Gonadotropin-releasing Hormone Agonists and Acute Kidney Injury in Patients with Prostate Cancer

Background

Androgen deprivation therapy (ADT) might increase the risk of acute kidney injury (AKI) in patients with prostate cancer (PCa).

Objective

To examine the impact of ADT on AKI in a large contemporary cohort of patients with nonmetastatic PCa representing the US population.

Design, setting, and participants

Overall, 69 292 patients diagnosed with nonmetastatic PCa between 1995 and 2009 were abstracted from the Surveillance Epidemiology and End Results–Medicare database.

Outcomes measurements and statistical analyses

Patient in both treatment arms (ADT vs no ADT) were matched using propensity-score methodology. Ten-year AKI rates were estimated. Competing-risks regression analyses tested the association between ADT and AKI, after adjusting for the risk of death during follow-up.

Results and limitations

Overall, the 10-yr AKI rates were 24.9% versus 30.7% for ADT-naive patients versus those treated with ADT, respectively (p < 0.001). When patients were stratified according to the type of ADT, the 10-yr AKI rates were 31.1% versus 26.0% for men treated with gonadotropin-releasing hormone (GnRH) agonists and bilateral orchiectomy, respectively (p < 0.001). In multivariable analyses, the administration of GnRH agonists (hazard ratio [HR]: 1.24; 95% confidence interval [CI], 1.18–1.31; p < 0.001), but not bilateral orchiectomy (HR: 1.11; 95% CI, 0.96–1.29; p = 0.1), was associated with the risk of experiencing AKI. Our study is limited by its retrospective design.

Conclusions

ADT is associated with an increased risk of AKI in patients with nonmetastatic PCa. In particular, the administration of GnRH agonists, but not surgical castration, may substantially increase the risk of experiencing AKI. These observations should help provide physicians with better patient selection to reduce the risk of AKI.

Patient summary

The administration of gonadotropin-releasing hormone agonists, but not bilateral orchiectomy, increases the risk of acute kidney injury (AKI) in patients with prostate cancer (PCa). These observations should help provide physicians with better patient selection to reduce the risk of AKI in PCa patients.     

Androgen-deprivation Therapy and Risk for Biliary Disease in Men with Prostate Cancer

Background

Androgen-deprivation therapy (ADT) by either a gonadotropin-releasing hormone (GnRH) agonist or bilateral orchiectomy improves disease-related outcomes of men with prostate cancer but has a variety of adverse metabolic effects including obesity, increased abdominal girth, increased triglycerides, and insulin resistance. Each is a risk factor for gallstone disease. Additionally, GnRH agonist treatment was recently shown in metabolomic analyses to increase plasma levels of some bile acids.

Objective

To assess the relationship between ADT and the incidence of biliary disease in men with prostate cancer.

Design, setting, and participants

We studied 183 842 men >65 yr of age living in Surveillance, Epidemiology, and End Results regions who were diagnosed with prostate cancer from 1992 to 2007 and followed through 2009.

Outcome measurements and statistical analysis

We calculated incidence rates for biliary disease during treatment with GnRH agonists, orchiectomy, or no therapy. We used Cox proportional hazard models to assess the association of ADT with biliary disease.

Results and limitations

Among 183 842 men with locoregional prostate cancer, 48.4% received GnRH agonist treatment and 2.2% underwent bilateral orchiectomy during follow-up. GnRH agonist treatment was associated with a significantly higher incidence of biliary disease compared with no treatment (15.7 vs 13.4 cases per 1000 person-years; p < 0.001). In adjusted analyses, GnRH agonist use was associated with the risk of biliary disease (adjusted hazard ratio: 1.10; 95% confidence interval, 1.05–1.15; p < 0.001). Orchiectomy was not significantly associated with biliary disease.

Conclusions

GnRH agonist treatment may be associated with a greater risk of incident biliary disease.     

Detectable Prostate-Specific Antigen Nadir During Androgen-Deprivation Therapy Predicts Adverse Prostate Cancer–Specific Outcomes: Results from the SEARCH Database

Background

A prostate-specific antigen (PSA) level <0.2 ng/ml 8 mo after starting on androgen-deprivation therapy (ADT) is correlated with better outcomes. However, not all men reach a nadir PSA level within 8 mo. Whether the lowest PSA on ADT—specifically, <0.2 ng/ml—can be used for risk stratification is untested.

Objective

We examined the predictive value of small but detectable PSA nadir values on prostate cancer (PCa)–specific outcomes in men treated with early ADT after radical prostatectomy (RP).

Design, setting, and participants

We performed a retrospective review of men treated with ADT after RP before metastases from the SEARCH database. We identified 402 men treated with ADT for elevated PSA following RP, of whom 294 men had complete data. Median follow-up after PSA nadir was 49 mo. All men had a PSA nadir <4 ng/ml; 223 men (76%) had an undetectable nadir.

Intervention

ADT for an elevated PSA following RP with no radiographic evidence of metastatic disease.

Outcome measurements and statistical analysis

PSA nadir on ADT was defined as the lowest PSA value during ADT. Proportional hazards models and the C index were used to test the association and predictive accuracy, respectively, between PSA nadir and PCa-specific outcomes.

