What is the problem
Anaemia, defined by the World Health Organization (WHO) as Hb <120g/L in females and <130g/L in males1, is independently associated with poor surgical outcomes in cancer patients, including an increased risk of death. Although it is not clear if interventions to reduce anaemia can modify this risk, correction of anaemia can improve quality of life in cancer patients and minimise the risk of requiring a blood transfusion. Therefore, international guidelines recommend detecting and treating anaemia before major cancer surgery2,3.
Who should be tested
All patients should be screened for anaemia and its common causes prior to cancer surgery with a predicted potential blood loss of 500ml or greater4. The most common cause of anaemia in cancer patients is iron deficiency, and rates may be particularly high in colorectal and gynae-oncology patients due to the high rates of symptomatic bleeding in these patients. Other causes include anaemia of chronic disease, vitamin B12 and folate deficiency, renal failure, and rare haematologic disorders such as thalassaemia.
What tests should be ordered
Patients should be tested for iron deficiency, with a serum ferritin and transferrin saturation (TSAT). Additionally, to minimise visits for blood draws, FBE, UEC, CRP and vitamin B12 and folate levels are recommended in cases of anaemia unexplained by low tissue iron levels4.
See figure 1 below for a flowchart for identifying anaemia and its causes pre-operatively. A laboratory haematology referral should be considered in patients with low total vitamin B12 levels, low serum folate levels, or unclear iron status. Additionally, patients with religious or other objection to blood transfusion should be referred to laboratory haematology if perioperative optimisation is required.
Figure 1: Flowchart for investigation of preoperative anaemia
What defines iron deficiency
In otherwise healthy individuals, serum ferritin is the best measure of total body iron stores, and absolute iron deficiency is defined by a ferritin value <30ug/L5. However, in patients with active cancer, ferritin levels may be falsely elevated as ferritin is also a marker of inflammation. In clinical practice, a ferritin level <100ug/L or transferrin saturation (TSAT) <20% is commonly used to define iron deficiency in individuals with systemic inflammation, including active cancer. This state is frequently referred to as ‘functional iron deficiency’.
Serum iron is an unhelpful measure of total body iron stores, as it fluctuates dramatically depending on the time of day and may also transiently rise after taking iron tablets or an iron-rich meal. It should be noted that TSAT is not measured directly but rather is a value which is calculated from the serum iron and a second variable, the total iron binding capacity (Figure 2). As such, the TSAT is also influenced by factors that interfere with the serum iron assay.
Due to the limitations of serum iron studies described above, recognizing iron deficiency can be difficult in clinical practice. Clinical guidelines and trials may therefore use definitions of absolute and functional iron deficiency that vary from this toolkit.
Figure 2: Formula for calculating the transferrin saturation (TSAT)
How should iron deficiency be treated and timing for surgery
In patients with active inflammation, including active cancer, intestinal absorption of iron is decreased and IV iron formulations are preferred to oral formulations. They have the advantage of allowing a rapid response to treatment and avoiding the very common intolerance from oral iron tablets. A typical dose for iron deficiency is 1g of either IV ferric carboxymaltose (Ferrinject®) or ferric derisomaltose (Monofer®). While benefits can be seen even with supplementation as close as 1 day prior to the day of surgery, it is preferred to give IV iron up to 4-6 weeks prior to surgery, to allow time for formation of new red blood cells and provide relief of symptoms of iron deficiency during surgical prehabilitation.
Modern iron infusions are very safe, with very low risks of systemic anaphylaxis. Risks to be aware of when prescribing IV iron include skin “tattoos” or staining from accidental extravasation of iron6, as well as hypophosphataemia with ferric carboxymaltose. Hypophosphataemia may cause muscle weakness or fatigue, and may last up to 10 weeks after infusion7. Patients who report worsening fatigue weeks-months following an iron infusion should have their Hb and phosphate levels checked. Hypophosphataemia can be effectively treated with oral or intravenous replacement. Additionally, IV iron may promote bacterial growth and should not be prescribed during active infection8.
Other common side effects include nausea, headache, metallic taste in the mouth, bowel habit changes – either constipation or diarrhoea – and abdominal discomfort.
What if my patient doesn’t meet the definition of iron deficiency
Iron does not help to improve haemoglobin levels in anaemia without iron deficiency.
If there is B12 or folate deficiency, a laboratory haematologist can provide advice regarding appropriate supplementation and retesting.
Other causes of anaemia in the pre-surgical setting may include chemotherapy effects, anaemia of kidney disease, anaemia of chronic disease, and other rare causes. As these are unlikely to be correctable prior to surgery, they are beyond the scope of this toolkit.
How will the effectiveness be evaluated
Any intervention should be regularly evaluated for its effectiveness, as part of the continuous process of quality improvement. Outcome measures from this intervention will include:
- Defining local epidemiology, including rates of anaemia and iron, B12 and folate deficiency in surgical oncology patients across sites.
- Measuring compliance, defined as the proportion of patients identified as iron deficient who successfully complete at least one treatment with IV iron.
- The efficacy of IV iron therapy, including median time from IV iron to day of surgery in days, and mean difference in Hb from first measurement in prehabilitation clinic to the date of surgery.