“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.

“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 6.5–7.9 6.5–7.9 6.5–7.9

4 <6.5 <6.5 <6.5 <6.5 <6.5 <6.5

Values are hemoglobin in g/dLWHO = 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

Cancer Cancer

37.539.5

43.9

40.0 41.1

25.9

39.5

16.3

8.4

14.1 14.0

4.98.3

12.4

0

5

10

15

20

25

30

35

40

45

50

Lung Cancer MetastaticBreast Cancer

AdvancedOvarian Cancer

Lymphomas AdvancedColorectal

Advanced Headand Neck

Total

Anemia Grade 1 or 2 Anemia Grade 3 or 4

Pat

ient

s (%

)

Source: Groopman JE, Itri LM. J Natl Cancer Inst. 1999;91:1616–1634.

Treatment n

Anemia

Grade 1–2 (%)

Anemia

Grade 3–4 (%)

Docetaxel 34

37

97

NR

0

14 (grade 3)

Paclitaxel 30 93 7 (grade 3)

Vinorelbine 59

143

67

71

14

5

Groopman. J Natl Cancer Inst. 1999;91:1616.

Incidence and Severity of Anemia in Previously Untreated Patients

With Breast Cancer

NR = not reported

Single-Agent Chemotherapy

Treatment nAnemia

Grade 1–2 (%)Anemia

Grade 3–4 (%)

• Cyclophosphamide +Doxorubicin +5-Fluorouracil +

Methotrexate

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 and Severity of Anemia in Previously Untreated Patients

With Breast Cancer Combination Chemotherapy

Lawless. Blood. 2000;96(11 suppl 2):(abstr 5447).

Incidence of Anemia in Patients With Breast Cancer

Cumulative Anemia in Patients With Breast Cancer Receiving AC

AC = doxorubicin + cyclophosphamideHb = Hemoglobulin

Cycle n

Hb 10 g/dL

Prechemotherapy

(% patients)

Hb 10 g/dL

Postchemotherapy

(% 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

Combination Chemotherapy

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

Glaspy Open-label Yes LASA(1997)

Demetri Open-label Yes LASA, FACT-An (1998)

Gabrilove Open-label Yes LASA, FACT-An (2001)

Littlewood Randomised, Yes LASA, FACT-An, (2001) placebo-controlled FACT-F, SF-36

Österborg Randomised, Yes FACT-G, FACT-F, (2002) placebo-controlled FACT-An

Boogaerts Randomised Yes FACT-G, FACT-F, (2002) FACT-An, SF-36

Pirker Randomised, Yes FACT-F(2002) Placebo-conrolled

QOL impactTrial typeStudy QOL tool(s)

30

35

40

45

50

55

60

65

70

7 8 9 10 11 12 13 14Hemoglobin Level (g/dL)

LA

SA S

core

(mm

)

CS-1

CS-2

Cross-Sectional Community Study 1and 2

30

35

40

45

50

55

60

65

70

7 8 9 10 11 12 13 14

Hemoglobin level (g/dL)

LA

SA

Sco

re

MalesFemales

Cross-Sectional Cut by GenderCommunity Study 2

Mean change in Hct vs

Mean change in Overall QoL

Standardized change in QoL

1.51.0.50.0-.5

Change in Hct

20

15

10

5

0

SETTING

Renal

Cancer

Cancer Patients are Human

Critical Issues for BCIRG - 2002Critical 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)

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

Shortenedsurvival

AIS

RBCs

ReducedEPO

production

Impairediron

utilization

SuppressedBFU-eCFU-e

TNFErythrophagocytosis

Dyserythropoiesis

IFN-IL-1TNF1-antitrypsin

IFN-IL-1TNF

IL-1 , TNF

Activatedimmune system

Macrophages

Tumor cells

Anemia of Chronic Anemia of Chronic Disease:Disease:

Traditional ModelTraditional ModelDiseaseDisease

AnemiaAnemia DiseaseDiseaseProgressionProgression

InflammatoryInflammatoryFactorsFactors

Anemia of Chronic Anemia of Chronic Disease:Disease:

