eortc, german, nice and other guidelines for … · mortality with g-csf vs no g-csf by cancer type...

EORTC, German, NICE and other guidelines for neutropenia prevention and G-CSF usage.

Where do we stand?

Hartmut Link, MD, PhDHead of Dept. Internal Medicine, Hematology and

OncologyWestpfalz-Klinikum, Kaiserslautern

Academic Hospital of Mainz University andHeidelberg University

Germany1

Solid and Nonsolid Tumours: Major Comorbidities and Infections Significantly Increase Mortality

• US retrospective database analysis of cancer patients hospitalised with FN (n = 41,779)

– Solid and nonsolid tumours

• Major comorbid illnesses in addition to cancer and FN were reported in 48.8% of patients

– In total, 19.1% reported 2 or more major comorbidities

Kuderer NM, et al. Cancer. 2006;106:2258-2266.

In patients with FN, comorbid conditions and infectious complications were significantly associated with increased mortality

Impact of Comorbidities on Length of Stay and Mortality in Hospitalized Patients with Cancer and Febrile Neutropenia

135,309 patients with cancer hospitalized with neutropenic events

3

Solid tumors Lymphoma Leukemia

No. of

comorbid

ities

No. of

patients

% died % with

LOS≥10

days

No. of

patients

% died % with

LOS≥10

days

No. of

patients

% died % with

LOS≥10

days

0 17,858 0.9 11.2 8,189 0.6 17.0 10,395 0.8 53.5

1 18,172 3.4 17.9 7,751 2.6 26.6 11,380 3.4 63.2

2 14,250 8.9 27.2 5,386 8.1 41.0 8,603 9.7 69.9

3 7,499 18.0 38.4 2,861 18.4 55.2 5,040 22.8 77.7

4 2,705 25.1 51.4 1,060 33.6 70.5 2,004 38.1 83.1

≥ 5 602 35.2 62.3 278 39.9 80.6 577 49.0 87.0

All

patients*61,086 7.0 22.6 25,525 6.6 32.2 37,999 9.2 65.4

Culakova E, Poniewierski MS, Crawford J, Dale DC, & Lyman GH. (2014). Impact of Comorbidities on Lengthof Stay and Mortality in Hospitalized Patients with Cancer and Febrile Neutropenia. Blood, 124(21), 2601

LOS – length of stay; * 10,699 patients with other type or multiple tumors not included in the table

SCLC: Febrile Neutropenia (FN) Is the Most Common Treatment-Related Death (TRD) in Phase III Trials Over the Last 2 Decades

• Meta-analysis of 97 trials including nearly 25,000 patients

• The most common cause of death was FN without any significant time trend in its incidence over the years examined (P = .139)

• Deaths due to FN and all causes in patients treated with non-platinum chemotherapy increased significantly (P = .033)

Ochi N, et al. PLoS One. 2012;7:e42798.

Time Trend in the Incidence of TRDs in Relation to FNAll analyses were weighted by sample size

DOSE REDUCTION TO PREVENTTOXICITY

5

• Combined Belgian and UK data (n = 289)

– Lymphoma patients receiving CHOP-21

NHL: Chemotherapy Dose Reductions Negatively Affect Survival

Pettengell R, et al. Ann Hematol. 2008;87:429-430.

Delivering full chemotherapy dose intensity remains an important goal in NHL patients who receive CHOP-21 chemotherapy

Breast Cancer: Delays and Reductions in Chemotherapy Negatively Affect Overall Survival (1/2)

• Retrospective database analysis of early breast cancer patients who received adjuvant anthracycline-based nontaxane chemotherapy (n = 793)

– Disease-free survival was also significantly affected by the number of delayed cycles (P<.0001), the number of delayed days (P<.0001), and the RDI (P = .0029)

Chirivella I, et al. Breast Cancer Res Treat. 2009;114:479-484.

