Global update on defining and treating high-risk localized prostate cancer with leuprorelin: an Asian perspective

Data from the Japanese Urological Society showed that, in Japan, almost half of patients with localized prostate cancer are treated with hormone therapy (HT), regardless of disease stage, and that radiation therapy (RT) is also widely used to treat high-risk patients. A retrospective study was undertaken in Japan to evaluate the potential benefits of using primary HT in locally advanced prostate cancer. Of 628 patients in the study, 63.5% were treated with combined androgen blockade (CAB; luteinizing hormone-releasing hormone agonists plus an antiandrogen) and 36.5% with medical or surgical castration. CAB treatment was significantly better than hormone monotherapy for disease-specific survival. The results also showed that, even if a patient is classified as 'high-risk', a good prognosis could normally be predicted based on certain variables: if their initial prostate-specific antigen (PSA) level was < or = 20 ng/mL, their Gleason score was < or = 6, and their nadir PSA decreased to < or = 0.2 ng/mL within 6 months of HT. In this subgroup of 'good responders', any treatment, be it prostatectomy, RT or CAB, is likely to be effective. However, in 'poor responders', combined therapies with CAB and high-dose rate brachytherapy are likely to be needed for a clinical response. While HT is effective, it might be associated with a reduction in the patient's quality of life (QoL) due to adverse effects, e.g. a reduction in sexual function. Results from the analysis of QoL questionnaires completed by men of different ages with prostate cancer found that only sexual function, and not other QoL variables, in men aged 50-59 years appeared to be reduced in men who had HT, compared to age-matched controls.     

Global update on defining and treating high-risk localized prostate cancer with leuprorelin: a Japanese perspective--the effect of primary androgen deprivation therapy on stage C prostate cancer

Stage C prostate cancer, where the tumour has extended beyond the capsule of the prostate, is typically a high-risk disease. According to the National Cancer Institute Physician Data Query the treatments of choice for stage C disease comprise external beam radiation therapy (with or without the addition of adjuvant hormone therapy), androgen deprivation by either surgery or hormone therapy, radical prostatectomy, or careful observation. From 2001, the Japanese Urological Association initiated computer-based registration of all patients with prostate cancer in Japan. Data show that overall, 57% of all patients and 46% of those with T1c to T3 disease had primary androgen deprivation therapy (PADT). Similarly, the Japanese Prostate Cancer Group undertook a large-scale epidemiological surveillance study in Japan and found that the most commonly used hormone therapy is PADT, regardless of disease stage. To date, two randomized, controlled trials of the effect of PADT on stage C prostate cancer in elderly (> or =75 years old) patients have been undertaken in Japan. The results showed that patients with locally advanced prostate cancer treated with PADT are likely to have a life-expectancy similar to that of the normal population. In one study, combined androgen blockade (CAB) with leuprorelin plus chlormadinone appeared to prolong time to disease progression when compared with leuprorelin monotherapy, but there was no difference in survival between these treatment groups. In a second study CAB with an luteinizing hormone-releasing hormone (LHRH) agonist plus bicalutamide was found to prolong time to progression when compared with LHRH agonist monotherapy, but survival results for these regimens are still awaited.     

Global update on defining and treating high-risk localized prostate cancer with leuprorelin: a USA perspective--identifying men at diagnosis who are at high risk of prostate cancer death after surgery or radiation therapy

Prostate-specific antigen doubling time (PSA-DT) after surgery or radiotherapy (RT) is known to be a predictive factor for death from prostate cancer (prostate cancer-specific mortality, PCSM). An analysis of two multi-institutional databases, including 8669 men with prostate cancer treated with surgery or RT, found that a PSA-DT of <3 months, and the specific value of the PSA-DT when > or = 3 months, appeared to be surrogate endpoints for PCSM after surgery or RT. While many PSA failures occur after local therapy for localized prostate cancer, few of these patients go on to die from their disease, so it is important to identify other factors associated with PCSM, so that the subgroup of high-risk patients can be identified. An analysis was undertaken to determine whether patients at risk of PCSM could be identified using information available at diagnosis. The results showed that risk factors for PCSM were a PSA velocity of >2.0 ng/mL/year, a Gleason score of 8-10 and an increasing PSA level. However, the most important risk factor that had an impact on both PCSM and all-cause mortality was a PSA velocity of >2.0 ng/mL/year. PSA kinetics are being increasingly used in the setting of rising PSA levels after radical prostatectomy or RT, and several studies showed that the rate of increase in PSA level at the time of recurrence is closely associated with time to cancer death. A PSA-DT of <3 months is associated with a poor prognosis, and represents 15-20% of PSA failures in the general population and 6-7% of PSA failures in a screened population, such as those included in clinical trials. Better risk-assessment models are needed to help to identify at an early stage men who are at high risk of prostate cancer death and those who are at low risk, so that each subgroup can receive the most appropriate therapy for their disease.     

