Transcript Slide 1

Does the use of erythropoietinstimulating agents in breast
cancer patients with
chemotherapy-induced
anaemia impact on clinical
outcomes?
Olivia Kelada
Anaemia
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Anaemia is “The condition of having less than the
normal number of red blood cells or less than the
normal quantity of haemaglobin in the blood. The
oxygen-carrying capacity of the blood is, therefore,
decreased.” (Medline)
Anaemia can result from the tumour itself (Anaemia of
cancer) as well as from cancer treatments, especially
myleosuppressive chemotherapy (chemotherapyinduced anaemia)
According to The European Cancer Anaemia survey
(ECAS), anaemia affects 67% of cancer patients.
Treatment of Anaemia
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Blood transfusion for severe anaemia, while mild and
moderate cases were not treated at all
This method remains the best way of ameliorating
anaemic symptoms
However, the effect of the treatment is short-lived and
there are several risks involved even with the
widespread testing of donors
Erythropoietin
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Erythropoietin (EPO) is the glycoprotein hormone
involved in controlling erythrocyte (Red blood cell)
production (erythropoiesis)
In 1985, Lin et al isolated EPO and coded its gene
sequence.
This discovery led to the advent of recombinant EPO
(rHuEPO) and eventually a number of erythropoietin
stimulating agents (ESAs)
3 main types of ESAs used to enhance Hb production
are Epoetin Alfa (EA), Epoetin Beta (EB) and
Darbepoetin Alfa (DA)
Impact of ESAs
In the early 1990s ESAs were shown to alleviate
anemia in cancer patients receiving chemotherapy
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ESAs were found to:
1)
Increase Haemoglobin (Hb) levels
2)
Reduce the need for red blood cell transfusions
3)
Improve quality of life (QoL) through alleviation of
anaemic symptoms e.g. fatigue
4)
Increase overall survival
However…some research suggests a decrease in overall
survival and association with tumour progression,
thromboembolic events, hypertension and even
death.
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Controversy
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Studies by Littlewood et al, Aapro et al and LeylandJones et al yielded mixed results in relation to overall
survival in breast cancer patients
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Why?
Factors influencing efficacy
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Trials differed greatly in relation to ESA and patient
characterisitcs
ESA characteristics e.g. Hb baseline level upon ESA
administration and target Hb level may influence the
effect of ESAs on clinical outcomes in CIA patients.
Patient characteristics e.g. type of cancer, its site of
origin, tumour stage and treatment administered can
influence the severity of anaemia and in turn, the effect
of ESAs on alleviation of anaemia
Aim 1:
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1)
2)
3)
4)
5)
6)
To investigate whether EA, EB or DA alleviate anaemia
in breast cancer patients with chemotherapy-induced
anaemia (BC-CIA) in respect to:
Hb response,
Need for red blood cell transfusion (RBCT)
Quality of life (QoL)
Overall survival (OS)
Tumour response (TR)
Serious adverse events e.g. thromboembolic events
(TEEs) and hypertension.
Aim 2:
To investigate the factors associated with patient
population
Patient:
ESA:
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Age
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Hb level at admin
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Life expectancy (LE)
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Target Hb level
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Stage of disease (SOD)  Dose of ESA
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Performance status
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Dose schedule and
(PS)
changes
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Comorbidities
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Method of admin
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Chemo type
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ESA duration
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Iron supplementation
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Method
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Electronic searches in Pubmed, EMBASE, Springerlink,
The Cochrane Library, ScienceDirect and Google
Scholar.
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Search terms: erythropoietin-stimulating agents,
anaemia/anemia, and cancer
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For some clinical trials only the abstracts were available.
Method
1)Type of Studies:
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Any that used EA, EB and DA to treat anaemia in BC-CIA.
In English
Conducted on humans
ESA versus placebo, control or no treatment
Method
2) Type of participants:
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Not all of the clinical trials consisted of breast cancer
patients only.
All patients had to be diagnosed with a solid tumour or
non-myeloid malignancy
All patients had to have CIA (those with anaemia of
cancer were excluded) and receive ESA treatment or
placebo.
Patients of any age, LE, SOD, PS, comorbidities and
chemo type were included.
