Copyright AFSOS, version 14/07/2014 1

Copyright AFSOS, version 14/07/2014 1

Copyright AFSOS, version 14/07/2014 2

Prophylaxie de la Neutropénie Fébrile (NF) REFERENTIEL AFSOS Date : 14/07/2014 Copyright AFSOS, version 14/07/2014 3

Coordination médicale Nicolas Jovenin (Oncocha) Coordination méthodologique Nicolas Jovenin (Oncocha) Membres du groupe de travail Contributeurs Matti AAPRO (Genève), Nicolas JOVENIN (Oncocha), Didier KAMIONER (OncoRIF), Didier MAYEUR (OncoRIF) Contributeurs : participants aux ateliers du 19/12/2013 Frédéric BALES (Clermont-Ferrand), Denis BERTOLI (Champagne sur Seine), Patricia BOULOT (Trevoux), Marie-Dominique BRIDON (Sens), Sylvie CAYEUX (Amiens), Amandine CHENET (Nantes), Claire COLOMBANO (Orléans), Virginie DUBOIS (Nancy), Isabelle DUFRENE (Valence), Roxane ECHERNIER (Thonon les Bains), Laurence GILLES-AFCHAIN (Lyon), Pascale IBANEZ- MARTIN (St Chamond), Claire JOGUET (Clermont-Ferrand), Didier KAMIONER (Trappes), Vanessa MARQUANT (Tarbes), Didier MAYEUR (Le Chesnay), Marie-Caroline MAYEUX (Nancy), Isabelle MESGUICH-DE POLIGNAC (St Jorioz), Bich Nga PHAM (Lyon), Elisabeth THOMAS (Vandoeuvre les Nancy), Nicolas JOVENIN (Reims), Hélène LABROSSE-CANAT (Lyon), Sophie DUPLOMB (Lyon), Ziad RIDA (La Réunion), Karine VIRGINIE-THERESA (Martinique), Joël FLEURY (Clermont-Ferrand) Copyright AFSOS, version 14/07/2014 4

Contexte La neutropénie fébrile (NF) est associée à : Une morbidité et une mortalité importantes annexe 1 Un coût élevé pour la société Pour le patient Hospitalisation, antibiothérapie Retard de traitement (chimiothérapie), diminution de dose Accroissement de la mortalité Importance de la prophylaxie de la neutropénie fébrile Utilisation des G-CSF = méthode validée N.B. : - le traitement curatif de la NF n est pas abordé ici (Cf. référentiel) - la chimiothérapie intensifiée n est pas abordée ici Copyright AFSOS, version 14/07/2014 5

UN DOMAINE MAL EXPLORE: G-CSF ET ASTHENIE, MUCITE, DIARHEE Febrile neutropenia Grade 3 4 asthenia Grade 3 4 mucositis Grade 3 4 diarrhoea NO 23.9% 21.1% 6.4% 6.4% Prophylactic G-CSF YES 3.5% 3.5% 2.6% 0.9% Martin M et al. Ann Oncol. 2006 Aug;17(8):1205-12.

Les types de prophylaxies Copyright AFSOS, version 14/07/2014 7

Les types de prophylaxies Prophylaxie primaire Attitude ayant pour but de diminuer les risques de NF dès le 1 er cycle de chimiothérapie Prophylaxie secondaire Attitude ayant pour but de diminuer les risques de NF après un événement neutropénique ( 2 ème cycle de chimiothérapie) Copyright AFSOS, version 14/07/2014 8

COMMENT JUSTIFIER UNE PROPHYLAXIE SECONDAIRE CHEZ UN PATIENT A RISQUE?

First course : the most difficult FN events occurring in the first cycle (%) 90 80 70 60 50 40 30 20 10 58% 50% 71% 80% 53% 57% 54% 0 Breast cancer NSCLC SCLC Colon cancer Non- Hodgkin s lymphoma Hodgkin disease Ovarian cancer Crawford J, et al. J Natl Compr Canc Netw. 2008;6:109 18.

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 In patients with FN, comorbid conditions and infectious complications were significantly associated with increased mortality Kuderer NM, et al. Cancer. 2006;106:2258-2266.

Solid and Nonsolid Tumours: Primary G-CSF Prophylaxis Reduces Mortality 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) Relative Risk and Absolute Risk Decrease for All-Cause Mortality with G-CSF vs No G-CSF by Cancer Type 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 CLs, confidence limits; N, number of trials; *P < 0.05; **P <0.01; ***P <0.001. Lyman GH, et al. Ann Oncol. 2013;24:2475-2484.

