Risk-Based Selection for Active Surveillance: Results of the Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) Initiative.

PURPOSE: We sought to identify and validate known predictors of disease reclassification at 1 or 4 years to support risk-based selection of patients suitable for active surveillance. MATERIALS AND METHODS: An individual participant data meta-analysis using data from 25 established cohorts within the Movember Foundations GAP3 Consortium. In total 5,530 men were included. Disease reclassification was defined as any increase in Gleason grade group at biopsy at 1 and 4 years. Associations were estimated using random effect logistic regression models. The discriminative ability of combinations of predictors was assessed in an internal-external validation procedure using the AUC curve. RESULTS: Among the 5,570 men evaluated at 1 year, we found 815 reclassifications to higher Gleason grade group at biopsy (pooled reclassification rate 13%, range 0% to 31%). Important predictors were age, prostate specific antigen, prostate volume, T-stage and number of biopsy cores with prostate cancer. Among the 1,515 men evaluated at 4 years, we found 205 reclassifications (pooled reclassification rates 14%, range 3% to 40%), with similar predictors. The average areas under the receiver operating characteristic curve at internal-external validation were 0.68 and 0.61 for 1-year and 4-year reclassification, respectively. CONCLUSIONS: Disease reclassification occurs typically in 13% to 14% of biopsies at 1 and 4 years after the start of active surveillance with substantial between-study heterogeneity. Current guidelines might be extended by considering prostate volume to improve individualized selection for active surveillance. Additional predictors are needed to improve patient selection for active surveillance.

Minimizing Population Health Loss in Times of Scarce Surgical Capacity During the Coronavirus Disease 2019 Crisis and Beyond: A Modeling Study.

OBJECTIVES: Coronavirus disease 2019 has put unprecedented pressure on healthcare systems worldwide, leading to a reduction of the available healthcare capacity. Our objective was to develop a decision model to estimate the impact of postponing semielective surgical procedures on health, to support prioritization of care from a utilitarian perspective. METHODS: A cohort state-transition model was developed and applied to 43 semielective nonpediatric surgical procedures commonly performed in academic hospitals. Scenarios of delaying surgery from 2 weeks were compared with delaying up to 1 year and no surgery at all. Model parameters were based on registries, scientific literature, and the World Health Organization Global Burden of Disease study. For each surgical procedure, the model estimated the average expected disability-adjusted life-years (DALYs) per month of delay. RESULTS: Given the best available evidence, the 2 surgical procedures associated with most DALYs owing to delay were bypass surgery for Fontaine III/IV peripheral arterial disease (0.23 DALY/month, 95% confidence interval [CI]: 0.13-0.36) and transaortic valve implantation (0.15 DALY/month, 95% CI: 0.09-0.24). The 2 surgical procedures with the least DALYs were placing a shunt for dialysis (0.01, 95% CI: 0.005-0.01) and thyroid carcinoma resection (0.01, 95% CI: 0.01-0.02). CONCLUSION: Expected health loss owing to surgical delay can be objectively calculated with our decision model based on best available evidence, which can guide prioritization of surgical procedures to minimize population health loss in times of scarcity. The model results should be placed in the context of different ethical perspectives and combined with capacity management tools to facilitate large-scale implementation.

The Movember Foundation's GAP3 cohort: a profile of the largest global prostate cancer active surveillance database to date.

