Role of multidisciplinary team meetings in implementation of chemohormonal therapy in metastatic prostate cancer in daily practice.

BACKGROUND: The recommended treatment for a subset of patients with metastatic prostate cancer (mPC) changed from androgen deprivation therapy (ADT) to combinations with chemotherapy such as docetaxel. Implementation of new evidence from trials is however complex and challenging. We investigated the effect of multidisciplinary team meetings (MDTs) on adopting the newest emerging combination therapy in patients with mPC and assessed the overall survival of chemohormonal therapy in a real-world setting. METHODS: All mPC patients diagnosed between October 2015 and April 2016 in the Netherlands were identified from the population-based Netherlands Cancer Registry (n = 962). Logistic regression analyses were performed to examine the role of patient- and tumor characteristics, with special emphasis on MDTs, on receiving chemohormonal therapy versus ADT monotherapy. Kaplan-Meier survival curves were used to assess overall survival (OS). RESULTS: As many patients received ADT monotherapy as chemohormonal therapy (both n = 452). Being discussed in a MDT as patient, younger age, less comorbidities, a better performance status and high-volume disease were significantly associated with receiving chemohormonal therapy compared to ADT monotherapy. After adjustment for these factors, the presence of a MDT was independently associated with the administration of chemohormonal therapy (OR 2.77, 95% CI 1.68-4.59). The 2-year OS was 82.1% (95% CI: 78.5-85.6%) for patients receiving chemohormonal therapy and 59.9% (95% CI: 55.4-64.4%) for patients receiving ADT monotherapy. CONCLUSION: Being discussed in a MDT is independently associated with the administration of chemohormonal therapy in this group of patients with mPC. This supports the hypothesis that implementation of innovative treatment options is facilitated by an organizational structure with MDTs.

Adjustment disorder in cancer patients after treatment: prevalence and acceptance of psychological treatment.

PURPOSE: To investigate the prevalence of adjustment disorder (AD) among cancer patients and the acceptance of psychological treatment, in relation to sociodemographic, clinical, and psychological factors. METHODS: Breast, prostate, and head and neck cancer patients of all stages and treatment modalities (N = 200) participated in this observational study. Patients completed the Hospital Anxiety and Depression Scale, Checklist Individual Strength, Distress Thermometer and problem list. Patients with increased risk on AD based on these questionnaires were scheduled for a diagnostic interview. Patients diagnosed with AD were invited to participate in a randomized controlled trial on the cost-effectiveness of psychological treatment. Participation in this trial was used as a proxy of acceptance of psychological treatment. Logistic regression analyses were used to investigate associated factors. RESULTS: The overall prevalence of AD was estimated at 13.1%. Sensitivity analyses showed prevalence rates of AD of 11.5%, 15.0%, and 23.5%. Acceptance of psychological treatment was estimated at 65%. AD was associated both with being employed (OR = 3.3, CI = 1.3-8.4) and having a shorter time since diagnosis (OR = 0.3, CI = 0.1-0.8). CONCLUSION: Taking sensitivity analysis into account, the prevalence of AD among cancer patients is estimated at 13 to 15%, and is related to being employed and having a shorter time since diagnosis. The majority of cancer patients with AD accept psychological treatment.

The effects of new life-prolonging drugs for metastatic castration-resistant prostate cancer (mCRPC) patients in a real-world population.

