Early palliative care for adults with advanced cancer New

Abstract

Abstract
Background

Incurable cancer, which often constitutes an enormous challenge for patients, their families, and medical professionals, profoundly affects the patient's physical and psychosocial well‐being. In standard cancer care, palliative measures generally are initiated when it is evident that disease‐modifying treatments have been unsuccessful, no treatments can be offered, or death is anticipated. In contrast, early palliative care is initiated much earlier in the disease trajectory and closer to the diagnosis of incurable cancer.

Objectives

To compare effects of early palliative care interventions versus treatment as usual/standard cancer care on health‐related quality of life, depression, symptom intensity, and survival among adults with a diagnosis of advanced cancer.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, OpenGrey (a database for grey literature), and three clinical trial registers to October 2016. We checked reference lists, searched citations, and contacted study authors to identify additional studies.

Selection criteria

Randomised controlled trials (RCTs) and cluster‐randomised controlled trials (cRCTs) on professional palliative care services that provided or co‐ordinated comprehensive care for adults at early advanced stages of cancer.

Data collection and analysis

We used standard methodological procedures as expected by Cochrane. We assessed risk of bias, extracted data, and collected information on adverse events. For quantitative synthesis, we combined respective results on our primary outcomes of health‐related quality of life, survival (death hazard ratio), depression, and symptom intensity across studies in meta‐analyses using an inverse variance random‐effects model. We expressed pooled effects as standardised mean differences (SMDs, or Hedges' adjusted g). We assessed certainty of evidence at the outcome level using GRADE (Grading of Recommendations Assessment, Development, and Evaluation) and created a 'Summary of findings' table.

Main results

We included seven randomised and cluster‐randomised controlled trials that together recruited 1614 participants. Four studies evaluated interventions delivered by specialised palliative care teams, and the remaining studies assessed models of co‐ordinated care. Overall, risk of bias at the study level was mostly low, apart from possible selection bias in three studies and attrition bias in one study, along with insufficient information on blinding of participants and outcome assessment in six studies.

Compared with usual/standard cancer care alone, early palliative care significantly improved health‐related quality of life at a small effect size (SMD 0.27, 95% confidence interval (CI) 0.15 to 0.38; participants analysed at post treatment = 1028; evidence of low certainty). As re‐expressed in natural units (absolute change in Functional Assessment of Cancer Therapy‐General (FACT‐G) score), health‐related quality of life scores increased on average by 4.59 (95% CI 2.55 to 6.46) points more among participants given early palliative care than among control participants. Data on survival, available from four studies enrolling a total of 800 participants, did not indicate differences in efficacy (death hazard ratio 0.85, 95% CI 0.56 to 1.28; evidence of very low certainty). Levels of depressive symptoms among those receiving early palliative care did not differ significantly from levels among those receiving usual/standard cancer care (five studies; SMD ‐0.11, 95% CI ‐0.26 to 0.03; participants analysed at post treatment = 762; evidence of very low certainty). Results from seven studies that analysed 1054 participants post treatment suggest a small effect for significantly lower symptom intensity in early palliative care compared with the control condition (SMD ‐0.23, 95% CI ‐0.35 to ‐0.10; evidence of low certainty). The type of model used to provide early palliative care did not affect study results. One RCT reported potential adverse events of early palliative care, such as a higher percentage of participants with severe scores for pain and poor appetite; the remaining six studies did not report adverse events in study publications. For these six studies, principal investigators stated upon request that they had not observed any adverse events.

Authors' conclusions

This systematic review of a small number of trials indicates that early palliative care interventions may have more beneficial effects on quality of life and symptom intensity among patients with advanced cancer than among those given usual/standard cancer care alone. Although we found only small effect sizes, these may be clinically relevant at an advanced disease stage with limited prognosis, at which time further decline in quality of life is very common. At this point, effects on mortality and depression are uncertain. We have to interpret current results with caution owing to very low to low certainty of current evidence and between‐study differences regarding participant populations, interventions, and methods. Additional research now under way will present a clearer picture of the effect and specific indication of early palliative care. Upcoming results from several ongoing studies (N = 20) and studies awaiting assessment (N = 10) may increase the certainty of study results and may lead to improved decision making. In perspective, early palliative care is a newly emerging field, and well‐conducted studies are needed to explicitly describe the components of early palliative care and control treatments, after blinding of participants and outcome assessors, and to report on possible adverse events.

