A semiparametric joint model for terminal trend of quality of life and survival in palliative care research

Palliative medicine is an interdisciplinary specialty focusing on improving quality of life (QOL) for patients with serious illness and their families. Palliative care programs are available or under development at over 80% of large US hospitals (300+ beds). Palliative care clinical trials present unique analytic challenges relative to evaluating the palliative care treatment efficacy which is to improve patients’ diminishing QOL as disease progresses towards end of life (EOL). A unique feature of palliative care clinical trials is that patients will experience decreasing QOL during the trial despite potentially beneficial treatment. Often longitudinal QOL and survival data are highly correlated which, in the face of censoring, makes it challenging to properly analyze and interpret terminal QOL trend. To address these issues, we propose a novel semiparametric statistical approach to jointly model the terminal trend of QOL and survival data. There are two sub‐models in our approach: a semiparametric mixed effects model for longitudinal QOL and a Cox model for survival. We use regression splines method to estimate the nonparametric curves and AIC to select knots. We assess the model performance through simulation to establish a novel modeling approach that could be used in future palliative care research trials. Application of our approach in a recently completed palliative care clinical trial is also presented.     

Societal costs of home and hospital end‐of‐life care for palliative care patients in Ontario,Canada

In Canada, health system restructuring has led to a greater focus on home‐based palliative care as an alternative to institutionalised palliative care. However, little is known about the effect of this change on end‐of‐life care costs and the extent to which the financial burden of care has shifted from the acute care public sector to families. The purpose of this study was to assess the societal costs of end‐of‐life care associated with two places of death (hospital and home) using a prospective cohort design in a home‐based palliative care programme. Societal cost includes all costs incurred during the course of palliative care irrespective of payer (e.g. health system, out‐of‐pocket, informal care‐giving costs, etc.). Primary caregivers of terminal cancer patients were recruited from the Temmy Latner Centre for Palliative Care in Toronto, Canada. Demographic, service utilisation, care‐giving time, health and functional status, and death data were collected by telephone interviews with primary caregivers over the course of patients' palliative trajectory. Logistic regression was conducted to model an individual's propensity for home death. Total societal costs of end‐of‐life care and component costs were compared between home and hospital death using propensity score stratification. Costs were presented in 2012 Canadian dollars ($1.00CDN = $1.00USD). The estimated total societal cost of end‐of‐life care was $34,197.73 per patient over the entire palliative trajectory (4 months on average). Results showed no significant difference (P > 0.05) in total societal costs between home and hospital death patients. Higher hospitalisation costs for hospital death patients were replaced by higher unpaid caregiver time and outpatient service costs for home death patients. Thus, from a societal cost perspective, alternative sites of death, while not associated with a significant change in total societal cost of end‐of‐life care, resulted in changes in the distribution of costs borne by different stakeholders.     

Temporal trends in place of death for end‐of‐life patients: Evidence from Toronto,Canada

Understanding the temporal trends in the place of death among patients in receipt of home‐based palliative care can help direct health policies and planning of health resources. This paper aims to assess the temporal trends in place of death and its determinants over the past decade for patients receiving home‐based palliative care. This paper also examines the impact of early referral to home‐based palliative care services on patient's place of death. Survey data collected in a home‐based end‐of‐life care program in Toronto, Canada from 2005 to 2015 were analysed using a multivariate logistic model. The results suggest that the place of death for patients in receipt of home‐based palliative care has changed over time, with more patients dying at home over 2006–2015 when compared to 2005. Also, early referral to home‐based palliative care services may not increase a patient's likelihood of home death. Understanding the temporal shifts of place of death and the associated factors is essential for effective improvements in home‐based palliative care programs and the development of end‐of‐life care policies.     

Quality-of-Life Concerns of Chinese Patients With Advanced Cancer

This study aimed to examine the quality of life (QOL) of patients with advanced cancer in Hong Kong. Ninety participants were recruited from the oncology ward of the study hospital. They responded to a 28-item, 8-subscale multidimensional questionnaire and a single-item scale that measured QOL in a face-to-face interview. Participation in health care decisions, food-related concerns, and existential distress were some QOL concerns that require health care professionals' attention. Walking ability predicted the level of QOL in certain QOL domains that surfaces patients' need for rehabilitation. That the QOL domain value of life was the most important domain that predicted overall QOL calls for meaning-of-life interventions for palliative care.     

