“In anemia of chronic disease, hemoglobin levels are
usually 8 grams or greater and are not associated with
any symptoms unless there is significant underlying
lung or heart disease. Therefore, no treatment is
necessary. The main importance of the anemia of
chronic disease is as a clue to the existence of that
underlying disease. Treatment of the secondary
anemia does not alter that disease”
-Medical School Classnotes, 1976
Toxicity Grading Systems for Anemia
Grade WHO
NCI
ECOG SWOG CALGB GOG
0
11
WNL
WNL
WNL
WNL
WNL
1
9.5–10.9
10.0
10.0
10.0
10.0
10.0
2
8.0–9.4 8.0–10.0 8.0–10.0 8.0–9.9 8.0–10.0 8.0–10.0
3
6.5–7.9
6.5–7.9
6.5–7.9
4
<6.5
<6.5
<6.5
6.5–7.9 6.5–7.9
<6.5
<6.5
6.5–7.9
<6.5
Values are hemoglobin in g/dL
WHO = World Heatlh Organization; NCI = National Cancer Institute; ECOG = Eastern
Co-operative Oncology Group; SWOG = Southwest Oncology Group; CALGB = Cancer and
Leukemia Group B; GOG = Gynecologic Oncology Group; WNL = within normal limits
Incidence of Anemia in Cancer Patients
Anemia Grade 1 or 2
50
43.9
45
Patients (%)
40
Anemia Grade 3 or 4
37.5
41.1
40.0
39.5
39.5
35
30
25.9
25
20
16.3
14.1
15
10
14.0
12.4
8.4
8.3
4.9
5
0
Lung Cancer Metastatic
Breast
Cancer
Advanced Lymphomas
Ovarian
Cancer
Advanced Advanced Head
Colorectal
and Neck
Cancer
Source: Groopman JE, Itri LM. J Natl Cancer Inst. 1999;91:1616–1634.
Cancer
Total
Incidence and Severity of Anemia in
Previously Untreated Patients
With Breast Cancer
Single-Agent Chemotherapy
Treatment
n
Anemia
Grade 1–2 (%)
Docetaxel
34
37
97
NR
0
14 (grade 3)
Paclitaxel
30
93
7 (grade 3)
Vinorelbine
59
143
67
71
14
5
NR = not reported
Anemia
Grade 3–4 (%)
Groopman. J Natl Cancer Inst. 1999;91:1616.
Incidence and Severity of Anemia in
Previously Untreated Patients
With Breast Cancer
Combination Chemotherapy
Treatment
• Cyclophosphamide +
Doxorubicin +
5-Fluorouracil +
Methotrexate
n
Anemia
Grade 1–2 (%)
Anemia
Grade 3–4 (%)
266
27
1 (grade 3)
• Paclitaxel +
Doxorubicin
9
25
78
84
11
8
• Cisplatin +
Epirubicin +
Paclitaxel
63
NR
25
Groopman. J Natl Cancer Inst. 1999;91:1616.
Frasci. Breast Cancer Res Treat. 1999;56:239.
Incidence of Anemia in Patients
With Breast Cancer
Combination Chemotherapy
Cumulative Anemia in Patients With Breast Cancer Receiving AC
Cycle
n
Hb  10 g/dL
Prechemotherapy
(% patients)
1
536
2.7
4.2
2
530
3.6
9.3
3
528
5.8
16.1
4
518
6.5
24.2
AC = doxorubicin + cyclophosphamide
Hb = Hemoglobulin
Hb  10 g/dL
Postchemotherapy
(% patients)
Lawless. Blood. 2000;96(11 suppl 2):(abstr 5447).