Method
3) Type of intervention
 Trials evaluating EA, EB and DA
 All dose administration methods, dosages, dose
adaptations and durations were included
 Hb level supplementation such as iron and RBC
transfusion was allowed
Method
4) Type of outcome
measures
Primary Outcomes:
 Hb response
 Need for RBCT
 QoL
Secondary Outcomes:
 Overall Survival
 Tumour response
(complete or partial
response)
 SAEs including
Thromboembolic events
(TEEs) and hypertension
Data Collection Form
1) Intervention
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Construct: ESAs
(epoetin alfa, epoetin
beta and darbepoetin)
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1)
2)
3)
4)
5)
6)
7)
8)
9)
Operations:
Type ESA
Hb level at of admin
Target Dose
ESA duration
Multicenter
Randomized trial
Double-blinded
Open-label
No. of arms (ESA vs.
placebo/no treatment)
Data Collection form
2) Participants
 Construct: Female breast
cancer patients with
chemotherapy-induced
anaemia
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1)
2)
3)
4)
5)
6)
7)
8)
9)
Operations:
Breast cancer patients
included in population
Age
Life expectancy
Stage of disease
Performance Status
Presence of
comorbidities
Type of chemo: Platinum
vs. non-platinum
No. of participants in
total and per arm
Iron supplementation
Data Collection Form
3) Outcomes
Constructs:
1)
Hb response
2)
Rate of RBC transfusion:
Number of units transfused
3)
Change in QoL i.e. relief of
anaemia and anemia-related
symptoms
4)
Overall survival
5)
Tumour response
6)
Serious adverse events
caused by treatment (TEEs,
hypertension & other)
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Operation: ESA arm vs. nonESA arm
Intervention
Study
ESA
Hb level (g/dL) for ESA
Target Hb (g/dL)
Dose (U/kg)
Dose schedule
Admin
ESA duration (w)
Dose res/chgs
Abels 96
EA
<10.5
38-40% HCT
150
3W
sc
12
N - VAGUE
Aapro 08
EB
<12.9
>2 from baseline
30,000 U
1W
sc
24
Y
Boogaerts 03
EB
<11
12-14
150 IU
3W
sc
12
Y
Chang 05
EA
<12
12-14
40,000
1W
sc
12
Y
Del Mastro 97
EA
>12 +< 14
Not clear
150
3W
sc
14
Y
Fairclough 03
EA
<10.5
NR
150-300
3W
sc
28
Y (dose range)
Gabrilove 01
EA
<11
12
40,000
1W
sc
16
Y
Gabrilove 07
DA
<10+>10
>11
200ug
2W
sc
24
Y
Hudis 05
EA
>10+<14
Abstract
40,000 U
1W
sc
12-14
Abstract
Iconomou 03
EA
<11
>2 from baseline
10,000 U
3W
sc
12
Y
Leyland-Jones 05
EA
<13
12-14
40,000 U
1W
sc
52
Y
Littlewood 01
EA
<10.5
12
150
3W
sc
28
Y
Mobus 07
EA
Abstract
Abstract
150
3W
sc
Abstract
Abstract
Nitz 08
DA
<12/13
<14
500 ug
3W
sc
24
Y
Oberhoff
EA
<11
>2 from baseline
450
1W
sc
12
N
O'Shaughnessy 05
EA
Abstract
Abstract
40,000 U
1W
sc
12
Abstract
Pat 09
DA
<11
12
500 ug
1/3W
sc
16
N
Pronzato 02
EA
10-12
>12
10,000-20,000
2W
sc
28
Abstract
Quirt 01
EA
<11
>2 from baseline
150
3W
sc
16
Y
Ray-Coquard 09
EA
<12
12
150
1/2W
sc
12
Y
Suzuki 08
EB
<11
>2 from baseline
36,000 U
1W
sc
12
Y
Taylor 05
DA
<11
>11 + <13
300 ug
1/3W
sc
15
Y
Untch 08
DA
Abstract
12-14
Abstract
2W
Ab
12
Abstract
Witzig 05
EA
M: <11.5 W: <10.5
>2 from baseline
40,000 U
1W
sc
16
Y
