Case Studies: Strategies for Managing Anemia and Neutropenia in Patients With Breast Cancer

Julie A. Ponto, RN, MS, APRN-BC, AOCN®

Oncology Clinical Nurse Specialist

Rochester, Minnesota

Review of Anemia and Neutropenia in Patients With Cancer

The first section will review anemia guidelines for patients with cancer

Since there are no published guidelines for neutropenia management in patients with cancer, data supporting neutropenia recommendations will be discussed

Summary of Current Anemia Guidelines for Patients With Cancer

NCCN

Organization/Workup Cessation of Treatment

Therapy Continuation Treatment Initiation

• Hb <11.0 g/dL (if <10.0 g/dL, strongly consider)

• Epoetin alfa (150 U/kg TIW or, off-label, 40K U QW) or darbepoetin alfa (2.25 mcg/kg QW on-label or 200 mcg Q2W, off-label)

• Assess after 4 or6 weeks

• Titrate dosage to maintain optimal Hb level (11.0-12.0 g/dL)

• Periodic monitoring of iron status

• Adult patients with cancer- or treatment- related anemia

• Assessment of iron status recommended

ASH/ASCO• Hb 10.0 g/dL (clinical

decision if <12.0 g/dL and >10.0 g/dL)

• Epoetin alfa 150 U/kg TIW for minimum of 4 weeks (40K U QW used off-label)

• Double dose after a minimum of 4 weeks if response is inadequate

• Titrate when Hb reaches 12.0 g/dL; maintain level

• Periodic monitoring of iron status

• Adult patients with CIA and MDS

• No recommendations regarding AoC

• Assessment of iron status recommended

• Continuing Epoetin alfa treatment beyond 6 to 8 weeks without response not beneficial

• Insufficient evidence to support “normalization” of Hb (>12.0 g/dL)

• Discontinue therapy if no response after dose escalation

• Erythropoietic agents are not recommended at Hb >12.0 g/dL

CIA = chemotherapy-induced anemia; MDS = myelodysplasia; AoC = anemia of cancer; Hb = hemoglobin.

Adapted from: NCCN. Clinical Practice Guidelines in Oncology: Cancer and Treatment-Related Anemia. V.2.2004. Available at: www.nccn.org; Rizzo JD et al. Blood. 2002;100:2303-2320.

First-Cycle ANC Nadir: A Predictor of Events in Subsequent Cycles

*1.0 x 109/L is a commonly used ANC benchmark for therapy. ANC = absolute neutrophil count. Silber JH et al. J Clin Oncol. 1998;16:2392-2400.

P = .0003

Cycle

100

80

60

40

20

0

1 2 3 4 5 6

Eve

nt-

Fre

e P

rob

abil

ity

(%)

Group with first-cycle ANC 1.0 x 109/L (n = 49)

Group with first-cycle ANC 1.0 x 109/L* (n = 46)

First-Cycle ANC Nadir: Validating Its Ability to Predict Neutropenia Risk

Silber JH et al. J Clin Oncol. 1998;16:2392-2400; Thomas ES et al. Proc Am Soc Clin Oncol. 2001;20:37a. Abstract 144.

Thomas et al Silber et al

Est

imat

ed R

elat

ive

Ris

k

4.2 4.4

0

2

4

6

8

10

First-Cycle ANC Nadir: Applying a Risk Model in Daily Practice Prospective evaluation of a neutropenia risk model High risk defined as first-cycle ANC nadir 0.5

109/L 528 patients with stage I through III breast cancer

treated with AC, CMF, and CAF Patients identified as being at high risk given

G-CSF in all subsequent cycles Outcomes, including neutropenia-related

hospitalizations and chemotherapy dose modifications, were compared with those in a recent survey (historical control and matched-case control)AC = doxorubicin/cyclophosphamide; CMF = cyclophosphamide/methotrexate/

5-fluorouracil; CAF = cyclophosphamide/doxorubicin/5-fluorouracil; G-CSF = granulocyte colony-stimulating factor. Rivera E et al. SABCS 2001; San Antonio, Tex. Abstract 3.

