Improving Care for Patients Living with Prolonged Incurable Cancer

SIMPLE SUMMARY: Not all patient with cancer can be cured. However, some patients with incurable cancer may expect to live for a substantial period of time. The number of patients in this group is increasing. These patients with ‘prolonged incurable cancer’ are often overlooked in research and clinical practice. They may have questions related to palliative care (e.g., about the end of life) and related to survivorship care (e.g., about late treatment effects). By itself, a palliative or survivorship perspective may therefore be insufficient to cover the wide range of physical and psychosocial problems that patients with prolonged incurable cancer encounter. Elements from both fields should therefore be delivered concordantly. This proposed new care model can further optimize care pathways for these patients. Furthermore, enhanced clinical awareness for this patient population as well as further research are urgently needed. ABSTRACT: The number of patients that can no longer be cured but may expect to live with their cancer diagnosis for a substantial period is increasing. These patients with ‘prolonged incurable cancer’ are often overlooked in research and clinical practice. Patients encounter problems that are traditionally seen from a palliative or survivorship perspective but this may be insufficient to cover the wide range of physical and psychosocial problems that patients with prolonged incurable cancer may encounter. Elements from both fields should, therefore, be delivered concordantly to further optimize care pathways for these patients. Furthermore, to ensure future high-quality care for this important patient population, enhanced clinical awareness, as well as further research, are urgently needed

Awareness of dying: it needs words

Purpose: The purpose of this research is to study to what extent dying patients are aware of the imminence of death, whether such awareness is associated with patient characteristics, symptoms and acceptance of dying, and whether medical records and nurses' and family caregivers' views on patients' awareness of dying agree. Methods: Nurses and family caregivers of 475 deceased patients from three different care settings in the southwest Netherlands were requested to fill out questionnaires. The two groups were asked whether a patient had been aware of the imminence of death. Also, medical records were screened for statements indicating that the patient had been informed of the imminence of death. Results: Nurses completed questionnaires about 472 patients, family caregivers about 280 patients (response 59%). According to the medical records, 51% of patients had been aware of the imminence of death; according to nurses, 58%; according to family caregivers, 62%. Patients who, according to their family caregiver, had been aware of the imminence of death were significantly more often in peace with dying and felt more often that life had been worth living. Inter-rater agreement on patients' awareness of dying was fair (Cohen's kappa = 0.23-0.31). Conclusions: Being aware of dying is associated with acceptance of dying, which supports the idea that open communication in the dying phase can contribute to the quality of the dying process. However, views on whether or not patients are aware of the imminence of death diverge between different caregivers. This suggests that communication in the dying phase of patients is open for improvement

Improving the quality of palliative and terminal care in the hospital by a network of palliative care nurse champions: the study protocol of the PalTeC-H project

BACKGROUND: The quality of care of patients dying in the hospital is often judged as insufficient. This article describes the protocol of a study to assess the quality of care of the dying patient and the contribution of an intervention targeted on staff nurses of inpatient wards of a large university hospital in the Netherlands. METHODS/DESIGN: We designed a controlled before and after study. The intervention is the establishment of a network for palliative care nurse champions, aiming to improve the quality of hospital end-of-life care. Assessments are performed among bereaved relatives, nurses and physicians on seven wards before and after introduction of the intervention and on 11 control wards where the intervention is not applied. We focus on care provided during the last three days of life, covered in global ratings of the quality of life in the last three days of life and the quality of dying, and various secondary endpoints of treatment and care affecting quality of life and dying. DISCUSSION: With this study we aim to improve the understanding of and attention for patients’ needs, and the quality of care in the dying phase in the hospital and measure the impact of a quality improvement intervention targeted at nurses

Role of intestinal P-glycoprotein in the plasma and fecal disposition of docetaxel in humans

Multidrug resistance (MDR)-1-P-glycoprotein (P-gp) is a drug-transporting protein that is abundantly present in biliary ductal cells and epithelial cells lining the gastrointestinal tract. Here, we have determined the role of P-gp in the metabolic disposition of the antineoplastic agent docetaxel (Taxotere) in humans. Pharmacokinetic profiles were evaluated in five cancer patients receiving treatment cycles with docetaxel alone (100 mg/m2 i.v. over a 1-h period) and in combination with a new potent inhibitor of P-gp activity, R101933 (200-300 mg b.i.d.). The terminal disposition half-life and total plasma clearance of docetaxel were not altered by treatment with oral R101933 (P > or = 0.27). The cumulative fecal excretion of docetaxel, however, was markedly reduced from 8.47 +/- 2.14% (mean +/- SD) of the dose with the single agent to less than 0.5% in the presence of R101933 (P = 0.0016). Levels of the major cytochrome P450 3A4-mediated metabolites of docetaxel in feces were significantly increased after combination treatment with R101933 (P = 0.010), indicating very prominent and efficient detoxification of reabsorbed docetaxel into hydroxylated compounds before reaching the systemic circulation. It is concluded that intestinal P-gp plays a principal role in the fecal elimination of docetaxel by modulating reabsorption of the drug after hepatobiliary secretion. In addition, the results indicate that inhibition of P-gp activity in normal tissues by effective modulators, and the physiological and pharmacological consequences of this treatment, cannot be predicted based on plasma drug monitoring alone

