Does the use of erythropoietin-

stimulating agents in breast cancer patients

with chemotherapy-induced anaemia impact on clinical

outcomes?

Olivia Kelada

Anaemia 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 (chemotherapy-induced anaemia)

According to The European Cancer Anaemia survey (ECAS), anaemia affects 67% of cancer patients.

Treatment of Anaemia 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 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 ESAs were found to: 1) Increase Haemoglobin (Hb) levels2) Reduce the need for red blood cell transfusions3) Improve quality of life (QoL) through alleviation of

anaemic symptoms e.g. fatigue4) Increase overall survival However…some research suggests a decrease in overall

survival and association with tumour progression, thromboembolic events, hypertension and even death.

Controversy Studies by Littlewood et al, Aapro et al and

Leyland-Jones et al yielded mixed results in relation to overall survival in breast cancer patients

Why?

Factors influencing efficacy 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: To investigate whether EA, EB or DA alleviate

anaemia in breast cancer patients with chemotherapy-induced anaemia (BC-CIA) in respect to:

1) Hb response, 2) Need for red blood cell transfusion (RBCT) 3) Quality of life (QoL) 4) Overall survival (OS) 5) Tumour response (TR)6) Serious adverse events e.g. thromboembolic

events (TEEs) and hypertension.

Aim 2:

Patient: Age Life expectancy (LE) Stage of disease

(SOD) Performance status

(PS) Comorbidities Chemo type Iron supplementation

ESA: Hb level at admin Target Hb level Dose of ESA Dose schedule and

changes Method of admin ESA duration

To investigate the factors associated with patient population

Method Electronic searches in Pubmed, EMBASE,

Springerlink, The Cochrane Library, ScienceDirect and Google Scholar.

Search terms: erythropoietin-stimulating agents, anaemia/anemia, and cancer

For some clinical trials only the abstracts were available.

Method

1)Type of Studies:

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

Method2) Type of participants:

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

Method4) 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 Form1) Intervention Construct: ESAs

(epoetin alfa, epoetin beta and darbepoetin)

Operations: 1) Type ESA2) Hb level at of admin3) Target Dose 4) ESA duration5) Multicenter6) Randomized trial7) Double-blinded8) Open-label9) No. of arms (ESA vs.

placebo/no treatment)

Data Collection form

2) Participants Construct: Female

breast cancer patients with chemotherapy-induced anaemia

Operations:1) Breast cancer patients

included in population2) Age3) Life expectancy4) Stage of disease5) Performance Status6) Presence of

comorbidities7) Type of chemo: Platinum

vs. non-platinum8) No. of participants in

total and per arm9) Iron supplementation

Data Collection Form3) OutcomesConstructs:1) Hb response2) Rate of RBC transfusion:

Number of units transfused3) Change in QoL i.e. relief of

anaemia and anemia-related symptoms

4) Overall survival5) Tumour response6) Serious adverse events

caused by treatment (TEEs, hypertension & other)

Operation: ESA arm vs. non-ESA arm

Intervention

Study ESAHb 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

Key: EA = Epoetin Alfa DA = Darbepoetin Alfa EB = Epoetin Beta W = week Y = Yes N = No sc = subcutaneously

Participants

StudyNo. 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

Key: Y = Yes N = No NR = Not reported Non-plat = non-platinum based chemo Mix = platinum and non-platinum chemo

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

Key: I = Increase D = Decrease NE = No effect NR = Not reported Ab = Abstract

Quality

Study Data type Multicenter Randomised Double-blinded Open label Trial Arms

Abels 96 CT N N Y N E v P

Aapro 08 CT Y Y Y Y E v C

Boogaerts 03 CT Y Y N Y E v C

Chang 05 CT Y Y N Y E v C

Del Mastro 97 CT N Y N N E v C

Fairclough 03 CT Y Y Y N E v P

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 E v C

Leyland-Jones 05 CT Y Y Y N E v P

Littlewood 01 CT N Y Y N E v P

Mobus 07 Abstract Y Y N N E v C

Nitz 08 Abstract Y Y N N E v C

Oberhoff CT N Y N Y E v C

O'Shaughnessy 05 Abstract N Y Y N E v P

Pat 09 CT Y N N N E

Pronzato 02 Abstract Y Y N Y E v C

Quirt 01 CT Y N N Y E

Ray-Coquard 09 CT Y Y N Y E v C

Suzuki 08 CT Y N N Y E

Taylor 05 Abstract Y Y Y N E v P

Untch 08 Abstract N Y N N E v C

Witzig 05 CT Y Y Y N E v P

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 OutcomesEffect 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 OutcomesSAEs: 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 riskHypertension: 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 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 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.