an increase in both IGFBP-1 (p=0.001) and, to a lesser extent, IGFBP-3 (p=0.5). CONCLUSIONS: The concurrent administration of tamoxifen and bicalutamide reduces the synthesis and bioavailability of IGF-1. Moreover, increased binding protein levels might exert antiproliferative and proapoptotic effects on prostate cancer cells, independently of the IGF-1/IGF receptor-mediated survival system. Both effects might have a synergistic inhibitory influence on prostate cancer growth.     

Clinical experience with gene therapy for the treatment of prostate cancer

Localized prostate cancer can be treated effectively with radical prostatectomy or radiation therapy. The treatment options for metastatic prostate cancer are limited to hormonal therapy; hormone-refractory cancer is treated with taxane-based chemotherapy, which provides only a modest survival benefit. New treatments are needed. The gene for the initiation of prostate cancer has not been identified; however, gene therapy can involve tumor injection of a gene to kill cells, systemic gene delivery to target and kill metastases, or local gene expression intended to generate a systemic response. This review will provide an overview of the various strategies of cancer gene therapy, focusing on those that have gone to clinical trial, detailing clinical experience in prostate cancer patients.