Scopolaminebutyl given prophylactically for death rattle: Study protocol of a randomized double-blind placebo-controlled trial in a frail patient population (the SILENCE study)

Background: Death rattle (DR), caused by mucus in the respiratory tract, occurs in about half of patients who are in the dying phase. Relatives often experience DR as distressing. Anticholinergics are recommended to treat DR, although there is no evidence for the effect of these drugs. Anticholinergic drugs decrease the production of mucus but do not affect existing mucus. We therefore hypothesize that these drugs are more effective when given prophylactically. Methods: We set up a randomized double-blind, placebo-controlled, multi-center study evaluating the efficacy of prophylactically given subcutaneous scopolaminebutyl for the prevention of DR in the dying phase. The primary outcome is the occurrence of DR defined as grade ≥ 2 according to the scale of Back measured by a nurse at 2 consecutive time points with an interval of 4 h. Secondary outcomes include adverse effects, quality of dying, quality of life in the last three days and bereavement. A sub-study will explore the experience of participating in a clinical trial in the dying phase from the perspective of relatives. Four hospices will include 200 patients. Discussion: This is the first double-blind placebo-controlled study to prevent DR in patients in the hospice setting. Research in dying patients is challenging. We will apply ethical and organizational strategies as suggested in the literature

Cremophor EL-mediated alteration of paclitaxel distribution in human blood: clinical pharmacokinetic implications

We have determined the in vitro and in vivo cellular distribution of the antineoplastic agent paclitaxel (Taxol) in human blood and the influence of Cremophor EL (CrEL), the vehicle used for i.v. drug administration. In the absence of CrEL, the blood:plasma concentration ratio was 1.07+/-0.004 (mean+/-SD). The addition of CrEL at concentrations corresponding to peak plasma levels achieved after the administration of paclitaxel (175 mg/m2 i.v. over a 3-h period; ie., 0.50%) resulted in a significant decrease in the concentration ratio (0.690+/-0.005; P < 0.05). Kinetic experiments revealed that this effect was caused by reduced erythrocyte uptake of paclitaxel by polyoxyethyleneglycerol triricinoleate, the major compound present in CrEL. Using equilibrium dialysis, it was shown that the affinity of paclitaxel for tested matrices was (in decreasing order) CrEL > plasma > human serum albumin, with CrEL present at or above the critical micellar concentration (approximately 0.01%). Our findings in the present study demonstrate a profound alteration of paclitaxel accumulation in erythrocytes caused by a trapping of the compound in CrEL micelles, thereby reducing the free drug fraction available for cellular partitioning. It is proposed that the nonlinearity of paclitaxel plasma disposition in patients reported previously should be reevaluated prospectively by measuring the free drug fractions and whole blood:plasma concentration ratios

High sensitivity assays for docetaxel and paclitaxel in plasma using solid-phase extraction and high-performance liquid chromatography with UV detection

BACKGROUND: The taxanes paclitaxel and docetaxel have traditionally been used in high doses every third week in the treatment of cancer. Lately there has been a trend towards giving weekly low doses to improve the therapeutic index. This article describes the development of high performance liquid chromatographic (HPLC) methods suitable for monitoring taxane levels in patients, focusing on patients receiving low-dose therapy. METHODS: Paclitaxel and docetaxel were extracted from human plasma by solid phase extraction, and detected by absorbance at 227 nm after separation by reversed phase high performance liquid chromatography. The methods were validated and their performance were tested using samples from patients receiving paclitaxel or docetaxel. RESULTS: The limits of quantitation were 1 nM for docetaxel and 1.2 nM for paclitaxel. For both compounds linearity was confirmed from the limit of quantitation up to 1000 nM in plasma. The recoveries ranged between 92% and 118% for docetaxel and between 76% and 104% for paclitaxel. Accuracy and precision were within international acceptance criteria, that is within ± 15%, except at the limit of quantitation where values within ± 20% are acceptable. Low-dose patients included in an on going clinical trial had a median docetaxel concentration of 2.8 nM at 72 hours post infusion. Patients receiving 100 mg/m(2 )of paclitaxel had a mean paclitaxel concentration of 21 nM 48 hours after the end of infusion. CONCLUSION: We have developed an HPLC method using UV detection capable of quantifying 1 nM of docetaxel in plasma samples. The method should be useful for pharmacokinetic determinations at all relevant doses of docetaxel. Using a similar methodology paclitaxel can be quantified down to a concentration of 1.2 nM in plasma with acceptable accuracy and precision. We further demonstrate that the previously reported negative influence of Cremophor EL on assay performance may be overcome by degradation of the detergent by incubation with lipase

