Abstract
Background
Anaemia occurs in 68% to 77% of patients with advanced cancer, however, only a minority of patients who are admitted to a hospice receive a blood transfusion. It is unclear what the benefit of blood transfusion is in advanced cancer, who is most likely to respond and also for how long. Hence we conducted a systematic review to assess the use of blood transfusion in advanced cancer.
Objectives
To synthesise the existing clinical evidence and summarise knowledge gaps regarding blood transfusions for treating anaemia in patients with advanced cancer.
Search methods
We searched MEDLINE, EMBASE, CINAHL, Web of Science, ZETOC and CENTRAL in November 2011. In addition, we checked and citation‐tracked the reference lists of all relevant studies and reports. We contacted investigators who were known to be researching this area for unpublished data or knowledge of the grey literature.
Selection criteria
Randomised controlled trials (RCTs), before and after studies and interrupted time series (ITS) studies in adults and children, reporting the outcome of blood transfusions in advanced cancer.
Data collection and analysis
Two independent (NP and AH) review authors extracted data and quality scored studies. There were insufficient data to carry out an analysis.
Main results
No RCTs were found. We identified 12 before and after studies which included 653 participants and showed a subjective response rate of 31% to 70%. Five studies specifically assessed response using a range of fatigue scales which indicated an early response post transfusion, which was beginning to wane by day 14. Similar results were found for breathlessness. Overall survival ranged from two to 293 days but there was a significant proportion of participants (23% to 35%) who died within two weeks of their transfusion.
Authors' conclusions
Higher‐quality studies are required to determine the effectiveness of blood transfusion at the end of life and, in particular, to determine which patients are most likely to respond and which are not, and the duration of any response. Potential harms of blood transfusion at the end of life (indicated by high 14‐day mortality) need to be distinguished from inappropriate transfusion in patients who are dying from advanced cancer.
Keywords: Humans, Blood Transfusion, Blood Transfusion/mortality, Anemia, Anemia/etiology, Anemia/mortality, Anemia/therapy, Dyspnea, Dyspnea/etiology, Dyspnea/mortality, Dyspnea/therapy, Erythrocyte Transfusion, Erythrocyte Transfusion/mortality, Fatigue, Fatigue/etiology, Fatigue/mortality, Fatigue/therapy, Neoplasms, Neoplasms/complications, Neoplasms/mortality, Recurrence, Time Factors
Plain language summary
Blood transfusion for anaemia in patients with advanced cancer
Many patients admitted to a hospice are anaemic but only a small proportion receive a blood transfusion. Two of the main symptoms of anaemia are fatigue and breathlessness. This review aimed to identify whether blood transfusion was a useful treatment for patients with advanced cancer who were anaemic. We identified only 12 relevant studies but all were of low quality. They indicated that fatigue and breathlessness improved immediately after the transfusion but this began to wane after a period of two weeks. Of those receiving a transfusion, 31% to 70% had a transient benefit that lasted about two weeks.
Background
The most common indication for blood transfusion in patients with advanced cancer is anaemia accompanied by fatigue or breathlessness. Anaemia occurs in 68% to 77% of patients with advanced disease (Dunn 2003) and a causal relationship is assumed between anaemia and these symptoms, despite their aetiology being multifactorial. However, not everyone with advanced cancer and with these symptoms receives a blood transfusion, with many being managed with general supportive care (Brown 2007). There are no systematic reviews or randomised controlled trials (RCTs) to assess the usefulness of transfusions in advanced cancer or to identify which groups of patients are more likely to benefit from them.
Description of the condition
Anaemia
Anaemia is defined by the World Health Organization (WHO) as a reduction in the concentration of haemoglobin (Hb), the molecule in red blood cells (RBC) that binds oxygen. Recognised levels for a diagnosis of anaemia are < 130 g/L for men and < 120 g/L for women (Izaks 1999). Anaemia is present in 77% of men and 68% of women receiving palliative care (Dunn 2003). The aetiology of anaemia in this context is often multifactorial but anaemia of chronic disease (caused by reduced production of erythropoietin) appears to predominate. Other factors include specific disease‐related processes such as bone marrow infiltration, malnutrition and blood loss.
The relationship between anaemia, fatigue and breathlessness is unclear. Although the correlation between Hb and symptoms has been confirmed in patients with earlier‐stage disease receiving anticancer therapy (Demetri 1998; Gabrilove 2001; Glaspy 1997; Littlewood 2001), there are conflicting data regarding the relationship in palliative care (Noergaard Munch 2005; Stone 1999; Stone 2000). Moreover, anaemia is present in only 20% of cancer patients with breathlessness (Dudgeon 1998).
Fatigue and dyspnoea
Fatigue and breathlessness (dyspnoea) correlate in advanced cancer (Bruera 2000; Stone 2000), chronic obstructive pulmonary disease (COPD) (Meek 2003) and heart failure populations (Falk 2006). The aetiology of both is multifactorial and incompletely understood (Abernethy 2003; Stone 1999).