Results and limitations

Men with a PSA nadir between 0.01 and 0.2 ng/ml had a greater risk of progression to castration-resistant PCa (CRPC) (hazard ratio [HR]: 5.14; p < 0.001), metastases (HR: 3.98; p = 0.006), and PCa-specific mortality (PCSM) (HR: 5.33; p = 0.003) than men with an undetectable nadir. When data were restricted to men followed with ultrasensitive PSA values (sensitivity of 0.01 ng/ml), the C index of PSA nadir alone for predicting CRPC, metastases, and PCSM was 0.88, 0.91, and 0.96, respectively.

Conclusions

A PSA nadir on ADT, even at a very low level, strongly predicts progression to CRPC, metastases, and PCSM. Men with a detectable PSA nadir during ADT should be considered for clinical trials.     

Addition of radiotherapy to long-term androgen deprivation in locally advanced prostate cancer: an open randomised phase 3 trial

Background

Radiotherapy combined with androgen-deprivation therapy (ADT) is superior to radiotherapy alone in localised prostate cancer; however, data comparing ADT alone are somewhat limited.

Objective

To compare 3-yr ADT plus radiotherapy with ADT alone in locally advanced prostate cancer patients.

Design, setting, and participants

A multicentre randomised open controlled phase 3 trial in 264 histologically confirmed T3–4 or pT3N0M0 prostate cancer patients randomised from March 2000 to December 2003.

Intervention

ADT (11.25 mg subcutaneous depot injection of leuprorelin every 3 mo for 3 yr) plus external-beam radiotherapy or ADT alone. Flutamide (750 g/d) was administered for 1 mo.

Outcome measurements and statistical analysis

The primary objective was 5 yr progression-free survival (PFS) according to clinical or biologic criteria, using the American Society for Therapeutic Radiology and Oncology (ASTRO) and the newer (Phoenix) definition (nadir plus 2 ng/ml), by intention to treat. Secondary objectives included time to locoregional recurrence and distant metastases, and overall and disease-specific survival. Our Analyses: intent-to-treat analysis, multivariate analyses using a Cox model with a 5% threshold from univariate analysis, and Kaplan-Meier estimates.

Results and limitations

ADT alone was administered to 130 patients and combined therapy to 133. With a median follow-up of 67 mo, 5-yr PFS was 60.9% for combined therapy versus 8.5% with ADT alone (ASTRO; p < 0.0001), and 64.7% versus 15.4%, respectively, for Phoenix (p < 0.0011). Locoregional progression was reported in 9.8% of combined-therapy patients versus 29.2% with ADT alone (p < 0.0001) and metastatic progression in 3.0% versus 10.8%, respectively (p < 0.018). Overall survival was 71.4% with combined therapy versus 71.5% with ADT alone; disease-specific survival was 93.2% versus 86.2%. Limitations included the relatively small population and a relatively short follow-up period.

Conclusions

Combined therapy strongly favoured improved PFS, locoregional control, and metastasis-free survival. Longer follow-up is needed to assess the potential survival impact.     

Lifestyle Changes for Improving Disease-specific Quality of Life in Sedentary Men on Long-term Androgen-Deprivation Therapy for Advanced Prostate Cancer: A Randomised Controlled Trial

Background

Prostate cancer is a key driver of cancer-related global disability-adjusted life-years. Androgen-deprivation therapy (ADT) for advanced disease is linked to fatigue, reduced physical function, and quality of life (QoL).

Objective

To evaluate the effect of a lifestyle intervention on disease-specific QoL, diastolic blood pressure, and cancer-related fatigue in sedentary men receiving long-term ADT for advanced prostate cancer.

Design, setting, and participants

A total of 100 hundred sedentary men with locally advanced or metastatic prostate cancer on long-term ADT were randomised to an intervention or usual care group.

Intervention

A 12-wk lifestyle intervention consisting of aerobic and resistance exercise with parallel dietary advice.

Outcome measurements and statistical analysis

Disease-specific QoL was measured using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Functional Assessment of Cancer Therapy-Fatigue (FACT-F) questionnaires at 12 wk postintervention and at 6 mo following withdrawal of support. Analysis of covariance and mixed regression were conducted.

Results and limitations

Clinically relevant improvements in FACT-P were seen at 12 wk in the intervention group compared with controls (mean difference: 8.9 points; 95% confidence interval [CI], 3.7–14.2; adjusted p = 0.001). No difference was apparent at 6 mo (mean difference: 3.3 points; 95% CI, −2.6 to 9.3; adjusted p = 0.27). No difference in diastolic blood pressure was seen at either follow-up (all p > 0.05). Clinically relevant improvements in FACT-F were seen at 12 wk (mean difference: 5.3 points; 95% CI, 2.7–7.9; adjusted p < 0.001) and maintained following withdrawal of supervision (mean difference: 3.9 points; 95% CI, 1.1–6.8; adjusted p = 0.007). Improvements in exercise tolerance and behaviour were maintained at 6 mo (adjusted p < 0.001 and 0.038).

