Management of Anemia in Breast Cancer

1
Management of Anemia in Breast Cancer

• Frankie Ann Holmes, MD
• Texas Oncology, PA
• Houston, Texas

2
Overview of 4 Main Discussion Areas

• Review of anemia in patients with breast cancer
• Anemia causes, incidence, and grading systems
• The role of erythropoietic agents in the
  treatment of anemia in patients with breast
  cancer
• Comparison of available agents
• Recent clinical data regarding treatment regimens
  with erythropoietic agents
• New studies from ASCO, 2004
• Data from SABC symposium, 2003
• Review of data regarding possible negative
  effects of erythropoietic agents in patients
  with cancer

ASCO American Society of Clinical Oncology
SABC San Antonio Breast Cancer.
3
Anemia in Cancer PatientsEtiology

• Cancer-related anemia may be attributed to many
  factors
• Chemotherapy/radiation therapy
• Anemia of chronic disease
• Blunted erythropoietin response
• Blood loss
• Bone marrow infiltration by tumor
• Nutritional deficiency
• Hemolysis

Groopman JE, Itri LM. J Natl Cancer Inst.
1999911616-1634 Miller CB et al. N Engl J Med.
19903221689-1692 Smith RE Jr, et al. Br J
Cancer. 2003881851-1858.
4
Toxicity Grading Systems for Anemia
WHO World Health Organization NCI National
Cancer Institute WNL within normal limits.
Values are hemoglobin (Hb) in g/dL. Groopman J,
Itri LM. J Natl Cancer Inst. 1999911616-1634.
5
Incidence of Anemia in Common Chemotherapy
Regimens for Breast Cancer
No incidence of grade 4 anemia. Patients with
baseline normal Hb level. FEC 100
5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2,
cyclophosphamide 500 mg/m2 Q3W for 6 weeks.
6
Role of Erythropoietic Agents in Anemia Management
7
NCCN Guidelines for the Management of
Chemotherapy-Induced Anemia

• Evaluate patient if Hb lt11.0 g/dL
• Patient symptomatic
• Consider erythropoietic therapy if Hb 10.0 to
  11.0 g/dL
• Strongly consider erythropoietic therapy if Hb
  lt10.0 g/dL (generally approved for reimbursement
  in all states)
• Patient asymptomatic
• Consider erythropoietic therapy if risk factors
  for developing anemia are present
• Titrate dose of erythropoietic agents to maintain
  optimal Hb level (11.0 to 12.0 g/dL)
• Monitor patient for side effects

NCCN National Comprehensive Cancer Network Hb
hemoglobin. NCCN. Clinical Practice Guidelines
in Oncology Cancer and Treatment-Related Anemia.
V.2.20041-4.
8
Erythropoietic Agents

• Exogenous erythropoietin
• Epoetin alfa (global)
• Epoetin beta (non-US, international)
• Darbepoetin alfaa novel erythropoiesis-
  stimulating protein
• Hematologic effects identical to endogenous
  erythropoietin
• Clinical studies indicate effectiveness in
  chemotherapy-induced anemia and anemia of cancer

Darbepoetin alfa package insert. 2002 Epoetin
alfa package insert. 2004 Epoetin alfa
package insert. 1997 Glaspy J et al. J Clin
Oncol. 1997151218-1234 Glaspy J et al. Br J
Cancer. 200184(suppl 1)17-23 Quirt I et al,
and the Canadian Eprex Oncology Study Group. J
Clin Oncol. 2001194126-4134 Seidenfeld J et
al. J Natl Cancer Inst. 2001931204-1214 Smith
R et al. ASCO 2002. Orlando, Fla. Abstract and
poster Smith RE Jr et al. Br J Cancer.
20018424-30.
9
Comparison of Molecular Structures
Sialic acid Carbohydrate chains
Epoetin alfa
darbepoetin alfa

• 3 N-linked CHO chains
• ?14 sialic acid residues
• 40 carbohydrate
• 30,400 daltons

• 5 N-linked CHO chains
• ?22 sialic acid residues
• 52 carbohydrate
• 38,500 daltons

