La Neutropenia Marco Danova Oncologia Medica Universita e IRCCS San Matteo Pavia.

La Neutropenia

Marco Danova

Oncologia MedicaUniversita e IRCCS San Matteo

Pavia

Grading of Chemotherapy-Induced Neutropenia

LLN** Grade 1

1.5Grade 2

1.0Grade 3

Mild Moderate SevereSevere/life-threatening

0.5Grade 4

*Absolute neutrophil count; **Lower limit of normal

ANC* x 109/L

Common Toxicity Criteria for Adverse Effects Version 3.0 [electronic document]. Bethesda, Md: National Cancer Institute; 1999Available at: http://ctep.info.nih.gov/reporting/ctc.html. Accessed January 4 2005

Neutropenia A Devastating Side Effect of

Chemotherapy

Boxer L, et al. Semin Hematol 2002;39:75-81. Crawford J, et al. Cancer. 2004;100:228-237

• Neutropenia = Deficiency of neutrophils

• A common side effect in patients receiving chemotherapy treatment

• Predisposes to life-threatening infections

• Neutropenic complications after myelosuppressive chemotherapy can lead to

– Morbidity

– Mortality

High-dosechemotherapy

Neutropenia

FebrileNeutropenia

Risk Factors for Neutropenia

*Non-Hodgkin's lymphoma; **Breast cancer Silber JH, et al. J Clin Oncol 1998;16:2392-400Scott S, Am. J Health Syst Pharm 2002; 59 (15 suppl 4):S16-S19Ozer H, et al. J. Clin. Oncol. 2000;18:3558-3585Crivellari D, et al. J Clin Oncol 2000;18:1412-1422

• Advanced age > 65 years

• Advanced cancer

• Performance status (ECOG II-IV)

• Bone marrow involvement

• Infection, open wounds

• Renal disease* Above normal LDH* Serum albumin > 3.5 g/dL*

Independent and disease-related risk factors

Prior therapy-related risk factors

• Low cycle 1 nadir ANC**

• History of recurrent chemotherapy-induced neutropenia

• Pre-existing neutropenia due to:- Extensive myelosuppressive therapy - Radiation therapy to pelvis or other large regions of bone marrow

Why Guidelines?

• To assist clinicians in evidence-based treatment decisions

• To ensure optimal resource allocation

• To standardise high quality of care

• Guidelines are created and updated when – Issues of significant clinical or economic importance

arise

– There are variations in treatment/access to care

– There are new data

– There are ethical considerations

Why Guidelines to Prevent Neutropenia?

• Neutropenia is a common side effect in patients receiving chemotherapy treatment and predisposes patients to life-threatening infections

• Neutropenic complications after myelosuppressive chemotherapy can lead to morbidity and mortality

• Neutropenic events often result in dose-reductions or treatment delays and therefore may compromise clinical outcome

‘Neutropenia is the major dose-limiting toxicity of conventional chemotherapy’

Crawford J, et al. Cancer 2004;100:228-237Johnston EM and Crawford J. Semin Oncol 1998;25:552-561

What are the Potential Short- and Long-Term Consequences of

neutropenia?

Short-term impact1 Long-term impact2

InfectionsCT dose

delay/reduction

HospitalisationReduced efficacy

of treatment3

1Kuderer NM, et al. Proc Am Soc Clin Oncol 2004;22: Abstract 60492Leonard RCF, et al. Br J Cancer 2003;89:2062-20683Bonadonna G, et al. N Engl J Med 1995;332:901-906

G-CSF Decreases the Depth and Duration of Neutropenia

Median ANC during cycle 1,CAE chemotherapy in small-cell lung cancer

Study day

0.01

0.1

0.51.0

10.0

100.0

0 4 8 12 16 20 24

Start G-CSF/placebo Placebo (n = 110)G-CSF (n = 101)

Severe neutropenia (ANC 500)

ANC ( 109/L)

Crawford J, et al. N Engl J Med 1991;325:164-170

A History of Growth Factor Guidelines: ASCO 1994-2000

• CSFs are recommended as primary preventive care for patients:– At > 40% risk of FN– At high risk of CT-induced infectious complications