Anemia in Oncology:
A Historical Perspective

1901-1990
– Focus on severe anemia (Hb < 8.5 gm/dl)
– Red cell transfusion therapy

1991-1997
– rHuEPO to decrease transfusions
– Focus on severe anemia

1997-2002
– Mild and moderate anemia recognized as QOL drivers
– rHuEPO to improve QOL

Future
– New insights (schedule, cost savings, Fe)
– New endpoints (cognition, survival, cost-effectiveness)
Anemia Rx and QOL During
Cancer Chemotherapy
Study
Trial type
QOL impact
QOL tool(s)
Glaspy
(1997)
Open-label
Yes
LASA
Demetri
(1998)
Open-label
Yes
LASA, FACT-An
Gabrilove
(2001)
Open-label
Yes
LASA, FACT-An
Littlewood
(2001)
Randomised,
placebo-controlled
Yes
LASA, FACT-An,
FACT-F, SF-36
Österborg
(2002)
Randomised,
placebo-controlled
Yes
FACT-G, FACT-F,
FACT-An
Boogaerts
(2002)
Randomised
Yes
FACT-G, FACT-F,
FACT-An, SF-36
Pirker
(2002)
Randomised,
Placebo-conrolled
Yes
FACT-F
70
Cross-Sectional
Community Study 1and 2
65
LASA Score (mm)
60
55
CS-1
50
CS-2
45
40
35
30
7
8
9
10
11
12
Hemoglobin Level (g/dL)
13
14
70
Cross-Sectional Cut by Gender
Community Study 2
65
LASA Score
60
55
50
45
Males
Females
40
35
30
7
8
9
10
11
Hemoglobin level (g/dL)
12
13
14
Cancer Patients are Human
M e a n c h a n g e in H c t v s
M e a n c h a n g e i n O v e r a ll Q o L
20
15
C
h 10
a
n
g
e
i
n
H
c
t
5
S E T T IN G
R e nal
0
Canc er
- .5
0 .0
.5
S ta n d a r d iz e d c h a n g e in Q o L
1 .0
1 .5
Critical Issues for BCIRG - 2002
• Is there a biological basis for questioning
the role of anemia in the progression of
chronic diseases?
• Are there appropriate mechanistic models
suggesting that anemia may impact the
survival of cancer treated with:
• Radiotherapy?
• Chemotherapy?
• Observation/Palliation?
• Is it time for clinical trials?
Etiology of the Anemia of Cancer
(Anemia of Chronic Disease)
Tumor
cells
Activated
immune system
AIS
RBCs
Macrophages
Erythrophagocytosis
Dyserythropoiesis
Shortened
survival
ANEMIA
TNF
IL-1 a, b
TNF
Reduced
EPO
production
IFN-g
IL-1
TNF
a1-antitrypsin
Suppressed
BFU-e
CFU-e
IFN-g
IL-1
TNF
Impaired
iron
utilization
AIS = anemia-inducing substance; BFU-e = erythroid burst-forming unit; CFU-e = erythroid colony-forming unit;
EPO = erythropoietin; IFN = interferon; IL-1 = interleukin-1; RBCs = red blood cells; TNF = tumor necrosis factor.
Nowrousian M, et al. In: Smyth J, Boogaerts M, Ehmer B. rhErythropoietin in Cancer Supportive
Treatment. New York, NY: Marcel Dekker Inc.;1996:13–34.
Anemia of Chronic Disease:
Traditional Model
Disease
Inflammatory
Factors
Anemia
Disease
Progression
Anemia of Chronic Disease:
Novel Model
Disease
Inflammatory
Factors
Anemia
Disease
Progression
Median survival times for anemic
and non-anemic patients
Lung
Anemic (months)
Ovarian
150
Head & neck
Prostate
125
Lymphoma
100
Leukaemia
Other
75
Multiple myeloma
Colorectal
50
Ampulla vater
25
Mesothelioma
Renal
0
0
25
50
75
100
125
150
Metastatic transitional
Cervix
Non-anemic (months)
Caro et al. Cancer 2001; 91: 2214-21
Possible Mechanisms of Decreased
Survival by Anemia
• Effects on the tumor
– Increased angiogenesis
– Decreased p53
– Resistance to apoptosis
• Effects on the treatment
– Radiation therapy - oxygen radicals
– Chemotherapy - oxygen radicals and resistance
mutations
• Efffects on the host
– Reduced tolerance of therapy
– Reduced QOL
– Reduced immune function
Relative Radiosensitivity Versus
Oxygen Tension
3.0
2.5
Venous End
Air
Arterial End
2.0
3 mm Hg
Or About
1/2%
Relative
Radiosensitivity 1.5
< 70µ
100%
Oxygen
70µ
1.0
Normoxic
Hypoxic Viable
Anoxic Cells
10
20
30
40
50
60
70
Oxygen Tension (mm Hg at 37°C)
Hall. Radiobiology for the Radiologist. 4th ed. 1994:133.
155
760
Oxygenation Of Tumorous And
Normal Cervical Tissue
Normal Cervix
Tumorous Cervix
50
40
40
30
30
Frequency
(%)
20
20
10
10
0
0
0
20
40
60
80
0
20
Oxygen Partial Pressure (mm Hg)
Kallinowski et al. Int J Radiat Oncol Biol Phys. 1990;19:953.