Neoadjuvant therapy before radical prostatectomy in high-risk localized prostate cancer: defining appropriate endpoints

High-risk localized prostate cancer remains a vexing problem for clinicians. Definitive local treatments such as surgery and radiation therapy cure only a minority of these patients. As a result, efforts are being made to reduce the risk of recurrence by using chemotherapy and new agents before, during or after definitive local therapy. Neoadjuvant androgen deprivation therapy has yielded disappointing results when combined with surgery. Chemotherapy in the management of localized disease is evolving, and preliminary studies are just now being completed. Although these agents have established activity and acceptable toxicity in the hormone-refractory setting, more extensive use of them in patients with androgen-dependent disease will require data from randomized studies to determine overall efficacy. New molecular-targeted therapies are promising and hold the greatest hope that outcomes in early disease may be improved with early use of systemic therapy. The neoadjuvant surgical model also has promise in assessing the activity of new drugs, because it provides a means to determine molecular effects of specific agents, along with standard pathologic and clinical parameters of efficacy.     

Neoadjuvant mitoxantrone and docetaxel for high-risk localized prostate cancer

PURPOSE: Currently available treatment modalities for high-risk clinically localized prostate cancer have limited chances of achieving complete tumor elimination because of either inadequate local or metastatic tumor eradication. The goal of this phase I/II study is to evaluate the safety and efficacy of neoadjuvant docetaxel and mitoxantrone before prostatectomy. MATERIALS AND METHODS: A total of 22 men with high-risk clinically localized prostate cancer underwent weekly treatment with docetaxel (35 mg/m(2)), with increasing doses of mitoxantrone (2-5 mg/m(2)) for a 12 of 16-week treatment cycle before prostatectomy. Testosterone and prostate-specific antigen (PSA) measurements were made before and after chemotherapy. RESULTS: The maximally tolerated dose for mitoxantrone was 4 mg/m(2), and the primary toxicity was neutropenia. Testosterone levels were maintained throughout treatment. PSA reductions were observed in 95% of patients, with a median reduction of 41%. The surgery was well tolerated after chemotherapy, without any major complications. Negative surgical margins were attained in 76% of patients. CONCLUSIONS: Administration of multi-agent chemotherapy before prostatectomy was safe in this population. This regimen appeared to have antineoplastic activity as evidenced by PSA reductions in the absence of significant testosterone changes. The benefit of chemotherapy for improving surgical margin rates could not be determined outside of a phase III trial because the effect of patient or surgeon factors could not be dissected from the potential effect of neoadjuvant therapy. Continued study of novel agents in the neoadjuvant setting is warranted because this approach allows for the rapid identification of active agents and for molecular investigation into the mechanism of drug activity.     

Molecular correlates of intermediate- and high-risk localized prostate cancer

Clinicopathologic parameters, including Gleason score, remain the most validated prognostic factors for patients diagnosed with localized prostate cancer (PCa). However, patients of the same risk groups have exhibited heterogeneity of disease outcomes. To improve risk classification, multiple molecular risk classifiers have been developed, which were designed to inform beyond existing clinicopathologic classifiers. Alterations affecting tumor suppressors and oncogenes, such as PTEN, MYC, BRCA2, and TP53, which have been long associated with aggressive PCa, demonstrated grade-dependent frequency of alterations in localized PCas. In addition to these genetic hallmarks, several RNA-based commercial tests have been recently developed to help identify men who would benefit from earlier interventions. Large genomic studies also correlate germline genetic alterations and epigenetic features with adverse outcomes, further strengthening the link between the risk of metastasis and a stepwise accumulation of driver molecular lesions.     

