Biology Reference
In-Depth Information
ally approach the overall cost of erythropoietic therapy, however, one must
know the cost of anemia in oncology, which is certainly substantial but much
more difficult to estimate. In addition to the direct healthcare costs of pre-
ventable transfusions and their complications, randomized, placebo-con-
trolled trials suggest that patients who are fatigued because they are not treat-
ed for anemia consume more hospital days and other direct healthcare
resources [82, 83]. Moreover, evidence exists that patients who are not treat-
ed for anemia, or who are treated suboptimally, are depressed and less pro-
ductive in terms of employment and family responsibilities [84-87]. These
indirect, health-related costs have value for society. One of the most important
directions for erythropoietic research will be to provide reliable estimates of
the cost offsets, directly to the healthcare system and indirectly to society,
associated with erythropoietic therapy. When these are known, they can be
subtracted from the acquisition costs of the drugs and the incremental cost, if
any, of treating patients to improve fatigue and quality of life can be mean-
ingfully estimated.
Because anemia is a negative prognostic factor for most tumor types [88],
an area of intense interest is the potential for erythropoietic therapy to improve
survival for patients with cancer [89]. Even mild and moderate degrees of ane-
mia may diminish the effectiveness of treatment with radiotherapy, chemother-
apy, or modern targeted therapies. It has long been understood that mild ane-
mia (hemoglobin concentration <12 g/dL) may compromise the effectiveness
of radiotherapy for cervical and head-and-neck carcinomas by inducing
demonstrable areas of hypoxia and radio-resistance in these tumors [90-100].
More recently, it has been shown that sub-lethal hypoxia confers
in vitro
resist-
ance to several chemotherapeutic agents, including alkylating agents, plat-
inum-containing complexes, and anthracyclines, and that anemia decreases the
in vivo
efficacy of cyclophosphamide [101, 102]. Moreover, it is now recog-
nized that the normal cellular response to hypoxia, mediated by hypoxia-
inducible factor-1 (HIF-1), increases the expression of vascular endothelial
growth factor (VEGF) and may mediate some of the effects of HER-2/neu and
other pathways relevant to tumor progression and modern targeted therapies
[103-109]. One plausible explanation for the repeated observation that anemia
is associated with decreased survival is that even mild anemia may compro-
mise the efficacy of all forms of cancer treatment. It is possible that anemia
decreases survival through its effects on the host, for whom severe fatigue may
be a barrier to completing aggressive therapy and to surviving. Even for can-
cers for which treatment does little to change survival, quality of life remains
one of the best predictors of prognosis [110].
Two clinical observations have increased awareness of the potential of ery-
thropoietic therapy to improve survival. In a randomized,placebo-controlled
trial of epoetin alfa in patients with cancer receiving chemotherapy, Littlewood
and colleagues observed a trend favoring increased survival in the patients
receiving epoetin alfa [111]. This study was not designed or powered to
address the effects of anemia on survival, but it represents a hypothesis-gener-
