Henk Vergunst

Active Surveillance for Low-Risk Prostate Cancer Worldwide: The PRIAS Study

BACKGROUNDnOverdiagnosis and subsequent overtreatment are important side effects of screening for, and early detection of, prostate cancer (PCa). Active surveillance (AS) is of growing interest as an alternative to radical treatment of low-risk PCa.nnnOBJECTIVEnTo update our experience in the largest worldwide prospective AS cohort.nnnDESIGN, SETTING, AND PARTICIPANTSnEligible patients had clinical stage T1/T2 PCa, prostate-specific antigen (PSA) ≤ 10 ng/ml, PSA density <0.2 ng/ml per milliliter, one or two positive biopsy cores, and Gleason score ≤ 6. PSA was measured every 3-6 mo, and volume-based repeat biopsies were scheduled after 1, 4, and 7 yr. Reclassification was defined as more than two positive cores or Gleason >6 at repeat biopsy. Recommendation for treatment was triggered in case of PSA doubling time <3 yr or reclassification.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnMultivariate regression analysis was used to evaluate predictors for reclassification at repeat biopsy. Active therapy-free survival (ATFS) was assessed with a Kaplan-Meier analysis, and Cox regression was used to evaluate the association of clinical characteristics with active therapy over time.nnnRESULTS AND LIMITATIONSnIn total, 2494 patients were included and followed for a median of 1.6 yr. One or more repeat biopsies were performed in 1480 men, of whom 415 men (28%) showed reclassification. Compliance with the first repeat biopsy was estimated to be 81%. During follow-up, 527 patients (21.1%) underwent active therapy. ATFS at 2 yr was 77.3%. The strongest predictors for reclassification and switching to deferred treatment were the number of positive cores (two cores compared with one core) and PSA density. The disease-specific survival rate was 100%. Follow-up was too short to draw definitive conclusions about the safety of AS.nnnCONCLUSIONSnOur short-term data support AS as a feasible strategy to reduce overtreatment. Clinical characteristics and PSA kinetics during follow-up can be used for risk stratification. Strict monitoring is even more essential in men with high-risk features to enable timely recognition of potentially aggressive disease and offer curative intervention. Limitations of using surrogate end points and markers in AS should be recognized.nnnTRIAL REGISTRATIONnThe current program is registered at the Dutch Trial Register with ID NTR1718 (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1718).

Prospective Multicentre Evaluation of PCA3 and TMPRSS2-ERG Gene Fusions as Diagnostic and Prognostic Urinary Biomarkers for Prostate Cancer ☆

BACKGROUNDnProstate cancer antigen 3 (PCA3) and v-ets erythroblastosis virus E26 oncogene homolog (TMPRSS2-ERG) gene fusions are promising prostate cancer (PCa) specific biomarkers that can be measured in urine.nnnOBJECTIVEnTo evaluate the diagnostic and prognostic value of Progensa PCA3 and TMPRSS2-ERG gene fusions (as individual biomarkers and as a panel) for PCa in a prospective multicentre setting.nnnDESIGN, SETTING, AND PARTICIPANTSnAt six centres, post-digital rectal examination first-catch urine specimens prior to prostate biopsies were prospectively collected from 497 men. We assessed the predictive value of Progensa PCA3 and TMPRSS2-ERG (quantitative nucleic acid amplification assay to detect TMPRSS2-ERG messenger RNA [mRNA]) for PCa, Gleason score, clinical tumour stage, and PCa significance (individually and as a marker panel). This was compared with serum prostate-specific antigen and the European Randomised Study of Screening for Prostate Cancer (ERSPC) risk calculator. In a subgroup (n=61) we evaluated biomarker association with prostatectomy outcome.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnUnivariate and multivariate logistic regression analysis and receiver operating curves were used.nnnRESULTS AND LIMITATIONSnUrine samples of 443 men contained sufficient mRNA for marker analysis. PCa was diagnosed in 196 of 443 men. Both PCA3 and TMPRSS2-ERG had significant additional predictive value to the ERSPC risk calculator parameters in multivariate analysis (p<0.001 and resp. p=0.002). The area under the curve (AUC) increased from 0.799 (ERSPC risk calculator), to 0.833 (ERSPC risk calculator plus PCA3), to 0.842 (ERSPC risk calculator plus PCA3 plus TMPRSS2-ERG) to predict PCa. Sensitivity of PCA3 increased from 68% to 76% when combined with TMPRSS2-ERG. TMPRSS2-ERG added significant predictive value to the ERSPC risk calculator to predict biopsy Gleason score (p<0.001) and clinical tumour stage (p=0.023), whereas PCA3 did not.nnnCONCLUSIONSnTMPRSS2-ERG had independent additional predictive value to PCA3 and the ERSPC risk calculator parameters for predicting PCa. TMPRSS2-ERG had prognostic value, whereas PCA3 did not. Implementing the novel urinary biomarker panel PCA3 and TMPRSS2-ERG into clinical practice would lead to a considerable reduction of the number of prostate biopsies.

