Anemia in Cancer Patients: Significance, Epidemiology, and Current Therapy

September 3, 2002

Anemia in cancer patients is associated with a decline in energy levels, activity levels, and quality of life, and these variables improve when hemoglobin levels rise. Importantly, the impact of improved hemoglobin levels on response to chemotherapy, radiation therapy, and survival time is under study.

ABSTRACT: Anemia in cancer patients is associated with a decline in energy levels, activity levels, and quality of life, and these variables improve when hemoglobin levels rise. Importantly, the impact of improved hemoglobin levels on response to chemotherapy, radiation therapy, and survival time is under study. This line of research follows favorable preliminary data in clinical studies suggesting improved treatment outcomes with reversal of anemia. It is estimated that there are 10 million people in the United States with cancer. Of the 1.3 million cancer patients who are anemic with hemoglobin levels less than 12 g/dL, about 800,000 are receiving chemotherapy and 500,000 are not. The predominant treatable cause of anemia in these patients is a relative lack of erythropoietin; overall, only 20% of anemic cancer patients receive a trial of erythropoietic therapy. About one-fourth (26%) of patients whose hemoglobin is less than 12 g/dL and who are receiving chemotherapy for cancer are currently receiving erythropoietic therapy. A review of the patients in our oncology practice revealed that 37% were anemic (hemoglobin

Anemia is an important aspect of cancer care because it is common, associated with symptoms such as poor quality of life and declining physical function, and treatable.[1-5] Fatigue, a prevalent problem in oncology patients, is also linked to anemia and is a key component of physical function (Figure 1).[6-8] Furthermore, recent research has revealed potentially important implications of anemia as a variable that has impact on the efficacy of cancer therapies including radiation therapy,[9,10] chemotherapy,[11] and combined- modality treatment.[12-14] While research is ongoing, it is assumed that variations in tissue oxygenation are probably responsible, at least in part, for these findings.

Anemia in Cancer Patients

The malignancy itself, or chemotherapy or other therapies cancause decreased erythropoietin production or a reduced responsiveness in thebone marrow to erythropoietin.[15] The presence of an invasive malignant processtriggers an immune response with the release of various cytokines that, in turn,interfere with bone marrow function and shorten red cell survival. These areprobably the most common causes of cancer-related anemia. Other causes includeiron and vitamin B-12 deficiencies; additional vitamin and nutritionaldeficiencies; bleeding; bone marrow metastases; various types of hemolysis;infection; renal diseases; inflammatory disorders; a variety of hematologic diseases, including hemoglobinopathies; and endocrinopathies.

During the 1960s and 1970s, blood product transfusion supportwas a mainstay of therapy encouraged by the advances in transfusion medicine. Inthe last 20 years, increased recognition of the potential for transmission ofviral infections, as well as a limited blood supply, brought the need fortransfusion alternatives into the forefront.

Current Therapeutic Approaches

The advent of erythropoietic therapy over the past 10 yearshas allowed physicians to reduce the need for transfusions. The recognition thatanemia treatment can improve the quality of life for patients has revolutionizedthe field of oncology practice.

Other than red cell transfusions and/or erythropoietinadministration, specific therapies for anemia are only helpful in a few cases.One such new and interesting therapy is the use of the CD20 monoclonal antibodyrituximab (Rituxan) in the treatment of autoimmune hemolytic anemias, pure redcell aplasias, and cold agglutinin disease.[16-25] Iron replacement, vitaminB-12 replacement, and the identification of occult (usually gastrointestinal)bleeding are also important in some patients.

National Statistics:Cancer and Anemia

It is estimated that there will be 1.28 million new cases of cancer in the United States this year[26]; at any given time, there are approximately 10 million people with cancer. Of the 1.24 million people presently receiving cytotoxic chemotherapy (Tandem cancer audit 1/00-12/00 on file at Amgen), about 800,000 are anemic with hemoglobin levels less than 12 g/dL, and about 210,000 (26%) are currently receiving recombinant human erythropoietin (Epogen, Procrit). Interestingly, six tumor types account for more than 75% of all cases of chemotherapy-induced anemia (Figure 2), and seven tumor types account for 75% of erythropoietin use in this setting (Figure 3).

Another 475,000 cancer patients who are not receivingchemotherapy are anemic, but only 38,000 (8%) of these patients are receivingerythropoietin treatment. Worldwide, it is estimated that about 3 millionpatients are receiving erythropoietic therapy when all indications, including kidneydisease, are considered.[27]

The use of erythropoietin increases overall with lower levels of hemoglobin: 4% of cancer patients on chemotherapy with hemoglobin levels > 12.1 g/dL; 13% of patients with hemoglobin of 10.1 to 12.0 g/dL; and 34% of those with hemoglobin < 10.0 g/dL are receiving erythropoietic therapy (Figure 4).

Recent studies indicate that the largest improvements in patients’ quality of life are associated with a rise in hemoglobin at levels between 10 and 13 g/dL (Figure 5).[28] This information may be of value to physicians and patients, since it challenges the view that only hemoglobin levels < 10 g/dL need attention. Our personal clinical experience is that some patients clearly report major improvements of fatigue and physical function as their hemoglobin levels rise to > 11 g/dL. These patients often are unable to carry out their daily activities unless they receive ongoing erythropoietic therapy.

