Radical prostatectomy vs radiation therapy and androgen-suppression therapy in high-risk prostate cancer

Study Type – Therapy (retrospective cohort analysis) Level of Evidence 2b What's known on the subject? and What does the study add? Prostate cancer is generally considered to be high risk when the prostate‐specific antigen (PSA) concentration is >20 ng/mL, the Gleason score is ≥8 or the American Joint Commission on Cancer (AJCC) tumour (T) category is ≥2c. There is no consensus on the best treatment for men with prostate cancer that includes these high‐risk features. Options include external beam radiation therapy (EBRT) with androgen suppression therapy (AST), treatment with a combination of brachytherapy, EBRT and AST termed combined‐modality therapy (CMT) or radical prostatectomy (RP) followed by adjuvant RT in cases where there are unfavourable pathological features, e.g. positive surgical margin, extracapsular extension and seminal vesicle invasion. While outcomes for both approaches have been published independently these treatments have not been compared in the setting of a prospective RCT where confounding factors related to patient selection for RP or CMT would be minimised. These factors include age, known prostate cancer prognostic factors and comorbidity. RCTs that compare RP to radiation‐based regimens have been attempted but failed to accrue.

OBJECTIVE

• ? To assess the risk of prostate cancer‐specific mortality after therapy with radical prostatectomy (RP) or combined‐modality therapy (CMT) with brachytherapy, external beam radiation therapy (EBRT) and androgen‐suppression therapy (AST) in men with Gleason score 8–10 prostate cancer.

PATIENTS AND METHODS

• ? Men with localised high‐risk prostate cancer based on a Gleason score of 8–10 were selected for study from Duke University (285 men), treated between January 1988 and October 2008 with RP or from the Chicago Prostate Cancer Center or within the 21st Century Oncology establishment (372) treated between August 1991 and November 2005 with CMT.
• ? Fine and Gray multivariable regression was used to assess whether the risk of prostate cancer‐specific mortality differed after RP as compared with CMT adjusting for age, cardiac comorbidity and year of treatment, and known prostate cancer prognostic factors.

RESULTS

• ? As of January 2009, with a median (interquartile range) follow‐up of 4.62 (2.4–8.2) years, there were 21 prostate cancer‐specific deaths.
• ? Treatment with RP was not associated with an increased risk of prostate cancer‐specific mortality compared with CMT (adjusted hazard ratio [HR] 1.8, 95% confidence interval [CI] 0.6–5.6, P= 0.3).
• ? Factors associated with an increased risk of prostate cancer‐specific mortality were a PSA concentration of <4 ng/mL (adjusted HR 6.1, 95% CI 2.3–16, P < 0.001) as compared with ≥4 ng/mL, and clinical category T2b, c (adjusted HR 2.9; 95% CI 1.1–7.2; P= 0.03) as compared with T1c, 2a.

CONCLUSION

• ? Initial treatment with RP as compared with CMT was not associated with an increased risk of prostate cancer‐specific mortality in men with Gleason score 8–10 prostate cancer.

     

Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Prostate Cancer Results Study Group

What's known on the subject? and What does the study add? Very few comparative studies to date evaluate the results of treatment options for prostate cancer using the most sensitive measurement tools. PSA has been identified as the most sensitive tool for measuring treatment effectiveness. To date, comprehensive unbiased reviews of all the current literature are limited for prostate cancer. This is the first large scale comprehensive review of the literature comparing risk stratified patients by treatment option and with long-term follow-up. The results of the studies are weighted, respecting the impact of larger studies on overall results. The study identified a lack of uniformity in reporting results amongst institutions and centres. A large number of studies have been conducted on the primary therapy of prostate cancer but very few randomized controlled trials have been conducted. The comparison of outcomes from individual studies involving surgery (radical prostatectomy or robotic radical prostatectomy), external beam radiation (EBRT) (conformal, intensity modulated radiotherapy, protons), brachytherapy, cryotherapy or high intensity focused ultrasound remains problematic due to the non-uniformity of reporting results and the use of varied disease outcome endpoints. Technical advances in these treatments have also made long-term comparisons difficult. The Prostate Cancer Results Study Group was formed to evaluate the comparative effectiveness of prostate cancer treatments. This international group conducted a comprehensive literature review to identify all studies involving treatment of localized prostate cancer published during 2000-2010. Over 18,000 papers were identified and a further selection was made based on the following key criteria: minimum/median follow-up of 5 years; stratification into low-, intermediate- and high-risk groups; clinical and pathological staging; accepted standard definitions for prostate-specific antigen failure; minimum patient number of 100 in each risk group (50 for high-risk group). A statistical analysis (standard deviational ellipse) of the study outcomes suggested that, in terms of biochemical-free progression, brachytherapy provides superior outcome in patients with low-risk disease. For intermediate-risk disease, the combination of EBRT and brachytherapy appears equivalent to brachytherapy alone. For high-risk patients, combination therapies involving EBRT and brachytherapy plus or minus androgen deprivation therapy appear superior to more localized treatments such as seed implant alone, surgery alone or EBRT. It is anticipated that the study will assist physicians and patients in selecting treatment for men with newly diagnosed prostate cancer.     