CHO carbohydrate. Macdougall IC. Semin Nephrol.
200020375-381.
10
Darbepoetin alfa Has a Longer Half-life Than
Epoetin alfa
100
darbepoetin alfa (dialysis 0.5 mcg/kg, n
11) Epoetin alfa (dialysis 100 U/kg, n 10)
10
t1/2 25.3 hours
Mean (SD) Baseline-Corrected Serum Concentration
(ng/mL)
1
t1/2 8.5 hours
0.1
0.01
0 25 50 75 100
Time Postintravenous Injection (hours)
Single-dose pharmacokinetics. Macdougall IC et
al. J Am Soc Nephrol. 1999102392-2395.
11
Clinical Data for Dosing and Use of
Erythropoietic Agents
12
Darbepoetin alfa Q2W Dosing Study Design
darbepoetin alfa3.0 mcg/kg Q2W
End ofTreatment
Follow-up
End ofStudy
Screening
Enrollment
Chemotherapy
Week
1 Q
7
9 Q
17 Q
15
At week 7, if Hb increased lt1.0 g/dL, then dose
was increased to 5.0 mcg/kg Q2W for 5 doses. Hb
measured at baseline 1 (week 1) and Q2W until the
end of treatment. Follow-up occurred 2 weeks
after last dose of darbepoetin alfa Q indicates
when PRO questionnaires were administered. Q2W
once every 2 weeks PRO patient-reported
outcomes. Blayney D et al. SABCS 2003. San
Antonio, Texas. Poster.
13
All Patients Showed an Increase in Hb at Week 17
ITT
Available Data
2.2
2.5
2.1
1.9
1.7
2.0
Mean (95 CL) Change in Hb (g/dL) From Baseline
at Week 17
1.5
1.0
0.5
0
Breast(n 413)
All(N 1462)
Breast(n 254)
All(N 765)

• Additional data In this study, 80 of breast
  cancer patients had a hematopoietic response (n
  424), and 70 of all patients had a hematopoietic
  response (N 1462).

96 (all dataset) and 9 (breast cancer subset)
patients were missing a baseline Hb value. Change
from baseline scores was calculated for PRO
missing values were not imputed. ITT
intent-to-treat. Blayney D et al. SABCS 2003.
San Antonio, Texas. Poster.
14
RBC Transfusions With Treatment for Breast Cancer
Patients and All Patients
Month 1
Month 4
18
16
14
14
12
Proportion (95 CL) of Patients With an RBC
Transfusion (month 1 vs month 4)
10
7
8
5
6
2
4
2
0
Breast(n 424)
All(N 1558)
Breast(n 365)
All(N 1206)

• From month 1 to month 4, the reduction in
  transfusions was 71 for breast cancer patients
  and 64 for all patients.
• There was an increase in mean FACT-Fatigue score
  of 8.2 in patients with breast cancer and of 6.7
  in all patients at week 17.

