Management Options for Anaemia in Patients with Cancer Focus on Erythropoietin

1
Management Options for Anaemia in Patients with
CancerFocus on Erythropoietin

• Damir Nemet
• Division of Haematology
• Clinical Hospital Centre and School of Medicine
  Zagreb

2
CONCLUSIONCompelling evidence to treat anaemia

• Anaemia is highly prevalent among cancer patients
• Anaemia adversely impacts patients in several
  ways
• substantially impair Quality of Life
• associated with poor tumour control
• negative prognostic factor for survival, reduces
  overall survival
• therefore, cancer-related anaemia represents a
  significant burden for patients and caregivers
• Anaemia is underestimated and undertreated
• Treating anaemia with epoetin
• increases haemoglobin levels
• reduces need for transfusions
• improves tumour control
• may improve survival

3
Epoetin in cancerIssues to be addressed

• Epidemiology of anaemia in cancer
• Epoetin a standard treatment approach
• Recommendations for the treatment of anaemia in
  cancer
• New approaches

4
Epoetin in cancerIssues to be addressed

• Epidemiology of anemia in cancer
• Epoetin a standard treatment approach
• Recomendations for the treatment of anemia in
  cancer
• New approaches

5
The European Cancer Anaemia Survey (ECAS) A
Large, Multinational, Prospective Survey Defining
the Prevalence, Incidence, and Treatment of
Anemia in Cancer Patients
6
Results Participation

• 750 cancer centers in 24 European countries
• Over 1000 participating physicians
• 15,367 patients were enrolled

7
Frequency of Anemia During ECAS by Treatment
Overall 67 of patients were ever anemic during
ECAS
Patients Ever Anemic During the Survey
CT Combination Concomitant NoTreatment
RT CT/RT CT/RT n 8470 1955 299 1145 1543
Missing data n216 Analysis Population n
14,912
8
Percent Ever Anemic During Survey by Tumor Type
(n 13,412)
Overall 67 of patients were ever anemic during
ECAS
All Patients
Missing data n216Other n 587 60 ever anemic
9
Distribution of Anemia Treatments for Patients
Ever Anemic (n 9118)
14.9 TRANSFUSION(alone or with iron)
17.4 EPOETIN(alone or with iron and/or
transfusion)
6.5 IRON ONLY
61.1 NO TREATMENT
Overall mean Hb at treatment initiation 9.7 g/dL
10
Discussion

• Cancer-associated anemia is not optimally treated
• 60 of cancer patients who were anemic during
  ECAS did not receive anemia treatment
• 25 of anemic patients not treated had Hb 10 -
  11.9 g/dL
• 14 of anemic patients not treated had Hb lt10
  g/dL
• 51 of anemic patients with WHO PS of 2 or more
  did not receive anemia treatment
• Use of transfusion (14.9) was similar to use of
  epoetin (17.4)
• Treatment was not generally initiated until Hb
  level was lt9 g/dL

11
Epoetin in cancerIssues to be addressed

• Epidemiology of anemia in cancer
• Epoetin a standard treatment approach
• Recomendations for the treatment of anemia in
  cancer
• New approaches

12
Recormon Dosing and Response I
Complete anaemia correction
15
14
13
12
Titrate dose to maintain Hb within normal range
11
Hb level (g/dl)
10
Hb increase gt2 g/dl
9
8
NeoRecormon 30 000 IU qw
NeoRecormon 5000 IU qw
15 000 IU qw
7
6
0
2
4
6
8
10
12
14
16
Time (weeks)
qw Once Weekly
13
NeoRecormon Hb Response in 67 of Patients
with Poor Prognosis Haematological Malignancies
100
80
NeoRecormon 67
plt0.0001
60
Patients with Hb increase 2 g/dl ()
? 40 improvement
40
20
Placebo27
0
8
10
12
14
16
4
6
Time (weeks)
without blood transfusion in previous 6 weeks

• Österborg et al. J Clin Oncol 2002 20 248694

14
NeoRecormon Improves Hb in Patients with
Metastatic Breast Cancer
12
11
Mean Hb levels (g/dl)
NeoRecormon 5000 IU tiw
10
NeoRecormon 1000 IU tiw
Control group
2
4
8
20
24
16
12
Weeks
Hb values from 43 patients with metastatic
breast cancer not treated with epoetin registered
after completion of study enrolment
Olsson et al. Acta Oncol 2002 41 51724
15
NeoRecormon Increases Transfusion-Free Survival
in Patients with Haematological Malignancies
1.0
p0.0012
0.8
NeoRecormon
43 risk reduction
0.6
Transfusion-free survival
Placebo
0.4
0.2
Transfusion- and severe anaemia-free survival
51 risk reduction (plt0.0001)
0
4
6
8
10
12
14
16
Weeks