Role of radical prostatectomy in metastatic prostate cancer: A review

Context

Recent demonstration of efficacy with the use of chemohormonal therapy for men with metastatic prostate cancer (mPCa) has expanded the therapeutic options for these patients. Furthermore, multimodal therapy to treat systemic disease in the context of locoregional control has gained increasing interest. Concomitantly, the role of radical prostatectomy (RP) in multimodal treatment for locally advanced prostate cancer is expanding. As a result, there is interest in investigating the potential benefit of cytoreductive RP in mPCa.

Trends and predictors of aggressive therapy for clinical locally advanced prostate carcinoma

OBJECTIVE: To determine the patterns and predictors of aggressive local therapies for patients with clinically advanced (cT3) prostate carcinoma, as the USA National Cancer Institute considers external beam radiotherapy (EBRT) to be the most appropriate treatment for these patients, and currently there is less evidence supporting the use of radical prostatectomy (RP). PATIENTS AND METHODS: We used the Surveillance, Epidemiology and End Results (SEER) cancer registries to identify patients diagnosed with cT3 disease between 1995 and 2001. Sociodemographic and clinical data included patient age, race/ethnicity, marital status, SEER registry, year of diagnosis, tumour stage and grade, and treatment. Multivariate logistic regression was used to identify significant predictors of receiving (i) RP vs EBRT, (ii) any aggressive local treatment (RP or EBRT) or no treatment. RESULTS: Between 1995 and 2001, the proportion of men receiving aggressive local therapy for cT3 disease increased by 11% (58.4% to 69.4%), with a 20% increase in EBRT (40.3% to 60.2%) but a decline by half in RP (18.1% to 9.3%). Younger age was the strongest predictor of receiving RP rather than EBRT, and younger age with being married being a predictor of receiving aggressive local therapy (adjusted relative risk for marriage 1.33, 95% confidence interval 1.18-1.87). Black men were significantly less likely than non-Hispanic white men to receive aggressive therapy, with a relative risk of 0.56 (0.45-0.69). CONCLUSION: By 2001, 70% of patients with cT3 disease were receiving aggressive local therapy, with EBRT 6.5 times more common than RP. Clinical trials are needed to rigorously assess the effects of different local treatment strategies on clinical outcomes in men with cT3 prostate carcinoma.     

What is the optimal management of high risk,clinically localized prostate cancer?

ObjectivesTo summarize the presentations and debate regarding the optimal treatment of localized high-risk prostate cancer as presented at the 2009 Spring Meeting of the Society of Urologic Oncology.Materials and methodsThe debate was centered on presentations arguing for radical prostatectomy (RP) or radiotherapy as the optimal treatment for this condition. The meeting presentations are summarized by their respective presenters herein.ResultsDr. James Eastham presents the varied definitions for “high-risk” prostate cancer as strongly influencing which patients end up in this cohort. Based upon this, between 3% and 38% of patients with high-risk features could be defined as “high-risk”. Despite that, these men do not have a uniformly poor prognosis after RP, and attention to surgical principles as outlined improve outcomes. Disease-specific survival at 12 years is excellent and up to one-half of these men may not need adjuvant or salvage therapies, depending on their specific disease characteristics. Adjuvant or salvage radiotherapies improve outcomes and are part of a sequential approach to treating these patients. Dr. Anthony Zietman presented radiotherapy as the gold-standard based upon large, randomized clinical trials of intermediate- and high-risk prostate cancer patients. Compared with androgen deprivation alone, the addition of radiotherapy provided a 12% cancer-specific survival advantage and 10% overall survival advantage. Dose escalation seems to confer further improvements in cancer control without significant escalation of toxicities, with more data forthcoming.ConclusionsThere are no randomized trials comparing RP to radiotherapy for any risk category. In high-risk prostate cancer patients, both approaches have potential benefits and cumulative toxicities that must be matched to disease characteristics and patient expectations in selecting a treatment course.     

