Revised European Association for Palliative Care (EAPC) recommended framework on palliative sedation: An international Delphi study.

BACKGROUND: The European Association for Palliative Care (EAPC) acknowledges palliative sedation as an important, broadly accepted intervention for patients with life-limiting disease experiencing refractory symptoms. The EAPC therefore developed 2009 a framework on palliative sedation. A revision was needed due to new evidence from literature, ongoing debate and criticism of methodology, terminology and applicability. AIM: To provide evidence- and consensus-based guidance on palliative sedation for healthcare professionals involved in end-of-life care, for medical associations and health policy decision-makers. DESIGN: Revision between June 2020 and September 2022 of the 2009 framework using a literature update and a Delphi procedure. SETTING: European. PARTICIPANTS: International experts on palliative sedation (identified through literature search and nomination by national palliative care associations) and a European patient organisation. RESULTS: A framework with 42 statements for which high or very high level of consensus was reached. Terminology is defined more precisely with the terms suffering used to encompass distressing physical and psychological symptoms as well as existential suffering and refractory to describe the untreatable (healthcare professionals) and intolerable (patient) nature of the suffering. The principle of proportionality is introduced in the definition of palliative sedation. No specific period of remaining life expectancy is defined, based on the principles of refractoriness of suffering, proportionality and independent decision-making for hydration. Patient autonomy is emphasised. A stepwise pharmacological approach and a guidance on hydration decision-making are provided. CONCLUSIONS: This is the first framework on palliative sedation using a strict consensus methodology. It should serve as comprehensive and soundly developed information for healthcare professionals.

A critical appraisal of the four systematic reviews and meta-analysis on stereotactic body radiation therapy versus external beam radiotherapy for painful bone metastases and where we go from here.

Radiotherapy is an important treatment modality for pain control in patients with bone metastases. Stereotactic body radiation therapy (SBRT), which allows delivering a much higher dose per fraction while sparing critical structures compared to conventional external beam radiotherapy (cEBRT), has become more widely used, especially in the oligometastatic setting. Randomized controlled trials (RCTs) comparing the pain response rate of SBRT and cEBRT for bone metastases have shown conflicting results, as have four recent systematic reviews with meta-analyses of these trials. Possible reasons for the different outcomes between these reviews include differences in methodology, which trials were included, and the endpoints examined and how they were defined. We suggest ways to improve analysis of these RCTs, particularly performing an individual patient-level meta-analysis since the trials included heterogeneous populations. The results of such studies will help guide future investigations needed to validate patient selection criteria, optimize SBRT dose schedules, include additional endpoints (such as the time to onset of pain response, durability of pain response, quality of life (QOL), and side effects of SBRT), and better assess the cost-effectiveness and trade-offs of SBRT compared to cEBRT. An international Delphi consensus to guide selection of optimal candidates for SBRT is warranted before more prospective data is available.

Appropriateness of the 30-day expected mortality metric in palliative radiation treatment: a narrative review.

BACKGROUND AND OBJECTIVE: The 30-day expected mortality rate is frequently used as a metric to determine which patients benefit from palliative radiation treatment (RT). We conducted a narrative review to examine whether its use as a metric might be appropriate for patient selection. METHODS: A literature review was conducted to identify relevant studies that highlight the benefits of palliative RT in timely symptom management among patients with a poor performance status, the accuracy of predicting survival near the end of life and ways to speed up the process of RT administration through rapid response clinics. KEY CONTENT AND FINDINGS: Several trials have demonstrated substantial response rates for pain and/or bleeding by four weeks and sometimes within the first two weeks after RT. Models of patient survival have limited accuracy, particularly for predicting whether patients will die within the next 30 days. Dedicated Rapid Access Palliative RT (RAPRT) clinics, in which patients are assessed, simulated and treated on the same day, reduce the number of patient visits to the radiation oncology department and hence the burden on the patient as well as costs. CONCLUSIONS: Single-fraction palliative RT should be offered to eligible patients if they are able to attend treatment and could potentially benefit from symptom palliation, irrespective of predicted life expectancy. We discourage the routine use of the 30-day mortality as the only metric to decide whether to offer RT. More common implementation of RAPRT clinics could result in a significant benefit for patients of all life expectancies, but particularly those having short ones.