Novel ModelNovel ModelDiseaseDisease

AnemiaAnemia

DiseaseDiseaseProgressionProgression

InflammatoryInflammatoryFactorsFactors

Median survival times for anemic and non-anemic patients

Caro et al. Cancer 2001; 91: 2214-21

0

25

50

75

100

125

150

0 25 50 75 100 125 150

Non-anemic (months)

Anemic (months) Lung

Ovarian

Head & neck

Prostate

Lymphoma

Leukaemia

Other

Multiple myeloma

Colorectal

Ampulla vater

Mesothelioma

Renal

Metastatic transitional

Cervix

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

RelativeRadiosensitivity

Oxygen Tension (mm Hg at 37°C)

10

1.0

1.5

2.0

2.5

3.0

20 30 40 50 60 70 155 760

Air 100% Oxygen

Relative Radiosensitivity Versus Oxygen Tension

Hall. Radiobiology for the Radiologist. 4th ed. 1994:133.

3 mm HgOr About1/2%

Venous End

Arterial End

70µ

< 70µ

Normoxic Hypoxic ViableAnoxic Cells

0

10

20

30

40

0 20 40 60 800

10

20

30

40

50

0 20 40 60 80

Frequency (%)

Oxygen Partial Pressure (mm Hg)

Tumorous CervixNormal Cervix

Kallinowski et al. Int J Radiat Oncol Biol Phys. 1990;19:953.

Oxygenation Of Tumorous And Normal Cervical Tissue

0.0

0.2

0.4

0.6

0.8

1.0

0.0 0.5 1.0 1.5 2.0 2.5 3.0

Years From Diagnosis

Disease-Free Survival

P=.02

Median pO2 5 mm Hg (N = 35)

Median pO2 <5 mm Hg (N = 39)

Oxygenation Associated With Disease-Free Survival After Radiation: Cervical Cancer

Fyles et al. Radiother Oncol. 1998;48:149.

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

1-year treatment failure 56% 22% .046

Strauss et al. Int J Radiat Oncol Biol Phys. 1999;45(3S):364.

Importance Of Hemoglobin Level During Radiotherapy For Cervical Cancer

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 1 2 3 4 5 6

Survival(%)

YearGrogan et al. Cancer. 1999;86:1528.

B: LHD: HH

A: LLC: HL

L: Hb <120 g/L

H: Hb 120 g/L

P<.0002

Median = 15

Median = 5

0

5

10

15

20

25

Median pO2 (mm Hg) P <.0001

Tumor Oxygenation Associated With Hemoglobin Level: Head And Neck Cancer

Hb <11.0 g/dL(N = 20)

Hb 11.0 g/dL (N = 113)

Becker et al. Int J Radiat Oncol Biol Phys. 2000;46:459.

Anemia Is Associated With Decreased Survival: Head And Neck Cancer

Hb >13 g/dL Hb <13 g/dL P Value

Median pO2 >10 mm Hg 16/38 3/25 .04

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.

pO2 >10 mm Hg pO2 <10 mm Hg P Value

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 30 36

Months After Treatment

OverallSurvival

(%)

Hb 14.5 g/dL

Hb <14.5 g/dL + rHuEPO

Hb <14.5 g/dL No rHuEPO

Hb 14.5 g/dL vs Hb <14.5 g/dL No rHuEPO .04

Hb <14.5 g/dL No rHuEPO vs Hb <14.5 g/dL + rHuEPO .001

Hb 14.5 g/dL vs Hb <14.5 g/dL + rHuEPO .7

Effect Of Chemoradiotherapy And rHuEPO On Survival: Head And Neck Cancer

Glaser et al. Int J Radiat Oncol Biol Phys. 2001;50:705.