Benefits and Risks of Primary Treatments for High-risk Localized and Locally Advanced Prostate Cancer: An International Multidisciplinary Systematic Review

ContextThe optimal treatment for men with high-risk localized or locally advanced prostate cancer (PCa) remains unknown.ObjectiveTo perform a systematic review of the existing literature on the effectiveness of the different primary treatment modalities for high-risk localized and locally advanced PCa. The primary oncological outcome is the development of distant metastases at ≥5 yr of follow-up. Secondary oncological outcomes are PCa-specific mortality, overall mortality, biochemical recurrence, and need for salvage treatment with ≥5 yr of follow-up. Nononcological outcomes are quality of life (QoL), functional outcomes, and treatment-related side effects reported.Evidence acquisitionMedline, Medline In-Process, Embase, and the Cochrane Central Register of Randomized Controlled Trials were searched. All comparative (randomized and nonrandomized) studies published between January 2000 and May 2019 with at least 50 participants in each arm were included. Studies reporting on high-risk localized PCa (International Society of Urologic Pathologists [ISUP] grade 4–5 [Gleason score {GS} 8–10] or prostate-specific antigen [PSA] >20 ng/ml or ≥ cT2c) and/or locally advanced PCa (any PSA, cT3–4 or cN+, any ISUP grade/GS) or where subanalyses were performed on either group were included. The following primary local treatments were mandated: radical prostatectomy (RP), external beam radiotherapy (EBRT) (≥64 Gy), brachytherapy (BT), or multimodality treatment combining any of the local treatments above (±any systemic treatment). Risk of bias (RoB) and confounding factors were assessed for each study. A narrative synthesis was performed.Evidence synthesisOverall, 90 studies met the inclusion criteria. RoB and confounding factors revealed high RoB for selection, performance, and detection bias, and low RoB for correction of initial PSA and biopsy GS. When comparing RP with EBRT, retrospective series suggested an advantage for RP, although with a low level of evidence. Both RT and RP should be seen as part of a multimodal treatment plan with possible addition of (postoperative) RT and/or androgen deprivation therapy (ADT), respectively. High levels of evidence exist for EBRT treatment, with several randomized clinical trials showing superior outcome for adding long-term ADT or BT to EBRT. No clear cutoff can be proposed for RT dose, but higher RT doses by means of dose escalation schemes result in an improved biochemical control. Twenty studies reported data on QoL, with RP resulting mainly in genitourinary toxicity and sexual dysfunction, and EBRT in bowel problems.ConclusionsBased on the results of this systematic review, both RP as part of multimodal treatment and EBRT + long-term ADT can be recommended as primary treatment in high-risk and locally advanced PCa. For high-risk PCa, EBRT + BT can also be offered despite more grade 3 toxicity. Interestingly, for selected patients, for example, those with higher comorbidity, a shorter duration of ADT might be an option. For locally advanced PCa, EBRT + BT shows promising result but still needs further validation. In this setting, it is important that patients are aware that the offered therapy will most likely be in the context a multimodality treatment plan. In particular, if radiation is used, the combination of local with systemic treatment provides the best outcome, provided the patient is fit enough to receive both. Until the results of the SPCG15 trial are known, the optimal local treatment remains a matter of debate. Patients should at all times be fully informed about all available options, and the likelihood of a multimodal approach including the potential side effects of both local and systemic treatment.Patient summaryWe reviewed the literature to see whether the evidence from clinical studies would tell us the best way of curing men with aggressive prostate cancer that had not spread to other parts of the body such as lymph glands or bones. Based on the results of this systematic review, there is good evidence that both surgery and radiation therapy are good treatment options, in terms of prolonging life and preserving quality of life, provided they are combined with other treatments. In the case of surgery this means including radiotherapy (RT), and in the case of RT this means either hormonal therapy or combined RT and brachytherapy.     

