Introduction

The recent emergence of growth factors such as darbepoetin alfa and epoetin alfa has greatly aided physicians and patients in managing chemotherapy induced anemia, one of the most common side effects associated with chemotherapy. With the use of growth factor agents, patients are now able to maintain a higher quality of life, reduce the need for blood transfusions, and maintain scheduled doses of treatment while undergoing therapy for their disease.

Research continues to press the issue of development of risk-assessment models to provide preventive measures against chemotherapy-induced anemia with the use of growth factors among high-risk patients. It now appears that prevention against anemia may be the optimal approach compared to treating it once it has occurred.

Overview

Chemotherapy-induced anemia is one of the most common side effects experienced by cancer patients, occurring in approximately 70%-90% of those undergoing treatment for their disease, and approximately 60% of all cancer patients.[1] Anemia is defined as a condition in which the level of red blood cells is lower than normal, however, hemoglobin levels are also commonly utilized in the diagnosis and monitoring of anemia.[2]

Anemia affects all realms of patient health: physiologic status, psychosocial well-being, and quality of life.[3] Medical costs, time utilization for the patient, caregiver and medical team are also important considerations when evaluating the impact of CIA.

Results from numerous studies have attempted to quantify the effects of anemia on cancer patient psychosocial well-being and quality of life, with nearly all data pointing to patients suffering from severe fatigue, weakness, anxiety, dizziness, cognitive impairment, loss of sexual desire, inability to perform daily functions and/or depression associated with anemia.[4],[5],[6],[7] Studies are now trying to provide a clear picture regarding the physiologic risks associated with anemia, particularly patient outcomes including survival and responses to therapy.[8],[9],[10],[11]

Darbepoetin Alfa

With the recent dosing approval for darbepoetin alfa—once every three weeks for the prevention of anemia in non-myeloid malignancies—there is now an easy and effective option for the management of anemia in cancer patients undergoing therapy.[22]

As risk-assessment models and protocols are becoming established for the management of anemia, darbepoetin alfa may become more routinely utilized for early intervention or prevention of chemotherapy-induced anemia.

Darbepoetin alfa is a long-acting erythropoiesis-stimulating agent that was approved by the FDA in 2002 for the treatment of anemia caused by concomitant chemotherapy in non-myeloid malignancies.19 Compared with epoetin alfa, darbepoetin alfa has two additional N-linked carbohydrate chains that allow for the addition of up to eight sialic acid molecules from 14 to 22. Although receptor-binding affinity decreases with the increased carbohydrate content of darbepoetin alfa, serum half-life increases and in vivo activity increases compared to epoetin alfa.[23]

NCCN Guidelines for Classifying and Managing Anemia

There are varying degrees of severity of anemia, typically based on hemoglobin levels. The National Comprehensive Cancer Network (NCCN) utilizes these classifications of anemia to determine appropriate therapy: [16]

Table 1: NCCN Anemia Classifications

The following are the updated NCCN guidelines for the management of cancer and treatment related anemia:16

Perform assessment:

• If hemoglobin levels are less than 11 g/dl, assess symptoms of the patient for possible signs that anemia is affecting health or quality of life.
• Take comorbidities and function into consideration.
• Evaluate the risk factors for developing symptomatic anemia.

Initiate Treatment:

• If hemoglobin is between 10-11 g/dl, consider treatment; if hemoglobin less than 10 g/dl, strongly consider treatment.
• Assess response at four to six weeks
• Titrate dosage to maintain an optimal hemoglobin level (12 g/dl)

Stop Treatment:

• If no response after dose escalation at 4-6 weeks.
• Erythropoietin is not recommended if hemoglobin levels are greater than 12 g/dl.

Although guidelines have been established to grade and manage anemia in cancer patients, it is also important to allow for individual variances in the interpretations of these guidelines. For example, patients with significant pulmonary and/or cardiac co-morbidities and/or patients who appear to be developing significant symptoms associated with anemia may benefit from more aggressive management of anemia than their counterparts with the same RBC or hemoglobin levels.

It is also imperative that patients are monitored throughout their treatment, with flow charts available to determine if they are trending down towards anemia, maintaining appropriate RBC/hemoglobin levels, or making improvements if being treated for anemia.

Different Types of Anemia

Adequate laboratory tests prior to administration of growth factors in anemic patients provide important information as to how to proceed with treatment. For example it is important that iron, B12 and folic acid deficiencies can either be ruled out as a cause of different types of anemia, or corrected to either restore adequate RBC and hemoglobin production, or corrected prior to use of darbepoetin alfa.

