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Introduction
Anemia is a common finding in cancer patients, occurring in >40% of patients with solid tumors and in >70% of patients with hematological malignancies.1 In patients receiving chemotherapy, the incidence of anemia is even higher.
Consequences of anemia can be profound, affecting both quality of life and survival. Impaired tissue oxygenation leads to symptoms such as fatigue, dyspnea, palpitations, and dizziness. Compromised oxygen delivery also influences tumor behavior, inducing changes in genetic expression that can increase tumor aggressiveness, promote angiogenesis, decrease sensitivity to chemotherapy and/or radiation, and decrease survival.2,3
Evaluating anemia in cancer patients is challenging. The etiology is often multifactorial and may be attributed to the malignancy itself, cytotoxic treatments, and underlying comorbidities. Most commonly, anemia in cancer is due to the production of inflammatory cytokines and/or the effects of myelosuppressive chemotherapy. Correctly identifying the source(s) of anemia is essential for appropriate treatment.
Pathophysiology
Cancer-Associated Anemia
Inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF-a) play a major role in the pathophysiology of anemia in cancer, also known as anemia of chronic disease (ACD).4 Inflammatory cytokines induce changes in iron homeostasis and suppress production of erythropoietin (EPO), leading to a reduction in red blood cell production in the bone marrow.5 Erythrophagocytosis induced by inflammatory cytokines may also contribute to ACD. 6
The identification of hepcidin has enabled a better understanding of the relationship between iron homeostasis and anemia of chronic disease.7 Hepcidin is produced by hepatocytes and plays a central role in the regulation of iron balance and transport. In cancer and other chronic inflammatory conditions, IL-6 induces hepcidin production, resulting in inhibited iron absorption by duodenal enterocytes and the blocking of iron release from macrophages and hepatocytes.8 In addition, IL-1 and TNF-a induce ferritin transcription, which increases iron storage in the reticuloendothelial system. The combined effect results in reduced iron availability for erythropoiesis, creating a "functional iron deficiency."9
Under normal physiological conditions, EPO levels vary inversely with hematocrit. Hypoxia stimulates EPO release, which stimulates bone marrow erythrocyte production. However, in ACD, the EPO response is thought to be blunted by IL-1 and TNF-a, leading to a relative decrease in EPO production.10
Table 1: Laboratory Differentiation of Anemia of Chronic Disease versus Iron Deficiency Anemia
Biomarker
Serum iron
Transferrin (TIBC)
Transferrin saturation
Ferritin
Inflammatory markers
sTFR/log ferritin ratio
Serum hepcidin
|
ACD
Low
Low
Low
High
High
Low
High |
IDA
Low
High
Low
Low
Negative
High
Low
|
ACD + IDA
Low
Low
Low
High or Normal
High
High
High |
Chemotherapy-Associated Anemia
Chemotherapy is another common cause of anemia in cancer patients with cumulative effects over the course of treatment. Chemotherapy agents can induce anemia by impairing hematopoiesis as well as damaging mature hematopoietic cells.11 Nephrotoxic chemotherapy agents, such as platinum-based regimens, can also lead to anemia through decreased erythropoietin production by the kidney.
Assessment
The National Cancer Institute categorizes anemia as follows.12 An Hgb level below 11 g/dl warrants evaluation according to National Comprehensive Cancer Network (NCCN) guidelines:
- mild (grade 1): Hgb 10 g/dL – lower limit of normal
- moderate (grade 2): Hgb 8–9.9 g/dL
- severe (grade 3): Hgb 6.5–7.9 g/dL
- life-threatening (grade 4): Hgb < 6.5 g/dL
An initial assessment should include a complete blood count, peripheral blood smear, detailed history, and physical exam. The goal is to characterize the anemia and identify underlying comorbidities that can be corrected. Coagulation disorders, hemolysis, bleeding, renal insufficiency, and nutritional deficiencies should all be considered.
Differentiating between ACD and iron deficiency anemia (IDA) and identifying coexistence pose a challenge. However, an accurate diagnosis is necessary for appropriate and effective treatment. Bone marrow biopsy is considered gold standard for assessing iron stores, but due to invasiveness and cost, the test is not routinely performed. Additional measurements, such as serum transferrin receptor (sTFR) and sTFR/ferritin may help differentiate between ACD and IDA. Serum transferrin receptor is primarily expressed in cells that require iron, and in contrast to serum ferritin, levels are unaffected by inflammation.13 The ratio of sTFR to the log of ferritin has been shown to increase the diagnostic accuracy; a ratio <1 indicates ACD, whereas ratios >2 suggests IDA. Measuring hepcidin levels would be another useful diagnostic tool, but assays aren't yet readily available.