Management of High-Risk Localised Prostate Cancer

ContextHigh-risk localised prostate cancer (PCa) is defined as significant likelihood of death from PCa or development of distant metastases. It is important to identify patients at high risk of progression who may benefit from neoadjuvant or adjuvant therapies.ObjectiveTo review definitions for high-risk localised PCa and review outcomes of different treatment modalities.Evidence acquisitionRandomised and nonrandomised clinical trials addressing the characterisation of patients with high-risk PCa and treatment options for this patient population were reviewed, mainly focusing on comparison of monotherapy with multimodality approaches.Evidence synthesisRadical prostatectomy (RP) represents a treatment option for selected high-risk patients and can result in long-term progression-free survival (PFS) in a subset without hormone therapy (HT). HT prior to RP is not considered as a standard treatment in high-risk, clinically localised PC, because survival advantage has never been conclusively demonstrated. Adjuvant “early” androgen-deprivation therapy (ADT) is not recommended for patients with high-risk disease except for pathologically confirmed nodal disease. Adjuvant radiotherapy (RT) after RP in patients with adverse risk factors decreases biochemical recurrence risk with improved local control but without a clear advantage in overall survival (OS). RT with long-term adjuvant HT improves OS. However, the exact period of HT is still controversial, and one must consider the cardiovascular comorbidity status of the patients before initiating ADT. Neoadjuvant chemotherapy can be administered safely in patients with high-risk disease prior to definitive therapy. Although complete responders are very rare, prostate-specific antigen (PSA) responses were present in a substantial number of patients. Early results of adjuvant chemotherapy trials are promising, but ongoing phase 3 trials should be completed to establish any survival advantage.ConclusionsIntegrating local and systemic therapies may be beneficial in the management of high-risk localised or locally advanced PCa.     

Treatment decision-making in localized prostate cancer: why patients chose either radical prostatectomy or external beam radiation therapy

Study Type – Therapy (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? Our patients’ personal preferences are of major importance for decision‐making in localized prostate cancer. The study evaluates strategies in choosing either RP or EBRT. Typical modes of reasoning consist of personal beliefs in patients choosing RP and fear of treatment related side‐effects in the EBRT group.

OBJECTIVES

? To evaluate patients’ treatment decision‐making for localized prostate cancer. ? To determine their willingness to participate in a randomized controlled trial (RCT) comparing radical prostatectomy (RP) with external beam radiation therapy (EBRT).

PATIENTS AND METHODS

? We investigated 31 patients with localized prostate cancer who had opted for either RP (n= 18) or EBRT (n= 13) as primary therapy. ? A semi‐structured interview and a short questionnaire were completed a few days after the start of treatment, covering all aspects of treatment decision.

RESULTS

? Most patients wanted to decide on their treatment together with their physician and were generally satisfied with the information provided. Internet resources were used more frequently by the RP group (14/18 patients) than by the EBRT group (three of 13 patients, P < 0.01). ? Physicians’ advice and other patients’ experiences were highly influential in the final treatment decisions. ? Patients deciding on RP were younger and their personal beliefs were their typical decision criteria (RP, six of 18 patients vs EBRT, none; P= 0.03). By contrast, possible treatment‐related side‐effects were a major concern for patients choosing EBRT (RP, two of 18, vs EBRT, seven of 14; P= 0.02). ? Only two patients (of 31, 6%) would have consented to random assignment to either RP or EBRT, while six (19%) patients were not averse.

CONCLUSIONS

? Patients are satisfied with the information provided and with their decision‐making process. ? Typical modes of reasoning can be found and mainly consist of personal beliefs in patients choosing RP and fear of treatment related side‐effects in those choosing EBRT. ? According to the sample, the participation rate for a RCT comparing RP to EBRT would not exceed 25% without further efforts.     

Radical prostatectomy versus external beam radiation therapy for high-grade,clinically localized prostate cancer: Emulation of a target clinical trial

PurposeThe comparative effectiveness of surgery and radiation therapy for high-grade, clinically localized prostate cancer remains a seminal, open question in urologic oncology, with no randomized controlled trials to inform management. We therefore emulated a hypothetical target clinical trial of radical prostatectomy (RP) versus external beam radiotherapy (EBRT) for high-grade, clinically localized prostate cancer.Materials and MethodsWe conducted observational analyses using the National Cancer Database from 2006-2015 to emulate a target clinical trial in men 55-69 years with cT1-3cN0cM0, PSA<20 ng/mL, Gleason 8 to 10 prostate adenocarcinoma treated with RP or 75 to 81 Gy EBRT with androgen deprivation therapy (EBRT+ADT). The associations of treatment type with overall survival (OS) were estimated using Cox regression with stabilized inverse probability weights (IPW).ResultsA total of 26,806 men formed the study cohort (RP: 23,990; EBRT+ADT: 2,816). Baseline characteristics were well-balanced after IPW-adjustment. Median follow-up was 48.4 (IQR 25.5-76.2) months. After IPW-reweighting, RP was associated with improved OS compared to EBRT+ADT (HR 0.54;95% CI 0.48-0.62; P<0.001), with 5- and 10-year OS of 93% vs 87%, and 76% vs 60%, respectively. RP was associated with improved OS across all categories of Gleason score, PSA, cT stage, age, and Charlson comorbidity index examined. In sensitivity analyses adjusting for biopsy tumor volume and a biopsy-specific Gleason score, RP remained associated with improved OS compared to EBRT+ADT (HR 0.62;95% CI 0.49-0.78; P<0.001).ConclusionsIn observational analyses designed to emulate a target clinical trial of men with high-grade, clinically localized prostate cancer, RP was associated with improved OS compared with EBRT+ADT.     