Several types of medications and/or other co-morbidities may also play a role in iron, B12 and/or folic acid deficiencies, so a thorough physical examination including a list of all medications, alcohol habits and history can help to create an overall picture of why a patient may be anemic.

The NCCN has recommended the following laboratory tests to evaluate anemia:16

• Complete blood count with indices
• Peripheral smear
• Reticulocyte count
• Iron studies
• Vitamin B12
• Folate
• Lactate dehydrogenase
• Additional tests as indicated based on individual variables have also been recommended by the NCCN:
• Fractionated bilirubin
• Stool guaiac
• Bone marrow examination
• Coombs test
• Haptoglobin level
• Hemoglobin electrophoresis

Only through thorough patient assessment by healthcare providers are able to provide optimal individualized care for their patients. Furthermore, correcting underlying issues such as vitamin or mineral deficiencies enables treatment with growth factors to provide effective relief from anemia if anemia persists.

Effects of Anemia on Patients

Several quality of life parameters associated with anemia have already been identified, including fatigue, weakness, dizziness, headache, cognitive impairment, loss of sexual desire, depression, anxiety, shortness of breath, and impaired ability to perform daily functions. Issues surrounding the effects of anemia on patient outcomes in terms of survival and treatment response are gaining more attention.

Caro et al. evaluated the impact of anemia on survival in patients with various cancers, and found that patients with anemia had significantly poorer survival than those without anemia (Table 2).[17]

Table 2: Relative Risk of Death in Patients with Anemia for Head and Neck, Lymphoma, Prostate and Lung Cancers

McRae et al. also performed a study on the effects of hemoglobin levels on survival of patients with lung cancer, and found that decreasing hemoglobin levels following diagnosis were directly associated with reduced median survival (Table 3).[18]

Table 3: Effect of Hemoglobin Level on Survival of Patients With Lung Cancer

The present challenge is to conduct trials to evaluate if treatment with darbepoetin alfa or epoetin alfa may help improve survival among these anemic patients, or if prophylactic use of these growth agents may provide overall improved survival.

In addition to quality of life and patient outcomes, patient and societal economic impact are also greatly affected by anemia. The following factors must be weighed when considering economics in patients plagued with anemia and its associated effects:

• Time off work for treatment of anemia.
• Time off work due to fatigue or cognitive dysfunction associated with anemia.
• Cost to caregiver for providing transportation and getting time off from work for transporting patients for treatment of anemia.
• Cost to businesses in terms of lost work days for employees getting treatment for anemia, or who are not able to work due to effects of anemia.
• Burden on the healthcare system to perform transfusions and attend to possible adverse effects.

Erythropoietin is also detected in brain astrocytes, with receptors on cells within the central nervous system (CNS). Erythropoietin levels within the CNS increase in response to hypoxia, metabolic disturbances, brain injury or brain inflammation.[19] Research has indicated that erythropoietin may actually be a neuroprotective agent, which lends evidence to the fact that cancer patients with anemia have exacerbated cognitive deficits including loss of short-term memory, “chemo-brain,” and the inability to return to baseline cognitive functioning.[20],[21]

Management of Anemia

There are several factors that come into play when deciding upon the most appropriate clinical management decisions for anemia. First, the severity of anemia is associated not just with RBC or hemoglobin levels, but with individualized patient variables such as age, co-morbidities, time course of therapy and symptoms. The purpose of treatment for anemia must also be taken into consideration, as transfusions provide a rapid rise in hemoglobin levels, but do not provide a durable response, whereas treatment with darbepoetin alfa does not provide the immediate rise in hemoglobin, but is a durable treatment measure, and without the risks associated with transfusions.

Importantly, identifying patients who are at a high risk for developing anemia may provide the optimal overall strategy for dealing with anemia, as prevention of its development altogether and/or early intervention with the use of growth factors can ultimately circumvent the need for transfusions, side effects, and maybe most importantly, a delay in treatment.

Conclusion

Through the use of preventive or early intervention efforts through risk assessment models, appropriate laboratory testing, and appropriate monitoring of patients, CIA may ultimately become a side effect that is experienced by only a minority of patients undergoing treatment for cancer.

Several trials evaluating survival outcomes and possible associations to CIA and treatment with erythropoietic agents are ongoing to uncover its effects on long-term outcomes among patients with cancer. Furthermore, optimal use and scheduling of growth factors such as darbepoetin alfa continues to be evaluated so effective management of CIA can be implemented with increasing convenience, such as administration of darbepoetin alfa just once every three weeks.