• Intervention for subsequent cycles:– Physicians should consider dose reduction as a primary therapeutic

option• List of FN risk factors:

– Pre-existing neutropenia due to disease– Extensive prior chemotherapy– Previous radiation to the pelvis or other areas with large amounts of

bone-marrow– A history of recurrent FN while receiving earlier chemotherapy of similar

or lesser dose intensity– Conditions potentially enhancing the risk of serious infection

(e.g. poor performance status, more advanced cancer, decreased immune function, open wounds, already-active tissue infections)

American Society of Clinical Oncology. J Clin Oncol 1994;12:2471-2508Ozer H, et al. J Clin Oncol 2000;18:3558-3585

Implementation of CSF Guidelines can reduce the impact of neutropenia

19

10

52

60

4

28

00

10

20

30

40

50

60

< 85% Full doseon time

Dose reduction Dose delay Hospitalisationfor FN

Patients

(%)

Before guideline implementation After guideline implementation

Data from the West Michigan Cancer CentreWhite N et al. Cancer Nurs 2005;28:62-69

G-CSF Therapy at > 20% FN Risk Provides Clinical Benefits

• Recent publications have demonstrated efficacy of G-CSF for patients at a moderate risk of FN

• Use of G-CSF significantly reduced the incidence of

– FN1,2

– FN-related hospitalisation2

– use of IV anti-infectives2

1Timmer-Bonte J, et al. Proc Am Soc Clin Oncol 2004;22:726. Abstract 80022Vogel CL, et al. J Clin Oncol 2005;23:1178-1184

Patient-Related FN Risk Factors

• Advanced age

• Female gender

• Poor nutrition

• Low PS

• Low pre-treatment blood count

• Low lymphocyte count

• Low haemoglobin

• High LDH

• Bone marrow involvement

• Patient comorbidities

– Chronic lung disease

– Diabetes

Komrokji RS and Lyman GH. Expert Opin Biol Ther 2004;4:1897-1910

NCCN 2005 Guidelines

• The NCCN guidelines take into account new data that was not available to ASCO in 2000

• NCCN 2005 G-CSF guidelines focus on risk assessment of chemotherapy regimen and patients

• Taking new data into account, NCCN recommend routine use of G-CSF for patients at > 20% risk of FN

NCCN Clinical Practice Guidelines in Oncology: Myeloid Growth Factors in Cancer Treatment. Available at http://www.nccn.org. Accessed July 2005.

Comparison of NCCN 2005 & ASCO 2000 Guidelines for G-CSF

NCCN 2005 ASCO 2000

Recommend first cycle G-CSF use

Consider G-CSF

risk of FN > 20%

10–20% FN risk

risk of FN > 40%

-

Patient risk factors Extensive list Limited list

Recommendations for dose-dense regimens

Include dose in risk assessment CSF not justified to increase dose intensity

Intervention for subsequent cycles

Review FN risk and use of G-CSF at each cycle. Provide

G-CSF support if there has been a dose-limiting neutropenic event or

episode of FN in the previous cycle and the same schedule is

planned for the next cycle

In the setting of many tumours exclusive of curable tumours

(e.g. germ cell tumours), dose reduction after an episode of severe neutropenia should be

considered as a primary therapeutic option

Recommended products Category 1 evidence for filgrastim and pegfilgrastim*

None

*Filgrastim (daily dose 5 mcg/kg s.c. administered from 1-3 days after chemotherapy until neutrophils reach normal level)Pegfilgrastim (single dose per chemotherapy cycle starting 24 hr after initiation of chemotherapy)

Implementing New Guidelines in Clinical Practice

Case-Study Examples

Algorithm for Primary Preventive Growth Factor Support

Disease

Intermediate

10 – 20% FN Risk

Consider

G-CSF

Use G-CSF

No G-CSF

1. Patient 2. Risk 3. Protect

Chemotherapy Regimen

Patient Risk Factors

Treatment Intent

High

> 20% FN Risk

Low

< 10% FN Risk

Adapted from: Lyman GH. JNCCN 2005;3:557-571

Case 1

• 37-year-old female with relapsed high grade NHL

• First-line treatment was R-CHOP 21

• Did not experience neutropenic complications with first-line chemotherapy

• Now receives ESHAP second-line chemotherapy

• Average risk of FN for relapsed patients with this treatment is over 30%1-3

Q: Is G-CSF support appropriate for primary preventive care in this case?