• Österborg et al. J Clin Oncol 2002 20 248694

16
NeoRecormon Once Weekly is as Effective as
Three-times Weekly
13
12
Mean Hb (g/dl)
NeoRecormon 30 000 IU Once Weekly
11
NeoRecormon 10 000 IU tiw
10
0
4
8
12
16
? Hb 1 g/dl
? Hb 2 g/dl
Time (weeks)

• Cazzola et al. Br J Haematol 2003 122 38693

17
Outcomes of EPO-treated Cancer Patients
Independent Meta-analysis

• 27 randomised trials included 3284 patients
• EPO significantly reduced risk of RBC
  transfusions (relative risk 0.67, 95 CI
  0.620.73)
• EPO significantly improved haematological
  response (relative risk 3.60, 95 CI 3.074.23)
• EPO shows a trend towards improved overall
  survival hazard ratio 0.80, 95 CI 0.651.00

Bohlius et al. Blood 2003 102 A709
18
Epoetin in cancerIssues to be addressed

• Epidemiology of anemia in cancer
• Epoetin a standard treatment approach
• Recomendations for the treatment of anemia in
  cancer
• New approaches

19
Guideline Recommendations for Anaemia Management
in Patients with Cancer

• EHA (MM and CLL patients)
• Initiate epoetin in patients with
• Hb lt10 g/dl
• Hb 12 g/dl and WHO performance status III due
  to anaemia
• Hb 12 g/dl and Hb decrease 1.5 g/dl/month
  during chemotherapy
• Once weekly or tiw increase dose x 1.5 and x 2,
  respectively, if Hb increase lt1 g/dl
  after 4 weeks
• Maintain Hb at 12 g/dl discontinue if Hb 14
  g/dl and reinstate with 25 reduction
  in dose if Hb falls to lt12 g/dl

• Ludwig et al. Hematol J 2002 3 12130

20
Updated EORTC Guidelines on Use of Erythropoietin
in Cancer Patients

• Bokemeyer C, Aapro MS, Courdi A, et al.
• Eur J Cancer. 2004402201-2216.

21
Main Findings

• 78 papers and 50 abstracts identified
• 18 recommendations
• Initiate EPO if Hb 90-110 g/L in symptomatic
  patients
• Prophylactic use of EPO is not recommended
• Target Hb concentration 120-130 g/L
• Goals of therapy to improve quality of life and
  decrease need for transfusion
• Not for increased survival
• Fixed doses are generally adequate
• Dose escalation must be decided on case-by-case
  basis
• Slight increase in thromboembolic events
• May be related to Hb level achieved

Bokemeyer C, et al. Eur J Cancer.
2004402201-2216.
22
Key Conclusions

• Algorithm for EPO dosing
• Start initial therapy at 90-110 g/L Hb
• After 4-6 weeks, reevaluate
• If no symptomatic improvement or response in Hb
  level, either raise dose, continue on same dose,
  or stop
• After 4 more weeks, reevaluate again
• If still no response, continue at elevated dose
  or stop
• If responsive at either initial dose or elevated
  dose, continue or stop
• Depends on patient symptoms rather than Hb
  concentration

Bokemeyer C, et al. Eur J Cancer.
2004402201-2216.
23
Epoetin in cancerIssues to be addressed

• Epidemiology of anemia in cancer
• Epoetin a standard treatment approach
• Recomendations for the treatment of anemia in
  cancer
• New approaches

24
Use of Epoetin Beta in Anemic Patients on
Chemotherapy

• Meta-analysis of 5 randomized controlled trials
  of epoetin beta in anemic patients with lymphoid
  malignancies receiving chemotherapy
• No significant improvement in global treatment
  outcomes or disease progression with epoetin beta
• Short-term mortality and thromboembolic event
  rates similar between treatment and control arms

Coiffier B, et al. ASH 2004. Abstract 3149.
25
Evaluation of Epoetin Alfa Dosing Schedules

• NCCTG study NO2C2 multicenter phase 3 trial

11 Randomizationat Week 3
Week 21
Stratified by degree of anemia, age,
chemotherapy use, tumor type
Epoetin alfa 40,000 U weekly (n 183)
Epoetin alfa 40,000 U weekly for 3 wks
Anemic cancer patients (N 365)
Epoetin alfa 120,000 U every 3 wks (n 182)
All patients took oral ferrous sulfate 325 mg
daily
Steensma et al. ASCO 2005. Abstract 8031.
26
Evaluation of Epoetin Alfa Dosing Schedules