Click here to take the post test 

Disclosures

References

[2] National Cancer Institute. Dictionary of Cancer Terms. Available at: http://www.cancer.gov/templates/db_alpha.aspx?expand=A. Accessed May 2006.

[3] Littlewood T, et al. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients, receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. Journal of Clinical Oncology. 2001; 19: 2865-2874.

[4] Mancuso A, et al. Correlation Between Anemia and Functional/Cognitive Capacity in Elderly Lung Cancer Patients Treated with Chemotherapy. Annals of Oncology. 2006; 17:146-150.

[5] Cleeland C, et al. Assessing symptom burden in breast cancer patients treated with darbepoetin alfa 200 mcg every two weeks (Q2W) using the MD Anderson Symptom Inventory (MDASI). Proceedings from the 27th annual San Antonio Breast Cancer Symposium. December 2004. Abstract #6034.

[6] Stasi R, et al. Cancer-Related Fatigue: Evolving Concepts in Evaluation and Treatment. Cancer. 2003;98:1786-1801.

[7] Wilkinson P, et al. Epoetin alfa in platinum-treated ovarian cancer patients: results of a multinational, multicentre, randomized trial. British Journal of Cancer. 2006;94:947-954.

[8] Freemantle N, et al. Impact of Darbepoetin Alfa on Transfusion, Hemoglobin Response, and Survival in Cancer Patients with Chemotherapy-Induced Anemia: Results of a Meta-Analysis of Randomized, Placebo-Controlled Trials. Blood. 2005;106:871a, abstract #3116.

[9] Hedenus M, et al. Darbepoetin alfa for the treatment of chemotherapy-induced anemia: disease progression and survival analysis from four randomized, double-blink, placebo-controlled trials. Journal of Clinical Oncology. 2005;23:6941-6948.

[10] Peters-Engl C, et al. Impact of haemoglobin levels during adjuvant chemotherapy on the survival of patients with primary breast cancer. Acta Oncologica. 2005;44:129-133.

[11] Juan O, et al. Impact of Hemoglobin Level on the Outcome of Advanced Non-Small-Cell Lung Cancer (NSCLC) Treated with Cisplatin and Gemcitabine. Proceedings from the 17th International Symposium of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology (MASCC-ISOO). Barcelona, Spain. July 2005. Abstract 02-008.

[12] Brines M, et al. Erythropoietin Crosses the Blood-Brain Barrier to Protect Against Experimental Brain Injury. Proceedings of the National Academy of Science USA. 2000;97:10526-1-531.

[13]Beard C, et al. Risk of Alzheimer’s Disease Among Elderly Paitents with Anemia: Population-Based Investigations in Olmsted County, Minnesota. Annals of Epidemiology. 1997;7:219-224.

[14]Milward E, et al. Evidence for Association of Anemia with Vascular Dementia. Neuroreport. 1999;10:2377-2381.

[15]Miller C, et al. Decreased Erythropoietin Response in Patients with the Anemia of Cancer. New England Journal of Medicine.1990;322:1689-1692.

[16]National Comprehensive Cancer Network. Cancer – and-Treatment Related Anemia. Available at: http://www.nccn.org/professionals/physician_gls/PDF/anemia.pdf. Accessed May 2006.

[17]Caro J, et al. Anemia is an Independent Prognostic Factor for Survival in Patients with Cancer: A Systemic, Quantitative Review. Cancer. 2001;91:2214-2221.

[18]McRae R, et al. Significance of Hemoglobin Changes During  Chemoradiotherapy in Non-Small Cell Lung Cancer (NSCLC): An Analysis of Three Sequential Trials. Proceedings of the American Society of Clinical Oncology. 2001. 20: 335a. Abstract # 1336.

[19]Brines M, et al. Erythropoietin Crosses the Blood-Brain Barrier to Protect Against Experimental Brain Injury. Proceedings of the National Academy of Science USA. 2000;97:10526-1-531.

[20]Beard C, et al. Risk of Alzheimer’s Disease Among Elderly Paitents with Anemia: Population-Based Investigations in Olmsted County, Minnesota. Annals of Epidemiology. 1997;7:219-224.

[21]Milward E, et al. Evidence for Association of Anemia with Vascular Dementia. Neuroreport. 1999;10:2377-2381.

[22]Amgen. Aranesp® Package Insert. Available at: http://www.aranesp.com/professional/cia/#. Accessed May 2006.

[23]]Egrie J, Browne J. Development and characterization of darbepoetin alfa. Oncology. 2002;16:13-22.