1Velasquez WS, et al. J Clin Oncol 1994;12:1169-11762Johnson PW, et al. Ann Oncol 1993;4:63-673Ozturk MA, et al. Chemotherapy 2002;48:252-258

Case 1: Additional Patient Notes

Age - 37

Histology - High; diffuse large B-cell lymphoma

Stage - IIA

No. extranodal sites - 0

ECOG PS - 1

LDH - Normal

IPI- 0

No other co-morbidities

Case 1: Algorithm for Primary Preventive Growth Factor Support

Disease

Intermediate

10–20% FN Risk

Consider

G-CSF

Use G-CSF

No G-CSF




Treatment Intent

High

> 20%FN Risk

Low

< 10% FN Risk

ESHAP = 30%

Female gender Prior chemotherapy

Lymphoma

Curative


Examples of NHL Regimens with High (> 20%) FN Risk

– ESHAP1

– DHAP2

– VAPEC-B3

– A(N)CVB4

• Note that these regimens carry a > 20% risk of FN, independent of other risk factors1Velasquez WS, et al. J Clin Oncol 1994;12:1169-11762Velasquez WS, et al. Blood 1988;71:117-1223Pettengell R, et al. Blood 1992;80:1430-14364Gisselbrecht C, et al. Leuk Lymphoma 1997;25:289-300

Case 2

• 50-year-old male

• Newly diagnosed with small cell lung cancer (SCLC)

• Naive to chemotherapy

• Prescribed etoposide and carboplatin (EP) chemotherapy and concomitant radiotherapy

• The treatment carries an average FN risk of 10% to 20%1


1NCCN Clinical Practice Guidelines in Oncology: Myeloid Growth Factors in Cancer Treatment. Accessed from the following website 07/2005:http://www.nccn.org/professionals/physician_gls/PDF/myeloid_growth.pdf


Age - 50

Gender - male

Histology - small cell lung cancer

Stage – limited stage

ECOG PS - 2

Comments – overweight, coronary artery disease


Disease

Intermediate

10–20% FN Risk

Consider

G-CSF

Use G-CSF

No G-CSF




Treatment Intent

High

> 20% FN Risk

Low

< 10% FN Risk

EP

ECOG = 2CAD

obese

SCLC (limited stage)

Palliative

?


Examples of SCLC Regimens

• High (> 20%) FN risk:

– CAE1-3

– Topotecan1,4

– Topotecan/paclitaxel1

• Intermediate (10 – 20%) FN risk:

– Etoposide/carboplatin1

– Topotecan/cisplatin1,5

1NCCN Clinical Practice Guidelines in Oncology: Myeloid Growth Factors in Cancer Treatment. Accessed from the following website 07/2005:http://www.nccn.org/professionals/physician_gls/PDF/myeloid_growth.pdf2Crawford J, et al. Ann Oncol 1997;8:1117-11243Crawford J, et al. N Engl J Med 1991;325:164-1704Von Pawel J, et al. J Clin Oncol 1999;17:658-6675Ardizzoni A, et al. Clin Cancer Res 2003;9:143-150

Case 3

• 55-year-old male

• Presents with localised lymphadenopathy

• Diagnosed with NHL

• Receives R-CHOP 21 chemotherapy

• The average FN risk with this regimen is approximately 20%1


1Calculated from data in Lyman GH and Delgado DJ. Cancer 2003;98:2402-2409


Age - 55

Gender - male

Histology - Intermediate; follicular, predominantly large cell

Stage - I

No. extranodal sites - 0

ECOG PS - 1

LDH - Elevated

IPI- 1

Comments - no major co-morbidities, chemotherapy naïve


Disease




Treatment Intent

R-CHOP 21

Planned RDI > 80%Anthracycline chemotherapy

Low grade NHLElevated LDH

Curative

Intermediate

10–20% FN Risk

Consider

G-CSF

Use G-CSF

No G-CSF

High

> 20% FN Risk

Low

< 10% FN Risk

?