Comparison of Three Schedules of Intravesical Epirubicin in Patients with Non–Muscle-Invasive Bladder Cancer

OBJECTIVESnTo study the additive effect of either an early instillation or maintenance instillations of adjuvant intravesical epirubicin, as compared to the epirubicin standard treatment schedule only, in patients with non-muscle-invasive bladder cancer.nnnMETHODSnPatients with intermediate- and high-risk urothelial cell carcinoma of the bladder, except carcinoma in situ, were randomised for adjuvant intravesical instillations with 50mg epirubicin/50 ml NaCl for 1h. Group 1 received 4 weekly and 5 monthly instillations (standard schedule), group 2 received the same schedule as group 1, but with an additional instillation <48 h after transurethral resection of bladder tumour (TURBT), and group 3 received the same scheme as group 1, but with additional instillations at 9 and 12 mo (maintenance schedule). Standard follow-up was 5 yr and consisted of cystoscopy, cytology, and registration of adverse events.nnnRESULTSnA total of 731 patients were eligible for quasi intention-to-treat analysis. Side-effects were minimal for all treatment groups. After 5-yr follow-up, respectively, 44.4%, 42.7%, and 45.0% (log-rank test, p=0.712) of the patients in groups 1, 2, and 3 were recurrence free, and 90.0%, 87.7%, and 88.2% (log-rank test, p=0.593) of the patients, respectively, were progression free.nnnCONCLUSIONSnIn the quasi intention-to-treat analysis there is no difference in the 5-yr recurrence-free period between the treatment groups, despite one instillation within 48 h of TURBT or two maintenance instillations up to 1 yr, in addition to the standard schedule.

Feasibility of 3T Dynamic Contrast-Enhanced Magnetic Resonance-Guided Biopsy in Localizing Local Recurrence of Prostate Cancer After External Beam Radiation Therapy

Objectives:The objective of this study was to assess the feasibility of the combination of magnetic resonance (MR)-guided biopsy (MRGB) and diagnostic 3T MR imaging in the localization of local recurrence of prostate cancer (PCa) after external beam radiation therapy (EBRT). Materials and Methods:Twenty-four consecutive men with biochemical failure suspected of local recurrence after initial EBRT were enrolled prospectively in this study. All patients underwent a diagnostic 3T MR examination of the prostate. T2-weighted and dynamic contrast-enhanced MR images (DCE-MRI) were acquired. Two radiologists evaluated the MR images in consensus for tumor suspicious regions (TSRs) for local recurrence. Subsequently, these TSRs were biopsied under MR-guidance and histopathologically evaluated for the presence of recurrent PCa. Descriptive statistical analysis was applied. Results:Tissue sampling was successful in all patients and all TSRs. The positive predictive value on a per patient basis was 75% (15/20) and on a per TSR basis 68% (26/38). The median number of biopsies taken per patient was 3, and the duration of an MRGB session was 31 minutes. No intervention-related complications occurred. Conclusions:The combination of MRGB and diagnostic MR imaging of the prostate was a feasible technique to localize PCa recurrence after EBRT using a low number of cores in a clinically acceptable time.

Detection of High-grade Prostate Cancer Using a Urinary Molecular Biomarker-Based Risk Score.

