Biology Reference
In-Depth Information
might explain the lack of uniform adoption of an aggressive anemia treatment
standard analogous to the one used in nephrology.
It may be possible to design more successful approaches to initiating ery-
thropoietic therapy in patients with cancer. The relationship between dose and
both response rate and time to response for darbepoetin alfa during cancer
chemotherapy has been studied in a dose-escalation trial in which all data were
analyzed with imputation to eliminate the effects of transfusions and an intent-
to-treat approach to missing data points [32]. Similarly designed and analyzed
dose-escalation trials, including very high doses (>100,000 U/week) of
rHuEPO have not been reported. The resulting dose-response curve, shown in
Figure 1, suggests a biphasic relationship of dose to the proportion of patients
who demonstrate a hematopoietic response. For some doses of darbepoetin alfa,
including those used in current clinical practice, a proportion of patients will
respond and a significant remainder will be termed non-responders. While pro-
ducing responses indistinguishable in a randomized trial from current
approaches to rHuEPO use, these doses were found to be suboptimal. At doses
of 4.5 µg/kg/week or greater, substantially higher response rates were achieved.
Given that these data were analyzed using an intent-to-treat approach, few, if
any, patients remain on therapy and have not responded. Hence, the dose of an
erythropoietic agent is the best and most important predictor of response in
oncology and, as in the renal failure setting, most patients will respond if treat-
ed with sufficient doses. It may be more appropriate to seek predictors of dose
than predictors of response. Importantly, when the optimal dose of darbepoetin
alfa is administered,the time to response is shortened by approximately 30%
compared with standard approaches to patient treatment (Fig. 2).
Unlike patients receiving dialysis, in whom rapid volume expansion can be
associated with hypertension, a rapid rise in hemoglobin concentration in the
oncology setting is safe and beneficial to the patient. The minimum dose of
darbepoetin alfa associated with optimal response rate and time to response in
cancer patients is 4.5 µg/kg/week; this dose has not yet been determined for
rHuEPO. It is possible that administering the optimal dose as the initial dose,
with dose decreases as patients respond, will be both better for patients with
cancer and more cost effective as well (Fig. 3). To explore this possibility, a
randomized pilot trial compared the effects of darbepoetin alfa, given with
frontloaded dosing (4.5 µg/kg/week with dose decreases in some cohorts after-
four weeks) to epoetin alfa given by the conventional backloaded approach,
with the usual starting dose and escalation for non-response in the treatment of
anemia during cancer chemotherapy [76]. In this pilot trial, patients treated
with the frontloaded approach enjoyed both more rapid improvement in hemo-
globin concentration and more substantial gains in quality of life, as well as
less dependence on caregivers. A large, randomized trial is underway compar-
ing the effects of frontloaded darbepoetin alfa to conventional therapy. It is
hoped that by defining more appropriate, consistently effective, rapid,and
cost-effective approaches to the treatment of anemic patients with cancer will
increase enthusiasm for erythropoietic therapy in oncology.
