Prophylaxis of febrile neutropenia :experiences with adjuvant TAC

Transcription

1 Prophylaxis of febrile neutropenia :experiences with adjuvant TAC 30 th Apr, 2016 Jihyoun Lee Breast center, Department of Surgery Soonchunhyang University Hospital

2 Chemotherapy and the risk of febrile neutropenia G-CSF administration in current guidelines Prophylaxis of febrile neutropenia in breast cancer treatment Experiences of long-acting G-CSF

3 Neutrophils First line of defense against the bacterial pathogens Immediately able to recognize, attack, and kill invading organisms Recruits other cells Promotes inflammation Phagocytosis

4 Kolaczkowska et al. Nat Rev Immunol 2013

5 Chemotherapy and the immune system The administration of chemotherapy Decrease the number of neutrophils Produce chemotactic and phagocytic defects Prolonged neutropenia is related to risk of infection The risk of infection can be modified by Alterations of physical defense barriers patient s cellular or humoral immune system Endogenous microflora

6 Mitotic pool Sensitivity to CT: very high Sensitivity to G-CSF: moderate Maturation pool Sensitivity to CT: moderate Sensitivity to G-CSF: very high Peripheral pool Sensitivity to CT: No Sensitivity to G-CSF: High Lambertini et al. Expert Opi Biol Ther 2015

7 Toxicity grading for neutropenia Toxicity Grade Grade 1 Grade 2 Grade 3 Grade 4 Definition Mild ANC < LLN to 1.5 x 10 9 /L Moderate ANC < 1.5 to 1.0 x 10 9 /L Severe ANC < 1.0 to 0.5 x 10 9 /L Life threatening ANC < 0.5 x 10 9 /L * ANC, absolute neutrophil count; LLN, lower limit of normal. Common Terminology Criteria for Adverse Events (CTCAE) version Published June 14, 2010

8 Fever may be the sole Sx of infection Fever may not be present in neutropenic infection: Steroids NSAIDs Clostridium septicum endogenous cytokines (IL-6 and TNF) are released with the possible development of fever even in the absence of infection

9 Febrile Neutropenia(FN) Febrile neutropenia is defined as a single temperature of >38.3 C (101 F) orally or sustained temperature of 38.0 C (100.4 F) over >1 h <500 neutrophils/mcl or <1,000 neutrophils/mcl and a predicted decline to 500/mcL over the next 48 hours NCCN guidelines ver Myeloid growth factors

10 Chemotherapy regimens with a high risk of febrile neutropenia (>20%) CHEMOTHERAPY REGIMEN EORTC NCCN Doxorubicin, cyclophosphamide docetaxel Docetaxel doxorubicin, cyclophosphamide Doxorubicin and docetaxel Doxorubicin and paclitaxel Docetaxel, doxorubicin, and cyclophosphamide (TAC) DDb fluorouracil, epirubicin, and cyclophosphamide (FEC) DDb doxorubicin, cyclophosphamide, and paclitaxel (ACT) Docetaxel and trastuzumab Doxorubicin and cyclophosphamide (AC) Epirubicin and cyclophosphamide (EC) Doxorubicin, cyclophosphamide docetaxel and trastuzumab Docetaxel Epirubicin Cyclophosphamide, methotrexate, and fluorouracil (CMF classic) Fluorouracil, epirubicin, and cyclophosphamide (FEC) docetaxel Cyclophosphamide, epirubicin, and 5-FU (CEF) Capecitabine and docetaxel Cortes de Miguel et al. Support Care Cancer. 2015

11 Individual risk of FN development of febrile neutropenia after a specific cycle of chemotherapy: Bozeuk et al. Support Care Cancer. 2015

12 Identification of high risk patients The Multinational Association for Supportive Care in Cancer(MASCC) risk index score a scoring system for identifying low-risk cancer patients with febrile neutropenia (Klastersky et al. 2000) Predicting model for risk of neutropenic complications clinical and biological parameters chemotherapy characteristics (Lyman et al., 2011)