Role of radical prostatectomy in the treatment of high-risk prostate cancer

Controversy remains regarding the preferred therapy for high-risk, clinically localized prostate cancer. High-risk prostate cancer represents a diverse disease entity for which accurate risk assessment is critical to informed counseling and clinical decision making. For men with high-risk features, electing surgery as a local definitive therapy should be based on the best available evidence rather than a surgeon’s bias and experience. Patients classified with high-risk prostate cancer by common definitions do not have a uniformly poor prognosis after radical prostatectomy. Many cancers that are clinically categorized as high risk are actually pathologically confined to the prostate, and most of these men do not require additional long-term therapy after surgery. For some high-risk patients, an integrated approach combining local and systemic therapy may be advantageous. Available studies using adjuvant and neoadjuvant strategies have their individual strengths and weaknesses; unfortunately, none has provided persuasive evidence to dictate the standard of care in the high-risk setting. Therefore, results are eagerly anticipated from ongoing randomized trials exploring the merits of perioperative chemohormonal therapy in high-risk patients. This review discusses current limitations and challenges in accurately identifying high-risk patients and focuses on radical prostatectomy alone or as part of multimodal therapy for men with high-risk prostate cancer.     

Neoadjuvant and Adjuvant Hormone Therapy: How and When?

ContextA significant proportion of patients with prostate cancer (PCa) will experience clinical or biochemical failure after local treatment with radical prostatectomy (RP) or radiotherapy (RT). It is still a matter of debate whether hormone therapy (HT) in either a neoadjuvant or adjuvant setting can offer a survival benefit for these patients.ObjectiveThis review paper discusses how and when neoadjuvant and adjuvant HT could be applied for treatment of PCa. Furthermore, the paper outlines the optimal duration of adjuvant HT to RT for treatment of patients with high-grade localised or locally advanced PCa.Evidence acquisitionThis paper is based on a presentation given at a satellite symposium held at the European Association of Urology (EAU) 2008 annual congress in Milan, Italy. Data were retrieved from recent review articles, original articles, and abstracts on neoadjuvant or adjuvant HT in PCa.Evidence synthesisLuteinising hormone-releasing hormone agonists have become the standard of care in HT. Neoadjuvant androgen deprivation therapy (ADT) to RP seems to have potential to downstage PCa disease but does not offer a survival benefit over RP alone in patients with localised PCa. On the other hand, short-term neoadjuvant ADT to RT appears to improve treatment outcomes compared with RT alone in patients with locally advanced PCa but seems to be specifically indicated in patients with Gleason score 2–6. Adjuvant ADT with RT seems to offer a survival benefit over RT alone in high-risk localised and locally advanced PCa. Recent data indicate that 6-mo ADT is inferior in terms of survival to 3-yr adjuvant ADT after RT for patients with locally advanced PCa. The role of immediate ADT for men with node-positive PCa after RP should be further investigated.ConclusionsNeoadjuvant and adjuvant ADT to local treatment may be indicated in carefully selected patients with PCa.     

Genome gender diversity in affected sib-pairs with familial vesico-ureteric reflux identified by single nucleotide polymorphism linkage analysis

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Despite a lack of randomised controlled trials, most men with locally advanced prostate cancer are recommended to undergo external beam radiotherapy (EBRT), often combined with long‐term androgen‐deprivation therapy (ADT). Many of these men are not offered radical prostatectomy (RP) by their treating urologist. Additionally, it is know that EBRT with long‐term ADT does provide good cancer control (88% at 10 years). We have previously published intermediate‐term follow‐up of a large series of men treatment with RP for cT3 prostate cancer. We report long‐term follow‐up of a large series of men treated with RP as primary treatment for cT3 prostate cancer. Our study shows that with long‐term follow‐up RP provides excellent oncological outcomes even at 20 years. While most men do require a multimodal treatment approach, many men can be managed successfully with RP alone.

OBJECTIVE

• ? To present long‐term survival outcomes after radical prostatectomy (RP) for patients with cT3 prostate cancer, as the optimal treatment for patients with clinical T3 prostate cancer is debated.