Comparison Groups P Value

For Many Chemotherapy Drugs, the Effects of Hypoxia are as Profound as for Radiotherapy

TreatmentOxygen

enhancement ratio

Teicher et al. Cancer Res 1990; 50: 3339–44

Cyclophosphamide

BCNU

Carboplatin

Melphalan

Antibiotics

Alkylating agents

Adriamycin

Mitomycin C

Antimetabolite 5-Fluorouracil

X-rays

6.3

3.2

2.4

2.2

2.2

0.3

2.3

2.8

2.5

00

* p<0.05, **p<0.01 Anemic versus non-anemic animals Adapted from Thews et al. Cancer Res 2001; 61: 1358–61

Tumour volume (mL)

2.0

1.5

1.0

0.5

211512963

Days

Cyclo-phosphamide60 mg/kg i.p.

Non-anaemic

Anaemic

Non-anaemic control(untreated)

Anaemic+ rhEPO

*

**

*

Anemia and Chemotherapy: Murine Fibrosacoma Model

18

*

Anemia/Hypoxia Interacts with the Anemia/Hypoxia Interacts with the Heregulin/HER2 Pathway in VEGF InductionHeregulin/HER2 Pathway in VEGF Induction

Laughner E et al. Mol Cell Biol. 2001;21;3995-4004.

Hypoxia

Ubiquitinationand degradation

VEGF gene expression

VHLp53/MDM2

3 2

X

AktS6KBad

PI(3)K

HIF-1protein

HIF-1mRNA

PTEN

HIF-1protein

Anemia

Source: Ania et al. J AM Ger Soc. 1997;45:825.

0

0

Sur

viva

l (%

)

Expected

Observed

Time Period (yrs)

100

80

60

40

20

1 2 3 4 5 76

Observed and expected survival among Olmstead County, Minnesota,618 residents (65 YOA) with anemia first recognized in 1986.

Anemia and Survival in Geriatrics

Higher Hct Associated with Lower Mortality in ESRD Patients

1.33

1.12

1.00 0.96

1.25

1.11

1.00 0.97

0

0.2

0.4

0.6

0.8

1

1.2

1.4

<27 27 to <30 30 to <33 33 to <36

Hct (%)

*Rel

ativ

e R

isk

(RR

)

All-cause deathCardiac-related death

N = 75,283 *After adjustment for medical diseases.Source: Ma JZ et al. J Am Soc Nephrol. 1999;10:610–619.

Anemia, rHu-EPO and Survival in a Murine Myeloma Model: Interaction of Anemia and Host Defense

20 30 40 50 60 70 80

Su

rviv

al %

control

rhEPO

100

80

60

40

20

0

Days post tumor challenge

Anti-CD8mAb + rhEPO

Normal + rhEPO

Mittelman et al. PNAS 2001; 98: 5181–6

Anti-CD4mAb + rhEPO

100

80

60

40

20

0

20 30 40 50 60 70 80

Days post tumor challenge

Years

Dancey et al. Qual Life Res 1997; 6: 151–8

0

20

40

60

80

100

0.0 0.5 1.5 2.0 2.5 3.0 3.5 4.0

Global QoL score <60

1.0

Patients (%)

Global QoL score 60

QoL and survival of cancer patients

MDS = myelodysplastic syndrome.Ludwig et al. Ann Oncol. 1993;4:161.

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)

Littlewood, et. al. JCO 19:2865, 2001.

Randomized Placebo-Controlled QOL TrialRandomized Placebo-Controlled QOL Trial

Littlewood, et. al. JCO 19:2865, 2001.

Randomized Placebo-Controlled QOL TrialRandomized Placebo-Controlled QOL Trial

Littlewood, et. al. JCO 19:2865, 2001.

Randomized Placebo-Controlled QOL TrialRandomized Placebo-Controlled QOL Trial

Effect Of Anemia Therapy OnDisease Progression: Lung Cancer

Cumulative%

Cumulative%

100

80

60

40

20

0

1 6 11 16 21 26 31 36 41 46 51 58 61 66

100

80

60

40

20

0

1 6 11 16 21 26 31 36 41 46 51 58 61 66

Study Week

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 approximately6 months from study day 1.

Small-Cell Lung Cancer

Non-Small-Cell Lung Cancer

Placebo 23.0 Weeks

Darbepoetin 34.0 Weeks

Median Time To Disease Progression

Placebo 19.0 Weeks

Darbepoetin 20.5 Weeks

Median Time To Disease Progression

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