In ACD the serum iron concentration, the transferrin saturation, and the transferrin level (TIBC) are all decreased. The serum ferritin concentration is usually elevated, but may not accurately reflect iron stores because ferritin is also an acute phase reactant. ACD may also be accompanied by an increase in inflammatory cytokines such as IL-6 and elevated inflammatory markers such as fibrinogen, erythrocyte sedimentation rate, and C-reactive protein.
IDA is characterized by low serum iron, low transferrin saturation, and elevated transferrin levels. A serum ferritin of less than 15 ng/ml is diagnostic for iron deficiency anemia.
Conventional Treatment
While definitive treatment for cancer-related anemia relies on eradication of the underlying malignancy, in many cases this is not possible. Current treatment options include transfusion of packed red blood cells and the use of erythropoiesis-stimulating agents (ESAs).
Transfusion of packed red blood cells (PRBC) provides the best option for patients requiring rapid correction of anemia, as it results in the quickest increase in hemoglobin levels.14 Transfusion of 1 unit of packed red blood cells is estimated to increase the Hgb level by 1 g/dl in a normal-sized adult.15 A number of studies have evaluated the impact of transfusion on survival and disease progression in cancer patients, with conflicting results. One study of 56 esophageal cancer patients, receiving chemoradiation therapy and PBRC, demonstrated an increase in overall survival. However, other evidence suggests that blood transfusions may promote cancer progression.16
Risks associated with transfusions include transfusion-related reactions, congestive heart failure, bacterial contamination, viral infections, and iron overload.17 Improvements in donor screening have dramatically reduced the risk of infection. In addition, incidence of transfusion-related reactions has decreased considerably due to prestorage leukoreduction.18 Iron overload occurs most frequently in patients with myelodysplastic syndrome, as they require frequent transfusions over a long period of time.19
ESAs, synthetic recombinant human erythropoietin, were initially used to treat anemia in patients with chronic renal failure. In cancer patients, treatment with ESAs has been shown to raise Hgb levels and reduce transfusion rates, but there are concerns over safety of ESAs in terms of mortality, disease progression, and risk of thromboembolism.20
In 2007, the FDA added a "black box" warning to the safety labeling of ESAs based on the results of 8 randomized studies showing a decrease in overall survival and/or decreased disease control with ESA usage in patients with advanced breast, cervical, head and neck, and non-small cell lung cancers.21 All 8 trials, however, had an off-label target Hgb level of 12 g/dl. When a 2010 meta-analysis was done considering only patients with a target Hgb of <12 g/dl, no increase in mortality risk was found.22
The use of ESAs carries a significant risk of thromboembolism. The most recent Cochran meta-analysis of 91 controlled trials using ESAs to manage anemia in cancer patients demonstrated a significantly increased risk of thromboembolism in patients receiving ESAs.23 Patients should be monitored for other risk factors for thromboembolism such as history of venous thromboembolism, heritable mutation, hypercoagulability, elevated platelet counts, recent surgery, hormonal agents, prolonged inactivity, steroids, and comorbidities such as hypertension.24 Risks of death from thromboembolism should be weighed against possible benefit of ESA usage.
Naturopathic Considerations
Naturopathic medicine provides a safe and effective option to support cancer patients with anemia. Appropriate support relies on identifying the etiology of the anemia. If the underlying cause is inflammation, use botanicals and nutrients to control the inflammation. Consider lactoferrin, curcumin, boswellia, and omega-3 fatty acids for their ability to reduce inflammatory cytokines.25-28
If anemia is the result of myelosuppressive and/or nephrotoxic effects of chemotherapy, consider melatonin for its potential to help protect the bone marrow and the kidneys from the cytotoxic effects of chemotherapy.29-31
Assess and treat nutritional deficiencies such as iron, vitamin B12, and folic acid. If iron deficiency is suspected, confirm that it is not due to a functional deficiency prior to supplementation. Lactoferrin should also be considered for IDA. When given orally to patients with IDA, lactoferrin increased hemoglobin, serum iron, and ferritin.32 Macrocytosis frequently occurs in those receiving antimetabolite chemotherapy agents. Testing for B12 and folic acid deficiency should be conducted prior to supplementation, as nutrient deficiency is rarely the cause. Folic acid supplementation is specifically contraindicated with many antimetabolite agents and so should be avoided.
Evaluate patients for known risk factors for cancer-associated anemia such as low-normal hemoglobin level, history of prior transfusion, previous radiotherapy, prior myelosuppressive chemotherapy, and comorbidities such as chronic inflammatory diseases. Those with higher risk require more aggressive intervention.
Conclusion
Given the prevalence and complications of anemia in cancer patients, it is important to understand the underlying etiology of anemia in cancer to order to provide the most effective treatment for individual patients.
Notes
1. Dicato M, Plawny L, Diederich M. Anemia in cancer. Ann Oncol. 2010;21 Suppl 7:vii167–72.
2. Chang Q, Jurisica I, Do T, Hedley D. Hypoxia predicts aggressive growth and spontaneous metastasis formation from orthotopically grown primary xenografts of human pancreatic cancer. Cancer Res. 2011;71:3110–3120.