PATIENTS AND METHODS

• ? We identified 843 men who underwent RP for cT3 tumours between 1987 and 1997.
• ? Survival was estimated using the Kaplan–Meier method.
• ? Cox proportional hazards regression models were used to evaluate the association of clinicopathological features with outcome

RESULTS

• ? The median (range) postoperative follow‐up was 14.3 (0.1–23.5) years.
• ? Down‐staging to pT2 disease occurred in 26% (223/843) at surgery.
• ? Local recurrence‐free, systemic progression‐free and cancer‐specific survival for men with cT3 prostate cancer after RP was 76%, 72%, and 81%, respectively, at 20 years.
• ? On multivariate analysis, increasing RP Gleason score (hazard ratio [HR] 1.8; P= 0.01), non‐diploid chromatin content (HR 1.8; P= 0.01), positive surgical margins (HR 2.1; P= 0.007), and seminal vesicle invasion (HR 2.1; P= 0.005) were associated with a significant risk of prostate cancer death, while a more recent year of surgery was associated with a decreased risk of cancer‐specific mortality (HR 0.88; P= 0.01)

CONCLUSIONS

• ? RP affords accurate pathological staging and may be associated with durable cancer control for cT3 prostate cancer, with 20 years of follow‐up presented here.
• ? RP as part of a multimodal treatment strategy therefore remains a viable treatment option for patients with cT3 tumours.

     

Radical prostatectomy for high-risk prostate cancer

OBJECTIVES: Consensus recommendations for the identification and treatment of men whose apparent organ confined prostate cancer has high risk features are lacking. Despite ongoing refinements in surgical technique and improvements in morbidity and functional outcomes, the tradition of steering high-risk patients away from radical prostatectomy (RP) remains steadfast. METHODS: We performed a medical literature search in English using MEDLINE/PubMed that addressed high risk prostate cancer. We analyzed the literature with respect to the historical evolution of this concept, current risk stratification schemes and treatment guidelines and related short and long term outcomes following RP. RESULTS: Contemporary evidence suggest that patients classified with high-risk prostate cancer by commonly used definitions do not have a uniformly poor prognosis after RP. Many cancers categorized clinically as high risk are actually pathologically confined to the prostate, and most men with such cancers who undergo RP are alive and free of additional therapy long after surgery. RP in the high-risk setting appears to be associated with a similar morbidity as in lower-risk patients. CONCLUSION: Men with clinically localized high-risk prostate cancer should not be categorically disqualified from local definitive therapy with RP. With careful attention to surgical technique, cancer control rates should improve further, and adverse effects on quality of life after RP should continue to decrease.     

Adjuvant and salvage treatment options for patients with high-risk prostate cancer treated with radical prostatectomy

The management of high-risk prostate cancer following radical prostatectomy remains a treatment dilemma. Multimodality approaches incorporating surgery, radiation therapy and systemic agents offer the hope of improved cure rates; however, most randomized studies to date are either immature or negative. The systemic treatment options best studied is androgen deprivation, which has been shown to demonstrate a survival advantage in patients with lymph node-positive disease. Systemic chemotherapy has demonstrated a modest survival advantage in androgen-independent disease. Current studies are exploring its role in the adjuvant and neo-adjuvant setting. Lastly, recent randomized trials have demonstrated a biochemical advantage to adjuvant radiation therapy, but it remains to be seen if this will translate to an improvement is survival end points or if salvage radiation therapy would be just as effective. In this update article, we review the use of external beam radiation therapy and systemic agents in combination with surgery for high-risk prostate cancer patients.     

Oncological results, functional outcomes and health-related quality-of-life in men who received a radical prostatectomy or external beam radiation therapy for localized prostate cancer： a study on long-term patient outcome with risk stratification

