Anemia, Thrombosis, Transfusion Therapy, and Cancer Outcomes

Burden of Anemia and Iron Deficiency in Cancer Patients

Iron deficiency and anemia contribute to cancer-associated morbidity. These reflect blood loss (particularly in tumors of the gastrointestinal tract) and the inflammatory response to the tumor and neoadjuvant therapy. The European Cancer Survey highlighted the prevalence of anemia in different cancer types; 39% of patients were anemic at time of diagnosis, with 68% becoming anemic within 6 months of starting treatment, a reflection of the additive effects of multiple rounds of chemotherapy and/or surgery.

Emerging evidence suggests that iron deficiency, even in the absence of anemia, should be considered an actionable pathology in its own right. Data on the prevalence of iron deficiency as an independent laboratory abnormality in the oncological population are highest in the colorectal cancer population, ranging from 50%–60% in some series, as a reflection of chronic blood loss. ^, However, even in patients where ongoing bleeding is not a hallmark of the malignancy, iron deficiency is also found in up to 46% of cases.

Pathophysiology of Anemia in Cancer

Causes of anemia can be divided into three categories:

• 1

  Blood loss;

• 2

  Increased red cell destruction;

• 3

  Decreased red cell production.

Although certain tumors enable chronic, ongoing blood loss, most cancer-associated anemia is caused by diminished red cell production and is often due to iron deficiency ( Fig. 8.1 ). Broadly speaking, iron deficiency can be defined as:

• a lack of stored iron due to chronic losses (absolute iron deficiency), and

• inability to access stored iron (functional iron deficiency).

Functional iron deficiency is a consequence of the inflammatory response. A key contributor to the associated “anemia of inflammation” is dysregulation of the cytokine interleukin-6 (IL-6). Overexpression of IL-6 has been found in almost all types of tumor, promoting tumorigenesis, suppressing erythropoietin, and increasing expression of the iron regulatory hormone hepcidin. Hepcidin downregulates ferroportin-1, a transmembrane protein that enables iron to be transported across cell membranes. Consequently, iron cannot be absorbed from the gut, and stored iron cannot be accessed by bone marrow. This restricts erythropoiesis and limits the efficacy of oral iron supplementation. Additionally, overexpression of tumor necrosis factor-α (TNF-α) suppresses the hemoglobinization of erythroid progenitor cells, cytotoxic therapies impair hematopoiesis, and nephrotoxic therapeutics impact the production of erythropoietin. Consequently, perioperative risk is increased in patients who have undergone neoadjuvant treatment.

Influence of Anemia and Iron Deficiency on Outcome in Cancer Patients

Separate to the perioperative period, anemia is associated with poor outcome in cancer patients, both due to worsening of local tumor control and increased requirement for allogeneic blood transfusion. While some authors maintain that anemia is a marker of increased concomitant comorbidity, rather than an independent risk factor in its own right, major randomized controlled trial data are lacking. Most guidelines promote hemoglobin concentration as a therapeutic target prior to proceeding to major surgery.

Iron deficiency, independent of anemia, is gaining attention in the perioperative sphere. While clinicians often consider the two to be synonymous, physiological effects of iron deficiency (particularly fatigue and exercise intolerance) may be noted before hemoglobin drops below the anemic threshold. This is because iron is a key contributor to basic cellular function, with roles in energy metabolism, cell signaling, gene expression, and regulation of cell growth. Most iron is inserted into protoporphyrin IX as the final step in the production of heme to allow oxygen binding to hemoglobin. Additionally, iron serves as a prosthetic group for other oxygen-carrying molecules, notably myoglobin, cytochromes, and nitric oxide synthase, and is integral to the function of enzyme systems responsible for DNA synthesis and repair, energy metabolism via the function of the respiratory chain, and production of ADP. Hence iron deficiency can impact respiratory chain and skeletal muscle function adversely, affecting fatigability and recovery from exercise. Early retrospective data from colorectal cancer populations have highlighted a possible association between iron deficiency and poor postoperative outcomes independent of anemia. ^, Consequently, some consensus statements recommend correction of iron deficiency in patients presenting to major surgery regardless of the starting hemoglobin concentration. Prospective evidence for this practice is limited.

Diagnosing Iron Deficiency in the Preoperative Cancer Patient

Differentiation and identification of iron deficiency as part of a program of preoperative optimization can be challenging, as ferritin (an acute phase reactant) may be elevated for a variety of reasons, possibly reflecting cellular damage and leakage of ferritin from storage sites into the bloodstream. Indeed, serum ferritin in the normal reference range in the setting of a C-reactive protein greater than 5 mg/L will only be 39% sensitive for iron deficiency. An alternative metric is transferrin saturation (TSAT). Taken as the quotient of serum iron divided by transferrin concentration and expressed as a percentage, TSAT is a more direct measure of the physiological demand for iron (although it may still be affected by inflammation independent of iron status). A value of less than 20% is interpreted as being reflective of iron deficiency ( Table 8.1 ). Therefore a patient presenting for surgery with serum ferritin less than 100 µg/L regardless of TSAT, or a TSAT of less than 20% in the setting of serum ferritin at 100–300 µg/L, should be considered iron depleted.

More sensitive markers of iron deficiency have been described. These include soluble transferrin receptor, serum hepcidin, reticulocyte hemoglobin concentration, and percentage hypochromic red cells. Although these are increasingly being cited in best practice guidelines, they have not yet entered widespread use. ^,