OBJECTIVES: The Movember Foundation launched the Global Action Plan Prostate Cancer Active Surveillance (GAP3) initiative to create a global consensus on the selection and monitoring of men with low-risk prostate cancer (PCa) on active surveillance (AS). The aim of this study is to present data on inclusion and follow-up for AS in this unique global AS database. PATIENTS AND METHODS: Between 2014 and 2016, the database was created by combining patient data from 25 established AS cohorts worldwide (USA, Canada, Australasia, UK and Europe). Data on a total of 15 101 patients were included. Descriptive statistics were used to report patients' clinical and demographic characteristics at the time of PCa diagnosis, clinical follow-up, discontinuation of AS and subsequent treatment. Cumulative incidence curves were used to report discontinuation rates over time. RESULTS: At diagnosis, the median (interquartile range [IQR]) patient age was 65 (60-70) years and the median prostate-specific antigen level was 5.4 (4.0-7.3) ng/mL. Most patients had clinical stage T1 disease (71.8%), a biopsy Gleason score of 6 (88.8%) and one tumour-positive biopsy core (60.3%). Patients on AS had a median follow-up time of 2.2 (1.0-5.0) years. After 5, 10 and 15 years of follow-up, respectively, 58%, 39% and 23% of patients were still on AS. The current version of GAP3 has limited data on magnetic resonance imaging (MRI), quality of life and genomic testing. CONCLUSIONS: GAP3 is the largest worldwide collaboration integrating patient data from men with PCa on AS. The results will allow individual patients and clinicians to have greater confidence in the personalized decision to either delay or proceed with active treatment. Longer follow-up and the evaluation of MRI, new genomic markers and patient-related outcomes will result in even more valuable data and eventually in better patient outcomes.

Using continuous sedation until death for cancer patients: a qualitative interview study of physicians' and nurses' practice in three European countries.

BACKGROUND: Extensive debate surrounds the practice of continuous sedation until death to control refractory symptoms in terminal cancer care. We examined reported practice of United Kingdom, Belgian and Dutch physicians and nurses. METHODS: Qualitative case studies using interviews. SETTING: Hospitals, the domestic home and hospices or palliative care units. PARTICIPANTS: In all, 57 Physicians and 73 nurses involved in the care of 84 cancer patients. RESULTS: UK respondents reported a continuum of practice from the provision of low doses of sedatives to control terminal restlessness to rarely encountered deep sedation. In contrast, Belgian respondents predominantly described the use of deep sedation, emphasizing the importance of responding to the patient's request. Dutch respondents emphasized making an official medical decision informed by the patient's wish and establishing that a refractory symptom was present. Respondents employed rationales that showed different stances towards four key issues: the preservation of consciousness, concerns about the potential hastening of death, whether they perceived continuous sedation until death as an 'alternative' to euthanasia and whether they sought to follow guidelines or frameworks for practice. CONCLUSION: This qualitative analysis suggests that there is systematic variation in end-of-life care sedation practice and its conceptualization in the United Kingdom, Belgium and the Netherlands.

Physicians' experiences and perspectives regarding the use of continuous sedation until death for cancer patients in the context of psychological and existential suffering at the end of life.

OBJECTIVE: The use of continuous sedation until death for terminally ill cancer patients with unbearable and untreatable psychological and existential suffering remains controversial, and little in-depth insight exists into the circumstances in which physicians resort to it. METHODS: Our study was conducted in Belgium, the Netherlands, and the UK in hospitals, PCUs/hospices, and at home. We held interviews with 35 physicians most involved in the care of cancer patients who had psychological and existential suffering and had been continuously sedated until death. RESULTS: In the studied countries, three groups of patients were distinguished regarding the origin of their psychological and existential suffering. The first group had preexisting psychological problems before they became ill, the second developed psychological and existential suffering during their disease trajectory, and the third presented psychological symptoms that were characteristic of their disease. Before they resorted to the use of sedation, physicians reported that they had considered an array of pharmacological and psychological interventions that were ineffective or inappropriate to relieve this suffering. Necessary conditions for using sedation in this context were for most physicians the presence of refractory symptoms, a short life expectancy, and an explicit patient request for sedation. CONCLUSIONS: Physicians in our study used continuous sedation until death in the context of psychological and existential suffering after considering several pharmacological and psychological interventions. Further research and debate are needed on how and by whom this suffering at the end of life should be best treated, taking into account patients' individual preferences.

