Low-Dose Cytarabine Improves Survival of Older Patients with Leukemia
Acute myeloid leukemia, elderly, cytarabine, hydroxyurea, all-trans retinoic acid. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)
Low doses of the chemotherapy drug cytarabine increased overall survival compared with the drug hydroxyurea in patients with acute myeloid leukemia who were not healthy enough to receive the standard treatment of high-dose, intensive chemotherapy.
Cancer, March 15, 2007 (see the journal abstract).
(Cancer 2007 Mar 15; 109 :1117-1124)
Leukemia is a cancer of the blood and bone marrow. Normally, stem cells produced by the bone marrow develop into one of three types of mature blood cells: red blood cells, white blood cells, or platelets. In leukemia, stem cells remain immature and produce blood cells called blasts that cannot perform their normal functions. Blasts build up in the bone marrow and blood, taking space away from normal blood cells. The resulting shortage of normal blood cells can lead to infection, anemia, and other life-threatening conditions.
Acute myeloid leukemia (AML) occurs when stem cells produce too many immature white blood cells, called myeloblasts. Intensive chemotherapy (using very high doses of anti-cancer drugs) has been shown in clinical trials to help induce remission in patients with AML. However, patients who are older or who have other illnesses may not be able to tolerate the side effects of high-dose chemotherapy. Few clinical trials have tested new treatments for this group of patients, and an established standard of care does not exist.
This randomized trial enrolled patients with AML or myelodysplastic syndrome (a condition that can lead to leukemia) who were considered by their physicians to be unfit for intensive chemotherapy. The investigators randomly assigned patients to receive either low doses of a chemotherapy drug called cytarabine or a drug called hydroxyurea (HU), which helps control the number of white blood cells circulating in the body.
Within both groups, patients were also randomly assigned to receive either no additional treatment or a drug called all-trans retinoic acid, which may help cytarabine kill cancer cells. Patients in both groups received supportive care as needed.
The investigators compared the number of patients who had a complete response to the treatment. A complete response was defined as the number of blasts reduced to less than 5 percent of cells in the bone marrow, and mature white blood cells and platelets in the blood returning to adequate levels. The investigators also compared overall survival and side effects between the groups.
The trial was organized by the United Kingdom National Cancer Research Institute and enrolled patients from 75 treatment centers in the United Kingdom. The lead author of the study was Alan K. Burnett, M.D., from Cardiff University in Wales. (See the protocol summary.)
All but four patients enrolled in the trial were older than 60, and most were older than 70. One hundred three patients received cytarabine and 99 received HU. In both groups, at least 90 percent of patients received at least one course of treatment.
Side effects did not differ significantly between the two groups. The need for most types of supportive care also did not differ significantly between the two groups, except for the need for day visits to the hospital, which was greater in patients receiving cytarabine.
Patients receiving cytarabine had significantly more complete responses to therapy than patients receiving HU (18 percent compared to 1 percent). Patients receiving cytarabine who had a complete response had a median disease-free survival of eight months.
Overall survival was also significantly higher for patients receiving cytarabine, because only patients who experienced a complete response to treatment had increased overall survival. The addition of all-trans retinoic acid did not significantly improve response or survival in either group.
A limitation of the study, explains Anthony Murgo, M.D., of the National Cancer Institute’s Division of Cancer Treatment and Diagnosis, is that the investigators did not specifically define what criteria made a patient unfit for intensive therapy. Instead, the decision was left up to individual physicians. “If [someone is] going to be making [treatment] decisions based on categorizing a patient as unfit for intensive therapy…they should have criteria for categorizing which patients are considered unfit,” said Murgo.
The authors address the need for future research in this area: “The basis on which patients are not considered fit for an intensive or a nonintensive approach to treatment is not clear…Parameters need to be identified that predict at diagnosis which patients are at risk of early mortality with an intensive treatment approach.”
This study “establishes low-dose cytarabine as an accepted standard of care in elderly patients with AML who are deemed unfit for chemotherapy, against which other investigational agents may be evaluated,” said Hagop M. Kantarjian, M.D., in an accompanying editorial.
Despite the improvement in survival seen in this study, the authors stress the need for the development of newer, better therapies for older patients with AML: “Although a very significant benefit in survival has been demonstrated with [cytarabine] compared with HU, the outlook for patients who receive low-dose [cytarabine] remains unsatisfactory…The number of patients with AML who required treatment will increase as the general population in this age group increases, and new chemotherapy agents are being developed that may be useful for this group of patients.”
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