Crude proportion. RBC red blood cell. Blayney
D et al. SABCS 2003. San Antonio, Texas. Poster.
15
Dosing of Erythropoietic Agents in Patients With
Cancer Study Design
END OF TREATMENT (EOT) 2 weeks afterlast dose
ofdarbepoetin alfa or 1 week afterlast dose
ofEpoetin alfa
END OF STUDY 2 weeks afterEOT visit
R A N D O M I ZA T I O N 11
darbepoetin alfa200 mcg Q2W
Epoetin alfa40,000 U QW
Concurrent Chemotherapy
1
5
9
13
17
19
(Baseline)
Study Week
After 4 weeks, if patients did not achieve a
gt1.0-g/dL increase in Hb, darbepoetin alfa was
increased to 300 mcg Q2W Epoetin alfa was
increased to 60,000 U QW. If Hb gt13.0 g/dL, doses
of either agent were withheld until it decreased
to lt13.0 g/dL therapy was then restarted at
previous dose. The Patient Satisfaction
Questionnaire (PSQ-An) was administered at week 5
and every 4 weeks throughout treatment.
Schwartzberg L et al. ASCO 2004. New Orleans,
Louisiana. Poster 25. Abstract 8063.
16
Change in Hb and Hematopoietic Response With Q2W
darbepoetin alfa or QW Epoetin alfa
Q2W darbepoetin alfa QW Epoetin alfa
100
88
3.0
2.4
81
74
2.2
90
1.7
1.7
1.6
62
2.5
80
59
1.4
70
49
2.0
60
Proportion (95 CL) of Patients Achieving a
Hematopoietic Response ()
Mean (95 CL) Change in Hb at End of Treatment
(g/dL)
50
1.5
40
1.0
30
20
0.5
10
0
0
Breast
Lung
Gyn
Breast
Lung
Gyn
Mean BL Hemoglobin 10.5 10.5 10.5 10.5 10.1 10.3
N 58 40 19 20 21 24
N 72 69 51 51 34 35
Crude proportions ITT analysis
set. Hematopoietic response Hb gt12.0 g/dL or
gt2.0-g/dL increase in Hb from baseline.
Imputed data approach. CL confidence limit BL
baseline.
Schwartzberg L et al. ASCO 2004. New Orleans,
Louisiana. Poster 25. Abstract 8063.
17
Proportion of Patients Requiring a Transfusion
Is Similar With Q2W darbepoetin alfa or QW
Epoetin alfa Across Tumor Type
Q2W darbepoetin alfa QW Epoetin alfa
27
21
17
18
16
Proportion (95 CL) of PatientsRequiring a
Transfusion ()
Plt.05
6
N 72 69 51 51 34 35
Hb values within 28 days of an RBC transfusion
were excluded Crude proportions ITT analysis
set. Schwartzberg L et al. ASCO 2004. New
Orleans, Louisiana. Poster 25. Abstract 8063.
18
Q3W Dose-Finding Study Schema With darbepoetin
alfa in CIA
E N D OF STUDY
darbepoetin alfa 4.5, 6.75, 9.0,12.0, 13.5, and
15.0 mcg/kg administered Q3W for 12 weeks
SCREENING AND RANDOMIZATION
Placebo administered Q3W for 12 weeks
Concurrent Chemotherapy
12
Week
1
Double-blind Treatment
Q3W once every 3 weeks CIA
chemotherapy-induced anemia. Kotasek D et al.
Eur J Cancer. 2003392026-2034.
19
Q3W Dose-Finding Study Results for darbepoetin
alfa in CIA
K-M Kaplan-Meier. Kotasek D et al. Eur J
Cancer. 2003392026-2034.
20
Early Intervention With darbepoetin alfa (Q3W)
END OF TREATMENT
RANDOMIZATION
Early Intervention Group darbepoetin alfa
administered at 300 mcg Q3W
SCREENING
Hemoglobin?10.5 g/dLand?12.0 g/dL
Observation/Late Intervention Group No treatment
unless patients Hb lt10.0 g/dL, in which case
darbepoetin alfa was administered at 300
mcg Q3W
Week 13 (primary endpoint assessment)
Week 1
Week 22
1-7 days
Test Period
Treatment Period
Chemotherapy on Study
Rearden T et al. ASCO 2004. Poster 26. Abstract
8064.
21
Fewer Patients in Early Intervention Group
Developed Hb Levels lt10.0 g/dL
100
90


