Introduction

Although modern oncology drugs employ mechanisms distinct from classical 20th-century cytotoxic therapies, cancer-related anemia (CRA) remains an underestimated issue. It is not always solely a consequence of antineoplastic treatments. The prevalence of anemia, varying from 30% to 90%, depends on factors such as neoplasm type, disease progression, or treatment method [1–4]. Anemia ranges from causing mild, persistent symptoms like fatigue to life-threatening conditions, especially for individuals with concurrent chronic diseases. Without a doubt, it significantly impairs quality of life (QOL) for cancer patients [5–6].

General definitions

According to the World Health Organization (WHO), anemia is a state where hemoglobin levels or red blood cell counts fall below the lower limits of normal (women <12 g/dl, men <13 g/dl) [7]. Cancer-related anemia (CRA) can result from cancer treatment (chemotherapy-induced anemia [CIA]) or the disease itself. Neoplasms can affect red blood cell (RBC) production (erythropoiesis), RBC breakdown (hemolysis), and blood loss (bleeding). For anemia resulting from oncological therapy, the Common Terminology Criteria for Adverse Events (CTCAE) grading system is used [8]. However, there are inconsistencies between WHO values and those of CTCAE (tab. I).

Pathogenesis and diagnostic approach

Anemia diagnosis must consider the intricate interplay of RBC production and usage across various organs (the intestines, liver, spleen, kidney, bone marrow) [9]. In most cases, CRA is primarily attributed to two causes – iron deficiency and concurrent antineoplastic therapy. Key indicators in CRA diagnosis are serum ferritin (SF) and transferrin saturation (TSAT; serum iron/total iron binding capacity x 100). Other iron-related parameters are often influenced by external factors and are unreliable predictors (e.g., MCV, soluble transferrin receptor) or are not routinely available (e.g., zinc protoporphyrin or hepcidin levels).

Functional and absolute iron deficiency

Typically, CRA patients exhibit normocytic anemia accompanied by iron deficiency (TSAT < 20%) and normal or elevated SF > 100 ng/ml [10–13]. This condition is referred to as functional iron deficiency anemia (FIDA). Another situation arises when TSAT is <20% and ferritin is <100 ng/ml, leading to absolute iron deficiency anemia (AIDA) [14]. These two clinical scenarios have distinct underlying causes. AIDA is usually linked to blood loss or inadequate iron intake/malabsorption. FIDA, on the other hand, arises due to iron sequestration driven by chronic inflammation (involving hepcidin) [15], and/or iron-restricted erythropoiesis prompted by endogenous erythropoietin production or erythropoiesis-stimulating agents [16].

Role of inflammation and hepcidin

Inflammation is a hallmark of cancer [17], impacting erythropoiesis via cytokines like IL-1, IL-6, IL-10, IFN-γ, TNF-α, and raising reactive oxygen species (ROS) levels. The levels of these cytokines can predict hemoglobin concentrations [18]. Hepcidin, a liver-produced iron regulatory hormone, is affected by both inflammatory cytokines and ROS. Hepcidin inhibits iron release to erythropoiesis from macrophages and hepatocytes, and also influences iron absorption in enterocytes. This hormone binds to ferroportin, an iron exporter, causing its degradation [19–20]. Consequently, oral iron absorption is limited in cancer patients, reducing its availability for dietary supplementation.

Treatment-induced anemia

In the past five years, over 200 cancer drugs have been approved, with 14% surpassing the prior standard of care [21]. Chemotherapy-induced anemia remains a significant concern, as it is still widely used, especially in neoadjuvant and adjuvant settings for solid tumors. Up to 90% of solid tumor patients experience anemia during chemotherapy [22], with incidence varying by regimen, tumor type and stage.

