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  • 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

    LOS10

    days

    No. of

    patients

    % died % with

    LOS10

    days

    No. of

    patients

    % died % with

    LOS10

    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

  • 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 (0.900.96; P

  • 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; 0.850.94; P

  • 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)

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

    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

  • 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 1020% FN risk

  • 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

  • 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

  • Risk of febrile neutropenia lymphoma chemotherapy

    1Aapro M, et al. Eur J Can. 2011;47:832;2Ballova V, et al. Ann Oncol. 2005;16:12431;

    3NCCN 2013; Pettengell R, et al. Support Care Cancer. 2008;16:12991309

    CT regimen with

    20% risk of FN

    CT regimen with

    10-20% risk of FN

    CT regimen with

  • ASCOs Top 5 List

    Dont 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

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

    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/L for 7 days

    Lymphopenia ALC < 700/L (ANC surrogate)

    Monocytopenia AMC < 150/L (ANC surrogate)

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

  • 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: 3.386.49]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: 3.579.22]

    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;117:19171927

  • 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 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

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    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 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.

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

  • 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-CSFonly as an integral part of the chemo-therapy regimen

    >20%

  • 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%