Publications by authors named "Reindert J A van Moorselaar"

26 Publications

  • Page 1 of 1

Being Transparent About Brilliant Failures: An Attempt to Use Real-World Data in a Disease Model for Patients with Castration-Resistant Prostate Cancer.

Drugs Real World Outcomes 2022 Jun 21;9(2):275-285. Epub 2022 Mar 21.

Erasmus School of Health Policy and Management, Erasmus University Rotterdam, Rotterdam, The Netherlands.

Background: Real-world disease models spanning multiple treatment lines can provide insight into the (cost) effectiveness of treatment sequences in clinical practice.

Objective: Our objective was to explore whether a disease model based solely on real-world data (RWD) could be used to estimate the effectiveness of treatments for patients with castration-resistant prostate cancer (CRPC) that could then be suitably used in a cost-effectiveness analysis.

Methods: We developed a patient-level simulation model using patient-level data from the Dutch CAPRI registry as input parameters. Time to event (TTE) and overall survival (OS) were estimated with multivariate regression models, and type of event (i.e., next treatment or death) was estimated with multivariate logistic regression models. To test internal validity, TTE and OS from the simulation model were compared with the observed outcomes in the registry.

Results: Although patient characteristics and survival outcomes of the simulated data were comparable to those in the observed data (median OS 20.6 vs. 19.8 months, respectively), the disease model was less accurate in estimating differences between treatments (median OS simulated vs. observed population: 18.6 vs. 17.9 [abiraterone acetate plus prednisone], 24.0 vs. 25.0 [enzalutamide], 20.2 vs. 18.7 [docetaxel], and 20.0 vs. 23.8 months [radium-223]).

Conclusions: Overall, the disease model accurately approximated the observed data in the total CRPC population. However, the disease model was unable to predict differences in survival between treatments due to unobserved differences. Therefore, the model is not suitable for cost-effectiveness analysis of CRPC treatment. Using a combination of RWD and data from randomised controlled trials to estimate treatment effectiveness may improve the model.
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http://dx.doi.org/10.1007/s40801-022-00294-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9114194PMC
June 2022

Symptomatic Skeletal Events and the Use of Bone Health Agents in a Real-World Treated Metastatic Castration Resistant Prostate Cancer Population: Results From the CAPRI-Study in the Netherlands.

Clin Genitourin Cancer 2022 02 2;20(1):43-52. Epub 2021 Nov 2.

Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.

Background: Patients with metastatic castration resistant prostate cancer (mCRPC) are at risk of symptomatic skeletal events (SSE). Bone health agents (BHA, ie bisphosphonates and denosumab) and new life-prolonging drugs (LPDs) can delay SSEs. The aim of this study is to investigate the use of BHAs in relation to SSEs in treated real-world mCRPC population.

Patients And Methods: We included patients from the CAPRI registry who were treated with at least one LPD and diagnosed with bone metastases prior to the start of first LPD (LPD1). Outcomes were SSEs (external beam radiation therapy (EBRT) to the bone, orthopedic surgery, pathologic fracture or spinal cord compression) and SSE-free survival (SSE-FS) since LPD1.

Results: One-thousand nine hundred and twenty-three patients were included with a median follow-up from LPD1 of 16.7 months. Fifty-two percent (n = 996) started BHA prior or within 4 weeks after the start of LPD1 (early BHA). In total, 41% experienced at least one SSE. SSE incidence rate was 0.29 per patient year for patients without BHA and 0.27 for patients with early BHA. Median SSE-FS from LPD1 was 12.9 months. SSE-FS was longer in patients who started BHA early versus patients without BHA (13.2 vs. 11.0 months, P = .001).

Conclusion: In a real-world population we observed an undertreatment with BHAs, although patients with early BHA use had lower incidence rates of SSEs and longer SSE-FS. This finding was irrespective of type of SSE and presence of risk factors. In addition to LPD treatment, timely initiation of BHAs is recommended in bone metastatic CRPC-patients with both pain and/or opioid use and prior SSE.
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http://dx.doi.org/10.1016/j.clgc.2021.10.008DOI Listing
February 2022

Patient reported outcome measures concerning urinary incontinence after robot assisted radical prostatectomy: development and validation of an online prediction model using clinical parameters, lower urinary tract symptoms and surgical experience.

J Robot Surg 2021 Aug 15;15(4):593-602. Epub 2020 Sep 15.

Department of Urology, Amsterdam UMC, VU University Medical Center, room 4F27, De Boelelaan 1117, Postbus 7057, Amsterdam, 1081HV, The Netherlands.

The prediction of post-prostatectomy incontinence (PPI) after robot-assisted radical prostatectomy (RARP) depends on multiple clinical, anatomical and surgical factors. There are only few risk formulas, tables or nomograms predicting PPI that may assist clinicians and their patients in adequate risk counseling on postoperative side-effects. Prospective data collection of 1814 patients who underwent RARP between 2009 and 2017 was done. Pre-operative parameters were age, body mass index (BMI), prostate volume, the American Society of Anesthesiologists (ASA) score, severity of Lower Urinary Tract Symptoms (LUTS), type of planned nerve-sparing surgery and surgical experience. The continence status was reported using Patient Reported Outcome Measurements (PROMs) using the validated pad-use questionnaire EPIC26. Continence was defined as either the use of zero pads or one safety pad. Multivariable logistic regression analysis was performed to identify predictors of PPI within one year after RARP. An online prediction tool was developed and validated. The median follow-up was 36 months (range 12-108). The response rate was high at 85.2%. A total of 85% (1537/1814) of patients was continent on follow-up. One-year continence rate was 80.1% (95% CI 78.3-81.9%) (1453/1814) and increased to 87.4% (95% CI 85.4-89.4%) after 5 years. On multivariable analysis, severity of LUTS (OR = 0.56 p = 0.004), higher age (OR = 0.73 p = 0.049), extend of nerve-sparing surgery (OR = 0.60 p = 0.001) and surgeon experience (OR = 1.48 p = 0.025) were significant independent predictors for PPI. The online prediction model performed well in predicting continence status with poor discrimination and good calibration. An intuitive online tool was developed to predict PPI after RARP that may assist clinicians and their patients in counseling of treatment.
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http://dx.doi.org/10.1007/s11701-020-01145-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295126PMC
August 2021

Hospital-specific probability of cystectomy affects survival from muscle-invasive bladder cancer.

Urol Oncol 2020 12 8;38(12):935.e9-935.e16. Epub 2020 Sep 8.

Department of Research and Development, Netherlands Comprehensive Cancer Organisation, Utrecht, the Netherlands; Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.

Objectives: Radical cystectomies (RCs) are increasingly centralized, but bladder cancer can be diagnosed in every hospital The aim of this study is to assess the variation between hospitals of diagnosis in a patient's chance to undergo a RC before and after the volume criteria for RCs, to identify factors associated with this variation and to assess its effect on survival.