Fatigue occurs in 80% of patients receiving palliative care (Conill 1997) and it has a significant impact on quality of life (QOL) (Cella 2001). Cancer‐related fatigue has been defined as "a distressing, persistent, subjective sense of tiredness or exhaustion" that interferes with function (Mock 2007). Various studies have demonstrated an association between fatigue and biochemical, physical and psychological factors (Hwang 2003; Shafqat 2005; Sood 2005). Fatigue in advanced disease can occur without antecedent activity, is incompletely relieved by rest (Morgan 2010) and may not correlate with muscle weakness (Stone 1999). It consists of global weakness and difficulty initiating activities, a reduced ability to sustain activity, mental fatigue associated with impaired concentration and memory, and heightened emotional lability (Yennurajalingam 2007).
The incidence of breathlessness in patients with advanced cancer is 70% (Reuben 1986). It is present in 68% of patients dying of AIDS, in 37% of patients post cerebrovascular accident, 50% of patients with amyotrophic lateral sclerosis and 70% of patients with dementia (Indelicato 2006). Breathlessness is "a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity. The experience derives from interactions between multiple physiological, psychological, social and environmental factors" (American Thoracic Society 1999). These include the underlying disease, cachexia and deconditioning (Abernethy 2003). It is present in patients without cardiopulmonary pathology, hypoxia or hypercapnia (Abernethy 2003; Reuben 1986).
Description of the intervention
In the UK, it is standard practice to transfuse blood components rather than ‘whole blood’ though practice varies internationally.
The red cell component in the UK is "red cells, leucocyte‐depleted, in additive solution". Dosage is expressed in ‘red cell units’, despite variability in Hb concentration between units. Red cells are transfused intravenously and a unit can be given to a stable patient in 90 minutes. Transfusion must occur within four hours of removal from controlled temperature storage due to bacterial proliferation (McClelland 2007). Red cell transfusion will be referred to as blood transfusion from this point forward.
How the intervention might work
Central to the management of fatigue and breathlessness is the correction of reversible causes, allied with palliative interventions (Bausewein 2008; Cramp 2008; Jennings 2001; Minton 2010; Spathis 2009). Anaemia may be one treatable cause (Chan 2005; Sweeney 2005). Interventions for anaemia may include haemorrhage management, haematinic replacement (iron and vitamin B complex), erythropoietin therapy and blood transfusion (Turner 2005). The availability of oxygen to body tissues depends upon blood oxygen content. Transfusion of blood increases Hb concentration and the oxygen‐carrying capacity of blood. Impaired oxygen transport is likely to result in breathlessness, fatigue, decreased activity and performance status. Oxygen release from haemoglobin is dependant on the level of the haemoglobin ligand 2,3‐diphosphoglycerate (DPG) in red blood cells. Stored blood is often low in DPG. As a result, oxygen binding to Hb increases, impairing oxygen release. It can take up to 48 hours before DPG levels and oxygen dissociation normalise in transfused blood (Ledingham 1977).
Why it is important to do this review
Blood is a finite resource (Anon 2009) and demand is anticipated to increase within ageing populations (Wells 2002). The annual UK cost of transfusion increased by 256% between 1994/5 and 2000/2001 (Varney 2003). Total cost per unit is estimated at GBP 635 in the UK (Varney 2003), CAD 469 in Canada (Cremieux 2000) and is as much as USD 2400 in the US (Basha 2006). Transfusion is an invasive treatment associated with significant adverse events including fever, overload, allergic reaction and potentially fatal adverse events due to anaphylaxis (McClelland 2007).
Despite the presence of anaemia in over two‐thirds of patients at the end of life (Dunn 2003) pooled estimates from four studies demonstrated that only 326/4696 (7%) of patients are transfused (Brown 2007; Laird 2008; Martinsson 2009; Monti 1996). Studies have found that pre‐transfusion Hb level does not correlate with response to transfusion (Gleeson 1995; Monti 1996) and maintenance of post transfusion Hb is not associated with sustained symptomatic improvement (Mercadante 2009). There are few studies employing validated tools to measure response (Brown 2010). It is vital that clinicians identify which patients are likely to benefit from transfusion so that patients are protected from unnecessary risk, and scarce resources are utilised cost‐effectively. This review will explore the evidence for blood transfusion for anaemia in patients with advanced cancer. The findings will help clinicians and consumers make evidence‐based decisions regarding transfusion and identify research objectives.
Outcome measures
Eleven fatigue assessment tools have been identified for use with palliative care patients (Yennurajalingam 2007). Not all tools are validated and the validation process has not always been sufficiently robust (Nekolaichuk 2008). The Functional Assessment of Cancer Therapy – Fatigue subscale (FACT F – fatigue subscale) and Brief Fatigue Inventory (BFI) have been validated in cancer populations (Mendoza 1999; Yellen 1997). Both tools are short yet retain strong psychometric properties (Schwartz 2002).