根治性前列腺切除术和放射疗法治疗高危前列腺癌的研究进展

目前,临床上对高危前列腺癌(PCa)的定义尚未统一,但其中D'Amico危险分层系统更为学界所接受。其对高危PCa的定义为PSA20μg/L,Gleason评分8~10分,临床分期≥T2c。由于高危PCa在治疗后易复发和转移,因此选择合适的治疗方案成为关键。目前针对高危PCa最重要的一线治疗方法为根治性前列腺切除术(RP)或放射治疗(RT),然而其最佳治疗方案仍未达成共识。本文综述RP和RT治疗高危PCa的研究进展。     

Radical prostatectomy for high-risk clinically localized prostate cancer: a prospective single institution series

Objective:

The objective of this paper is to report on the pathologic and biochemical progression-free outcomes of patients who underwent radical prostatectomy for high-risk localized prostate cancer.

Methods:

Data was collected prospectively from 299 patients who underwent radical prostatectomy for high-risk clinically localized prostate cancer by 2 surgeons at a single institution. High risk was defined as 1 or more of 3 adverse factors: prostate-specific antigen (PSA) >20, biopsy Gleason score 8 to 10 and clinical stage T3. PSA recurrence was defined as PSA >0.4 ng/mL or any salvage therapy.

Results:

Median age was 63.3 years (46.1–75.9). Median follow-up was 4.7 years (range 0.5–17.3 years). PSA at diagnosis was >20 ng/mL in 31.4%. Biopsy Gleason score was 8 to 10 in 66.9%. Clinical stage was T3 in 24.4%. 81.6% of patients had a single baseline risk factor, 15.7% had 2 risk factors and 2.7% had all 3 risk factors. Neoadjuvant therapy was administered to 184 patients (61.5%). Pathologic stage was organ-confined in 39.6%, specimen-confined in 26%, non-specimen-confined in 26.4%, and 8% had lymph node positive disease. Overall survival, cancer-specific survival and biochemical progression-free survival was 99%, 99.67% and 70.2%, respectively. Univariate analysis showed that PSA at diagnosis, percentage of cores positive and number of risk factors were predictors of PSA recurrence (p < 0.05). Multivariate analysis showed that PSA at diagnosis was an independent predictor of PSA recurrence (p < 0.05).

Conclusion:

Radical prostatectomy is associated with favourable biochemical progression-free, clinical and overall survival in selected men with high-risk localized prostate cancer, and should therefore be considered an option in these patients. Baseline PSA >20 ng/mL is a significant independent predictor of PSA recurrence.     

Prevention of prostate cancer with finasteride: US/European perspective

PURPOSE: Prostate cancer is the most common male cancer, affecting one man in six. Prevention of this disease, even in a subset of patients would have a significant impact on public health. The results of the National Cancer Institute-sponsored Prostate Cancer Prevention Trial demonstrate that finasteride causes a substantial risk reduction across all known risk groups. We herein amplify on the results of this trial to assist patients and physicians in reaching individualized decisions. MATERIALS AND METHODS: The results of the Prostate Cancer Prevention Trial were reviewed. RESULTS: The PCPT demonstrated a 24.8% reduction in prostate cancer risk with the administration of finasteride. High-grade cancers were noted in 6.4% of finasteride patients compared to 5.1% of men receiving placebo. The increase in high-grade tumors was seen within one year of finasteride exposure and did not increase over time. This observation, combined with previous evidence demonstrating an alteration in cytologic and architectural features of prostate cancer with hormonal therapy suggests that the differences in high-grade disease may be an artifact and that application of Gleason grading to these tumors may not be appropriate. DISCUSSION: Men should be presented the benefits and risks of taking finasteride and be assisted in integrating their sexual and urinary symptoms into their decision-making process. Blanket statements for or against the use of this medication ignore patient preferences and differential risk-benefit profiles from finasteride.     