Author(s)

Markus W Haun, Stephanie Estel, Gerta Rücker, Hans‐Christoph Friederich, Matthias Villalobos, Michael Thomas, Mechthild Hartmann

Abstract

Plain language summary

 Early palliative care for adults with advanced cancer 

 Review question 

What is the evidence for the effects of early palliative care on quality of life, survival, depression, and symptom intensity in people with advanced cancer?

 Background 

Frequently, cancer is diagnosed at a late stage, and the disease might have progressed through anticancer treatment. Patients can choose to start or continue anticancer treatment at the potential cost of side effects. Standard care means that all patients are offered palliative care towards the end of life. However, patients may be able to receive palliative care a lot earlier. This approach, which is known as early palliative care, begins at the time of, or shortly after, the diagnosis of advanced cancer. Often, early palliative care is combined with anticancer treatment such as chemotherapy or radiotherapy. Early palliative care, whether provided by the attending oncologist or by specialist teams, involves empathetic communication with patients about their prognosis, advance care planning, and symptom assessment and control.

 Study characteristics 

In October 2016, we searched for clinical trials on early palliative care in adults with advanced cancer. We included seven studies and found 20 ongoing studies. Most of the studies included participants older than 65 years of age on average, diagnosed with different tumour types and receiving treatment in tertiary care centres in North America. Most of these studies compared early palliative care with standard oncological (cancer) care. All studies were funded by government agencies.

 Key results 

When evaluated together in a meta‐analysis, studies showed that in patients with advanced cancer, early palliative care may slightly increase quality of life. It may also decrease symptom intensity to a small degree. Effects on survival and depression are uncertain. A single study reported side effects (adverse events), for example, more pain and reduced appetite. For the remaining six studies, information about side effects was not published, but trial authors told us they had not observed any.

 Certainty of the evidence 

We rated the certainty of the evidence using four levels: very low, low, moderate, and high. Evidence of very low certainty means that we have little confidence in the results. Evidence of high certainty means that we are very confident in the results. We found that certainty of the evidence was low for health‐related quality of life and symptom intensity, and was very low for depression and survival. We downgraded certainty of the evidence for various reasons, for example, problems in the way studies were carried out, differences between studies, and the small number of studies. We remain uncertain about the effects of early palliative care; therefore we have to interpret the results with caution. When published, ongoing studies may provide more evidence, and this may affect the certainty of the results.

Author(s)

Markus W Haun, Stephanie Estel, Gerta Rücker, Hans‐Christoph Friederich, Matthias Villalobos, Michael Thomas, Mechthild Hartmann

Reviewer's Conclusions

Authors' conclusions

Implications for practice

All stakeholders shall be advised that besides the seven included studies, we identified 20 ongoing studies and 10 studies awaiting assessment. Therefore, the evidence base for early palliative care in cancer is growing, and conclusions remain preliminary.

For people with advanced cancers

Available evidence of very low to low certainty suggests that patients with advanced cancers could benefit from early palliative care with respect to small improvements in quality of life and symptom intensity. At this point, effects on survival and/or on depressive symptoms remain uncertain. Nevertheless, to improve quality of life and reduce symptoms, patients could approach their attending physician and request referral to palliative care at an early stage of disease.

For clinicians

From a practitioner's perspective, some previous reviews have reported definitive success of early palliative care interventions for improving quality of life, controlling bodily symptoms and depressive symptoms, and prolonging life. However, according to our results, these claims were likely to be at least premature for the entire group of patients with advanced cancer. Besides studies favouring such outcomes, we also detected a study with possibly negative effects on symptoms and survival. More research is needed before solid conclusions regarding routine care can be drawn. Included studies were heterogeneous in many aspects. Although we found some possibly clinically relevant evidence for the effectiveness of early palliative care in terms of quality of life and symptom intensity, the certainty of this evidence was low to very low. Results of our review do not support that early palliative care leads to prolonged survival in general. Therefore, at this point, clinicians could consider early palliative interventions on a case‐by‐case basis to address quality of life alongside symptom intensity and counsel patients adequately (Peppercorn 2011), but refrain from claiming that these interventions will have an additional impact on survival, or that they offer the only way to target quality of life. The patient should be informed adequately and his or her wishes should be respected during treatment planning.