Monitoring the clinical practice of palliative sedation (PALSED) in patients with advanced cancer: an international, multicentre, non-experimental prospective observational study protocol.

BACKGROUND: Palliative sedation involves the intentional lowering of consciousness at the end of life. It can be initiated to relieve a patient's burden caused by refractory symptoms at the end of life. The impact of palliative sedation needs to be clinically monitored to adjust the proper dose and regimen of sedative medication to ensure that patients are at ease and comfortable at the end of their lives. Although there is consensus among health care professionals and within guidelines that efficacy of palliative sedation needs to be closely monitored, there is no agreement about how, when, and by whom, this monitoring should be performed. The aim of this study is to evaluate the effects of palliative sedation by measuring the discomfort levels and sedation/agitation levels of the patients at regular timepoints. In addition, the clinical trajectories of those patients receiving palliative sedation will be monitored and recorded. METHODS: The study is an international prospective non-experimental observational multicentre study. Patients are recruited from in-patient palliative care settings in Belgium, Germany, Italy, Spain and the Netherlands. Adult patients with advanced cancer are monitored by using proxy observations of discomfort (DS-DAT) and depth of sedation/agitation levels (RASS-PAL) during palliative sedation. After the palliative sedation period, the care for the specific participant case is evaluated by one of the attending health care professionals and one relative via a questionnaire. DISCUSSION: This study will be the first international prospective multicenter study evaluating the clinical practice of palliative sedation including observations of discomfort levels and levels of sedation. It will provide valuable information about the practice of palliative sedation in European countries in terminally ill cancer patients. Results from this study will facilitate the formulation of recommendations for clinical practice on how to improve monitoring and comfort in patients receiving palliative sedation. TRIAL REGISTRATION: This study is registered at Clinicaltrials.gov since January 22, 2021, registration number: NCT04719702.

Ethics of sedation for existential suffering: palliative medicine physician perceptions - qualitative study.

OBJECTIVES: Palliative sedation for existential suffering (PS-ES) is considered a controversial practice to control refractory suffering at the end of life. This study aims to explore Belgian palliative care physicians' perceptions regarding the ethics of PS-ES. METHODS: This nationwide qualitative study follows a Grounded Theory approach. We conducted semistructured interviews with 25 palliative care physicians working in 23 Belgian hospitals and hospices (Flanders, Brussels, Wallonia). We analysed the data using the Qualitative Analysis Guide Of Leuven and we followed the Consolidated Criteria for Reporting Qualitative Research guidelines. RESULTS: The data revealed that Belgian palliative care physicians have difficulty characterising ES and distinguishing it from other types of suffering. They express mixed attitudes towards PS-ES and employ a wide range of ethical arguments in favour and against it, which are mainly linked to the four principles of biomedical ethics. CONCLUSION: Since there is a lack of consensus among Belgian palliative care physicians about PS-ES, further research is needed to clarify their attitudes. A better understanding of physicians' underlying presuppositions can provide more insight into their perceptions of ES and PS-ES and provide further insight for establishing good practices in ES management at the end of life.

Regulations on palliative sedation: an international survey across eight European countries.

BACKGROUND: Palliative sedation is a commonly accepted medical practice. This study aims to clarify how palliative sedation is regulated in various countries and whether this may impact its practice. METHODS: An online survey requesting regulations on palliative sedation was conducted in Belgium, Germany, Hungary, Italy, The Netherlands, Spain, Romania and the UK. Purposive sampling strategy was used to identify clinicians from different medical fields and legal experts for each country. Regulations were analyzed using the principles of the European Association for Palliative Care Framework on palliative sedation. Country reports describing how palliative sedation is regulated were elaborated. RESULTS: One hundred and thirty-nine out of 223 (62%) participants identified 31 laws and other regulations affecting palliative sedation. In Spain, 12 regional laws recognize palliative sedation as a right of the patient at the end of life when there are refractory symptoms. In Italy, the law of informed consent and advance directives specifically recognizes the doctor can use deep sedation when there are refractory symptoms. There are also general medical laws that, while not explicitly referring to palliative sedation, regulate sedation-related principles: the obligation of doctors to honour advance directives, informed consent, the decision-making process and the obligation to document the whole process. In Germany, the Netherlands and the UK, palliative sedation is also regulated through professional guidelines that are binding as good practice with legal significance. CONCLUSIONS: Palliative sedation is considered in the general law of medical practice, in laws regarding the patient's autonomy, and through professional guidelines.