P = .0008 P = .0055

Delays and/or reductions of chemotherapy should be avoided to achieve maximal benefit

Delayed Cycles RDI

Potential Short- and Long-Term Effects of Febrile Neutropenia

Short-term effects1

Infections

Hospitalization

1Kuderer NM, et al. J Clin Oncol. 2004;22:Abstract 60492Leonard RCF, et al. Br J Cancer. 2003;89:2062-2068

3Bonadonna G, et al. N Engl J Med. 1995;332:901-906

Complicated infection

bacteremia

Potential Short- and Long-Term Effects of Febrile Neutropenia

Short-term effects1 Long-term effects2

Infections Dose reduction/

cycle delay

Hospitalization Reduced clinical

efficiency of

chemotherapy3

1Kuderer NM, et al. J Clin Oncol. 2004;22:Abstract 60492Leonard RCF, et al. Br J Cancer. 2003;89:2062-2068

3Bonadonna G, et al. N Engl J Med. 1995;332:901-906

Complicated infection

bacteremia

EVIDENCE FOR BENEFITS OF PRIMARY PROPHYLAXIS WITH G-CSF

Solid and Nonsolid Tumours: Primary G-CSF Prophylaxis Reduces Mortality (1/2)

• Systematic review and meta-analysis of 59 RCTs

• Relative risk (RR) with G-CSF support for all-cause mortality across all RCTs was 0.93 (0.90–0.96; P<.001)

Lyman GH, et al. Ann Oncol. 2013;24:2475-2484.

Cancer Type N RR 95% CLs ARD (%) 95% CLs (%)

Breast 20 0.954 0.898, 1.013 −1.5* −2.9, −0.2

Genitourinary 7 0.946 0.884, 1.013 −4.2* −7.8, −0.7

Lung 16 0.930** 0.882, 0.980 −5.6*** −8.5, −2.7

Lymphoma 16 0.895*** 0.841, 0.952 −4.8*** −7.1, −2.4

Other 2 0.867 0.630, 1.193 −8.3 −18.0, 1.4

Relative Risk and Absolute Risk Decrease for All-Cause Mortality with G-CSF vs No G-CSF by Cancer Type

The greatest reductions in all-cause mortality were seen in lymphoma and lung cancer patients

CLs, confidence limits; N, number of trials; *P < 0.05; **P <0.01; ***P <0.001.

Solid and Nonsolid Tumours: Primary G-CSF Prophylaxis Reduces Mortality (2/2)

• The greatest impact was observed in patients receiving dose-dense schedules (12 RCTs; n = 6,302) (RR = 0.89; 0.85–0.94; P<.001)


All-Cause Mortality With or Without G-CSF Support: Dose-Dense Chemotherapy

Solid and Nonsolid Tumours: G-CSF Reduces Overall Mortality in Elderly Patients

• Systematic review and meta-analysis of 59 RCTs

• Primary G-CSF prophylaxis reduced all-cause mortality

• Additionally, reductions in mortality were found for RCTs limited to elderly patients (RR = 0.90; P = .007)


Subgroup RCTs, N RR 95% CLs ARD (%) 95% CLs (%)

Elderly only 8 0.898** 0.830, 0.971 –5.7** –9.5, –1.8

Relative Risk and Absolute Risk Decrease for All-Cause Mortality with G-CSF vs No G-CSF

CLs, confidence limits; N, number of trials; **P <0.01

Meta-regression of RDI on log RR of all-cause mortality with G-CSF-supported chemotherapy

versus control.

