Genetic Aspects and Molecular Testing in Prostate Cancer: A Report from a Dutch Multidisciplinary Consensus Meeting.

Background: Germline and tumour genetic testing in prostate cancer (PCa) is becoming more broadly accepted, but testing indications and clinical consequences for carriers in each disease stage are not yet well defined. Objective: To determine the consensus of a Dutch multidisciplinary expert panel on the indication and application of germline and tumour genetic testing in PCa. Design setting and participants: The panel consisted of 39 specialists involved in PCa management. We used a modified Delphi method consisting of two voting rounds and a virtual consensus meeting. Outcome measurements and statistical analysis: Consensus was reached if ≥75% of the panellists chose the same option. Appropriateness was assessed by the RAND/UCLA appropriateness method. Results and limitations: Of the multiple-choice questions, 44% reached consensus. For men without PCa having a relevant family history (familial PCa/BRCA-related hereditary cancer), follow-up by prostate-specific antigen was considered appropriate. For patients with low-risk localised PCa and a family history of PCa, active surveillance was considered appropriate, except in case of the patient being a BRCA2 germline pathogenic variant carrier. Germline and tumour genetic testing should not be done for nonmetastatic hormone-sensitive PCa in the absence of a relevant family history of cancer. Tumour genetic testing was deemed most appropriate for the identification of actionable variants, with uncertainty for germline testing. For tumour genetic testing in metastatic castration-resistant PCa, consensus was not reached for the timing and panel composition. The principal limitations are as follows: (1) a number of topics discussed lack scientific evidence, and therefore the recommendations are partly opinion based, and (2) there was a small number of experts per discipline. Conclusions: The outcomes of this Dutch consensus meeting may provide further guidance on genetic counselling and molecular testing related to PCa. Patient summary: A group of Dutch specialists discussed the use of germline and tumour genetic testing in prostate cancer (PCa) patients, indication of these tests (which patients and when), and impact of these tests on the management and treatment of PCa.

Personalised versus non-individualised case-based CME: A randomised pilot study.

The PinPoint Case Platform (PPCP) offers independent online case-based CME. To align with personal learning needs, a functionality of needs assessments ("QuickScan") was developed, directing users to follow personalised case journeys. A randomised study was conducted, comparing its effectiveness, time efficiency and user experience with a format of non-individualised case-based learning. Forty-two residents in urology from five European countries were randomly assigned to follow non-individualised case-based learning (control group) or a needs assessment plus personalised case journeys on different topics in prostate cancer. After performing a pre- and post-assessment, both groups showed a similar increase in test scores (Mann-Whitney U = 247; p = .113), but the time needed for completing the learning exercise was significantly lower in the group with the personalised approach (median: 45 vs 90 minutes; Mann-Whitney U = 97.5; p = .0141). The quality of the two learning methods was similarly well received by both groups. In conclusion, learners who followed personalised case journeys learned similarly effective but more time efficient than non-individualised case-based learners. Future studies should determine if these findings can be extrapolated to board-certified physicians following CME activities.

Standardizing HIPEC and perioperative care for patients with ovarian cancer in the Netherlands using a Delphi-based consensus.

OBJECTIVE: Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is standard of care in the Netherlands in patients with stage III epithelial ovarian cancer following interval cytoreductive surgery (CRS). Differences in patient selection, technical aspects, and perioperative management exist between centers performing HIPEC. Standardization aims to reduce unwanted variation in clinical practice. As part of an implementation process, we aimed to standardize perioperative care for patients treated with CRS and HIPEC using a Delphi-based consensus approach. METHODS: We performed a two-phase modified Delphi method involving a multidisciplinary panel of 40 experts who completed a survey on CRS and HIPEC. During a consensus meeting, survey outcomes and available scientific evidence was discussed. Items without consensus (<75% agreement) were adjusted and evaluated in a second survey. RESULTS: Consensus was reached in the first round on 51% of items. After two rounds, consensus was reached on the majority of items (82%) including patient selection, preoperative workup, technical aspects of CRS and HIPEC, and postoperative care. No consensus was reached on the role of HIPEC in rare ovarian cancer types, preoperative bowel preparation, timing to create bowel anastomoses, and manipulation of the perfusate. CONCLUSIONS: Dutch experts reached consensus on most items regarding interval CRS and HIPEC for ovarian cancer. This consensus study may help to align treatment protocols and to minimize practice variation. Topics without consensus may be put on the research agenda of HIPEC for ovarian cancer.