Conclusions

A lifestyle intervention resulted in a clinically meaningful improvement in disease-specific QoL that was not maintained postintervention. No effect on blood pressure occurred. Durability of response was seen in fatigue and exercise behaviour. Further evaluation of support structures is essential.

Trial registration

ISRCTN88605738.     

Patterns and Predictors of Amelioration of Genitourinary Toxicity After High-dose Intensity-modulated Radiation Therapy for Localized Prostate Cancer: Implications for Defining Postradiotherapy Urinary Toxicity

Background

Treatment-related toxicity and quality of life (QoL) considerations are important when counseling patients with localized prostate cancer (PCa).

Objective

To determine the incidence and longitudinal pattern of late genitourinary (GU) toxicity and QoL after high-dose, intensity-modulated radiotherapy (IMRT).

Design, setting, and participants

A total of 268 patients with localized PCa were treated between June 2004 and December 2008 at a tertiary referral center. Median follow-up was 5 yr (range: 3–7.7 yr).

Intervention

Patients underwent IMRT to a total dose of 86.4 Gy; 50% of patients underwent neoadjuvant and concurrent androgen-deprivation therapy.

Outcome measurements and statistical analysis

Patients were evaluated with the prospectively obtained International Prostate Symptom Score (IPSS) questionnaire. GU toxicity was also scored using the Common Terminology Criteria for Adverse Events (CTCAE) v.4.0; toxicity events were defined as increase over baseline. Differences in increases in IPSS sums and QoL index between baseline IPSS sum and QoL index groups were analyzed using the Kruskal-Wallis and Mann-Whitney tests. Univariate and multivariate Cox regression models were applied.

Results and limitations

The overall median IPSS sum increase during follow-up was 3 and was less pronounced among patients with severe baseline symptoms compared with those with mild baseline symptoms (median increase: 0 vs 4; p < 0.0001). Overall QoL index was unchanged after IMRT but appeared to improve in patients with dissatisfied baseline QoL compared with satisfied baseline QoL (p < 0.0001). Fifty-five (20%) and 2 (1%) patients developed grade 2 and 3 late GU toxicities, respectively; however, in 28 of 57 patients (49%), toxicity resolved during follow-up. Even though the IPSS data were prospectively obtained, most patients were not treated within a prospective protocol.

Conclusions

Late GU toxicity after high-dose IMRT was mild; severe, late GU toxicity was rare. Changes in IPSS sum and QoL index were dependent on the baseline GU function, which might be useful for future patient counseling.     

Cardiovascular Morbidity Associated with Gonadotropin Releasing Hormone Agonists and an Antagonist

Background

Androgen deprivation therapy (ADT) is associated with increased cardiovascular morbidity.

Objective

To determine whether cardiovascular morbidity differs following initiation of gonadotropin-releasing hormone (GnRH) agonists compared with an antagonist.

Design, setting, and participants

Pooled data from six phase 3 prospective randomized trials that recruited 2328 men between 2005 and 2012 to compare the efficacy of GnRH agonists against an antagonist. Men recruited had pathologically confirmed prostate cancer, an Eastern Cooperative Oncology Group score <2, a minimum life expectancy of 12 mo, and were naïve to ADT. Men were excluded if they had a prolonged baseline QT/corrected QT interval, other risk factors for heart failure, hypokalemia or a family history of long QT syndrome, or had another cancer diagnosed within 5 yr.

Intervention

Men were randomized to receive a GnRH agonist or an antagonist for either 3–7 mo (n = 642) or 12 mo (n = 1686). Treatment groups were balanced for common baseline characteristics.

Outcome measurements and statistical analysis

Event analysis was based on death from any cause or cardiac events. Data documenting adverse experiences were classified based on the Medical Dictionary for Regulatory Activities. The following conditions defined a cardiac event: arterial embolic or thrombotic events, hemorrhagic or ischemic cerebrovascular conditions, myocardial infarction, and other ischemic heart disease. Kaplan-Meier curves and log-rank tests were used to compare time to a cardiovascular event or death.

Results and limitations

Among men with preexisting cardiovascular disease, the risk of cardiac events within 1 yr of initiating therapy was significantly lower among men treated with a GnRH antagonist compared with GnRH agonists (hazard ratio: 0.44; 95% confidence interval, 0.26–0.74; p = 0.002). Since our analysis is post hoc, our findings should only be interpreted as hypothesis generating.

Conclusions

GnRH antagonists appear to halve the number of cardiac events experienced by men with preexisting cardiovascular disease during the first year of ADT when compared to GnRH agonists.     

A New Risk Classification System for Therapeutic Decision Making with Intermediate-risk Prostate Cancer Patients Undergoing Dose-escalated External-beam Radiation Therapy

Background

The management of intermediate-risk prostate cancer (PCa) is controversial, in part due to the heterogeneous nature of patients falling within this classification.

Objective

We propose a new risk stratification system for intermediate-risk PCa to aid in prognosis and therapeutic decision making.

