It is increasingly recognized that
fatigue in cancer patientsprimarily caused by anemia resulting from chemotherapy or other aspects of the
disease processis associated with debilitating effects on quality of life and
functioning.[1,2] Surveys performed by the multidisciplinary Fatigue Coalition
indicated that fatigue was the primary complaint in one-quarter of patients
after chemotherapy (ahead of nausea at 13%), and that 61% of cancer patients
felt their lives were affected more by fatigue than by pain associated with
their disease. Cancer-related anemia has traditionally been treated with red
blood cell transfusions; however, concerns over the safety of the blood supply
and potential adverse effects of transfusions in cancer patients have led to the
development of erythropoietic agents as a safer alternative for increasing
hemoglobin levels in these patients.
Improved understanding of the deleterious effects of anemia and the
availability of recombinant human erythropoietin (rHuEPO) have led to a great
deal of active investigation of the benefits of erythropoietic therapy in
patients with chemotherapy-induced anemia. Most recently, with the development
of darbepoetin alfa (Aranesp) and research into once-weekly therapy for rHuEPO (rHuEPO
is licensed for this indication at a dose of 150 U/kg three times weekly),
considerable efforts have been focused on reducing the need for frequent
injections. For patients with cancer (and their caregivers), each injection can
be a reminder of their disease; for those for whom self-injection is not an
option, each clinic visit is an interruption of normal life and may create
significant logistic challenges relating to transportation, child care, or work.
For clinic staff, administrative work and time are increased. A recent study of
patients with chronic renal insufficiency reported that, on average, these
patients spent 90 minutes traveling to/from the clinic and waiting to be seen,
and 49% relied on someone else for transportation. It is likely that these
findings would also be true for cancer patients. Thus, reducing the dosing
frequency of erythropoietic agents given to patients with chemotherapy-induced
anemia would be beneficial.
Weekly administration was shown to be effective in patients with
chemotherapy-induced anemia in a large, open-label, uncontrolled study using a
single subcutaneous injection of 40,000 U of rHuEPO (this dose could be
increased to 60,000 U if a 1.0-g/dL hemoglobin increase had not been observed
after 4 weeks). With this regimen, 68% of patients achieved a hematopoietic
response (a hemoglobin concentration ³ 12.0 g/dL and/or an increase
of ³ 2.0 g/dL without preceding transfusions) by the end of the 16-week
treatment period, which is comparable to the response observed with
three-times-weekly dosing.[5,6] However, this dose represents an increase of
approximately 33% over the more routinely studied dose and schedule of 150 U/kg
three times weekly[7-9] or the dosing regimen of 10,000 U of rHuEPO three times
weekly, which has also been reported. Based on these results, weekly dosing
is now accepted in clinical practice in the United States, although not in other
Darbepoetin alfa, a unique recombinant protein produced by modifying the gene
for erythropoietin, is a more potent erythropoietic agent. Darbepoetin alfa
stimulates erythropoiesis through the same mechanism as endogenous
erythropoietin and rHuEPO. However, darbepoetin alfa was engineered to have
additional carbohydrate side chains (five total N-linked glycosylation side
chains with up to 22 sialic acid residues) compared with rHuEPO (three total
N-linked glycosylation side chains with up to 14 sialic acid residues).
Sialic acid content is directly correlated with in vivo activity, possibly due
to the degree of clearance by the asialoglycoprotein receptor in the liver;
the increased sialic acid content of darbepoetin alfa reduces its clearance and
results in an extended serum residence time.
Darbepoetin alfa was initially approved for use in patients with renal
failure. Pharmacokinetic studies in this indication showed that darbepoetin alfa
had an approximately threefold longer terminal half-life than rHuEPO (25.3 vs
8.5 hours). An extensive clinical development program has evaluated the
pharmacokinetics, efficacy, and safety of various dose and schedule combinations
of darbepoetin alfa during cancer chemotherapy. Phase I and II studies explored
dosing intervals ranging from weekly to every-4-week administration.[14-21]
These included an every-2-week dosing schedule, which appeared to be effective
in alleviating anemia in patients with solid tumors receiving
Comparisons between rHuEPO studies (or between rHuEPO studies and darbepoetin
alfa studies) may be confounded due to differences in factors such as study
design, populations, treatment duration, analytical methodologies, response
definitions, or the use of analysis sets other than the intent-to-treat set. To
obtain a more precise estimate of the effect of darbepoetin alfa administered at
3.0 µg/kg every 2 weeks, and to evaluate the relative effect of this dose
and schedule compared with rHuEPO, data from three clinical studies of similar
design have been pooled.[14-17,19,20] Unlike comparisons with historical
literature, this approach eliminates differences in analytical methodologies,
treatment duration, and other potentially confounding factors. This report
describes the results of this combined analysis.
The population evaluated and the design of each of the three studies included
in these analyses were similar. All study centers were in the United States.
Eligible patients were men or women ³ 18 years of age who were
receiving multicycle chemotherapy and had anemia (hemoglobin concentration
£ 11.0 g/dL). Patients were required to have adequate renal and hepatic
function and could not be iron deficient (defined as both transferrin saturation
< 15% and ferritin < 10 ng/mL). Patients with known cardiac
disease or hematologic disorders that could cause anemia were not eligible. Each
center’s independent ethics committee or central ethics committee approved the
protocol, and patients provided written informed consent before any
study-specific procedures were done.
The principal difference between the eligibilty criteria in the three studies
was tumor type (solid tumors were specified in two studies and nonmyeloid
malignancies in the third). However, as most patients in both groups had solid
tumors, and no difference has been noted between the effect of erythropoietic
agents on patients with hematologic malignancies and those with solid
tumors,[5,6] this is not thought to have an impact on the validity of the
conclusions from this pooled analysis.