A community‐of‐care: the integration of a palliative approach within residential aged care facilities in Australia

In developed countries, residential aged care facilities (RACFs) are increasingly becoming the place of care and site of death for older people with complex chronic illnesses. Consequently, it is becoming ever more relevant for these facilities to provide appropriate complex, as well as end‐of‐life care for this growing group of people. Evidence‐based guidelines for providing a ‘palliative approach’ were developed and introduced in Australia in 2004, with the emphasis on improving symptom control earlier in the disease trajectory. The aim of the study reported here was to explore the extent to which a palliative approach was being used in the organisation and provision of care for older people with complex needs living in mixed‐level (a combination of low‐ and high‐level care) RACFs. This paper primarily reports on the qualitative findings. Two residential aged care organisations, one in rural New South Wales and the other in Sydney, Australia, participated. Data were collected over a 9‐month period from May until December 2008. Residents, family members and aged care staff were interviewed. Thematic analysis of participant interviews shows that while the various elements of a palliative approach are incorporated into the care of high‐level care residents, the discourse itself is not used. In this paper, we argue for a new conceptualisation of care for people in mixed‐level care facilities: a community‐of‐care, in which a palliative approach is one of several components of the care provided. The findings illuminate aged care staff experiences of providing care to high‐level care residents. They also provide valuable insights into high‐level care residents’ perceptions of their health, care provided and the way in which they foresee their care being provided in future. These findings will be important for informing clinical practice, research and policy in these settings.     

Performance of care for end‐of‐life cancer patients in Tuscany: The interplay between place of care,aggressive treatments,opioids, and place of death. A retrospective cohort study

Supportive and palliative care at the end of life (EOL) is a core component of health systems. Providing care at the EOL may require the interaction of several care providers working in different settings including nursing homes, home care, hospices, and hospitals. This work aims to (a) provide evidence on the performance of EOL care for cancer patients across healthcare organizations, with a focus on the place of care, aggressive treatments, opioids, and the place of death and (b) analyze factors associated with dying in hospital. A population‐based retrospective study was performed using administrative data from Tuscany region (Italy). Thirteen thousand sixty‐six cancer patients who died in 2016 were considered. There is a marked variability in EOL care within regional areas, with the multilevel logistic regression highlighting a greater likelihood of dying in hospital for patients who were admitted to intensive care units or previously hospitalized. There is a lower probability of dying in acute care setting for patients assisted in hospices and in both hospital and hospices/home care and for patients treated with opioids. This intraregional variation highlights the need to improve EOL planning and rethink the delivery of supportive/palliative care. Further investigations on the preferences of patients may lead to more understanding.     

Quality of life scores: An independent prognostic variable in a general population of cancer patients receiving chemotherapy

This report examines the prognostic associations between QOL scores measured by the EORTC QLQ-C30 and survival in a large heterogeneous population of cancer patients. Eight hundred and fifty-one cancer patients who were to receive chemotherapy were enrolled in two National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) antiemetic trials. All patients completed the EORTC QLQ-C30 immediately prior to their first chemotherapy. Survival data were available and obtained for 474 of 639 patients (74%). Cox's proportional hazards model was used to assess the independent impact of QOL and demographic variables on survival. Presence of metastatic disease, diagnosis of lung or ovarian cancer, ECOG performance status, global quality of life and emotional functioning were significantly associated with survival. Global QOL was predictive in all patients, in subgroups of patients with metastatic disease, with breast and lung cancer and other tumour types. In patients with low global quality of life scores, patients with low emotional functioning ratings lived longer than did patients with high emotional functioning ratings. Patients with high global QOL live significantly longer than do patients with low global QOL. The relationship between emotional functioning in patients with low global QOL and survival needs confirmation.     