Methods And Materials: Patients diagnosed with muscle-invasive bladder cancer (cT2-4a,N0/X,M0/X) without nodal or distant metastases between 2008 and 2016 were identified through the Netherlands Cancer Registry. Multilevel logistic regression analysis was used to investigate the hospital specific probability of undergoing a cystectomy. Cox proportional hazard regression analysis was used to assess the case-mix adjusted effect of hospital-specific probabilities on survival.

Results: Of the 9,215 included patients, 4,513 (49%) underwent a RC. The percentage of RCs varied between 7% and 83% by hospital of diagnosis before the introduction of the first volume criteria (i.e., 2008-2009; minimum of 10 RCs). This variation decreased slightly to 17%-77% after establishment of the second volume criteria (i.e., 2015-2016; minimum of 20 RCs). Age, cT-stage and comorbidity were inversely and socioeconomic status was positively associated with RC. Both being diagnosed in a community hospital and/or being diagnosed in a hospital fulfilling the RC volume criteria were associated with increased use of RC compared to academic hospitals and hospitals not fulfilling the volume criteria. For each 10% increase in the percentage of RC in the hospital of diagnosis, 2-year case-mix adjusted survival increased 4% (hazard ratio 0.96, 95% confidence interval 0.94-0.98).

Conclusion: Probability of RC varied between hospitals of diagnosis and affected 2-year overall survival. Undergoing a RC was associated with age, cT-stage, socioeconomic status, type of hospital, and whether the hospital of diagnosis fulfilled the RC volume criteria. Future research is needed to identify patient, tumor, and hospital characteristics affecting utilization of curative treatment as this may benefit overall survival.
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http://dx.doi.org/10.1016/j.urolonc.2020.08.014DOI Listing
December 2020

Machine learning-based analysis of [F]DCFPyL PET radiomics for risk stratification in primary prostate cancer.

Eur J Nucl Med Mol Imaging 2021 02 31;48(2):340-349. Epub 2020 Jul 31.

Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Radiology and Nuclear Medicine, Cancer Center Amsterdam, De Boelelaan, 1117, Amsterdam, the Netherlands.

Purpose: Quantitative prostate-specific membrane antigen (PSMA) PET analysis may provide for non-invasive and objective risk stratification of primary prostate cancer (PCa) patients. We determined the ability of machine learning-based analysis of quantitative [F]DCFPyL PET metrics to predict metastatic disease or high-risk pathological tumor features.

Methods: In a prospective cohort study, 76 patients with intermediate- to high-risk PCa scheduled for robot-assisted radical prostatectomy with extended pelvic lymph node dissection underwent pre-operative [F]DCFPyL PET-CT. Primary tumors were delineated using 50-70% peak isocontour thresholds on images with and without partial-volume correction (PVC). Four hundred and eighty standardized radiomic features were extracted per tumor. Random forest models were trained to predict lymph node involvement (LNI), presence of any metastasis, Gleason score ≥ 8, and presence of extracapsular extension (ECE). For comparison, models were also trained using standard PET features (SUVs, volume, total PSMA uptake). Model performance was validated using 50 times repeated 5-fold cross-validation yielding the mean receiver-operator characteristic curve AUC.

Results: The radiomics-based machine learning models predicted LNI (AUC 0.86 ± 0.15, p < 0.01), nodal or distant metastasis (AUC 0.86 ± 0.14, p < 0.01), Gleason score (0.81 ± 0.16, p < 0.01), and ECE (0.76 ± 0.12, p < 0.01). The highest AUCs reached using standard PET metrics were lower than those of radiomics-based models. For LNI and metastasis prediction, PVC and a higher delineation threshold improved model stability. Machine learning pre-processing methods had a minor impact on model performance.

Conclusion: Machine learning-based analysis of quantitative [F]DCFPyL PET metrics can predict LNI and high-risk pathological tumor features in primary PCa patients. These findings indicate that PSMA expression detected on PET is related to both primary tumor histopathology and metastatic tendency. Multicenter external validation is needed to determine the benefits of using radiomics versus standard PET metrics in clinical practice.
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http://dx.doi.org/10.1007/s00259-020-04971-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835295PMC
February 2021

Renal biopsies performed before versus during ablation of T1 renal tumors: implications for prevention of overtreatment and follow-up.

Abdom Radiol (NY) 2021 01 20;46(1):373-379. Epub 2020 Jun 20.

Department of Urology, OLVG, Oosterpark 9, 1091 AC, Amsterdam, The Netherlands.

Purpose: To assess the difference between renal mass biopsy (RMB) performed either before or during the ablation procedure.

Methods: A retrospective multicenter study was performed in patients with a cT1 renal mass treated with ablation between January 2007 and July 2019, including a search in the national pathology database for patients with a RMB planned for ablation. Patient and tumor characteristics and information on malignant, benign, and non-diagnostic biopsy results were collected to establish rates of overtreatment and number of ablations avoided in case of benign or non-diagnostic histology.

Results: RMB was performed in 714 patients, of which 231 patients received biopsy before planned ablation, and 483 patients at the time of ablation. Pathology results before ablation were malignant in 63% (145/231), benign in 20% (46/231) and non-diagnostic in 17% (40/231). Pathology results at the time of ablation were malignant in 67.5% (326/483), benign in 16.8% (81/483) and non-diagnostic in 15.7% (76/483), leading to a total of 32.5% of ablation of benign or non-diagnostic lesions. Of the patients with a benign biopsy obtained before ablation, 80.4% (37/46) chose not to undergo ablation. Patients with inconclusive biopsy before planned ablation chose an informed individualized approach including ablation, repeated biopsy, or no intervention in 56%, 34% and 10%.

Conclusion: This study emphasizes the importance of obtaining a biopsy prior to the ablation procedure in a separate session to lower the rate of potentially unnecessary ablations.
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http://dx.doi.org/10.1007/s00261-020-02613-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864836PMC
January 2021

Third-line Life-prolonging Drug Treatment in a Real-world Metastatic Castration-resistant Prostate Cancer Population: Results from the Dutch Castration-resistant Prostate Cancer Registry.

Eur Urol Focus 2021 Jul 30;7(4):788-796. Epub 2020 Apr 30.

Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands.

Background: Evidence concerning third-line life-prolonging drugs (LPDs) in the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients is incomplete.

Objective: To evaluate third-line LPD outcomes in a real-world cohort of mCRPC patients, identify variables associated with overall survival (OS), and establish a prognostic model.

Design, Setting, And Participants: Patients with mCRPC who were progressive on second-line LPD before July 1, 2017 were retrospectively identified from the Dutch Castration-resistant Prostate Cancer Registry (CAPRI) and followed until December 31, 2017.

Outcome Measurements And Statistical Analysis: Association of potential risk factors with OS was tested by Cox proportional hazard models after multiple imputation of missing baseline characteristics. A predictive score was computed from the regression coefficient and used to classify patients into risk groups.