40
60
80
Oxygenation Associated With Disease-Free
Survival After Radiation: Cervical Cancer
1.0
Median pO2 5 mm Hg (N = 35)
0.8
0.6
Disease -Free
Survival
0.4
Median pO2 <5 mm Hg (N = 39)
0.2
P=.02
0.0
0.0
0.5
1.0
1.5
2.0
Ye ars From Diagnosis
Fyles et al. Radiother Oncol. 1998;48:149.
2.5
3.0
Hemoglobin Level Associated With Oxygenation
And Disease Control: Cervical Cancer
Hemoglobin (g/dL)
<13
13
P Value
Number of patients
33
19
—
Mean pO2 (mm Hg)
12.4 ± 10.7
28.1 ± 24.8
.003
56%
22%
.046
1-year treatment failure
Strauss et al. Int J Radiat Oncol Biol Phys. 1999;45(3S):364.
Importance Of Hemoglobin Level During
Radiotherapy For Cervical Cancer
1.0
L: Hb <120 g/L
0.9
H: Hb 120 g/L
0.8
B: LH
D: HH
0.7
0.6
Survival
(%)
A: LL
C: HL
0.5
0.4
0.3
P<.0002
0.2
0.1
0.0
0
1
2
3
Year
Grogan et al. Cancer. 1999;86:1528.
4
5
6
Tumor Oxygenation Associated With
Hemoglobin Level: Head And Neck Cancer
25
20
Median pO2
(mm Hg)
M edian = 15
15
10
P <.0001
M edian = 5
5
0
Hb <11.0 g/dL
(N = 20)
Becker et al. Int J Radiat Oncol Biol Phys. 2000;46:459.
Hb 11.0 g/dL
(N = 113)
Anemia Is Associated With Decreased Survival:
Head And Neck Cancer
Hb >13 g/dL
Median pO2 >10 mm Hg
16/38
Hb <13 g/dL
3/25
pO2 >10 mm Hg pO2 <10 mm Hg
P Value
.04
P Value
3-year locoregional control
73%
30%
.01
3-year disease-free survival
73%
26%
.005
3-year survival
83%
35%
.02
Brizel et al. Radiother Oncol. 1999;53:113.
Effect Of Chemoradiotherapy And rHuEPO On
Survival: Head And Neck Cancer
100
90
Hb 14.5 g/dL
80
Hb <14.5 g/dL + rHuEPO
70
60
Overall
Survival
(%)
Hb <14.5 g/dL No rHuEPO
50
40
Comparison Groups
30
P Value
Hb 14.5 g/dL vs Hb <14.5 g/dL No rHuEPO
Hb <14.5 g/dL No rHuEPO vs Hb <14.5 g/dL + rHuEPO
Hb 14.5 g/dL vs Hb <14.5 g/dL + rHuEPO
20
10
0
0
6
12
18
24
Months After Treatment
Glaser et al. Int J Radiat Oncol Biol Phys. 2001;50:705.
30
36
.04
.001
.7
For Many Chemotherapy Drugs, the Effects of
Hypoxia are as Profound as for Radiotherapy
Oxygen
enhancement ratio
Treatment
Alkylating agents
Antibiotics
Antimetabolite
X-rays
Cyclophosphamide
6.3
BCNU
3.2
Carboplatin
2.4
Melphalan
2.2
Adriamycin
2.2
Mitomycin C
0.3
5-Fluorouracil
2.3
2.8
Teicher et al. Cancer Res 1990; 50: 3339–44
Anemia and Chemotherapy:
Murine Fibrosacoma Model
Tumour volume (mL)
Non-anaemic control
(untreated)
2.5
*
Anaemic
2.0
1.5
Cyclophosphamide
60 mg/kg i.p.
1.0
Non-anaemic
*
**
0.5
Anaemic
+ rhEPO
*
0
0
3
6
* p<0.05, **p<0.01
Anemic versus non-anemic animals
9
12
15
18
21
Days
Adapted from Thews et al. Cancer Res 2001; 61: 1358–61
Anemia/Hypoxia Interacts with the
Heregulin/HER2 Pathway in VEGF Induction
Anemia
3 2
X
PI(3)K
PTEN
HIF-1a
mRNA
Hypoxia
Akt
Bad S6K
HIF-1b
protein
HIF-1a
protein
VHL
p53/MDM2
VEGF gene expression
Laughner E et al. Mol Cell Biol. 2001;21;3995-4004.