Health-related quality-of-life （HRQOL） after a radical prostatectomy （RP） or extemal beam radiation therapy （EBRT） has not been studied in conjunction with oncological outcomes in relation to disease risk stratification. Moreover, the long-term outcomes of these treatment approaches have not been studied. We retrospectively analyzed oncological outcomes between consecutive patients receiving RP （n = 86） and EBRT （n = 76） for localized prostate cancer. HRQOL and functional outcomes could be assessed in 62 RP （79%） and 54 EBRT （79%） patients over a 3-year follow-up period （median： 41 months） using the Medical Outcomes Study Short Form-36 （SF-36） and the University of Califomia Los Angeles Prostate Cancer Index （UCLA PCI）. The 5-year biochemical progression-free survival did not differ between the RP and EBRT groups for low-risk （74.6% vs. 75.0%, P = 0.931） and intermediate-risk （61.3% vs. 71.1%, P = 0.691） patients. For high-risk patients, progression-free survival was lower in the RP group （45.1%） than in the EBRT group （79.7%） （P = 0.002）. The general HRQOL was comparable between the two groups. Regarding functional outcomes, the RP group reported lower scores on urinary function and less urinary bother and sexual bother than the EBRT group （P 〈 0.001, P 〈 0.05 and P 〈 0.001, respectively）. With risk stratification, the low- and intermediate-risk patients in the RP group reported poorer urinary function than patients in the EBRT group （P 〈 0.001 for each）. The sexual function of the high-risk patients in the EBRT group was better than that of the same risk RP patients （P 〈 0.001）. Biochemical recurrence was not associated with the UCLA PCI score in either group. In conclusion, low- to intermediate-risk patients treated with an RP may report relatively decreased urinary function during long-term follow-up. The patient＇s HRQOL after treatment did not depend on biochemical recurrence.     

Chemotherapy and novel therapeutics before radical prostatectomy for high-risk clinically localized prostate cancer

Although both surgery and radiation are potential curative options for men with clinically localized prostate cancer, a significant proportion of men with high-risk and locally advanced disease will demonstrate biochemical and potentially clinical progression of their disease. Neoadjuvant systemic therapy before radical prostatectomy (RP) is a logical strategy to improve treatment outcomes for men with clinically localized high-risk prostate cancer. Furthermore, delivery of chemotherapy and other systemic agents before RP affords an opportunity to explore the efficacy of these agents with pathologic end points.Neoadjuvant chemotherapy, primarily with docetaxel (with or without androgen deprivation therapy), has demonstrated feasibility and safety in men undergoing RP, but no study to date has established the efficacy of neoadjuvant chemotherapy or neoadjuvant chemohormonal therapies. Other novel agents, such as those targeting the vascular endothelial growth factor receptor, epidermal growth factor receptor, platelet-derived growth factor receptor, clusterin, and immunomodulatory therapeutics, are currently under investigation.     

A retrospective study of the treatment of locally advanced prostate cancer by six institutions in eastern and north-eastern Japan

OBJECTIVE: To investigate patients with locally advanced prostate cancer treated at six academic institutions in eastern and north-eastern Japan from 1988 to 2000, to facilitate the establishment of Japanese guidelines for the diagnosis and treatment of locally advanced prostate cancer. PATIENTS AND METHODS: The study included 391 eligible patients with locally advanced prostate cancer who were treated by radical prostatectomy (RP), radiotherapy and/or primary hormone therapy. Disease-specific survival rates for these patients were assessed in relation to their clinicopathological characteristics and the types of treatment they received. The Mann-Whitney U-test, Kruskal-Wallis, chi-square and log-rank test were used for statistical analysis, as appropriate. RESULTS: In all, 128 patient with lower prostate-specific antigen levels (P = 0.023) and/or better performance status (P = 0.001) had RP. Neoadjuvant hormone therapy before RP was the treatment in 68 (53%) of these 128 patients; 66 (52%) received immediate adjuvant hormone therapy. Of 87 patients treated with radiotherapy, 75 (86%) had external beam radiotherapy (EBRT) as the primary treatment with no brachytherapy, and 12 (14%) had brachytherapy as the primary method. Neoadjuvant hormone therapy was given to 56 of the 87 patients (64%); 48 (55%) received immediate adjuvant hormone therapy. Of the 176 patients treated with primary hormone therapy alone, combined androgen blockade and surgical or medical castration was the treatment in 76 (43%) and 85 (48%), respectively. Disease-specific survival rates at 5 years for patients treated with RP, EBRT and primary hormone therapy were 90%, 98%, and 89%, respectively. CONCLUSION: The treatments provided by the participating institutions did not differ significantly from those set out in European and American guidelines, and short-term disease-specific survival rates for each treatment did not differ significantly from those of historical controls. Further investigation may facilitate the establishment of Japanese guidelines for the diagnosis and treatment of locally advanced prostate cancer.     

Radical prostatectomy versus high dose permanent prostate brachytherapy using iodine-125 seeds for patients with high risk prostate cancer: a matched cohort analysis

Objective

To compare the biochemical outcomes reported after radical prostatectomy (RP) versus high dose permanent prostate brachytherapy (HDPPB) using iodine-125 seeds in the treatment of matched high risk prostate cancer (HiPCa).