Design, setting, and participants

Between 1992 and 2007, 1024 patients with National Comprehensive Cancer Network intermediate-risk PCa and complete biopsy information were treated with definitive external-beam radiation therapy (EBRT) utilizing doses ≥81 Gy. Unfavorable intermediate-risk (UIR) PCa was defined as any intermediate-risk patient with a primary Gleason pattern of 4, percentage of positive biopsy cores (PPBC) ≥50%, or multiple intermediate-risk factors (IRFs; cT2b–c, prostate-specific antigen [PSA] 10–20, or Gleason score 7).

Intervention

All patients received EBRT with ≥81 Gy with or without neoadjuvant and concurrent androgen-deprivation therapy (ADT).

Outcome measurements and statistical analysis

Univariate and multivariate analyses were performed using a Cox proportional hazards model for PSA recurrence-free survival (PSA-RFS) and distant metastasis (DM). PCa-specific mortality (PCSM) was analyzed using a competing-risk method.

Results and limitations

Median follow-up was 71 mo. Primary Gleason pattern 4 (hazard ratio [HR]: 3.26; p < 0.0001), PPBC ≥50% (HR: 2.72; p = 0.0007), and multiple IRFs (HR: 2.20; p = 0.008) all were significant predictors of increased DM in multivariate analyses. Primary Gleason pattern 4 (HR: 5.23; p < 0.0001) and PPBC ≥50% (HR: 4.08; p = 0.002) but not multiple IRFs (HR: 1.74; p = 0.21) independently predicted for increased PCSM. Patients with UIR disease had inferior PSA-RFS (HR: 2.37; p < 0.0001), DM (HR: 4.34; p = 0.0003), and PCSM (HR: 7.39; p = 0.007) compared with those with favorable intermediate-risk disease, despite being more likely to receive neoadjuvant ADT. Short follow-up and retrospective study design are the primary limitations.

Conclusions

Intermediate-risk PCa is a heterogeneous collection of diseases that can be separated into favorable and unfavorable subsets. These groups likely will benefit from divergent therapeutic paradigms.     

Might Men Diagnosed with Metastatic Prostate Cancer Benefit from Definitive Treatment of the Primary Tumor? A SEER-Based Study

Background

Few data exist regarding the impact on survival of definitive treatment of the prostate in men diagnosed with metastatic prostate cancer (mPCa).

Objective

To evaluate the survival of men diagnosed with mPCa based on definitive treatment of the prostate.

Design, setting, and participants

Men with documented stage IV (M1a–c) PCa at diagnosis identified using Surveillance Epidemiology and End Results (SEER) (2004–2010) and divided based on definitive treatment of the prostate (radical prostatectomy [RP] or brachytherapy [BT]) or no surgery or radiation therapy (NSR).

Outcome measurements and statistical analysis

Kaplan-Meier methods were used to calculate overall survival (OS). Multivariable competing risks regression analysis was used to calculate disease-specific survival (DSS) probability and identify factors associated with cause-specific mortality (CSM).

Results and limitations

A total of 8185 patients were identified: NSR (n = 7811), RP (n = 245), and BT (n = 129). The 5-yr OS and predicted DSS were each significantly higher in patients undergoing RP (67.4% and 75.8%, respectively) or BT (52.6 and 61.3%, respectively) compared with NSR patients (22.5% and 48.7%, respectively) (p < 0.001). Undergoing RP or BT was each independently associated with decreased CSM (p < 0.01). Similar results were noted regardless of the American Joint Committee on Cancer (AJCC) M stage. Factors associated with increased CSM in patients undergoing local therapy included AJCC T4 stage, high-grade disease, prostate-specific antigen ≥20 ng/ml, age ≥70 yr, and pelvic lymphadenopathy (p < 0.05). The major limitation of this study was the lack of variables from SEER known to influence survival of patients with mPCa, including treatment with systemic therapy.

Conclusions

Definitive treatment of the prostate in men diagnosed with mPCa suggests a survival benefit in this large population-based study. These results should serve as a foundation for future prospective trials.

Patient summary

We used a large population-based cancer database to examine survival in men diagnosed with metastatic prostate cancer (mPCa) undergoing definitive therapy for the prostate. Local therapy (LT) appeared to confer a survival benefit. Therefore, we conclude that prospective trials are needed to further evaluate the role of LT in mPCa.     

Metformin and Prostate Cancer: Reduced Development of Castration-resistant Disease and Prostate Cancer Mortality

Background

In vitro data and early clinical results suggest that metformin has desirable antineoplastic effects and has a theoretical benefit on castration-resistant prostate cancer (CRPC).

Objective

To determine whether the use of metformin would be associated with improved clinical outcomes and a reduction in the development of CRPC.

Design, setting, and participants

Data from 2901 consecutive patients (157 metformin, 162 diabetic non-metformin, and 2582 nondiabetic) with localized prostate cancer treated with external-beam radiation therapy from 1992 to 2008 were collected from a single institution in the United States.

Intervention

Use of metformin in localized prostate cancer.