M1a prostate cancer: Results of a Dutch multidisciplinary consensus meeting.

Objectives: To determine the consensus of a Dutch multidisciplinary expert panel on the diagnostic evaluation and treatment of de novo and recurrent metastatic prostate cancer (PCa) limited to non-regional lymph nodes (M1a) in daily clinical practice. Materials and methods: The panel consisted of 37 Dutch specialists from disciplines involved in the management of M1a PCa (urology, medical and radiation oncology, radiology, and nuclear medicine). We used a modified Delphi method consisting of two voting rounds and a consensus meeting (video conference). Consensus (good agreement) was defined as the situation in which ≥ 75% of the panelists chose the same option. Results: Consensus existed for 57% of the items. The panel agreed that prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT) is the most appropriate standard imaging modality to identify de novo (100%) and recurrent (97%) M1a PCa. Androgen deprivation therapy (ADT) combined with radiotherapy to the prostate ± the M1a lesion(s) was most frequently considered an option for de novo M1a PCa. For M1a as recurrent disease, ADT alone, deferring treatment, or local radiotherapy to the M1a lesion(s) were judged to be the most important treatment options. However, no specific indications for treatment choice in relation to disease characteristics could be formulated. Conclusions: The Dutch consensus panel preferred PSMA-PET/CT as the standard diagnostic modality to detect M1a PCa. Although potential treatment options were identified, explicit recommendations could not be formulated. This might (partly) be explained by the absence of high-level clinical evidence in this subset of patients. Further research is, therefore, strongly encouraged.

Oligometastatic Prostate Cancer: Results of a Dutch Multidisciplinary Consensus Meeting.

BACKGROUND: Oligometastatic prostate cancer (OMPC) is a heterogeneous disease state that is imperfectly understood, and its clinical implications are unclear. OBJECTIVE: To determine the consensus of a Dutch multidisciplinary expert panel on biological aspects, treatment goals, and management of OMPC in daily clinical practice. DESIGN, SETTING, AND PARTICIPANTS: The study comprised a modified Delphi method including an explorative survey with various statements and questions, followed by a consensus meeting to discuss and determine the agreement with revised statements and related items. The panel consisted of 34 Dutch representatives from urology, medical and radiation oncology, radiology, nuclear medicine, and basic research. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Agreement was determined with statements (five-point scale). Consensus was defined as ≥75% panel agreement with a statement. RESULTS AND LIMITATIONS: Consensus existed for 56% of statements. The panel agreed that OMPC comprises a limited metastatic spread in the hormone-sensitive setting, in both the synchronous and the metachronous presentation. Limited metastatic spread was believed to involve three to five metastases and a maximum of two organs. Prostate-specific membrane antigen positron emission tomography/computed tomography scan was currently perceived as the most accurate diagnostic imaging modality. Although there was a consensus that targeted treatment of all metastases in OMPC will delay further dissemination of the disease, opinions on specific treatment regimens were divided. Panel outcomes were limited by the lack of scientific evidence on OMPC. CONCLUSIONS: A multidisciplinary panel reached a consensus that OMPC is a specific disease state requiring a tailored treatment approach. OMPC registries and clinical studies should focus on both the biology and the clinical parameters in relation to optimal treatment strategies in synchronous and metachronous OMPC. PATIENT SUMMARY: A group of Dutch medical specialists agreed that prostate cancer patients having few metastases may benefit from a new therapeutic approach. Clinical studies need to determine which treatment is best for each specific situation.

The appropriate management of persisting pain after spine surgery: a European panel study with recommendations based on the RAND/UCLA method.