Results And Limitations: Of 1011 mCRPC patients progressive on second-line LPD, 602 (60%) received third-line LPD. Patients receiving third-line LPD had a more favorable prognostic profile at baseline and longer median OS than patients with best supportive care (10.4 vs 2.4 mo, p < 0.001). Eastern Cooperative Oncology Group performance status 1 and ≥2 (hazard ratio [HR] 1.51, p < 0.007 and HR 3.08, p < 0.001, respectively), opioid use (HR 1.55, p = 0.019), visceral metastases (HR 2.09, p < 0.001), hemoglobin <7 mmol/l (HR 1.44, p < 0.002), prostate-specific antigen ≥130 μg/l (HR 1.48, p = 0.001), alkaline phosphatase ≥170 U/l (HR 1.52, p < 0.001), and lactate dehydrogenase ≥250 U/l (HR 1.44; p = 0.015) were associated with shorter survival. Harrell's C-index was 0.74. The median OS values for low-, low-intermediate-, high-intermediate-, and high-risk groups were 14, 7.7, 4.7, and 1.8 mo, respectively. Limitations include the retrospective design.

Conclusions: We developed a prognostic model and identified a subgroup of patients in whom third-line LPD treatment has no meaningful benefit. Our results need to be confirmed by prospective clinical trials.

Patient Summary: We reported outcomes from third-line life-prolonging drugs in metastatic prostate cancer patients and developed a prognostic model that could be used to guide treatment decisions.
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http://dx.doi.org/10.1016/j.euf.2020.03.009DOI Listing
July 2021

Detection of Recurrent Prostate Cancer Using Prostate-specific Membrane Antigen Positron Emission Tomography in Patients not Meeting the Phoenix Criteria for Biochemical Recurrence After Curative Radiotherapy.

Eur Urol Oncol 2021 10 20;4(5):821-825. Epub 2020 Feb 20.

Prostate Cancer Network Amsterdam, Amsterdam, The Netherlands; Department of Urology, Amsterdam University Medical Centers, VU University, Amsterdam, The Netherlands.

Biochemical recurrence of prostate cancer (PCa) after curative radiotherapy is defined as a prostate-specific antigen (PSA) rise of ≥2 ng/ml above the nadir ("Phoenix criteria", 2005). With the introduction of prostate-specific membrane antigen positron emission tomography (PSMA-PET), the ability to localise PCa recurrences has increased markedly. Here, we reviewed 315 patients scanned with PSMA-PET after curative radiotherapy in the Prostate Cancer Network Amsterdam (2015-2018). Sixty-three patients (20.3%) were scanned below the Phoenix threshold (PSA rise <2.0 ng/ml). In 53 of these patients (84.1%), PSMA-PET-avid lesions were detected nonetheless: 21 patients (33.3%) revealed a local recurrence as a single site of disease, 32 patients (50.8%) harboured metastatic PCa. Besides rising PSA, no predictors were identified that prompted early PSMA-PET imaging. In this communication, we report on the frequent detection of metastatic PCa with PSMA-PET in men below the Phoenix PSA threshold. These findings are a plea for re-evaluation of current diagnostic work-up for rising PSA values after radiotherapy, as early detection of recurrences might refine salvage and/or adjuvant therapies. PATIENT SUMMARY: This study reports on the unexpected detection of prostate cancer (PCa) recurrences with prostate-specific membrane antigen positron emission tomography in patients treated with radiotherapy. This calls for re-evaluation of the current criteria for recurrent PCa after radiotherapy.
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http://dx.doi.org/10.1016/j.euo.2020.01.002DOI Listing
October 2021

Repeatability of Quantitative F-DCFPyL PET/CT Measurements in Metastatic Prostate Cancer.

J Nucl Med 2020 09 10;61(9):1320-1325. Epub 2020 Jan 10.

Department of Radiology and Nuclear Medicine, Cancer Center Amsterdam, Amsterdam University Medical Centers, VU University, Amsterdam, The Netherlands.

Quantitative evaluation of radiolabeled prostate-specific membrane antigen (PSMA) PET scans may be used to monitor treatment response in patients with prostate cancer (PCa). To interpret longitudinal differences in PSMA uptake, the intrinsic variability of tracer uptake in PCa lesions needs to be defined. The aim of this study was to investigate the repeatability of quantitative PET/CT measurements using F-DCFPyL ([2-(3-(1-carboxy-5-[(6-F-fluoro-pyridine-3-carbonyl)-amino]-pentyl)-ureido)-pentanedioic acid], a second-generation F-PSMA-ligand) in patients with PCa. Twelve patients with metastatic PCa were prospectively included, of whom 2 were excluded from final analyses. Patients received 2 whole-body F-DCFPyL PET/CT scans (median dose, 317 MBq; uptake time, 120 min) within a median of 4 d (range, 1-11 d). After semiautomatic (isocontour-based) tumor delineation, the following lesion-based metrics were derived: mean, peak, and maximum tumor-to-blood ratio; SUV, SUV, and SUV normalized to body weight; tumor volume; and total lesion uptake (TLU). Additionally, patient-based total tumor volume (TTV) (sum of PSMA-positive tumor volumes) and total tumor burden (TTB) (sum of all lesion TLUs) were derived. Repeatability was analyzed using repeatability coefficients (RC) and intraclass correlation coefficients. Additionally, the effect of point-spread function (PSF) image reconstruction on the repeatability of uptake metrics was evaluated. In total, 36 F-DCFPyL PET-positive lesions were analyzed (≤5 lesions per patient). The RCs for mean, peak, and maximum tumor-to-blood ratio were 31.8%, 31.7%, and 37.3%, respectively. For SUV, SUV, and SUV, the RCs were 24.4%, 25.3%, and 31.0%, respectively. All intraclass correlation coefficients were at least 0.97. Tumor volume delineations were quite repeatable, with an RC of 28.1% for individual lesion volumes and 17.0% for TTV. TTB had an RC of 23.2% and 33.4% when based on SUV and mean tumor-to-blood ratio, respectively. Small lesions (<4.2 cm) had worse repeatability for volume measurements. The repeatability of SUV, TLU, and all patient-level metrics was not affected by PSF reconstruction. F-DCFPyL uptake measurements are quite repeatable and can be used for clinical validation in future treatment response assessment studies. Patient-based TTV may be preferred for multicenter studies because its repeatability was both high and robust to different image reconstructions.
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http://dx.doi.org/10.2967/jnumed.119.236075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456167PMC
September 2020

Health-related Quality of Life and Pain in a Real-world Castration-resistant Prostate Cancer Population: Results From the PRO-CAPRI Study in the Netherlands.

Clin Genitourin Cancer 2020 06 5;18(3):e233-e253. Epub 2019 Dec 5.

Institute for Medical Technology Assessment, Erasmus School of Health Policy and Management, Erasmus University Rotterdam, Rotterdam, the Netherlands.

Background: The purpose of this study was to determine generic, cancer-specific, and prostate cancer-specific health-related quality of life (HRQoL), pain and changes over time in patients with metastatic castration-resistant prostate cancer (mCRPC) in daily practice.