A model of open-loop control of equilibrium position and stiffness of the human elbow joint

According to the equilibrium point theory, the control of posture and movement involves the setting of equilibrium joint positions (EP) and the independent modulation of stiffness. One model of EP control, the α-model, posits that stable EPs and stiffness are set open-loop, i.e. without the aid of feedback. The purpose of the present study was to explore for the elbow joint the range over which stable EPs can be set open-loop and to investigate the effect of co-contraction on intrinsic low-frequency elbow joint stiffness (

Efficacy of halopeRIdol to decrease the burden of Delirium In adult Critically ill patiEnts (EuRIDICE): study protocol for a prospective randomised multi-centre double-blind placebo-controlled clinical trial in the Netherlands

Introduction Delirium in critically ill adults is associated with prolonged hospital stay, increased mortality and greater cognitive and functional decline. Current practice guideline recommendations advocate the use of nonpharmacological strategies to reduce delirium. The routine use of scheduled haloperidol to treat delirium is not recommended given a lack of evidence regarding its ability to resolve delirium nor improve relevant short-term and longer-term outcomes. This study aims to evaluate the efficacy and safety of haloperidol for the treatment of delirium in adult critically ill patients to reduce days spent with coma or delirium. Methods and analysis EuRIDICE is a prospective, multicentre, randomised, double-blind, placebo-controlled trial. Study population consists of adult intensive care unit (ICU) patients without acute neurological injury who have delirium based on a positive Intensive Care Delirium Screening Checklist (ICDSC) or Confusion Assessment Method for the ICU (CAM-ICU) assessment. Intervention is intravenous haloperidol 2.5mg (or matching placebo) every 8 hours, titrated daily based on ICDSC or CAMICU positivity to a maximum of 5mg every 8 hours, until delirium resolution or ICU discharge. Main study endpoint is delirium and coma-free days (DCFD) up to 14 days after randomisation. Secondary endpoints include (1) 28-day and 1-year mortality, (2) cognitive and functional performance at 3 and 12 months, (3) patient and family delirium and ICU experience, (4) psychological sequelae during and after ICU stay, (4) safety concerns associated with haloperidol use and (5) cost-effectiveness. Differences in DCFDs between haloperidol and placebo group will be analysed using Poisson regression analysis. Study recruitment started in February 2018 and continues. Ethics and dissemination The study has been approved by the Medical Ethics Committee of the Erasmus University Medical Centre Rotterdam (MEC2017-511) and by the Institutional Review Boards of the participating sites. Its results will be disseminated via peer-reviewed publication and conference presentations

Live well, die well – an international cohort study on experiences, concerns and preferences of patients in the last phase of life: the research protocol of the iLIVE study

Introduction Adequately addressing the needs of patients at the end of life and their relatives is pivotal in preventing unnecessary suffering and optimising their quality of life. The purpose of the iLIVE study is to contribute to high-quality personalised care at the end of life in different countries and cultures, by investigating the experiences, concerns, preferences and use of care of terminally ill patients and their families. Methods and analysis The iLIVE study is an international cohort study in which patients with an estimated life expectancy of 6 months or less are followed up until they die. In total, 2200 patients will be included in 11 countries, that is, 200 per country. In addition, one relative per patient is invited to participate. All participants will be asked to fill in a questionnaire, at baseline and after 4 weeks. If a patient dies within 6 months of follow-up, the relative will be asked to fill in a post-bereavement questionnaire. Healthcare use in the last week of life will be evaluated as well; healthcare staff who attended the patient will be asked to fill in a brief questionnaire to evaluate the care that was provided. Qualitative interviews will be conducted with patients, relatives and healthcare professionals in all countries to gain more in-depth insights. Ethics and dissemination The cohort study has been approved by ethics committees and the institutional review boards (IRBs) of participating institutes in all countries. Results will be disseminated through the project website, publications in scientific journals and at conferences. Within the project, there will be a working group focusing on enhancing the engagement of the community at large with the reality of death and dying. Trial registration number NCT04271085