Ubiquitination
and degradation
Anemia and Survival in Geriatrics
100
Expected
Observed
Survival (%)
80
60
40
20
0
0
1
2
3
4
5
Time Period (yrs)
6
7
Observed and expected survival among Olmstead County, Minnesota,
618 residents (65 YOA) with anemia first recognized in 1986.
Source: Ania et al. J AM Ger Soc. 1997;45:825.
Higher Hct Associated
with Lower Mortality in ESRD Patients
1.4
1.33
All-cause death
Cardiac-related death
1.25
*Relative Risk (RR)
1.2
1.12
1.11
1.00
1
1.00
0.96
0.97
0.8
0.6
0.4
0.2
0
<27
27 to <30
Hct (%)
*After adjustment for medical diseases.
Source: Ma JZ et al. J Am Soc Nephrol. 1999;10:610–619.
30 to <33
33 to <36
N = 75,283
Survival %
Anemia, rHu-EPO and Survival in a Murine
Myeloma Model: Interaction of Anemia and
Host Defense
100
100
80
80
60
60
rhEPO
40
Normal + rhEPO
40
Anti-CD4mAb + rhEPO
20
20
control
0
Anti-CD8mAb + rhEPO
0
20
30
40
50
60
70
Days post tumor challenge
80
20
30
40
50
60
70
80
Days post tumor challenge
Mittelman et al. PNAS 2001; 98: 5181–6
QoL and survival of cancer
patients
Patients (%)
100
80
Global QoL score 60
60
40
Global QoL score <60
20
0
0.0
0.5
1.0
1.5
2.0
Years
2.5
3.0
3.5
4.0
Dancey et al. Qual Life Res 1997; 6: 151–8
The Old Responder’s Analysis
• Patients with advanced stages of selected hematologic malignancies
and solid tumors (N = 42); Hb <11 g/dL
• Criteria
– rHuEPO 150 IU/kg TIW in all patients; increased to
300 IU/kg at week 6 if no response
– response at least 2 g/dL from initial baseline level
• Response
– 77% multiple myeloma, 10% MDS, 44% breast,
40% colon
• Survival in nonresponders (9.2 months) significantly shorter than in
responders (28 months) (P<.005)
MDS = myelodysplastic syndrome.
Ludwig et al. Ann Oncol. 1993;4:161.
Randomized Placebo-Controlled QOL Trial
Littlewood, et. al. JCO 19:2865, 2001.
Randomized Placebo-Controlled QOL Trial
Littlewood, et. al. JCO 19:2865, 2001.
Randomized Placebo-Controlled QOL Trial
Littlewood, et. al. JCO 19:2865, 2001.
Effect Of Anemia Therapy On
Disease Progression: Lung Cancer
100
Cumulative
%
Median Time To Disease Progression
80
Placebo
60
Darbepoetin 34.0 Weeks
23.0 Weeks
40
20
0
Small-Cell Lung Cancer
1
6
11
16
21
26
31
36
41
46
51
58
61
66
Study Week
100
Median Time To Disease Progression
80
Cumulative
%
Placebo
60
19.0 Weeks
Darbepoetin 20.5 Weeks
40
20
0
Non-Small-Cell Lung Cancer
1
6
11
16
21
26
31
36
41
46
51
58
61
66
Study Week
Pirker et al. Presented at ASCO; May 12-15, 2001; San Francisco, CA.
NOTE: The median length of follow-up was approximately 1 year, with a minimum length of follow-up of approximately
6 months from study day 1.
Conclusions
• Anemia and tissue hypoxia may impact the
progression of chronic diseases, including
cancer.
• There are mechanistic models which suggest
that treatment for anemia may improve survival
outcomes in cancer treated with:
– Existing “targeted” therapies such as anti-HER2 and
anti-VEGF
– Radiotherapy
– Chemotherapy (including alkylators and antibiotics)
– Immunotherapy
– Observation
Conclusions
• Survival-focused clinical trials are ongoing in
several cancer settings.
• Issues in survival-focused clinical trials include:
–
–
–
–
The need for intermediate markers of success
The control group: what hgb is ethical/feasible?
The duration of intervention
The tension between a need for a rapid answer and
the most appropriate clinical setting
• Survival-focused non-radiotherapy studies
should incorporate what has been learned in
anti-angiogenesis studies