Outcome measurements and statistical analysis

Univariate and multivariate regression models utilizing k-sample, Fine and Gray, Cox regression, log-rank, and Kaplan-Meier methods to assess prostate-specific antigen-recurrence-free survival (PSA-RFS), distant metastases-free survival (DMFS), prostate cancer–specific mortality (PCSM), overall survival (OS), and development of CRPC.

Results and limitations

With a median follow-up of 8.7 yr, the 10-yr actuarial rates for metformin, diabetic non-metformin, and nondiabetic patients for PCSM were 2.7%, 21.9%, and 8.2% (log-rank p ≤ 0.001), respectively. Metformin use independently predicted (correcting for PSA, T stage, Gleason score, age, diabetic status, and androgen-deprivation therapy use) improvement in all outcomes compared with the diabetic non-metformin group; PSA-RFS (hazard ratio [HR]: 1.99 [1.24–3.18]; p = 0.004), DMFS (adjusted HR: 3.68 [1.78–7.62]; p < 0.001), and PCSM (HR: 5.15 [1.53–17.35]; p = 0.008). Metformin use was also independently associated with a decrease in the development of CRPC in patients experiencing biochemical failure compared with diabetic non-metformin patients (odds ratio: 14.81 [1.83–119.89]; p = 0.01). The retrospective study design was the primary limitation of the study.

Conclusions

To our knowledge, our results are the first clinical data to indicate that metformin use may improve PSA-RFS, DMFS, PCSM, OS, and reduce the development of CRPC in prostate cancer patients. Further validation of metformin's potential benefits is warranted.     

Does Comorbidity Influence the Risk of Myocardial Infarction or Diabetes During Androgen-Deprivation Therapy for Prostate Cancer?

Background

Androgen-deprivation therapy (ADT) for prostate cancer (PCa) may be associated with cardiovascular disease and diabetes. Some data suggest that men with certain conditions may be more susceptible to developing cardiovascular disease than others.

Objective

To assess whether the risk of myocardial infarction (MI) or diabetes during ADT is modified by specific baseline comorbidities.

Design, setting, and participants

We conducted a population-based observational study of 185 106 US men ≥66 yr of age diagnosed with local/regional PCa from 1992 to 2007. We assessed comorbidities monthly over the follow-up period.

Outcome measurements and statistical analysis

Cox proportional hazards models with time-varying variables assessing incident diabetes or MI.

Results and limitations

A total of 49.9% of the men received ADT during follow-up. Among men with no comorbidities, ADT was associated with an increase in the adjusted hazard of MI (adjusted hazard ratio [AHR]: 1.09; 95% confidence interval [CI], 1.02–1.16) and diabetes (AHR: 1.33; 95% CI, 1.27–1.39). Risks of MI and diabetes were similarly increased among men with and without specific comorbid illnesses (p > 0.10 for all interactions, with one exception). Previous MI, congestive heart failure, peripheral arterial disease, stroke, hypertension, chronic obstructive pulmonary disease, and renal disease were associated with new MI and diabetes, and obesity and rheumatologic disease were also associated with diabetes. Limitations include the observational study design, reliance on administrative data to ascertain outcomes, and lack of information on risk factors such as smoking and family history.

Conclusions

Traditional risk factors for MI and diabetes were also associated with developing these conditions during ADT but did not significantly modify the risk attributable to ADT. Strategies to screen and prevent diabetes and cardiovascular disease in men with PCa should be similar to the strategies recommended for the general population.     

Multicentric Oncologic Outcomes of High-Intensity Focused Ultrasound for Localized Prostate Cancer in 803 Patients

Background

High-intensity focused ultrasound (HIFU) is an emerging treatment for select patients with localized prostate cancer (PCa).

Objectives

To report the oncologic outcome of HIFU as a primary care option for localized prostate cancer from a multicenter database.

Design, setting, and participants

Patients with localized PCa treated with curative intent and presenting at least a 2-yr follow-up from February 1993 were considered in this study. Previously irradiated patients were excluded from this analysis. In case of any residual or recurrent PCa, patients were systematically offered a second session. Kaplan-Meier analysis was performed to determine disease-free survival rates (DFSR).

Measurements

Prostate-specific antigen (PSA), clinical stage, and pathologic results were measured pre- and post-HIFU.

Results and limitations

A total of 803 patients from six urologic departments met the inclusion criteria. Stratification according to d’Amico's risk group was low, intermediate, and high in 40.2%, 46.3%, and 13.5% of patients, respectively. Mean follow-up was 42 ± 33 mo. Mean PSA nadir was 1.0 ± 2.8 ng/ml with 54.3% reaching a nadir of ≤0.3 ng/ml. Control biopsies were negative in 85% of cases. The overall and cancer-specific survival rates at 8 yr were 89% and 99%, respectively. The metastasis-free survival rate at 8 yr was 97%. Initial PSA value and Gleason score value significantly influence the DFSR. The 5- and 7-yr biochemical-free survival rates (Phoenix criteria) were 83–75%, 72–63%, and 68–62% (p = 0.03) and the additional treatment-free survival rates were 84–79%, 68–61%, and 52–54% (p < 0.001) for low-, intermediate-, and high-risk patients, respectively. PSA nadir was a major predictive factor for HIFU success: negative biopsies, stable PSA, and no additional therapy.

