Cheer 2004
Cheer 2004
Cheer 2004
0012-6667/04/0003-0323/$34.00/0
EVALUATION
2004 Adis Data Information BV. All rights reserved.
Epoetin Beta
A Review of its Clinical Use in the Treatment of Anaemia in
Patients with Cancer
Susan M. Cheer and Antona J. Wagstaff
Adis International Limited, Auckland, New Zealand
Data Selection
Sources: Medical literature published in any language since 1996 on epoetin beta, identified using Medline and EMBASE, supplemented
by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published
articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: Medline search terms were ‘epoetin beta’. EMBASE search terms were ‘epoetin beta’. AdisBase search terms were
‘epoetin beta’. Searches were last updated 19 January 2004.
Selection: Studies in patients with cancer-related or chemotherapy-induced anaemia who received epoetin beta. Inclusion of studies was
based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology
were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Anaemia, cancer, epoetin beta, recombinant human erythropoietin, pharmacodynamics, pharmacokinetics, therapeutic use.
Contents
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
324
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
2. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . 328
2.1 Effects on Erythropoiesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
328
2.2 Other Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . 330
3.1 Absorption and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
330
3.2 Metabolism and Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
331
3.3 Site of Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
4.1 Chemotherapy-Induced Anaemia in Patients with Solid Tumours . . . . . . . . . . . . . . . . . . . . . . . . . 332
4.2 Anaemia in Patients With Haematological Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
4.3 Factors Affecting Response to Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
4.3.1 Tumour Type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
337
4.3.2 Impact of Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
4.3.3 Early Predictors of Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
4.4 Effects on Quality of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
338
4.4.1 Malignant Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
4.4.2 Haematological Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
4.4.3 Solid Tumours . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
339
5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . 339
6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
6.1 Patients with Solid Tumours . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
340
3
Epoetin Beta: A Cheer & 3
Summary
Abstract Epoetin beta (NeoRecormon) is a recombinant form of erythropoietin. It
increases reticulocyte counts, haemoglobin (Hb) levels and haematocrit.
Epoetin beta administered subcutaneously once weekly corrected anaemia and
had equivalent efficacy to that of epoetin beta administered three times weekly in
patients with haematological malignancies. Subcutaneous epoetin beta reduced
transfusion requirements and increased Hb levels versus no treatment in patients
with solid tumours and chemotherapy-induced anaemia in nonblind, randomised
trials. Anaemia and quality of life were also improved, and blood transfusion
requirements were reduced to a significantly greater extent than placebo or no
treatment (with supportive blood transfusion) in patients with haematological
malignancies. Most patients were receiving chemotherapy.
Subcutaneous epoetin beta was well tolerated by patients with cancer; adverse
events with the drug occurred with a similar incidence to those with placebo or
no treatment (with supportive blood transfusion). Hypertension was relatively
uncommon with epoetin beta in clinical trials.
Patients with haematological malignancies and a baseline platelet count 100
109/L, Hb levels of 9 g/dL or lower erythropoietin levels have demonstrated
better responses to epoetin beta than other patients in clinical trials. However,
neither baseline erythropoietin level nor the observed to predicted ratio of
erythro- poietin levels correlated with the response to epoetin beta in patients
with solid tumours and chemotherapy-induced anaemia. A decrease of <1
g/dL or an increase in Hb with epoetin beta during the first chemotherapy
cycle indicated a low transfusion need in subsequent cycles in patients with
ovarian carcinoma.
In general, the efficacy of epoetin beta is not limited by tumour type.
Response to the drug occurred irrespective of the nature (platinum- or
nonplatinum-based) or presence of chemotherapy treatment in randomised trials.
Conclusion: Epoetin beta has shown efficacy in the management of cancer-relat-
ed anaemia in patients with haematological malignancies and of chemotherapy-
-induced anaemia in patients with solid tumours. Once-weekly administration
provides added convenience for patients and may be cost saving, although
additional research into the potential pharmacoeconomic benefits of this regimen
are required. The drug is well tolerated in patients with cancer and is associated
with little injection-site pain when administered subcutaneously. Epoetin beta is
an important option in the prevention of chemotherapy-induced anaemia, and a
valid and valuable alternative to blood transfusion therapy for the treatment of
cancer-related or chemotherapy-induced anaemia.
Epoetin beta produces dose-proportional increases in reticulocyte counts and
haematocrit and haemoglobin (Hb) levels. The increases in Hb levels with
recommended dosages of epoetin beta were significantly greater than those with
Pharmacodynamic
Profile no treatment (with supportive blood transfusion) or placebo in randomised trials
in patients with anaemia and cancer.
The correction of anaemia with epoetin beta is associated with beneficial
changes in cardiovascular parameters in patients with chronic renal failure (CRF)
Dosage and Epoetin beta is indicated for the prevention and treatment of anaemia in adults
Administration with solid tumours undergoing platinum-based chemotherapy if the patient’s Hb
level is 13 g/dL (8.1 mmol/L) at the start of antineoplastic treatment, and for the
treatment of anaemia in adults with haematological malignancies who have
relative erythropoietin deficiencies and are receiving anti-tumour therapy. The
initial recommended epoetin beta dosage is 450 IU/kg/week administered subcu-
taneously; this may be doubled to a maximum of 900 IU/kg/week if Hb increase
is not satisfactory after 4 weeks. In patients with haematological malignancies,
the licensed dose is once weekly; the weekly dose may be divided into 3–7
single doses if required in this patient group or when administered to those
with solid tumours. Treatment should be maintained for up to 3 (solid
tumours) or 4 (haematological malignancies) weeks after the termination of
chemotherapy. The dosage may be reduced or treatment temporarily
interrupted if the Hb level increases above that recommended in the
manufacturer’s prescribing information.
Epoetin beta is contraindicated in patients with poorly controlled
hypertension; it should be used with caution in patients with refractory anaemia
with excess blasts in transformation, and in those with epilepsy, thrombocytosis
or chronic liver failure. Folic acid and vitamin B12 deficiencies should be ruled
out before administration of the drug, and serum potassium levels, BP, platelet
counts and iron parameters should be monitored regularly. Oral iron substitution
(200–300mg Fe2+/day) is recommended in all patients with serum ferritin values
below 100 g/L or transferrin saturation below 20%.
More recently, recombinant human erythropoie- duce an anaemia-inducing substance that shortens
tin (r-HuEPO) has provided an additional option in the survival of RBCs;[1,22] erythropoiesis in patients
the treatment of anaemia in patients with cancer; it with cancer is unable to compensate for this.[22]
has been shown to ameliorate anaemia in this patient The pharmacodynamic effects of epoetin beta
in group, reduce the need for blood transfusions and these groups have been previously reviewed in
improve patients’ QOL (reviewed in Beguin [12]). Drugs[14] and, thus, are only briefly overviewed in
Epoetin beta (NeoRecormon1) is an r-HuEPO that this section. A summary of the main pharmacody-
was developed after the cloning of the human er- namic properties of epoetin beta is presented in
table ythropoietin gene and its subsequent expression in I.
Chinese hamster ovary cells.[13] Erythropoietin is
essential for the proliferation and maturation of ery- 2.1 Effects on Erythropoiesis
throid progenitor cells in bone marrow (section 2).