BACKGROUND: In 2004 docetaxel was the first life-prolonging drug (LPD) registered for metastatic castration-resistant prostate cancer (mCRPC) patients. Between 2011 and 2014 new LPDs for mCRPC (cabazitaxel, abiraterone, enzalutamide, and radium-223) were introduced in the Netherlands. The objective of this study is to assess the impact of the introduction of new LPDs on treatment patterns and overall survival (OS) over time. PATIENTS AND METHODS: CRPC patients diagnosed in the years 2010-2016 in the observational, retrospective CAPRI registry (20 hospitals) were included and followed up to 2018. Two subgroups were analyzed: treatment-naïve patients (subgroup 1, n = 3600) and post-docetaxel patients (subgroup 2, n = 1355). RESULTS: In both subgroups, the use of any LPD increased: from 57% (2010-2011) to 69% (2014-2015) in subgroup 1 and from 65% (2011-2012) to 79% (2015-2016) in subgroup 2. Chemotherapy as first mCRPC-treatment (i.e., docetaxel) and first post-docetaxel treatment (i.e., cabazitaxel or docetaxel rechallenge) decreased (46-29% and 20-9% in subgroup 1 and 2, respectively), while the use of androgen-receptor targeting treatments (ART) increased from 11% to 39% and 46% to 64% in subgroup 1 and 2, respectively. In subgroup 1, median OS (mOS) from diagnosis CRPC increased from 28.5 months to 31.0 months (p = 0.196). In subgroup 2, mOS from progression on docetaxel increased from 7.9 months to 12.5 months (p < 0.001). After multiple imputations of missing values, in multivariable cox-regression analysis with known prognostic parameters, the treatment period was independent significant for OS in subgroup 1 (2014-2015 vs. 2010-2011 with HR 0.749, p < 0.001) and subgroup 2 (2015-2016 vs. 2011-2012 with HR 0.811, p = 0.037). CONCLUSION: Since 2010, a larger proportion of mCRPC patients was treated with LPDs, which was related to an increased mOS.

Histopathological re-evaluations of biopsies in prostate cancer: a nationwide observational study.

BACKGROUND: Grading prostate biopsies has an important role in determining treatment strategy. Histopathological evaluations suffer from interobserver variability and therefore biopsies may be re-evaluated. OBJECTIVE: To provide insight into the extent of, characteristics associated with and clinical implications of prostate biopsy re-evaluations in daily clinical practice. METHODS: Patients diagnosed with prostate cancer (PCa) by biopsy between October 2015 and April 2016 identified through the Netherlands Cancer Registry were included. The proportion of re-evaluations was assessed and characteristics were compared between patients with and without biopsy re-evaluation. Interobserver concordance of ISUP grade and EAU prognostic risk classification was determined by calculating Cohen's kappa. RESULTS: Biopsy re-evaluation was performed in 172 (3.3%) of 5214 patients. Primary reason for re-evaluation in patients treated with curative intent was referral to another hospital. Most referred patients treated with curative intent (n = 1856) had no re-evaluation (93.0%, n = 1727). Patients with biopsy re-evaluation were younger and underwent more often prostatectomy compared to patients without re-evaluation. The disagreement rate for ISUP grade was 26.1% and interobserver concordance was substantial (κ-weighted = 0.74). Re-evaluation resulted in 21.1% (n = 14) of patients with localised PCa in a different prognostic risk group. More tumours were downgraded (57.1%) than upgraded (42.9%). Interobserver concordance was very good (κ weighted = 0.85). CONCLUSION: Pathology review of prostate biopsies is infrequently requested by clinicians in the Netherlands but in a non-negligible minority of patients with localised PCa the pathology review led to a change in prognostic risk group which might impact their treatment.

Urinary incontinence and erectile dysfunction in patients with localized or locally advanced prostate cancer: A nationwide observational study.