• Transfusion rates similar between groups (P
  .22)
• 18 with every-3-weeks vs 23 with conventional
  weekly dosing
• Mean Hb at study end 12.0 g/dL with weekly dosing
  vs 11.5 g/dL with every-3-weeks dosing (P
  .0006)
• Hb level ? 13 g/dL, 65 vs 43, respectively (P lt
  .0001)
• No survival difference between treatment arms
• Ischemic and thrombotic adverse events similar
  between treatment arms 9 vs 8 (P .80)
• Thrombotic events and pattern of Hb increase not
  correlated
• Leukopenia more common with every-3-week dosing
• 17 vs 10 with weekly dosing (P .03)

Steensma et al. ASCO 2005. Abstract 8031.
27
Darbepoetin alfa

• Darbepoetin alfa is a long-acting erythropoietic
  agent with significantly increased biological
  activity
• The discovery of darbepoetin alfa resulted from
  basic research on the structure and function of
  r-HuEPO and its attached carbohydrate
• The longer serum residence time and greater
  biological activity of darbepoetin alfa result
  from the addition of two carbohydrate side chains

28
Epoetin Alfa vs Darbepoetin Alfa in Anemic
Patients on Chemotherapy

• Phase 3 study outcomes measured by noninferiority

Treated up to 16 wks
Darbepoetin alfa 200 mg every 2 wks (n 606)
Patients with CIA, nonmyeloid malignancy and
8 wks planned chemotherapy, Hb 11 g/dL ECOG PS
0-2 (N 1209)
17-19 wks follow-up
Epoetin alfa 40,000 U weekly (n 603)
Glaspy et al. ASCO 2005. Abstract 8125.
29
Epoetin Alfa vs Darbepoetin Alfa in Anemic
Patients on Chemotherapy

• Increase in Hb and transfusion requirements
  similar
• Changes in fatigue scores similar with either
  treatment
• Cardiovascular or thromboembolic events
• Darbepoetin alfa, 6 Epoetin alfa, 7

Glaspy et al. ASCO 2005. Abstract 8125.
30
Use of Darbepoetin Alfa in Early Prevention vs
Later Intervention of Anemia

• Randomized, open-label, multicenter study

• Mean initial Hb levels
• Early intervention arm
• 11.1 g/dL
• Late intervention arm
• 11.2 g/dL

Patients with Hb 10.5 and lt 12 g/dL (N 201)
If Hb lt 10 g/dL, darbepoetin alfa increased to
500 µg every 3 wks. If Hb lt 9 g/dL, or if lt 10
g/dL following 2 cycles of darbepoetin alfa, dose
increased to 500 µg every 3 wks.
Charu V, et al. ASH 2004. Abstract 233.
31
Use of Darbepoetin Alfa in Early Prevention vs
Later Intervention of Anemia

• Intent-to-treat analysis
• Early intervention prevented severe anemia at 13
  and 21 weeks
• Hb declined to lt 10 g/dL in 65 of patients in
  late intervention arm
• Fewer transfusions with early vs late
  intervention
• 17 vs 26 of patients

Charu V, et al. ASH 2004. Abstract 233.
32
Erythropoietic Growth Factors Conclusions

• Epoetin alfa enables safe dose-dense chemotherapy
  in high-risk breast cancer patients
• Undetermined whether epoetin superior to
  darbepoetin
• Transfusion rates similar
• No increase in toxicity
• No difference in quality of life improvements
• Conflicting data regarding time to increase in
  hemoglobin

33
Erythropoietic Growth Factors Conclusions

• Weekly epoetin alfa schedule superior to 3-week
  dosing
• Higher increase in hemoglobin
• Less leukopenia
• No difference in transfusion requirements or
  survival rates

34
QoL, Pharmaeconomics MF 4421

• Conclusions
• Epoetin beta was significantly superior to
  standard care
• increasing the Hb concentration,
• reducing transfusion requirements
• enhancing QoL
• these benefits were observed irrespective of the
  type of tumour, the presence or the nature of
  chemotherapy
• With QoL as a target in supportive cancer care,
  epoetin beta therapy may be considered a safe and
  cost effective option compared to standard care
  which does not succeed in improving or
  maintaining QoL over time.