13 Validation studies of MASCC risk index score Reference N of episodes Patients with hematological malignancy (%) Predicted at low risk (%) Paesmans et al. 1, Se (%) Sp (%) PPV (%) Stratum of hematological tumors Stratum of solid tumor patients Uys et al Cherif et al Klastersky et al Innes et al Baskaran et al Hui et al Caromana-Bayonas et al NA NA NA NPV (%) Klastersky et al. Support Care Cancer. 2013

14 Multinational Association for Supportive Care in Cancer(MASCC) risk index score MASCC Risk Index Factors and Weights CHARACTERISTIC WEIGHT Burden of febrile neutropenia with no or mild symptoms 5 No hypotension (systolic BP>90 mmhg) 5 No chronic obstructive pulmonary disease 4 Solid tumor or hematological malignancy with no previous fungal infection No dehydration requiring parenteral fluids 3 Burden of febrile neutropenia with moderate symptoms 3 Outpatients status 3 Age <60 years 2 4 <21

15 Identification of high risk patients Measurement of procalcitonin, CRP, IL-6 potential useful markers predicting severe infection in FN PCT had the best positive likelihood ratio (Wu et al., 2015) Prognostic model for FN (Ahn et al., 2015)

16 Chemotherapy and the risk of febrile neutropenia G-CSF administration in current guidelines Prophylaxis of febrile neutropenia in breast cancer treatment Experiences of long-acting G-CSF

17 The role of G-CSF G-CSF plays a central role in neutrophil formation Usually levels are low but may be increased during infections or inflammatory status Enhances the proliferation and differentiation of neutrophils from progenitor cells Increase the survival and function of mature neutrophils resulting in peripheral neutrophilia

18 Mitotic pool Sensitivity to CT: very high Sensitivity to G-CSF: moderate Maturation pool Sensitivity to CT: moderate Sensitivity to G-CSF: very high Peripheral pool Sensitivity to CT: No Sensitivity to G-CSF: High Lambertini et al. Expert Opi Biol Ther 2015

19 The role of G-CSF The use of G-CSFs before cytotoxic therapy should be avoided since it renders the mitotic pool highly sensitive to chemotherapy all major guidelines recommend the use of G-CSFs h after chemotherapy administration

20 Recombinant G-CSF Balugrastim Empegfilgrastim Lambertini et al. Expert Opi Biol Ther 2015

21 Pegylation: daily vs long acting G-CSF Filgrastim Recombinant methionyl human G-CSF Pegfilgrastim (Neulasta ) covalent attachment of a monomethoxy polyethylene glycol chain to the filgrastim Escape from renal clearance self regulating clearance by neutrophil

22 Pegylation: daily vs long acting G-CSF Pegfilgrastim serum level vs ANC after single 6-mg Neulasta dose ANC level Serum concentration of Pegfilgrastim(Neulasta ) Green et al. J Clin Oncol 2003

23 Structure Filgrastim Human G-CSF produced by recombinant DNA technology Pharmacokinetics Elimination half-life: Approximately 3.5 h Dosing Starting dose of 5mcg/kg/day as a single daily injection by subcutaneous (SC) bolus, short IV infusion, or continuous SC or IV infusion Pegfilgrastim (Neulasta ) Polyethylene glycol molecule bound to N-terminal of filgrastim Elimination half-life: h after subcutaneous injection Once-per-cycle injections - A single subcutaneous injection of 6 mg administered once per cycle in adults Clearance Primarily renal Pegylation enables selfregulating, neutrophil-mediated clearance Cortes de Miguel et al. Support Care Cancer 2015

