Patient experiences of randomised placebo-controlled trial participation during end-of-life palliative cancer care.

BACKGROUND: Performing clinical trials in palliative cancer care is known to be challenging. OBJECTIVE: This study aimed to explore how patients with advanced cancer experienced their participation in a randomised, placebo-controlled trial while receiving palliative cancer care at end of life. METHOD: A descriptive design with a qualitative approach was used. 14 patients who had participated in the 'Palliative-D' study were interviewed. Data were analysed using content analysis. RESULTS: Three categories were identified understanding the study design, willingness to participate and collaboration with the research team alongside standard care. Being randomised, with the risk of receiving placebo, was perceived as non-problematic since it was understood as being important for the quality of the research. Patients showed a willingness to participate for the sake of others and also for their own sake, hoping for a cure or at least to live as long as possible. Patients felt proud of being useful and contributing to research. Consent to participate was made autonomously without discussing with others. Patients considered the study design uncomplicated and well-integrated into the standard care. CONCLUSION: Study participation in a randomised, placebo-controlled trial can be a positive and meaningful experience for patients despite advanced cancer in end of life. Participation may support patients' autonomy and give hope, and therefore, might have a positive effect on quality of life. A carefully planned and simple study design, well integrated into standard care, can facilitate the feasibility of clinical studies in specialised palliative home care.

Methylphenidate for treating fatigue in palliative cancer care - effect and side effects in real-world data from a palliative care unit.

BACKGROUND: Methylphenidate can be used for the treatment of cancer-related fatigue (CRF), although randomized controlled trials have shown conflicting results. The aim of this study was to use 'real-world' data to evaluate the effect and side effects of using methylphenidate in palliative cancer care with a focus on the late palliative phase and dose-response. METHOD: A retrospective review of medical records from a palliative care unit in Sweden was performed to evaluate the effect and adverse events (AEs) of using methylphenidate to treat CRF. Univariable and multivariable regression was performed and odds ratio (OR) calculated. Adjustments were made for sex, age, cancer type, dose and starting treatment <4 weeks before death. RESULTS: Of the 2,419 screened patients, 112 had been treated with methylphenidate for CRF. The treatment was assessed as being effective in 51 patients (46%). Twenty-six patients (23%) experienced AEs that were generally mild, including anxiety, palpitations, and insomnia. Patients starting the treatment <4 weeks before death (n = 54) were less likely to have an effect from treatment compared to those starting earlier; adjusted OR 0.24 (95% CI 0.10-0.55). Doses of 20 mg and above were well-tolerated and had a higher frequency of effect in the crude data but not after adjustment for confounding factors. CONCLUSION: Methylphenidate is generally effective and well-tolerated for the treatment of CRF in palliative care. However, patients with a short life expectancy (<4 weeks) seem to benefit less from the treatment regardless of age, cancer type and dose.

Appetite and its association with mortality in patients with advanced cancer - a Post-hoc Analysis from the Palliative D-study.

BACKGROUND: Loss of appetite is a common nutrition symptom in patients with cancer. Understanding the trajectory of appetite could be of clinical use for prognostication in palliative cancer care. Our primary aim was to explore the association between self-assessed appetite and mortality in patients suffering from advanced cancer. Secondary aims included the relation between fatigue, albumin levels and CRP/albumin ratio and mortality. We also aimed to study potential sex-differences in the associations. METHODS: Post-hoc analyses were performed using data from the Palliative D-study comprising 530 patients with cancer admitted to palliative care. Appetite and fatigue were assessed with the Edmonton Symptom Assessment System (ESAS). Cox proportional hazards models were used to calculate Hazard ratios (HR) with 95% confidence intervals (CI) for exposures of appetite, fatigue, albumin and CRP/albumin ratio, and time from study inclusion to death or censoring. Analyses were also performed stratified by sex. RESULTS: The follow-up time ranged between 7 to 1420 days. Moderate and poor appetite were significantly associated with a higher mortality rate compared to reporting a good appetite; HR 1.44 (95%CI: 1.16-1.79) and HR 1.78 (95%CI: 1.39-2.29), respectively. A higher mortality rate was also seen among participants reporting severe fatigue compared to those reporting no fatigue; HR 1.84 (95%CI:1.43-2.36). Participants with low albumin levels (< 25 g/L) and those in the highest tertile of CRP/albumin ratio, had higher mortality rates, HR 5.35 (95%CI:3.75-7.63) and HR 2.66 (95%CI:212-3.35), compared to participants with high albumin levels (> 36 g/L) and those in lowest tertile of CRP/albumin ratio. These associations were more pronounced in men than in women. CONCLUSION: Poor appetite, severe fatigue, low albumin level and a high CRP/albumin ratio were associated with increased mortality rates among patients with advanced cancer. All these variables might be clinically useful for prognostication in palliative cancer care. TRIAL REGISTRATION: Clinicaltrial.gov. Identifier: NCT03038516;31, January 2017.