Epoetin beta is an established treatment for the Epoetin beta replicates the mechanism of action
of endogenous erythropoietin. It prevents cells from
management of anaemia in patients with chronic
apoptosing, allowing them to proliferate, differ-
renal failure (CRF) [see previous review in
entiate and mature into morphologically recognis-
Drugs[14]]. This review evaluates the efficacy and
able normoblasts.[14] The main target cells for the
tolerability of epoetin beta in the management of
drug are erythroid colony-forming units, although
cancer-related and chemotherapy-induced anaemia.
other responsive erythrocytic progenitors include
2. Pharmacodynamic Properties erythroid burst-forming units and erythroblasts. [14]
Increases in platelet and monocyte production were
Erythropoietin, a glycoprotein hormone, has an observed in some studies of r-HuEPO, but counts
apparent molecular weight of 34 kDa; did not exceed normal limits (reviewed by Faulds
carbohydrates (sialic acid, hexose and N- and Sorkin[44]).
acetylglucosamine) ac-
count for 30% of this.[14] The sialic acid residues Mean reticulocyte counts increased from 1.1% to
prevent rapid catabolism of the molecule and are 2.4% at day 15 in 10 of 12 patients with anaemia
and therefore essential for its function in vivo (reviewed solid tumours who responded (Hb levels >10
g/dL) by Krantz[15] and Ehmer and Scigalla[16]). Endoge- to subcutaneous epoetin beta (75–150 IU/kg 5
times nous erythropoietin is synthesised mainly in the weekly).[26] Similarly, significant increases in
retic- kidney in adult humans; its production, which is ulocyte count were observed with subcutaneous
or regulated by a negative feedback system, increases intravenous epoetin beta in healthy adult
volun- markedly in response to tissue hypoxia.[13,15,17,18] teers[23-25] or patients with CRF[27-30] in trials
of up to After its production and secretion into renal venous 12 months’ duration (table I). These
increases were blood, erythropoietin is delivered to the bone mar- dose-proportional with single-dose
intravenous row where it binds to and activates receptors on epoetin beta 10–1000 IU/kg in a
placebo-controlled, erythroid progenitor cells.[18,19] These cells proceed double-blind study in 16
healthy volunteers (the to develop into mature erythrocytes; in the absence 1000 IU/kg dose was
administered in a nonblind of the erythropoietin-receptor complex, the progeni- fashion).[23] Increases
[19,20]
in reticulocyte count were ac- tor cells apoptose and die. companied by dose-
proportional increases in Hb
Cancer-related anaemia appears to result, in part, and haematocrit (reviewed in Dunn and Mark-
from a reduction in erythropoietin production.[1,21,22] ham[14]).
Anaemia of chronic disease associated with activa- Subcutaneous epoetin beta (up to 450–900
IU/kg/ tion of the immune system leads to increased levels week or up to 10 000 IU/day) significantly
increased of inflammatory cytokines (i.e. interleukin-1, tu- mean or median Hb levels compared with
placebo (p mour necrosis factor and interferon-) which sup- < 0.01),[32] baseline (p < 0.05)[32] or no
r-HuEPO press the differentiation of erythroid precursors in treatment (p < 0.01)[31,33] in
[1,21,22]
randomised trials in bone marrow. In addition, tumour cells pro- patients (n = 22–262) with
anaemia and cancer
1 Use of tradenames is for product identification purposes only and does not imply endorsement.
2004 Adis Data Information BV. All rights Drugs 2004; 64
3
Epoetin Beta: A Cheer & 3
Table I. Major pharmacodynamic properties of epoetin beta (EPO). Data are from studies in patients with cancer-related or chemotherapy-
induced anaemia, patients with chronic renal failure (CRF) or healthy volunteers
Patient group Dosage, duration and route of administration Effect
Erythropoietic
Healthy adult volunteers (n = Single-dose EPO (IV 10–1000 IU/kg)[23,25] or Increased reticulocyte counts from
16–87),[23-25] patients with solid tumours multiple-dose EPO (IV 50–1000 IU/kg 3 times baseline[25-30] or vs placebo;[23,24] increases
(n = 12)[26] or CRF (n = 11–122)[27-30] wkly,[24,29] 50–100 IU/kg after each dialysis,[27] were dose related with single dose EPO
6000 IU/wk[28] or 240 IU/kg/wk,[30] or SC up to 10–1000 IU/kg[23]
75–150 IU/kg 5 times wkly[26]) for up to 12mo
Patients (n = 22–262) with cancer- SC EPO (up to 450–900 IU/kg/wk[31,32] or up to Increased mean or median Hb levels vs
related or chemotherapy-induced 10 000 IU/d[33]) for up to 12wk placebo (p < 0.01),[32] baseline (p < 0.05)[32]
anaemia or no r-HuEPO therapy (p < 0.01);[31,33]
increases were dose proportional with EPO
2000–10 000 IU/d[33]
Patients with advanced gastrointestinal SC EPO (up to 450–900 IU/kg/wk)[34,35] Increased haematocrit values[34,35]
cancer (n = 84)[34] or haematological
malignancy (n = 343)[35]
Haemodynamic and cardiovascular
Patients undergoing HD (n = EPO (IV initial dosage 100 IU/kg/d,[36] 4500 IU/ SBP and/or DBP were either increased[36-38]
6–229)[36-38] or CAPD (n = 15)[39] or wk[37] or 250–1000 IU/kg 3 times wkly,[24] or SC or unchanged[24,39] from baseline[24,37-39] or vs
healthy volunteers (n = 84)[24] 10 IU/kg/d[39] or 50 IU/kg 3 times wkly[38]) for placebo[24,36]
26d to 16wk
Patients undergoing HD (n = 151)[36] IV EPO (initial dosage 100 IU/kg/d) Resting HR decreased from baseline (p <
0.05)
Patients undergoing HD (n = 10)[40] IV EPO (120 IU/kg twice wkly) for 12mo Left ventricular mass reduced (p < 0.01) from
baseline
Patients undergoing HD (n = 10)[40] IV EPO (120 IU/kg twice wkly) for 12mo Gradual increase in whole-blood viscosity
(changes not statistically significant)
Patients undergoing HD (n = 10)[40] IV EPO (120 IU/kg twice wkly) for 12mo Maximum oxygen consumption increased (p
< 0.05) from baseline
Patients undergoing HD (n = 7 or IV EPO (40 IU/kg 3 times wkly[41] or 120 IU/kg Treadmill exercise duration increased (both p
10)[40,41] twice wkly[40]) for up to 12mo < 0.01) from baseline[40,41]
Other
Healthy volunteers undergoing serial EPO IV (250–1000 IU/kg 3 times wkly,[24] 6000 Platelet counts increased vs placebo (p <
phlebotomy (n = 87),[24] patients with IU/wk[28]) or SC (2000–10 000 IU/d[42]) for up to 0.05) but did not exceed normal limits,[24] or
haematological malignancies (n = 82)[42] 24wk were unchanged from baseline[28,42]
or predialysis CRF (n = 11)[28]
Patients undergoing HD (n = 16)[43] or EPO (IV 250–1000 IU/kg 3 times wkly,[24] or IV Platelet aggregation increased[43] or was
healthy volunteers undergoing serial or SC 120 IU/kg/wk[43]) unchanged[24]
phlebotomy (n = 87)[24]
Healthy volunteers undergoing serial EPO (IV 250–1000 IU/kg 3 times wkly[24] or No effect on prothrombin time or partial
phlebotomy (n = 87)[24] or patients with 6000 IU/wk[28]) for up to 8wk thromboplastin time vs placebo[24] or from
predialysis CRF (n = 11)[28] baseline[28]
Patients with predialysis CRF (n = 11)[28] IV EPO 6000 IU/wk for 8wk Unchanged serum levels of fibrinopeptide-A,
fibrin and fibrinogen degeneration products,
platelet factor-4 or -thromboglobulin
Patients with CRF undergoing HD (n = IV EPO (initial dose 50–100 IU/kg after dialysis Unchanged serum total cholesterol or
12)[27] for 12mo) triglyceride
CAPD = continuous ambulatory peritoneal dialysis; DBP = diastolic blood pressure; Hb = haemoglobin; HD = haemodialysis; HR = heart
rate; IV = intravenous; r-HuEPO = recombinant human erythropoietin; SBP = systolic blood pressure; SC = subcutaneous.