PURPOSE: Management of patients with persisting pain after spine surgery (PPSS) shows significant variability, and there is limited evidence from clinical studies to support treatment choice in daily practice. This study aimed to develop patient-specific recommendations on the management of PPSS. METHODS: Using the RAND/UCLA appropriateness method (RUAM), an international panel of 6 neurosurgeons, 6 pain specialists, and 6 orthopaedic surgeons assessed the appropriateness of 4 treatment options (conservative, minimally invasive, neurostimulation, and re-operation) for 210 clinical scenarios. These scenarios were unique combinations of patient characteristics considered relevant to treatment choice. Appropriateness had to be expressed on a 9-point scale (1 = extremely inappropriate, 9 = extremely appropriate). A treatment was considered appropriate if the median score was ≥ 7 in the absence of disagreement (≥ 1/3 of ratings in each of the opposite sections 1-3 and 7-9). RESULTS: Appropriateness outcomes showed clear and specific patterns. In 48% of the scenarios, exclusively one of the 4 treatments was appropriate. Conservative treatment was usually considered appropriate for patients without clear anatomic abnormalities and for those with new pain differing from the original symptoms. Neurostimulation was considered appropriate in the case of (predominant) neuropathic leg pain in the absence of conditions that may require surgical intervention. Re-operation could be considered for patients with recurrent disc, spinal/foraminal stenosis, or spinal instability. CONCLUSIONS: Using the RUAM, an international multidisciplinary panel established criteria for appropriate treatment choice in patients with PPSS. These may be helpful to educate physicians and to improve consistency and quality of care. These slides can be retrieved under Electronic Supplementary Material.

The Appropriate Management Of Osteoporotic Vertebral Compression Fractures : A Single Institute Evaluation Using The VCF Monitor.

From the Department of Orthopaedics and Trauma Surgery, Klinikum Bayreuth, Bayreuth, Germany Osteoporosis-related vertebral compression fractures (OVCF) are commonly seen in clinical practice. Treatment choice is often challenging due to heterogeneity of the patient population. A European multidisciplinary expert panel developed patient-specific recommendations for reatment choice that were embedded in an online evaluation tool (VCF Monitor). This study aimed to evaluate the appropriateness of treatment choice in patients with OVCF in a German hospital. The prospective observational study included 190 patients with OCVF (2013-2015). Using the VCF Monitor, treatment choices were compared with the recommendations of the European expert panel. Treatment choices included balloon kyphoplasty (61%), non-surgical management (36%) and other surgical procedures (3%). Compared to the panel recommendations, 70% of treatment choices were appropriate, 24% uncertain, and 3% inappropriate. Less appropriate choices were partly due to patient preferences. The VCF Monitor proved to be a helpful tool for quality assurance in the management of OVCF.

Clinical judgment versus biomarker prostate cancer gene 3: which is best when determining the need for repeat prostate biopsy?

OBJECTIVE: To assess the value of best clinical judgment (BCJ) and the prostate cancer gene 3 (PCA3) assay in guiding the decision to perform a repeat prostate biopsy (PBx) after a previous negative PBx. MATERIALS AND METHODS: Using the RAND/UCLA Appropriateness Method, 12 European urologists established recommendations (BCJ) for the appropriateness of PBx according to the prostate-specific antigen level, digital rectal examination findings, number of previous negative PBxs, prostate volume, and life expectancy, with and without consideration of the PCA3 scores. These recommendations were applied to 1024 subjects receiving placebo in the Reduction by Dutasteride of Prostate Cancer Events trial, including men with a previous negative PBx, a baseline prostate-specific antigen level of 2.5-10 ng/mL, and a PCA3 test performed before the protocol-mandated 2- and 4-year repeat PBxs. Three scenarios (ie, BCJ alone, BCJ with PCA3, and the PCA3 score alone) were tested for their ability to reduce the repeat PBx rate versus missing Gleason sum ≥ 7 prostate cancer (PCa). RESULTS: BCJ with PCA3 would have avoided 64% of repeat PBxs compared with 26% for BCJ alone and 55% for PCA3 alone (cutoff score 20). Of 55 PCa cases (Gleason sum ≥ 7), 13 would have been missed using BCJ alone compared with 7 using PCA3 (cutoff score 20) alone and 8 using BCJ plus PCA3. The diagnostic accuracy for Gleason sum ≥ 7 PCa of the BCJ with PCA3 scenario was superior to that of the other scenarios, with a negative predictive value of 99%. CONCLUSION: Application of the BCJ together with PCA3 testing can reduce the number of repeat PBxs while maintaining the sensitivity to detect Gleason sum ≥ 7 PCa.

Impact of adoption of a decision algorithm including PCA3 for repeat biopsy on the costs for prostate cancer diagnosis in France.