Examples of NHL Regimens with Intermediate (10 - 20%) FN risk

– R-CHOP1,2

– Fludarabine/mitoxantrone1,3

– ACOD1,4

• Note that these regimens carry an FN risk of 10-20%, independent of other risk factors

1NCCN Clinical Practice Guidelines in Oncology: Myeloid Growth Factors in Cancer Treatment. Accessed from the following website 07/2005:http://www.nccn.org/professionals/physician_gls/PDF/myeloid_growth.pdf2Lyman GH and Delgado DJ. Cancer 2003;98:2402-24093Dimopoulos MA, et al. Leuk Lymphoma 2002;43:111-1144Martinelli G, et al. Leuk Lymphoma 2003;44:801-806

Case 3: Continued

• This patient did not receive G-CSF primary prophylaxis and experienced FN during cycle 1, starting day 10

• This patient required hospitalisation and i.v. antibiotics

• This patient has now recovered and has returned for his second cycle of chemotherapy

Q: Is G-CSF support appropriate for intervention for subsequent cycles in this case?

Case 4

• 32-year-old female presents with lymphadenopathy

• Diagnosed with Hodgkin’s lymphoma

• Patient is chemotherapy-naive

• AVBD given as first-line chemotherapy

• The risk of neutropenia for this treatment is less than 10%1


1Silvestri F, et al. Tumori 1994;80:453-458


Age – 32

Gender - female

Histology – nodular sclerosis

Lymphadenopathy size – 1.5 cm

No. nodal sites – 3

Stage – III1A

Bone marrow biopsy results - negative

WBC – 10 x 109 /L

ECOG PS - 1


Disease




Treatment Intent

AVBD

Planned RDI > 80%Anthracycline chemotherapy

Hodgkin’s lymphoma

Curative

Intermediate

10–20% FN Risk

Consider

G-CSF

Use G-CSF

No G-CSF

High

> 20% FN Risk

Low

< 10% FN Risk


Case 5

• 34-year-old woman, newly diagnosed with breast cancer

• 6 positive axillary lymph nodes

• She is prescribed 6 cycles of adjuvant TAC chemotherapy as first-line treatment

• This regimen carries an FN risk of approximately 24%1


1Martin M, et al. Proc Am Soc Clin Oncol 2004;22:Abstract 620


Age - 34

Gender – female

Histology – ductal cell carcinoma

- HR negative, HER-2-new negative

Stage – IIIA (T2, N2, M0)

No. lymphatic nodes - 6

ECOG PS - 0

ANC – 4 x 109/L

Serum bilirubin – 1.2 mg/dL

Serum creatine – 1.45 mg/dL


Disease

Intermediate

10–20% FN Risk

Consider

G-CSF

Use G-CSF

No G-CSF




Treatment Intent

High

> 20% FN Risk

Low

< 10% FN Risk

TAC

Female gender Planned RDI > 80%

Breast cancer

Curative


Examples of Breast Cancer Regimens

• High (> 20%) FN risk:

– AC→T1

– Doxorubicin/paclitaxel2,3

– Doxorubicin/docetaxel4,5

– TAC6

• Intermediate (10 – 20%) FN risk:– Docetaxel7,8

– Doxorubicin/vinorelbine9

– AC10

– 5-FU/docetaxel7

1Perez EA, et al. Ann Oncol 2002;13:1225-12352Gianni L, et al. J Clin Oncol 1995;13:2688-26993Biganzoli L, et al. J Clin Oncol 2002;20:3114-31214Alba E, et al. J Clin Oncol 2004;22:2586-25935Nabholtz JM, et al. J Clin Oncol 2003;21:968-975

10NCCN Clinical Practice Guidelines in Oncology: Myeloid Growth Factors in Cancer Treatment. Accessed from the following website 07/2005:http://www.nccn.org/professionals/physician_gls/PDF/myeloid_growth.pdf

6Martin M, et al. Proc Am Soc Clin Oncol 2004;22:Abstract 6207O’Shaughnessy J, et al. J Clin Oncol 2002;20:2812-28238Vogel CL, et al. J Clin Oncol 2005;23:1178-11849Norris B, et al. J Clin Oncol 2000;18:2385-2394

La Neutropenia Marco Danova Oncologia Medica Universita e IRCCS San Matteo Pavia.

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