Conclusions

Local control and DFSR achieved with HIFU were similar to those expected with conformal external-beam radiation therapy (EBRT). The excellent cancer-specific survival rate is also explained by the possibility to repeat HIFU and use salvage EBRT.     

Complications and Early Postoperative Outcome in 1080 Patients After Thulium Vapoenucleation of the Prostate: Results at a Single Institution

Background

Thulium vapoenucleation of the prostate (ThuVEP) has been introduced as a minimally invasive treatment for benign prostatic obstruction (BPO).

Objective

To analyze immediate outcomes and the institutional learning curve of ThuVEP, and to report its standardized complication rates, using the modified Clavien classification system (CCS) to grade perioperative complication rates.

Design, settings, and participants

A prospective evaluation of 1080 patients undergoing ThuVEP from January 2007 until May 2012 at our institution.

Intervention

ThuVEP was performed using the 2-μm, continuous-wave, thulium:yttrium-aluminum-garnet laser.

Outcome measurements and statistical analysis

Preoperative status, surgical details, and immediate outcome were recorded for each patient. Perioperative complications were classified according to the modified CCS.

Results and limitations

Median prostate size was 51 ml (interquartile range [IQR]: 36–78.7). Median operation time was 56 min (IQR: 40–80), and median enucleation time was 32.5 min (IQR: 22-50). Median catheterization time was 2 d (IQR: 2–2); median length of hospital stay was 4 d (IQR: 3–5). Median resected tissue weight was 30 g (IQR: 16.00–51.25). Incidental carcinoma of the prostate was detected in 59 (5.5%) patients. Median maximum urinary flow rate (8.9 vs 18.4 ml/s) and postvoid residual urine volume (120 vs 20 ml) changed significantly (p < 0.001). Minor complications occurred in 24.6% of the patients (Clavien 1: 20.8%; Clavien 2: 3.8%). Early reinterventions were necessary in 6.6% of the patients (Clavien 3a: 0.6%; Clavien 3b: 6%). One Clavien 4 complication occurred (0.09%). The overall complication rates decreased significantly over time due to decreasing Clavien 1, 2, and 3b events. The major limitations of the study are the prospective, unicentric study design, the lack of a control group, and that only short-term data were documented on morbidity and efficacy of the ThuVEP procedure.

Conclusions

ThuVEP is a safe and effective procedure for the treatment of symptomatic BPO, with low perioperative morbidity.     

Improved toxicity profile following high-dose postprostatectomy salvage radiation therapy with intensity-modulated radiation therapy

Background

With salvage radiation therapy (SRT) in the postprostatectomy setting, the need to deliver sufficient radiation doses to achieve a high probability of tumor control is balanced with the risk of increased toxicity. Intensity-modulated radiation therapy (IMRT) in the postprostatectomy salvage setting is gaining interest as a treatment strategy.

Objective

Compare acute and late toxicities in patients treated with IMRT and three-dimensional conformal radiation therapy (3D-CRT) in the postprostatectomy salvage setting.

Design, setting, and participants

A total of 285 patients who were treated at our institution between 1988 and 2007 with SRT after radical prostatectomy for biochemical recurrence were identified. All medical records were reviewed and toxicity recorded. Median follow-up was 60 mo.

Intervention

All patients were treated with SRT with either 3D-CRT (n = 109) or IMRT (n = 176). A total of 205 patients (72%) were treated with doses ≥70 Gy.

Measurements

Late gastrointestinal (GI) and genitourinary (GU) toxicities were recorded using the Common Terminology Criteria for Adverse Events v. 3.0 definition.

Results and limitations

The 5-yr actuarial rates of late grade ≥2 GI and GU toxicity were 5.2% and 17.0%, respectively. IMRT was independently associated with a reduction in grade ≥2 GI toxicity compared with 3D-CRT (5-yr IMRT, 1.9%; 5-yr 3D-CRT, 10.2%; p = 0.02). IMRT was not associated with a reduction in risk of grade ≥2 GU toxicity (5-yr IMRT, 16.8%; 5-yr 3D-CRT, 15.8%; p = 0.86), urinary incontinence (5-yr IMRT, 13.6%; 5-yr 3D-CRT, 7.9%; p = 0.25), or grade 3 erectile dysfunction (5-yr IMRT, 26%; 5-yr 3D-CRT, 30%; p = 0.82). Of patients who developed late grade ≥2 GI or GU toxicity, 38% and 44%, respectively, experienced resolution of their symptoms prior to the last follow-up.

Conclusions

Our experience with high-dose IMRT in the postprostatectomy salvage setting demonstrates that the treatment can be delivered safely with an associated reduction in late GI toxicity.     

Prostate-Specific Antigen Kinetics and Outcomes in Patients with Bone Metastases from Castration-Resistant Prostate Cancer Treated with or Without Zoledronic Acid

Background

Zoledronic acid (ZOL) is a standard therapy for the prevention of skeletal-related events (SREs) in patients with castration-resistant prostate cancer (CRPC). Although prostate-specific antigen (PSA) is an established marker for monitoring prostate cancer patients, correlations between PSA and disease outcomes during ZOL therapy are unclear.