G. H. Lyman et al. Ann Oncol 2013;24:2475-2484

Significant reductions in the relative risk for mortality wereobserved across trials where survival was the primary outcome with actual dose intensity difference

Guidelines Myeloid Growth Factors

EORTC1 European Organisation for Research and Treatment of Cancer

ASCO2 American Society of Clinical Oncology

DGHO3 German Society for Haematology and Oncology Germany

NCCN4 National Comprehensive Cancer Network USA

NEJM5 New England Journal of Medicine

ESMO6 European Society for Medical Oncology

NICE7 National Institute for Health and Care Excellence England

15

1. Aapro, M.S., et al., Eur J Cancer, 2011. 47(1): p. 8-32.2. Smith, T.J., et al., 2006. 24: p. 3187-3205.3. Vehreschild, J.J., et al., Ann Oncol, 2014. 25(9): p. 1709-18.4. Crawford, J. v.2.2014; Myeloid Growth Factors. National Comprehensive Cancer Network, 2014.5. Bennett, C.L., et al., New England Journal of Medicine, 2013. 368(12): p. 1131-1139.6. Crawford, J., et al., Annals of Oncology, 2010. 21(suppl 5): p. v248-v251.7. NICE, Prevention and management of neutropenic sepsis in cancer patients,. 2012.

EORTC Guideline

FN: Febrile neutropenia

Step 1

Assess frequency of FN associated with the planned chemotherapy regimen

FN risk ≥20% FN risk 10–20% FN risk <10%

Step 3

Define the patient’s overall FN risk for planned chemotherapy regimen

Overall FN risk ≥20% Overall FN risk <20%

Prophylactic G-CSF recommended Prophylactic G-CSF not indicated

Reassess

at each

cycle

Step 2

Assess factors that increase the frequency/risk of FN

High risk Age >65 years

Increased risk (level I and II evidence)

Advanced disease

History of prior FN

No antibiotic prophylaxis, no G-CSF use

Other factors (level III and IV evidence)

Poor performance and/or nutritional status

Female gender

Hemoglobin <12g/dL

Liver, renal or cardiovascular disease

Note that antibacterial and antifungal prophylaxis would

generally not be indicated when CSF prophylaxis effectively

reduces the depth and duration of neutropenia.Aapro MS, et al. EORTC guidelines. Eur J Cancer 2011;47:8-32.

Evidence for Patient-Related Risk Factors for FN

aAge ≥59 years; bInteraction between haemoglobin level and planned chemotherapy intensity; cP = .14, cycle 1; P = .02,

all cycles.

1. Phase III RCT data model; 2. Phase III RCT; 3. Prospective observational study.

Aapro M, et al. Eur J Cancer. 2011;47;8-32.

Cancer BC1 Ovarian2 SCLC2 NHL3 NHL3 Various3 Haematological3

Patient risk factorsOlder age (≥65 years) II+a III+ III+ III+ III+ III+

Advanced disease/metastasis III+

No antibiotic prophylaxis

Prior episode of FN

No G-CSF use III+ III+ III+c III+ III+

Female gender III+

Haemoglobin <12 g/dL/anaemia III+ III+b

Cardiovascular disease III+

Renal disease III+

Abnormal liver transaminases III+

Planned high chemotherapy dose intensity III+ III+ III+ III+

Poor performance and/or nutritional status II+

≥1 comorbidity III-

Body surface area <2.0 m2 III+ III+

Lower weight

Low pre-treatment or pre-cycle ANC II+ II+

Serum albumin <3.5 g/dL III+

Prior chemotherapy III+ III+

Prior infection III+

Patient risk factorsEORTC guideline

High risk Age >65 years

Increased risk(level I and II evidence)

Advanced diseaseHistory of prior FNNo antibiotic prophylaxis, no G-CSF use

Other factorslevel III and IV evidence

Poor performance and/or nutritional statusFemale genderHaemoglobin <12g/dLLiver, renal or cardiovascular disease

19

Aapro, M.S., et al., Eur J Cancer, 2011. 47(1): p. 8-32.

