Wolfgang Loidl

Immediate or Deferred Androgen Deprivation for Patients With Prostate Cancer Not Suitable for Local Treatment With Curative Intent: European Organisation for Research and Treatment of Cancer (EORTC) Trial 30891

PURPOSE This study (EORTC 30891) attempted to demonstrate equivalent overall survival in patients with localized prostate cancer not suitable for local curative treatment treated with immediate or deferred androgen ablation. PATIENTS AND METHODS We randomly assigned 985 patients with newly diagnosed prostate cancer T0-4 N0-2 M0 to receive androgen deprivation either immediately (n = 493) or on symptomatic disease progression or occurrence of serious complications (n = 492). RESULTS Baseline characteristics were well balanced in the two groups. Median age was 73 years (range, 52 to 81). At a median follow-up of 7.8 years, 541 of 985 patients had died, mostly of prostate cancer (n = 193) or cardiovascular disease (n = 185). The overall survival hazard ratio was 1.25 (95% CI, 1.05 to 1.48; noninferiority P > .1) favoring immediate treatment, seemingly due to fewer deaths of nonprostatic cancer causes (P = .06). The time from randomization to progression of hormone refractory disease did not differ significantly, nor did prostate-cancer specific survival. The median time to the start of deferred treatment after study entry was 7 years. In this group 126 patients (25.6%) died without ever needing treatment (44% of the deaths in this arm). CONCLUSION Immediate androgen deprivation resulted in a modest but statistically significant increase in overall survival but no significant difference in prostate cancer mortality or symptom-free survival. This must be weighed on an individual basis against the adverse effects of life-long androgen deprivation, which may be avoided in a substantial number of patients with a deferred treatment policy.

Using PSA to Guide Timing of Androgen Deprivation in Patients with T0–4 N0–2 M0 Prostate Cancer not Suitable for Local Curative Treatment (EORTC 30891)

OBJECTIVE EORTC trial 30891 compared immediate versus deferred androgen-deprivation therapy (ADT) in T0-4 N0-2 M0 prostate cancer (PCa). Many patients randomly assigned to deferred ADT did not require ADT because they died before becoming symptomatic. The question arises whether serum prostate-specific antigen (PSA) levels may be used to decide when to initiate ADT in PCa not suitable for local curative treatment. METHODS PSA data at baseline, PSA doubling time (PSADT) in patients receiving no ADT, and time to PSA relapse (>2 ng/ml) in patients whose PSA declined to <2 ng/ml within the first year after immediate ADT were analyzed in 939 eligible patients randomly assigned to immediate (n=468) or deferred ADT (n=471). RESULTS In both arms, patients with a baseline PSA>50 ng/ml were at a>3.5-fold higher risk to die of PCa than patients with a baseline PSA<or=8 ng/ml. If baseline PSA was between 8 and 50 ng/ml, the risk of PCa death was approximately 7.5-fold higher in patients with PSADT<12 mo than in patients with PSADT>12 mo. Time to PSA relapse after response to immediate ADT correlated significantly with baseline PSA, suggesting that baseline PSA may also reflect disease aggressiveness. CONCLUSIONS Patients with a baseline PSA>50 ng/ml and/or a PSADT<12 mo were at increased risk to die from PCa and might have benefited from immediate ADT, whereas patients with a baseline PSA<50 ng/ml and a slow PSADT (>12 mo) were likely to die of causes unrelated to PCa, and thus could be spared the burden of immediate ADT.

180-W XPS GreenLight Laser Vaporisation Versus Transurethral Resection of the Prostate for the Treatment of Benign Prostatic Obstruction: 6-Month Safety and Efficacy Results of a European Multicentre Randomised Trial—The GOLIATH Study

