Blood Transfusions in Patients with Advanced Cancer at the End-of-Life: Are They Really Beneficial?

INTRODUCTION

Anaemia is common in individuals with advanced cancer at the end of life, with studies reporting a prevalence rate as high as 50% for any palliative care (PC) admission to 90% in the last admission before death.^[1] The World Health Organization defines anaemia with haemoglobin level under 12 g/dL in women and 13 g/dL in men respectively.^[2] Anaemia aetiology includes chronic inflammation, erythropoietin deficiency, bone marrow infiltration, bleeding events and treatment side effects.^[1] While several types of anaemia exist, iron deficiency anaemia (IDA) is most commonly linked to malignancy.^[3] IDA implies a lack of sufficient mineral iron to help the body produce red blood cells (RBCs). However, research carried out by Natalucci et al. (2021) suggests that the majority of cancer-related anaemia is, in fact, multifactorial.^[4] In an endof-life context, RBC transfusions are regularly administered to address bothersome symptoms such as fatigue, dyspnoea, or in patients with active bleeding^.[5] Recent reviews found that most patients report symptomatic benefits that can extend even to a few weeks, with minimal adverse events.^[1] However, there are still no baseline predictors of who will most likely benefit.^[1] The decision to transfuse patients in PC can be complex. In this context, goals of care are individualised, and clinical endpoints usually involve the short-term alleviation of symptoms rather than the restoration of health. Thus, the transfusion decision thresholds differ from the one used in non-palliative patients.^[6] Transfusions are not without risks, including adverse reactions, fluid overload, and infection.^[7] Furthermore, benefits seen in non-palliative patients cannot be extrapolated to patients at the end of life, given their disease extent, cachexia, and poor functional status at baseline.^[7] Factors such as other underlying comorbidities, poor nutritional intake and deficiencies, deconditioning and expected survival time all confound usual RBCs transfusion risks and benefits assessments.^[6] Multiple unresolved questions remain about the place of RBC transfusions in the therapeutic arsenal to alleviate symptoms in PC. What are the symptomatic benefits? What are the effects on the overall quality of life? What is the impact on the overall survival post-RBC transfusion? Evidence of the risks and benefits of RBCs in a PC setting remains scarce.^[1,6,8]

In addition, RBCs are a valuable and limited resource.^[6] In emergencies, they are regularly urgently required for their life-saving effect, thus raising ethical considerations in balancing the availability of resources, patient’s needs, and the wider population requirements.^[1]

There are currently no clinical practice guidelines or randomised controlled trials to evaluate the effectiveness of transfusions or to determine which groups of patients with advanced cancer are most likely to benefit.^[9] This study aimed to examine the indications, practices and outcomes of RBC transfusions at the end-of-life in hospitalised patients with advanced cancer, with the goal of contributing to the evidence needed for the future development of clinical practice guidelines for RBC transfusions in PC settings.

MATERIALS AND METHODS

RESULTS

RBCs transfusion indications and practices

The primary non-exclusive indications for the RBCs transfusion were a low haemoglobin level (n = 151; 95%), followed by shortness of breath (n = 31; 19.5%), tiredness (n = 28; 17.6%) and weakness (n = 24; 15.1%). Other less common indications included paleness, dizziness, irregular heartbeat, chest pain, and headache [Figure 1]. PC physicians requested most transfusions (n = 109; 68.5%). The mean pretransfusion haemoglobin level was 64.5 g/L (9.3) and ranged from 40 to 87 g/L. The mean platelet count was 229 × 10⁹/L (205), ranging from 1 to 1322 × 10⁹/L. Active bleeding was present in 50 participants (31.4%). The mean time between the prescription and transfusion initiation was 5.6 h (SD = 3.9). Most of the transfusions were considered non-urgent. Most patients received either 1 (n = 75; 47.2%) or 2 (n = 83; 52.2%) RBCs unit(s) per transfusion episode, with only one patient (0.6%) receiving three units. 144 patients (90.6%) had a transfusion history in the past six months.

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Figure 1:

Frequency of nonexclusive indications for blood transfusions. n = 159 transfusion episodes. X axis represents symptoms and Y axis represents frequency (%).