BACKGROUND: Although urinary adverse events after treatment of prostate cancer (CaP) are common, population-based studies on functional outcomes are scarce. The aim of this study is to evaluate the occurrence of urinary incontinence (UI) and erectile dysfunction (ED) in daily clinical practice using a nationwide Dutch cohort of patients with localized or locally advanced CaP. BASIC PROCEDURES: Patients were invited to complete the EPIC-26 questionnaire before treatment (baseline) and at 12 and 24 months after diagnosis. We calculated the mean EPIC-26 domain scores, stratified by treatment modality (i.e., radical prostatectomy, external radiotherapy, and no active treatment), and the proportions of patients with UI (defined as ≥ 2 pads per day) and ED (defined as erections not firm enough for sexual intercourse). Logistic regression modeling was used to explore the factors related to UI and ED after surgery. MAIN FINDINGS: In total 1,759 patients participated in this study. Patients undergoing radical prostatectomy experienced clinically relevant worsening in the urinary incontinence domain. After excluding patients who reported UI at baseline, 15% of patients with prostatectomy reported UI 24 months after diagnosis. Only comorbidity was associated with UI in surgically treated patients. Regardless of treatment, patients reported a clinically significant reduced sexual functioning over time. Before treatment, 54% of patients reported ED. Among the 46% remaining patients, 87% of patients treated with radical prostatectomy reported ED 24 months after diagnosis, 41% after radiotherapy, and 46% in patients without active treatment. Bilateral nerve-sparing surgery was the only factor associated with ED after 24 months. PRINCIPAL CONCLUSIONS: UI and ED frequently occur in patients with localized and locally advanced CaP, in particular after radical prostatectomy. The higher occurrence rate of UI and ED, compared with clinical trial participants, supports the importance of real-world data, which can be used for local treatment recommendations and patient information, but also to evaluate effects of future initiatives, such as treatment centralization and research aimed at improving functional outcomes.

68Ga-PSMA-PET/CT and Diffusion MRI Targeting for Cone-Beam CT-Guided Bone Biopsies of Castration-Resistant Prostate Cancer Patients.

INTRODUCTION: Precision medicine expands the treatment options for metastatic castration-resistant prostate cancer (mCRPC) by targeting druggable genetic aberrations. Aberrations can be identified following molecular analysis of metastatic tissue. Bone metastases, commonly present in mCRPC, hinder precision medicine due to a high proportion of biopsies with insufficient tumor cells for next-generation DNA sequencing. We aimed to investigate the feasibility of incorporating advanced target planning and needle guidance in bone biopsies and whether this procedure increases biopsy tumor yield and success rate of molecular analysis as compared to the current standards, utilizing only CT guidance. MATERIALS AND METHODS: In a pilot study, ten mCRPC patients received 68Ga-prostate-specific membrane antigen (PSMA)-PET/CT and diffusion-weighted MRI as biopsy planning images. These datasets were fused for targeting metastatic lesions with high tumor densities. Biopsies were performed under cone-beam CT (CBCT) guidance. Feasibility of target planning and needle guidance was assessed, and success of molecular analysis and tumor yield were reported. RESULTS: Fusion target planning and CBCT needle guidance were feasible. Nine out of ten biopsies contained prostate cancer cells, with a median of 39% and 40% tumor cells by two different sequencing techniques. Molecular analysis was successful in eight of ten patients (80%). This exceeds previous reports on CT-guided biopsies that ranged from 33 to 44%. In two patients, important druggable aberrations were found. DISCUSSION: A biopsy procedure using advanced target planning and needle guidance is feasible and can increase the success rate of molecular analysis in bone metastases, thereby having the potential of improving treatment outcome for patients with mCRPC. LEVEL OF EVIDENCE: Level 4, case series.

Blood-based and urinary prostate cancer biomarkers: a review and comparison of novel biomarkers for detection and treatment decisions.