BACKGROUND The comparative outcome with GreenLight (GL) photoselective vaporisation of the prostate and transurethral resection of the prostate (TURP) in men with lower urinary tract symptoms due to benign prostatic obstruction (BPO) has been questioned. OBJECTIVE The primary objective of the GOLIATH study was to evaluate the noninferiority of 180-W GL XPS (XPS) to TURP for International Prostate Symptom Score (IPSS) and maximum flow rate (Qmax) at 6 mo and the proportion of patients who were complication free. DESIGN, SETTING, AND PARTICIPANTS Prospective randomised controlled trial at 29 centres in 9 European countries involving 281 patients with BPO. INTERVENTION 180-W GL XPS system or TURP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Measurements used were IPSS, Qmax, prostate volume (PV), postvoid residual (PVR) and complications, perioperative parameters, and reintervention rates. Noninferiority was evaluated using one-sided tests at the 2.5% level of significance. The statistical significance of other comparisons was assessed at the (two-sided) 5% level. RESULTS AND LIMITATIONS The study demonstrated the noninferiority of XPS to TURP for IPSS, Qmax, and complication-free proportion. PV and PVR were comparable between groups. Time until stable health status, length of catheterisation, and length of hospital stay were superior with XPS (p<0.001). Early reintervention rate within 30 d was three times higher after TURP (p=0.025); however, the overall postoperative reintervention rates were not significantly different between treatment arms. A limitation was the short follow-up. CONCLUSIONS XPS was shown to be noninferior (comparable) to TURP in terms of IPSS, Qmax, and proportion of patients free of complications. XPS results in a lower rate of early reinterventions but has a similar rate after 6 mo. TRIAL REGISTRATION ClinicalTrials.gov, identifier NCT01218672.

Impact of 18F-Choline PET/CT in Prostate Cancer Patients with Biochemical Recurrence: Influence of Androgen Deprivation Therapy and Correlation with PSA Kinetics

We evaluated the potential of 18F-fluoromethyldimethyl-2-hydroxyethyl-ammonium (FCH) PET/CT in the detection of recurrent disease or distant metastases and correlated its diagnostic accuracy with prostate-specific antigen (PSA) levels in prostate cancer patients with biochemical evidence of recurrence. Furthermore, the influences of androgen deprivation therapy (ADT) and its duration on 18F-FCH PET were assessed in this study. Methods: This prospective study included 250 prostate cancer patients with PSA relapse who underwent 18F-FCH PET/CT. At the time of 18F-FCH PET/CT imaging, the mean PSA level was 46.9 ± 314.7 ng/mL and 55.2% (138/250) of patients were receiving ADT. Overall, ADT was performed on 67.2% (168/250) of patients after initial treatment. Imaging was performed on an integrated PET/CT system. Acquisition started 1 min after intravenous injection of 18F-FCH (4.07 MBq/kg of body weight) with dynamic PET images in the pelvic region during 8 min (1 min/frame) followed by a static semi–whole-body acquisition. The final diagnosis of positive PET lesions was based on histopathology or a consensus of clinical findings, additional imaging, or follow-up imaging modalities. Results: 18F-FCH PET/CT was able to correctly detect malignant lesions in 74% (185/250) of patients but was negative in 26% (65/250). In 28% of patients, only 1 lesion was detected (69/250); from these, 65.2% (45 patients) had a local recurrence, 18.8% (13 patients) a single lymph node, and 15.9% (11 patients) a solitary bone metastasis. The sensitivity of the 18F-FCH PET was significantly higher (P = 0.001) in patients with ongoing ADT (85%; confidence interval, 80%–91%) than in patients without ADT (59.5%; confidence interval, 50%–69%). 18F-FCH PET sensitivity was 77.5%, 80.7%, 85.2%, and 92.8% for the trigger PSA levels of more than 0.5, 1.0, 2.0, and 4.0 ng/mL, respectively. Scan sensitivity was 33% in patients with a trigger PSA level of less than 0.3 ng/mL and 77% in patients with a trigger PSA level of greater than 0.3 ng/mL, respectively (P = 0.001). Using a binary logistic regression analysis model, we showed trigger PSA and ADT to be the only significant predictors of positive PET findings. Conclusion: 18F-FCH PET/CT proved its potential as a noninvasive 1-stop diagnostic modality enabling us to correctly detect occult disease in 74% of patients and to differentiate localized from systemic disease. In patients with biochemical recurrence, it also guides to an optimal treatment approach after initial treatment. Trigger PSA and ADT are the 2 significant predictors of 18F-FCH–positive PET lesions. ADT seems not to impair 18F-FCH uptake in hormone-refractory prostate cancer patients.