Analyzing longitudinal data with patients in different disease states during follow‐up and death as final state

This paper considers the analysis of longitudinal data complicated by the fact that during follow‐up patients can be in different disease states, such as remission, relapse or death. If both the response of interest (for example, quality of life (QOL)) and the amount of missing data depend on this disease state, ignoring the disease state will yield biased means. Death as the final state is an additional complication because no measurements after death are taken and often the outcome of interest is undefined after death. We discuss a new approach to model these types of data. In our approach the probability to be in each of the different disease states over time is estimated using multi‐state models. In each different disease state, the conditional mean given the disease state is modeled directly. Generalized estimation equations are used to estimate the parameters of the conditional means, with inverse probability weights to account for unobserved responses. This approach shows the effect of the disease state on the longitudinal response. Furthermore, it yields estimates of the overall mean response over time, either conditionally on being alive or after imputing predefined values for the response after death. Graphical methods to visualize the joint distribution of disease state and response are discussed. As an example, the analysis of a Dutch randomized clinical trial for breast cancer is considered. In this study, the long‐term impact on the QOL for two different chemotherapy schedules was studied with three disease states: alive without relapse, alive after relapse and death. Copyright © 2009 John Wiley & Sons, Ltd.     

Predictors of caregiver burden across the home‐based palliative care trajectory in Ontario,Canada

Family caregivers of patients enrolled in home‐based palliative care programmes provide unpaid care and assistance with daily activities to terminally ill family members. Caregivers often experience caregiver burden, which is an important predictor of anxiety and depression that can extend into bereavement. We conducted a longitudinal, prospective cohort study to comprehensively assess modifiable and non‐modifiable patient and caregiver factors that account for caregiver burden over the palliative care trajectory. Caregivers (n = 327) of patients with malignant neoplasm were recruited from two dedicated home‐based palliative care programmes in Southern Ontario, Canada from 1 July 2010 to 31 August 2012. Data were obtained from bi‐weekly telephone interviews with caregivers from study admission until death, and from palliative care programme and home‐care agency databases. Information collected comprised patient and caregiver demographics, utilisation of privately and publicly financed resources, patient clinical status and caregiver burden. The average age of the caregivers was 59.0 years (SD: 13.2), and almost 70% were female. Caregiver burden increased over time in a non‐linear fashion from study admission to patient death. Increased monthly unpaid care‐giving time costs, monthly public personal support worker costs, emergency department visits and low patient functional status were associated with higher caregiver burden. Greater use of hospice care was associated with lower burden. Female caregivers tended to report more burden compared to men as death approached, and burden was higher when patients were male. Low patient functional status was the strongest predictor of burden. Understanding the influence of modifiable and non‐modifiable factors on the experience of burden over the palliative trajectory is essential for the development and targeting of programmes and policies to support family caregivers and reduce burden. Supporting caregivers can have benefits such as improved caregiver health outcomes, and enhancing their ability to meet care‐giving demands, thereby potentially allowing for longer patient care in the home setting.     

Pattern mixture models for longitudinal quality of life studies in advanced stage disease

Analyses of longitudinal quality of life (QOL) for patients with advanced stage disease are frequently plagued by problems of non-random drop-out attributable to deteriorating health and/or death. As an example, Moinpour et al. cite specific challenges which limited their report and assessment of QOL for patients treated for advanced stage colorectal cancer in a clinical trial of several chemotherapeutic regimes performed by the Southwest Oncology Group. A particular source of confusion that arises in studies of advanced stage disease is whether or not to differentiate loss of follow-up due to death from drop-out where the patient is still alive but has dropped from the study. In this paper we examine exploratory data techniques for longitudinal QOL data with non-random missingness due to drop-out and censorship by death. We propose a pattern mixture model for longitudinal QOL, time of drop-out and survival, which allows for straightforward implementation of sensitivity analyses and explicit comparisons to the raw data. Our method is illustrated in the context of analysing the data and addressing the challenges posed by Moinpour et al.     

Multilevel latent variable models for global health-related quality of life assessment

Quality of life (QOL) assessment is a key component of many clinical studies and frequently requires the use of single global summary measures that capture the overall balance of findings from a potentially wide-ranging assessment of QOL issues. We propose and evaluate an irregular multilevel latent variable model suitable for use as a global summary tool for health-related QOL assessments. The proposed model is a multiple indicator and multiple cause style of model with a two-level latent variable structure. We approach the modeling from a general multilevel modeling perspective, using a combination of random and nonrandom cluster types to accommodate the mixture of issues commonly evaluated in health-related QOL assessments--overall perceptions of QOL and health, along with specific psychological, physical, social, and functional issues. Using clinical trial data, we evaluate the merits and application of this approach in detail, both for mean global QOL and for change from baseline. We show that the proposed model generally performs well in comparing global patterns of treatment effect and provides more precise and reliable estimates than several common alternatives such as selecting from or averaging observed global item measures. A variety of computational methods could be used for estimation. We derived a closed-form expression for the marginal likelihood that can be used to obtain maximum likelihood parameter estimates when normality assumptions are reasonable. Our approach is useful for QOL evaluations aimed at pharmacoeconomic or individual clinical decision making and in obtaining summary QOL measures for use in quality-adjusted survival analyses.     