Estimating the potential life-shortening effect of continuous sedation until death: a comparison between two approaches.

CONTEXT: In some cases, physicians estimate that continuous sedation until death may have a life shortening effect. The accuracy of these estimations can be questioned. AIM: The aim of this study is to compare two approaches to estimate the potential life-shortening effect of continuous sedation until death. METHODS: In 2008, 370 Dutch physicians filled out a questionnaire and reported on their last patient who received continuous sedation until death. The potential life-shortening effect of continuous sedation was estimated through a direct approach (question: Did continuous sedation, according to your estimation,hasten the patient's death? If yes: by how much time?)and an indirect approach (estimated life expectancy minus duration of sedation). The intrarater agreement between both approaches was determined with a weighted κ. RESULTS: According to the direct approach, sedation might have had a life-shortening effect in 51% of the cases and according to the indirect approach in 84%.The intrarater agreement between both approaches was fair (weighted κ=0.38). In 10% of all cases, the direct approach yielded higher estimates of the extent to which life had been shortened; in 58% of the cases, the indirect approach yielded higher estimates. CONCLUSIONS: The results show a discrepancy between different approaches to estimate the potential life shortening effect of continuous sedation until death.

Continuous sedation until death: the everyday moral reasoning of physicians, nurses and family caregivers in the UK, The Netherlands and Belgium.

BACKGROUND: Continuous sedation is increasingly used as a way to relieve symptoms at the end of life. Current research indicates that some physicians, nurses, and relatives involved in this practice experience emotional and/or moral distress. This study aims to provide insight into what may influence how professional and/or family carers cope with such distress. METHODS: This study is an international qualitative interview study involving interviews with physicians, nurses, and relatives of deceased patients in the UK, The Netherlands and Belgium (the UNBIASED study) about a case of continuous sedation at the end of life they were recently involved in. All interviews were transcribed verbatim and analysed by staying close to the data using open coding. Next, codes were combined into larger themes and categories of codes resulting in a four point scheme that captured all of the data. Finally, our findings were compared with others and explored in relation to theories in ethics and sociology. RESULTS: The participants' responses can be captured as different dimensions of 'closeness', i.e. the degree to which one feels connected or 'close' to a certain decision or event. We distinguished four types of 'closeness', namely emotional, physical, decisional, and causal. Using these four dimensions of 'closeness' it became possible to describe how physicians, nurses, and relatives experience their involvement in cases of continuous sedation until death. More specifically, it shined a light on the everyday moral reasoning employed by care providers and relatives in the context of continuous sedation, and how this affected the emotional impact of being involved in sedation, as well as the perception of their own moral responsibility. CONCLUSION: Findings from this study demonstrate that various factors are reported to influence the degree of closeness to continuous sedation (and thus the extent to which carers feel morally responsible), and that some of these factors help care providers and relatives to distinguish continuous sedation from euthanasia.

Consistent Biopsy Quality and Gleason Grading Within the Global Active Surveillance Global Action Plan 3 Initiative: A Prerequisite for Future Studies.

Within the Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) initiative, 25 centers across the globe collaborate to standardize active surveillance (AS) protocols for men with low-risk prostate cancer (PCa). A centralized PCa AS database, comprising data of more than 15000 patients worldwide, was created. Comparability of the histopathology between the different cohorts was assessed by a centralized pathology review of 445 biopsies from 15 GAP3 centers. Grade group 1 (Gleason score 6) in 85% and grade group ≥2 (Gleason score ≥7) in 15% showed 89% concordance at review with moderate agreement (κ=0.56). Average biopsy core length was similar among the analyzed cohorts. Recently established highly adverse pathologies, including cribriform and/or intraductal carcinoma, were observed in 3.6% of the reviewed biopsies. In conclusion, the centralized pathology review of 445 biopsies revealed comparable histopathology among the 15 GAP3 centers with a low frequency of high-risk features. This enables further data analyses-without correction-toward uniform global AS guidelines for men with low-risk PCa. PATIENT SUMMARY: Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) initiative combines data from 15000 men with low-risk prostate cancer (PCa) across the globe to standardize active surveillance protocols. Histopathology review confirmed that the histopathology was consistent with low-risk PCa in most men and comparable between different centers.