(table I; section 4). Increases in median Hb levels multicentre trial involving 146 patients with
were dose-proportional with subcutaneous epoetin haematological malignancies.[33] The observed in-
beta 2000–10 000 IU/day in a randomised, 8-week, creases in Hb levels were paralleled by increases in
haematocrit values in patients with advanced gastro- formulations may be caused by differences in the
intestinal cancer[34] or haematological malignan- composition of the solution or in the
oligosaccharide cies[35] (table I), with haematocrit levels being sig- configuration of the epoetin.[48] In
a randomised, nificantly increased (p < 0.005) compared with pla- double-blind, crossover trial using
epoetin alfa that cebo after 2–16 weeks’ treatment with epoetin beta contained a phosphate rather than a
citrate buffer, (initial dosage 450 IU/kg/week) in patients with there was no difference in injection
site pain (mea- MM, NHL or Chronic Lymphocytic Leukaemia sured using VAS) between the two
r-HuEPO formu- (CLL) [n = 343].[35] lations (4000 IU/0.4mL) when
they were adminis-
tered to 20 healthy adult volunteers.[51]
2.2 Other Effects
3. Pharmacokinetic Properties
Hypertension is infrequent (10%) in clinical
trials in patients receiving epoetin beta for cancer- The pharmacokinetics of epoetin beta have been
studied in small trials in healthy volunteers and
related or chemotherapy-induced anaemia (section
patients with CRF; there are no pharmacokinetic
5), although the manufacturer’s prescribing infor- data for this drug in patients with cancer-related or
mation recommends blood pressure (BP) monitor-
chemotherapy-induced anaemia. The pharmaco-
ing during therapy with the drug (section 6).[45]
kinetics of epoetin beta have been studied for vari-
The correction of anaemia with intravenous ous parenteral routes including intravenous and sub-
epoetin beta (120 IU/kg twice weekly for 12 cutaneous administration; lower peak plasma con-
months) resulted in beneficial cardiovascular effects centrations (C ) were maintained for longer
max
in patients undergoing haemodialysis (HD; n = 10); periods with the latter route of administration.[52,53]
these included reduced left ventricular hypertrophy, Subcutaneous epoetin beta, which has been studied
and increased exercise capacity and maximum oxy- in clinical trials and is approved for use in patients
gen consumption (table I).[40] The cardiovascular with anaemia and cancer, is the primary focus of
this effects of epoetin beta have not been evaluated in review, although data for intravenous
administration patients with cancer. are presented when subcutaneous
data are unavaila-
Platelet counts may be increased during epoetin ble.
beta therapy, but normal limits were not exceeded
in
a placebo-controlled study in healthy volunteers.[24] 3.1 Absorption and Distribution
Furthermore, platelet counts were unchanged with
subcutaneous epoetin beta (2000–10 000 IU/day for Mean Cmax (40.5–176 IU/L) values were reached
24 weeks) in patients with haematological malig- 12–18 hours (tmax) after subcutaneous administra-
nancies.[42] The drug was not associated with any tion of single-dose epoetin beta 40–120 IU/kg in
change in platelet aggregation in healthy volun- adult patients with CRF undergoing HD or continu-
teers[24] but whole blood platelet aggregation (spon- ous ambulatory peritoneal dialysis (CAPD) [n =
taneous and collagen- or adenosine diphosphate- 8–12].[52-55] Corresponding area under the concen-
induced) increased significantly (p < 0.05) after tration-time curve (AUC) values were 1372–9610
subcutaneous or intravenous treatment with epoetin IU h/L.[52-55] Similar results with subcutaneous
beta (120 IU/kg/week) in 16 patients undergoing epoetin beta 100 IU/kg were reported in 9 healthy
HD.[43] volunteers in a randomised, double-blind, crossover
Subcutaneous injection of epoetin beta (up to study; Cmax, tmax and AUC values did not differ
8000 IU/mL) is relatively pain free, producing less from those reported with epoetin alfa 100 IU/kg (n
injection-site pain (analysed using various methods =
9).[25]
including a visual analogue scale [VAS]) than sub- The absolute bioavailability of epoetin beta is
cutaneous epoetin alfa (containing a citrate buffer) low (21.5–46.4% in patients with CRF undergoing
[up to 4000 IU/mL] in patients receiving HD (n = HD or CAPD).[52-55] Absorption kinetics were not
2004 Adis Data Information BV. All rights Drugs 2004; 64
3
6–50) inBeta:
Epoetin double-blind
A [46-49]
or single-blind[50] trials. significantly altered with administration (over 36
Cheer &
The differences in pain scores between the two weeks[52] or 4–17 months[56]) of subcutaneous epoe-
tin beta (40 IU/kg three times weekly[52] or a median 3.3 Site of Administration
dose of 78.5 IU/kg/week[56]) in patients with CRF
who were undergoing HD or CAPD.[52,56] There were no significant differences in Cmax,
tmax or bioavailability after subcutaneous adminis-
The apparent volume of distribution of single- tration of epoetin beta 100 IU/kg at different injec-
dose intravenous epoetin beta 10–1000 IU/kg was tion sites (thigh or abdominal wall) in 11 healthy
0.04–0.09 L/kg in healthy men (n = 12)[23] and volunteers.[64] However, mean residence time was
0.03–0.07 L/kg in patients with renal dysfunction (n significantly longer (p < 0.03) when the drug was
= 8 and 10);[54,55,57] values were 1–2 times that of the administered to the thigh (32.7 hours) compared
plasma volume.[23,57] with the abdomen (26.2 hours), probably because of
delayed absorption; the absorption half-life values
were 14.9 and 12.3 hours (p < 0.05). The authors
3.2 Metabolism and suggested that these differences were possibly at-
Elimination tributable to physical activity and regional varia-
The mechanisms of epoetin beta excretion are tions in lymph flow.[64] However, absorption was
unknown,[56] although experiments in rats suggest more rapid, Cmax higher and bioavailability greater
that the liver may contribute, especially after the after subcutaneous injection into the thigh than into
removal of terminal sialic acid residues.[58] Early the arm or abdomen in an earlier study in healthy
reports from studies in animals[59,60] and patients volunteers.[65]
with deficient erythropoiesis[61] suggest that urinary
excretion of endogenous erythropoietin accounts for 4. Therapeutic Efficacy
10% of the total daily elimination. In line with this,
renal clearance of single-dose intravenous epoetin The efficacy of subcutaneous epoetin beta has
been evaluated for the treatment of cancer-related or
beta 130–152 IU/kg accounted for <3% of total
chemotherapy-induced anaemia in adult patients
body clearance in ten adult patients with CRF under-
(aged 18 years) [n = 22–343] with haematological
going HD.[57] Clearance of the drug was not affected malignancies (MM, NHL or CLL,[31,33,35,42,66] or re-
by declining renal function in this study.[57] How- lapsed Hodgkins disease or NHL[67]) or solid
ever, in a further study, median terminal elimination tumours (including ovarian, breast, lung, prostate or
half-life (t1/2) was significantly increased (8.31 vs gastrointestinal tumours, or head and neck carcino-
4.92 hours; p < 0.001) and clearance significantly ma).[31,32,34,68-72] Trials were of 8 to 24 weeks’
reduced (0.3 vs 0.5 L/h; p < 0.01) in uraemic pa- duration; all were randomised and parallel-group in
tients compared with values in healthy volunteers design, most were nonblind[31,33,42,66,68-71] (two were
after intravenous epoetin beta 100 IU/kg.[62] In con- double-blind[35,72]), and all except one[32] were mul-
trast, reduced hepatic function due to liver cirrhosis ticentre. The control or comparator groups consisted
did not affect the metabolism and elimination of the of patients treated with placebo,[32,35] various dos-
drug (100 IU/kg) after intravenous administration in ages of epoetin beta[33,34,42,69-71] or no r-HuEPO
12 patients compared with data from ten healthy treat- ment (blood transfusion therapy permit- ted).