Although there is no universally accepted measurement scale to assess breathlessness in adult palliative care patients, a recent systematic review identified the Numeric Rating Scale, Chronic Respiratory Questionnaire breathlessness subscale, modified Borg and Japanese Cancer Dyspnoea Scale as most suitable for use in palliative care (Dorman 2007).
Objectives
To synthesise the existing clinical evidence and summarise knowledge gaps regarding blood transfusions for treating anaemia in patients with advanced cancer.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs)
Cluster‐randomised trials (CRTs)
Controlled clinical trials (CCTs)
Controlled before and after studies (CBAs)
Interrupted time series analyses (ITSs)
Controlled prospective studies (CPSs)
We excluded studies if there were fewer than 10 participants.
Types of participants
Inclusion
Adults and children from specialist palliative care or hospice settings (inpatient or community) or participants in any care setting with a diagnosis of advanced cancer being treated with palliative intent
Participants with symptoms that a physician judges to warrant a blood transfusion
Exclusion
Participants receiving cancer treatment such as chemotherapy and radiotherapy
Types of interventions
Blood transfusions versus no intervention/standard care
Blood transfusions versus any control arm
Comparison of two different doses of blood transfusion
Types of outcome measures
Primary outcomes
Our primary outcome measures were:
dyspnoea and fatigue scores.
Secondary outcomes
Our secondary outcome measures were:
symptom relief as measured in the primary studies including tools specifically aimed at children;
performance status as measured in the primary studies;
survival from transfusion;
quality of life as measured in the primary studies;
adverse events.
Search methods for identification of studies
The search strategy used a combination of controlled terms (MESH headings, EMTREE etc) and free‐text terms. An example search strategy is shown in Appendix 1 and we adapted this for use in other databases and search engines as detailed under Electronic searches. We searched all databases from their inception.
Limits
Human. There were no limits on language, date or geographical coverage.
Electronic searches
General databases
The Cochrane Library (via Wiley), to include the Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL) and Database of Reviews of Effects
MEDLINE (via OVID ) from 1996 onwards ‐ including MEDLINE in process and as supplied by publishers records
EMBASE (via OVID) from 1980 onwards
Web of Science
CINAHL (via EBSCO) from 1981 onwards
British Nursing Index (via NHS Evidence)
Google Scholar
Theses and dissertations
Proquest Digital Dissertations
Index to Theses
DART‐Europe E‐Theses portal
Universal index of Doctoral Dissertations in Progress
Conferences
Web of Science
ZETOC
Clinical trials
CENTRAL (Cochrane)
UKCRN
Current Controlled Trials
Clinical Trials.gov
ICTRP
Web search engines
SCIRUS
Mednar
Other websites
We searched other websites for conference presentations, reports and unpublished literature, including the following.
European Association of Palliative Care
American Society of Clinical Oncology
European Haematology Association
National Hospice and Palliative Care Organization (US)
National Palliative Care Research Center (US)
Canadian Hospice Palliative Care Association
British Society for Haematology
Searching other resources
Cited by searches
We carried out 'cited by' searches on key references in those databases which support this, i.e. Web of Science and EMBASE.
Handsearching
We screened references from retrieved articles for additional publications. We also scanned the reference lists from relevant chapters in key resources, e.g. Oxford Textbook of Palliative Care.
Unpublished studies
We contacted investigators who were known to be carrying out work in this area for unpublished data and grey literature.
Data collection and analysis
Selection of studies
We (JB) screened all titles and abstracts of studies identified by the search for relevance. We identified potentially eligible studies and retrieved full papers. Two review authors (NP, AH) independently assessed each study for inclusion in the review and any disagreements were resolved by a third review author (MB) and discussion.
Data extraction and management
Two review authors (NP, AH) extracted data independently from each included study. We resolved disagreements through discussion and referral to a third review author (MB). Data collected included:
-
Study ID and publication details including:
Study aim
Study design
Primary and secondary outcomes
Any control
Numbers of participants in treatment groups
Study quality
Participant characteristics
Interventions including dose, duration and place of treatment
Outcome measures used including symptom scales (such as fatigue, breathlessness etc)
Pre and post transfusion haemoglobin
-
Adverse events:
Major such as anaphylaxis, pulmonary oedema and death
Minor such as local site reactions, fever and raised blood pressure
Indications for transfusion
B12 and folate levels
Confounding variables such as use of steroids
Any comments from participants
Information given to patients about transfusion
We requested additional data from review authors as required.
Assessment of risk of bias in included studies
We identified no experimental studies to assess for bias. However, they would have been assessed for:
randomisation;
allocation concealment;
losses to follow‐up;
baseline comparability; and
absence of performance bias.
No controlled prospective studies (CPs) were found but had they been we would have assessed them for:
control for confounders;
completeness of follow‐up.