An update on randomized clinical trials in localized and locoregional prostate cancer

It is important that treatment decisions be based upon scientific data, as opposed to anecdotal experience and expert opinion. The goal of this article is to provide an update on phase III clinical trials in localized and locoregional prostate cancer. Studies comparing surgery and observation for localized disease are reviewed, as are studies comparing various forms of radiotherapy. The effectiveness of certain neoadjuvant and adjuvant therapies is also addressed. Although there are numerous phase III studies ongoing in these areas, there are still large gaps in our understanding of the treatment of localized disease, and additional clinical trials are needed.     

Disease-specific quality of life among patients with localized prostate cancer: an Australian perspective

OBJECTIVES: To examine differences in sexual, urinary and bowel function, and bother, in patients with prostate cancer after treatment with radical prostatectomy (RP) or external beam radiation (EBRT), compared to a convenience sample of men with no diagnosis of prostate cancer, as little is known about the disease-specific health-related quality of life (HRQoL) of men in Australia after treatment for clinically localized prostate cancer. PATIENTS AND METHODS: The study was a retrospective cross-sectional survey of 95 controls, 82 men with localized prostate cancer treated with RP and 39 with EBRT at > or = 2 years before data were collected. Disease-specific HRQoL was assessed using the University of California Los Angeles Prostate Cancer Index, a validated measure that includes six subscales addressing sexual, urinary and bowel symptoms, and level of bother associated with the symptoms. Univariate analyses were conducted to ascertain differences in disease-specific HRQoL among the three groups. To minimize the influence of other factors, age and comorbid medical conditions were included as covariates. RESULTS: Men treated with RP had more sexual and urinary symptoms (both P < 0.001) than those treated with EBRT, and more sexual bother (P < 0.001). Men treated with EBRT reported significantly worse bowel function (P = 0.02) and more bother (P < 0.001) with these symptoms than those who had RP. CONCLUSIONS: Except for bowel dysfunction and the bother associated with these symptoms, disease-specific HRQoL was generally worse after RP than EBRT.     

Radical prostatectomy in high-risk and locally advanced prostate cancer: Mayo Clinic perspective

PurposeMen diagnosed with high-risk prostate cancer represent the cohort of prostate cancer patients at greatest risk for subsequent disease-specific mortality. Unfortunately, however, the classification of high-risk tumors remains imprecise and heterogeneous. There has been a historical reluctance to offer such patients aggressive local treatment, and considerable debate exists regarding the optimal management in this setting.MethodsWe present here our institutional experience, as well as data from several other centers, with radical prostatectomy for high-risk tumors.ResultsWe discuss that surgery affords accurate pathological staging, thereby improving the identification of patients for secondary therapies. Moreover, prostatectomy not only provides durable local disease control but in addition numerous contemporary surgical series in high-risk patients have shown radical prostatectomy to be associated with excellent long-term cancer-specific survival. Further, although studies comparing surgical and radiotherapy modalities in high-risk prostate patients have been wrought with methodological challenges, consistently these observational studies have found equivalent to improved oncologic outcomes when surgery is utilized as the primary treatment.ConclusionsHerein, we review the advantages, long-term outcomes, and technique of surgery for high-risk prostate cancer.     

Management of high-risk localized prostate cancer: the integration of local and systemic therapy approaches

Using a combination of PSA, Gleason score, and clinical stage, it is possible to identify a group of patients with prostate cancer who have a high risk of relapse following initial treatment (e.g., radiotherapy or radical prostatectomy). For these patients, multi-modal therapy may result in improved outcomes. We reviewed published literature to identify methods to identify high-risk patients as well as options for adjuvant or neoadjuvant therapy to reduce risk of disease recurrence. At the present time, the most promising adjuvant therapy is hormonal therapy following radiotherapy for locally advanced disease (T3-T4, or N1). In phase III trials in these patients, survival is improved. For all other applications, including adjuvant and neoadjuvant hormonal therapy, chemotherapy, or radiotherapy, the benefits are unclear. Perhaps most promising at this time, and the subject of a current phase III trial, is the utility of adjuvant chemotherapy in high-risk patients. It will be through the conduct of phase III trials that the benefits of multi-modal therapy will be evaluated. Patients with high-risk prostate cancer undergoing radiotherapy or surgery should be offered participation in these clinical trials.