Active surveillance for prostate cancer: a systematic review of contemporary worldwide practices.

In the last decade, active surveillance (AS) has emerged as an acceptable choice for low-risk prostate cancer (PC), however there is discordance amongst large AS cohort studies with respect to entry and monitoring protocols. We systematically reviewed worldwide AS practices in studies reporting ≥5 years follow-up. We searched PubMed and Medline 2000-now and identified 13 AS cohorts. Three key areas were identified: (I) patient selection; (II) monitoring protocols; (III) triggers for intervention-(I) all studies defined clinically localised PC diagnosis as T2b disease or less and most agreed on prostate-specific antigen (PSA) threshold (<10 µg/L) and Gleason score threshold (3+3). Inconsistency was most notable regarding pathologic factors (e.g., number of positive cores); (II) all agreed on PSA surveillance as crucial for monitoring, and most agreed that confirmatory biopsy was required within 12 months of initiation. No consensus was reached on optimal timing of digital rectal examination (DRE), general health assessment or re-biopsy strategies thereafter; (III) there was no universal agreement for intervention triggers, although Gleason score, number or percentage of positive cancer cores, maximum cancer length (MCL) and PSA doubling time were used by several studies. Some also used imaging or re-biopsy. Despite consistent high progression-free/cancer-free survival and conversion-to-treatment rates, heterogeneity exists amongst these large AS cohorts. Combining existing evidence and gathering more long-term evidence [e.g., the Movember's Global AS database or additional information on use of magnetic resonance imaging (MRI)] is needed to derive a broadly supported guideline to reduce variation in clinical practice.

Expert consensus document: Semantics in active surveillance for men with localized prostate cancer - results of a modified Delphi consensus procedure.

Active surveillance (AS) is broadly described as a management option for men with low-risk prostate cancer, but semantic heterogeneity exists in both the literature and in guidelines. To address this issue, a panel of leading prostate cancer specialists in the field of AS participated in a consensus-forming project using a modified Delphi method to reach international consensus on definitions of terms related to this management option. An iterative three-round sequence of online questionnaires designed to address 61 individual items was completed by each panel member. Consensus was considered to be reached if ≥70% of the experts agreed on a definition. To facilitate a common understanding among all experts involved and resolve potential ambiguities, a face-to-face consensus meeting was held between Delphi survey rounds two and three. Convenience sampling was used to construct the panel of experts. In total, 12 experts from Australia, France, Finland, Italy, the Netherlands, Japan, the UK, Canada and the USA participated. By the end of the Delphi process, formal consensus was achieved for 100% (n = 61) of the terms and a glossary was then developed. Agreement between international experts has been reached on relevant terms and subsequent definitions regarding AS for patients with localized prostate cancer. This standard terminology could support multidisciplinary communication, reduce the extent of variations in clinical practice and optimize clinical decision making.

Active surveillance for prostate cancer: a narrative review of clinical guidelines.

In the past decade active surveillance (AS) of men with localized prostate cancer has become an increasingly popular management option, and a range of clinical guidelines have been published on this topic. Existing guidelines regarding AS for prostate cancer vary widely, but predominantly state that the most suitable patients for AS are those with pretreatment clinical stage T1c or T2 tumours, serum PSA levels <10 ng/ml, biopsy Gleason scores of 6 or less, a maximum of one or two tumour-positive biopsy core samples and/or a maximum of 50% of cancer per core sample. Following initiation of an AS programme, most guidelines recommend serial serum PSA measurements, digital rectal examinations and surveillance biopsies to check for and identify pathological indications of tumour progression. Definitions of disease reclassification and progression differ among guidelines and multiple criteria for initiation of definitive treatment are proposed. The variety of descriptions of criteria for clinically insignificant prostate cancer indicates a lack of consensus on optimal AS and intervention thresholds. A single set of guidelines are needed in order to reduce variations in clinical practice and to optimize clinical decision-making. To enable truly evidence-based guidelines, further research that combines existing evidence, while also gathering information from more long-term studies is needed.