Risk of febrile neutropenia – lymphoma chemotherapy

1Aapro M, et al. Eur J Can. 2011;47:8–32;2Ballova V, et al. Ann Oncol. 2005;16:124–31;

3NCCN 2013; Pettengell R, et al. Support Care Cancer. 2008;16:1299–1309

CT regimen with

20% risk of FN

CT regimen with

10-20% risk of FN

CT regimen with

<10% risk of FN

A, doxorubicin; B, bleomycin; C, cyclophosphamide; Cyta, cytarabine; Dex, dexamethasone; d, day; Epirub,

epirubicin; Mitox, mitoxantrone; Pred, prednisone; Procarb, procarbazine; R, rituximab; S, methylprednisolone;

Vincris, vincristine

FN

ris

k (

%)

80

ACVBPA/C/Vindes/

B/Pred

R-CHOP-21R/C/A/Vincris/Pred

DHAPCis/Cyta/Dex

BEACOPP2

B/Etop/A/C/Vincris/

Procarb/Pred

Cytotoxic regimen

ABVD3

A/B/Vincris/

dacarbazine

70

60

50

40

30

20

10

0

ASCO‘s Top 5 List

Don’t use white cell stimulating factors for primary prevention of febrile neutropenia for patients with less than 20% risk for this complication.

ASCO guidelines recommend using white cell stimulating factors when the risk of febrile neutropenia, secondary to a recommended chemotherapy regimen, is approximately 20% and equally effective treatment programs that do not require white cell stimulating factors are unavailable.

Exceptions should be made when using regimens that have a lower chance of causing febrile neutropenia if it is determined that the patient is at high risk for this complication (as a result of age, medical history, or disease characteristics). Source: Smith TJ, Khatcheressian J, Lyman GH, et al: ASCO 2006 update of recommendations for the

use of white blood cell growth factors: An evidencebased clinical practice guideline. J Clin Oncol24:3187-3205, 2006.

22

Schnipper, Lowell E., et al. (2012), 'American Society of Clinical Oncology Identifies Five Key Opportunities to Improve Care and Reduce Costs: The Top Five List for Oncology', Journal of Clinical Oncology, 30, 1715-24.

Factors to Consider in Assessing Risk of an FNE in Patients Undergoing Cytotoxic Chemotherapy for Malignancy ASCO 1/4

23

Factor Effect on Risk

Patient characteristic

Advanced age Risk increases if age ≥ 65 years

ECOG PS Risk increases if PS ≥ 2

Nutritional status Risk increases if albumin < 35 g/L

Prior FN episodeRisk in cycles two to six is four-fold greater if FN

episode occurs in cycle one

ComorbiditiesFN odds increase by 27%, 67%, and 125%,

respectively, for one, two, or ≥ three comorbidities

Flowers CR, et al. J Clin Oncol. 2013;31(6):794-810

Factors to Consider in Assessing Risk of an FNE in Patients Undergoing Cytotoxic Chemotherapy for Malignancy –ASCO 2/4

24


Factor Effect on RiskCancer stage Risk increases for advanced stage (≥ 2)

Remission status Risk increases if not in remission

Treatment response Risk is lowest if patient has a CR

If patient has a PR, FN risk is greater for acute

leukemia than for solid tissue malignancies

FN risk is higher if persistent, refractory, or

progressive disease despite treatment

Factors to Consider in Assessing Risk of an FNE in Patients Undergoing Cytotoxic Chemotherapy for Malignancy- ASCO 3/4

25Flowers CR, et al. J Clin Oncol. 2013;31(6):794-810

Underlying malignancyReported FN

Rate (%)

95% CI

(%)

Acute leukemia/MDS 85-95

Soft tissue sarcoma 27 19 to 34.5

NHL/myeloma 26 22 to 29

Germ cell carcinoma 23 16.6 to 29

Hodgkin lymphoma 15 6.6 to 24

Ovarian carcinoma 12 6.6 to 17.7

Lung cancers 10 9.8 to 10.7

Colorectal cancers 5.5 5.1 to 5.8

Head and neck carcinoma 4.6 1.0 to 8.2

Breast cancer 4.4 4.1 to 4.7

Prostate cancer 1 0.9 to 1.1

Factors to Consider in Assessing Risk of an FNE in Patients Undergoing Cytotoxic Chemotherapy for Malignancy- ASCO

Cytopenias

26

Degree and duration of:

Neutropenia ANC < 500/μL for ≥ 7 days

Lymphopenia ALC < 700/μL (ANC surrogate)

Monocytopenia AMC < 150/μL (ANC surrogate)


Smith, T.J., et al., 2006. 24: p. 3187-3205.