First-Cycle ANC Nadir: A Practical Tool for Focusing Proactive Measures and Improving Chemotherapy Delivery

Managed with first-cycle ANC nadir risk modelManaged without risk model

Rivera E et al. SABCS 2001; San Antonio, Tex. Abstract 3.

Hospitalization forFebrile Neutropenia

85% Chemotherapy Planned Dose on Time

Pat

ien

ts (

%)

2.74.7

7.1

20.1

0

5

10

15

20

25

Summary of Management Strategies

The anemia treatment guidelines and treatment based on first-cycle ANC nadir can be used to manage anemia and neutropenia in patients with breast cancer

In the next section, 3 case studies will be reviewed; these cases illustrate how anemia guidelines and first-cycle ANC nadir can be utilized to manage anemia and neutropenia in patients with breast cancer

Case Study 1Patient With Node-Positive

Breast Cancer

Patient History and Cancer Management Patient history

45-year-old woman Lump in right breast detected on routine self-examination No other comorbid conditions Leads an active lifestyle, including playing tennis 2 to 3 times a week

Cancer diagnosis Biopsy resulted in a diagnosis of a stage III infiltrating ductal carcinoma

Cancer management Surgery and results

Breast-conserving lumpectomy with axillary lymph node dissection performed

2.1-cm tumor mass with 2 of 10 positive lymph nodes Tumor was ER- and PR-negative as well as negative for HER2

using FISH Postoperative ECOG status of 0

ER = estrogen receptor; PR = progesterone receptor; HER2 = human epidermal growth factor receptor 2; FISH = fluorescence in situ hybridization; ECOG = Eastern Cooperative Oncology Group.

Cancer and Neutropenia Management

Patient was started on adjuvant chemotherapy Doxorubicin 60 mg/m2 IV day 1 +

cyclophosphamide 600 mg/m2 IV day 1 (repeat cycle every 21 days for 4 cycles)

Paclitaxel 175 mg/m2 IV over 3 hours (repeat cycle every 21 days for 4 cycles)

Prophylactic Filgrastim (5 mcg/kg/day) given on days 3 through 10 of each cycle in both phases

Filgrastim [package insert]. 2002.

Follow-up and Laboratory Results Baseline (pre-chemotherapy)

Hb: 13.1 g/dL Hct: 39% WBC count: 4.2 x 109/L ANC: 2.1 x 109/L Iron and vitamin B12

replete No evidence of occult

blood loss

Post cycle 1 of chemotherapyHb: 11.8 g/dLHct: 35%WBC count: 4.0 x 109/L ANC: 1.9 x 109/L Iron and vitamin B12

repleteNo evidence of occult

blood lossPatient is asymptomatic

Hb = hemoglobin; Hct = hematocrit; WBC = white blood cell.

Follow-up 2 and Laboratory Results

Post cycle 2 of chemotherapy Hb: 9.9 g/dL Hct: 30% WBC count: 3.5 x 109/L ANC: 1.5 x 109/L Iron and vitamin B12 replete

No evidence of occult blood loss Symptoms: Patient complains of reduced energy

and difficulty in performing her daily activities

Follow-up 2: Evaluation of Laboratory Results

Change from baseline to post cycle 2 Hb: 3.2 g/dL Hct: 9% WBC: 0.7 x 109/L ANC: 0.6 x 109/L

What steps would you take next?

Follow-up 2: Recommended Treatment

Anemia Patient’s Hb level is dropping with each

chemotherapy cycle and is now below the level where erythropoietic agents are recommended by both the NCCN and ASH/ASCO guidelines

Patient is not iron or vitamin B12 deficient and has no blood loss

Patient is symptomatic Recommendation: Initiate erythropoietic agent

(either darbepoetin alfa or Epoetin alfa)NCCN = National Comprehensive Cancer Network; ASH = American Society of Hematology; ASCO = American Society of Clinical Oncology.NCCN. Clinical Practice Guidelines in Oncology: Cancer and Treatment-Related Anemia. V.2.2004. Available at: www.nccn.org; Rizzo JD et al. Blood. 2002;100:2303-2320.

