Optimal Treatment of Anemia Requires Thorough Work-up of Patients

COLUMBIA, South Carolina—Anemia impairs quality of life and functional status, can interfere with cancer therapies, and now seems linked to poorer prognosis and shortened life span, at least in some cancer patients, according to Robert E. Smith, Jr., MD, president of South Carolina Oncology Associates and clinical associate professor at the University of South Carolina School of Medicine in Columbia. In his experience, and that of other oncologists, recombinant human erythropoietin (rHuEPO) and darbepoetin alfa (Aranesp) can increase hemoglobin levels, decrease fatigue, and improve quality of life for cancer patients. To get optimal treatment results with erythropoietic agents, however, requires understanding the full range of etiologies of anemia and its signs and symptoms, and a thorough work-up of patients.

"Anemia is not a diagnosis, except in those few cases where there’s an inborn or acquired red blood cell abnormality, but in most cases, it’s a sign of an underlying pathology," Dr. Smith explained. Anemia is due either to decreased effective life span of red blood cells or bone marrow that responds inadequately to erythropoietin so that production of red blood cells is impaired.

The underlying causes of anemia (see Figure 1) include impaired ability of the kidneys to produce erythropoietin due to antibiotics, other toxins, or the myelosuppressive effects of chemotherapy and radiation, and decreased sensitivity of EPO due to inflammatory cytokines or replacement of bone marrow by cancer or fibrosis. Other etiologies include nutritional deficiencies (iron, B12), hemolysis, and blood loss. The diagnosis of anemia of chronic disease is often made by eliminating other causes.

Anemia of chronic disease is characterized by a deficiency in EPO production and a bone marrow that fails to properly respond to EPO. According to current belief, Dr. Smith said, reduced EPO production results from a blunted EPO response rather than a quantitative deficiency.
The secondary release of cytokines can also suppress EPO production
in cancer patients. One study showed that interferons suppress erythroid-myeloid precursors in bone marrow.

The work-up of the patient should include questions about cancer treatment as well as other toxic exposures. How much chemotherapy and/or radiation has the patient received? Prior blood work should be reviewed to determine if there was an abrupt fall in the red blood cell count that might indicate bleeding or hemolysis, or a more gradual trending down over several months. During the physical exam, the physician should look for signs of wasting, splenomegaly, and venous engorgement.

Laboratory Tests

Lab work should include a CBC with indices, a reticulocyte count to look for indications of bleeding or hemolysis, and indirect bilirubin that might indicate hemolysis. The blood smear should be reviewed "for spherocytes that might indicate a hemolytic process, fragmented red blood cells that might indicate disseminated intravascular coagulation or a microangiopathic process going on, nucleated red blood cells that would tip you off that there may be fibrosis or extensive tumor replacing bone marrow, and things like rouleaux that might indicate a paraprotein," Dr. Smith said. He did not include erythropoietin levels in the list of lab test measurements because the levels usually do not affect the decision-making process in the case of anemia of chronic disease, he said.

Symptoms of cancer-related anemia include fatigue, anorexia, nausea, pallor, reduced libido, labored breathing and palpitations, vertigo, depression, and impaired cognitive function and impaired immune function. Anemia impairs quality of life and can compromise the efficacy and tolerability of treatment.

One of the most significant impacts of anemia is its association with poor prognosis and increased mortality. There are several reasons for the poor prognosis. Anemia can delay treatment or decrease dose intensity among patients who are inactive or have pneumonia. "Also, tumor hypoxia can greatly compromise our treatment with chemotherapy and radiation," Dr. Smith said.

Four Treatment Options

Dr. Smith presented four treatment options for anemia (see Table 1): transfusions, EPO, EPO plus transfusion, and a watch-and-wait approach. For EPO therapy, "we normally start at a hemoglobin of 10.5 g/dL and we use EPO once weekly at 40,000 units," Dr. Smith said. "If there is less than 1 g increase in 4 to 6 weeks, we normally escalate to 60,000 units...We use it to a hemoglobin of 13 g/dL and at that point, we either dose reduce or frequency reduce.’’

While agreeing "with studies that a hemoglobin of 12 g/dL is where you see the most improvement in quality of life," Dr. Smith said that levels might need to be higher for patients with diseases such as lung cancer to see an improvement in quality of life.

Pharmacologically Improved Recombinant Growth Factor

Exogenous rHuEPO has been used clinically for more than 10 years and produces the same types of hematologic and immunologic effects as endogenous EPO. As shown in large-scale clinical trials, rHuEPO is effective in various tumor types and treatment modalities, such as chemotherapy and radiation. With darbepoetin alfa, "we now have a recombinant growth factor that’s pharmacologically improved," Dr. Smith said. "We do need to do the studies that will show us
the optimal way to dose this in relationship to when it is given with chemotherapy and what hemoglobin to start at."

Darbepoetin alfa has been tested in an alternate week dosing regimen concomitant with chemotherapy without loss of efficacy. It has also been shown to reduce transfusion need (compared to placebo) in lung cancer patients and a retrospective review of that study showed a prolonged time to progression in patients with small-cell carcinoma.