A Multinational, Multi-institutional Study Comparing Positive Surgical Margin Rates Among 22 393 Open, Laparoscopic, and Robot-assisted Radical Prostatectomy Patients

BACKGROUND Positive surgical margins (PSMs) are a known risk factor for biochemical recurrence in patients with prostate cancer (PCa) and are potentially affected by surgical technique and volume. OBJECTIVE To investigate whether radical prostatectomy (RP) modality and volume affect PSM rates. DESIGN, SETTING, AND PARTICIPANTS Fourteen institutions in Europe, the United States, and Australia were invited to participate in this study, all of which retrospectively provided margins data on 9778 open RP, 4918 laparoscopic RP, and 7697 robotic RP patients operated on between January 2000 and October 2011. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES The outcome measure was PSM rate. Multivariable logistic regression analyses and propensity score methods identified odds ratios for risk of a PSM for one modality compared with another, after adjustment for age, preoperative prostate-specific antigen, postoperative Gleason score, pathologic stage, and year of surgery. Classic adjustment using standard covariates was also implemented to compare PSM rates based on center volume for each minimally invasive surgical cohort. RESULTS AND LIMITATIONS Open RP patients had higher-risk PCa at time of surgery on average and were operated on earlier in the study time period on average, compared with minimally invasive cohorts. Crude margin rates were lowest for robotic RP (13.8%), intermediate for laparoscopic RP (16.3%), and highest for open RP (22.8%); significant differences persisted, although were ameliorated, after statistical adjustments. Lower-volume centers had increased risks of PSM compared with the highest-volume center for both laparoscopic RP and robotic RP. The study is limited by its nonrandomized nature; missing data across covariates, especially year of surgery in many of the open cohort cases; lack of standardized histologic processing and central pathology review; and lack of information regarding potential confounders such as patient comorbidity, nerve-sparing status, lymph node status, tumor volume, and individual surgeon caseload. CONCLUSIONS This multinational, multi-institutional study of 22 393 patients after RP suggests that PSM rates might be lower after minimally invasive techniques than after open RP and that PSM rates are affected by center volume in laparoscopic and robotic cases. PATIENT SUMMARY In this study, we compared the effectiveness of different types of surgery for prostate cancer by looking at the rates of cancer cells left at the margins of what was removed in the operations. We compared open, keyhole, and robotic surgery from many centers across the globe and found that robotic and keyhole operations appeared to have lower margin rates than open surgeries. How many cases a center and surgeon do seems to affect this rate for both robotic and keyhole procedures.

A European Multicenter Randomized Noninferiority Trial Comparing 180 W GreenLight XPS Laser Vaporization and Transurethral Resection of the Prostate for the Treatment of Benign Prostatic Obstruction: 12-Month Results of the GOLIATH Study

PURPOSE We present the 1-year results of the GOLIATH prospective randomized controlled trial comparing transurethral resection of the prostate to GreenLight XPS for the treatment of men with nonneurogenic lower urinary tract symptoms due to prostate enlargement. The updated results at 1 year show that transurethral resection of the prostate and GreenLight XPS remain equivalent, and confirm the therapeutic durability of both procedures. We also report 1-year followup data from several functional questionnaires (OABq-SF, ICIQ-SF and IIEF-5) and objective assessments. MATERIALS AND METHODS A total of 291 patients were enrolled at 29 sites in 9 European countries. Patients were randomized 1:1 to undergo GreenLight XPS or transurethral resection of the prostate. The trial was designed to evaluate the hypothesis that GreenLight XPS is noninferior to transurethral resection of the prostate on the International Prostate Symptom Score at 6 months. Several objective parameters were assessed, including maximum urinary flow rate, post-void residual urine volume, prostate volume and prostate specific antigen, in addition to functional questionnaires and adverse events at each followup. RESULTS Of the 291 enrolled patients 281 were randomized and 269 received treatment. Noninferiority of GreenLight XPS was maintained at 12 months. Maximum urinary flow rate, post-void residual urine volume, prostate volume and prostate specific antigen were not statistically different between the treatment arms at 12 months. The complication-free rate at 1 year was 84.6% after GreenLight XPS vs 80.5% after transurethral resection of the prostate. At 12 months 4 patients treated with GreenLight XPS and 4 who underwent transurethral resection of the prostate had unresolved urinary incontinence. CONCLUSIONS Followup at 1 year demonstrated that photoselective vaporization of the prostate produced efficacy outcomes similar to those of transurethral resection of the prostate. The complication-free rates and overall reintervention rates were comparable between the treatment groups.