[31,33,42,68,69]
In a noninferiority study, epoetin beta
volunteers.[63]
once weekly was compared with administration
After an initial distribution phase, the mean t1/2
of the drug three times weekly.[66] There are no
was 16.1[52] or 11.2[54] hours after subcutaneous head-to-head comparisons of epoetin beta with
administration of epoetin beta 40 IU/kg to patients epoetin alfa or darbepoetin alfa.
with CRF undergoing HD or CAPD; this was longer All patients in the available trials had anaemia,
than that observed after intravenous administration which was generally defined as Hb levels 11 g/
(6.7 or 8.8 hours).[52,54] There were no significant dL,[31,33,66,68,71] although higher Hb levels were spec-
changes in t1/2 after treatment with subcutaneous ified in some trials.[32,69,72] Patients were also re-
epoetin beta 40 IU/kg three times weekly for 6 quired to have a WHO performance status of 2 or
weeks.[52] 3[31,33,35,42,66,69] and a life expectancy of >2 to >6
months.[31,33,35,42,66,69-72] Most or all patients were and could be altered depending on changes in Hb
treated concomitantly with chemother- levels or according to study design.
apy;[31-35,42,66,68,69,71,72] antineoplastic agents includ- Several criteria were used to assess the efficacy
ed cisplatin[32,68,69] or carboplatin[68,69] in some trials. of epoetin beta. Primary efficacy criteria included
Many patients had received chemotherapy before the percentage of patients free of transfusion (mea-
entering the trials. sured over various periods),[35,68,69] the number of
transfusions required,[67] transfusion- and anaemia-
Exclusion criteria varied, but in most trials pa- free (Hb 8.5 g/dL) survival,[35] and clinical res-
tients were excluded if they had refractory ponse (generally defined as an increase in Hb 2 g/
hyperten- sion,[31,33-35,42,66,68,70-72] epilepsy, dL from baseline without blood transfusion over
[31,33,35,42,66,68,69] acute various periods[31-33,42] or an increase in blood Hb
infection,[31,33,34,42,68,69]
noncancer-related anaemia (e.g. iron deficiency levels of >10 g/L[34]). Time-adjusted Hb area under
anaemia),[31,33,66,68,69] or acute or chronic bleeding the curve for weeks 5–16 was the primary efficacy
for an unstated period[68] or for 3 months variable in the non-inferiority study.[66] The volume
of packed RBCs transfused during 4-week inter-
prior to the study.[33,35,42,66,68,70] Patients
vals,[68] time to first RBC transfusion,[69] change in
with untreated iron,[42,69-71] vitamin B12 or
folic[34,35,42,66,70]
acid deficien-
cies, haemolysis (haptoglobin level
<30 or <50[35] mg/dL), acute or severe liver dis- Hb levels from
[66] baseline to 1 week after treatment
[33,42] [69]
termination[32] or per week during the observation
ease or impaired liver function, renal insuffi-
[31,35,69]
phase[33] were also evaluated in some trials. Analy-
ciency (often defined as serum creatinine
ses were carried out for the intent-to-treat (ITT)
>2.5 mg/dL[31,35]), thrombocytopenia (platelets sample[31,33,35,66,70,71] or for evaluable pa-
[35]
<20 or <50 [66]
109/L) or thrombocytosis (plate- tients.[34,42,66-69,72]
lets >450 109/L[35,66] or 500 x 109/L[68,69]) were
Predictors of response to epoetin beta[33,35,42,69]
also excluded from some trials, as were pregnant or
and the effect of the drug on QOL[31,34,35,70,71] were
lactating women and women who were using unreli- also investigated in some trials. Details on method-
able methods of contraception.[31,33,72] ology associated with these parameters are recorded
The epoetin beta treatment regimen varied in their respective sections (sections 4.3 and 4.4).
among trials. In the non-inferiority study,[66] patients
received epoetin beta three times weekly (10 000IU 4.1 Chemotherapy-Induced Anaemia in
per dose) or once weekly (30 000IU per dose). If Patients with Solid Tumours
patients did not respond after 4 weeks’ treatment
(i.e. they required a blood transfusion in the pre- Subcutaneous epoetin beta 5000 IU/day or 450
or vious week or Hb levels increased by <0.5 g/dL), the 900 IU/kg/week in three divided doses
dose of epoetin beta was doubled to 20 000IU three transfusion requirements by 37–90%
reduced
compared with times weekly or 30 000IU twice weekly. The dose no r-HuEPO treatment,[68,69] and
epoetin beta was reduced by 50% if a patient’s Hb level increased 3000–30 000 IU/week or 300–600
[66] [31,35]
IU/kg/week in- by >2 g/dL. In two recent comparative trials, creased Hb levels by 0.89–2.7 g/dL
from baseline in patients received subcutaneous epoetin beta at an 34–189 evaluable patients
undergoing chemother- initial dosage of 450 IU/kg/week (30 000IU) in apy for the treatment of
solid tumours in random- three divided doses. The dose was doubled (to a ised, nonblind or
double-blind trials of 8 to 24 maximum dosage of 900 IU/kg/week) if Hb levels weeks’ duration;
[31,35]
[34,71,72]
results are summarised in were increased by <0.5 g/dL, or were <8.5 g/ table II.
dL[35] after 3–4 weeks or were increased by <1 g/dL Compared with no treatment, subcutaneous
epoe- after 6–8 weeks.[31] The dose was reduced by 50% or tin beta (5000 IU/day for 12 weeks)
significantly treatment was interrupted if Hb levels increased by reduced the volume of transfused
packed RBCs
Epoetin Beta: A
2004 Adis Data Information BV. All rights
untreated control groups (CON),[68,69] placebo (PL)[72] or between differing dosages of EPO;[34,70,71] 28–227 patients were randomised to treatment in these nonblind or double-
blind[72] clinical trials
Reference Type of tumour Trial duration No. of patients Dosage Patients requiring Response (%) Mean increase in
(wk) randomised transfusions (%) Hb levels from
(evaluated) baseline (g/dL)
Glimelius et al.[34] Advanced GI cancer 18 49 (41)a EPO 10 000IU 3 times NR 63b [73c**] 2.7d*
wkly
51 (43)a EPO 2000IU 3 times wkly NR 26b [35c] 1.3d
[70] e f
Johansson et al. Hormone-refractory 12 90 EPO 1000IU 3 times wkly 54 25
prostate cancer
90 EPO 5000IU 3 times wklyg 40 43f*
[72]
Kunikane et al. Non-small cell lung 8 (18) EPO 200 IU/kg 3 times 6 NR 1.72
cancer wklyh
(16) EPO 100 IU/kg 3 times 13 NR 0.89
wklyh
(19) PL 0 NR –0.65
Oberhoff et al.[68] Predominantly ovarian, 12 117 (101) EPO 5000 IU/d 26 38i NR
breast or lung cancer
110 (88) CON 41 9i NR
Olsson et al.[71] Metastatic breast 24 90 EPO 1000IU 3 times wklyj 36 51k [68l] 1.7
cancer
90 EPO 5000IU 3 times wklym 34 58k [66l] 2.3n
o
ten Bokkel Huinink et Ovarian cancer 24 (median) 42 (42) EPO 300 IU/kg 3 times 14 NR NR
al.[69] wklyp
46 (45) EPO 150 IU/kg 3 times 4 NR NR
wklyp
34 (33) CON 39 NR NR
a Data are only for patients receiving chemotherapy (n = 84).
b An increase in Hb levels from baseline of 2 g/dL without blood transfusion over a median period of 4–10wk.
c An increase in Hb levels from baseline of 1 g/dL without blood transfusion over a median period of 4–10wk.
d Estimated from a graph.
e No increase in dosage permitted. The dosage was reduced from three to two times/wk if Hb exceeded 13 g/dL, and treatment was withdrawn if Hb exceeded 14 g/dL until
Hb levels dropped below 13 g/dL.
f Increase of 2 g/dL over baseline at 12wk.
g The dose was doubled if Hb increase was <1.5 g/dL after 4wk or <2 g/dL after 8wk of EPO treatment. The dosage was reduced from three to two times/wk if Hb
exceeded 13 g/dL, and treatment was withdrawn if Hb exceeded 14 g/dL until Hb levels dropped below 13 g/dL.