BACKGROUND: The diagnosis of prostate cancer (PCa) is currently based on serum PSA testing and/or abnormal digital rectal examination and histopathologic evaluation of prostate biopsies. The main drawback of PSA testing is the lack of specificity for PCa. To improve early detection of PCa more specific biomarkers are needed. In the past few years, many new promising biomarkers have been identified; however, to date, only a few have reached clinical practice. METHODS: In this review, we discuss new blood-based and urinary biomarker models that are promising for usage in PCa detection, follow-up and treatment decision-making. These include Prostate Health Index (PHI), prostate cancer antigen 3 (PCA3), four-kallikrein panel (4K), transmembrane protease serine 2-ERG (TMPRSS2-ERG), ExoDx Prostate Intelliscore, SelectMDx and the Mi-Prostate score. Only few head-to-head studies are available for these new fluid-based biomarkers and/or models. The blood-based PHI and urinary PCA3 are two US Food and Drug Administration-approved biomarkers for diagnosis of PCa. In the second part of this review, we give an overview of published studies comparing these two available biomarkers for prediction of (1) PCa upon prostate biopsy, (2) pathological features in radical prostatectomy specimen and (3) significant PCa in patients eligible for active surveillance. RESULTS: Studies show opposing results in comparison of PHI with PCA3 for prediction of PCa upon initial and repeat prostate biopsy. PHI and PCA3 are able to predict pathological findings on radical prostatectomy specimen, such as tumor volume and Gleason score. Only PHI could predict seminal vesicle invasion and only PCA3 could predict multifocality. There is some evidence that PHI outperforms PCA3 in predicting significant PCa in an active surveillance population. CONCLUSIONS: Future research should focus on independent validation of promising fluid-based biomarkers/models, and prospective comparison of biomarkers with each other.

The predictive value of endorectal 3 Tesla multiparametric magnetic resonance imaging for extraprostatic extension in patients with low, intermediate and high risk prostate cancer.

PURPOSE: We determined the positive and negative predictive values of multiparametric magnetic resonance imaging for extraprostatic extension at radical prostatectomy for different prostate cancer risk groups. MATERIALS AND METHODS: We evaluated a cohort of 183 patients who underwent 3 Tesla multiparametric magnetic resonance imaging, including T2-weighted, diffusion weighted magnetic resonance imaging and dynamic contrast enhanced sequences, with an endorectal coil before radical prostatectomy. Pathological stage at radical prostatectomy was used as standard reference for extraprostatic extension. The cohort was classified into low, intermediate and high risk groups according to the D'Amico criteria. We recorded prevalence of extraprostatic extension at radical prostatectomy and determined sensitivity, specificity, positive predictive value and negative predictive value of multiparametric magnetic resonance imaging for extraprostatic extension in each group. Univariate and multivariate analyses were performed to identify predictors of extraprostatic extension at radical prostatectomy. RESULTS: The overall prevalence of extraprostatic extension at radical prostatectomy was 49.7% ranging from 24.7% to 77.1% between low and high risk categories. Overall staging accuracy of multiparametric magnetic resonance imaging for extraprostatic extension was 73.8%, with sensitivity, specificity, positive predictive value and negative predictive value of 58.2%, 89.1%, 84.1% and 68.3%, respectively. Positive predictive value of multiparametric magnetic resonance imaging for extraprostatic extension was best in the high risk cohort with 88.8%. Negative predictive value was highest in the low risk cohort with 87.7%. With an odds ratio of 10.3 multiparametric magnetic resonance imaging is by far the best preoperative predictor of extraprostatic extension at radical prostatectomy. CONCLUSIONS: For adequate patient counseling, knowledge of predictive values of multiparametric magnetic resonance imaging for extraprostatic extension is of utmost importance. High negative predictive value, important for decisions on nerve sparing strategies at radical prostatectomy, is only reached in low risk subjects.

Quality of life after prostate cancer treatments in patients comparable at baseline.

BACKGROUND: Previous studies on the effects of different prostate cancer treatments on quality of life, were confounded because patients were not comparable. This study examined treatment effects in more comparable groups. METHODS: From 2008-2011, 240 patients with localised prostate cancer were selected to be eligible for both radical prostatectomy (RP) and external beam radiotherapy (EBRT). Brachytherapy (BT) was a third option for some. Health-related quality of life was measured by expanded prostate cancer index composite (EPIC) up to 12 months after treatment. RESULTS: In the sexual domain, RP led to worse summary scores (P<0.001) and more often to a clinically relevant deterioration from baseline than BT and EBRT (79%, 33%, 34%, respectively). In the urinary domain, RP also led to worse summary scores (P=0.014), and more deterioration from baseline (41%, 12%, 19%, respectively). Only on the irritative/obstructive urinary scale, more BT patients (40%) showed a relevant deterioration than RP (17%) and EBRT patients (11%). In the bowel domain, the treatment effects did not differ. CONCLUSION: This study provides a more unbiased comparison of treatment effects, as men were more comparable at baseline. Our results suggest that, for quality of life, radiotherapy is as least as good an option as RP for treating localised prostate cancer.