A Multicenter Randomized Noninferiority Trial Comparing GreenLight-XPS Laser Vaporization of the Prostate and Transurethral Resection of the Prostate for the Treatment of Benign Prostatic Obstruction: Two-yr Outcomes of the GOLIATH Study

BACKGROUND The GOLIATH study is a 2-yr trial comparing transurethral resection of prostate (TURP) to photoselective vaporization with the GreenLight XPS Laser System (GL-XPS) for the treatment of benign prostatic obstruction (BPO). Noninferiority of GL-XPS to TURP was demonstrated based on a 6-mo follow-up from the study. OBJECTIVE To determine whether treatment effects observed at 6 mo between GL-XPS and TURP was maintained at the 2-yr follow-up. DESIGN, SETTING, AND PARTICIPANTS Prospective randomized controlled trial at 29 centers in nine European countries involving 281 patients with BPO. INTERVENTION Photoselective vaporization using the 180-W GreenLight GL-XPS or conventional (monopolar or bipolar) TURP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary outcome was the International Prostate Symptom Score for which a margin of three was used to evaluate the noninferiority of GL-XPS. Secondary outcomes included Qmax, prostate volume, prostate specific antigen, Overactive Bladder Questionnaire Short Form, International Consultation on Incontinence Questionnaire Short Form, occurrence of surgical retreatment, and freedom from complications. RESULTS AND LIMITATIONS One hundred and thirty-six patients were treated using GL-XPS and 133 using TURP. Noninferiority of GL-XPS on International Prostate Symptom Score, Qmax, and freedom from complications was demonstrated at 6-mo and was sustained at 2-yr. The proportion of patients complication-free through 24-mo was 83.6% GL-XPS versus 78.9% TURP. Reductions in prostate volume and prostate specific antigen were similar in both arms and sustained over the course of the trial. Compared with the 1(st) yr of the study, very few adverse events or retreatments were reported in either arm. Treatment differences in the Overactive Bladder Questionnaire Short Form observed at 12-mo were not statistically significant at 24-mo. A limitation was that patients and treating physicians were not blinded to the therapy. CONCLUSIONS Twenty-four-mo follow-up data demonstrated that GL-XPS provides a durable surgical option for the treatment of BPO that exhibits efficacy and safety outcomes similar to TURP. PATIENT SUMMARY The long-term effectiveness and safety of GLP-XLS was similar to conventional TURP for the treatment of prostate enlargement.

Differences in Time to Disease Progression Do Not Predict for Cancer-specific Survival in Patients Receiving Immediate or Deferred Androgen-deprivation Therapy for Prostate Cancer: Final Results of EORTC Randomized Trial 30891 with 12 Years of Follow-up

BACKGROUND Trials assessing the benefit of immediate androgen-deprivation therapy (ADT) for treating prostate cancer (PCa) have often done so based on differences in detectable prostate-specific antigen (PSA) relapse or metastatic disease rates at a specific time after randomization. OBJECTIVE Based on the long-term results of European Organization for Research and Treatment of Cancer (EORTC) trial 30891, we questioned if differences in time to progression predict for survival differences. DESIGN, SETTING, AND PARTICIPANTS EORTC trial 30891 compared immediate ADT (n=492) with orchiectomy or luteinizing hormone-releasing hormone analog with deferred ADT (n=493) initiated upon symptomatic disease progression or life-threatening complications in randomly assigned T0-4 N0-2 M0 PCa patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Time to first objective progression (documented metastases, ureteric obstruction, not PSA rise) and time to objective castration-resistant progressive disease were compared as well as PCa mortality and overall survival. RESULTS AND LIMITATIONS After a median of 12.8 yr, 769 of the 985 patients had died (78%), 269 of PCa (27%). For patients receiving deferred ADT, the overall treatment time was 31% of that for patients on immediate ADT. Deferred ADT was significantly worse than immediate ADT for time to first objective disease progression (p<0.0001; 10-yr progression rates 42% vs 30%). However, time to objective castration-resistant disease after deferred ADT did not differ significantly (p=0.42) from that after immediate ADT. In addition, PCa mortality did not differ significantly, except in patients with aggressive PCa resulting in death within 3-5 yr after diagnosis. Deferred ADT was inferior to immediate ADT in terms of overall survival (hazard ratio: 1.21; 95% confidence interval, 1.05-1.39; p [noninferiority]=0.72, p [difference] = 0.0085). CONCLUSIONS This study shows that if hormonal manipulation is used at different times during the disease course, differences in time to first disease progression cannot predict differences in disease-specific survival. A deferred ADT policy may substantially reduce the time on treatment, but it is not suitable for patients with rapidly progressing disease.

