In the treatment of patients diagnosed with colorectal cancer, (preoperative) anemia* and allogeneic blood transfusions are generally considered independent risk factors for poor (surgical) outcomes. [1] Severe (preoperative) anemia may promote tumor progression and aggression, while allogeneic blood transfusions may induce immunosuppression and promote cancer recurrence and metastasis.

Approximately 30% to 60% of the general surgical population is commonly affected by preoperative anemia*.  This form of anemia is associated with an increased risk of postoperative morbidity, prolonged hospital stay, and impaired recovery.[1] Hence, planning potentially high-blood-loss surgery, especially patients with preoperative anemia, requires proper advance planning to allow time for adequate identification, assessment, and management to avoid adverse events.

In colorectal cancer, anemia is more prevalent, affecting between 60% and 80% of patients.  And while surgery is the most common treatment for resectable colorectal cancer, with some major improvements seen over the last decades on preoperative assessment, as well as instrument use, surgical techniques, intraoperative monitoring and postoperative care, (preoperative) anemia remains a common problem. In patients undergoing colorectal surgery this is primarily due to bleeding from the gut and blood loss during the operation.[1]**

Not a Harmless Problem
Although anemia has long been accepted to a relatively harmless problem, it should however, be viewed as a serious, but treatable, medical condition that can be easily corrected, rather than simply an abnormal laboratory value. The seriousness of (preoperative) anemia has been demonstrated in multiple studies showing an association between preoperative anemia and increased postoperative mortality and morbidity.[6][7]

As many as 40% of non-anemic patients diagnosed with colorectal cancer experience iron deficiency, which is also considered an important but modifiable risk factor for surgical patients.

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To-date, to increase or maintain circulating (blood) volume, treatment of (hospitalized) patients with preoperative anemia may include allogeneic or homologous blood transfusion. However, transfusions are not without risks. And while the risk-benefit profile for allogeneic blood transfusion to treat anaemia is uncertain, in some situations they may most certainly contribute to adverse patient outcomes.***

In general, a patient’s ability to tolerate anaemia largely depends on their clinical condition and the presence of significant co-morbidities. Hence, in contrast to a liberal transfusion policy, adopting a more restrictive approach or using alternatives to allogeneic blood transfusions, could be recognized as a better standard of care. [4]

In a study published in 2019 in the Journal of the American Medical Association (JAMA), preoperative anemia was strongly associated with increased in-hospital mortality (odds ratio [OR], 2.09; 95% confidence interval [CI], 1.48-2.95) and increased morbidity. [6] The outcomes of this study confirm that an allogeneic blood transfusion is not a panacea or universal remedy that compensates for the poor outcomes conferred by preoperative anemia. And independent of preoperative anemia, blood transfusions have been associated with an overall increased risks of postoperative complications and mortality. [8][9]

A longitudinal, uncontrolled observational study evaluating patients undergoing operations between January 1, 2005 and December 31, 2009 in 177 hospitals in the United States, compared outcomes from patients who received an intraoperative allogeneic blood transfusion and those who did not. These outcomes confirmed a dose-dependent adverse effect of intraoperative transfusion. The authors of this study concluded that it is likely that a small, possibly discretionary amount of intraoperative transfusion leads to increased mortality, morbidity, and resource use, suggesting that caution should be used with intraoperative transfusions for mildly hypovolemic or anemic patients. [8]

An unrelated study demonstrated that low-risk patients have between an 8- and 10-fold excess risk of adverse outcomes when they receive an allogeneic blood transfusion.[7] This study queried the American College of Surgeons National Surgical Quality Improvement Project database containing patient information entered between 2010 and 2012 to identify differences in mortality and morbidity among patients receiving an allogeneic blood transfusion within 72 hours of their operative procedure compared with those who did not receive any blood.[9]  Based on these outcomes, the authors of this study are confident that a careful preoperative assessment of transfusion risk and intervention could minimize operative morbidity and mortality. [9]

And while there have been no randomized controlled trials yet to confirm that treating preoperative anemia definitively improves postoperative patient outcomes, the benefit of decreasing allogeneic blood transfusion, in terms of the known risks of transfusion, offers a real and proper justification to proceed with preoperative anemia screening and management, particularly when simple and less expensive treatment options for reversible causes are readably available. [10]

Iron-deficiency anemia – a treatable cause
Among the most common treatable cause of preoperative anemia is iron-deficiency anemia.****  [4] The management of this form of anemia includes iron supplementation with IV iron therapy when oral iron is ineffective or not tolerated, there is severe anemia, and there is insufficient time to surgery (<4 weeks).

Although IV Iron therapy is commonly used to treat anemia, generally with a full course of treatment being administered intravenously in 15-30 minutes, to date IV iron infusion has only been used sparingly because the available data has not always been clear whether treating patients before major surgery would indeed reduce the need for allogeneic blood transfusions.[1]

In other situations, erythropoiesis-stimulating agents (ESA) ^ designed to boost the production of red blood cells in the bone marrow, may be considered.  This may be particularly for patients with religious objections to blood transfusion. [5] And while long term use of ESAs has, in a number of studies, been associated with an increased cardiovascular risk, chronic kidney disease and, in the setting of cancer, with tumor progression and increased mortality, the use of ESAs was, in these studies, prolonged for at least >16 months in chronic kidney disease and >8 weeks in cancer use.