New agents like tyrosine kinase inhibitors (TKIs), small molecules and immunotherapy (ICI) can induce or exacerbate preexisting anemia differently from traditional cytotoxic agents. TKIs often lead to hematological toxicities [23], with mechanisms varying. Some TKIs, such as sunitinib, imatinib and pazopanib, can cause macrocytosis, which may serve as a predictor of patient survival [24–26]. The mechanism might relate to c-KIT inhibition [26]. Rarely do drugs like alectinib induce hemolytic anemia [27].

Immunotherapy can also lead to anemia via autoantibody-induced hemolysis, requiring treatment with steroids and rituximab [28]. In extremely rare cases, lethal aplastic anemia has been described [29].

CRA treatment

Three main strategies address CRA, either individually or in combination. Correcting deficiencies (iron, vitamin B12, folate) is paramount. Erythropoiesis-stimulating agents (ESAs) and red blood cell concentrates (transfusions) follow.

Iron treatment

While oral iron is standard for general iron deficiency anemia treatment, it has limitations in cancer patients due to gastrointestinal (GI) intolerance. GI symptoms often accompany cancer treatments, making oral supplementation difficult [30]. Moreover, heightened hepcidin levels impair proper iron utilization. Studies suggest alternating dosing schedules could decrease hepcidin levels and enhance iron absorption [31–32]. Intravenous (iv) iron is preferred for CRA patients due to its more direct delivery and bypassing GI issues [33–34]. Intravenous iron, alone or with ESA, effectively treats chemotherapy-induced anemia, saves costs and improves QOL [35–38]. Intravenous iron suits both functional and absolute iron deficiency scenarios.

Intravenous iron treatment

Intravenous iron formulations have been utilized in human medicine for nearly a century; however, some physicians continue to harbor unnecessary concerns reminiscent of the early days of its introduction [39]. The prospective European ECAS study, conducted at the beginning of the 21st century to gather data on the prevalence and treatment of anemia, revealed that only 6.5% of patients received iron treatment [40]. These concerns likely stem from apprehensions about potential side effects.

Safety and side effects of intravenous iron supplementation

Contemporary iron products (as outlined in table II) all possess an iron core enveloped by a carbohydrate shell, a feature that distinguishes them from one another. Intravenous iron infusions seldom lead to hypersensitivity reactions, and although such reactions can be life-threatening, severe anaphylactic-type reactions are exceedingly rare [41]. High molecular weight iron dextrans, previously used, had significantly higher rates of serious adverse drug events, leading to their discontinuation. The new formulations are designed to be safer. A comprehensive systemic review that evaluated the safety of intravenous iron across randomized clinical trials established that intravenous iron is not correlated with an increased risk of serious adverse events [42]. The European Medical Agency has issued recommendations for managing allergic reactions associated with intravenous iron-containing medications, concluding that the benefits of these medications outweigh the associated risks [43]. As a result, administering a test dose with these new formulations is no longer advised.

Prevention and management protocols for infusion reactions have been well-delineated and align with approaches used in managing other infusion-related reactions observed in the field of oncology [44, 45]. There is contradictory data concerning cardiotoxicity and the risk of exacerbating infections when using intravenous iron [42, 46, 47]. Consequently, intravenous iron administration should be avoided in patients with active infections and on the same day as cardiotoxic chemotherapy administration.

In conclusion, the use of more recent intravenous iron formulations is regarded as safer compared to other commonly used methods in addressing anemia among cancer patients [42]. Nonetheless, determining the optimal dosing and treatment schedule for intravenous iron remains an ongoing effort, with variations among the different available products.

Erythropoiesis-stimulating agents

Erythropoietin (EPO), a hormone produced in the kidneys and liver, increases red blood cell production in response to hypoxia. Recombinant EPO was synthesized in the 1980s, revolutionizing chronic kidney disease treatment [48]. ESAs entered oncology in the 1990s, gaining popularity but later encountering safety concerns [49]. Modern erythropoiesis-stimulating agents (ESAs) (tab. III) are indicated for adult cancer patients with non-myeloid malignancies receiving chemotherapy, aiming to raise hemoglobin from 8–10 g/dl to no more than 12 g/dl. ESA treatment necessitates reevaluation after 4–6 weeks, adjusting doses based on response or cessation if no response is observed.