Two review authors (NP, AH) independently assessed the methodological quality of the included studies. We categorised the eligible studies:
low risk bias (studies meeting all the quality criteria considered);
moderate risk bias (studies partly meeting one or more quality criteria);
high risk bias (studies not meeting one or more of the quality criteria).
We established a threshold for exclusion for non‐randomised or controlled studies. The criteria to exclude papers was incomplete information about the study population.
Measures of treatment effect
No gold standard exists to measure improvement in a patient’s condition following a blood transfusion in end of life care. We extracted findings for fatigue and breathlessness and assessed responses. We compared haemoglobin levels to any recorded outcome measures.
Where available we had intended to handle data as follows:
Continuous data
We would have extracted continuous data which measured quality of life, pain control, symptom control (ordinal data derived from measurement scales and treated as continuous data) and time spent in hospital from the studies. We would have measured treatment effect by calculating the mean difference (MD) when available. When different scales were used we would have calculated the standardised mean difference (SMD). However, there were insufficient data to measure MD or SMD.
Dichotomous data
We extracted dichotomous data on satisfaction with care, preference and opinion (binary data or ordinal data derived from measurement scales and treated as binary data) and death at home from studies where available. However, there was insufficient information to calculate odds ratio (OR) to measure treatment effect.
Unit of analysis issues
No randomised controlled trials were identified. We had intended to conduct analysis in RevMan 5 (RevMan 2011) using relevant techniques for the type of study included. However, we were unable to perform any sort of analysis suitable for a meta‐analysis due to the different outcomes included and missing data. We would have analysed RCTs, CCTs, ITS, CBA and CPSs separately had data been available.
Dealing with missing data
We contacted study authors to clarify any missing data. Most studies had incomplete recording making it difficult to establish how much this impacted on the overall results. We would have evaluated the amount of data missing from the studies included in the review and the impact of their omission on the overall results but there were insufficient data to warrant this. We would have chosen the appropriate method of intention‐to‐treat (ITT) analysis if data allowed.
Assessment of heterogeneity
Many studies failed to report tumour type and what treatment participants were receiving. Hence it was difficult to establish the heterogeneity of the sample. Had we been able to assess clinical heterogeneity, we would have collected details on the intervention and control treatment, participant characteristics and would have extracted the outcomes evaluated from study reports. Instead, as these data were missing, we asked study authors by e‐mail to provide them. If possible, we would have checked statistical heterogeneity when two or more studies were included in the meta‐analysis. We would have calculated the inconsistency across studies using the I2 statistic and we would not have performed a meta‐analysis if substantial statistical heterogeneity was found (I2 > 50%).
Assessment of reporting biases
We performed no assessment of publication bias.
Data synthesis
Meta‐analysis was not possible and therefore we have summarised results narratively. Had meta‐analysis been appropriate, we would have viewed convergence between the meta‐analysis results and the narrative review as an indication of strong evidence of the effect. We synthesised data to show means and ranges where possible. We summarised the adverse effects in the studies in a qualitative manner. Minimal subgroup analysis was possible, except when comparing inpatient and outpatient populations where available.
Subgroup analysis and investigation of heterogeneity
Insufficient data were available to perform subgroup analysis. Had there been any heterogeneity we would have performed subgroup analyses comparing the results of participants:
treated as in‐ and outpatients; and
from different countries.
Sensitivity analysis
We did not perform sensitivity analysis due to limited data. Had data been available we would have performed sensitivity analysis according to the methodological quality and robustness of the results.
Results
Description of studies
We found no randomised controlled trials (RCTs) or interrupted time series (ITS) which had evaluated the use of blood transfusion in advanced cancer. Hence the EPOC 1998 guidelines were not used. However, we identified 12 before and after studies which included 653 participants purporting to report on the use of blood transfusion in patients with advanced cancer.
Results of the search
The initial title search revealed 726 titles. From these we identified 13 potential studies (Brown 2007; Brown 2010; Gleeson 1995; Laird 2008; Lau 2006; Martinsson 2009; Mercadante 2009; Monti 1996; Morey 2003; Tanneberger 2004; Vassallo 2006; Wachtel 1985; Yang 2011) and all were before and after designs.
Included studies
Twelve studies detailed the use of blood transfusion in patients with advanced cancer and involved 653 participants. All were before and after case series designs and included four which were retrospective (Lau 2006; Monti 1996; Tanneberger 2004; Yang 2011).
Excluded studies
We excluded the study by Martinsson 2009 because it included participants from an oncology unit receiving chemotherapy as well as a subset of participants who did not have a cancer diagnosis.
Risk of bias in included studies
All studies are biased by the nature of their design and therefore provide weak evidence.
Allocation
Not applicable to the studies identified.
Blinding
No RCTs were identified which used blinding. All studies included were before and after studies where both researchers and participants knew the treatment they were getting. Hence all studies were biased.
Incomplete outcome data
We contacted study authors for additional information (Morey 2003; Yang 2011).
Selective reporting
All outcome data are reported in the Characteristics of included studies table. These include fatigue and dyspnoea scales, well being, survival and haemoglobin levels.