Appetite in Palliative Cancer Patients and Its Association with Albumin, CRP and Quality of Life in Men and Women-Cross-Sectional Data from the Palliative D-Study.

Albumin is an important biochemical marker in palliative cancer care, used for assessment of nutritional status, disease severity and prognosis. Our primary aim was to investigate sex differences in the association between appetite and albumin levels in palliative cancer patients. We also aimed to study associations between appetite and C-reactive protein (CRP), Quality of Life (QoL), pain and fatigue. In the Palliative D-cohort, consisting of 266 men and 264 women, we found a correlation between appetite and albumin; low appetite, measured with the Edmonton Symptom Assessment System, correlated significantly with low albumin in men: (r = -0.33, p < 0.001), but not in women (r = -0.03, p = 0.65). In a regression analysis adjusted for confounding factors, results were similar. Lower appetite was correlated with higher CRP in men (r = 0.27, p < 0.001), but not in women (r = 0.12, p = 0.05). Appetite was correlated with QoL, fatigue and pain in both men and women; those with a low appetite had a low QoL and high fatigue- and pain-scores (p < 0.001). In conclusion, our results indicated possible sex differences in the associations between appetite and albumin, and between appetite and CRP, in palliative care patients. Understanding these associations could provide additional value for clinical practice.

25-Hydroxyvitamin D in Cancer Patients Admitted to Palliative Care: A Post-Hoc Analysis of the Swedish Trial 'Palliative-D'.

The purpose of this study is to explore 25-hydroxyvitamin D (25-OHD) levels in patients with cancer in the palliative phase in relation to season, sex, age, tumor type, colectomy, and survival. To this end, we performed a post-hoc analysis of 'Palliative-D', a randomized placebo-controlled, double-blind trial investigating the effect of daily supplementation with 4000 IU of vitamin D for 12 weeks on pain in patients in palliative cancer care. In the screening cohort (n = 530), 10% of patients had 25-OHD levels < 25 nmol/L, 50% < 50, and 84% < 75 nmol/L. Baseline 25-OHD did not differ between seasons or tumor type and was not correlated with survival time. In vitamin D deficient patients supplemented with vitamin D (n = 67), 86% reached sufficient levels, i.e., >50 nmol/L, after 12 weeks. An increase in 25-OHD was larger in supplemented women than in men (53 vs. 37 nmol/L, p = 0.02) and was not affected by season. In the placebo-group (n = 83), decreased levels of 25-OHD levels were noted during the study period for patients recruited during the last quarter of the year. In conclusion, cancer patients in palliative phase have adequate increase in 25-OHD after vitamin D supplementation regardless of season, age, tumor type, or colectomy.

Sex Differences in the Effect of Vitamin D on Fatigue in Palliative Cancer Care-A Post Hoc Analysis of the Randomized, Controlled Trial 'Palliative-D'.

In the randomized, placebo-controlled, double-blind trial 'Palliative-D', vitamin D treatment of 4000 IE/day for 12 weeks reduced opioid use and fatigue in vitamin-D-deficient cancer patients. In screening data from this trial, lower levels of vitamin D were associated with more fatigue in men but not in women. The aim of the present study was to investigate possible sex differences in the effect of vitamin D in patients with advanced cancer, with a specific focus on fatigue. A post hoc analysis of sex differences in patients completing the Palliative-D study (n = 150) was performed. Fatigue assessed with the Edmonton Symptom Assessment Scale (ESAS) was reduced in vitamin-D-treated men; -1.50 ESAS points (95%CI -2.57 to -0.43; p = 0.007) but not in women; -0.75 (95%CI -1.85 to 0.36; p = 0.18). Fatigue measured with EORTC QLQ-C15-PAL had a borderline significant effect in men (-0.33 (95%CI -0.67 to 0.03; p = 0.05)) but not in women (p = 0.55). The effect on fatigue measured with ESAS in men remained the same after adjustment for opioid doses (p = 0.01). In conclusion, the positive effect of the correction of vitamin D deficiency on fatigue may be more pronounced in men than in women. However, studies focused on analyzing sex differences in this context must be performed before firm conclusions can be drawn.