Drugs 2004; 64
3
3
Epoetin Beta: A Cheer & 3
Patients received EPO throughout treatment with chemotherapy and for an additional 3–24wk after the last cycle given. Median duration of evaluation was 170d
The dose of EPO was reduced by 50% if Hb levels increased by >2 g/dL during chemotherapy, or treatment was stopped if Hb levels exceeded 15 g/dL at any
The dose was doubled if Hb increase was <1 g/dL after 4wk or <2 g/dL after 8wk of EPO treatment. The dosage was reduced from three to two times/wk if Hb
for primary malignant bone tumours; in this patient
group, epoetin beta significantly reduced the mean
number of transfused RBC units compared with
placebo (2.1 vs 8.4IU; p < 0.01). [73] Treatment with
for untreated patients, 167d for patients receiving EPO 150 IU/kg three times wkly and 168d for those receiving EPO 300 IU/kg three times wkly.
epoetin beta was initiated when Hb levels fell below
11 g/dL (a mean 16 days after the start of chemo-
therapy).[73]
Treatment with subcutaneous epoetin beta (see
table II) also reduced the proportion of patients
requiring blood transfusions compared with no
treatment; patients (n = 189[68] or 120[69]) received
chemotherapy for solid tumours. The time to first
blood transfusion in patients undergoing platinum-
based chemotherapy for ovarian carcinoma was sig-
EPO was stopped in the case of unacceptable toxicity or when Hb levels were >16 g/dL in men or >14 g/dL in
until
m
i
gastrointestinal cancer, mean Hb levels exceeded IU/day) in an 8-week, nonblind, multicentre, dose-
12.5 g/dL after 6 (30 000 IU/week) and 14 (6000 IU/ finding trial (table III).
[33]
week) weeks of treatment with epoetin beta.[34] An intent-to-treat analysis of 343 patients with
haematological malignancies indicated that rates of
4.2 Anaemia in Patients With transfusion-free survival (67% vs 48%, p = 0.0012)
Haematological Malignancies and transfusion- and severe anaemia-free (Hb 8.5
g/dL) survival (p = 0.0001) were significantly im-
Subcutaneous epoetin beta 30 000IU adminis- proved at 16 weeks with subcutaneous epoetin beta
tered once weekly corrected anaemia in most pa- (initial dosage 150 IU/kg three times weekly) com-
tients and had equivalent efficacy to epoetin beta pared with placebo; this equated to relative risk
10 000IU administered three times weekly in a ran- reductions of 43% and 51%[35] (also see section
domised, non-blind, non-inferiority study in 241 4.3.1). In addition, significantly fewer patients re-
patients with haematological malignancies (table ceiving subcutaneous epoetin beta fixed dosage
III).[66] The median Hb-AUC5–16 (primary endpoint; 10 000 IU/day or titrated dosage 2000–10 000 IU/
ITT population) was similar in the once-weekly
day than those receiving no treatment required
blood group to that in the three-times-weekly group; the
transfusions during months 2–6 in a
overall difference was –0.22 (analysis of covari-
randomised nonblind trial (both p < 0.05 vs
ance, 90% CI –0.53, 0.10) and differences between
control) [table III].[42]
groups did not exceed 0.6 g/dL at any time, and
were
similar regardless of the malignancy present. The In support of the above results and those in
percentage of patients who responded to treatment section 4.1, significantly (3.6-fold) more patients
(72% vs 75%), were transfusion free (91% vs 86%), with chronic anaemia associated with solid or
or required IV (44% vs 39%) or oral (75% vs 67%) haematological malignancy receiving subcutaneous
iron supplementation in the once-weekly treatment epoetin beta than those in the control group (receiv-
group were similar to those in the three-times- ing blood transfusion support) responded to treat-
week-
ly group.[66] ment in a 12-week, randomised nonblind trial (table
In other randomised trials (mostly nonblind, one III).[31] Epoetin beta also increased Hb levels from
double-blind[35]) in 121–343 evaluable patients with baseline (table III) and significantly reduced trans-
anaemia associated with haematological malignan- fusion requirements compared with control after the
cies, 2.5-fold more patients responded (an increase first 4 weeks of treatment (a 49% decrease, p < 0.01)
in Hb of 2 g/dL from baseline without need for [table III].[31] QOL results from this trial are present-
transfusion) to epoetin beta 14 000–70 000 IU/week ed in section 4.4.
than to no treatment or placebo over 8–24 weeks
Epoetin beta appears to reduce blood transfusion
(table III).[33,35,42] Similarly, the number of patients
requiring transfusions in this period was reduced by Increases in median Hb levels were dose-propor-
18–46% with epoetin beta compared with no treat- tional with subcutaneous epoetin beta (2000–10 000
ment or placebo (table III). [33,35,42,67] The increase in
Hb levels (0.2 to 2.1 g/dL) was 3–14.5 times greater
with epoetin beta 14 000–70 000 IU/week than with
no treatment in two trials (table III). [33,42] In another
trial, Hb levels decreased during chemotherapy
treatment in patients receiving epoetin beta and in
untreated controls (table III); however, after finish-
ing the chemotherapy cycle, Hb levels were signifi-
cantly higher in the epoetin treatment group than in
the untreated group (9.4 vs 8.6 g/dL; p = 0.009). [67]
Table III. Clinical efficacy of subcutaneous epoetin beta (EPO) in the treatment of cancer-related anaemia. Patients had haematological
malignancies[31,33,35,42,66,67] or solid tumours (including ovarian cancer or tumours of the bone, connective tissue, skin or breasts).[31] Data
are from comparisons with placebo (PL),[35] control groups not receiving r-HuEPO but permitted blood transfusion therapy (CON)[31,33,42,67]
or between different dosages of EPO.[66] All trials were randomised and parallel-group in design; with the exception of one trial, which
was double-blind,[35] all trials were nonblind
Reference Trial duration No. of patients Dosage Patients requiring Response Median increase in
(wk) randomised transfusions (%) (%)a Hb levels
(evaluated) (g/dL)
Haematological malignanciesb
Cazzola et al.[33] 8 26 EPO 10 000 IU/dc 15 62d 0.58††††
c
31 EPO 5000 IU/d 19 61d 0.43†
29 EPO 2000 IU/dc 17 31d 0.22
31 EPO 1000 IU/dc 23 7 d –0.04
29 CON 28 7 d 0.04
Cazzola et al.[66] 16 119 (115) EPO 30 000 IU/wke 9 72 NR
122 (114) EPO 10 000IU 3 times 14 75 NR
wklyf
Glossmann et al.[67] NCg (20) EPO 10 000IU 3 times 75 NR –2.3
wkly
(24) CON 92 NR –2.7
O¨ sterborg et al.[35] 16 173 (170)h EPO 150 IU/kg 3 times 33* 67** NR
wklyi
176 (173)h PL 52 27 NR
O¨ sterborg et al.[42] 24 (44) EPO 10 000 IU/dj 58† 60† 2.1
(38) EPO 2000–10 000 IU/djk 64† 60† 1.5
(39) CON 83 24 0.5
4.3 Factors Affecting Response to Therapy prestudy transfusion requirement (2 units) were the
best predictors of transfusion-free survival (during
4.3.1 Tumour Type weeks 5–16 of treatment with epoetin beta 31 500
Data from randomised trials of 12–24 weeks’ IU/week) in a randomised, double-blind, placebo-
duration suggest that epoetin beta is effective in all controlled trial in 343 patients with haematological
tumour types.[31,35,42] A univariate regression ana- malignancies.[35] The risk reduction for epoetin beta
lysis in patients with haematological malignancy versus placebo was greater in patients with higher
found that the type of underlying disease (MM or platelet counts (55% risk reduction) and Hb levels
NHL) was not of prognostic significance.[42] In a (51%) than in those with lower platelet counts
trial powered to analyse the effect of epoetin beta (21%) and Hb levels (26%).[35]
(initial dosage 450 IU/kg/week) on malignancy sub- Univariate analyses in two randomised trials in
type (MM, NHL or CLL; n = 343), rates of transfu- patients with haematological malignancies indicated
sion-free and severe anaemia-free survival were sig- that serum erythropoietin levels and/or the observed
nificantly higher with epoetin beta than with placebo to predicted ratio of erythropoietin levels (O/P
ratio) for all groups, although relative risk reduction was can significantly affect response to
treatment with greater for patients with MM (66%) than for those epoetin beta.[33,42] These factors
were the best prog- with NHL (40%) or CLL (40%), which may nostic determinants of response
(Hb increase of 2 g/ indicate an additional benefit with epoetin beta use dL within 6 weeks) to the drug
(5000 or 10 000 IU/ in this patient group.[35] Statistical analysis of the day) in a multivariate
(classification and regression efficacy of epoetin beta by tumour type was not tree) analysis in the
larger (n = 146) of the two done in this trial.[35] trials.[33]
Approximately 70–80% of patients with serum erythropoietin levels 50 IU/L or an O/P ratio
4.3.2 Impact of Chemotherapy
of 0.9 were predicted to respond to treatment com-
Response with epoetin beta (initial dosage 450
pared with only 25–30% of patients with a serum
IU/kg/week or 1000–10 000 IU/day) occurred irre-
erythropoietin level >50 IU/L or an O/P ratio of
spective of the nature and/or presence of chemother-
>0.9.[33] These data support the proposed efficacy
apy in randomised trials of 12–24 weeks’ duration in
epoetin beta in patients with anaemia and
of
inadequate
patients with solid tumours or haematological ma-
[31,33,42] endogenous erythropoietin production.