Estimates regarding the frequency of anemia in cancer patients need to include overall population growth projections (Figure 6), as well as data on the aging of the population. In many instances, cancer is becoming a chronic illness requiring chronic therapies often associated with anemia and its sequelae on the quality of life. It is estimated that the US population will approach 300 million by the year 2010, and that new cancer cases will approach 1.5 million per year by the same time. Because of a growing and aging population, it is anticipated that there will be a rather explosive growth of cancer thereafter, with 2.5 million new cases per year (involving patients 55 years and over) by the year 2020 (Figure 7). The lifetime probability of developing cancer presently is 43% for men and 38% for women.[26] These statistics indicate that cancer-associated anemia may become more prevalent in the future.

National estimates regarding the frequency of anemia by chemotherapy regimen are shown on Figure 8. The estimated US distribution of chemotherapy schedules of administration from 1996 through 2000 is shown in Figure 9.

Anemia in Cancer Chemotherapy Patients

Pacific Shores Experience

We retrospectively reviewed the records of 350 consecutive cancer patients who received chemotherapy between January 2000 and January 2002 at Pacific Shores Medical Group, a subspecialty oncology/hematology practice in Southern California. We evaluated only patients with a proven diagnosis of malignant disease who had complete blood count results available for a period of at least 12 weeks after initiating chemotherapy. Hemoglobin levels were reviewed at baseline (before a specific chemotherapy regimen was started) and for three consecutive 4-week periods (through week 12) after initiation of chemotherapy. We also studied tumor types, chemotherapy regimens, and their relationships with hemoglobin levels and erythropoietic therapy. Table 1 outlines the demographic characteristics of the patients and their tumor types.

Table 2 reports hemoglobin levels at the various time intervals and the percentage of patients who received erythropoietic therapy/transfusions of red cells. A total of 128 (37%) of patients were anemic (hemoglobin < 12.0 g/dL) at baseline. Of the 222 patients who were not anemic at baseline, 144 (65%) became anemic during the first 12 weeks of chemotherapy. Overall, 272 of the 350 patients (78%) were anemic at baseline or at some point during the 12 weeks of chemotherapy. Importantly, 163 out of the 350 patients (46%) had hemoglobin levels £ 11 g/dL at baseline or by 12 weeks of chemotherapy, and only 72 (20%) had a hemoglobin level of 10 g/dL or less at baseline or by 12 weeks of chemotherapy. In fact, excluding the 26 patients with hemoglobin levels of 10 g/dL or less at baseline, only 46 of 324 (13%) patients had hemoglobin levels decrease to £ 10 g/dL by 12 weeks of chemotherapy.

During the period of review, we generally followed local Medicare guidelines, which allowed erythropoietic therapy when hemoglobin levels were £ 10.8 g/dL in cancer patients receiving chemotherapy. Recent guidelines, which became active on July 15, 2002, allow erythropoietic therapy for patients with symptomatic cancer-associated anemia or chemotherapy-associated anemia when the hematocrit is < 36% or the hemoglobin is < 12 g/dL.[29] Of our patients on chemotherapy, 107 of 194 (55%) received erythropoietin during treatment, and 22 (6%) received packed red cells transfusions. The incidence of anemia by tumor type and the incidence of therapy with erythropoietin are reported in Table 3. The incidence of anemia by type of chemotherapy used and the use of erythropoietin in this setting are shown in Table 4.

Conclusions

The information presented indicates that anemia as acomplication of cancer or its therapy is very prevalent and likely to increasein occurrence. The importance of anemia as a factor affecting the quality oflife and physical functioning of patients is well established. Its effects oncognitive and psychologic outcomes, the efficacy of cancer therapy, and survivalduration are now being studied. Declines in erythropoietin are largelyresponsible for the anemia associated with cancer and chemotherapy, anderythropoietic therapy is often effective in reversing anemia and improvingphysical function and quality of life. While US estimates indicate that 25% ofanemic cancer patients (hemoglobin < 12 g/dL) on chemotherapy have receivederythropoietic therapy, in our practice 71% of anemic patients did. Ourstatistics may reflect recent increases in anemia awareness and treatment. Wealso attribute the difference to the fact that our nursing and physician staffsmay have an increased focus on quality-of-life issues like fatigue and treatmentof anemia.

Recent research indicates that the chronic anemia of cancerpatients not receiving chemotherapy is highly responsive to erythropoietictherapy as well; new guidelines by insurers are now including thisindication.[29,30] Barriers to the use of erythropoietic agents include cost andreimbursement issues, the need for frequent parenteral administration, limitedefficacy, and indication restrictions. The recognition that quality of life isimproved with increases of hemoglobin in the range of 10 to 13 g/dL isredefining the parameters that physicians, patients, and insurers look at indeciding when to intervene. The advent of the longer-acting erythropoietic agentdarbepoetin alfa (Aranesp)[31-35] provides relief from frequent injections, adevelopment that will be certainly welcomed by patients. More efficient andconvenient approaches to anemia prevention and therapy are now available withthe use of the long-acting erythropoietic agent darbepoetin.[36-42]

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