Objective

To evaluate the relationships among PSA kinetics, bone-directed therapy with ZOL, and clinical outcomes in men with bone metastases from CRPC using a ZOL phase 3 trial database.

Design, setting, and participants

Exploratory analyses from a phase 3 trial in men with bone metastases from CRPC (n = 643) randomized to ZOL or placebo every 3 wk.

Outcome measurements and statistical analysis

PSA levels during the first 3 mo of the study were evaluated in linear and logarithmic (log) models stratified using prognostic factors established in a ZOL phase 3 trial and a CRPC nomogram. Relative risks of SREs, bone disease progression (BDP), and death were calculated per 1 log (nanograms per milliliter) PSA increase. Baseline PSA models used the study median (PSA: 77.3 ng/ml) as the high/low cut-off point.

Results and limitations

A total of 202 placebo- and 434 ZOL-treated patients were assessable. In both groups, PSA increases correlated with significantly increased risks of death, BDP, and first SRE. In the placebo and ZOL groups, associated increases in risk per 1 log (nanograms per milliliter) PSA increase were 29% (p < 0.0001) and 10% (p < 0.0074), respectively, for BDP, and 24% (p = 0.0010) and 13% (p = 0.0079), respectively, for first SRE. Limitations include the retrospective nature of these analyses and the potential confounding effects of concurrent antineoplastic therapies.

Conclusions

PSA is an important prognostic tool for survival in patients with bone metastases from CRPC, and these analyses show that PSA is also prognostic for BDP and SREs regardless of bone-targeted therapy.     

Additional Analysis of the Secondary End Point of Biochemical Recurrence Rate in a Phase 3 Trial (CS21) Comparing Degarelix 80 mg Versus Leuprolide in Prostate Cancer Patients Segmented by Baseline Characteristics

Background

Recent data suggest prostate-specific antigen (PSA) progression may predict overall survival in prostate cancer patients.

Objective

To compare the activity of degarelix and leuprolide regarding PSA recurrence-free survival.

Design, setting, and participants

Phase 3, 1-yr, multicentre, randomised, open-label trial comparing the efficacy and safety of degarelix at 240 mg for 1 mo, and then 80 mg monthly (240/80 mg); degarelix at 240 mg for 1 mo, and then 160 mg monthly; and leuprolide at 7.5 mg/mo. Overall, 610 patients with histologically confirmed prostate cancer (all stages), for whom androgen deprivation therapy was indicated, were included. The primary end point of this trial has been reported previously; the protocolled and exploratory subgroup analyses reported in this paper focus on degarelix at 240/80 mg (dose approved by the US Food and Drug Administration and the European Medicine Evaluation Association for the treatment of patients with hormone-naive advanced prostate cancer).

Measurements

PSA progression-free survival (two consecutive increases in PSA of 50% compared with nadir and ≥5 ng/ml on two consecutive measurements at least 2 wk apart or death) and change in PSA were reviewed. Effects of baseline disease stage (localised, locally advanced, and metastatic) and PSA level (<10, 10–20, >20–50, and >50 ng/ml) were analysed.

Results and limitations

Patients receiving degarelix showed a significantly lower risk of PSA progression or death compared with leuprolide (p = 0.05). PSA recurrences occurred mainly in patients with advanced disease and exclusively in those with baseline PSA >20 ng/ml. Patients with PSA >20 ng/ml had a significantly longer time to PSA recurrence with degarelix (p = 0.04). The relatively low number of patients in each subgroup is a limitation of this study.

Conclusions

These results generate the hypothesis that degarelix at 240/80 mg offers improved PSA control compared with leuprolide. PSA recurrences occurred almost exclusively in patients with metastatic prostate cancer or high baseline PSA during this 1-yr study. Further studies are warranted to confirm these findings.     

The Impact of Solitary and Multiple Positive Surgical Margins on Hard Clinical End Points in 1712 Adjuvant Treatment–Naive pT2–4 N0 Radical Prostatectomy Patients

Background

Positive surgical margins (PSMs) increase the risk of biochemical recurrence (BCR) after radical prostatectomy (RP), but their impact on hard clinical end points is a topic of ongoing discussion.

Objective

To evaluate the influence of solitary PSMs (sPSMs) and multiple PSMs (mPSMs) on important clinical end points.

Design, setting, and participants

Data from 1712 patients from the Centre Hospitalier Universitaire de Québec with pT2–4 N0 prostate cancer (PCa) and undetectable prostate-specific antigen after RP were analyzed.

Intervention

RP without neoadjuvant or adjuvant treatment.

Outcome measurements and statistical analysis

Kaplan-Meier analysis estimated survival functions, and Cox proportional hazards models addressed predictors of clinical end points.