For policy makers

Access to additional specialised palliative care teams is currently limited and availability of services is often absent even in developed countries (Kelley 2015). Hence, policy makers face the challenge of systematically introducing early palliative care into environments with potentially limited available resources. At this point, we have found no evidence that specialised palliative care teams (as part of integrated care) are superior to those providing a generic palliative care approach (co‐ordinated care). In addition, cost utility of early palliative care remains unclear at this point. However, findings of our review do support strong implementation of elements of early palliative care in clinical routines. These elements may consist of advanced communication for identification of patient priorities, care co‐ordination towards symptom control, and comprehensive psychosocial care potentially involving caregivers (Janssens 2016).

Implications for research
General

With only seven studies included, we clearly need additional sufficiently powered and well‐designed studies. Especially with respect to effect estimates of outcomes other than health‐related quality of life and symptom intensity, we are in need of larger (i.e. multi‐centred) studies to establish robust evidence. Besides uniform and significant effects, we found that studies differed in average effect size or even in the direction of effects. To explain this heterogeneity with respect to entity, interventions, dose, and study methods further, we need to continue to work on an even clearer, evidence‐based definition for early palliative care (Lee 2015). A clearer definition would constitute the foundation for establishing and comparing interventions across studies, and first efforts would stem from qualitative studies on core interventional elements (Hui 2015a; Jacobsen 2011; Janssens 2015; Yoong 2013). In general, we consider it essential to better describe training as well as therapist adherence. It is equally important to provide more information on the usual care provided locally. To ensure clear interpretation of findings, we should provide a thorough and extensive description of both experimental and control conditions.

Against the background of evidence presented here, it has to be considered that early palliative care in cancer is still a relatively new treatment approach that has so far almost exclusively been evaluated in the context of tertiary care contexts; and is not a clearly defined and homogeneous type of intervention; but that research is important because early palliative care may have the potential to improve current clinical practice in advanced cancer diseases.

Design

Interventions should be described under the different models proposed for early palliative care, and frequency and duration of treatment should be stated. For strengthening the internal validity of effect estimates, future studies need to be rigorous in both design (ideally controlling for palliative care skills/training of oncologists/palliative care physicians and high‐ vs low‐volume centres) and delivery, and should be based on sufficient power. Specifically, investigators in future studies should use all available measures to control for selection bias (i.e. to ensure adequate allocation concealment), performance bias (i.e. to blind study participants), detection bias (i.e. to blind outcome assessors), and selective reporting (i.e. to report studies as indicated in the preregistration). It is most important that investigators provide detailed descriptions of the several components of both intervention and control conditions. Notwithstanding, for ethical and disease‐inherent reasons, conducting RCTs and restricting attrition are major challenges in palliative care (Wee 2008). With respect to setting, interventions should be expanded beyond high‐volume tertiary referral hospitals in Western countries. It has been shown that clinical expertise and centre volume impact treatment effect (Choudhry 2005). Specifically, treatment in comprehensive cancer centres is often linked with superior survival (Wolfson 2015). Although research on the transferability of early palliative care interventions to more naturalistic contexts has already commenced, we would encourage investigators to focus first on rigorous RCTs that follow conventional designs to determine internal validity, substantiate findings, and increase the certainty of evidence. Concerning homogeneity of samples, it might be worthwhile to investigate 'tumour homogeneous' samples to better account for specific disease trajectories and patient characteristics (e.g. male gender and young age in patients with lung cancer, as recently demonstrated by Nipp 2016) that are likely to specifically impact the effectiveness of an early palliative care approach. Only in a second step, that is, when certainty of effect estimates is higher, may pragmatic studies looking at implementability of early palliative care be initiated (Treweek 2009). If early palliative care proves effective in the future, we regard continuation of studies along this pragmatic‐explanatory continuum as crucial (Loudon 2015; Thorpe 2009).

Measurement (endpoints)

Concerning measurements, health‐related quality of life and symptom intensity have emerged as appropriate outcomes that are possibly sensitive to change and can be recommended for routine collection. In addition, affective symptoms should be assessed, as they constitute a particular salient distress factor in patients with advanced cancer (Haun 2014; Mehnert 2014). Compared with these endpoints, survival is controversial, as it is not the primary aim of palliative interventions. However, in terms of further advancements, information on how the intervention may work and on essential components should be derived. Moreover, future studies need to harmonise measurements with respect to applied scales and predefined time points. The most common follow‐up for primary outcomes currently occurs at 12 weeks. Blinding of outcome assessment is essential, as is its explicit reporting in publications.

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