A single institution experience with biochemical recurrence after radical prostatectomy for tumors that on pathology are of small volume or "insignificant".

OBJECTIVE: Small volume prostate cancers (<0.5 cc, svPC), and insignificant prostate cancers (<0.5 cc and Gleason scores <7, InsigPC) are considered clinically insignificant by some investigators. The aim of this study is to determine the biochemical recurrence rate (BCR) of svPC and InsigPC in prostatectomy specimens. METHODS: In total, 502 patients with prostate cancer, treated with radical prostatectomy (RP) between 1992 and 2005 and with detailed pathological classification, were included in the present study. Patients were postoperatively followed for a median period of 39.5 months (0.6-150). A total of 82 specimens (16.3%) with svPC including 64 (12.8%) with InsigPC were identified. BCR was defined as 2 consecutive PSA levels >0.10 ng/ml. RESULTS: In the total group, the median age at the time of surgery was 62.7 years (42.4-73.4) and the median preoperative PSA level was 8.0 ng/ml. Patients with InsigPC had Gleason scores of 4 in 7%, 5 in 37%, and 6 in 56%. Positive surgical margins were identified in 13 (15.9%) svPC and in 8 (12.7%) InsigPC specimens. The 5-year risk of BCR for the svPC group and the insigPC group was 10% (95% CI 2-18%, 7 and 5 patients, respectively) vs. 35% (95% CI 29-41%) in the rest of the cohort (log rank P = 0.001). CONCLUSION: Patients with svPC and patients with InsigPC have a significantly lower risk of BCR. However, even in this seemingly very favorable patient group, 1 in 10 patients will develop a BCR after RP. Therefore, new studies are needed to examine what the prognostic relevance is of small-volume tumors.

Maximum tumor diameter is not an independent prognostic factor in high-risk localized prostate cancer.

OBJECTIVES: Previous studies suggest that maximum tumor diameter (MTD) is a predictor of recurrence in prostate cancer (PC). This study investigates the prognostic value of MTD for biochemical recurrence (BCR) in patients with PC, after radical prostatectomy (RP), with emphasis on high-risk localized prostate cancer. METHODS: RP specimens of 542 patients were evaluated with a median follow-up of 39.5 months (range 0.6-150 months). MTD was defined as the largest diameter of the largest tumor; high-risk as >or=T2c or PSA level>20 ng/ml or Gleason score>or=8 and BCR as two consecutive PSA levels>0.10 ng/ml. Proportional hazards multivariable regression models were composed to determine prognostic factors for BCR. RESULTS: Overall, 114 patients developed BCR after RP. The overall 5-year risk of BCR was 25% (95% CI=20.4-29.6), and median MTD was 24 mm (range 1-65). MTD in the total and high-risk group was associated with total tumor volume, volume of the largest tumor, pre-operative PSA levels, and Gleason score. In a univariable analyses, MTD was weakly associated with risk of BCR (HR=1.02 per mm increase, 95% CI=1.002-1.035, P=0.024) in the total group; in the high-risk group this association was lost (HR=1.01, 95%CI=0.99-1.03, P=0.18). Multivariable analyses indicated that positive surgical margins, higher Gleason score, advanced pathological stage, and multiple tumors were the main prognostic factors for BCR irrespective of the risk profile. MTD did not provide additional information. CONCLUSIONS: MTD is not an independent prognostic factor for BCR in patients treated with RP, irrespective of the risk profile.