Follow-up 2: Recommended Treatment (cont’d) Neutropenia

WBC and ANC are decreasing with each cycle of chemotherapy

ANC has not dropped to 1.0 to 0.5 x 109/L, the range indicating elevated risk for neutropenic events

Patient is already receiving Filgrastim Optional: Could increase dose of Filgrastim

since WBC and ANC levels are low and will likely continue to drop with additional rounds of chemotherapy

Filgrastim [package insert]. 2002; Rivera E et al. SABCS 2001; San Antonio, Tex. Abstract 3.

Follow-up 2: Recommended Treatment (cont’d) Re-evaluate patient after next cycle

Request Hb, WBC, and ANC levels Assess symptoms

Educate patient regarding anemia and neutropenia Discuss behavioral changes patient can make to

reduce fatigue and avoid infection Make a list prioritizing daily activities; do the

important items first; skip low-priority items Ask for help from family and friends (eg, with

laundry or meals) Exercise each day; try walking or gardening Nap or rest when tired Make time to do something enjoyable

Case Study 2

Patient With Node-Negative

Breast Cancer

History and Cancer Management Patient history

60-year-old grandmother Lump in right breast detected on routine self-examination No other comorbid condition Has an active lifestyle that includes taking care of young

grandchildren on weekdays Cancer diagnosis

Biopsy resulted in diagnosis of a stage II infiltrating ductal carcinoma

Cancer management Surgery

Breast-conserving lumpectomy with axillary lymph node dissection performed

1.5-cm tumor mass with 0 positive lymph nodes Tumor was ER- and PR-negative and negative for HER2

using FISH Postoperative ECOG status of 0

Cancer Management: Adjuvant Chemotherapy

Patient was started on adjuvant chemotherapy Doxorubicin 60 mg/m2 IV day 1 +

cyclophosphamide 600 mg/m2 IV day 1 (repeat cycle every 21 days)

Laboratory Evaluation Baseline pre-chemotherapy

Hb: 13.0 g/dL Hct: 39% WBC count: 4.2 x 109/L ANC: 2.1 x 109/L Iron and vitamin B12

replete No evidence of occult

blood loss

Post cycle 1 of chemotherapy Hb: 11.5 g/dL Hct: 34% WBC count: 2.8 x 109/L ANC nadir: 0.5 x 109/L

ANC prior to cycle 2 0.9 x 109/L

Iron and vitamin B12 replete No evidence of occult

blood loss Patient does not report any

symptoms

Follow-up: Evaluation of Laboratory Results

Changes in laboratory values (baseline to post cycle 1) Hb: 1.5 g/dL Hct: 5% WBC: 1.4 x 109/L ANC: 1.6 x 109/L (pre-cycle to nadir)

What steps would you recommend next?

Follow-up: Recommended Treatment ANC nadir reached 0.5 x 109/L during the first chemotherapy

cycleData suggest patients who reach this nadir at first cycle

are at high risk for neutropenia-associated events Clinical decisions

Delay chemotherapy 1 week Initiate pegfilgrastim (which has a longer half-life than

Filgrastim, allowing for less frequent dosing)Monitor symptoms for neutropenia-associated events,

ANC, and WBC at each cycleMonitor Hb levels, which have declined slightlyEducate patient about neutropenia-associated events

and anemia

Filgrastim [package insert]. 2002; Pegfilgrastim [package insert]. 2002; Rivera E et al. SABCS 2001; San Antonio, Tex. Abstract 3.

Follow-up 2: Laboratory Evaluation

Post cycle 2 of chemotherapy Hb: 9.8 g/dL Hct: 28% WBC count: 3.5 x 109/L ANC: 1.6 x 109/L Iron and vitamin B12 replete

No evidence of occult blood loss Patient complains of reduced energy and

difficulty in performing her daily activities

Follow-up 2: Recommended Treatment Anemia: clinical status

Patient’s Hb level has declined to <10.0 g/dL, the level at which treatment for anemia is recommended both by the NCCN and ASH/ASCO guidelines

Patient is symptomatic Recommendation: Initiate darbepoetin alfa*

Neutropenia: clinical status Patient’s ANC and WBC counts have risen above post cycle 2

values Continue pegfilgrastim

Monitor patient following each cycle Symptoms Hb, WBC, and ANC levels

*Epoetin alfa is also a treatment option.Darbepoetin alfa [package insert]. 2002; NCCN. Clinical Practice Guidelines in Oncology: Cancer and Treatment-Related Anemia. V.2.2004. Available at: www.nccn.org; Rizzo JD et al. Blood. 2002;100:2303-2320.