Impact of Smoking on Outcomes of Patients with a History of Recurrent Nonmuscle Invasive Bladder Cancer

PURPOSE We investigated the effects of cigarette smoking status, cumulative exposure and time from cessation on disease recurrence and progression in patients with a history of recurrent nonmuscle invasive bladder cancer. MATERIALS AND METHODS A total of 390 patients with recurrent nonmuscle invasive bladder cancer were treated with transurethral resection of the bladder, of whom 159 (41%) received instillation therapy immediately postoperatively and 73 (19%) received adjuvant intravesical immunotherapy or chemotherapy. Smoking history included smoking status, number of cigarettes per day, smoking duration in years and years since smoking cessation. Cumulative smoking exposure was categorized as light short-term--19 or fewer cigarettes per day and 19.9 years or less, moderate--all combinations except light short-term and heavy long-term, and heavy long-term--20 or greater cigarettes per day and 20 years or greater. RESULTS A total of 91 (23%), 192 (49%) and 107 patients (28%) were never, former and current smokers, respectively. Of ever smokers 56 (19%), 156 (52%) and 87 (29%) were light short-term, moderate and heavy long-term smokers, respectively. There was no difference in the risk of disease recurrence and progression among current, former and never smokers. On univariable analyses in ever smokers the risk of disease recurrence and progression increased with augmented smoking intensity (p ≤ 0.015), duration (p <0.001) and cumulative exposure (p <0.001). On multivariable analyses cumulative smoking exposure was an independent risk factor for disease recurrence and progression (p ≤ 0.003). Smoking cessation greater than 10 years before treatment was independently associated with decreased disease recurrence compared to current smoking (HR 0.4, p <0.001). In addition, current smokers had worse survival than former smokers, who in turn had worse survival than never smokers (p >0.05). CONCLUSIONS There is a dose-response relationship of smoking exposure and smoking cessation with disease recurrence and progression in ever smokers with a history of recurrent nonmuscle invasive bladder cancer. These findings support counseling on smoking cessation benefits.

Association of Cigarette Smoking and Smoking Cessation with Biochemical Recurrence of Prostate Cancer in Patients Treated with Radical Prostatectomy

BACKGROUND Cigarette smoking seems to be associated with prostate cancer (PCa) incidence and mortality. OBJECTIVE To elucidate the association between pretreatment smoking status, cumulative smoking exposure, and time since smoking cessation and the risk of biochemical recurrence (BCR) of PCa in patients treated with radical prostatectomy (RP). DESIGN, SETTING, AND PARTICIPANTS Retrospective analysis of 6538 patients with pathologically node-negative PCa treated with RP between 2000 and 2011. Clinicopathologic and smoking variables, including smoking status, number of cigarettes per day (CPD), duration in years, and time since smoking cessation were collected. INTERVENTION RP without neoadjuvant therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Univariable and multivariable Cox regression analyses assessed the association between smoking and risk of PCa BCR. RESULTS AND LIMITATIONS Of 6538 patients, 2238 (34%), 2086 (32%), and 2214 (34%) were never, former, and current smokers, respectively. Median follow-up for patients not experiencing BCR was 28 mo (interquartile range 14-42). RP Gleason score (p=0.3), extracapsular extension (p=0.2), seminal vesicle invasion (p=0.8), and positive surgical margins (p=0.9) were comparable among the three groups. In multivariable Cox regression analysis, former smokers (hazard ratio [HR] 1.63, 95% confidence interval [CI] 1.30-2.04; p<0.001) and current smokers (HR 1.80, 95% CI 1.45-2.24; p<0.001) had a higher risk of PCa BCR compared with non-smokers. Smoking cessation for ≥10 yr mitigated the risk of BCR in multivariable analyses (HR 0.96, 95% CI 0.68-1.37; p=0.84). In multivariable analysis, no significant association between cumulative smoking exposure and risk of BCR could be detected. Limitations of the study include the retrospective design and potential recall bias regarding smoking history. CONCLUSION Smoking seems to be associated with a higher risk of PCa BCR after RP. The effects of smoking appear to be mitigated by ≥10 yr of cessation. Smokers should be counseled regarding the detrimental effects of smoking on PCa prognosis. PATIENT SUMMARY We investigated the effect of smoking on the risk of prostate cancer recurrence in patients with treated with surgery. We found that former smokers and current smokers were at higher risk of cancer recurrence compared to patients who never smoked; the detrimental effect of smoking was mitigated after 10 yr or more of smoking cessation. We conclude that smokers should be counseled regarding the detrimental effects on prostate cancer outcomes.