• Giving medicines that stimulate the bone marrow to produce red blood cells (ESAs) with iron supplements probably decreases the number of blood transfusions, but may also cause more deaths and increase the number of unwanted effects, such as blood clots.
• Because of missing data from the studies we could not compare the different treatment options to each other and rank them.
• We need more studies that compare these medicines directly against each other.
What is anaemia and why do people with cancer develop it?
Anaemia develops when levels of red blood cells are too low. Red blood cells contain a protein called haemoglobin. Iron molecules in the haemoglobin bind to oxygen and carry it around the body. A lack of oxygen to the organs and tissues in the body makes people feel tired and lack energy, and they may be at greater risk of infections. People with cancer are particularly likely to suffer from anaemia. This might be because the cancers cause inflammation and prevent red blood cell production. Or it might be because treatments like chemotherapy slow down production of red blood cells in bone marrow.
People suffering from anaemia may need blood transfusions. However, treatment with medicines that stimulate the production of red blood cells in bone marrow (called erythropoiesis-stimulating agents or ESAs) and iron supplements may reduce the need for transfusions.
What did we want to find out?
We wanted to identify the most effective treatments for anaemia in people with cancer and whether they cause any unwanted effects. We were interested in whether iron supplements or ESAs given alone or together affect:
• haemoglobin levels;
• blood transfusions; and
• unwanted effects.
We also wanted to know the best way to give the medicines: by injection (intravenous), or swallowed (oral).
What did we do?
We searched for studies that compared intravenous, oral or no iron with or without ESAs for the prevention or treatment of anaemia resulting from chemotherapy, radiotherapy, combination therapy or the underlying malignancy in people with cancer. We compared and summarised their results, and rated our confidence in the evidence, based on factors such as study methods and numbers of participants. We used statistical methods to compare multiple treatments against each other and rank them in order of effectiveness and unwanted effects.
What did we find?
We found 96 relevant studies with 25,157 people. People in the studies were different ages and were receiving a mix of anti-cancer treatments or no treatment. They had different types of cancer.
Ninety-two studies reported data for our review. They included 24,603 people and compared 12 different treatment options for anaemia. The treatments included combinations of ESAs with intravenous or oral iron and placebo (something that looks, tastes and smells the same as the iron supplement or ESA but with no active ingredient).
Not every study reported everything we were interested in, so we did not have enough information to compare each treatment with each of the other treatments.
Treatment with ESAs when used on their own or with iron probably increases levels of red blood cells and reduces the need for red blood cell transfusions when compared with no treatment. We cannot rule out an increase in the risk of mortality with ESA in combination with iron, which also appeared to cause more deaths and lead to increased risk of harm caused by the formation of clots in the blood vessels.
Our confidence in the findings
Overall, we are moderately confident in the evidence that one treatment is better or worse than another. Our confidence is limited because we sometimes found very different results for the same treatments, meaning they could have been both good and bad for patients - we did not have enough evidence to reach firm conclusions. Also, due to a lack of evidence we could not rank the treatments.
How up to date is the evidence?
The evidence is up-to-date to June 2021.
When considering ESAs with iron as prevention for anaemia, one has to balance between efficacy and safety. Results suggest that treatment with ESA and iron probably decreases number of blood transfusions, but may increase mortality and the number of thromboembolic events. For most outcomes the different comparisons within the network were not fully connected, so ranking of all treatments together was not possible. More head-to-head comparisons including all evaluated treatment combinations are needed to fill the gaps and prove results of this review.
Anaemia is common among cancer patients and they may require red blood cell transfusions. Erythropoiesis-stimulating agents (ESAs) and iron might help in reducing the need for red blood cell transfusions. However, it remains unclear whether the combination of both drugs is preferable compared to using one drug.
To systematically review the effect of intravenous iron, oral iron or no iron in combination with or without ESAs to prevent or alleviate anaemia in cancer patients and to generate treatment rankings using network meta-analyses (NMAs).
We identified studies by searching bibliographic databases (CENTRAL, MEDLINE, Embase; until June 2021). We also searched various registries, conference proceedings and reference lists of identified trials.
We included randomised controlled trials comparing intravenous, oral or no iron, with or without ESAs for the prevention or alleviation of anaemia resulting from chemotherapy, radiotherapy, combination therapy or the underlying malignancy in cancer patients.
Two review authors independently extracted data and assessed risk of bias. Outcomes were on-study mortality, number of patients receiving red blood cell transfusions, number of red blood cell units, haematological response, overall mortality and adverse events. We conducted NMAs and generated treatment rankings. We assessed the certainty of the evidence using GRADE.