Incorporation of nested frailties into semiparametric multi‐state models

Proportional hazards models are among the most popular regression models in survival analysis. Multi‐state models generalize them by jointly considering different types of events and their interrelations, whereas frailty models incorporate random effects to account for unobserved risk factors, possibly shared by clusters of subjects. The integration of multi‐state and frailty methodology is an interesting way to control for unobserved heterogeneity in the presence of complex event history structures and is particularly appealing for multicenter clinical trials. We propose the incorporation of correlated frailties in the transition‐specific hazard function, thanks to a nested hierarchy. We studied a semiparametric estimation approach based on maximum integrated partial likelihood. We show in a simulation study that the nested frailty multi‐state model improves the estimation of the effect of covariates, as well as the coverage probability of their confidence intervals. We present a case study concerning a prostate cancer multicenter clinical trial. The multi‐state nature of the model allows us to evidence the effect of treatment on death taking into account intermediate events. Copyright © 2015 JohnWiley & Sons, Ltd.     

Evaluation of treatment efficacy using a Bayesian mixture piecewise linear model of longitudinal biomarkers

Prostate‐specific antigen (PSA) is a widely used marker in clinical trials for patients with prostate cancer. We develop a mixture model to estimate longitudinal PSA trajectory in response to treatment. The model accommodates subjects responding and not responding to therapy through a mixture of two functions. A responder is described by a piecewise linear function, represented by an intercept, a PSA decline rate, a period of PSA decline, and a PSA rising rate; a nonresponder is described by an increasing linear function with an intercept and a PSA rising rate. Each trajectory is classified as a linear or a piecewise linear function with a certain probability, and the weighted average of these two functions sufficiently characterizes a variety of patterns of PSA trajectories. Furthermore, this mixture structure enables us to derive clinically useful endpoints such as a response rate and time‐to‐progression, as well as biologically meaningful endpoints such as a cancer cell killing fraction and tumor growth delay. We compare our model with the most commonly used dynamic model in the literature and show its advantages. Finally, we illustrate our approach using data from two multicenter prostate cancer trials. The R code used to produce the analyses reported in this paper is available on request. Copyright © 2015 John Wiley & Sons, Ltd.     

Joint modeling of progression‐free survival and death in advanced cancer clinical trials

Progression‐related endpoints (such as time to progression or progression‐free survival) and time to death are common endpoints in cancer clinical trials. It is of interest to study the link between progression‐related endpoints and time to death (e.g. to evaluate the degree of surrogacy). However, current methods ignore some aspects of the definitions of progression‐related endpoints. We review those definitions and investigate their impact on modeling the joint distribution. Further, we propose a multi‐state model in which the association between the endpoints is modeled through a frailty term. We also argue that interval‐censoring needs to be taken into account to more closely match the latent disease evolution. The joint distribution and an expression for Kendall's τ are derived. The model is applied to data from a clinical trial in advanced metastatic ovarian cancer. Copyright © 2010 John Wiley & Sons, Ltd.     

Adjusting for age-related competing mortality in long-term cancer clinical trials

Mortality related to causes other than the treated disease may have a significant impact on overall survival in long-term clinical trials. We present a model that adjusts for age-related competing mortality when cause of death is missing or only partially available. Through use of a piecewise exponential survival model, we extend relative survival methods to continuous follow-up data, allowing the competing mortality to differ from that of the general population by a scale parameter. An EM algorithm provides a simple way to compute the maximum likelihood estimators (MLEs) and to test hypotheses using widely available software. We compare the bias and relative efficiency of this model to a piecewise exponential Cox model for overall survival. Theoretical results are confirmed by simulations and illustrated with data from a clinical trial in colorectal cancer. This example also shows how age-related and disease-related mortality can be confounded in an analysis of overall survival. We conclude with a discussion of the advantages and disadvantages of the model.     