lignancies (section 4.2). In one trial, signifi-
cantly fewer patients with solid tumours who were Chemotherapy-Induced Anaemia in Patients with
treated with platinum-based chemotherapy required Solid Tumours
blood transfusions with epoetin beta than those re- A decrease in the Hb level of <1 g/dL or an
ceiving no r-HuEPO treatment (25% vs 43%, p = increase after epoetin beta treatment (450 or 900 IU/
0.04). In contrast, there was no significant differ- kg/week) during the first cycle of chemotherapy
ence in blood transfusions between epoetin beta was associated with a low transfusion requirement
recipients and those receiving no r-HuEPO treat- throughout the following chemotherapy cycles in
ment in patients receiving chemotherapy without patients with ovarian carcinoma. [69] In addition, pa-
platinum (27% vs 38%). Nonetheless, combined tients with an O/P ratio of 0.8 demonstrated the
data indicate that a similar percentage of patients greatest response to epoetin beta therapy in this
receiving platinum-based chemotherapy to those re- trial; more epoetin beta recipients with an O/P of
ceiving chemotherapy without platinum required 0.8 than those with an O/P of >0.8 were transfusion-
blood transfusion (25% and 27%).[68] free (95% vs 83%), whereas there was no
difference in the proportion of patients transfusion-
free regardless
4.3.3 Early Predictors of Response
of O/P status in the untreated group.[69] However,
Anaemia in Patients with there was no significant correlation between base-
Haematological Malignancy line serum erythropoietin levels,[34] erythropoietin
Exploratory multivariate Cox proportional haz- deficiency[68] or baseline O/P ratio <0.9[68] and Hb
ard analysis indicated that a baseline platelet count response to epoetin beta 6000–35 000 IU/week in
of 100 109/L, Hb levels of 9 g/dL and a lower two trials[34,68] in patients with solid tumours (n = 84
and 189), although baseline erythropoietin levels included in this analysis or were published subse-
were not determined in 31% of patients in one quent to it.
trial.[68]
4.4.1 Malignant Disease
Subcutaneous epoetin beta (initial dosage 450
4.4 Effects on Quality of Life
IU/kg/week) significantly improved QOL compared
with control (with supportive blood transfusion) in
Patients with cancer-related or chemotherapy- patients with solid tumours or haematological ma-
induced anaemia may experience reduced QOL, lignancies (MM, NHL, CLL) in a randomised,
largely as a result of fatigue (section 1).[6] The nonblind trial.[31] At 12 weeks, SF-36 PCS and
impact of subcutaneous epoetin beta on QOL in FACT-F scores were significantly improved (both p
adult patients (evaluable n = 84–265) with anaemia < 0.05 vs control) and FACT-An scores tended
and malignancy (including solid tumours or towards improvement in 104 patients treated with
haematological malignancy) has been assessed in subcutaneous epoetin beta compared with 109 pa-
randomised trials,[31,34,35,70,71] from which data on tients in the control group (last-observation-carried-
transfusion requirements and/or Hb levels have al- forward analysis). Changes in SF-36 PCS and
ready been presented in sections 4.1 and 4.2. QOL FACT-F scores were significantly (p < 0.01) corre-
was the primary endpoint in one trial.[31] lated with changes in Hb levels (which differed
In 265 evaluable patients with haematological between the two treatment groups [section 4.2]).[31]
malignancies in a double-blind placebo-controlled The improvement in QOL (SF-36 PCS, FACT-F
trial,[35] QOL was assessed using a Functional As- and FACT-An) with epoetin beta for patients pre-
sessment of Cancer Therapy (FACT) anaemia and viously exposed to chemotherapy was similar to that
fatigue questionnaire. This comprised a FACT-G for patients who were chemotherapy naive.[31] There
questionnaire, which evaluated general aspects of were no significant differences in QOL improve-
QOL over several dimensions (physical, social/fam- ments with epoetin beta for those with haematologi-
ily, emotional and functional well-being), and the cal malignancy versus those with solid tumours.[31]
FACT-F and Fact-An subscales, which measured
symptoms of fatigue and anaemia. These scales 4.4.2 Haematological Malignancies
have proven validity and reliability in the measure- Patients with haematological malignancies ex-
ment of QOL in patients with cancer and anaemia.[5] perienced significantly greater improvements in
The FACT anaemia and fatigue subscales, along QOL from baseline (assessed using the FACT anae-
with the Short Form 36 physical component summa- mia and fatigue questionnaire) with
subcutaneous ry (SF-36 PCS) scores, were also used as primary epoetin beta (450 IU/kg/week) than
with placebo efficacy parameters in a multicentre, nonblind trial after 12 (13% vs 7% improvement; p
< 0.05) and 16 in 213 patients with anaemia associated with solid (15% vs 9%; p < 0.05) weeks of
treatment.[35] Sig- tumours or haematological malignancy.[31] In nificant differences with epoetin
beta versus placebo nonblind trials in patients with advanced gastroin- were also observed in several
dimensions of the testinal cancer,[34] hormone refractory prostate can- FACT-G scale at week 12
(emotional [p < 0.05] and cer[70] or metastatic breast cancer,[71] QOL was as- social/family [p < 0.01]
well-being) and week 16 sessed with the European Organization for Research (social/family [p <
0.05] and physical [p < 0.05] and Treatment of Cancer (EORTC) QOL question- well-being). In
contrast, the FACT-F or FACT-An naire-C30. subscale mean
scores did not differ between treat-
One trial[34] was included in a review[74] of QOL ments at any assessment point.[35]
data for r-HuEPO (predominantly epoetin alfa); it Improvement in FACT anaemia and fatigue
was critiqued for its small sample size, the lack of questionnaire scores was significantly greater after
allocation concealment, and the inability of the 8, 12 and 16 weeks of epoetin beta treatment for
EORTC QOL questionnaire to detect fatigue in pa- responders (patients with an increase in Hb level of
tients with anaemia. Other trials investigating QOL 2 g/dL without transfusion after 6 weeks) than for
in patients receiving epoetin beta were either not nonresponders (all p < 0.05).[35] Similar results were
50
40
30
20
10
0
Fig. 1. Adverse events occurring in patients with anaemia and haematological malignancies (n = 144) after subcutaneous epoetin beta
(dose titration 2000–10 000 IU/day or fixed dose 10 000 IU/day) or no treatment.[42] Data are from a 24-week, randomised, nonblind,
multicentre, parallel-group trial; statistical analysis was not reported.