80
70
60
K-M Proportion of Patients With Hb Remaining
gt10.0 g/dL ()
50
40
30
20
Early intervention group Late intervention group
10
0
0
5
9
13
17
22
Weeks
Early Intervention (N) 99 85 72 67 61 41 Late
Intervention (N) 102 60 39 32 25 20
Plt.0001. The 95 confidence intervals were
determined from the last noncensored time point
and are displayed at weeks 13 and 22. Rearden T
et al. ASCO 2004. Poster 26. Abstract 8064.
22
Mean Hb Maintained Near 12.0 g/dL in Early
Intervention Group
Early intervention group Late intervention group
14.0
13.0
12.0
Mean (95 CL) Hemoglobin (g/dL)
11.0
10.0
9.0
1
4
7
10
13
16
19
22
Study Week
Intent-to-treat analysis of all patients with a
baseline Hb value. Missing Hb values were
excluded from the analysis (n 2 late and n 1
early intervention groups). Box target Hb range
(11.0 g/dL to 13.0 g/dL) line 12.0
g/dL. Rearden T et al. ASCO 2004. Poster 26.
Abstract 8064.
23
Lower Rate of Transfusion in Early Intervention
Group
Early intervention group, n 99 Late
intervention group, n 102
35
30
26
25
22
K-M Percent (95 CL) of Patients Transfused
20
17
14
15
10
5
0
Test Period (weeks 1 to 13)
Treatment Period (weeks 1 to 22)
Rearden T et al. ASCO 2004. Poster 26. Abstract
8064.
24
Effect of Epoetin alfa on Cognitive Function
Study Design
Epoetin alfa 40,000 U QW
End of Chemo-therapy
Hb 9.0 g/dL and 14.0 g/dL
6-Month Follow-up
Randomization
Placebo
12 Weeks (4 cycles
of chemotherapy)
Cycle 4
Cycle 1
OShaughnessy J et al. SABCS 2002. San Antonio,
Texas. Poster. .
25
Mean Change in FACT-An and EXIT25 Scores With
Epoetin alfa
EXIT25
Cycle 4
6-MonthFollow-up
FACT-An
Epoetin alfa Placebo
0.6
P .011
Mean Change in EXIT25 Score
-2.5
-3
Change in FACT-An
0.3
0
-1.3
-9.4
From baseline to cycle 4. P value calculated by
Wilcoxon Rank Sum test. FACT-An Functional
Assessment of Cancer TherapyAnemia EXIT25
Executive Interview, 25 questions. OShaughnessy
J et al. SABCS 2002. San Antonio, Texas.
Poster.
26
Mean Change in LASA Scores Over Baseline
Epoetin alfa Placebo
7.5
6.6
Change in LASA (mm)
3.8
3.7
3.7
2.9
LASA Linear Analog Scale Assessment.
OShaughnessy J et al. SABCS 2002. San Antonio,
Texas. Poster.
27
Canadian Eprex Study Study Design
Epoetin alfa40,000 IU/week16-28 dosesDay 1
Epoetin alfaDose Titration Week 4 (4-week
cycle)Week 6 (3-week cycle)
RandomizationHb lt12.0 g/dL)andgt12
weekschemotherapy remain
ScreeningPhaseHb lt15.0 g/dL
End ofTreatmentPhaseWeek 16 or 4 weeks
afterlast cycle of chemotherapy or early
termination
Follow-upPhase
PrimaryEndpointAssessment
Best Supportive Care Day 1
Week -12 to 0
Chemotherapy
Week 4/6
Week 12
16-28 Weeks
Follow-up24 months
Chang J, Couture F, for the Canadian Eprex Study
Group. Proc Am Soc Clin Oncol. 200322727.
Abstract 2923.
28
Change in QOL (FACT) Scores Baseline to Week 12
Epoetin alfa, n 168Best supportive care, n
170
2.16
1.55
0.31
Plt.0001
Plt.0001
Plt.001
Change in Score
-0.88
-3.55
-4.43
FACT-An
FACT-Fatigue
Non-Fatigue
Chang J, Couture F, for the Canadian Eprex Study
Group. Proc Am Soc Clin Oncol. 200322727.
Abstract 2923.
29
Change in CLASBaseline to Week 12
Epoetin alfa, n 166Best supportive care, n
169
3.76
3.75
3.34
Plt.014
Plt.01
Plt.001
Change in Score
-4.60
-4.91
-6.19
Energy Level
Ability to DoDaily Activities
Overall QOL
CLAS Cancer Linear Analog Scale. Chang J,
Couture F, for the Canadian Eprex Study Group.
Proc Am Soc Clin Oncol. 200322727. Abstract
2923.
30
Hb Responses Increased and Transfusion
Requirements Decreased With Epoetin alfa
Hemoglobin Response
Transfusion Requirements
Plt.0001
Plt.0001
52
55
Patients Receiving Transfusions ()
23
50
24
45
20
40
35
16
Responders ()
30
25
12
20
8.7
8
15
10
5.1
4
5
0
0
Epoetin alfa(n 175)
BSC(n 175)
Epoetin alfa (n 175)
BSC (n 175)
ITT population. BSC best supportive care.
Chang J, Couture F, for the Canadian Eprex Study
Group. Proc Am Soc Clin Oncol. 200322727.
Abstract 2923.
31
Safety Concerns With Erythropoietic Proteins