24 Pegylation: daily vs long acting G-CSF Pegfilgrastim (Neulasta ) Pegylation of filgrastim leads to reduced renal clearance and sustained plasma concentration, which result in: Once-per-cycle subcutaneous dosing Self-regulated neutrophil-mediated clearance Given as a 6-mg fixed dose appropriate for adult patients across a wide range of body weights ( 45 kg) Given once per cycle and should not be administered in the period between 14 days before and 24 h after cytotoxic chemotherapy

25 Toxicity risks with myeloid growth factors Acute respiratory distress syndrome (ARDS) Allergic reactions Alveolar hemorrhage and hemoptysis Bleomycin-containing regimens: pulmonary toxicity Severe sickle cell crises Splenic rupture MDS and AML Bone pain and pain in extremity

26 Mechanisms of bone pain Lambertini et al. Crit Rev Oncol Hematol 2014

27 Lambertini et al. Crit Rev Oncol Hematol 2014

28 Pegylation: daily vs long acting G-CSF Doxorubicin and docetaxel(60 mg/m 2 and 75 mg/m 2 ) Daily filgrastim Pegfilgrastim Green et al. J Clin Oncol 2003

29 Primary vs secondary prophylaxis Primary prophylaxis First and subsequent-cycle use of prophylactic antibiotics or growth factors Secondary prophylaxis Addition of growth factors for patients who experienced a neutropenic complication from a prior cycle of chemotherapy (for which primary prophylaxis was not received)

30 Primary prophylaxis Primary prophylaxis Prevent FN, hospitalizations, infection-related deaths. Prophylactic use of G-CSF reduces the incidence, length, and severity of chemotherapy-induced neutropenia in breast cancer patients.

31 Lambertini et al. Expert Opi Biol Ther 2015

32 Primary prophylaxis

33 Chemotherapy and the risk of febrile neutropenia G-CSF administration in current guidelines Prophylaxis of febrile neutropenia in breast cancer treatment Experiences of long-acting G-CSF

34 FN is related to RDI NCCN guidelines ver Myeloid growth factors

35 Reduced RDI and worse prognosis 793 patients with early-stage breast cancer treated with anthracycline-based non-taxane adjuvant chemotherapy Relative dose intensity (RDI) administered ( 85%, <85%). HR,1.65; 95% CI, ; HR, 1.73; 95% CI, ; p = p = Disease-Free Survival (years) Overall Survival (years) Chirivella et al. Breast Cancer Res Treat 2009

36 Primary prophylaxis in breast cancer Tx GEPATRIO study A phase III study of neoadjuvant TAC Primary prophylaxis of Ciprofloxacin Daily G-CSF Pegfilgrastim Pegfilgrastim+ciprofloxacin Von Mickwitz et al. Ann Oncol 2008

37 Risks of FN and FN-Related complications were generally lower for prophylaxis with pegfilgrastim versus short-acting G-CSFs Mitchell et al. J Oncol Pharm Pract. 2016

38 Chemotherapy regimens with a high risk of febrile neutropenia (>20%) CHEMOTHERAPY REGIMEN EORTC NCCN Doxorubicin, cyclophosphamide docetaxel Docetaxel doxorubicin, cyclophosphamide Doxorubicin and docetaxel Doxorubicin and paclitaxel Docetaxel, doxorubicin, and cyclophosphamide (TAC) DDb fluorouracil, epirubicin, and cyclophosphamide (FEC) DDb doxorubicin, cyclophosphamide, and paclitaxel (ACT) Docetaxel and trastuzumab Doxorubicin and cyclophosphamide (AC) Epirubicin and cyclophosphamide (EC) Doxorubicin, cyclophosphamide docetaxel and trastuzumab Docetaxel Epirubicin Cyclophosphamide, methotrexate, and fluorouracil (CMF classic) Fluorouracil, epirubicin, and cyclophosphamide (FEC) docetaxel Cyclophosphamide, epirubicin, and 5-FU (CEF) Capecitabine and docetaxel Cortes de Miguel et al. Support Care Cancer. 2015