All three studies were multicenter and open-label in design. The dose of
rHuEPO could be increased in both studies contributing rHuEPO data (at week 8 or
week 6), and the dose of darbepoetin alfa could be increased in one of the two
studies contributing darbepoetin alfa data (at week 7). The requirement for
withholding drug due to reaching specified maximum hemoglobin concentrations
(14 g/dL for women, 15 g/dL for men) was the same in all studies. Red
blood cell transfusions were recommended if hemoglobin decreased to £ 8.0
g/dL or patients had symptoms
1. Cella D: The Functional Assessment of Cancer Therapy-Anemia (FACT-An)
Scale: A new tool for the assessment of outcomes in cancer anemia and fatigue.
Semin Hematol 34(3 suppl 2):13-19, 1997.
2. Cella D: Factors influencing quality of life in cancer patients: Anemia
and fatigue. Semin Oncol 25(3 suppl 7):43-46, 1998.
3. Curt GA: Impact of fatigue on quality of life in oncology patients. Semin
Hematol 37:14-17, 2000.
4. Lindberg J, Foret J, Pitts L, et al: Burden of frequent injections on
normal routines of anemic CRI patients. Paper presented at 33rd Annual Meeting
of the American Nephrology Nurses’ Association (ANNA), May 2002, Orlando, Fla.
5. Gabrilove JL, Cleeland CS, Livingston RB, et al: Clinical evaluation of
once-weekly dosing of epoetin alfa in chemotherapy patients: Improvements in
hemoglobin and quality of life are similar to three-times-weekly dosing. J Clin
Oncol 19:2875-2882, 2001.
6. Demetri GD, Kris M, Wade J, et al: Quality-of-life benefit in chemotherapy
patients treated with epoetin alfa is independent of disease response or tumor
type: Results from a prospective community oncology study. J Clin Oncol
7. Glaspy J, Bukowski R, Steinberg D, et al: Impact of therapy with epoetin
alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer
chemotherapy in community oncology practice. J Clin Oncol 15:1218-1234, 1997.
8. Littlewood TJ, Bajetta E, Nortier JW, et al: Effects of epoetin alfa on
hematologic parameters and quality of life in cancer patients receiving
nonplatinum chemotherapy: results of a randomized, double-blind,
placebo-controlled trial. J Clin Oncol 19:2865-2874, 2001.
9. Abels RI: Use of recombinant human erythropoietin in the treatment of
anemia in patients who have cancer. Semin Oncol 19(3 suppl 8):29-35, 1992.
10. Egrie JC, Dwyer E, Lykos M, et al: Novel erythropoiesis stimulating
protein (NESP) has a longer serum half-life and greater in vivo biological
activity than recombinant human erythropoietin (rHuEPO). Blood 90:56a, 1997.
11. Spivak JL, Hogans BB: The in vivo metabolism of recombinant human
erythropoietin in the rat. Blood 73:90-99, 1989.
12. Egrie JC, Browne JK: Development and characterisation of novel
erythropoiesis stimulating protein (NESP). Br J Cancer 84S (suppl 1):3-10, 2001.
13. Macdougall IC, Gray SJ, Elston O, et al: Pharmacokinetics of novel
erythropoiesis stimulating protein compared with epoetin alfa in dialysis
patients. J Am Soc Nephrol 10:2392-2395, 1999.
14. Glaspy J, Jadeja J, Justice G, et al: Randomized, active-controlled,
phase 1/2, dose-escalation study of NESP administered weekly and every 2 weeks
in patients with solid tumors. Proc Am Soc Clin Oncol 20:387a, 2001.
15. Glaspy J, Tchekmedyian S, Jadeja J, et al: Randomized, active-controlled
phase I/II, dose-escalation study of ARANESPÔ in solid tumor patients. Blood
16. Glaspy J, Jadeja JS, Justice G: A dose-finding and safety study of novel
erythropoiesis stimulating protein (NESP) for the treatment of anaemia in
patients receiving multicycle chemotherapy. Br J Cancer 84(suppl 1):17-23, 2001.
17. Glaspy J, Jadeja JS, Justice G, et al: A randomized, active-control,
pilot trial of front-loaded dosing regimens of darbepoetin alfa for the
treatment of anemia during cancer chemotherapy. Cancer. In press.
18. Kotasek D, the ARANESP 980291 Study Group, Berg R, et al: Randomized,
double-blind, placebo-controlled, phase I/II dose finding study of ARANESPÔ
administered once every 3 weeks in solid tumor patients. Blood 96:294a, 2000.
19. Glaspy JA, Jadeja JS, Justice G, et al: Darbepoetin alfa given every 1 or
2 weeks alleviates anaemia associated with cancer chemotherapy. Br J Cancer
20. Glaspy J, Jadeja J, Justice G, et al: Optimizing the management of anemia
in cancer patients: A randomized, active-controlled study investigating the
dosing of darbepoetin alfa. Proc Am Soc Clin Oncol 21:362a, 2002.
21. Kotasek D, Steger G, Faught W, et al: Darbepoetin alfa administered every
3 weeks alleviates anemia in patients with solid tumors receiving chemotherapy;
results of a double-blind, placebo-controlled, randomized study. J Clin Oncol
22. Kalbfleisch JD, Prentice RL: The Statistical Analysis of Failure Time
Data. Wiley, New York, 1980.
23. Dammacco F, Castoldi G, Rödjer S: Efficacy of epoetin alfa in the
treatment of anaemia of multiple myeloma. Br J Haematol 113:172-179, 2001.