DGHO guideline - Germany

28Vehreschild, J.J., et al., Ann Oncol, 2014. 25(9): p. 1709-18.

• Comprehensive literature search and expert panel consensus confirmed many key recommendations given by international guidelines.

• Evidence for growth factors during acute myeloid leukaemia induction chemotherapy and pegfilgrastimuse in haematological malignancies was rated lower compared with other guidelines.

Patient risk factorsDGHO guideline - Germany

• “Risk factors can be used to identify patients with a particularly high risk to develop FN in ambiguous cases.

• Recently, validated risk factors for FN include– prior chemotherapy

– abnormal hepatic and renal function

– low white blood count

– chemotherapy, and planned delivery of ≥85% of the dose of chemotherapy”

29

cited referenceLyman, G. H., et al. (2011), 'Predicting individual risk of neutropenic complications in patients receiving cancer chemotherapy', Cancer, 117 (9), 1917-27.

Vehreschild, J.J., et al., Ann Oncol, 2014. 25(9): p. 1709-18.

Cumulative risk of FN in a population at high and low risk as estimated by the FN risk model

0.00

.05

.10

.15

.20

.25

Pro

bab

ility

of

FN

0 10 20 30 40 50 60 70 80 90 100 110 120

Time (days)

High risk

Low risk

Cumulative risk of FN(derivation population)

HR = 4.68 [95% CI: 3.38–6.49]0.00

.05

.10

.15

.20

.25

Pro

bab

ility

of

FN

0 10 20 30 40 50 60 70 80 90 100 110 120

Time (days)

High risk

Low risk

HR=5.73 [95% CI: 3.57–9.22]

Cumulative risk of FN(validation population)

.014

.012

.010

.008

.006

.004

.002

0.000

0 10 20 30 40 50 60 70 80 90 100 110 120

Time (days)

Low Risk

High Risk

Hazard function for febrile neutropeniaderivation population

Haz

ard

feb

rile

neu

tro

pen

ia

Independent risk factors: previous chemotherapy, low WBC, renal or hepatic dysfunction,chemotherapy and planned delivery ≥85%, G-CSF protective

Cutpoint 10%, sensitivity 90%, specificity 59%, PPV 34%, NPV 96%

WBC, white blood cell; PPV, positive predictive value; NPV, negative predictive value

Lyman GH et al. Cancer 2011;117:1917–1927

Therapeutic strategies to preventfebrile neutropenia

NCCN Guidelines Version 2.2014; Myeloid Growth Factors

Patient risk factors

32

Older patient, notably patients age 65 and older

Previous chemotherapy or radiation therapy

Preexisting neutropenia or bone marrow involvement with tumor

Preexisting conditions

Neutropenia

Infection/open wounds

Recent surgery

Poor performance status

Poor renal function

Liver dysfunction, most notably elevated bilirubin

HIV-infected patient

Crawford, J. v.2.2014; Myeloid Growth Factors. National Comprehensive Cancer Network, 2014

Primary prophylaxisrisk factors in standard chemotherapy

Reduced marrow reserve (e.g. ANC <1.5 × 109/l) due to radiotherapy of >20% marrow

Human immunodeficiency virus

Patients aged ≥65 years treated with curative regimens (CHOP or more intensive regimens for patients with aggressive Non-HodgkinLymphoma)

33

Crawford, J., et al., Annals of Oncology, 2010. 21(suppl 5): p. v248-v251.