The language of sedation in end-of-life care: The ethical reasoning of care providers in three countries.

The application of ethically controversial medical procedures may differ from one place to another. Drawing on a keyword and text-mining analysis of 156 interviews with doctors and nurses involved in end-of-life care ('care providers'), differences between countries in care providers' ethical rationales for the use of sedation are reported. In the United Kingdom, an emphasis on titrating doses proportionately against symptoms is more likely, maintaining consciousness where possible. The potential harms of sedation are perceived to be the potential hastening of social as well as biological death. In Belgium and the Netherlands, although there is concern to distinguish the practice from euthanasia, rapid inducement of deep unconsciousness is more acceptable to care providers. This is often perceived to be a proportionate response to unbearable suffering in a context where there is also greater pressure to hasten dying from relatives and others. This means that sedation is more likely to be organised like euthanasia, as the end 'moment' is reached, and family farewells are organised before the patient is made unconscious for ever. Medical and nursing practices are partly responses to factors outside the place of care, such as legislation and public sentiment. Dutch guidelines for sedation largely tally with the practices prevalent in the Netherlands and Belgium, in contrast with those produced by the more international European Association for Palliative Care whose authors describe an ethical framework closer to that reportedly used by UK care providers.

Active surveillance for prostate cancer: a systematic review of clinicopathologic variables and biomarkers for risk stratification.

CONTEXT: Active surveillance (AS) is an important strategy to reduce prostate cancer overtreatment. However, the optimal criteria for eligibility and predictors of progression while on AS are debated. OBJECTIVE: To review primary data on markers, genetic factors, and risk stratification for patient selection and predictors of progression during AS. EVIDENCE ACQUISITION: Electronic searches were conducted in PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to April 2014 for original articles on biomarkers and risk stratification for AS. EVIDENCE SYNTHESIS: Patient factors associated with AS outcomes in some studies include age, race, and family history. Multiple studies provide consistent evidence that a lower percentage of free prostate-specific antigen (PSA), a higher Prostate Health Index (PHI), a higher PSA density (PSAD), and greater biopsy core involvement at baseline predict a greater risk of progression. During follow-up, serial measurements of PHI and PSAD, as well as repeat biopsy results, predict later biopsy progression. While some studies have suggested a univariate relationship between urinary prostate cancer antigen 3 (PCA3) and transmembrane protease, serine 2-v-ets avian erythroblastosis virus E26 oncogene homolog gene fusion (TMPRSS2:ERG) with adverse biopsy features, these markers have not been consistently shown to independently predict AS outcomes. No conclusive data support the use of genetic tests in AS. Limitations of these studies include heterogeneous definitions of progression and limited follow-up. CONCLUSIONS: There is a growing body of literature on patient characteristics, biopsy features, and biomarkers with potential utility in AS. More data are needed on practical applications such as combining these tests into multivariable clinical algorithms and long-term outcomes to further improve AS in the future. PATIENT SUMMARY: Several PSA-based tests (free PSA, PHI, PSAD) and the extent of cancer on biopsy can help to stratify the risk of progression during active surveillance. Investigation of several other markers is under way.

Risk factors for complicated grief in older adults.