ESAs concerns

The most common side effects include allergic reactions and cardiovascular complications. Allergic reactions range from more commonly occurring mild local injection site reactions to rare but serious reactions that require prompt attention. Early reports regarding thrombotic risk [50] led to concerns about the safety of ESAs and their potential impact on the survival of cancer patients. A recent systematic review of randomized controlled trials revealed that although this type of therapy is associated with adverse cardiovascular effects, including venous thromboembolism (VTE), it does not affect patients’ overall survival, and ESAs can be used safely [51]. Due to the lack of prospective trials, neither the National Comprehensive Cancer Network® (NCCN®) nor the European Society of Medical Oncology recommends the routine use of standard prophylactic anticoagulation in the absence of other risk factors [33, 52]. The use of validated scales predicting VTE events, such as the KHORANA scale, is strongly encouraged for patients receiving chemotherapy [53]. Another significant cardiovascular effect is arterial hypertension, which typically manifests at the beginning of therapy. The exact mechanism of this complication is not well understood. An important subgroup of patients includes those with chronic kidney disease or preexisting arterial hypertension. For these individuals, the introduction of ESAs should be cautious, and a gradual correction of anemia is advised [54].

ESAs and possible stimulation of cancer growth

Increased EPO signaling has been observed on cancer cells, particularly in the hypoxic regions of various tumors [55]. This observation led to the hypothesis of potential cancer growth stimulation. Early trials suggested inferior overall survival among patients receiving ESA during chemotherapy [56–57]. However, all trials that raised such concerns targeted hemoglobin levels above 12 g/dl. When ESAs are used within registered indications among patients receiving chemotherapy for non-myeloid cancers with hemoglobin levels below 10 g/dl and a target range up to 12 g/dl, no impact on overall survival was confirmed [51, 58–61]. Recent randomized, double-blinded, placebo-controlled studies focusing on this strategy appear to confirm the safety of ESAs and their lack of impact on overall survival (OS) and progression-free survival (PFS) for patients with solid tumors [62].

Combining intravenous iron and ESAs

Given the recommendation for correcting all deficiencies prior to initiating ESA treatment, a question arises about the combination of iv iron formulations and ESAs. This treatment approach should be administered on a regular daily basis, as demonstrated in a randomized controlled trial that showed significant improvements in both quality of life (QoL) and hemoglobin levels [16]. This combination also leads to a reduction in the need for transfusions when compared to the use of ESAs alone [63].

ESA future directions

Further research, particularly randomized controlled trials focused on the safety of ESAs, is necessary. With the growing interest in the potential immunomodulatory effects of erythropoietin (EPO) and its derivatives (given that ESAs might exhibit anti-inflammatory effects) [64], additional studies are required to determine the viability of their use in conjunction with modern treatment modalities like immunotherapy.

Transfusions

RBC transfusions are commonly used, because they provide quick relief, but come with risks like immune modulation [65, 66]. Transfusions negatively impact cancer patients, affecting progression-free and overall survival, recurrence and perioperative morbidity [67–74]. Some negative effects stem from immune activation, impacting oncology treatments [75–76]. Recent trials found decreased immunotherapy response rates with transfusions [77].

Considerations for optimizing RBC use in cancer patients

Although the precise hemoglobin (Hb) level or timing for blood transfusions in relation to the type of cancer treatment or disease stage has yet to be definitively established, there is existing data regarding different approaches to red blood cell (RBC) utilization.

Recognizing the adverse effects of transfusions on cancer patients at various stages of therapy, many healthcare professionals underscore the importance of adopting a more cautious approach to RBC transfusions. This approach is founded on the use of a lower Hb concentration as the threshold for initiating transfusions (typically around 7–8 g/dl), in contrast to a more liberal threshold (around 9–10 g/dl). Restrictive RBC transfusion strategies (Hb < 7–8 g/dl) align with reduced morbidity and mortality [78–79].

