IImpact and Therapeutic Implications of Anemia in Lung Cancer
Presenter: Corey Langer, MD
Affiliation: Fox Chase Cancer Center, Philadelphia, PA
Anemia in cancer patients is a common problem with a multifactorial etiology. It is well recognized that the presence of malignancy is associated with a blunted response to anemia; as hemoglobin (Hb) levels decrease, the normal compensatory increase in erythropoietin (EPO)production is not seen. Compounding this relative endogenous EPO deficiency is treatment-induced myelosuppression. Platinum-based regimens have been shown to cause grade 2 or higher anemia in as many as 80% of patients, with up to one-third requiring transfusion at some point during therapy.
The implications of anemia in cancer patients reach beyond symptom-related compromise in quality of life, which is in itself a serious consideration. However, data are emerging that anemia below a critical value (Hb < 11 g/dL) may be associated with decreased survival. Furthermore, the delivery of intensive chemotherapy and maximal radiation therapy is certainly limited by the presence of anemia, possibly compromising outcome. In an attempt to overcome this potential limitation, physicians have investigated the use of anemia-preventing strategies, including transfusions and exogenous growth factors like recombinant human EPO (rEPO).
In today's practice, the use of rEPO is preferable to transfusion in patients with moderate anemia, for its better side effect profile and ease of delivery, among other reasons. Several studies of rEPO have established its clinical benefit, with an average rise of 2 g/dL in hemoglobin levels by week 8 of rEPO 40,000 U/week. Patients who did not respond to rEPO by 8 weeks were more likely to have lower performance status, greater disease burden, or higher transfusion requirements.
More recent studies of rEPO in lung cancer include a phase III randomized protocol of immediate (ie: prophylactic, preemptive) vs. reactive use of rEPO in non-anemic patients with locally advanced NSCLC receiving at least 8 weeks of chemotherapy (Crawford et al. ASCO 2003). The dose of rEPO was 40,000 U/week either immediately, or after the Hb dropped under 10 g/dL. Preliminary results show that baseline Hb level was preserved in the immediate rEPO group, with over 80% of patients maintaining Hb over 10 g/dL. In contrast, at least half of the patients in the reactive arm required rEPO treatment during chemotherapy, and 44% had a Hb level < 10 g/dL. Quality-of-life was rated higher in the immediate use arm, although this difference was not statistically significant. Effects on disease progression and survival are not yet clear with the available data to date.
A newer growth factor, darbepoetin alfa, (DPO) is now being studied. It has a longer half-life than rEPO secondary to an increased carbohydrate content conferred by the presence of more sialic acid residues (up to 22 in DPO vs. max of 14 in rEPO). The improved pharmacokinetics may make DPO more biologically effective than rEPO, although preliminary data from a phase III trial comparing the two agents head-to-head presently suggest greater Hb response with rEPO. Longer follow-up and more mature data are eagerly awaited.
Future trials in this area will focus not only on the effect of anemia treatments on quality-of-life and Hb levels, but on survival and cognitive function. It is believed that the tissue hypoxia resulting from anemia leads to decreased radiosensitivity. Head and neck cancer patients receiving preoperative chemoradiation or definitive radiation with anemia have significantly higher local-regional control and worse long-term survival than non-anemic cohorts. However, the initial study evaluating the use of rEPO in this setting actually showed a slightly worse outcome with the addition of rEPO. Thus continued study is needed as there may be different effects depending on the tumor treated.