Biology Reference
In-Depth Information
responding patients, was associated with a significant decrease in transfusion
requirements [29].
It is clear from the available data that erythropoietic therapy is associated
with a reduction in transfusion requirements in patients with cancer receiving
chemotherapy [30]. These data, however, have several limitations [31]. First,
the doses and schedules of erythropoietic agents used in these placebo-con-
trolled studies have not been chosen to be optimal in terms of patient benefit
or cost-effectiveness, forcing the clinician to integrate data from open-label
and/or active-control trials into his/her approach to patient care. Early studies
with rHuEPO were focused on identifying doses that would be superior in
terms of transfusion rates compared with placebo in randomized trials, not on
ensuring that the chosen doses and schedules would be associated with the
highest proportion of responding patients, the most rapid responses, or the
greatest cost-benefit. To date, no studies have been published of the pharma-
cokinetics or pharmacodynamics of rHuEPO in patients with cancer undergo-
ing chemotherapy and the dose-response curves have not been fully explored,
especially at the higher doses that appeared promising in terms of optimal ben-
efit in early dose-finding studies. (See Chapter 6 for further information.)
Active-controlled, dose-finding studies of darbepoetin alfa done after the ran-
domized trial was underway suggest that doses lower than those used in the
placebo-controlled trial, including 1.5µg/kg per week or 3 µg/kg every two
weeks produce hematologic effects indistinguishable from those observed
with epoetin alfa given 150 U/kg three times a week or 40,000 U weekly,or
from weekly darbepoetin alfa doses of 2.25 µg/kg [32, 33]. These studies have
shown that this agent can be administered every two weeks without increasing
the total dose administered over time. In the United States, this finding has led
to a situation similar to that for epoetin alfa, in which clinicians use a dose and
schedule (3 µg/kg every two weeks) that is different from that which was used
in pivotal Phase III studies. The recent interest in every-other-week
chemotherapy for patients with lymphoma and for the adjuvant therapy of
breast cancer increases the importance, in terms of patient convenience, of
effective and efficient every-other-week erythropoietic support. Identifying
doses and schedules that are superior to placebo is a simpler matter than deter-
mining doses and schedules that are superior to all other doses and schedules,
or equal in terms of efficacy and of lower cost, and much of this work remains
to be done.
Impact of erythropoietic agents on quality of life
The early development of rHuEPO for oncology was focused on the efficacy
of this agent in preventing transfusions during cancer chemotherapy.
Nevertheless, in the randomized clinical trials, patients treated with rHuEPO
consistently had a higher mean hemoglobin concentration than patients receiv-
ing placebo from the second month of therapy onward, despite having fewer