34

???????

In April 2013 we were established in primary legislation, becoming a Non Departmental Public Body (NDPB)..As an NDPB, we are accountable to our sponsor department, the Department of Health, but operationally we are independent of government….The way NICE was established in legislation means that our guidance is officially England-only.

Bottom Line - ASCO• Interventions

– Antibacterial &/or antifungal prophylaxis and physical precautions to prevent infection of afebrile oncology outpatients with neutropenia;

• Target Audience

– Oncologists, primary care physicians, and oncology nurses• Key Recommendations

– Only use antibacterial and antifungal prophylaxis if ANC is expected to remain <100 per µL for >7 days, unless other factors (see Table 2 in text) increase risks for complications or mortality.

– If indicated, an oral fluoroquinolone is preferred for antibacterial prophylaxis and an oral triazole for antifungal prophylaxis.

– Interventions such as such as footware exchange, protected environments, respiratory or surgical masks, a “neutropenic” diet, or nutritional supplements are not recommended since evidence is lacking of clinical benefits to patients from their use.


C. R. Flowers, J. Seidenfeld, E. J. Bow, C. Karten, C. Gleason, D. K. Hawley, N. M. Kuderer, A. A. Langston, K. A. Marr, K. V. Rolston, S. D. Ramsey, Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 31, 794-810 (2013); published online EpubFeb 20 (10.1200/jco.2012.45.8661).

Antibacterial and antifungal prophylaxisASCO

• Note that antibacterial and antifungal prophylaxis would generally not be indicated when CSF prophylaxis effectively reduces the depth and duration of neutropenia.

C. R. Flowers, J. Seidenfeld, E. J. Bow, C. Karten, C. Gleason, D. K. Hawley, N. M. Kuderer, A. A. Langston, K. A. Marr, K. V. Rolston, S. D. Ramsey, Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adultstreated for malignancy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 31, 794-810 (2013); published online EpubFeb 20 (10.1200/jco.2012.45.8661).

G-CSF prophylaxis - comparison of recommendations

FN Risk EORTC1 ASCO2 DGHO3 NCCN4 NEJM5 ESMO6 NICE7

>40% * G-CSF

only as an integral part of the chemo-therapy regimen

>20%

<20% + risk factors

<10% + risk factors Serious RF

<20% no risk factors

<10% no risk factors

Maintain chemodose intensity

38

1. Aapro, M.S., et al., Eur J Cancer, 2011. 47(1): p. 8-32.2. Smith, T.J., et al., 2006. 24: p. 3187-3205.3. Vehreschild, J.J., et al., Ann Oncol, 2014. 25(9): p. 1709-18.4. Crawford, J. v.2.2014; Myeloid Growth Factors. National Comprehensive Cancer Network, 2014.5. Bennett, C.L., et al., New England Journal of Medicine, 2013. 368(12): p. 1131-1139.6. Crawford, J., et al., Annals of Oncology, 2010. 21(suppl 5): p. v248-v251.7. NICE, Prevention and management of neutropenic sepsis in cancer patients,. 2012.

G-CSF G-CSF in curative therapy

No G-CSF No statement

*prophylaxis with a fluoroquinolone

RF – risk factor

Summary of Treatment Guidelines

• G-CSFs should be used in patients treated with established cytotoxic chemotherapy for malignancy to reduce the incidence of FN and the duration of neutropenia

• G-CSFs should be used either in primary or secondary prophylaxis or as therapy

• Guidelines recommend G-CSFs in primary prophylaxis

– where the risk of FN is ≥20%

– where the risk of FN due to chemotherapy is below 20%, only if patient risk factors exist

• In general no G-CSF prophylaxis, if the FN risk is below 10%

eortc, german, nice and other guidelines for … · mortality with g-csf vs no g-csf by cancer type...

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