Participants
Study
No. of Breast pts
Age (yrs)
Life expect (m)
Stage of disease
PS
Comorbidities
Chemo
No. of participants
Iron
Abels 96
a- 11.5%
a-62
>3
Advanced
0-3
N
Mix
413
N
Aapro 08
All
a-57
>6
M1
0-2
N
non-plat
463
Y
Boogaerts 03
a- 8%
Med-62
>6
Any
0-2
N
Mix
259
Y
Chang 05
All
Mean 50
>6
Any
NR
N
Mix
354
Y
Del Mastro 97
All
54-56
NG
2
NR
N
non-plat
71
N
Fairclough 03
67%
58.7
NG
NG
NR
NR
non-plat
375
N
Gabrilove 01
18.20%
>18
>6
Any
NR
N
Mix
3012
NR
Gabrilove 07
23%
64
NG
NG
NR
N
Mix
2422
NR
Hudis 05
All
53
Abstract
1-3
AB
AB
Mix
1792
N
Iconomou 03
22
a - 61
NG
Any
NR
N
Mix
122
Y
Leyland-Jones 05
All
55-56
>6
M1
0-2
N
Mix
939
Y
Littlewood 01
114
59
>6
Solid T and 3-4
NR
N
Non-plat
375
Y
Mobus 07
All
<65
Abstract
N>1
AB
N
non-plat
658
Ab
Nitz 08
All
18-65
Abstract
Early
AB
Abstract
Mix
1234
Ab
Oberhoff
25%
a - 54
NG
Any - 43% @ 4
NR
N
Mix
227
NR
O'Shaughnessy 05
All
Abstract
Abstract
Abstract
Ab
Abstract
non-plat
94
Ab
Pat 09
64
63
NG
Any
NR
Y
Mix
293
NR
Pronzato 02
All
53-55
Abstract
Any - 47.2% @ 4
AB
Abstract
Mix
178
Ab
Quirt 01
15.10%
57.9
>6
Any
NR
N
Mix
218
Y
Ray-Coquard 09
Some
>18
NG
Any - 82.5% M1
>1
N
Mix
213
Y
Suzuki 08
25
58.2
>4
Any (Mostly S4)
0-2
N
Mix
104
Y
Taylor 05
23%
>18
Abstract
Any
AB
Abstract
Mix
391
Ab
Untch 08
All
Abstract
Abstract
Any
AB
Abstract
Mix
733
Ab
Witzig 05
16.10%
63.6
>6
Incurable
0-1
N
Mix
344
Y
Outcomes (in ESA arm)
Study
Hb response
Patient receving RBCT
QoL
OS
Tumour response
TEEs
Hypertension
Other AEs
Abels 96
I
NE
I
NR
NR
NE
NE
NE
Aapro 08
I
D
NE
NE
NE
I
NR
I
Boogaerts 03
I
D
I
NR
NR
NR
NR
I
Chang 05
I
D
I
NR
NR
I
NR
I
Del Mastro 97
I
D
NR
NR
NR
NR
NR
NE
Fairclough 03
I
D
I
NR
NR
NR
NR
NR
Gabrilove 01
I
D
I
NR
NR
NE
NE
NE
Gabrilove 07
I
D
I
NR
NR
NE
NR
NE
Hudis 05
I
Abstract
I
Abst
Abstract
I
NR
NR
Iconomou 03
I
NE
I
NR
NR
NR
NR
NE
Leyland-Jones 05
I
D
NE
D
D
I
NR
I
Littlewood 01
I
D
I
I
I
I
I
NE
Mobus 07
I
D
Ab
NE
NE
Ab
Abstract
Abstract
Nitz 08
I
Abstract
I
Abst
Abstract
I
I
I
Oberhoff
I
D
NR
NR
NR
NR
NE
NE
O'Shaughnessy 05
I
Abstract
I
Abst
Abstract
Ab
Abstract
Abstract
Pat 09
I
D
NE
NR
NR
NE
NR
NE
Pronzato 02
I
D
I
Abst
Abstract
Ab
Abstract
Abstract
Quirt 01
I
D
I
NR
NR
NR
NR
NR
Ray-Coquard 09
NR
D
NE
I
NE
I
NR
I
Suzuki 08
I
D
I
NR
NR
NE
NE
NE
Taylor 05
I
D
Ab
Abst
Abstract
NR
NR
NE
Untch 08
I
Abstract
Ab
NE
NE
NR
NR
I
Witzig 05
I
D
I
D
NE
NE
NR
NE
Quality
Study
Data type
Multicenter
Randomised
Double-blinded
Open label
Trial Arms
Abels 96
CT
N
N
Y
N
EvP
Aapro 08
CT
Y
Y
Y
Y
EvC
Boogaerts 03
CT
Y
Y
N
Y
EvC
Chang 05
CT
Y
Y
N
Y
EvC
Del Mastro 97
CT
N
Y
N
N
EvC
Fairclough 03
CT
Y
Y
Y
N
EvP
Gabrilove 01
CT
Y
N
N
Y
E
Gabrilove 07
CT
Y
N
N
Y
E
Hudis 05
CT
Y
N
N
Y
E
Iconomou 03
CT
N
Y
N
N
EvC
Leyland-Jones 05
CT
Y
Y
Y
N
EvP
Littlewood 01
CT
N
Y
Y
N
EvP
Mobus 07
Abstract
Y
Y
N
N
EvC
Nitz 08
Abstract
Y
Y
N
N
EvC
Oberhoff
CT
N
Y
N
Y
EvC
O'Shaughnessy 05
Abstract
N
Y
Y
N
EvP
Pat 09
CT
Y
N
N
N
E
Pronzato 02
Abstract
Y
Y
N
Y
EvC
Quirt 01
CT
Y
N
N
Y
E
Ray-Coquard 09
CT
Y
Y
N
Y
EvC
Suzuki 08
CT
Y
N
N
Y
E
Taylor 05
Abstract