Patients And Methods: PRO-CAPRI is an observational, prospective study in 10 hospitals in the Netherlands. Patients with mCRPC completed the EQ-5D, European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and Brief Pain Inventory-Short Form (BPI-SF) every 3 months and European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Prostate Cancer Module (EORTC QLQ-PR25) every 6 months for a maximum of 2 years. Subgroups were identified based on chemotherapy pretreatment. Outcomes were generic, cancer-specific, and prostate cancer-specific HRQoL and self-reported pain. Descriptive statistics were performed including changes over time and minimal important differences (MID) between subgroups.

Results: In total, 151 included patients answered 873 questionnaires. The median follow-up from the start of the study was 19.5 months, and 84% were treated with at least 1 life-prolonging agent. Overall, patients were in good clinical condition (Eatern Cooperative Oncology Group performance status 0-1 in 78%) with normal baseline hemoglobin, lactate dehydrogenase, and alkaline phosphatase. At inclusion, generic HRQoL was high with a mean EQ visual analog score of 73.2 out of 100. The lowest scores were reported on role and physical functioning (mean scores of 69 and 76 of 100, respectively), and fatigue, pain, and insomnia were the most impaired domains. These domains deteriorated in > 50% of patients.

Conclusion: Although most patients were treated with new treatments during follow-up, mCRPC has a negative impact on HRQoL with deterioration in all domains over time, especially role and physical functioning. These domains need specific attention during follow-up to maintain HRQoL as long as possible by timely start of adequate supportive care management.
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http://dx.doi.org/10.1016/j.clgc.2019.11.015DOI Listing
June 2020

Variation in the Prescription of Androgen Deprivation Therapy in Intermediate- and High-risk Prostate Cancer Patients Treated with Radiotherapy in the Netherlands, and Adherence to European Association of Urology Guidelines: A Population-based Study.

Eur Urol Focus 2021 03 17;7(2):332-339. Epub 2019 Nov 17.

Department of Research, Netherlands Comprehensive Cancer Organisation, Utrecht, The Netherlands; Radboud Institute for Health Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.

Background: According to (inter-)national guidelines, (neo-)adjuvant and concurrent androgen deprivation therapy (ADT) in combination with external beam radiotherapy (EBRT) is optional for intermediate-risk prostate cancer (PCa) patients and is the recommended standard treatment for high-risk PCa patients.

Objective: The aim of this study is to provide insight into the prescription of ADT in intermediate- and high-risk PCa patients treated with EBRT in the Netherlands, and to evaluate adherence to European Association of Urology guidelines and factors affecting prescription.

Design, Setting, And Participants: All intermediate- and high-risk PCa patients between October 2015 and April 2016 were identified through the population-based Netherlands Cancer Registry. Variation in the prescription of ADT in patients with EBRT was evaluated. Multivariable multilevel logistic regression analyses were performed to determine the probability of ADT and to examine the role of patient-, tumour-, and hospital-related factors.

Results And Limitations: Overall, 29% of patients with intermediate-risk PCa received ADT varying from 3% to 73% between institutions. From the multivariable regression analysis, higher Gleason grade, magnetic resonance imaging, and computed tomography (CT)-positron-emission tomography/CT prior to radiotherapy appeared to be associated with increased prescription of ADT. Among high-risk patients, 83% received ADT, varying from 57% to 100% between departments. A higher prostate-specific antigen level, more advanced tumour stage, and a higher Gleason grade were associated with increased prescription.

Conclusions: Less than one-third of intermediate-risk PCa patients treated with EBRT receive ADT. The variation in the prescription of ADT between different institutions is substantial. This suggests that the prescription is largely dependent on different institutional policies. The guideline adherence in high-risk PCa is fairly good, as the vast majority of patients received ADT as recommended. However, given the clear recommendations in the guidelines, adherence could be improved.

Patient Summary: In this review, we looked at the variation of hormonal treatment in intermediate- and high-risk prostate cancer patients. We found substantial variation between institutions.
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http://dx.doi.org/10.1016/j.euf.2019.11.005DOI Listing
March 2021

Real-world Outcomes of Sequential Androgen-receptor Targeting Therapies with or Without Interposed Life-prolonging Drugs in Metastatic Castration-resistant Prostate Cancer: Results from the Dutch Castration-resistant Prostate Cancer Registry.

Eur Urol Oncol 2021 08 8;4(4):618-627. Epub 2019 Oct 8.

Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: Cross resistance between androgen-receptor targeting therapies (ARTs) (abiraterone acetate plus prednisone [ABI+P] or enzalutamide [ENZ]) for treatment of metastatic castration-resistant prostate cancer (mCRPC) may affect responses to second ART (ART2).

Objective: To establish treatment duration and prostate-specific antigen (PSA) response of ART2 in real-world mCRPC patients treated with or without other life-prolonging drugs (LPDs; ie, docetaxel, cabazitaxel, or radium-223) between ART1 and ART2.

Design, Setting, And Participants: Castration-resistant prostate cancer patients, diagnosed between 2010 and 2016 were retrospectively registered in Castration-resistant Prostate Cancer Registry (CAPRI). Patients treated with both ARTs were clustered into two subgroups: ART1>ART2 or ART1>LPD>ART2.

Outcome Measurements And Statistical Analysis: Outcomes were ≥50% PSA response and treatment duration of ART2. Descriptive statistics and binary logistic regression after multiple imputations were performed.

Results And Limitations: A total of 273 patients were included with a median follow-up of 8.4 mo from ART2. Patients with ART1>ART2 were older and had favourable prognostic characteristics at ART2 baseline compared with patients with ART1>LPD>ART2. No differences between ART1>ART2 and ART1>LPD>ART2 were found in PSA response and treatment duration. Multivariate analysis suggested that PSA response of ART2 was less likely in patients with visceral metastases (odds ratio [OR] 0.143, p=0.04) and more likely in patients with a relatively longer duration of androgen-deprivation treatment (OR 1.028, p=0.01) and with ABI + P before ENZ (OR 3.192, p=0.02). A major limitation of this study was missing data, a common problem in retrospective observational research.

Conclusions: The effect of ART2 seems to be low, with a low PSA response rate and a short treatment duration irrespective of interposed chemotherapy or radium-223, especially in patients with short time on castration, visceral disease, and ENZ before ABI+P.

Patient Summary: We observed no differences in outcomes of patients treated with sequential abiraterone acetate plus prednisone (ABI+P) and enzalutamide (ENZ) with or without interposed chemotherapy or radium-223. In general, outcomes were lower than those in randomised trials, questioning the additional effect of second treatment with ABI+P or ENZ in daily practice.
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http://dx.doi.org/10.1016/j.euo.2019.09.005DOI Listing
August 2021

Lesion Detection and Interobserver Agreement with Advanced Image Reconstruction for F-DCFPyL PET/CT in Patients with Biochemically Recurrent Prostate Cancer.

J Nucl Med 2020 02 3;61(2):210-216. Epub 2019 Sep 3.

Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

Biochemically recurrent prostate cancer (BCR) is the main indication to perform prostate-specific membrane antigen PET/CT. However, localizing BCR with prostate-specific membrane antigen PET/CT remains challenging in patients with low prostate-specific antigen (PSA) values. Here, we studied the impact of advanced PET image reconstruction methods on BCR localization and interobserver agreement with F-DCFPyL PET/CT scans in patients with BCR and low PSA values. Twenty-four patients with BCR and a PSA level of less than 2.0 ng/mL were included. PET images were reconstructed with 4-mm voxels and 2-mm voxels, both with and without point-spread function. All scans were interpreted by 4 nuclear medicine physicians. Additionally, PET examinations of 5 patients with primary prostate cancer and confirmed absence of lymph node metastases (after lymph node dissection) were included, to assess the risk of introducing false-positive findings when using advanced reconstruction. Calculation of BCR localization rates (scan positivity) was based on consensus among our readers (≥3 readers regarding a scan positive for BCR), as well as the individual scan interpretations of the readers. In the consensus analysis, BCR localization rates were not higher using advanced reconstruction (62.5%-66.7%) than using 4-mm reconstruction (62.5%). On the basis of individual readings, however, more scans were positive using 2-mm reconstruction (74.0%; 95% confidence interval [CI], 65.0%-82.9%) ( = 0.027) and 2-mm reconstruction with point-spread function (75.0%; 95% CI, 66.2%-83.8%) ( = 0.014) than 4-mm reconstruction (65.6%; 95% CI, 56.0%-75.3%). A higher number of lesions was detected on the 2-mm scans (median, 2 lesions; interquartile range, 1-3) than the 4-mm scans (median, 1; interquartile range, 0-3; = 0.008). The advanced reconstruction methods did not increase interobserver agreement (80.6%-84.7%), compared with the 4-mm scans (75.7%, = 0.08-0.25). In the patients with primary prostate cancer, an equal number of false-positive lesions was observed among the different reconstruction methods (overall, 13). Applying advanced image reconstruction for F-DCFPyL PET/CT scans did not increase BCR localization in patients with BCR and low PSA values (reader consensus). Yet, the increased number of positive individual readings may imply that further development of image reconstruction methods holds potential to improve BCR localization. No improved interobserver agreement was observed with advanced reconstruction compared with standard 4-mm reconstruction.
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http://dx.doi.org/10.2967/jnumed.118.222513DOI Listing
February 2020

Reply: Quantification of F-DCFPyL Uptake: TBR Versus Patlak's Analysis.

J Nucl Med 2019 12 26;60(12):1834-1835. Epub 2019 Aug 26.

Amsterdam University Medical Center (VU University) De Boelelaan 1117, Room 1F-012 Amsterdam, 1081 HV, Netherlands E-mail:

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http://dx.doi.org/10.2967/jnumed.119.234047DOI Listing
December 2019

A Prospective Single-Arm Phase 2 Study of Stereotactic Magnetic Resonance Guided Adaptive Radiation Therapy for Prostate Cancer: Early Toxicity Results.

Int J Radiat Oncol Biol Phys 2019 12 13;105(5):1086-1094. Epub 2019 Aug 13.

Department of Radiation Oncology, Amsterdam University Medical Centers, Amsterdam, The Netherlands.

Purpose: Use of stereotactic body radiation therapy (SBRT) is increasing in patients with localized prostate cancer, but concerns about early and late gastrointestinal (GI) and genitourinary (GU) toxicity exist after moderately or extremely hypofractionated radiation therapy schemes. Magnetic resonance guided radiation therapy (MRgRT) was clinically introduced in 2014. MrgRT allows for SBRT delivery with smaller uncertainty margins and permits daily adaptive planning. A phase 2 study in patients with localized prostate cancer was performed to study early GI and GU toxicity after SBRT using MRgRT.

Methods And Materials: One hundred one patients with clinical stage T1-3bN0M0 prostate cancer were enrolled in this prospective phase 2 study. All but 4 patients had intermediate- or high-risk prostate cancer, and 82.2% received adjuvant hormonal treatment. MRgRT was delivered in 5 fractions of 7.25 Gy to the target volume using daily plan adaptation with simultaneous relative sparing of the urethra to a dose of 6.5 Gy per fraction. Early toxicity was studied using both clinician- (Common Terminology Criteria for Adverse Events and Radiation Therapy Oncology Group) and patient-reported outcome measurements (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30, Quality of Life Questionnaire PR25, and International Prostate Symptom Scoring).

Results: The maximum cumulative grade ≥2 early GU and GI toxicity measured by any symptom at any study time point was 23.8% and 5.0%, respectively. No early grade 3 GI toxicity was observed. Early grade 3 GU toxicity was 0% and 5.9% according to the Common Terminology Criteria for Adverse Events and Radiation Therapy Oncology Group and scoring systems, respectively, as a result of different grading of radiation cystitis. The low incidence of early GI toxicity was confirmed by patient-reported outcome data. GU grade ≥2 toxicity peaked to 19.8% at the end of MRgRT, followed by a return to the baseline average score at 3-month follow-up.

Conclusions: This prospective study of MRgRT in patients with localized prostate cancer observed a low incidence of early GI and GU toxicity, both in clinician- and patient-reported outcome measurements.
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http://dx.doi.org/10.1016/j.ijrobp.2019.08.007DOI Listing
December 2019

Simplified Methods for Quantification of F-DCFPyL Uptake in Patients with Prostate Cancer.

J Nucl Med 2019 12 18;60(12):1730-1735. Epub 2019 Apr 18.

Department of Radiology and Nuclear Medicine, Cancer Center Amsterdam, Amsterdam University Medical Centers (location VU University Medical Center), Amsterdam, The Netherlands

Radiolabeled prostate-specific membrane antigen (PSMA) PET has demonstrated promising results for prostate cancer (PCa) imaging. Quantification of PSMA radiotracer uptake is desired as it enables reliable interpretation of PET images, use of PSMA uptake as an imaging biomarker for tumor characterization, and evaluation of treatment effects. The aim of this study was to perform a full pharmacokinetic analysis of 2-(3-(1-carboxy-5-[(6-F-fluoro-pyridine-3-carbonyl)-amino]-pentyl)-ureido)-pentanedioic acid (F-DCFPyL), a second-generation F-labeled PSMA ligand. On the basis of the pharmacokinetic analysis (reference method), simplified methods for quantification of F-DCFPyL uptake were validated. Eight patients with metastasized PCa were included. Dynamic PET acquisitions were performed at 0-60 and 90-120 min after injection of a median dose of 313 MBq of F-DCFPyL (range, 292-314 MBq). Continuous and manual arterial blood sampling provided calibrated plasma tracer input functions. Time-activity curves were derived for each PCa metastasis, and F-DCFPyL kinetics were described using standard plasma input tissue-compartment models. Simplified methods for quantification of F-DCFPyL uptake (SUVs; tumor-to-blood ratios [TBRs]) were correlated with kinetic parameter estimates obtained from full pharmacokinetic analysis. In total, 46 metastases were evaluated. A reversible 2-tissue-compartment model was preferred for F-DCFPyL kinetics in 59% of the metastases. The observed was small, however, resulting in nearly irreversible kinetics during the course of the PET study. Hence, was fixated (0.015) and net influx rate, K, was preferred as the reference kinetic parameter. Whole-blood TBR provided an excellent correlation with K from full kinetic analysis ( = 0.97). This TBR could be simplified further by replacing the blood samples with an image-based, single measurement of blood activity in the ascending aorta (image-based TBR, = 0.96). SUV correlated poorly with K ( = 0.47 and = 0.60 for SUV normalized to body weight and lean body mass, respectively), most likely because of deviant blood activity concentrations (i.e., tumor tracer input) in patients with higher tumor volumes. F-DCFPyL kinetics in PCa metastases are best described by a reversible 2-tissue-compartment model. Image-based TBRs were validated as a simplified method to quantify F-DCFPyL uptake and might be applied to clinical, whole-body PET scans. SUV does not provide reliable quantification of F-DCFPyL uptake.
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http://dx.doi.org/10.2967/jnumed.119.227520DOI Listing
December 2019