Other potential sources of bias
We identified no other sources of bias.
Effects of interventions
Primary outcomes: fatigue and breathlessness
Subjective assessments of response ranged from 31% to 70%. Five studies assessed fatigue pre and post transfusion (Brown 2010; Gleeson 1995; Mercadante 2009; Tanneberger 2004; Vassallo 2006). Mercadante 2009 used the Edmonton Symptoms Assessment Scale (ESAS), and Brown 2010 and Vassallo 2006 used subscales of the Functional Assessment of Cancer Therapy (FACT) scale for fatigue and anaemia respectively. Gleeson 1995 used their own scale and Tanneberger 2004 did not specify the scale used. As different tools were used, the effects could not be pooled. However, a pattern emerged of a response to blood transfusion at around day two to seven which began to wane from day 14. Brown 2010 was the only one to use a predetermined measure of response. On the FACT‐F scale a drop of three points indicates a minimally clinical significant response. They found that 21 out of 30 (70%) participants had a response. The other studies only noted mean scores at the pre and post transfusion time points. The three studies which assessed breathlessness showed similar results with a benefit at day two which had reverted to pre transfusion levels by day 14 (Gleeson 1995; Mercadante 2009; Vassallo 2006). Each study used different scales to measure breathlessness.
Secondary outcomes
Performance status was assessed pre and post transfusion in three studies and this showed minimal or no improvement following transfusion (Brown 2007; Gleeson 1995; Vassallo 2006).
Quality of life was measured in three studies (Gleeson 1995; Mercadante 2009; Tanneberger 2004) using a variety of tools which could not be pooled. Quality of life appeared to improve initially at day two but the benefit started to deteriorate by day 14.
The mean Hb pre transfusion was 7.9 (7.1 to 8.4) g/dL. Only four studies (Laird 2008; Mercadante 2009; Monti 1996; Tanneberger 2004) checked haemoglobin post transfusion and this rose to around 10 g/dL (9.88 to 10.28). Most participants received two units of blood (2 to 3.7).
Eight studies gave survival data which ranged from two to 293 days, reflecting a wide variation in the definition of advanced cancer (Brown 2007; Laird 2008; Lau 2006; Mercadante 2009; Monti 1996; Tanneberger 2004; Vassallo 2006; Wachtel 1985). We calculated a median of all reported median or mean post transfusion survival data and this was 48 days when all eight studies were combined. However, six studies clearly identified all or some of their participants as palliative care inpatients and reported separate survival data for these groups (Brown 2007; Laird 2008; Lau 2006; Monti 1996; Vassallo 2006; Wachtel 1985). Combined median survival for these inpatients was 35 days. Similarly, four studies identified all or some of their participants as outpatients or home‐based participants (Brown 2007; Lau 2006; Tanneberger 2004; Wachtel 1985). Combined median survival for these outpatients was 86 days following transfusion.
Adverse events
We also identified a significant proportion of participants who died relatively soon after transfusion. Laird 2008 found 13.7% of participants died within seven days, Gleeson 1995, Morey 2003 and Yang 2011 found between 23% and 35% of participants died within 14 days and Mercadante 2009 found 16% died within 28 days.
Only three studies commented upon adverse events which had occurred in a minority of participants (3% to 7%) and were mild (Gleeson 1995; Lau 2006; Tanneberger 2004).
Discussion
We were unable to determine reliably the effectiveness of blood transfusion at the end of life because the included studies used before and after designs which are prone to bias, and outcomes and outcome measures varied making it difficult to pool results. However, we did find that between 31% and 70% of participants appeared to show some symptomatic response to blood transfusion between day two to seven, with scores (where measured) returning to near baseline levels by day 14. Mean haemoglobin level that triggered transfusion was 7.9 g/dL and most participants received about two units of blood. Mean post transfusion haemoglobin (where measured) was about 10 g/dL which may not be in the physiological range to make a functional difference to patients' symptoms. Few studies reported that they recorded adverse effects. The lack of additional clinical data meant that we were unable to characterise participants who responded from those that did not. However, one study (Brown 2010) showed that responders had significantly less baseline fatigue than non‐responders, suggesting that a threshold may exist below which response in patients with advanced cancer is unlikely.
We did find a significant proportion of participants (23% to 35%) who died within 14 days of transfusion, which requires further investigation. One explanation is that these participants were terminally ill and would have died without transfusion, implying potentially ineffective use of resource or the decision to transfuse even when death was expected. An alternative explanation is that in patients with advanced cancer, blood transfusion may have resulted in increased morbidity and mortality perhaps because of fluid overload or higher plasma viscosity. Overall survival for inpatients receiving transfusion was lower than that for outpatients (35 days versus 86 days respectively). A prospective study which followed up participants having a transfusion could collect the reason for the transfusion and their anticipated prognosis, which could help identify the reason for these early deaths.