Y
Y
Y
N
EvP
Untch 08
Abstract
N
Y
N
N
EvC
Witzig 05
CT
Y
Y
Y
N
EvP
Analysis – Primary Outcomes
Improved Hb response: 23/24 (95.8%) & Decrease in the
RBCT rate: 18/24 (75%)
 Consistent with the EORTC and Bohlius et al.
 Influenced by variation in trial arms
 Hb level at admin (>10 g/dL) may alter significance
 Trial quality
 Measurement timing
 No effect of target Hb level
 No link for ESA type, dose, dosing schedule or chemo
and outcome
Analysis - Primary Outcomes
Increase in QoL: 15/24 (62.5%)
 No linear relationship
 Some trials open label
 No target Hb level
 Variation in QoL assessment
 No link made to Hb baseline or chemo type
 Use of iron supplements
Analysis – Secondary Outcomes
Effect on Overall Survival & Tumour response: 7/24 (29.1%)
 Increase, decrease and no effect
 EORTC: No evidence of improved OS
 Poor trial quality: LE, SOD and chemo not considered
 No correlation for Hb level or dose
 Link between Hb baseline and target with OS decrease
 Some impact of chemo type and schedule
 Influence of patient characteristics
Analysis - Secondary Outcomes
SAEs: in 18/24 (75%) trials. Some demonstrated an increase
due to ESAs.
TEEs in 13/24 (54.2%) trials and 53.8% of them showed more
of these events in the ESA arm.
 EORTC: 1.6 fold increased risk
Hypertension: in 6/24 (25%) of studies only 33.3% recorded
an increase in this side-effect in ESA group.
 No link for ESA dose
 Impact of chemo type & schedule
 Increased risk with Hb target level outside of guidelines
 Influence of patient underlying conditions on outcome
Conclusions
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ESAs increase haemoglobin response, decrease the
need for red blood cell transfusion and increase quality
of life in BC-CIA despite variation in ESA and patient
characteristics between trials.
Hb level at baseline, target haemoglobin level, duration
of ESA and dose changes are the ESA characteristics
that impact on the effect of ESAs on primary outcomes
in BC-CIA.
Patient characteristics such as age, life expectancy,
stage of disease, performance status, chemotherapy
type and supplementary iron also all appear to impact
on the effect ESAs have on primary outcomes in BC-CIA.
Conclusions
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Results are not as conclusive for secondary outcomes.
Impact of ESAs on overall survival in BC-CIA is inconclusive
due to the poor study design of trials used.
ESAs appear to have no effect on tumour response but data
suggests an increase in serious adverse events, especially
thromboembolic events but not hypertension.
It is evident that the results of secondary outcomes may be
more definitive if clinical trials considered ESA and patient
characteristics and adhered to current guidelines.
This review can establish that the effect of ESAs on
secondary outcomes in BC-CIA patients is influenced by
target haemoglobin level, ESA duration and patient
characteristics including age, life expectancy, stage of
disease, performance status and comorbidities.