OBJECTIVE: A recent expert study (RAND Appropriateness Method (RAM)) including a panel of 12 European urologists reported that the PCA3 score may be instrumental in taking appropriate prostate biopsy (PBx) decisions, mainly for repeat PBx. This study determined the cost/benefit balance of introducing PCA3 in the decision-making for PBx in France. METHODS: Two RAM models, without and with PCA3, were retrospectively applied to a sample of 808 French men who had PBx in 2010 (78% first, 22% repeat). Outcome measures included the proportion of PBx that could have been avoided (i.e., judged inappropriate) in the French sample according to both RAM models, and the estimated impact of application of these models on the annual number of PBx and associated costs for France (based on most recent published data). RESULTS: Complete profiles were available for 698 men. In the model without PCA3, 2% of PBx were deemed inappropriate. Knowledge of PCA3 would have avoided another 7% of PBx. Repeat PBx would have been avoided in 5% of cases without PCA3 and in 37% with PCA3. For France, application of the RAM model including PCA3 would result in 18,345 fewer repeat PBx. It would be budget-neutral in the unlikely hypothesis of no complications or no costs incurred by complications and would save €1.7 million for a mean cost for complications of €100/procedure or €5 million for a mean cost for complications of €280/procedure, calculated based on US and Canadian data. LIMITATIONS: Limitations of the study are the theoretical nature of the analysis and the fact that PCA3 distributions had to be derived from other sources. CONCLUSIONS: Adoption of RAM expert recommendations including PCA3 for repeat PBx decisions in clinical practice in France would reduce the number of repeat PBx and control costs.

Biopsy and treatment decisions in the initial management of prostate cancer and the role of PCA3; a systematic analysis of expert opinion.

PURPOSE: The Prostate CAncer gene 3 (PCA3) assay may guide prostate biopsy decisions and predict prostate cancer (PCa) aggressiveness. This study explored the appropriateness of (1) PCA3 testing; (2) biopsy; (3) active surveillance (AS) and the value of the PCA3 Score for biopsy and AS decisions. METHODS: Using the RAND/UCLA appropriateness method, 12 urologists assessed the appropriateness of PCA3, biopsy and AS for theoretical patient profiles, constructed by combining clinical variables. They individually scored the appropriateness for all profiles using a 9-point scale. Based on the median score and extent of agreement, the appropriateness for each profile was calculated. RESULTS: The PCA3 Assay was mainly considered appropriate in men with ≥1 negative biopsy, PSA ≥ 3 ng/mL and life expectancy (LE) ≥10 years. A LE < 10 years, ≥2 negative biopsies and PCA3 Score <20 decreased biopsy appropriateness, while PSA ≥ 3 ng/mL and PCA3 Score >50 increased it. In men without a prior biopsy, LE ≥ 10 years and a suspicious DRE, PCA3 did not affect biopsy appropriateness. In other men, a PCA3 Score <20 discouraged biopsy, while a value ≥35 supported biopsy. AS was mainly considered appropriate if LE < 10 years, T1c PCa, ≤20% positive cores and PSA < 3 ng/mL. A PCA3 Score <20 pleads for and higher scores (particularly >50) against AS. CONCLUSIONS: These findings illustrate in which men PCA3 can be of additional value when taking biopsy and treatment decisions in clinical practice.

A tool to improve pre-selection for deep brain stimulation in patients with Parkinson's disease.

Determining the eligibility of patients with Parkinson's disease (PD) for deep brain stimulation (DBS) can be challenging for general (non-specialised) neurologists. We evaluated the use of an online screening tool (Stimulus) that aims to support appropriate referral to a specialised centre for the further evaluation of DBS. Implementation of the tool took place via an ongoing European multicentre educational programme, currently completed in 15 DBS centres with 208 referring neurologists. Use of the tool in daily practice was monitored via an online data capture programme. Selection decisions of patients referred with the assistance of the Stimulus tool were compared to those of patients outside the screening programme. Three years after the start of the programme, 3,128 patient profiles had been entered. The intention for referral was made for 802 patients and referral intentions were largely in accordance with the tool recommendations. Follow-up at 6 months showed that actual referral took place in only 28%, predominantly due to patients' reluctance to undergo brain surgery. In patients screened with the tool and referred to a DBS centre, the acceptance rate was 77%, significantly higher than that of the unscreened population (48%). The tool showed a sensitivity of 99% and a specificity of 12% with a positive and negative predictive value of 79 and 75%, respectively. The Stimulus tool is useful in assisting general neurologists to identify appropriate candidates for DBS consideration. The principal reason for not referring potentially eligible patients is their reluctance to undergo brain surgery.