BACKGROUND: Older adults grieving the death of a spouse have been found to have a higher risk of complicated grief compared with younger adults. OBJECTIVE: The study objective was to find out whether personal characteristics of the patient and the bereaved partner, or characteristics of the patient's illness, end-of-life care, and the nature of death are risk factors for complicated grief in older adults. METHODS: We performed a nested case-control study within the Rotterdam Study. We selected 100 couples of which one person had deceased and the other person experienced "complicated grief," and 100 control couples of which one person had deceased and the other person experienced "normal grief." Complicated grief was assessed with a 17-item Inventory of Complicated Grief (ICG). Determinants were assessed using several sources of information that were available for all participants of the Rotterdam Study. Additionally, medical files of the deceased were manually screened. Logistic regression analysis was performed. RESULTS: Only depression at baseline was significantly associated with complicated grief. Bereaved partners with depression at baseline had a higher risk of complicated grief compared to bereaved partners without depression (OR=3.48; 95% CI=1.40-8.68). CONCLUSIONS: Our results suggest that complicated grief in older adults is not clearly related to the circumstances of dying of the deceased partner. Preexisting conditions such as depression seem to be more important in explaining the occurrence of complicated grief.

Palliative sedation: a focus group study on the experiences of relatives.

BACKGROUND: Most studies that have investigated the practice of palliative sedation have focused on physicians' practices and attitudes. OBJECTIVE: The aim of this study was to explore relatives' experiences with palliative sedation and to gain more insight in positive and negative elements in their evaluation of palliative sedation. DESIGN: Focus groups and individual interviews. SETTING: Various care settings in the Netherlands. SUBJECTS: A total of 14 relatives of patients who received palliative sedation until death participated. RESULTS: Most relatives evaluated the provision of palliative sedation of their dying family member positively. Positive experiences were related to: the beneficial impact of palliative sedation on the patient's suffering, the opportunity that was offered to prepare for the patient's death, their involvement in the decision-making and care for the patient, and the pleasant care environment. However, the majority of the relatives were unsatisfied with one or more aspects of how information was being provided for. Some relatives were frustrated about the fact that nurses were not authorized to make decisions about the care for the patient and about the absence of physicians during weekends. None of the relatives mentioned the loss of the ability to communicate with the patient during the sedation and the possibility of "hastening death" as disadvantages of palliative sedation. CONCLUSION: Relatives tend to evaluate the provision of palliative sedation to their severely suffering family member positively because it contributes to a peaceful dying process. However, relatives indicated discontent with how information was being provided and with the communication in general.

The experiences of relatives with the practice of palliative sedation: a systematic review.

CONTEXT: Guidelines about palliative sedation typically include recommendations to protect the well-being of relatives. OBJECTIVES: The aim of this study was to systematically review evidence on the experiences of relatives with the practice of palliative sedation. METHODS: PubMed, Embase, Web of Science, PsycINFO, and CINAHL were searched for empirical studies on relatives' experiences with palliative sedation. We investigated relatives' involvement in the decision-making and sedation processes, whether they received adequate information and support, and relatives' emotions. RESULTS: Of the 564 studies identified, 39 were included. The studies (30 quantitative, six qualitative, and three mixed methods) were conducted in 16 countries; three studies were based on relatives' reports, 26 on physicians' and nurses' proxy reports, seven on medical records, and three combined different sources. The 39 studies yielded a combined total of 8791 respondents or studied cases. Caregivers involved relatives in the decision making in 69%-100% of all cases (19 quantitative studies), and in 60%-100% of all cases, relatives were reported to have received adequate information (five quantitative studies). Only two quantitative studies reported on relatives' involvement in the provision of sedation. Despite the fact that the majority of relatives were reported to be comfortable with the use of palliative sedation (seven quantitative studies, four qualitative studies), several studies found that relatives were distressed by the use of sedation (five quantitative studies, five qualitative studies). No studies reported specifically about the support provided to the relatives. CONCLUSION: Relatives' experiences with palliative sedation are mainly studied from the perspective of proxies, mostly professional caregivers. The majority of relatives seems to be comfortable with the use of palliative sedation; however, they may experience substantial distress by the use of sedation.