Biology Reference
In-Depth Information
use. These two preparations have identical amino acid sequences and they dif-
fer slightly in glycosylation pattern and resulting isoform composition [4];
they have similar half-lives and per-unit efficacy in the oncology setting.
Darbepoetin alfa is the product of a human
EPO
gene modified by site-direct-
ed mutagenesis to differ from rHuEPO in five amino acids; these modifications
provide two additional glycosylation sites resulting in a greater carbohydrate
content, an approximately three-fold longer half-life and greater per-molecule
in vivo
potency [5].
Erythropoeitic therapy for cancer patients receiving chemotherapy
As a chronic inflammatory illness, cancer is associated with an inappropriate-
ly low endogenous EPO response to anemia. It was logical to predict that ther-
apy with rHuEPO might be effective in the treatment of anemia in the oncolo-
gy setting. Although early studies of rHuEPO in patients with cancer suggest-
ed that patients receiving chemotherapy were somewhat less responsive to
rHuEPO therapy than patients with cancer who were not receiving chemother-
apy, the design of the pivotal randomized, placebo-controlled Phase III studies
was such that the clinical benefit to patients was only shown in patients receiv-
ing chemotherapy [6]. Regretably, the focus of erythropoietic therapy in oncol-
ogy since has been almost exclusively on patients receiving chemotherapy, and
these agents are much less frequently used to treat the ACD associated with
cancer, a setting in which they may be more effective than they are in the treat-
ment of the chemotherapy patient [7]. (See Chapter 11 for further information
on ACD). Moreover, because cisplatin-based chemotherapy is associated with
renal impairment and further compromise of endogenous EPO response [8, 9],
some studies have focused on this subset of patients. In many European coun-
tries, cisplatin-based therapy is the only oncology setting in which erythropoi-
etic therapy is used.
In the initial clinical trials in patients receiving cancer chemotherapy,
rHuEPO was administered in dose-escalation studies at 25, 50, 100, 200, or
300 U/kg five times weekly for four weeks (approximately 10,000 U to
120,000 U/week total dose) [10, 11]. The data suggested a relationship
between dose and the proportion of patients in whom a 2 g/dL increase in
hemoglobin concentration was observed,with the highest proportion of
responders observed at the highest doses. Subsequently, small randomized
studies comparing very low doses of rHuEPO (2,000 to 3,000 U) to higher
doses (6,000 to 10,000 U) three times a week suggested that the higher doses
were more effective in terms of hematologic response [12, 13]. In two studies,
patients receiving chemotherapy were randomized to rHuEPO 150 or
300 U/kg three times a week or to a control group [14, 15]. In both studies, the
treated group had higher hemoglobin values and a trend favoring decreased
transfusion rates than the control group, with no clear advantage of the higher
starting dose. In a study in patients with B-cell malignancies, weekly rHuEPO