Successful Strategies and Areas of Improvement-Lessons Learned from Design and Conduction of a Randomized Placebo-Controlled Trial in Palliative Care, 'Palliative-D'.

Clinical trials in palliative care are challenging to design and conduct. Burden on patients should be minimized, while gatekeeping by professionals and next-of kin needs to be avoided. Clinical deterioration due to disease progression affects attrition unrelated to intervention, and different care settings complicate comparisons and reduce the generalizability of the results. The aim of this review is to provide advice for colleagues planning to perform clinical trials in palliative care based on our own experiences from performing the Palliative-D study and by a thorough literature review on this topic. The Palliative-D study was a double-blind trial with 244 randomized patients comparing the effect of vitamin D3 to placebo in patients with advanced or metastatic cancer in the palliative phase of their disease trajectory who were enrolled in specialized palliative home care teams. Endpoints were opioid and antibiotic use, fatigue, and QoL. Recruitment was successful, but attrition rates were higher than expected, and we did not reach targeted power. For the 150 patients who completed the study, the completeness of the data was exceptionally high. Rather than patient reported pain, we choose the difference in the mean change in opioid dose between groups after twelve weeks compared to baseline as the primary endpoint. In this paper we discuss challenges in palliative care research based on lessons learned from the "Palliative-D" trial regarding successful strategies as well as areas for improvement.

CYP3A Activity in End-of-Life Cancer Patients Measured by 4ß-Hydroxycholesterol/cholesterol Ratio, in Men and Women.

More than 50% of all drugs are metabolized by the cytochrome P450 3A enzyme (CYP3A). The aim of this study was to investigate if the CYP3A activity, measured by the endogenous marker 4ß-hydroxycholesterol/cholesterol ratio (4ß-OHC/C), is changed during the last weeks and days of life in men and women. To this end, serum samples from 137 deceased patients (median age 70 years) collected at a single time point 1-60 days before death, were analyzed and compared to 280 young (median 27 years), and 30 elderly (median age 70 years) non-cancer controls. There were no significant differences in the 4ß-OHC/C ratio between men and women in end-of-life patients (p < 0.25). The median 4ß-OHC/C was significantly higher in end-of-life male patients compared to both young (p < 0.0001) and elderly (p < 0.05) male controls. In a similar manner, 4ß-OHC/C in end-of-life female patients was significantly higher compared to young and elderly female controls, p < 0.0001 and p < 0.001, respectively. There was no significant correlation between 4ß-OHC/C and survival time. The results from this study suggest maintained CYP3A activity to the very last days of life and even a capacity of induction of the enzyme in end-of-life cancer patients.

'Palliative-D'-Vitamin D Supplementation to Palliative Cancer Patients: A Double Blind, Randomized Placebo-Controlled Multicenter Trial.

The aim of the 'Palliative-D' study was to test the hypothesis that correction of vitamin D deficiency reduces opioid use in cancer patients admitted to palliative care. A multicenter randomized, placebo-controlled, double-blind trial in three home-based palliative care facilities in Sweden was performed. Patients with advanced cancer and 25-hydroxyvitamin D < 50 nmol/L were randomized to vitamin D3 4000 IU/day or placebo for 12 weeks. The primary endpoint was the difference of long-acting opioid use (fentanyl ug/h) between the groups during 12 weeks, based on four time points. Secondary outcomes included changes in antibiotic use, fatigue and Quality of Life (QoL). A total of 244 patients were randomized, and 150 patients completed the 12 weeks. The major reason for drop-out was death due to cancer. The vitamin D-group had a significantly smaller increase of opioid doses compared to the placebo-group; beta coefficient -0.56 (p = 0.03), i.e., 0.56 µg less fentanyl/h per week with vitamin D treatment. Vitamin D-reduced fatigue assessed with ESAS was -1.1 points after 12 weeks (p < 0.01). Antibiotic use or QoL did not differ significantly between the groups. The treatment was safe and well-tolerated. In conclusion, correction of vitamin D deficiency may have positive effects on opioid use and fatigue in palliative cancer patients, but only in those with a survival time more than 12 weeks.

