Sophie Bruinsma

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.

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.

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.

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

BackgroundContinuous 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.MethodsThis 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.ResultsThe 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.ConclusionFindings 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.

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.

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

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.

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.

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

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.

PD28-05 WORLDWIDE VARIATION IN DETERMINANTS FOR INCLUSION AND FOLLOW-UP IN ACTIVE SURVEILLANCE FOR LOW-RISK PROSTATE CANCER: RESULTS OF THE MOVEMBER FOUNDATION’S GLOBAL ACTION PLAN PROSTATE CANCER ACTIVE SURVEILLANCE (GAP3) INITIATIVE

INTRODUCTION AND OBJECTIVES: In August 2014, the Movember Foundation launched the GAP3 initiative, which covers the largest centralized prostate cancer (PCa) active surveillance (AS) database to date. Its primary goal is to create a global consensus on the selection and monitoring of men with low risk PCa. Ultimately, worldwide uniform guidelines will be developed. METHODS: The global database was created by combining patient data from established AS cohorts worldwide. The database contains information on clinical and demographic characteristics at time of PCa diagnosis for all men included in the GAP3 cohort, their clinical follow-up, including information on discontinuation of AS and potential following treatments. Descriptive analyses were performed by a team of statisticians from the five Movember regions around the world (the USA, Canada, Australasia, the UK and Europe). RESULTS: The GAP3 database illustrates variability in inclusion criteria and follow-up on 14,024 patients from 25 centers (Figure 1). At time of diagnosis, median age was 65 yr (IQR 60-70); median PSA was 5.4 ng/ml (IQR 4.0-7.3); median PSA density was 0.12 ng/ml (IQR 0.090.17); and median prostate volume was 44 cc (IQR 33-59). Most men had a clinical stage T1 (71%), a biopsy Gleason score of 6 (87%), one tumor-positive biopsy core (61%) and no comorbidity (64%). Men on AS had a median follow-up time of 2.4 years (IQR 1.1-4.7 years). Maximum follow-up time was 21.3 years. After 5, 10 and 15 years of follow-up, respectively, 57%, 37% and 22% of men were still on AS; 23%, 30% and 35% discontinued due to protocol-based progression (Figure 2). CONCLUSIONS: GAP3 is the largest worldwide data effort to date integrating patient data from men with PCa on AS protocols. The results of GAP3 will allow individual patients and clinicians to have greater confidence in the personalized decision to either delay or proceed with active treatment. Source of Funding: The Movember Foundation.

No Negative Impact of Palliative Sedation on Relatives' Experience of the Dying Phase and Their Wellbeing after the Patient's Death: An Observational Study.

Background Palliative sedation is the widely-used intervention of administering sedating agents to induce a state of unconsciousness to take away a dying patient’s perception of otherwise irrelievable symptoms. However, it remains questionable whether this ethically complex intervention is beneficial for patients and whether the associated lack of communication in the last phase of life has a negative impact on relatives’ wellbeing. Methods An observational questionnaire study was conducted among relatives of a consecutive sample of patients who died a non-sudden death in the Erasmus MC Cancer Institute or in the hospice ‘Laurens Cadenza’ (both in Rotterdam) between 2010 and 2013. Results Relatives filled in questionnaires regarding 151 patients who had been sedated and 90 patients who had not been sedated. The median time since all patients had passed away was 21 (IQR 14–32) months. No significant differences were found in relatives´ assessments of the quality of end-of-life care, patients´ quality of life in the last week before death and their quality of dying, between patients who did and did not receive sedation, or in relatives’ satisfaction with their own life, their general health and their mental wellbeing after the patient’s death. Conclusions The use of sedation in these patients appears to have no negative effect on bereaved relatives’ evaluation of the patient’s dying phase, or on their own wellbeing after the patient’s death.