Review of European Guidelines on Palliative Sedation: A Foundation for the Updating of the European Association for Palliative Care Framework.

In 2009, the European Association for Palliative Care (EAPC) developed a framework on palliative sedation, acknowledging this practice as an important and ethically acceptable intervention of last resort for terminally ill patients experiencing refractory symptoms. Before and after that, other guidelines on palliative sedation have been developed in Europe with variations in terminology and concepts. As part of the Palliative Sedation project (Horizon 2020 Funding No. 825700), a revision of the EAPC framework is planned. The aim of this article is to analyze the most frequently used palliative sedation guidelines as reported by experts from eight European countries to inform the discussion of the new framework. The three most reported documents per country were identified through an online survey among 124 clinical experts in December 2019. Those meeting guideline criteria were selected. Their content was assessed against the EAPC framework on palliative sedation. The quality of their methodology was evaluated with the Appraisal Guideline Research and Evaluation (AGREE) II instrument. Nine guidelines were included. All recognize palliative sedation as a last-resort treatment for refractory symptoms, but the criterion of refractoriness remains a matter of debate. Most guidelines recognize psychological or existential distress as (part of) an indication and some make specific recommendations for such cases. All agree that the assessment should be multiprofessional, but they diverge on the expertise required by the attending physician/team. Regarding decisions on hydration and nutrition, it is proposed that these should be independent of those for palliative sedation, but there is no clear consensus on the decision-making process. Several weaknesses were highlighted, particularly in areas of rigor of development and applicability. The identified points of debate and methodological weaknesses should be considered in any update or revision of the guidelines analyzed to improve the quality of their content and the applicability of their recommendations.

ESTRO ACROP guidelines for external beam radiotherapy of patients with complicated bone metastases.

This is the second part of the guidelines on the management of bone metastases. In the first part, the diagnosis and management of uncomplicated bone metastases have been addressed. Bone metastases may significantly reduce quality of life due to related symptoms and possible complications. The most common symptoms include pain and neurologic deficits. The most serious complications of bone metastases are skeletal-related events (SRE), defined as pathologic fracture, spinal cord compression, pain, or other symptoms requiring an urgent intervention such as surgery or radiotherapy. Diffuse bone metastases may lead to hypercalcaemia that can be fatal if untreated. The growing access to modern diagnostic tools allows early detection of asymptomatic bone metastases that could be successfully managed with local treatment if oligometastatic or systemic treatment for diffuse bone metastases to try to avoid the development of SRE.

ESTRO ACROP guidelines for external beam radiotherapy of patients with uncomplicated bone metastases.

After liver and lungs, bone is the third most common metastatic site (Nystrom et al., 1977). Almost all malignancies can metastasize to the skeleton but 80% of bone metastases originate from breast, prostate, lung, kidney and thyroid cancer (Mundy, 2002). Introduction of effective systemic treatment in many cancers has prolonged patients' survival, including those with bone metastases. Bone metastases may significantly reduce quality of life due to related symptoms and possible complications, such as pain and neurologic compromise. The most serious complications of bone metastases are skeletal-related events (SRE), defined as pathologic fracture, spinal cord compression, pain, or other symptoms requiring an urgent intervention such as surgery or radiotherapy. In turn, growing access to modern diagnostic tools allows early detection of asymptomatic bone metastases that could be successfully managed with local treatment avoiding development of SRE. The treatment for bone metastases should focus on relieving existing symptoms and preventing new ones. Radiotherapy is the standard of care for patients with symptomatic bone metastases, providing durable pain relief with minimal toxicity and reasonable cost-effectiveness. Historically, the dose was prescribed in one to five fractions and delivered using simple planning techniques. While 3D-conformal radiotherapy is still widely used for treating bone metastases, introduction of highlyconformal radiotherapy techniques such as stereotactic body radiotherapy (SBRT) have opened new therapeutic possibilities that should be considered in selected patients with bone metastases.