Les moyens prophylactiques Copyright AFSOS, version 14/07/2014 13

G-CSF disponibles en France Formes à injection quotidienne Nom Commercial DCI Dosages disponibles Granocyte Lénograstim (P) 13 et 34 MUI Neupogen Filgrastim (P) 30 et 48 MUI Nivestim Filgrastim (BS) 12, 30 et 48 MUI Ratiograstim Filgrastim (BS) 30 et 48 MUI Tevagrastim Filgrastim (BS) 30 et 48 MUI Zarzio Filgrastim (BS) 30 et 48 MUI Forme à injection unique Nom commercial DCI Dosage disponible Neulasta Pegfilgrastim (P) 6 mg Si traitement initié avec molécule princeps (P) ou biosimilaire (BS) : poursuivre le traitement avec le même produit pdt la ligne de traitement. Copyright AFSOS, version 14/07/2014 14

Formes à injection quotidienne G-CSF disponibles en France Nom Commercial DCI Dosages disponibles Granocyte Lénograstim (P) 13 et 34 MUI Neupogen Filgrastim (P) 30 et 48 MUI Nivestim Filgrastim (BS) 12, 30 et 48 MUI Et le lipegfilgrastim?. Ratiograstim Filgrastim (BS) 30 et 48 MUI Tevagrastim Filgrastim (BS) 30 et 48 MUI Zarzio Filgrastim (BS) 30 et 48 MUI Forme à injection unique Nom commercial DCI Dosage disponible Neulasta Pegfilgrastim (P) 6 mg Si traitement initié avec molécule princeps (P) ou biosimilaire (BS) : poursuivre le traitement avec le même produit pdt la ligne de traitement. Copyright AFSOS, version 14/07/2014 15

LES G-CSFs SONT-ILS TOUS LES MÊMES?

Short acting G-CSF versus long acting... 35 Current practice* Pegfilgrastim primary prophylaxis (PPP) 24 Proportion of patients experiencing FN (%) 30 25 20 15 10 5 9 3 16 5 15 3 6 10 3 16 5 Error bars show 95% CIs 0 First cycle All cycles First cycle All cycles First cycle All cycles Younger patients (< 65 years) 1 n = 2,024 CP: n = 875; PPP: n = 1149 Elderly patients ( 65 years) 2 n = 254 CP: n = 104; PPP: n = 150 All patients 3 n = 2,282 CP: n = 979; PPP: n = 1,303 *Current practice neutropenia management = any current strategy, including no G-CSF, or daily G-CSF or pegfilgrastim in any cycle Adapted from: 1 Schwenkglenks et al. EJC Supplements 2008:6:68(Abstract); 2 Aapro M, et al. Crit Rev Oncol Hematol. 2010;74:203 10; 3 von Minckwitz G, et al. Eur J Cancer. 2009;45:608 17.

MAIS. QUE FONT LES CANCEROLOGUES

SOLID TUMOURS: ADHERENCE TO CLINICAL GUIDELINES IS POOR AND PATIENTS ARE UNDERTREATED WITH G-CSF Patients with breast cancer, NSCLC, SCLC, or ovarian cancer receiving chemotherapy regimens with high ( 20%) risk of FN (n = 1,347) Multicentre, international, observational study; majority were public or university hospitals FN occurred in 127 patients overall; incidence was highest in SCLC G-CSF was either pegfilgrastim or a daily G-CSF Pegfilgrastim was the most commonly prescribed G-CSF in patients given PP, administered to 82% of patients receiving PP Daily G-CSF was given to 16% of patients who received PP 45% 80% of all patients did not receive G-CSF PP according to recommendations PP, primary prophylaxis. Krzemieniecki K, et al. Support Care Cancer. 2014;22(3):667-677.

SOLID TUMOURS: ADHERENCE TO CLINICAL GUIDELINES IS POOR AND PATIENTS ARE UNDERTREATED WITH G-CSF In breast cancer, pegfilgrastim PP was maintained for a greater number of continuous cycles than daily G-CSF PP Pegfilgrastim PP was maintained until the fourth cycle in 95% of patients and until the sixth cycle in 89% of patients Daily G-CSF PP was maintained until the fourth cycle in 62% of patients and until the sixth cycle in 56% of patients Post-hoc analysis: 39% of the 127 patients who experienced FN were not given on-schedule G-CSF prophylaxis in the cycle after the first FN event occurred Mean Number of Days of Daily G-CSF per Cycle 8 Mean Number of Days 7 6 5 4 3 2 4,88 3,95 4,95 3,67 FN risk assessment was predominantly based on clinical judgment and individual risk factors; guidelines for patients at high FN risk were not consistently followed 1 0 Breast NSCLC SCLC Ovarian Krzemieniecki K, et al. Support Care Cancer. 2014;22(3):667-677.

G-CSF guidelines to prevent febrile neutropenia Hartmut Link 1, Josef Nietsch 2, Markus Kerkmann 2, Petra Ortner 3 for the Supportive Care Working Group (ASORS) of the German Cancer Society (DKG) 1 Dept. Internal Medicine I, Hematology and Oncology, Westpfalz-Klinikum Kaiserslautern, Germany; 2 MMF GmbH, Dortmund; 3 c/o POMME-med GmbH, Munich, Germany Link H, et al. J Clin Oncol. 2013;31(suppl): Abstract 6591.