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Transfusion outcomes

Considering all episodes of RBC transfusion (n = 159), for 82.4% (n = 131) of these, there was no documentation of symptomatic relief post-transfusion. The symptomatic benefit was evaluated by reviewing the physician’s written documentation and patient reports, either through verbal feedback regarding the effects following the RBC transfusion or, on occasion, using the validated Arabic Questionnaire for Symptom Assessment (AQSA) tool. Among the remaining, improvement in tiredness (n = 9; 5.7%), shortness of breath (n = 7; 4.4%), bleeding (n = 6; 3.8%), paleness (n = 2; 1.3%), and dizziness (n = 2; 1.3%) were recorded [Figure 2]. For 6 patients (3.9%), the documentation indicated a ‘clinical improvement’ without specifying its nature. Only one transfusion adverse reaction was recorded as a febrile nonhaemolytic transfusion reaction.

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Figure 2:

Post-blood transfusion episode symptomatic outcomes. n = 159 transfusion episodes. X axis represents symptoms and Y axis represents frequency (%).

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There were no significant correlations between documented indications and documented symptomatic relief post-transfusion; for example, the Indications for transfusion (shortness of breath) and symptomatic benefit post-transfusion (improved shortness of breath) were pearson correlation test (r) = −0.022.

Survival analysis

The mean survival time post-transfusion was 31 days (SD = 33.2), with a median of 18 days with 95% CI (25, 36). In 25% of the RBC episodes, the patient survived for 7 days or less, and 50% survived for 18 days or less [Figure 3]. No significant differences in survival were found based on sex (t-test [t] = −0.3833, P = 0.7023) or primary diagnosis (t = 1.3029, p-value [P] = 0.2421). A moderate negative correlation was observed between age and survival days (r = −0.303), suggesting that older patients tended to have a shorter survival time post-transfusion. The Charlson Comorbidity Index showed a weak positive correlation with survival days (r = 0.134). The mean length of stay (LOS) during the transfusion episode was 33 days (SD = 41). Most patients (n = 132; 83%) died during the same hospitalisation that the transfusion was administered. For the remaining, some were discharged to a local hospital (n = 3; 1.9%), home (n = 1; 0.6%), or had an unknown disposition (n = 23; 14.5%). The survival probability decreases progressively over time, indicating that patients tend to experience a decline in survival as the number of days post-transfusion increases [Figure 4]. A sharp decline in survival probability is observed during the initial days post-transfusion. This suggests that a significant proportion of patients face death shortly after the transfusion. A smaller subset of patients survives beyond 100 days post-transfusion.

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Figure 3:

Distribution of the number of survival days’ post-blood transfusion episode.

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Figure 4:

Kaplan–Meier survival curve.

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DISCUSSION

This study aimed to assess RBC transfusion indications, practices, and outcomes at the end of life in a cohort of patients with advanced cancer admitted to a specialized PC unit. The results of this study indicate that the mean age of patients receiving a transfusion was 46.7 years. This mean age is significantly lower than in similar studies in Portugal and Canada.^[9,10] Saudi Arabia’s relatively young population could potentially explain these results.

In this study, a third of the RBC transfusion episodes occurred while the patient had active bleeding. Several medications increased the risks of bleeding, such as anticoagulants (35%) and anti-inflammatory drugs (27%), were found to be taken by patients. The place of such medications in an end-of-life context is still poorly understood, with scarce evidence regarding their benefits.^[11] Physicians often have mixed reviews about prescribing, pursuing, or discontinuing these medications in a PC setting.^[11]

The reasons guiding their choice to pursue these drugs were the lack of evidence supporting their discontinuation in this context, uncertainty about patients’ life expectancy, and the fear of harming patients.^[11] A retrospective review in Sweden investigated bleeding as a side effect of antithrombotic treatments in the last year of life.^[12] The researchers mapped the timing of de-prescribing these drugs (n = 1501 charts).^[12] The results highlighted the lack of clear guidance regarding the pursuit or discontinuation of antithrombotic agents in a PC settin g. They found these drugs to be associated with a high risk of bleeding, especially in the last years of life.^[12]