• Recently, 2 different studies have raised certain
  safety concerns regarding erythropoietic proteins
  (Epoetin alfa and Epoetin beta)
• Possible tumor progression and decreased survival
• Increased incidence of thromboembolic events

Henke M et al. Lancet. 20033621255-1260
Leyland-Jones B for the BEST Investigators and
Study Group. Lancet Oncol. 20034459-460.
32
Epoetin beta Possible Study Limitations

• A number of protocol violations were recorded in
  the study
• Per-protocol analysis revealed no statistically
  significant difference in survival between the 2
  groups
• Imbalances in baseline characteristics may have
  occurred in specific subgroups
• Hb raised to levels higher than the 11.0 to 12.0
  g/dL currently recommended as a goal by clinical
  guidelines for treated patients with anemia and
  cancer (but were not above normal Hb levels)

Henke M et al. Lancet. 20033621255-1260 NCCN.
Clinical Practice Guidelines in Oncology Cancer
and Treatment-Related Anemia. V.2.2004. Available
at www.nccn.org Rizzo JD et al. Blood.
20021002303-2320.
33
Effects of Epoetin alfa on Survival Possible
Study Limitations

• Hb levels corrected to 12.0 to 14.0 g/dL
• Study design did not include standard assessment
  or documentation of prognostic factors
• Unusual number of early deaths in both groups
• Small differences in Hb level between treatment
  and placebo groups
• An independent retrospective chart review
  suggested that the Epoetin alfa group was at a
  greater risk for lower survival and for
  thrombotic events at baseline

Leyland-Jones B for the BEST Investigators and
Study Group. Lancet Oncol. 20034459-460.
34
In Vivo Effects of Epoetin alfa on Tumor Growth
and Angiogenesis

• Methods
• gt200 nonanemic rodents randomized to Epoetin alfa
  or placebo
• Both breast and colon cancer cells were examined
• Erythropoietin receptors measured
• Tumor growth assessed
• Tumor proliferation assessed
• Angiogenesis assessed
• Results
• Significant increase in Hb
• Expression of erythropoietin receptor observed
• No effect on tumor growth or proliferation
• No change in angiogenesis

Hardee ME et al. ASCO 2004. Abstract 9530.
35
Epoetin alfa Has No Effect on Survival With
Dose-Dense Chemotherapy

• Methods
• Multicenter phase III study with 1284 patients
  who had 4 involved axillary lymph nodes
• Randomized to 3 courses each of epirubicin,
  paclitaxel, and cyclophosphamide (ETC) Q2W with
  G-CSF support
• These patients were secondarily randomized to
  Epoetin alfa or no Epoetin alfa Q3W
• Results
• No difference in disease-free survival or overall
  survival was observed between the group treated
  with Epoetin alfa and the non-Epoetin alfa group

G-CSF granulocyte colony-stimulating
factor. Mobus VJ et al. ASCO 2004. Abstract 513.
36
BEST Study Thrombotic Events

• In addition to reduced survival, the BEST study
  results suggested that Epoetin alfa might
  increase risk of thrombotic events
• Incidence of thrombotic events was 1 in the
  Epoetin alfa group and 0.2 in the placebo group
• As discussed, this trial sought to raise Hb
  levels above the recommended 12.0 g/dL
• An independent chart review suggested baseline
  differences between the groups

BEST Breast Cancer Erythropoietin Trial.
Leyland-Jones B for the BEST Investigators and
Study Group. Lancet Oncol. 20034459-460.
37
Summary

• Chemotherapy-induced anemia is common in patients
  with breast cancer
• Erythropoietic treatments for these patients
  include
• Epoetin alfa (QW)
• Darbepoetin alfa (Q2W or Q3W)
• Because of its longer half-life, less frequent
  dosing is needed compared with Epoetin alfa
• Therefore, dosing may be tailored to coincide
  with chemotherapy

38
Summary (contd)

• Based on clinical data, erythropoietic agents
  effectively
• Improve Hb levels
• Reduce the need for transfusions
• Improve QOL
• On the whole, review of the data indicates that
  using erythropoietic agents to maintain Hb levels
  lt12.0 g/dL is safe
• In patients with breast cancer and CIA,
  darbepoetin alfa Q2W appears to be as effective
  as Epoetin alfa QW and has the benefits and
  convenience of reduced frequency of dosing