Barni S, et al. MASCC 2011. ITALIAN STUDY RESULTS

Primary prophylaxis (Italian 2008 survey) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 5% 10% 15% 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Nadir Scheduled recycle Daily G-CSF Peg-filgrastim

MONITOR-GCSF MASCC 2014 Prophylaxis of chemotherapy-induced febrile neutropenia with biosimilar filgrastim: Description of patients, treatment patterns and outcomes in the MONITOR-GCSF Study M Aapro a, H Ludwig b, P Gascón c, M Boccadoro b, C Bokemeyer e, M Turner f, M Muenzberg f, I Abraham g,h, K Denhaerynck g, K MacDonald g a Institut Multidisciplinaire d Oncologie, Clinique de Genolier, Genolier, Switzerland b Medizinische Abteilung I Onkologie und Haematologie, Wilhelminenspital, Wien, Austria c Division of Medical Oncology, Department of Hematology-Oncology, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain d Dipartimento di Oncologia e Ematologia, Azienda Ospedaliero Universitaria S. Giovanni Battista di Torino, Torino, Italy e Universitaetsklinikum Hamburg Eppendorf, Hamburg, Germany f Sandoz Biopharmaceuticals, Holzkirchen, Germany g Matrix45, Tucson, AZ, USA h Center for Health Outcomes and Pharmacoeconomic Research, The University of Arizona, Tucson, AZ, USA MASCC : Multinational Association of Supportive Care in Cancer The trademark is the property of the respective owner.

Patients in final MONITOR G-CSF dataset 140 centers across 12 European countries 1447 patients, 6213 chemotherapy cycles + study end observation Gascón P, et al. Crit Rev Oncol Hematol. 2011;77:198-200

And on the other side of the ocean? Only 17% of patients treated with high-risk CT regimens received CSFs, compared with 18% and 10% of patients treated with intermediate- (10%-20% risk of FN) and low-risk (<10% risk of FN) CT regimens, respectively Overall, 96% of CSFs were administered in scenarios where CSF therapy is not recommended by evidencebased guidelines Potosky AL, et al. J Natl Cancer Inst. 2011;103:979-982.

ASCO TOP FIVE Avoid administering colony stimulating factors (CSFs) to patients undergoing chemotherapy who have less than a 20 percent risk for febrile neutropenia ASCO guidelines recommend these treatments only when the risk of febrile neutropenia from chemotherapy is greater than 20 percent and when effective alternatives to high risk therapy are unavailable. However, some exceptions exist, such as for patients at higher risk for chemotherapy-related febrile neutropenia because of other complications (including age, medical history, or disease characteristics). http://www.asco.org/ advocacy/oncology-top-five-list-identifies-opportunities-improve-quality-and-value-cancer-care Last accessed Nov 7, 2014

Mise en œuvre des G-CSF Prophylaxie Primaire Prophylaxie secondaire Copyright AFSOS, version 14/07/2014 28

Référence : EORTC Prophylaxie Primaire Quelle que soit l indication : curatif ou palliatif* : Néo-adjuvant, adjuvant ou métastatique À réévaluer à chaque cycle Étape 1 Risque de NF lié au protocole de chimiothérapie** prévu < 10% 10-20% > 20% Pas d indication de G-CSF Étape 2 Page suivante Indication de G-CSF * : Si palliatif, faire le choix (si possible) d un traitement non neutropéniant` ** : liste des protocoles : NCCN ou EORTC ou ASCO (liens en annexe 2 p36) Copyright AFSOS, version 14/07/2014 29

Référence : EORTC Prophylaxie Primaire Étape 2 Facteurs de risques individuels de NF? Évaluation des facteurs risque de NF Risque important Qui le risque Age > 65 ans Maladie avancée Antécédent de NF Ni ATB, ni G-CSF Autres facteurs Karnofsky bas et/ou dénutrition Sexe féminin Insuffisance hépatique, rénale Maladie cardiovasculaire Hb < 12 g/dl Étape 3 page suivante Copyright AFSOS, version 14/07/2014 30

Prophylaxie Primaire Étape 1 Page 30 Étape 2 Page précédente À réévaluer à chaque cycle Risque global faible Pas d indication de G-CSF Étape 3 Définir le Risque Global Risque global élevé Indication de G-CSF Référence : EORTC Copyright AFSOS, version 14/07/2014 31

CONCLUSIONS LE REFERENTIEL AFSOS DEVRAIT PERMETTRE UN EMPLOI RATIONNEL DES G-CSF et UNE MEILLEURE PREVENTION DE LA NF S IL ETAIT APPLIQUE COMME TOUT REFERENTIEL IL DEMANDE A ETRE REVU ET CORRIGE REGULIEREMENT