Biology Reference
In-Depth Information
doses of 70,000 U appeared to be superior to doses weekly doses of 14,000 U
[16]. In most studies, patients receiving chemotherapy have been treated three
times a week with starting rHuEPO doses of 150 U/kg, sometimes with a dou-
bling of dose in non-responders, with 2 g/dL increases in hemoglobin concen-
tration observed in approximately 60% of patients [17-24]. Possibly because
of cost considerations, subsequent work did not pursue the suggestion in the
initial dose finding studies that weekly rHuEPO doses >100,000 U may be
associated with optimal hematologic responses in patients with cancer receiv-
ing chemotherapy. Data have not been published to show that patients benefit
from the frequently used dose increases to doses <100,000 U/week for patients
who have not responded to the initial starting dose. It is possible that patients
in whom responses are observed after dose increases to a 60,000 U weekly
dose increase would have responded had they remained on the initial lower
starting dose.
Impact of erythropoietic agents on transfusion requirements
In Phase I and II studies, rHuEPO therapy was shown to be associated with
increases in hemoglobin concentration in patients receiving cancer
chemotherapy. For pivotal, placebo-controlled Phase III studies, it was neces-
sary to choose a more clinically meaningful outcome variable. For a variety of
reasons, including historical precedent in earlier nephrology studies, sufficient
statistical power achievable with modest sample sizes, and the ambient bias in
clinical oncology that the major deleterious effects of anemia was an increase
in transfusion requirements, the outcome chosen was transfusion requirement.
Randomized, placebo-controlled trials of rHuEPO at doses of 150 U/kg given
subcutaneously three times a week to patients with cancer receiving
chemotherapy, with doubling of dose after six to eight weeks in non-respond-
ing patients, reduced red blood cell transfusion requirements [6, 20, 25].
Similar results have been reported without the dose increase for non-respon-
ders [21, 26]. More recently, in an uncontrolled trial, weekly subcutaneous
dosing with epoetin alfa at a weekly dose of 40,000 U, increasing to 60,000 U
after four weeks in non-responding patients, has been associated with hema-
tologic responses similar to those observed with three-times-a-week dosing
[27]. The necessity of the 33% increase in weekly dose with once-weekly
ver-
sus
three-times-a-week treatment has not been shown in randomized trials,
and weekly dosing has not been compared with placebo in randomized clini-
cal trials. In the United States, rHuEPO is usually given weekly, starting at
40,000 U, because of the increased convenience for patients. More recently,
studies using similar doses have been done and show the ability of rHuEPO to
prevent rather than treat anemia in the setting of cancer chemotherapy [28].
In a randomized,placebo-controlled trial of darbepoetin alfa in patients
with lung cancer receiving cisplatin-based chemotherapy, subcutaneous doses
of 2.25 µg/kg administered weekly, with doubling of dose permitted in non-