Appropriate management of symptomatic GORD in primary care: has expert opinion changed between 2001 and 2005?

OBJECTIVE: To determine current opinions of clinical experts on the appropriate management of symptomatic GORD in primary care, and to compare these opinions with those from a similar study conducted in 2001. METHODS: In 2001, a panel of 6 Belgian general practitioners and 6 gastroenterologists assessed the appropriateness of referral versus short-term anti-secretory medication for 768 different patient profiles, using the RAND/UCLA method. Applying a similar methodology, the same panel repeated these assessments in 2005. In addition, panellists were asked to indicate the preferred type of medication for all patient profiles. RESULTS: Agreement between the results of 2001 and 2005 was high. Appropriateness ratings on referral versus medication were similar in 79% of patient profiles (weighted kappa value 0.77). Higher age and use of NSAIDs remained the dominant factors in favour of referral. Medication preference (not measured in 2001) showed marked differences between general practitioners and gastroenterologists. Gastroenterologists showed a higher preference for PPI high dose, whereas general practitioners more frequently chose for PPI low dose. H2-receptor antagonists were preferred in only few cases. CONCLUSIONS: This study showed that expert opinion on the appropriateness of referral for endoscopy in patients with symptomatic GORD has only slightly changed over the past few years. Preferences for low and high dose PPIs varied between the two groups of physicians, which is most likely to be ascribed to the different patient populations seen in either primary or specialised care.

Conditional reimbursement within the Dutch drug policy.

In The Netherlands, conditional reimbursement is considered to be a promising approach to achieving more effective and efficient pharmaceutical care. Because of its formal status and nationwide regulation, conditional reimbursement may allow governments to better control medical decision-making. To evaluate the effects of conditional reimbursement on medicine use and its performance as a policy tool, we compared observed volumes of medicine use with expected volumes. In addition, we mapped the annual growth by analysing trends in the volumes of use of all conditionally reimbursed drugs; starting with the year the drug entered the market (using macro-level data). Next we explored five cases in depth (using micro-level data) in order to explore what fraction of individual prescriptions met the requirements. We also performed qualitative research (document analysis, interviews (N=65)) in order to obtain the stakeholders' perspectives on how the measure functions, as well as to interpret the case studies data further. The findings suggest that conditional reimbursement may be an effective policy instrument, but that several changes are needed to optimize its impact. These changes are predominantly related to transparency (e.g. conditions are set following clear procedures and criteria), legitimacy (conditions should be consistent with criteria for prioritization), feasibility of procedures to control appropriate use, and timely and appropriate commitment of the stakeholders.

The valuation of the International Prostate Symptom Score (IPSS) for use in economic evaluations.

OBJECTIVE: Lower Urinary Tract Symptoms (LUTS) suggestive of Benign Prostatic Obstruction (BPO) cause a reduction in quality of life, but the magnitude of that reduction cannot be estimated empirically. This is because survey instruments currently available merely sum the symptoms found, but do not value their impact on quality of life. It is therefore difficult to determine whether the effects of treatments for LUTS suggestive of BPO justify the costs. This complicates economic evaluations. METHODS: We valued the impact on quality of life of patients with LUTS suggestive of BPO, by valuing health states defined by the International Prostate Symptom Score (IPSS) using the time trade-off (TTO). TTO values ranged from 1.0 for perfect health to 0.0 for the value of death, and can be used to calculate Quality-Adjusted Life Years (QALYs), the preferred outcome measure in health economics. RESULTS: We reduced the number of health states defined by the IPSS using factor analysis. The resulting nine health states were valued by a representative sample of the general public (N=170) using TTO. The worst IPSS health state was valued at 0.87. CONCLUSION: The values for health states defined by the IPSS revealed that LUTS suggestive of BPO has a mild impact on quality of life. The valuation of the IPSS facilitates economic evaluations of treatments for LUTS suggestive of BPO, because QALYs (the preferred outcome measure in health economics) can be determined empirically.