Methods

In this retrospective review, 55 HiPCa patients treated between March 2006 and August 2011, who underwent HDPPB using iodine-125 seeds combined with external beam radiation therapy (EBRT) or androgen deprivation therapy (ADT), were compared with 55 HiPCa patients who underwent RP. Patients were matched for age, prostate-specific antigen (PSA), clinical stage, and Gleason scores. The biochemical outcomes after HDPPB and RP were compared via Kaplan–Meier analysis.

Results

Of the 110 patients analyzed, the mean ages, PSA, and Gleason biopsy scores were similar between the two cohorts. Among patients who underwent HDPPB, 20 patients (36.4 %) had received adjuvant EBRT. Of this subsample, most patients (98.2 %) had received adjuvant ADT for 3 months. Among patients with RP, 20 patients (36.4 %) had received adjuvant EBRT, whereas 28 patients had received adjuvant ADT. The mean implanted seed numbers were 92.8, the mean D90 was 218.7 Gy, and the mean V100 was 96.1 % after HDPPB. With regard to oncological outcomes, biochemical disease-free survival rates were similar between the two cohorts (82.6 vs. 81.1 %, p = 0.982). Urethrorectal fistula developed in one patient with HDPPB.

Conclusion

RP and HDPPB, using iodine-125 seeds with combined treatment modalities, exhibited similar biochemical recurrence-free survival rates among HiPCa patients. Further prospective studies with greater sample sizes and longer follow-up periods are needed to validate these results.     

Permanent Interstitial Low-Dose-Rate Brachytherapy for Patients with Localised Prostate Cancer: A Systematic Review of Randomised and Nonrandomised Controlled Clinical Trials

Context

Prostate cancer (PCa) is the most common cancer in men. Permanent interstitial low-dose-rate brachytherapy (LDR-BT) is a short-distance radiation therapy in which low-energy radioactive sources are implanted permanently into the prostate.

Objective

To assess the effectiveness and safety of LDR-BT compared to treatment alternatives in men with localised PCa.

Evidence acquisition

Bibliographic databases (Medline, Embase, and the Cochrane Library) were searched from inception until June 2010 for randomised and nonrandomised controlled trials comparing LDR-BT with radical prostatectomy (RP), external-beam radiation therapy (EBRT), or no primary therapy (NPT). Primary outcome was overall survival (OS). Secondary outcomes were disease-free survival (DFS), biochemical recurrence-free survival (bRFS), physician-reported severe adverse events (SAE), and patient-reported outcomes (PRO).

Evidence synthesis

A total of 31 studies, including 1 randomised controlled trial (RCT), were identified. Risk of bias was high for all 31 studies. OS was reported in one nonrandomised controlled study; however, these data were not interpretable because of strong residual confounding. DFS was not reported. Comparison of bRFS between treatment groups is not validated; thus, results were not interpretable. Physician-reported urogenital late toxicity grade 2 to 3 was more common in the LDR-BT group when compared to the EBRT group. With respect to PRO, better scores for sexual and urinary function as well as urinary incontinence were reported for LDR-BT compared to RP. Better scores for bowel function were reported for LDR-BT compared to EBRT.

Conclusions

We found a low amount of evidence in studies that exclusively compared LDR-BT with other treatment modalities. LDR-BT may have some different physician-reported SAE and patient-reported outcomes. The current evidence is insufficient to allow a definitive conclusion about OS. Randomised trials focusing on long-term survival are needed to clarify the relevance of LDR-BT in patients with localised PCa.     

不同治疗方案与局部晚期前列腺癌患者前列腺特异性抗原进展及生存状况的Meta分析

目的 应用Meta分析探讨不同治疗方案对局部晚期前列腺癌前列腺特异性抗原(PSA)进展及生存状况的影响. 方法制订原始文献的纳入标准、剔除标准及检索策略.以优势比(OR)及其95%可信区间(95%CI)为效应尺度,应用Meta分析固定效应模型和随机效应模型对有关治疗局部晚期前列腺癌不同方案的纳入文献进行综合定量评价. 结果 符合纳入标准的8篇文献进入Meta分析,共3826例.5篇为前列腺根治性切除术(RP)联合辅助治疗与单纯用RP或不用RP进行比较,以PSA进展率为评价指标,合并后的OR值为0.86,95%CI为0.48～1.56;3篇为RP联合激素治疗与单纯用RP或不用RP进行比较,以疾病特异性死亡率为评价指标,合并后的OR值为0.72,95%CJ为0.51～1.02. 结论 RP联合辅助治疗可以显著减少局部晚期前列腺癌患者术后PSA进展,对疾病特异性死亡率却无显著影响.