Healthy Tissue Uptake of Ga-Prostate-Specific Membrane Antigen, F-DCFPyL, F-Fluoromethylcholine, and F-Dihydrotestosterone.

J Nucl Med 2019 08 10;60(8):1111-1117. Epub 2019 Jan 10.

Department of Radiology & Nuclear Medicine, Amsterdam University Medical Centers, VU University Medical Center, Amsterdam, The Netherlands

PET is increasingly used for prostate cancer (PCa) diagnostics. Important PCa radiotracers include Ga-prostate-specific membrane antigen HBED-CC (Ga-PSMA), F-DCFPyL, F-fluoromethylcholine (F-FCH), and F-dihydrotestosterone (F-FDHT). Knowledge on the variability of tracer uptake in healthy tissues is important for accurate PET interpretation, because malignancy is suspected only if the uptake of a lesion contrasts with its background. Therefore, the aim of this study was to quantify uptake variability of PCa tracers in healthy tissues and identify stable reference regions for PET interpretation. A total of 232 PCa PET/CT scans from multiple hospitals was analyzed, including 87 Ga-PSMA scans, 50 F-DCFPyL scans, 68 F-FCH scans, and 27 F-FDHT scans. Tracer uptake was assessed in the blood pool, lung, liver, bone marrow, and muscle using several SUVs (SUV, SUV, SUV). Variability in uptake between patients was analyzed using the coefficient of variation (COV%). For all tracers, SUV reference ranges (95th percentiles) were calculated, which could be applicable as image-based quality control for future PET acquisitions. For Ga-PSMA, the lowest uptake variability was observed in the blood pool (COV, 19.9%), which was significantly more stable than all other tissues (COV, 29.8%-35.2%; = 0.001-0.024). For F-DCFPyL, the lowest variability was observed in the blood pool and liver (COV, 14.4% and 21.7%, respectively; = 0.001-0.003). The least variable F-FCH uptake was observed in the liver, blood pool, and bone marrow (COV, 16.8%-24.2%; = 0.001-0.012). For F-FDHT, low uptake variability was observed in all tissues, except the lung (COV, 14.6%-23.6%; = 0.001-0.040). The different SUV types had limited effect on variability (COVs within 3 percentage points). In this multicenter analysis, healthy tissues with limited uptake variability were identified, which may serve as reference regions for PCa PET interpretation. These reference regions include the blood pool for Ga-PSMA and F-DCFPyL and the liver for F-FCH and F-FDHT. Healthy tissue SUV reference ranges are presented and applicable as image-based quality control.
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http://dx.doi.org/10.2967/jnumed.118.222505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6910637PMC
August 2019

Adding multiparametric MRI to the MSKCC and Partin nomograms for primary prostate cancer: Improving local tumor staging?

Urol Oncol 2019 03 15;37(3):181.e1-181.e6. Epub 2018 Dec 15.

Department of Urology, Amsterdam University Medical Centers, the Netherlands.

Introduction And Objectives: As a single diagnostic modality, multiparametric MRI (mpMRI) has imperfect accuracy to detect locally advanced prostate cancer (T-stages 3-4). In this study we evaluate if combining mpMRI with preoperative nomograms (Memorial Sloan Kettering Cancer Center [MSKCC] and Partin) improves the prediction of locally advanced tumors.

Materials And Methods: Preoperative mpMRI results of 430 robot-assisted radical prostatectomy patients were analyzed. MSKCC and Partin nomogram scores predicting extraprostatic growth were calculated. Logistic regression analysis was performed, combining the nomogram prediction scores with mpMRI results. The diagnostic value of the combined models was evaluated by creating receiver operator characteristics curves and comparing the area under the curve (AUC).

Results: mpMRI was a significant predictor of locally advanced disease in addition to both the MSKCC and Partin nomogram, despite its low sensitivity (45.3%). However, overall predictive accuracy increased by only 1% when mpMRI was added to the MSKCC nomogram (AUC MSKCC 0.73 vs MSKCC + mpMRI 0.74). Predictive accuracy for the Partin Tables increased 4% (AUC Partin 0.62 vs Partin + mpMRI 0.66).

Conclusion: The addition of mpMRI to the preoperative MSKCC and Partin nomograms did not increase diagnostic accuracy for the prediction of locally advanced prostate cancer.
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http://dx.doi.org/10.1016/j.urolonc.2018.10.026DOI Listing
March 2019

Immediate treatment vs. active-surveillance in very-low-risk prostate cancer: the role of patient-, tumour-, and hospital-related factors.

Prostate Cancer Prostatic Dis 2019 05 14;22(2):337-343. Epub 2018 Nov 14.

Netherlands Comprehensive Cancer Organisation, Utrecht, The Netherlands.

Background: To provide insight in the treatment variation of very-low-risk prostate cancer patients and to assess the role of hospital-related factors.

Methods: All patients diagnosed with very-low-risk prostate cancer (cT1c-cT2a, PSA < 10 ng/ml, Gleason score <7 and <3 positive cores) in 2015 and 2016 were identified through the population-based Netherlands Cancer Registry. Multilevel logistic regression analyses were performed to examine the crude and case-mix adjusted probability of immediate treatment vs. active-surveillance (AS) according to hospital of diagnosis and to evaluate the effect of patient-, tumour-, and hospital-related factors.

Results: In all, 2047 (85.4%) of the 2396 patients with very-low-risk prostate cancer were managed with AS. The crude proportion of patients with AS varied from 33.3 to 100% between hospitals. Case-mix adjusted probability varied from 71 to 97%. Tumour stage cT2a vs. cT1c (OR 2.0, 95%CI 1.1-3.6), two vs. one positive core (OR 2.8, 95%CI 1.6-4.7), diagnostic MRI (OR 2.8, 95%CI 1.5-5.2), discussion of a patient in a multi-disciplinary team (OR 2.2, 95%CI 1.1-4.5), discussion of treatment options with the patient (OR 3.3, 95%CI 1.5-7.4) and type of hospital (non-university referral hospital vs. community hospital: OR 0.5, 95%CI 0.2-0.9) were associated with immediate treatment.