Further research is required to identify which patients are more likely to respond to blood transfusions and to determine more accurately the duration of any response. It is difficult to conduct a randomised controlled trial (RCT) using blood transfusion when it is an established treatment. However, it is likely that a significant proportion of patients do not benefit, and duration is short in those who do. There is a need to research other supportive methods to manage these symptoms in this context which avoids the need to transfuse blood.
Summary of main results
No RCTs were identified. Results from generally low‐quality before and after studies showed 31% to 70% of patients with advanced cancer respond to blood transfusion by improvement in their fatigue, breathlessness or general well being, with duration of response of about 14 days or less. A subgroup of participants died 14 days after receiving a blood transfusion.
Overall completeness and applicability of evidence
More research needs to be conducted in this area due to the limited number of low‐quality studies identified. Research needs to:
identify the cause of the early deaths of those receiving a blood transfusion (i.e. expected or an adverse event);
investigate physicians' decision‐making regarding why they prescribe blood transfusion for some patients but not others with a similar symptom profile;
investigate the characteristics of patients who are more likely to benefit from a transfusion; and
identify whether there is a dose response.
Quality of the evidence
All studies were low quality due to their open design, i.e. they were before and after studies. It was unclear in some studies whether they only included participants with a cancer diagnosis and whether they were still receiving other anti‐cancer treatments which may have affected the results. The studies used different outcome measurement tools making any synthesis of data impossible. They all had various degrees of missing data.
Potential biases in the review process
All studies reported were open to bias by their design.
Agreements and disagreements with other studies or reviews
There is a range of findings within this review which are in keeping with other studies (Gleeson 1995; Laird 2008; Monti 1996; Vassallo 2006).
Authors' conclusions
Implications for practice.
Clinicians that treat patients with advanced cancer who present with anaemia, fatigue and breathlessness (not related to cancer treatment or haemorrhage) need to consider whether alternative management strategies should be tried before prescribing blood transfusion. Evidence from this review of 12 studies (including 654 participants) suggests that around one‐third of patients may not benefit and that duration of response is short in those who do. There may be risk of harm from blood transfusion in frail, ill patients at the end of life, potentially related to fluid overload or higher plasma viscosity. However, these findings are based on data from non‐randomised before and after studies and as such are low‐quality evidence.
Implications for research.
Higher‐quality studies are required to determine effectiveness of blood transfusion at the end of life and, in particular, to determine which patients are most likely to respond and which are not, and the duration of any response. Potential harms of blood transfusion at the end of life (indicated by high 14‐day mortality) need to be distinguished from inappropriate transfusion in patients who are clearly dying from advanced cancer.
What's new
| Date | Event | Description |
|---|---|---|
| 9 February 2016 | Review declared as stable | See Published notes. |
Notes
At February 2016, this review has been stabilised following discussion with the authors and editors. It is correct at the date of publication. There is no new evidence available that is likely to change conclusions. If new evidence likely to change the conclusions is published, the authors and editors will consider updating the review accordingly.
Acknowledgements
We would like to acknowledge the study authors who spent their time in finding additional information for us.
Appendices
Appendix 1. MEDLINE search strategy
The strategy below has been developed for use in MEDLINE via OVID, where .mp = title, original title, name of substance, word, subject heading.
"Blood Transfusion"[Mesh:NoExp]
Transfusion*.mp
#1 or #2
("Palliative Care"[Mesh] OR "Terminal Care"[Mesh:NoExp]) OR "Hospice Care"[Mesh] OR "Home Care Services"[Mesh])
((advanc* or late or last or end or final) adj4 (stage* or phase*)).mp
(palliat* or terminal* or endstage or end‐stage or “end stage” or hospice* or dying). mp
(end adj3 life).mp
4 or 5 or 6 or 7
3 and 8
Where MESH terms were not exploded it was because this would lead to the inclusion of inappropriate terms. For example exploding 'Terminal Care' in MESH would have included Euthanasia.
The same strategy was used in CINAHL as it also uses MESH headings.
In EMBASE the strategy was adapted to the EMTREE headings, but all the same free‐text terms were used as in the MEDLINE search.
Web of Science does not have a thesaurus and so the search was carried out using free‐text terms.
In British Nursing Index, the theses databases and ZETOC the free‐text terms were used.
'Cited by' searches were carried out in EMBASE, MEDLINE and Web of Science.