The prognostic value of E-cadherin and the cadherin-associated molecules alpha-, beta-, gamma-catenin and p120ctn in prostate cancer specific survival: a long-term follow-up study.

OBJECTIVES: To determine the value of loss of expression of E-cadherin and cadherin associated molecules as prognostic markers for prostate cancer patients in a long-term follow-up study. METHODS: Sixty-five prostate cancer specimens, obtained from patients with different stages of prostate cancer who underwent a radical prostatectomy or TUR-P between 1987 and 1991, were used for immunohistochemical analysis of the expression pattern of E-cadherin, alpha-, beta-, gamma-catenin and p120(ctn). Clinical records of these patients were studied for follow-up data and the prognostic value of expression of these adhesion molecules was determined by Kaplan-Meier survival analyses and multivariable proportional hazard regression analysis. RESULTS: Normal staining patterns were found in 36 cases (55.4%) for E-cadherin, 37 cases (56.9%) for alpha-catenin, 40 cases (61.5%) for beta-catenin, 25 cases (38.5%) for gamma-catenin, and 40 cases (61.5%) for p120(ctn). Overall, a strong correlation was found between the expression of E-cadherin and other cadherin-associated molecules. The 5-year survival rates for each staining were as follows: E-cadherin (normal 79.2%, aberrant 26.8%), alpha-catenin (normal 79.2%, aberrant 26.8%), beta-catenin (normal 73.1%, aberrant 27.3%), gamma-catenin (normal 86.4%, aberrant 37.1%), and p120(ctn) (normal 72.8%, aberrant 30.0%). There was a significant difference in survival between normal and aberrant expression in each staining (log rank P < 0.0001). The proportional hazard regression model including tumor stage and Gleason score revealed alpha-catenin expression as the best prognostic marker for patients with prostate cancer. CONCLUSIONS: Our data revealed a strong correlation between E-cadherin expression and other cadherin-associated molecules. Among these markers, alpha-catenin seems the best prognostic marker for prostate cancer specific survival. Larger studies are needed to confirm this result.

Does the tertiary Gleason pattern influence the PSA progression-free interval after retropubic radical prostatectomy for organ-confined prostate cancer?

INTRODUCTION: The Gleason sum is an important prognostic parameter for patients treated with radical prostatectomy for localized prostate cancer. However, frequently more than two predominant Gleason patterns are present in one specimen. In this study we investigated the prognostic significance of tertiary Gleason patterns in radical prostatectomy specimens. PATIENTS AND METHODS: Between 1994 and 2001, 277 patients underwent radical retropubic prostatectomy (RRP) for clinically localised prostate cancer in our institute. We collected information on Gleason score and cancer volume (CV) for all tumour localizations, clinical and pathological stage, seminal vesicle invasion (SVI) and extra capsular extension (ECE). In case one pattern was seen in more than 95% of the tumour, this pattern was used both for the primary and secondary Gleason pattern, and any other pattern (actually the secondary pattern) was called tertiary. Charts were examined retrospectively for clinical follow up. PSA progression was defined as two subsequent rising PSA measurements above 0.10 ng/ml. Kaplan-Meier time to PSA progression was compared between patients with and without a tertiary pattern. RESULTS: Overall, of the 223 patients, 106 (48%) were found to have a tertiary pattern, which on average, was 7% of the total tumour volume. Patients with a tertiary pattern had a 5-year risk of PSA progression of 37.3% versus 12.6% in case no tertiary Gleason pattern was present (log rank p=0.0002). There was no prognostic difference between patients with a higher-grade tertiary pattern as compared to those with a lower grade tertiary pattern. CONCLUSIONS: If present, a tertiary Gleason pattern, whether better or worse than the primary or secondary pattern, is an indication for a worse outcome, as indicated by a shorter time to PSA progression. This suggests that tumour multifocality, rather than the presence of a higher-grade tertiary Gleason pattern has prognostic value.