BACKGROUNDnTo reduce overdiagnosis and overtreatment, a test is urgently needed to detect clinically significant prostate cancer (PCa).nnnOBJECTIVEnTo develop a multimodal model, incorporating previously identified messenger RNA (mRNA) biomarkers and traditional risk factors that could be used to identify patients with high-grade PCa (Gleason score ≥7) on prostate biopsy.nnnDESIGN, SETTING, AND PARTICIPANTSnIn two prospective multicenter studies, urine was collected for mRNA profiling after digital rectal examination (DRE) and prior to prostate biopsy. The multimodal risk score was developed on a first cohort (n=519) and subsequently validated clinically in an independent cohort (n=386).nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnThe mRNA levels were measured using reverse transcription quantitative polymerase chain reaction. Logistic regression was used to model patient risk and combine risk factors. Models were compared using the area under the curve (AUC) of the receiver operating characteristic, and clinical utility was evaluated with a decision curve analysis (DCA).nnnRESULTS AND LIMITATIONSnHOXC6 and DLX1 mRNA levels were shown to be good predictors for the detection of high-grade PCa. The multimodal approach reached an overall AUC of 0.90 (95% confidence interval [CI], 0.85-0.95) in the validation cohort (AUC 0.86 in the training cohort), with the mRNA signature, prostate-specific antigen (PSA) density, and previous cancer-negative prostate biopsies as the strongest, most significant components, in addition to nonsignificant model contributions of PSA, age, and family history. For another model, which included DRE as an additional risk factor, an AUC of 0.86 (95% CI, 0.80-0.92) was obtained (AUC 0.90 in the training cohort). Both models were successfully validated, with no significant change in AUC in the validation cohort, and DCA indicated a strong net benefit and the best reduction in unnecessary biopsies compared with other clinical decision-making tools, such as the Prostate Cancer Prevention Trial risk calculator and the PCA3 assay.nnnCONCLUSIONSnThe risk score based on the mRNA liquid biopsy assay combined with traditional clinical risk factors identified men at risk of harboring high-grade PCa and resulted in a better patient risk stratification compared with current methods in clinical practice. Therefore, the risk score could reduce the number of unnecessary prostate biopsies.nnnPATIENT SUMMARYnThis study evaluated a novel urine-based assay that could be used as a noninvasive diagnostic aid for high-grade prostate cancer (PCa). When results of this assay are combined with traditional clinical risk factors, risk stratification for high-grade PCa and biopsy decision making are improved.

Identification of a Candidate Gene Panel for the Early Diagnosis of Prostate Cancer

Purpose: Serum PSA (sPSA) testing has led to the identification of patients with indolent prostate cancer, and inevitably overtreatment has become a concern. Progensa PCA3 urine testing was shown to improve the diagnosis of prostate cancer, but its diagnostic value for aggressive prostate cancer is limited. Therefore, urinary biomarkers that can be used for prediction of Gleason score ≥7 prostate cancer in biopsies are urgently needed. Experimental Design: Using gene expression profiling data, 39 prostate cancer biomarkers were identified. After quantitative PCR analysis on tissue specimens and urinary sediments, eight promising biomarkers for the urinary detection of prostate cancer were selected (ONECUT2, HOXC4, HOXC6, DLX1, TDRD1, NKAIN1, MS4A8B, PPFIA2). The hypothesis that biomarker combinations improve the diagnostic value for aggressive prostate cancer was tested on 358 urinary sediments of an intention-to-treat cohort. Results: A urinary three-gene panel (HOXC6, TDRD1, and DLX1) had higher accuracy [area under the curve (AUC), 0.77; 95% confidence interval (CI), 0.71–0.83] to predict Gleason score ≥7 prostate cancer in biopsies compared with Progensa PCA3 (AUC, 0.68; 95% CI, 0.62–0.75) or sPSA (AUC, 0.72; 95% CI, 0.65–0.78). Combining the three-gene panel with sPSA further improved the predictive accuracy (AUC, 0.81; 95% CI, 0.75–0.86). The accuracy of the three-gene predictive model was maintained in subgroups with low sPSA concentrations. Conclusions: The urinary three-gene panel (HOXC6, TDRD1, and DLX1) represents a promising tool to identify patients with aggressive prostate cancer, also in those with low sPSA values. The combination of the urinary three-gene panel with sPSA bears great potential for the early diagnosis of patients with clinically significant prostate cancer. Clin Cancer Res; 21(13); 3061–70. ©2015 AACR.

Cryosurgery for Prostate Cancer: an Update on Clinical Results of Modern Cryotechnology

CONTEXTnCryosurgery is an evolving treatment for localized prostate cancer in European centers. Modern cryotechnology is associated with a low complication rate, but its definitive role in the spectrum of different treatment modalities remains to be determined.nnnOBJECTIVEnThe primary objective of this review is to analyze the oncological results and complication rates of modern cryosurgery for prostate cancer. Secondarily, the impact of patient selection and the criteria for treatment success are discussed.nnnEVIDENCE ACQUISITIONnA structured literature review was performed by an online Pubmed search for data of primary and salvage cryosurgery of the prostate. Papers with relevant information on clinical outcome and complication rates were selected.nnnEVIDENCE SYNTHESISnThe introduction of gas-based third-generation cryotechnology has significantly decreased side effects with similar oncological results compared to older techniques. The occurrence of severe complications like rectourethral fistulas (<1%) has almost been eradicated, but the rates of erectile dysfunction remain high (90%). With salvage cryosurgery more side effects can be expected with an average incontinence rate of 8% and fistulas up to 3.4%. Nevertheless, this minimal invasive treatment remains an option for radiorecurrent prostate cancer. Focal cryosurgery is considered experimental, but is an interesting new development in cryosurgery. The intermediate-term biochemical disease free survival rates of 60%-90% are comparable to the results of other treatment modalities. However, the current data of cryosurgery in literature are of low-level evidence which should be discussed when counselling patients.nnnCONCLUSIONSnModern cryosurgery is reliable and results are promising with minimal morbidity. Focal cryosurgery in selected patients aims to reduce side effects, but is currently experimental treatment. Randomized trials comparing the outcomes of the different treatment modalities and long-term follow-up data are needed to define the ultimate role of cryosurgery in the treatment of localized prostate cancer.