Conclusion: The majority of Dutch very-low-risk prostate cancer patients is managed with AS but variation between hospitals exists. Part of the variation is explained by patient- and tumour characteristics but also hospital-related factors play a role. This implies that clinical practice could be improved.
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http://dx.doi.org/10.1038/s41391-018-0109-yDOI Listing
May 2019

Differences in Trial and Real-world Populations in the Dutch Castration-resistant Prostate Cancer Registry.

Eur Urol Focus 2018 09 13;4(5):694-701. Epub 2016 Oct 13.

Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: Trials in castration-resistant prostate cancer (CRPC) treatment have shown improved outcomes, including survival. However, as trial populations are selected, results may not be representative for the real-world population. The aim of this study was to assess the differences between patients treated in a clinical trial versus standard care during the course of CRPC in a real-world CRPC population.

Design, Setting, And Participants: Castration-resistant Prostate Cancer Registry is a population-based, observational, retrospective registry. CRPC patients from 20 hospitals in the Netherlands have been included from 2010 to 2013.

Outcome Measurements And Statistical Analysis: Baseline characteristics, systemic treatment, and overall survival were the main outcomes. Descriptive statistics, multivariate Cox regression, and multiple imputations with the Monte Carlo Markov Chain method were used.

Results And Limitations: In total, 1524 patients were enrolled of which 203 patients had participated in trials at any time. The median follow-up period was 23 mo. Patients in the trial group were significantly younger and had less comorbidities. Docetaxel treatment was more frequently used in trial patients (85% vs 40%). Despite an observed unadjusted median overall survival difference of 35 mo versus 24 mo between the trial and standard care group, this difference was not retained after adjustment for baseline characteristics and treatment effect.

Conclusions: At CRPC diagnosis, the baseline characteristics of the patients who had been enrolled in trials notably differed from patients who received standard treatment options only. The survival difference between the trial and standard care group could be explained by baseline differences and treatment effects. These results indicate that trial results cannot easily be translated to real-world practice.

Patient Summary: We observed that patients treated in clinical trials differed from patients who were not. We concluded that this may lead to differential treatment and survival. Caution is warranted when real-world outcomes are compared with trial results.
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http://dx.doi.org/10.1016/j.euf.2016.09.008DOI Listing
September 2018

Repeatability of Quantitative 18F-Fluoromethylcholine PET/CT Studies in Prostate Cancer.

J Nucl Med 2016 May 23;57(5):721-7. Epub 2015 Dec 23.

Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.

Unlabelled: Repeatable quantification is essential when using (18)F-fluoromethylcholine PET/CT to monitor treatment response in prostate cancer. It has been shown that SUV normalized to the area under the blood activity concentration curve (SUVAUC) provides a better correlation with full kinetic analysis than does standard SUV. However, the precision of SUVAUC is not known yet. The purpose of this study was to assess the repeatability of various semiquantitative (18)F-fluoromethylcholine parameters in prostate cancer.

Methods: Twelve patients (mean age ± SD, 64 ± 8 y) with metastasized prostate cancer underwent two sets of (18)F-fluoromethylcholine PET/CT scans, on consecutive days. Each set consisted of a 30-min dynamic PET/CT scan of the chest after intravenous administration of 200 MBq of (18)F-fluoromethylcholine, followed by a whole-body PET/CT scan at 40 min. The dynamic scan was used to derive the area under the blood activity concentration curve. Lesion uptake was derived from the whole-body scan using various types of volumes of interest: maximum, peak, and mean. Each of these parameters was normalized to injected activity per body weight, area under the blood activity concentration curve, and blood concentration itself at 40 min, resulting in several types of SUVs: SUV, SUVAUC, and SUVTBR The test-retest repeatability of these metrics, as well as metabolic tumor volume (MTV) and total uptake of choline in the lesion, were studied. The level of agreement between test-retest data and reliability was assessed using Bland-Altman plots, repeatability coefficients, and intraclass correlation coefficients (ICCs).

Results: A total of 67 choline-avid metastases were identified: 44 bone lesions and 23 lymph node lesions. In the case of SUVmax, the repeatability coefficients for SUV, SUVAUC, and SUVTBR were 26% (ICC, 0.95), 31% (ICC, 0.95), and 46% (ICC, 0.89), respectively. Similar values were obtained for SUVpeak and SUVmean The repeatability of SUVAUC was comparable to that of SUVmax, SUVpeak, and SUVmean. Tissue type and tumor localization did not affect repeatability. An MTV of less than 4.2 cm(3) had larger variability than larger volumes (repeatability coefficient, 45% vs. 29%; P = 0.048). The repeatability coefficient did not significantly differ between lesions with SUVpeak above or below the median value of 8.3 (19% vs. 28%; P = 0.264).

Conclusion: The repeatability of SUVAUC was comparable to that of standard SUV. The repeatability coefficients of various semiquantitative (18)F-fluoromethylcholine parameters (SUV, MTV, and total uptake in the lesion) were approximately 35%. Larger differences are likely to represent treatment effects.
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http://dx.doi.org/10.2967/jnumed.115.167692DOI Listing
May 2016

A Clinical and Experimental Comparison of Time of Flight PET/MRI and PET/CT Systems.

Mol Imaging Biol 2015 Oct;17(5):714-25

Department of Radiology and Nuclear Medicine, VU University Medical Center, PO Box 7057, 1007, MB, Amsterdam, The Netherlands.

Purpose: The purpose of the study was to compare image quality and quantitative accuracy of positron emission tomography/magnetic resonance imaging (PET/MRI) and PET/computed tomography (PET/CT) systems with time of flight PET gantries, using phantom and clinical studies.

Procedures: Identical phantom experiments were performed on both systems. Calibration, uniformity, and standardized uptake value (SUV) recovery were measured. A clinical PET/CT versus PET/MRI comparison was performed using [(18)F]fluoromethylcholine ([(18)F]FCH).

Results: Calibration accuracy and image uniformity were comparable between systems. SUV recovery met EANM/EARL requirements on both scanners. Thirty-four lesions with comparable PET image quality were identified. Lesional SUVmax differences of 4 ± 26% between PET/MRI and PET/CT data were observed (R (2) = 0.79, slope = 1.02). In healthy tissues, PET/MRI-derived SUVs were 16 ± 11% lower than on PET/CT (R (2) = 0.98, slope = 0.86).

Conclusion: PET/MRI and PET/CT showed comparable performance with respect to calibration accuracy, image uniformity, and SUV recovery. [(18)F]FCH uptake values for both healthy tissues and lesions corresponded reasonably well between MR- and CT-based systems, but only in regions free of MR-based attenuation artifacts.
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http://dx.doi.org/10.1007/s11307-015-0826-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4768240PMC
October 2015

Quantification of 18F-fluorocholine kinetics in patients with prostate cancer.

J Nucl Med 2015 Mar 12;56(3):365-71. Epub 2015 Feb 12.

Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.