A new concept in cancer care: the supportive care program

This article describes the findings of a pilot program designed to enter advanced prostate cancer patients into the hospice benefit while they are still being actively treated, but in situations where treatment is known to be primarily palliative in nature. The supportive care program (SCP) combines the medical model's goal to prolong life with the goal of hospice to palliate symptoms and improve quality of life (QOL). The concept of a SCP was developed to create a team approach where advanced prostate cancer patients who are starting investigational chemotherapy are concurrently enrolled into a hospice program. The objectives were to identify whether SCP improved QOL and continuity of care while remaining cost-effective. Data were collected on patient quality of life, performance status, use of health care resources, and costs for the 36 enrolled patients. A comparison was made to a matched set of 23 control patients. Our findings indicate that the SCP contributes to continuity of care while being cost-effective.     

Report from a National Cancer Institute (USA) workshop on quality of life assessment in cancer clinical trials

To promote the inclusion of quality of life (QOL) end-points in clinical research on cancer, the National Cancer Institute (USA) sponsored a workshop on QOL assessment in cancer clinical trials in July, 1990. Experts in clinical trials and QOL research formed four working groups to identify current areas of cancer treatment in which QOL end-points are most important; to discuss methodologic problems in QOL assessment; to address common problems in implementing clinical studies with QOL end-points; and to consider statistical issues in design, implementation, and data analysis. Recommendations made by the working groups are summarized in this paper.This article summarizes recommendations from the four working groups that comprised the workshop. Copies of the full reports are available from Dr Nayfield at the address above.     

Intravenous ω‐3 Fatty Acids Plus Gemcitabine

Background: Marine‐derived ω‐3 fatty acids (ω‐3FAs) have proven antitumor activity in vivo and in vitro and improve quality of life (QOL) in clinical cancer studies. These changes may be mediated by reduction in circulating proangiogenic and proinflammatory factors. In this first study of intravenous ω‐3FAs as a therapy in cancer patients, we aimed to assess if it could augment the antitumor activity of gemcitabine in patients with advanced pancreatic cancer and improve QOL. Materials and Methods: Patients were administered gemcitabine 1000 mg/m³ weekly followed by up to 100 g (200 mg/mL) of ω‐3 rich lipid emulsion for 3 weeks followed by a rest week. This was continued for up to 6 cycles, progression, unacceptable toxicity, patient request, or death. The primary outcome measure was objective response rate, with secondary outcome measures of overall and progression free survival, QOL scores, and adverse events. Results: Fifty patients were recruited. Response rate was 14.3% and disease control rate was 85.7%. Overall and progression free survival were 5.9 and 4.8 months, respectively. Increase in global health of > 10% over baseline was seen in 47.2% of patients. More than 50% of patients had > 10% increase in QOL scores in generic symptom scores and both disease‐specific domains. Grade 3/4 adverse events were thrombocytopenia (8%), neutropenia (12%), nausea or vomiting (4%), and chills (6%). Conclusion: Intravenous ω‐3FAs in combination with gemcitabine shows evidence of improved activity and benefit to QOL in patients with advanced pancreas cancer and is worthy of investigation in a randomized phase III trial.     

健康教育对晚癌患者生活质量及生存期研究

摘要:目的　探索健康教育对晚癌患者生活质量（Quality Of Life,QOL）及生存期的影响。方法　回顾性调查2013年8月-2014年2月期间接受华西宁养院家居服务的112例晚期癌症患者,对给予健康教育及躯体症状控制者纳入研究组（56例）,对仅给予躯体症状控制者作为对照组（56例）。分析两组患者基线资料可比性,比较两组患者QOL及生存期的差异。结果　两组间基线资料比较均无统计学差异（P＞0.05）;干预前两组患者间QOL评分比较无统计学差异（t＝0.110,P＝0.913）及QOL评分等级比较无统计学意义（Z＝0.180,P＝0.857）;干预后研究组QOL评分显著高于对照组（t＝5.093,P＜0.001）,研究组干预后较干预前QOL显著升高（t＝5.093,P＜0.001）;干预后研究组较对照组QOL评分等级明显改善（Z＝4.418,P＜0.001）。两组生存曲线整体比较具有统计学意义（χ2＝5.993,P＝0.014）。结论　健康教育能提高晚癌患者的生活质量及延长其生存期。