Foliate and vitamin B12 deficiency

Megaloblastic anemia stemming from deficiencies in vitamin B12 and folate is less frequent among cancer patients compared to iron deficiency. Such deficiencies may be linked to disease progression and malnutrition, as well as increased cellular turnover, particularly in cases of lymphomas and leukemias. Individuals who have undergone gastrectomy or have experienced significant infiltration of the intestine may also experience such deficiencies due to the altered absorption of these vitamins in these parts of the digestive system. Certain cytotoxic drugs, commonly employed in cancer treatment such as 5-fluorouracyl, methotrexate and hydroxycarbamide, can induce megaloblastic anemia by interfering with DNA synthesis [80].

Additional considerations for the treatment of cancer-related anemia

While the primary modalities of addressing cancer-related anemia (ESA, iron supplementation and transfusions) form the foundation of management, there are several other noteworthy aspects to be taken into account. These encompass lifestyle interventions and a range of supplementary approaches.

Physical activity

Compelling evidence underscores the pivotal role of exercise and various forms of physical activity in cancer prevention and treatment, notably in enhancing patients’ quality of life (primarily alleviating fatigue). Of all cancer-related fatalities worldwide, approximately 35% can be attributed to environmental factors, including sedentary lifestyles [81]. Different types of exercise have proven highly effective in mitigating cancer-related fatigue during treatment [82], as well as potentially improving overall cancer survival rates [83]. Given the key role inflammation plays in the development of cancer-related anemia, the potential anti-inflammatory effects of physical activity are noteworthy. Moreover, physical activity may influence hepcidin levels. Emerging data suggests that engaging in exercise can lead to improvements in hemoglobin levels in patients undergoing chemotherapy while using ESAs [84], in breast cancer patients during radiotherapy [85], and in breast cancer patients undergoing chemotherapy [86–87]. Nonetheless, an optimal type and intensity of physical activity has yet to be definitively established.

Hepcidin-directed therapy

Given the often-elevated levels of hepcidin in cancer patients, therapeutic approaches involving monoclonal antibodies that neutralize these proteins have gained attention. This form of treatment holds the potential to enhance ferroportin expression in enterocytes and macrophages, thereby facilitating the release of stored iron and promoting effective erythropoiesis. Initial clinical trials assessing the safety of such antibodies in addressing cancer-related anemia have yielded promising results [88]. Subsequent research in this domain is warranted, as it could potentially introduce another avenue for targeted treatment of cancer-related anemia.

Zinc deficiency

Zinc deficiency is prevalent in many countries and frequently coexists with iron deficiency. Among adults afflicted with chronic diseases, zinc deficiency has been associated with anemia [89]. While some recent analyses among non-cancer anemic patients have suggested a correlation between zinc levels and hemoglobin concentration [90], evidence in the context of cancer patients remains limited.

Conclusions

CRA’s impact is significant, but awareness and treatment approach vary. There are three main pillars guide treatment: correcting deficiencies, using ESAs and transfusions. Intravenous iron addresses iron deficiency more effectively. ESAs have associated concerns but remain valuable. Transfusions provide relief but may affect prognosis. Future research focuses on enhancing interventions and combining treatments to optimize CRA management.

Article information and declarations

Author contributions

Konrad Tałasiewicz – conceptualization, visualization, writing – original draft, writing – reviewing and editing.

Aleksandra Kapała – conceptualization, supervision, writing – reviewing and editing.

All authors discussed and commented on the manuscript.

Funding

None declared

Conflict of interest

None declared

Konrad Tałasiewicz

Maria Sklodowska-Curie National Research Institute of Oncology
Department of Oncology Diagnostics, Cardio-Oncology and Palliative Medicine
ul. Roentgena 5
02-781 Warszawa, Poland
e-mail: konrad.talasiewicz@nio.gov.pl

Received: 12 Aug 2023
Accepted: 6 Sep 2023

References