Fatigue in Cancer Patients in Palliative Care-A Review on Pharmacological Interventions.

Fatigue is one of the most distressing symptoms experienced by cancer patients. The suggested biological mechanism for cancer related fatigue (CRF) includes immune activation triggered by tumor tissue or by anticancer treatment but other mechanisms have also been proposed. Previous large meta-analysis of interventions on fatigue focuses mostly on patients early in the disease trajectory, with only one tenth of included studies performed in palliative cohorts. The aim of this narrative review is therefore to present a background on CRF with focus on the palliative setting. A summary of recent randomized, controlled trials on pharmacological interventions on CRF in palliative care is presented, including studies on psychostimulants, corticosteroids, testosterone and melatonin. Interestingly, in several of these studies there was a positive and similar effect on fatigue in both the intervention and the placebo arm-indicating an important placebo effect for any pharmacological treatment. In addition, studies on dietary supplements and on pharmacological complementary medicines are discussed. To conclude, the evidence is still weak for using pharmacological treatments on CRF in palliative care patients-although methylphenidate and corticosteroids might be considered.

Vitamin D and Fatigue in Palliative Cancer: A Cross-Sectional Study of Sex Difference in Baseline Data from the Palliative D Cohort.

Background: Fatigue is one of the most distressing symptoms in patients with advanced cancer. Previous studies have shown an association between low vitamin D levels and fatigue. Objectives: The aim of this study was to investigate the association between vitamin D levels and self-assessed fatigue in cancer patients admitted to palliative care, with focus on possible sex differences. Design: This is a cross-sectional study. Subjects: Baseline data from 530 screened patients, 265 women and 265 men, from the randomized placebo-controlled trial "Palliative-D" were analyzed. Measurements: Vitamin D status was measured as 25-hydroxyvitamin D (25-OHD) and fatigue was assessed with EORTC-QLQ-PAL15 and with Edmonton Symptom Assessment System (ESAS). Results: In men, there was a significant correlation between 25-OHD and fatigue measured with the "Tiredness question" (Q11) in EORTC-QLQ-PAL15 (p < 0.05), where higher 25-OHD levels were associated with less fatigue. No correlation between 25-OHD and fatigue was seen for women. Fatigue measured with ESAS did not show any significant association with 25-OHD levels neither in men nor in women. Conclusion: Low vitamin D levels were associated with more fatigue in men but not in women. The study underscores the importance of subgroup analysis of men and women when evaluating the effect of vitamin D in clinical trials since the effect may differ between the sexes. The ongoing "Palliative-D study" will reveal whether vitamin D supplementation may counteract fatigue in both men and women. ClinicalTrial.gov: NCT03038516.

Vitamin D supplementation to palliative cancer patients: protocol of a double-blind, randomised controlled trial 'Palliative-D'.

BACKGROUND: According to a small pilot study on palliative cancer patients at our ward, vitamin D supplementation had beneficial effects on pain (measured as opioid consumption), infections and quality of life (QoL) without having any significant side effects. OBJECTIVE: The primary objective of the 'Palliative-D' study is to test the hypothesis that vitamin D supplementation for 12 weeks reduces opioid consumption. The secondary objectives are to study if reduction of antibiotic consumption and fatigue as well as improvement in QoL assessments can be observed. Effect on the 25-hydroxy vitamin D (25-OHD) levels in serum after 12 weeks of treatment will be studied, as well as the change in opioid dose in relation to genetic polymorphism in genes involved in the effect and metabolism of vitamin D. METHOD: A randomised, double-blind placebo-controlled multicentre trial has been designed. The trial will include 254 adult palliative cancer patients with 25-OHD levels <50 nmol/L and a life expectancy of more than 3 months recruited from two advanced palliative home care centres in Stockholm. Included patients will be randomly assigned to 12 weeks of treatment with cholecalciferol (vitamin D3) 4000 IU/day or placebo. The study will start in November 2017 and will finish in December 2019. The study is approved by the Regional Ethical Committee, Dnr2017/405-31/1, by the Swedish Medical Products Agency, EudraCT: 2017-000268-14, and is registered at Clinicaltrial.gov: NCT03038516. The study is financed with research grants from the Swedish Cancer Society and the Stockholm County Council.