However, if administered for only a short period of time (<2 to 4 weeks), the use of ESAs are, especially in the preoperative setting, considered safe. [10]

A review, published in 2019 in Anesthesia & Analgesia, a peer-reviewed journal covering anesthesia, pain management, compared the outcomes of 32 randomized controlled trials (n = 4750 patients) receiving preoperative ESA (n = 2482 patients) to placebo (n = 2268 patients). The outcome associated preoperative ESA with a significant decrease in incidence of allogeneic blood transfusions among all patients (n = 28 studies; risk ratio [RR], 0.59; 95% confidence interval [CI], 0.47-0.73; P < .001) compared to placebo. In the same study, the authors confirmed that preoperative ESAs were also associated with fewer phase-specific allogeneic blood transfusion without an observed increase in thrombosis (odds ratio [OR], 1.07; 95% confidence interval [CI], 0.79-1.44). [10]

Of interest is that another systematic review, which included 25 different studies (n = 4739) comparing the administration of ESA + IV Iron therapy to placebo, demonstrated a decreased risk of allogeneic blood transfusions (relative risk [RR], 0.57; 95% confidence interval [CI], 0.46-0.71). The outcomes further showed no statistical differences in serious adverse events (mortality relative risk [RR], 1.31; 95% confidence interval [CI], 0.80-2.16; deep vein thrombosis RR, 1.48, 95% CI, 0.95-2.31). [11]

Clinical Practice
The outcomes are similar to a meta-analysis conducted by researchers from UCL (University College London) and the Royal Devon and Exeter Hospital, a large teaching hospital situated in Exeter, Devon, England, run by the Royal Devon University Healthcare NHS Foundation Trust. This analysis showed that change in clinical practice can have clear benefits for patients undergoing major colorectal surgery. [1]

The researchers especially considered the fact that, in comparison to other types of surgery, there has been concern that colorectal cancer patients may have higher rates of complications and cancer recurrence if they’ve had an allogeneic blood transfusions.[1]

The results of the analysis, published in The British Journal of Surgery, provides clear evidence that giving iron intravenously before colorectal surgery improves outcomes for patients, reducing the need for a blood transfusion during or after surgery by 33%.[1]

In the study, researchers from UCL conducted a meta-analysis of five randomized controlled trials. They focused on a subset of patients from those trials who had undergone colorectal surgery. In these trials, patients were split into two groups, a control group and a group who received iron intravenously prior to surgery.

Patient Benefit
“This is the first time that clinical trials have shown a patient benefit from treatment with an iron infusion before surgery, which has the potential to treat anemia and reduce the need for blood transfusion,” noted Professor Toby Richards, senior author of the study from UCL Division of Surgery & Interventional Sciences.

“Previous studies had not shown this benefit for all patients undergoing surgery in the NHS, but this analysis identifies a subset of patients undergoing bowel surgery who will see a benefit,” Richards added.

Reducing mortality
“With over 20,000 major colorectal cancer resections per year in the United Kingdom, the findings of this study have the potential to improve outcomes for the second most common cause of cancer mortality,” explained professor Neil Smart, a colorectal surgeon from the Royal Devon and Exeter Hospital and co-lead of the study.

“In the past, surgeons were uncertain whether the benefits of iron infusion could be realized in the short time frames of cancer care and consequently the uptake of this treatment was limited. Our findings show that improved outcomes can be achieved if iron infusion is given in the period between cancer diagnosis and surgery,” Smart added.

Avoiding transfusion
“The recent shortage of blood supply in the United Kingdom means it is more important than ever to focus on ways to avoid blood transfusions and the associated risks,” explained Sue Pavord, Vice President of British Society for Hematology.

“This analysis shows a reduction of over one-third in blood transfusions when anemic patients are treated with intravenous (IV) iron therapy before their colorectal surgery. If we could combine this insight with others from the previous PREVENTT study, then hospital readmissions could potentially be cut even more, which would be important for both patients and the NHS,” she said. [1]

However, in the end, it is important to recognize that in the preoperative setting anemia sound be considered a symptom and not a diagnoses. Understanding the  cause of preoperative anemia, which may include bleeding as a result of the prevalence of gastrointestinal lesions, remains, therefor, important in the overall planning of treatment.