Corrigendum to: Impact of lymphopenia on survival for elderly patients with glioblastoma: A secondary analysis of the CCTG CE.6 (EORTC 26062-22061, TROG 08.02) randomized clinical trial.

[This corrects the article DOI: 10.1093/noajnl/vdab153.].

The Decision-Making Process for Palliative Sedation for Patients with Advanced Cancer-Analysis from a Systematic Review of Prospective Studies.

BACKGROUND: The involvement of patients in decision making about their healthcare plans is being emphasized. In the context of palliative sedation, it is unclear how these decisions are made and who are involved in. The aim of the study is to understand how this decision-making is taken. METHOD: Information from a systematic review on clinical aspects of palliative sedation prospective studies were included. PubMed, CINAHL, Cochrane, MEDLINE, and EMBASE were searched (January 2014-December 2019). Data extraction and analysis regarded: (a) When and by whom the decision-making process is initiated; (b) patient involvement; (c) family involvement and (d) healthcare involvement. RESULTS: Data about decision making were reported in 8/10 included articles. Palliative sedation was reported in 1137 patients (only 16 of them were non-cancer). Palliative sedation was introduced by the palliative care team during the disease process, at admission, or when patients experienced refractory symptoms. Only two studies explicitly mentioned the involvement of patients in decision making. Co-decision between families and the regular health care professionals was usual, and the health care professionals involved had been working in palliative care services. CONCLUSION: Patient participation in decision making appeared to be compromised by limited physical or cognitive capacity and family participation is described. The possibility of palliative sedation should be discussed earlier in the disease process.

Impact of lymphopenia on survival for elderly patients with glioblastoma: A secondary analysis of the CCTG CE.6 (EORTC 26062-22061, TROG03.01) randomized clinical trial.

BACKGROUND: Lymphopenia may lead to worse outcomes for glioblastoma patients. This study is a secondary analysis of the CCTG CE.6 trial evaluating the impact of chemotherapy and radiation on lymphopenia, and effects of lymphopenia on overall survival (OS). METHODS: CCTG CE.6 randomized elderly glioblastoma patients (≥ 65 years) to short-course radiation alone (RT) or short-course radiation with temozolomide (RT + TMZ). Lymphopenia (mild-moderate: grade 1-2; severe: grade 3-4) was defined per CTCAE v3.0, and measured at baseline, 1 week and 4 weeks post-RT. Preselected key factors for analysis included age, sex, ECOG, resection extent, MGMT methylation, Mini-Mental State Examination, and steroid use. Multinomial logistic regression and multivariable Cox regression models were used to identify lymphopenia-associated factors and association with survival. RESULTS: Five hundred and sixty-two patients were analyzed (281 RT vs 281 RT+TMZ). At baseline, both arms had similar rates of mild-moderate (21.4% vs 21.4%) and severe (3.2% vs 2.9%) lymphopenia. However, at 4 weeks post-RT, RT+TMZ was more likely to develop lymphopenia (mild-moderate: 27.9% vs 18.2%; severe: 9.3% vs 1.8%; p<0.001). Developing any lymphopenia post-RT was associated with baseline lymphopenia (P < .001). Baseline lymphopenia (hazard ratio [HR] 1.3) was associated with worse OS (HR: 1.30, 95% confidence interval [CI] 1.05-1.62; P = .02), regardless of MGMT status. CONCLUSIONS: Development of post-RT lymphopenia is associated with addition of TMZ and baseline lymphopenia and not with RT alone in patients treated with short-course radiation. However, regardless of MGMT status, only baseline lymphopenia is associated with worse OS, which may be considered as a prognostic biomarker for elderly glioblastoma patients.

Stroke rate after external fractionated radiotherapy for benign meningioma.