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Brown 2007.
| Methods | Before and after study in a hospice | |
| Participants | 57 but data on 51 Unclear if all cancer UK | |
| Interventions | Blood transfusion | |
| Outcomes | Primary: Not measured Secondary: Physical functioning measured on the Barthel Index pre and 1 week post transfusion; Barthel dropped from 70 to 66 (51 participants) Mean pre Hb was 8.1 g/dl; Hb not checked post transfusion Overall median survival from this group and a larger survey of participants receiving a blood transfusion was 42 days. Median survival of inpatients was 36 days; for outpatients it was 104 days. |
|
| Notes | Subgroup of participants from a larger survey. Minimal reporting. No adverse events recorded. Included because although unclear from data whether all participants had cancer, the authors recollection was that they did. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | High risk | Before and after study so no blinding. Only secondary outcome measures reported. Population characteristics unclear. |
Brown 2010.
| Methods | Before and after feasibility study | |
| Participants | 48 but data on 30 Mean age 68 (53 to 91) 19 males and 11 females All advanced cancer UK | |
| Interventions | Blood transfusion | |
| Outcomes | Primary: Fatigue measured on FACT‐F Scale pre and at 24 hours and 3 days later. Outcome looking for a minimally significant clinical response (drop of 3 points on the scale). Fatigue measured on the Brief Fatigue Inventory (BFI) with predetermined outcome. 21/30 patients had a minimally clinical significant response according to the FACT‐F scale. Number of patients with a worst fatigue score of 7 or more on the BFI fell from 27/30 patients pre transfusion to 15/30 after. 22/30 reported that the transfusion had helped their fatigue, 3 were unsure and 5 recorded no noticeable difference Secondary: Pre mean Hb 7.96 g/dl; no post measurements; mean units transfused 2.53 No survival data |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | High risk | Before and after study so no blinding |
Gleeson 1995.
| Methods | Before and after study of participants | |
| Participants | 97 participants but data on 91 Mean age 65 (14 to 84) Males 40 and females 51 All advanced cancer UK |
|
| Interventions | Blood transfusion | |
| Outcomes | Primary: Fatigue and dyspnoea measured on an in‐house scale pre, and 2 and 14 days post transfusion. The higher the score the greater the improvement. No definition of a successful outcome/score. Strength/fatigue pre = 3.0, day 2 = 5.4 (P > 0.001) and day 14 = 4.9 (P = 0.001) Dyspnoea pre = 5.7, day 2 = 7.3 (P > 0.001) and day 14 = 6.3 (Not significant) Secondary: Performance status and well being measured on a non‐validated/in‐house scale pre, and 2 and 14 days post transfusion. The higher the score the greater the improvement. No definition of a successful outcome/score. Performance status pre = 3.7, day 2 = 3.6 and day 14 = 3.7 Well being pre = 4.2, day 2 = 5.9 (P > 0.001) and day 14 = 5.8 (P = 0.003) Pre mean Hb 7.9 g/dl; no post measurements; no difference in results if more anaemic, i.e. if Hb < 7.9 g/dl 31% died in less than 14 days |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | High risk | Before and after study so no blinding |
Laird 2008.
| Methods | Before and after study | |
| Participants | 73 participants Mean age 66.5 years (37 to 102) Males 35 and females 38 Predominantly (72/73) advanced cancer participants UK | |
| Interventions | Blood transfusion | |
| Outcomes | Primary: Not measured Secondary: Not specified except 'positive response' but 31% had a positive response Mean Hb pre = 7.9 and post = 10.0 (unclear which day measured on) Mean number of units transfused 2.2 Mean survival 47 days; 13.7% died within 7 days |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | High risk | Before and after study so no blinding. Only secondary outcome measures reported. Population characteristics unclear. |
Lau 2006.
| Methods | Retrospective before and after study | |
| Participants | 76 participants Mean age 70 Males 42 and females 34 All advanced cancer Taiwan | |
| Interventions | Blood transfusion | |
| Outcomes | Primary: Fatigue and dyspnoea measured as present or not with a third symptom 'dizziness'. No severity scores. Reporting unclear but did not show any significant difference in improvement. Secondary: Mean pre Hb 7.9 g/dl Mean survival: for 15 inpatients was 29 days; for 61 outpatients was 110 days |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | High risk | Before and after study so no blinding. Reporting difficult to interpret. Retrospective so may have more errors in reporting. |
Mercadante 2009.
| Methods | Before and after study | |
| Participants | 61 participants Mean age 59 (55 to 63) Males 32 and females 29 All advanced cancer but some may have been receiving chemotherapy Italy | |
| Interventions | Blood transfusion | |
| Outcomes | Primary: Edmonton Symptom Assessment Scale (ESAS) Fatigue pre = 6, day 1 = 4, day 14 = 5.3 Dyspnoea pre = 2.8, day 1 = 1.4, day 14 = 2.0 Secondary: Well being pre = 3.9, day 1 = 6.8, day 14 = 6.0 Mean pre Hb = 8, day 1 = 10.1, day 14 = 9.7 Mean survival 117 days but 16% died < 28 days |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | High risk | Before and after study so no blinding. Population characteristics unclear. |
Monti 1996.