Ninety-six trials (25,157 participants) fulfilled our inclusion criteria; 62 trials (24,603 participants) could be considered in the NMA (12 different treatment options). Here we present the comparisons of ESA with or without iron and iron alone versus no treatment. Further results and subgroup analyses are described in the full text.
We estimated that 92 of 1000 participants without treatment for anaemia died up to 30 days after the active study period. Evidence from NMA (55 trials; 15,074 participants) suggests that treatment with ESA and intravenous iron (12 of 1000; risk ratio (RR) 0.13, 95% confidence interval (CI) 0.01 to 2.29; low certainty) or oral iron (34 of 1000; RR 0.37, 95% CI 0.01 to 27.38; low certainty) may decrease or increase and ESA alone (103 of 1000; RR 1.12, 95% CI 0.92 to 1.35; moderate certainty) probably slightly increases on-study mortality. Additionally, treatment with intravenous iron alone (271 of 1000; RR 2.95, 95% CI 0.71 to 12.34; low certainty) may increase and oral iron alone (24 of 1000; RR 0.26, 95% CI 0.00 to 19.73; low certainty) may increase or decrease on-study mortality.
We estimated that 90 of 1000 participants without treatment for anaemia had a haematological response. Evidence from NMA (31 trials; 6985 participants) suggests that treatment with ESA and intravenous iron (604 of 1000; RR 6.71, 95% CI 4.93 to 9.14; moderate certainty), ESA and oral iron (527 of 1000; RR 5.85, 95% CI 4.06 to 8.42; moderate certainty), and ESA alone (467 of 1000; RR 5.19, 95% CI 4.02 to 6.71; moderate certainty) probably increases haematological response. Additionally, treatment with oral iron alone may increase haematological response (153 of 1000; RR 1.70, 95% CI 0.69 to 4.20; low certainty).
Red blood cell transfusions
We estimated that 360 of 1000 participants without treatment for anaemia needed at least one transfusion. Evidence from NMA (69 trials; 18,684 participants) suggests that treatment with ESA and intravenous iron (158 of 1000; RR 0.44, 95% CI 0.31 to 0.63; moderate certainty), ESA and oral iron (144 of 1000; RR 0.40, 95% CI 0.24 to 0.66; moderate certainty) and ESA alone (212 of 1000; RR 0.59, 95% CI 0.51 to 0.69; moderate certainty) probably decreases the need for transfusions. Additionally, treatment with intravenous iron alone (268 of 1000; RR 0.74, 95% CI 0.43 to 1.28; low certainty) and with oral iron alone (333 of 1000; RR 0.92, 95% CI 0.54 to 1.57; low certainty) may decrease or increase the need for transfusions.
We estimated that 347 of 1000 participants without treatment for anaemia died overall. Low-certainty evidence from NMA (71 trials; 21,576 participants) suggests that treatment with ESA and intravenous iron (507 of 1000; RR 1.46, 95% CI 0.87 to 2.43) or oral iron (482 of 1000; RR 1.39, 95% CI 0.60 to 3.22) and intravenous iron alone (521 of 1000; RR 1.50, 95% CI 0.63 to 3.56) or oral iron alone (534 of 1000; RR 1.54, 95% CI 0.66 to 3.56) may decrease or increase overall mortality. Treatment with ESA alone may lead to little or no difference in overall mortality (357 of 1000; RR 1.03, 95% CI 0.97 to 1.10; low certainty).
We estimated that 36 of 1000 participants without treatment for anaemia developed thromboembolic events. Evidence from NMA (50 trials; 15,408 participants) suggests that treatment with ESA and intravenous iron (66 of 1000; RR 1.82, 95% CI 0.98 to 3.41; moderate certainty) probably slightly increases and with ESA alone (66 of 1000; RR 1.82, 95% CI 1.34 to 2.47; high certainty) slightly increases the number of thromboembolic events. None of the trials reported results on the other comparisons.
Thrombocytopenia or haemorrhage
We estimated that 76 of 1000 participants without treatment for anaemia developed thrombocytopenia/haemorrhage. Evidence from NMA (13 trials, 2744 participants) suggests that treatment with ESA alone probably leads to little or no difference in thrombocytopenia/haemorrhage (76 of 1000; RR 1.00, 95% CI 0.67 to 1.48; moderate certainty). None of the trials reported results on other comparisons.
We estimated that 10 of 1000 participants without treatment for anaemia developed hypertension. Evidence from NMA (24 trials; 8383 participants) suggests that treatment with ESA alone probably increases the number of hypertensions (29 of 1000; RR 2.93, 95% CI 1.19 to 7.25; moderate certainty). None of the trials reported results on the other comparisons.