PURPOSE: Patients with a benign meningioma often have a long survival following the treatment of their meningioma. Since radiotherapy is frequently part of the treatment, long-term side effects are of considerable concern. A controversial long-term side effect of radiotherapy is stroke. Due to its severity, it is important to know the frequency of this side effect. The aim of this study was to assess the stroke incidence and risk factors among patients receiving radiotherapy for their benign meningioma. METHODS: We performed a retrospective database study of patients who underwent primary or adjuvant radiotherapy for their benign meningioma at University Hospitals Leuven from January 2003 to December 2017. RESULTS: We included 169 patients with a median age of 51 years (range 22-84). Every patient received fractionated radiotherapy using photons with a median dose of 56 Gy (range 54-56) in fractions of 2 Gy (range 1.8-2). The median follow-up was 5.3 years (range 0.1-14). The cumulative stroke incidence function showed an incidence of 11.6% after 9 years of follow-up, translating to a stroke incidence per year of 1.29%. We found two significant risk factors for stroke: medically treated arterial hypertension (p = 0.005) and history of previous stroke or transient ischemic attack (p < 0.001). 5-year local control and overall survival rates were respectively 97.4% and 91.2%. Other late grade III/IV toxicities occurred in 16.0% (27/169) of patients. CONCLUSION: Our study shows a higher incidence of stroke in patients who received radiotherapy for their benign meningioma compared to the general population.

Clinical Aspects of Palliative Sedation in Prospective Studies. A Systematic Review.

CONTEXT: Near the end of life when patients experience refractory symptoms, palliative sedation may be considered as a last treatment. Clinical guidelines have been developed, but they are mainly based on expert opinion or retrospective chart reviews. Therefore, evidence for the clinical aspects of palliative sedation is needed. OBJECTIVES: To explore clinical aspects of palliative sedation in recent prospective studies. METHODS: Systematic review was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and registered at PROSPERO. PubMed, CINAHL, Cochrane, MEDLINE, and EMBASE were searched (January 2014-December 2019), combining sedation, palliative care, and prospective. Article quality was assessed. RESULTS: Ten prospective articles were included, involving predominantly patients with cancer. Most frequently reported refractory symptoms were delirium (41%-83%), pain (25%-65%), and dyspnea (16%-59%). In some articles, psychological and existential distress were mentioned (16%-59%). Only a few articles specified the tools used to assess symptoms. Level of sedation assessment tools were the Richmond Agitation Sedation Scale, Ramsay Sedation Scale, Glasgow Coma Scale, and Bispectral Index monitoring. The palliative sedation practice shows an underlying need for proportionality in relation to symptom intensity. Midazolam was the main sedative used. Other reported medications were phenobarbital, promethazine, and anesthetic medication-propofol. The only study that reported level of patient's discomfort as a palliative sedation outcome showed a decrease in patient discomfort. CONCLUSION: Assessment of refractory symptoms should include physical evaluation with standardized tools applied and interviews for psychological and existential evaluation by expert clinicians working in teams. Future research needs to evaluate the effectiveness of palliative sedation for refractory symptom relief.

What Is Good Advance Care Planning According to Hospitalized Palliative Patients and Their Families? An Explorative Study.

BACKGROUND: Advance care planning is not well implemented in Belgian hospital practice. In order to obtain successful implementation, implementation theory states that the adopters should be involved in the implementation process. This information can serve as a basis for creating better implementation strategies. AIM: For this study, we asked hospitalized palliative patients and their families what they experienced as good advance care planning. METHODS: Twenty-nine interviews were taken from patients and families, following the Tape Assisted Recall procedure of Elliot. These interviews were analyzed using content analysis based on grounded theory. To improve reliability, 3 independent external auditors audited the analysis. RESULTS: Results show that hospitalized palliative patients and families want to have advance care planning communication about treatment and care throughout their disease and about different aspects: social, psychological, physical, practical, and medical. They prefer to have these conversations with their supervising physician. They report 4 important goals of advance care planning communication: establishing a trustful relationship with the physician, in which they feel the involvement of the physician; giving and receiving relevant information for the decision process, making a personal decision about which treatment and care are preferred; and finding consensus between the preferred decision of the physician, the patient and the family concerning the treatment and care policy. CONCLUSION: This study can contribute to advance care planning implementation in hospital practice because it gives in insight into which elements in advance care planning patients and families experience as necessary and when advance care planning is necessary to them.