| Methods | Retrospective case note review in an inpatient palliative care unit | |
| Participants | 31 participants Mean age 69.5 (57.5 to 81.5) Males 17 and females 14 All advanced cancer Italy | |
| Interventions | Blood transfusion | |
| Outcomes | Primary: Fatigue and dyspnoea measured pre transfusion on a 4‐point scale (absent, mild, moderate and severe) but no post transfusion measurements Secondary: Subjective assessment of benefit with 51.4% feeling some improvement and 48.6% no improvement Mean Hb pre = 7.27 ± 1.08 and post = 9.88 (± 1.48) Survival 49 days (median) with those who did not experience benefit having significantly shorter survival |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | High risk | Before and after study so no blinding. Retrospective so may have more errors in reporting. |
Morey 2003.
| Methods | Before and after study | |
| Participants | 118 participants Mean age 68 years (21 to 93) Males 72 and females 46 All advanced cancer UK | |
| Interventions | Blood transfusion | |
| Outcomes | Primary: Verbal unvalidated self report scale range of symptoms including well being including breathlessness, fatigue, diarrhoea, weakness, mobility. WHO Performance status but not recorded. Subjective improvement day 2 = 53% and day 14 = 28%. Secondary: Poorer baseline performance status was associated with reduced or no benefit post transfusion Mean pre Hb 8.4 g/dl; no post measurements No overall survival but 23% had died by day 14 |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | High risk | Before and after study so no blinding |
Tanneberger 2004.
| Methods | Before and after study ‐ probably retrospective | |
| Participants | 112 participants All advanced cancer All transfused at home Italy | |
| Interventions | Blood transfusion | |
| Outcomes | Primary: No specific reporting of fatigue and dyspnoea. Secondary: Health‐related quality of life but no information on instrument. Recording unclear but states mean time for control of symptoms was 18.5 days (95% CI 14.8 to 22.2). Mean Hb pre = 7.1; after 1 unit = 8.85; after 2 units = 10.28 Median survival 3 months (2.43 to 4.94) Adverse events: 5.9% slight flushing |
|
| Notes | Poor reporting of symptoms | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | High risk | Before and after study so no blinding. Incomplete data on study population. Only secondary outcome measures reported. Population characteristics unclear. |
Vassallo 2006.
| Methods | Before and after study | |
| Participants | 25 but data reported on 18 Age range 48 to 74 Males 14 and females 11 All advanced cancer Italy | |
| Interventions | Blood transfusion | |
| Outcomes | Primary: FACT‐AN (anaemia scale) Asthenia score: pre = 4 to 5, day 7 = 2 (lower score indicates lower symptom burden) Dyspnoea score: pre = 4 to 5, day 7 = 3 (lower score indicates lower symptom burden) Secondary: Performance status (PS) using Karnofsky Scale; unchanged Dizziness score: pre = 3 to 4, day 7 = 2 (lower score indicates lower symptom burden) Appetite score: pre = 3 to 4, day 7 = 2 (lower score indicates lower symptom burden) Hb pre 7.06; no post transfusion measurements Median survival = 32 days |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | High risk | Before and after study so no blinding |
Wachtel 1985.
| Methods | Before and after study | |
| Participants | 31 participants having a transfusion ‐ no more details All advanced cancer USA | |
| Interventions | Blood transfusion | |
| Outcomes | Primary: Not measured Secondary: Interviewed at 2‐weekly intervals No Hb data Mean survival data: Hospice participants had a 34‐day survival Hospital participants had a 47‐day survival Home care participants had a 59.5‐day survival |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | High risk | Before and after study so no blinding. Study population unclear and limited outcome reporting which was difficult to interpret. |
Yang 2011.
| Methods | Retrospective before and after study | |
| Participants | 54 transfusion episodes but full assessment on 26 episodes given to 22 participants Mean age 73 (47 to 93) All advanced cancer UK | |
| Interventions | Blood transfusion | |
| Outcomes | Primary: Inpatients had symptoms assessed the next day and outpatients at their next outpatient appointment Fatigue improved in 7/26 episodes Breathlessness improved in 2/26 episodes Well being improved in 7/26 episodes Secondary: Nausea in 1 recorded once but unknown out of how many episodes 12 had no improvement Mean Hb pre = 8.2 g/dl Mean number of units transfused 2.3 15/43 participants (35%) had died in less than 14 days |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | High risk | Before and after study so no blinding. Retrospective so increased risk of error in the data. |
CI: confidence interval; FACT‐F: Functional Assessment of Cancer Therapy – Fatigue subscale; Hb: haemoglobin; WHO: World Health Organization
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Martinsson 2009 | Potentially included a large number of participants with chemotherapy‐induced anaemia |
Differences between protocol and review
Nil.
Contributions of authors
The protocol was written collaboratively by all authors. AH concentrated on the background, NP on the methodology and JB on the search terms.
JB performed the search strategy.
NP and AH conducted the title search, collected the papers and performed the data extraction. MB acted as arbitrator.
NP entered the data into RevMan 5 (RevMan 2011).
NP and MB wrote the final report.
MB will be responsible for the update.
Sources of support
Internal sources
International Observatory on End of Life Care, Lancaster University, UK.
External sources
No sources of support supplied
Declarations of interest
None known.
Stable (no update expected for reasons given in 'What's new')
References
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