Results and limitations

Median follow-up was 74.9 mo. A total of 1121 patients (65.5%) were margin-negative, 281 patients (16.4%) had sPSMs, and 310 patients (18.1%) had mPSMs. A total of 280 patients (16.4%) experienced BCR, and 197 patients (11.5%) were treated with salvage radiotherapy (SRT). Sixty-eight patients (4.0%) received definitive androgen deprivation therapy, 19 patients (1.1%) developed metastatic disease, and 15 patients (0.9%) had castration-resistant PCa (CRPC). Thirteen patients (0.8%) died from PCa, and 194 patients (11.3%) died from other causes. Ten-year Kaplan-Meier estimates for BCR-free survival were 82% for margin-negative patients, 72% for patients with sPSMs, and 59% for patients with mPSMs (p < 0.0001). Time to metastatic disease, CRPC, PCa-specific mortality (PCSM), or all-cause mortality did not differ significantly among the three groups (p = 0.991, p = 0.988, p = 0.889, and p = 0.218, respectively). On multivariable analysis, sPSMs and mPSMs were associated with BCR (hazard ratio [HR]: 1.711; p = 0.001 and HR: 2.075; p < 0.0001), but sPSMs and mPSMs could not predict metastatic disease (p = 0.705 and p = 0.242), CRPC (p = 0.705 and p = 0.224), PCSM (p = 0.972 and p = 0.260), or all-cause death (p = 0.102 and p = 0.067). The major limitation was the retrospective design.

Conclusions

In a cohort of patients who received early SRT in 70% of cases upon BCR, sPSMs and mPSMs predicted BCR but not long-term clinical end points. Adjuvant radiotherapy for margin-positive patients might not be justified, as only a minority of patients progressed to end points other than BCR. PCSM was exceeded 15-fold by competing risk mortality.     

Early Complication Rates in a Single-Surgeon Series of 2500 Robotic-Assisted Radical Prostatectomies: Report Applying a Standardized Grading System

Background

Perioperative complications following robotic-assisted radical prostatectomy (RARP) have been previously reported in recent series. Few studies, however, have used standardized systems to classify surgical complications, and that inconsistency has hampered accurate comparisons between different series or surgical approaches.

Objective

To assess trends in the incidence and to classify perioperative surgical complications following RARP in 2500 consecutive patients.

Design, setting, and participants

We analyzed 2500 patients who underwent RARP for treatment of clinically localized prostate cancer (PCa) from August 2002 to February 2009. Data were prospectively collected in a customized database and retrospectively analyzed.

Intervention

All patients underwent RARP performed by a single surgeon.

Measurements

The data were collected prospectively in a customized database. Complications were classified using the Clavien grading system. To evaluate trends regarding complications and radiologic anastomotic leaks, we compared eight groups of 300 patients each, categorized according the surgeon's experience (number of cases).

Results and limitations

Our median operative time was 90 min (interquartile range [IQR]: 75–100 min). The median estimated blood loss was 100 ml (IQR:100–150 ml). Our conversion rate was 0.08%, comprising two procedures converted to standard laparoscopy due to robot malfunction. One hundred and forty complications were observed in 127 patients (5.08%). The following percentages of patients presented graded complications: grade 1, 2.24%; grade 2, 1.8%; grade 3a, 0.08%; grade 3b, 0.48%; grade 4a, 0.40%. There were no cases of multiple organ dysfunction or death (grades 4b and 5). There were significant decreases in the overall complication rates (p = 0.0034) and in the number of anastomotic leaks (p < 0.001) as the surgeon's experience increased.

Conclusions

RARP is a safe option for treatment of clinically localized PCa, presenting low complication rates in experienced hands. Although the robotic system provides the surgeon with enhanced vision and dexterity, proficiency is only accomplished with consistent surgical volume; complication rates demonstrated a tendency to decrease as the surgeon's experience increased.     

Androgen deprivation therapy for the treatment of prostate cancer: consider both benefits and risks

Context

Androgen deprivation therapy (ADT) is increasingly used for the treatment of prostate cancer (PCa), even in clinical settings in which there is no evidence-based proof of prolonged overall survival (OS). ADT, however, may be associated with numerous side effects, including an increased therapy-related cardiovascular mortality.

Objective

To discuss different clinical settings in which ADT is currently used and to critically weigh the benefits of ADT against its possible side effects.

Evidence acquisition

A MEDLINE search was conducted to identify original articles and review articles addressing the efficacy and side effects of ADT for the treatment of PCa. Keywords consisted of prostate cancer, hormonal therapy, adverse effects, radical prostatectomy, and radiotherapy. The articles with the highest level of evidence for the various examined end points were identified with the consensus of all authors and were reviewed.

Evidence synthesis

Even short-term use of ADT may lead to numerous side effects, such as osteoporosis, obesity, sarcopenia, lipid alterations, insulin resistance, and increased risk for diabetes and cardiovascular morbidity. Despite these side effects, ADT is commonly used in various clinical settings in which a clear effect on improved OS has not been shown.

Conclusions

ADT is associated with an increased risk of multiple side effects that may reduce quality of life and/or OS. Consequently, these issues should be discussed in detail with patients and their families before initiation of ADT. ADT should be used with knowledge of its potential long-term side effects and with possible lifestyle interventions, especially in settings with the highest risk–benefit ratio, to alleviate comorbidities.