Temozolomide and seizure outcomes in a randomized clinical trial of elderly glioblastoma patients.

INTRODUCTION: Tumor-related epilepsy may respond to chemotherapy. In a previously-published multi-centre randomized clinical trial of 562 elderly glioblastoma patients, temozolomide plus short-course radiotherapy conferred a survival benefit over radiotherapy alone. Seizure outcomes were not reported. METHODS: We performed an unplanned secondary analysis of this trial's data. The trial design has been previously reported. Seizures were recorded by clinicians as adverse events and by patients in quality of life questionnaires. A Chi-square test of seizure rates between the two groups (α = 0.05) and a Kaplan-Meier estimator of time-to-first self-reported seizure were planned. RESULTS: Almost all patients were followed until they died. In the radiotherapy alone group, 68 patients (24%) had a documented or self-reported seizure versus 83 patients (30%) in the temozolomide plus radiotherapy group, Chi-square analysis showed no difference (p = 0.15). Patients receiving radiotherapy alone tended to develop seizures earlier than those receiving temozolomide plus radiotherapy (p = 0.054). Patients with seizures had shorter overall survival than those without seizures (hazard ratio 1.24, p = 0.02). CONCLUSIONS: This study was not powered to detect differences in seizure outcomes, but temozolomide seemed to have minimal impact on seizure control in elderly patients with glioblastoma. CLINICAL TRIAL REGISTRATION: NCT00482677 2007-06-05.

Physicians' perceptions of palliative sedation for existential suffering: a systematic review.

BACKGROUND: Palliative sedation for existential suffering (PS-ES) is a controversial clinical intervention. Empirical studies about physicians' perceptions do not converge in a clear position and current clinical practice guidelines do not agree either regarding this kind of intervention. AIM: To gain deeper insight into physicians' perceptions of PS-ES, the factors influencing it, the conditions for implementing it and the alternatives to it. DESIGN: Systematic review of qualitative, quantitative and mixed-methods studies following the Peer Review Electronic Search Strategies and Preferred Reporting Items for Systematic Reviews and Meta-analyses protocols; quality appraisal and thematic synthesis methodology. DATA SOURCES: Seven electronic databases (PubMed, CINAHL, Embase, Scopus, Web of Science, PsycINFO, PsycARTICLES) were exhaustively searched from inception through March 2019. Two reviewers screened paper titles, abstracts and full texts. We included only peer-reviewed journal articles published in English, French, German, Dutch, Spanish, Italian or Portuguese that focused on physicians' perceptions of PS-ES. RESULTS: The search yielded 17 publications published between 2002 and 2017. Physicians do not hold clear views or agree if and when PS-ES is appropriate. Case-related and individual-related factors that influenced physicians' perceptions were identified. There is still no consensus regarding criteria to distinguish between necessary and sufficient conditions for invoking PS-ES. Some alternatives to PS-ES were identified. CONCLUSIONS: To date, there is still no consensus on physicians' perceptions of PS-ES. Further research is necessary to understand factors that influence physicians' perceptions and philosophical-ethical presuppositions underlying this perceptions.

'We need a physician who is a human being too': exploration of barriers and facilitators for hospitalised palliative patients and their families to discuss advance care planning.

BACKGROUND: Advance care planning (ACP) is not well implemented in hospital. Implementation theory stresses the importance of knowing what hospitalised palliative patients and their families experience as barriers or as facilitators in the uptake of ACP with their treating physician. AIMS: This study aimed to gain an in-depth understanding of what hospitalised palliative patients and their families experienced as barriers or facilitators for having ACP conversations. METHODS: We used a tape-assisted recall procedure to conduct 29 videotaped interviews with hospitalised patients and their families. We used content analysis based on grounded theory principles. RESULTS: Four major fields of tension were discovered: not knowing what to expect from the treating physician; not being sure the treating physician can be a trusted partner; daring to speak about ACP; and staying loyal to one's own wishes. CONCLUSIONS: Patients and families need physicians who are accessible and can be trusted ACP partners throughout the disease process.