Choice between prostatectomy and radiotherapy when men are eligible for both: a randomized controlled trial of usual care vs decision aid.

Many patients are eligible for more than one treatment option for prostate cancer. In usual care, urologists have a large influence on the treatment choice. Decision aids, providing balanced information on the pros and cons of different treatment options, improve the match between patient preferences and treatment received. In men eligible for both surgery and external beam radiotherapy, treatment choice differed by hospital. Across the participating hospitals, the decision aid consistently led to fewer patients remaining undecided on their treatment preference and more patients choosing brachytherapy.

Two-year follow-up of the phase II marker lesion study of intravesical apaziquone for patients with non-muscle invasive bladder cancer

ObjectivesTo study the time-to-recurrence and duration of response in non-muscle invasive bladder cancer (NMIBC) patients, with a complete ablative response after intravesical apaziquone instillations.MethodsTransurethral resection of bladder tumour(s) (TURBT) was performed in patients with multiple pTa-T1 G1-2 urothelial cell carcinoma (UCC) of the bladder, with the exception of one marker lesion of 0.5–1.0xa0cm. Intravesical apaziquone was administered at weekly intervals for six consecutive weeks, without maintenance instillations. A histological confirmed response was obtained 2–4xa0weeks after the last instillation. Routine follow-up (FU) was carried out at 6, 9, 12, 18 and 24xa0months from the first apaziquone instillation.ResultsAt 3xa0months FU 31 of 46 patients (67.4%) had a complete response (CR) to ablative treatment. Side-effects on the long-term were only mild. Two CR patients dropped out during FU. On intention-to-treat (ITT) analysis 49.5% of the CR patients were recurrence-free at 24xa0months FU, with a median duration of response of 18xa0months. Of 15 no response (NR) patients, only two received additional prophylactic instillations after TURBT. On ITT-analysis 26.7% of the NR patients were recurrence-free (log rank test, Pxa0=xa00.155). The overall recurrence-free survival was 39% (18 of 46 patients) at 24xa0months FU.ConclusionsThe CR of the marker lesion in 67% of patients was followed by a recurrence-free rate of 56.5% at 1-year FU, and 49.5% at 2-year FU. These long-term results are good in comparison with the results of other ablative studies.

Results of a Phase 1 Dose Escalation Study of Intravesical TMX-101 in Patients with Nonmuscle Invasive Bladder Cancer

PURPOSEnImiquimod, a toll like receptor 7 (TLR-7) agonist, is effective as a topical treatment for skin malignancies. TMX-101 is a liquid formulation of imiquimod. In this study we establish a safety profile of TMX-101 in patients with nonmuscle invasive bladder cancer.nnnMATERIALS AND METHODSnWe conducted a multicenter phase 1 dose escalation study in patients with nonmuscle invasive bladder cancer. Patients were included in 1 of 4 dose groups (0.05%, 0.1%, 0.2% or 0.4%) and treated with 6 weekly instillations of TMX-101, starting 2 weeks after transurethral resection of bladder tumor. Patients were evaluated weekly, and pharmacokinetic and pharmacodynamic parameters were measured.nnnRESULTSnA total of 16 patients were included in the study with 4 per dose group. Two patients dropped out after instillation 2 in dose groups 1 and 2. Overall, 88 instillations were administered without serious adverse events. There were 118 adverse events, of which 84 were related to the study drug. All adverse events were mild or moderate and number or severity was not correlated with dose group. Of the related adverse events 70% were confined to the genitourinary tract and resolved without intervention. There was a dose dependent systemic uptake with low plasma levels up to dose group 3 (0.2%, 100 mg). Maximum plasma concentration in dose group 4 (0.4%, 200 mg) was 71.7 ng/ml. This is below plasma concentrations of 123 and 128 ng/ml without significant side effects measured in healthy volunteers after subcutaneous (30 mg) or oral intake (100 mg) of imiquimod, respectively.nnnCONCLUSIONSnIntravesical treatment with TMX-101 is safe. The side effects are common but mild and mostly limited to the genitourinary tract. There is a low systemic uptake.