Case Study 3Patient With Anemia of Cancer

Patient History and Clinical Characteristics Patient history

Patient is 65 years old and a retired school teacher heavily involved in community activities

She does not exercise often Cancer diagnosis

Diagnosed with breast cancer (stage III right infiltrating ductal carcinoma) with the following tumor characteristics at primary diagnosis: Tumor size 4 cm 4 positive lymph nodes HER2 negative using FISH; ER- and PR-negative Chest and abdominal CT scans and bone scans

revealed no evidence of metastasisCT = computed tomography.

Cancer and Anemia Management

Surgery: Right modified radical mastectomy Adjuvant chemotherapy: AC followed by T

for 4 cycles Anemia management: Patient received darbepoetin

alfa 200 mcg Q2W during chemotherapy; drug discontinued 4 weeks after completion of chemotherapy

AC = doxorubicin/cyclophosphamide; T = paclitaxel.

Darbepoetin alfa [package insert]. 2002.

Follow-up

Current treatment regimen: The patient has been off chemotherapy for 12 weeks

On a routine clinic visit, the patient complains of persistent lack of energy and a reduced capacity to perform daily activities

She wants to resume her social activities but, due to fatigue, cannot participate in these activities

What is your next step?

Follow-up: Laboratory Results Based on the patient’s symptoms and her provider’s

knowledge of her prior cancer management, the following tests were requested and results obtained: Hb: 10.2 g/dL Hct: 30% WBC count: 4.4 x 109/L ANC: 2.2 x 109/L Serum iron: 65 mcg/dL and TSAT of 30%

Iron and vitamin B12 replete No evidence of occult blood loss

What steps would you take next?

TSAT = transferrin saturation.

Follow-up: Treatment Recommendations

Anemia The patient’s Hb is at the level where erythropoietic

agents should be considered She is symptomatic and not able to perform

activities of daily living Neither Epoetin alfa nor darbepoetin alfa are

currently indicated for anemia of cancer; however, both have been found to be safe and effective in this patient group in clinical studies

Recommendation: Prescribe an erythropoietic agentAbels RI. Acta Haematol. 1992;87(suppl 1):4-11; Charu V et al. ASCO 2004; New Orleans, Louisiana; Darbepoetin alfa [package insert]. 2002; Epoetin alfa [package insert]. 1997, 2000; Quirt I et al, and the Canadian Eprex Oncology Group. J Clin Oncol. 2001;19:4126-4134; Smith R et al, and the Darbepoetin alfa 99011 Study Group. ASCO 2002; Washington, DC.

Follow-up: Treatment Recommendations (cont’d)

Neutropenia The patient’s WBC and ANC are not

low enough to indicate need for treatment Recommendation: Monitor levels

Overall recommendations Monitor Hb, WBC, and ANC levels Educate patient regarding anemia Suggest behavioral changes that could

reduce fatigue

Conclusions Anemia

Erythropoietic agents (darbepoetin alfa and Epoetin alfa) are effective and safe in patients with chemotherapy-associated anemia and anemia of cancer

Clinical guidelines recommend treatment when Hb levels are <10.0 g/dL. Levels between 10.0 g/dL and 12.0 g/dL can be treated at the physician’s discretion

Dosing regimens for darbepoetin alfa and Epoetin alfa differ due to the longer half-life of darbepoetin alfa

Epoetin alfa [package insert]. 1997, 2000; Darbepoetin alfa [package insert]. 2002.

Conclusions (cont’d)

Neutropenia When given early during chemotherapy,

granulocyte colony-stimulating factors (Filgrastim and pegfilgrastim) appear to reduce the probability of neutropenia-related events by maintaining WBC levels

Clinical evidence suggests benefit in treatment at a first-cycle ANC nadir ranging from 1.0 x 109/L to 0.5 x 109/L

Filgrastim [package insert]. 2002; Pegfilgrastim [package insert]. 2002; Rivera E et al. SABCS 2001; San Antonio, Tex. Abstract 3.