three times weekly) [72%, n = 170[35] and 86%, n = Death occurred in 7–27% of epoetin beta recipi-
133[31]] were similar to those with placebo (76%, n ents (n = 95–170) during the treatment phase (8–24
= weeks) of randomised parallel-group trials in pa-
173) in patients with haematological malignancies tients with anaemia [33,35,42]
associated with haematological
(MM, CLL or NHL) [35]
or to control (standard malignancies or in those with chemotherapy-
[31] induced anaemia and solid tumours.[68] The inci-
blood transfusion permitted) [82%, n = 129 ] in
dence of death during the treatment period with
patients with malignant disease (solid tumours,
epoetin beta was similar to that with placebo (12%
MM, CLL or NHL) in short-term (12- or 16-week), vs 11%)[35] or no r-HuEPO treatment (10–32% vs
randomised, double-blind[35] or nonblind[31] trials. 3–29%)[33,42] in patients with haematological malig-
Serious ad- verse events occurred in 33%[35] or nancies and similar to that with no r-HuEPO treat-
42%[31] of epoe- tin beta recipients, 32% of placebo ment in patients with solid tumours (8% vs 13%).[68]
recipients[35] and In addition, the incidence of death during the study
33% of patients in the control group.[31] The most period (which varied but lasted the course of
common serious adverse events in the nonblind trial chemo- therapy treatment) or subsequent follow-up
were malignancy progression (epoetin beta 10% vs (up to an additional 24 weeks) was not different
control 13%) and anaemia (8% vs 13%).[31] There from that with no treatment (6.9% vs 6.1%) in 120
were no significant differences in the incidence of patients with ovarian carcinoma receiving platinum-
adverse events with epoetin beta 30 000IU once based chemotherapy.[69] In a nonblind trial in
weekly compared with epoetin beta 10 000IU three patients with haematological malignancies, more
times weekly; 10% and 18% of patients from each patients treated with epoetin beta (2000 titrated to
group were considered to have treatment-related 10 000 IU/day or
adverse events.[66]
Quantitative data from randomised clinical trials fixed-dose 10 000 IU/day) than untreated patients
(including a placebo-controlled, double-blind died from infections/septicaemia; however these
trial[35]) suggest that hypertensive events with sub- events were stated to be unrelated to epoetin beta
cutaneous epoetin beta occur in 10% of patients treatment. [42]
Deaths were attributed to the underly-
with cancer-related (n = 170 and 95)[35,42] or chemo- ing disease,[35,69] cardiovascular events,[35] respira-
therapy-induced anaemia (n = 87).[69] Hypertension tory infection[35] or chemotherapy treatment[69] in
was slightly more common with epoetin beta (initial some trials.
dosage 150 IU/kg three times weekly,[35] or 2000 There were no clinically relevant changes in
titrated to 10 000 IU/day[42] or fixed dose 10 000 IU/ laboratory parameters,[31,68] and patients did not de-
day[42]) than with placebo (9% vs 5%) in a double- velop antibodies against epoetin beta[68] or erythro-
blind trial[35] or with no treatment in a nonblind trial poietin[35] in studies in which these were reported.
(titration group 10% and fixed-dose group 8% vs Similar proportions of patients treated with epoetin
2%).[42] However, statistically significant differ- beta or untreated patients withdrew from trials as a
ences between treatment groups were not reported in result of adverse events (14–15% vs 7–12%).
[31,68,69]
clinical trials in patients with cancer-related anae- There is no evidence for an increased frequency of
mia. Furthermore, in the nonblind trial, [42] most thromboembolic events causally related to epoetin
cases of hypertension (7 of 9) were considered to be beta in patients with cancer.[45]
unrelated to the study drug.
Injection-site adverse events were relatively un- 6. Dosage and Administration
common in clinical trials, with local skin reactions
being reported in only two studies.[35,42] One percent 6.1 Patients with Solid Tumours
and 2% of patients (n = 170 and 95)[35,42] experi-
enced local skin reactions following subcutaneous Epoetin beta is approved for the prevention and
injection with epoetin beta (initial dosage 450 IU/ treatment of anaemia in adult patients with solid
kg/week,[35] or 2000–10 000 IU/day[42]); these tumours treated with platinum-based chemotherapy
ment is indicated if a patient’s Hb value is 13 g/dL continued for up to 4 weeks after the end of chemo-
(8.1 mmol/L) at the start of chemotherapy. therapy.
Epoetin beta is administered subcutaneously at The maximum dose of epoetin beta should not
an initial recommended weekly dose of 450 IU/kg exceed 900 IU/kg bodyweight.[45] If Hb increases by
bodyweight, which may be divided into 3–7 single >2 g/dL (>1.24 mmol/L) within 4 weeks, the
epoetin doses.[45] If Hb values have not reached satisfactory beta dose should be halved. If Hb exceeds
14 g/dL levels (not stated) after 4 weeks of treatment, the (8.69 mmol/L), treatment with epoetin
beta should dose should be doubled. Treatment should be main- be stopped until the Hb level is 13
g/dL (8.07 tained for up to 3 weeks after chemotherapy has mmol/L); therapy should then be
restarted at 50% ended. the previous weekly dose.
Hb levels should not increase by more than 2
g/dL (1.24 mmol/L) per month or beyond 14 g/dL 6.3 General Information
(8.69 mmol/L) in total.[45] If increases of more than
2 g/dL/month do occur, epoetin beta treatment Epoetin beta is contraindicated in patients with
should be reduced by 50%. Furthermore, if Hb poorly controlled hypertension; it should be used
values ex- ceed 14 g/dL, treatment with epoetin beta with caution in patients with refractory anaemia
should be interrupted until levels have decreased to with excess blasts in transformation, and in those
12 g/dL (7.45 mmol/L), at which time the drug with epilepsy, increased platelet count or chronic
should be restarted at a weekly dose 50% lower liver failure. Folic acid and vitamin B12
than that of the previous dose. If Hb levels fall by deficiencies reduce the effectiveness of epoetin beta
>1 g/dL (0.62 mmol/L) during the first cycle of and, thus, should [45]
be ruled out before administration
chemotherapy despite concomitant therapy with of the drug.
epoetin beta, con- tinued treatment with the drug Serum potassium levels should be monitored
may not be effective. reg- ularly in patients using epoetin beta, because
elevat- ed potassium levels have been observed in
patients
6.2 Patients with
with uraemia receiving the drug, although causality
Haematological Malignancies
has not been established. If potassium levels are
elevated or rising, epoetin beta treatment can be
Epoetin beta is indicated for the treatment of stopped until these levels have been corrected.[45] BP
anaemia in adult patients with MM, low-grade NHL should be monitored, particularly during the initial
or CLL who have a relative erythropoietin deficien- phase of treatment as occasional rises in BP (which
cy (i.e. an inappropriately low serum erythropoietin can be pharmacologically treated) may occur in
level in relation to the degree of anaemia) and are patients with cancer. A fall in iron parameters has
receiving anti-tumour therapy.[45] been observed in some patients with solid tumours.
The initial recommended weekly dose is 450 IU/ Functional iron deficiency may limit the efficacy of
kg bodyweight administered subcutaneously; the li- epoetin beta; therefore, oral iron substitution
censed dose is once weekly (this can be divided into (200–300mg Fe2+/day) is recommended in all pa-
3–7 doses if required).[45] If the Hb value has in- tients with serum ferritin values below 100 g/L or
creased by at least 1 g/dL (0.62 mmol/L) after 4 transferrin saturation below 20%. Platelet counts
weeks’ treatment, the current dose should be contin- should be monitored at regular intervals.
ued; if this Hb level has not been reached, a dose
increase to 900 IU/kg bodyweight per week given as 7. Place of Epoetin Beta in
the
2–7 divided doses may be considered. If Hb has not Management of Cancer-Related or
increased by at least 1 g/dL after 8 weeks’ treatment, Chemotherapy-Induced
Anaemia
response is unlikely and treatment should be discon-
tinued. Response to epoetin beta may be delayed by Anaemia in patients with cancer is most often
anaemia of chronic disease (section 2). Myelosup- ber of injections (thus making self-administration
pressive chemotherapy (particularly platinum-based easier) and may be cost-saving, although additional
regimens) may also induce anaemia or exacerbate research is required to confirm the potential
existing anaemia in patients with cancer (section pharmacoeconomic benefits of this new regimen.