3. Vaupel P. The role of hypoxia-induced factors in tumor progression. Oncologist. 2004;9:10–17.
4. Drews R. Hematologic consequences of malignancy: anemia and bleeding. In: Schrier S, ed. UpToDate. Waltham, MA. Accessed May 12, 2014.
5. Schrier S, Camaschella C. Anemia of chronic disease. In: Mentzer WC, ed. UpToDate. Waltham, MA. Accessed May 12, 2014.
6. Ibid.
7. Cullis J. Diagnosis and management of anaemia of chronic disease: current status. Br J Haematol. 2011;154:289–300.
8. Weiss G, Goodnough L. Anemia of chronic disease. N Engl J Med. 2005;352;1011–1023.
9. Cullis, op cit.
10. Schrier & Camaschella, op cit.
11. Dicato et al, op cit.
12. US Department of Health and Human Services; National Cancer Institute: Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events, Version 3.0 [online document]. ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. Accessed May 12, 2014.
13. Infusino I, Braga F, Dolci A, Panteghini M. Soluble transferrin receptor (sTfR) and sTfR/log ferritin index for the diagnosis of iron-deficiency anemia. A meta-analysis. Am J Clin Pathol. 2012;138:642–649.
14. National Comprehensive Cancer Network. Cancer- and Chemotherapy- Induced Anemia (Version 3..2014). www.nccn.org/professionals/hysician_gls/pddf/anemia.pdf. (Accessed May 27, 2014).
15. National Comprehensive Cancer Network. Cancer- and chemotherapy- induced anemia. Version 3. 2014. Available at www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed May 27, 2014.
16. Atzil S, Arad M, Glasner A et al: Blood transfusion promotes cancer progression: a critical role for aged erythrocytes. Anesthesiology 109, 989-997 (2008).
17. National Comprehensive Cancer Network, op cit.
18. Dicato et al, op cit.
19. National Comprehensive Cancer Network, op cit.
20. Dicato et al, op cit.
21. National Comprehensive Cancer Network, op cit.
22. Dicato et al, op cit.
23. Tonia T1, Mettler A, Robert N, et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev. 2012 Dec 12.
24. National Comprehensive Cancer Network, op cit.
25. Tung YT1, Chen HL, Yen CC, et al. Bovine lactoferrin inhibits lung cancer growth through suppression of both inflammation and expression of vascular endothelial growth factor. J Dairy Sci. 2013 Apr;96(4):2095–2106.
26. Panahi Y, Saadat A, et al. Adjuvant therapy with bioavailability-boosted curcuminoids suppresses systemic inflammation and improves quality of life in patients with solid tumors: a randomized double-blind placebo-controlled trial. Phytother Res. 2014. doi:10.1002/ptr.5149.
27. Ammon HP. Modulation of the immune system by Boswellia serrata extracts and boswellic acids. Phytomedicine. 2010 Sep;17(11):862–867.
28. Sabbatini M, Apicella L, et al. Effects of a diet rich in N-3 polyunsaturated fatty acids on systemic inflammation in renal transplant recipients. J Am Coll Nutr. 2013;32:6.
29. Anwar MM, Mahfouz HA, Sayed AS. Potential protective effects of melatonin on bone marrow of rats exposed to cytotoxic drugs. Comp Biochem Physiol A Mol Integr Physiol. 1998:119:493–501.
30. Pacini N, Borziani F. Action of melatonin on bone marrow depression induced by cyclophosphamide in acute toxicity phase. Neuro Endocrinol Lett. 2009;30(5):582–591.
31. Dziegiel P, Suder E, Surowiak P, et al. Role of exogenous melatonin in reducing the nephrotoxic effect of daunorubicin and doxorubicin in the rat. J Pineal Res. 2002 Sep;33(2):95–100.
32. Paesano R, Berlutti F, Pietropaoli M, et al. Lactoferrin efficacy versus ferrous sulfate in curing iron disorders in pregnant and non-pregnant women. Int J Immunopathol Pharmacol. 2010 Apr–Jun;23(2):577–587.
A Fellow of the American Board of Naturopathic Oncology (FABNO), Stacy Dunn has been involved in the health, nutrition, and fitness fields for nearly 20 years. She graduated from the University of Kansas with a bachelor's degree in exercise physiology. She then studied at the National College of Naturopathic Medicine in Portland, Oregon, where she earned both a doctorate degree in naturopathic medicine and a master's degree in Oriental medicine. Dunn is nationally certified as a Diplomate in Oriental Medicine by the National Certification Commission for Acupuncture and Oriental Medicine. In her free time, Dunn enjoys cooking, hiking, and spending time with her friends and family. She is the proud mother of two adorable little girls.
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