Unlabelled: Choline kinase is upregulated in prostate cancer, resulting in increased (18)F-fluoromethylcholine uptake. This study used pharmacokinetic modeling to validate the use of simplified methods for quantification of (18)F-fluoromethylcholine uptake in a routine clinical setting.

Methods: Forty-minute dynamic PET/CT scans were acquired after injection of 204 ± 9 MBq of (18)F-fluoromethylcholine, from 8 patients with histologically proven metastasized prostate cancer. Plasma input functions were obtained using continuous arterial blood-sampling as well as using image-derived methods. Manual arterial blood samples were used for calibration and correction for plasma-to-blood ratio and metabolites. Time-activity curves were derived from volumes of interest in all visually detectable lymph node metastases. (18)F-fluoromethylcholine kinetics were studied by nonlinear regression fitting of several single- and 2-tissue plasma input models to the time-activity curves. Model selection was based on the Akaike information criterion and measures of robustness. In addition, the performance of several simplified methods, such as standardized uptake value (SUV), was assessed.

Results: Best fits were obtained using an irreversible compartment model with blood volume parameter. Parent fractions were 0.12 ± 0.4 after 20 min, necessitating individual metabolite corrections. Correspondence between venous and arterial parent fractions was low as determined by the intraclass correlation coefficient (0.61). Results for image-derived input functions that were obtained from volumes of interest in blood-pool structures distant from tissues of high (18)F-fluoromethylcholine uptake yielded good correlation to those for the blood-sampling input functions (R(2) = 0.83). SUV showed poor correlation to parameters derived from full quantitative kinetic analysis (R(2) < 0.34). In contrast, lesion activity concentration normalized to the integral of the blood activity concentration over time (SUVAUC) showed good correlation (R(2) = 0.92 for metabolite-corrected plasma; 0.65 for whole-blood activity concentrations).

Conclusion: SUV cannot be used to quantify (18)F-fluoromethylcholine uptake. A clinical compromise could be SUVAUC derived from 2 consecutive static PET scans, one centered on a large blood-pool structure during 0-30 min after injection to obtain the blood activity concentrations and the other a whole-body scan at 30 min after injection to obtain lymph node activity concentrations.
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http://dx.doi.org/10.2967/jnumed.114.148007DOI Listing
March 2015

[18F]fluoromethylcholine as a chemotherapy response read-out in prostate cancer cells.

Mol Imaging Biol 2015 Jun;17(3):319-27

Department of Radiology and Nuclear Medicine, VU University Medical Center, PO Box 7057, 1007, MB, Amsterdam, The Netherlands.

Purpose: The objective of the present study is to determine whether uptake of [(18)F]fluoromethylcholine ([(18)F]FCH) in comparison with 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) accurately reflects chemotherapy efficacy at the tumor cell level in prostate cancer (PC).

Procedures: The effects of docetaxel and cabazitaxel on viable tumor cell number were explored in four PC cell lines. Cellular uptake of [(18)F]FDG and [(18)F]FCH was compared with the effects measured using sulforhodamine B (SRB) assay, cell counting and colony formation assay (CFA), as proximators of viable tumor cell number. Agreement between uptake and cell numbers was assessed by Bland-Altman plots.

Results: [(18)F]FCH uptake in all PC cell lines significantly correlated to the cell numbers surviving the respective drug concentrations. Bland-Altman analysis showed that [(18)F]FDG uptake resulted in signal overestimation and higher variability after chemotherapy.

Conclusions: [(18)F]FCH uptake correlates well with viable tumor cell numbers remaining after docetaxel and cabazitaxel exposure. Radiolabeled choline is a potential response monitoring biomarker after chemotherapy for PC.
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http://dx.doi.org/10.1007/s11307-014-0803-7DOI Listing
June 2015

ABCC4 Decreases docetaxel and not cabazitaxel efficacy in prostate cancer cells in vitro.

Anticancer Res 2013 Feb;33(2):387-91

Department of Radiology and Nuclear Medicine, Department of Urology, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, the Netherlands.

Background: This study aimed to investigate cabazitaxel efficacy in a model for docetaxel-resistant prostate cancer cells and to evaluate the involvement of ATP-cassette binding protein 4 (ABCC4) with regard to multidrug resistance.

Materials And Methods: Docetaxel and cabazitaxel sensitivity was measured in PC3 and R3327-MATLyLu (MLL) cell lines, using the sulforhodamine B (SRB) assay. ABCC4 expression was examined by western blotting and its functional involvement in drug sensitivity by blocking with MK571 inhibitor.

Results: The docetaxel-resistant MLL cells (4.5-fold compared to cabazitaxel; p<0.001) were shown to express high levels of ABCC4, while non-resistant PC3 cells had no detectable ABCC4 expression. Functional inhibition of ABCC4 in MLL cells resulted in a two-fold decrease in effective concentration of docetaxel and had no effect on toxicity of cabazitaxel.

Conclusion: Cabazitaxel showed an improved therapeutic efficacy over docetaxel in ABCC4-expressing prostate cancer cells. ABCC4 appears to be an important determinant of docetaxel resistance, since its inhibition almost completely reversed resistance.
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February 2013

Dual-phase PET-CT to differentiate [18F]Fluoromethylcholine uptake in reactive and malignant lymph nodes in patients with prostate cancer.

PLoS One 2012 31;7(10):e48430. Epub 2012 Oct 31.

Department of Nuclear Medicine and PET Research, VU University Medical Center, Amsterdam, The Netherlands.

Purpose: To investigate whether time-trends of enhanced [(18)F]Fluoromethylcholine ([(18)F]FCH) in lymph nodes (LN) of prostate cancer (PCa) patients can help to discriminate reactive from malignant ones, and whether single time point standardized uptake value (SUV) measurements also suffice.

Procedures: 25 PCa patients with inguinal (presumed benign) and enlarged pelvic LN (presumed malignant) showing enhanced [(18)F]FCH uptake at dual-phase PET-CT were analyzed. Associations between LN status (benign versus malignant) and SUV(max) and SUV(meanA50), determined at 2 min (early) and 30 min (late) post injection, were assessed. We considered two time-trends of [(18)F]FCH uptake: type A (SUV early > SUV late) and type B (SUV late ≥ SUV early). Histopathology and/or follow-up were used to confirm the assumption that LN with type A pattern are benign, and LN with type B pattern malignant.

Results: Analysis of 54 nodes showed that LN status, time-trends, and 'late' (30 min p.i.) SUV(max) and SUV(meanA50) parameters were strongly associated (P<0.0001). SUV(max) relative difference was the best LN status predictor. All but one inguinal LN showed a decreasing [(18)F]FCH uptake over time (pattern A), while 95% of the pelvic nodes presented a stable or increasing uptake (pattern B) type.

Conclusions: Time-trends of enhanced [(18)F]FCH uptake can help to characterize lymph nodes in prostate cancer patients. Single time-point SUV measurements, 30 min p.i., may be a reasonable alternative for predicting benign versus malignant status of lymph nodes, but this remains to be validated in non-enlarged pelvic lymph nodes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0048430PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3485217PMC
April 2013
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