1).[4,5] Anaemia may also result from nutritional Subcutaneous epoetin beta improved anaemia
deficiencies, underlying infectious or inflammatory and reduced transfusion requirements (by 18–90%)
processes, haemolytic diseases, occult blood loss or to a greater extent than placebo or no r-HuEPO
haemolysis (section 1); these conditions should be treatment (with supportive blood transfusions) in
corrected or managed before considering further patients with malignant disease (solid tumours or
treatment.[5,21] haematological malignancies) in randomised trials
Traditionally, blood transfusion therapy has been of 8–24 weeks’ duration irrespective of the presence
used for the treatment of cancer-related or chemo- of chemotherapy (sections 4.1 and 4.2). The per-
therapy-induced anaemia.[6,21,75] It is the fastest centage of patients experiencing beneficial effects
method for alleviating symptoms of anaemia[6,21,75] appears to be dose-dependent.
and has been associated with short term, although Transfusion requirements were also reduced and
unsustained, improvements in QOL.[76] Hb levels were increased with 8 to 24 weeks’
However, the risks associated with blood administration of subcutaneous epoetin beta in the
transfu- sion (such as acute transfusion reactions, group of patients with solid tumours who were re-
transfu- sion-related acute lung injury and ceiving chemotherapy, which suggests that concom-
bacteraemia, transmission of viruses and prions, itant use of the drug can prevent or reduce the
alloimmunisa- tion, and immunomodulation) have development of chemotherapy-induced anaemia.
resulted in delayed treatment by some patients or Nonetheless, well designed trials of prophylactic
their physi- cians, and a subsequent delay in the epoetin beta during treatment with chemotherapy in
maintenance of near-normal Hb levels. [75] Of chemotherapy-naive patients with cancer are re-
particular concern for patients with cancer are the quired to fully establish its efficacy in this area. The
immunomodulatory ef- fects of blood transfusion, efficacy of epoetin beta over periods longer than 6
which may be associated with stimulation of months has not been evaluated in patients with can-
tumour growth and increased susceptibility to cer.
infection, although the clinical sig-
nificance of these effects has yet to be fully re- Epoetin beta is well tolerated in patients with
solved.[6,12] In addition, despite the introduction of malignant disease, irrespective of tumour type; seri-
additional screening and sterilisation procedures, ous treatment-related adverse effects or treatment-
transfusions cannot be considered completely ster- related deaths were rare with subcutaneous adminis-
ile, especially with the emergence of new infectious tration (section 5). Most adverse events were attrib-
agents.[5,6,12] For these reasons, blood transfusion is utable to chemotherapy treatment or the underlying
generally reserved for patients with serious symp- malignancy, and injection site adverse events were
toms, in cases of acute emergency or when patients relatively uncommon in clinical trials. Reports of
with mild-to-moderate anaemia are at risk for dis- hypertension (incidence 10%) in a small propor-
ease-induced adverse cardiac events.[5] tion of patients receiving epoetin beta in clinical
Epoetin beta is an r-HuEPO, which is an impor- trials (section 5) suggest that BP should be moni-
tant option in the prevention of chemotherapy-in- tored during treatment (section 6).
duced anaemia, and a valid and valuable alternative A recent publication[77] from a study to explore
to blood transfusion therapy for the treatment of the hypothesis that anaemia correction with epoetin
both cancer-related and chemotherapy-induced beta might potentiate the response to radiotherapy
in anaemia.[6,75] Once-weekly administration of the patients with tumours of the head and neck
reported drug (30 000IU) corrects anaemia in the majority of a significantly greater risk of local tumour
progres- patients and has the same efficacy as the three- sion in the intention-to-treat population
treated with times-weekly 10 000IU regimen.[66] It provides ad- epoetin beta (p = 0.0008). However,
there was no ded convenience for patients by decreasing the num- corresponding significant difference
between epoe-
tin beta and placebo in the per-protocol population. in patients receiving chemotherapy for ovarian car-
In addition, differences in tumour progression were cinoma, neither baseline erythropoietin level nor O/
limited to small subgroup of patients with hypo- P ratio correlated with response to the study drug in
pharyngeal cancer with imbalances in baseline data other trials in patients with chemotherapy-induced
relating to smoking and relapsed cancer. Moreover, anaemia and solid tumours (section 4.3.3). Treat-
enhanced tumour progression following treatment ment with chemotherapy alters serum erythropoietin
with epoetin beta[31,35,66] or other r-HuEPOs[78] has levels, which may possibly account for the failure of
not been reported in any other clinical study. Indeed, baseline erythropoietin to predict response to
r- the existing consensus view is that r-HuEPO treat- HuEPO in patients with chemotherapy-induced
ment improves survival after radiotherapy.[79] anaemia.[22]
Patients with cancer often experience anaemia- Early changes in Hb levels after the initiation of
or chemotherapy-induced fatigue, which can result epoetin beta treatment may be more helpful in pre-
in reduced QOL.[6] Consideration of QOL is impor- dicting response to the drug in patients with chemo-
tant when determining treatment for anaemia in this
therapy-induced anaemia.[3] In a randomised trial in
patient group because reductions in QOL may com-
patients with ovarian carcinoma treated with a plati-
promise patient management,[10] and alter an indi-
num-based regimen, a decrease of <1 g/dL an in-
vidual’s tolerance of and response to antineoplastic
crease in Hb levels with epoetin beta during the first
treatments.[11] Recommended dosages of epoetin
cycle of chemotherapy indicated a low transfusion
beta significantly improved QOL over 12–16 weeks
need in subsequent cycles (section 4.3.3).[69]
(particularly in the areas of physical functioning or
well-being) compared with control in patients with Chemotherapy can directly inhibit bone marrow
malignant disease (section 4.4.1), or compared with activity, which results in decreased production of
placebo in patients with haematological malignan- blood cells and platelets. Stem cell damage incurred
cies (section 4.4.2). Improvements were significant- through previous chemotherapy is expected to im-
ly greater in patients responding to treatment with pair response to epoetin beta. This has yet to be
epoetin beta than in nonresponders, and correlate evaluated in clinical trials, although the poorer res-
with increases in Hb (section 4.4). Although short- ponse observed in patients with lower platelet
term improvements in QOL have been observed counts (section 4.3.3) may indicate such an effect.[3]
with blood transfusion therapy, improvements have Randomised trials in patients with solid tumours
not been maintained over sustained periods (up to 1 or haematological malignancies suggest that epoetin
year). Long-term improvements in QOL with epoe- beta is effective regardless of the type of concomi-
tin beta have yet to be evaluated,[6] as has the cost- tant chemotherapeutic treatment used (i.e. platinum-
effectiveness of epoetin beta relative to other thera- or nonplatinum-based regimens) [section 4.3.2]. Al-
pies in anaemia in patients with cancer. though the benefit with epoetin beta was statistically
Randomised trials suggest that patients with significantly more pronounced relative to control
anaemia associated with haematological malignan- (no r-HuEPO treatment) in patients with solid
cies and serum erythropoietin levels of 50 IU/L or tumours receiving platinum-based regimens than in
an O/P ratio of 0.9 have a greater response to those receiving chemotherapy without platinum
epoetin beta than patients with values greater than (section 4.3.2), the clinical significance of this result
these (section 4.3.3).[33] This is in keeping with the is debatable. Patients receiving chemotherapy of a
activity of erythropoietin, which increases RBC pro- moderate intensity are expected to respond as well
duction by preventing apoptosis of erythroid as to r-HuEPO as those not receiving concomitant
progenitors (section 2), and suggests that r-HuEPO chemotherapy; however, lower response rates to r-
may be more effective in patients with endogenous HuEPO are expected with more intensive chemo-
erythropoietin levels which are inappropriately low therapeutic regimens.[1,3] Response to r-HuEPO may
for the degree of anaemia. also be affected by the complications of chemother-
However, although an O/P ratio of 0.8 was apy, including inflammation, infections, nutritional
associated with response to epoetin beta in one trial deficiencies and bleeding.[1,3]
Tumour type does not appear to have a signif- 2. Griggs JJ, Blumberg N. Recombinant erythropoietin and blood
transfusions in cancer chemotherapy-induced anemia. Anti-
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91 (19): 1616-34
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