39 Discontinuing primary prophylaxis Increase in cost with primary G-CSF prophylaxis 167 patients randomized to comparing primary prophylaxis in first 2 cycles only and throughout all cycles TAC, FEC-D, docetaxel, TC OR 5.4 (95% CI, 2.3 to 12.6) Aarts et al. J Clin Oncol 2013

40 The Korean National Health Insurance Filgrastim,lenograstim - neutropenia: administer <500/mm 3 to 1,000/mm 3 - febrile neutropenia: administer <1,000/mm 3 to 3,000/mm 3 Pegfilgrastim (Neulasta ) pegteograstim, tripegfilgrastim, lipegfilgrastim - adjuvant TAC(docetaxel + doxorubicin + cyclophosphamide) - neoadjuvant dose-dense FEC (fluorouracil + epirubicin + cyclophosphamide)

41 BCIRG-005 trial Long-term outcomes after adjuvant treatment of sequential versus combination docetaxel with doxorubicin and cyclophosphamide in node-positive breast cancer - BCIRG-005 randomized trial AC-T TAC p value 10-year DFS rates 66.5% 66.3% Overall survival 79.9% 78.9% Febrile neutropenia 8% 17% (9%) < No difference in neutropenic infection Mackey et al. J Clin Oncol 2016

42 Mackey et al. J Clin Oncol 2016

43 FN in Korean patients without primary prophylaxis Lee et al. Breast Cancer 2014

44 Chemotherapy and the risk of febrile neutropenia G-CSF administration in current guidelines Prophylaxis of febrile neutropenia in breast cancer treatment Experiences of long-acting G-CSF

45 SCH Experiences of Adjuvant TAC 80 patients with adjuvant TAC (docetaxel plus doxorubicin and cyclophosphamide) (75/50/500 mg/m 2, every 3 weeks for 6 cycles) Grade 3/4 neutropenia Woo et al. J Breast Cancer 2012

46 SCH Experiences of Adjuvant TAC TAC AC-D Global health status(eortc QLQ-C30) Lee et al. Breast Cancer 2014

47 TAC with Long-acting G-CSF(Neulasta ) Adjuvant treatment of Node-positive breast cancer 38 patients(220 cycles) received TAC ANC profile Day 0,2 and 5 to 10 NRS report Day 1 to 10

48 ANC profile and nadir day0 day1 day2 day3 day4 day5 day6 day7 day8 day9 day10 106±23

49 ANC profile and nadir day0 day1 day2 day3 day4 day5 day6 day7 day8 day9 day10 (Data not shown in paper) TAC without primary prophylaxis(n=20) day0 day1 day2 day3 day4 day5 day6 day7 day8 day9 day10 day11 day12 day

50 Treatment-related events Incidence of FN: 15.7% Incidence of reduced RDI (<85%): 2.2% No treatment delay and treatment interruption Neutropenic infection: 0.9% (1 pneumonia and 1 UTI) Bone pain (NRS) day0 day1 day2 day3 day4 day5 day6 day7 day8 day9 day10 day21

51 FN in Korean patients without primary prophylaxis 15.7%

52 F/46 breast cancer patients Primary prophylaxis for Doxorubicin and docetaxel Left breast cancer with clinical stage IIIc (T3N2M0) Doxorubicin and docetaxel chemotherapy Primary prophylaxis of pegfilgrastim reimbursed by private insurance TA chemotherapy myalgia from day 5 to 7 In admission 1 st cycle Day 0 Day 2 Day 6 Day 7 Day 8 Day9 Day10 ANC(mcl) 3,175 5, ,153 3,583 5,495 2 nd cycle Day 0 Day 2 Day 6 ANC(mcl) 5,916 5, Outpatient visit

53 Summary Patients that have high risk of complication from FN should be identified and closely monitored Primary prophylaxis is recommended if the risk of FN is expected Primary prophylaxis of FN with long-acting G-CSF was useful during TAC treatment

54 Thank you for your attention