__

Note: * The World Health Organization (WHO) defines anemia, which is often also associated with feeling tired and unwell, and may result in a slower recovery and other complications following surgery, [2] as a decreased blood concentration of hemoglobin (Hb), irrespective of underlying cause, red blood cell morphology, or red blood cell function. In male patients, anemia is a hemoglobin <13 g/dL and in female patients as hemoglobin <12 g/dL. However, this definition may not accurately address the risk of preoperative anemia in women, because female patients have lower circulating blood volume and, in general, the amount of blood loss is mostly similar for similar procedure. Hence, women are at risk of losing a greater proportion of their red cell mass. Therefore, accepting a lower hemoglobin target puts female patients at higher risk of preoperative anemia blood transfusions and, as a result, potentially, postoperative complications of both anemia and transfusion. Furthermore, preoperative hemoglobin below 13 g/dL increases the risk of morbidity, mortality, and transfusion regardless of sex. [11][12]  Based on this understanding, especially in the setting of high-blood-loss surgery, in both men and women, a pre-surgery hemoglobin of 13 g/dL is to be recommended. [11][12][13]

** Blood loss during surgical procedures is independently associated with an increased risk of poorer clinical outcome. Hence, the use of hemostatic agents, and the use of minimally invasive surgical procedures can be instrumental in minimizing bleeding. To avoid adverse events when planning potentially high-blood-loss surgery (generally an expected blood loss of >500 mL), preoperative anemia is defined as hemoglobin <13 g/dL for both male and female patients. [3][17]

*** In addition to preoperative treatment of anemia results from a meta-analysis published in 2019 in the World Journal of Surgical Oncology showed that perioperative transfusion decreases the survival rate and increase the incidence rates of cancer recurrence and metastasis in colorectal cancer.  The results confirm that allogeneic transfusion causes a dramatically negative effect on long-term prognosis and increases the short-term complications after colorectal cancer surgery.[18]

**** Iron deficiency is generally defined by a serum ferritin <30 µg/L. However, ferritin is considered an acute-phase reactant that can be elevated in the presence of inflammation. [19] Hence, with an observed increased of inflammatory markers, such as C-reactive protein, a ferritin of 30 µg/L to 100 µg/L and a transferrin saturation <20% can still be used to diagnose iron-deficiency anemia. [20]

^ Because of the potential of increased cardiovascular risk as a result of the the use of erythropoiesis-stimulating agents (ESA), as well as issues related to chronic kidney disease and the observed risk of tumor progression and increased mortality, the role of ESAs in the management of preoperative anemia is not conclusively clear. Some guidelines recommend that ESAs should not be used routinely recommended unless the patient has a religious objection to the use of blood transfusions, or in situations where appropriate blood is not available due to red cell antibodies.[21][22]

Clinical trials
Preoperative Intravenous Iron to Treat Anaemia in Major Surgery (PREVENTT) – ClinicalTrials.gov Identifier: NCT01692418

Reference
[1] Lederhuber H, Massey LH, Abeysiri S, Roman MA, Rajaretnam N, McDermott FD, Miles LF, Smart NJ, Richards T. Preoperative intravenous iron and the risk of blood transfusion in colorectal cancer surgery: meta-analysis of randomized clinical trials. Br J Surg. 2023 Nov 23:znad320. doi: 10.1093/bjs/znad320. Epub ahead of print. PMID: 37994900.
[2] Fowler AJ, Ahmad T, Phull MK, Allard S, Gillies MA, Pearse RM. Meta-analysis of the association between preoperative anaemia and mortality after surgery. Br J Surg. 2015 Oct;102(11):1314-24. doi: 10.1002/bjs.9861. PMID: 26349842.
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[4] Spahn DR, Goodnough LT. Alternatives to blood transfusion. Lancet. 2013 May 25;381(9880):1855-65. doi: 10.1016/S0140-6736(13)60808-9. PMID: 23706802; PMCID: PMC9666052.
[5] Ferraris VA, Davenport DL, Saha SP, Austin PC, Zwischenberger JB. Surgical outcomes and transfusion of minimal amounts of blood in the operating room. Arch Surg. 2012 Jan;147(1):49-55. doi: 10.1001/archsurg.2011.790. PMID: 22250113.
[6] Ferraris VA, Hochstetler M, Martin JT, Mahan A, Saha SP. Blood transfusion and adverse surgical outcomes: The good and the bad. Surgery. 2015 Sep;158(3):608-17. doi: 10.1016/j.surg.2015.02.027. Epub 2015 May 29. PMID: 26032824.
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[22] Kotzé A, Harris A, Baker C, Iqbal T, Lavies N, Richards T, Ryan K, Taylor C, Thomas D. British Committee for Standards in Haematology Guidelines on the Identification and Management of Pre-Operative Anaemia. Br J Haematol. 2015 Nov;171(3):322-31. doi: 10.1111/bjh.13623. Epub 2015 Sep 6. Erratum in: Br J Haematol. 2016 Jan;172(1):148. PMID: 26343392.

Featured image: by Aman Chaturvedi on Unsplash Used with permission.


How to Cite

DOI: https://doi.org/10.14229/onco.2023.11.28.001

Peter Hofland, Ph.D 1
Preoperative Intravenous Iron Reduces the Need for Blood Transfusion in Colorectal Cancer Surgery – Onco Zine – The International Oncology Network, November 25, 2023.
DOI: 10.14229/onco.2023.11.28.001
1 Sunvalley Communication, LLC / Onco/Zine


 

 

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