In this study, for almost all the RBC transfusion episodes, the primary indication was a low haemoglobin value, followed in a much smaller proportion by shortness of breath, fatigue, and general weakness. If the proportion of patients who were administered RBCs due to a low haemoglobin level is much higher than found elsewhere, the other listed indications are similar to studies globally.^[4,10] Two retrospective chart reviews of RBC transfusion practices in a PC service in Canada indicated that RBC transfusions rarely occur.^[4,10] Similarly to our study, when administered, blood products are primarily used in patients with cancer to address fatigue and dyspnoea, with most patients reporting benefits.^[4,10] A study conducted in Portugal also reported fatigue as the primary indication, with dizziness and shortness of breath following.^[9] RBC transfusions were beneficial for 36% of patients.^[9] Fatigue was the most commonly targeted symptom in a large prospective series of RBC transfusions in PC.^[1] If 49% of patients reported symptomatic relief, no clear predictors of response were identified.^[1] Another retrospective cohort study reported that the most common indications for RBC transfusion were fatigue/lethargy (41/44, 93%), followed by shortness of breath (7/44, 16%), light-headedness (3/44, 7%) and active bleeding (6/44, 14%).^[7] The majority of patients (94%) reported symptomatic improvements.^[7]

Surprisingly, in this study, no outcomes in symptomatic relief post-RBC transfusion were documented for most patients. In other studies, clinicians commonly report improvement following RBC transfusion in 65–89% of patients.^[7] However, clinicians’ assessments are not exempt from biases. They can be overconfident in their ability to objectively assess their patients’ clinical situations, not systematically feeling the need to ask patients to self-assess their symptoms. Another interesting finding is the poor improvement in average scores recorded using validated symptom measurement tools such as the Resource Utilisation Groups-Activity of Daily Living, Australia Modified Karnofsky Scale, or Symptom Assessment Scale-Breathing and fatigue scales in studies.^[7] These tools are possibly not well adapted to assess the needs and benefits of RBC transfusions in the end-of-life context.

This study’s mean survival time post-transfusion was approximately 1 month, and in 75% of the RBC transfusion episodes, patients survived <2 or 5 weeks [Figure 3]. A similar result was found in a study assessing RBC transfusion’s impact on survival in patients with advanced cancer in the terminal stage.^[13] Anaemic patients who were transfused compared with anaemic patients who were not transfused had a survival time (15 days vs. 8 days, P < 0.001). In contrast, other studies have found longer survival times than our study. In a large retrospective cohort study (n = 885 patients transfused/6980 patients referred to PC between 2014 and 2018), the median survival post-transfusion was 56 days, 95% CI (19, 200).^[14] Another similar study reported a 30-day survival rate of 57% post-RBC transfusion.^[9] Among those surviving more than 30 days, having received transfusions was associated with a higher likelihood of death in a hospital setting.

The decision to administer an RBC transfusion is challenging, requiring a balance between symptomatic benefits and available resources. An alternative approach is to discuss the benefits, risks and prognosis of transfusions with patients and families to ensure alignment with their preferences. In addition, prioritizing RBC resources for patients who will gain significant comfort and avoiding transfusions with minimal benefit is suggested. A study on transfusion practices among PC physicians in Canada revealed that most physicians felt a lack of evidence to guide transfusion therapy and often relied on judgment and experience when making transfusion decisions.^[15]

In our study, older patients tended to have a shorter survival time post-transfusion. In a retrospective review exploring the 1-year mortality rate in 897 heart failure patients, the Charlson Comorbidity Index was used.^[16] However, in our study, the mean Charlson Comorbidity Index score was 7.8 (SD = 2.3), compared with a similar study (9), which showed a mean score of 8.9 (SD = 2.3). These findings can be explained by the marked difference in the mean age of the two studies; with this study’s mean age of 46.7 versus 80.2, a higher Charlson Comorbidity Index score is associated with older age.

Even if studies rarely report adverse effects of RBC transfusions, the high rate of deterioration linked to the disease progression observed in patients despite these transfusions still raises questions about their actual effect at this very end of life.^[17]

CONCLUSION

This study found limited benefits of RBCs transfusion in terms of symptomatic relief and increased survival time in hospitalised patients with advanced cancer. As illustrated in a systematic review, there is a lack of high-quality studies supporting the benefit of RBC transfusions in a PC context. In addition, a lack of validated pre- and post-transfusion assessment tools does not enable the recommendation of the practice at this stage. An optimal outcome assessment would ideally incorporate self-reported measures of specific symptoms and overall quality of life, including functional status. RBCs transfusions should not be indiscriminately offered to patients with anaemia, but rather given to those predicted to have the most significant benefit. This advice is consistent with recommendations from international guidelines.