Presentation on theme: "Prof. Jean Klastersky, MD, PhD"— Presentation transcript:
1Prof. Jean Klastersky, MD, PhD Febrile Neutropenia revisited : what has been learnt and what remains to be learned ?Prof. Jean Klastersky, MD, PhDInstitut Jules Bordet,Université Libre de BruxellesBrussels, Belgium
3The risk of infection increases with the severity and duration of neutropenia G.P. Bodey, Ann Int Med, 1966
4Febrile Neutropenia Historical Background First description around 1900Rare until development of chemotherapyIn the 1960s: mainly in acute leukemia with profound neutropenia Gram negative sepsis common with 90 % mortalityEmpirical therapy with synergistic combinations of antibiotics reduced mortality to + 10 %In the1980s: development of chemotherapy for solid tumors leading to less severe and less protracted neutropeniasFor multiple reasons, replacement of Gram negative infections by Gram positive severity of infections decreasesFN becomes a heterogeneous syndromeRisk-stratification models allow for identification of low risk patients with additional treatment optionsIncrease of fungal sepsis in specific groups of neutropenic patients leads to widespread use of empirical antifungal agents
5Prevention is essential; should the present indications for G-CSF use be extended ? 2) Empirical antimicrobial therapy remains a basic rule; can it be adapted to the risk of complications ?3) Occult fungal infections are common in patients with prolonged neutropenia; what do we need : empirical or pre-emptive treatment and/or earlier diagnosis ?
6Updated meta-analysis of prophylactic G-CSF: Infection-related mortality DiseaseCitation0.10.20.5125Relative Risk (95% CI)DoorijianGisselbrechtPettengell0.5410.9860.2970.9764.6910.2030.9516.4260.141All Lymphoma0.6081.0370.357BuiChevallierCrawfordFossaTrillet-LenoirTimmer-BonteVogel1.17456.8610.0240.96847.9920.0201.0955.2930.2260.3361.2130.0930.3283.0730.0350.4611.7820.1190.2014.1720.010All Solid Tumors0.4700.9340.237Combined0.5490.8360.360Favours G-CSFFavours No G-CSFN.M. Kuderer, JCO, 2007
7Current Guidelines for primary prophylaxis with G-CSFs FN risk levelASCOEORTCNCCNModerate to high(> 20 %)Use G-CSFsIntermediate(10-20 %)RecommendConsiderLow (< 10 %)NotspecifiedNot recommendedConsider other risk factors than intensity of chemotherapy++++++7
8Secondary prevention of subsequent FN in patients who had a first episode CRAWFORD (1991)(n=59 SCLC)LALAMI (2001)(n=48 breast ca)Incidence of FN after the first cycle of chemotherapy (without CSF)100%Incidence of FN after the second cycle of chemotherapy (with CSF)23%6%
9Outcome of FN and univariate analysis Resolution without complication : 363/416 (87%, 95% CI : 84%-90%)Resol.Compl.DeathRisk of FN < 10%18019 (9%)9 (4%)Risk of FN 10%-20%12315 (10%)9 (6%)Risk of FN > 20%6011 (16%)0 (0%)No use of prophylactic growth factors1671881061394810Use of growth factors117212
10Optimal schedule for G-CSF Schedules for G-CSF in breast cancer with a 7% risk of Febrile Neutropenia480 µg/day days 8 -14480 µg/day, days 8, 10,12,14300 µg/day days 8 -14300 µg/day days 8,10,12,14*300 µg/day days 8 and 12*equivalent to the other schedules with respect to grade 3 and 4 neutropeniaP. Papaldo et al., J Clin Oncol, 2005
11Incidence of febrile episodes, probable infections, and hospitalization for infection* Levofloxacin(N=781)Placebo(N=784)Relative Risk(95 % CI)P ValueNb of patients (%)Febrile episode27 (3.5)62 (7.9)0.44 (0.28 – 0.68)< 0.001Probable infection109 (14.0)152 (19.4)0.72 ( )0.005Hospitalization for infection52 (6.7)81 (10.3)0.64 (0.46 – 0.90)0.01* No effect on mortalityM. Cullen et al., NEJM, 2005
12Prophylactic levofloxacin to prevent bacterial infection in patients with hematological cancer and neutropeniaPlaceboLevofloxacinFebrile Neutropenia*308/363 (85 %)243/375 (65 %)*p = 0.001(Mortatility and tolerability : similar)GIMEMA, NEJM, 205
13Prevention (antibiotics or G-CSF’s) is essential; should the present indications be extended ? 2) Empirical therapy with broad spectrum antibiotics remains a basic rule; to be adapted to the risk of complications !3) Occult fungal infection should be suspected early in patients with prolonged neutropenia; do we need empirical or pre-emptive treatment ?
14Empirical therapy with carbenicillin plus gentamicin reduced dramatically (21 %) the mortality associated with Pseudomonas sepsisPs. aeruginosa
15Score derived from the logistic equation of the MASCC predictive model (1386 patients with FN) CharacteristicPointsBurden of illnessNo or mild symptoms5Moderate symptoms3No hypotensionNo chronic obstructive pulmonary disease4Solid tumor or no previous fungal infection in hematological caOutpatient statusNo dehydrationAge < 60 years2Threshold: score ≥ 21(maximum 26) predicting lessthan 5% of severe complicationsJ. Klastersky et al., J. Clin. Oncol. 2001
16Medical complications considered serious Hypotension : systolic blood pressure less than 90 mmHgRespiratory failure : arterial oxygen pressure less than 60 mmHgDisseminated intravascular coagulationConfusion or altered mental stateCongestive cardiac failure seen on chest x-ray and requiring treatmentBleeding severe enough to require transfusionArrhythmia or ECG changes requiring treatmentRenal failure requiring investigation and/or treatment with IV fluids, dialysis, or any other interventionJ. Klastersky et al., JCO, 2000
17Response to empiric antibiotic therapy 47 (81 %) 2 (9%) Response rates and final outcome of low- and not low-risk patients with febrile neutropenia as predicted y the MASCC risk-index scoreLow risk (n=58)Not low risk (n=22)Response to empiric antibiotic therapy47 (81 %)2 (9%)Resolution without complications57 (98 %)3 (14 %)Death before resolution0 (0%)8 (36 %)A. Uys et al., Supp. Care Cancer, 2004p < 0.001
18Innes et al., Brit. J. Cancer, 2003 Oral Antibiotics with early hospital discharge compared with In-patient intravenous antibiotics for low-risk FN in cancer patients: a prospective randomized studyIntravenous ABIn patient(60)Oral ABOut patient(66)Death1Serious complicationsIntolerance to AB3Persistance of fever56Mean cost per episode (£)840470Mean nursing hours per episode2111Innes et al., Brit. J. Cancer, 2003
21Occurrence of serious medical complications Overall (all orally treated patients)9/178 (5 %)Patients discharged early0/79 (0 %)Patients not discharged early9/99 (9 %). patients with persisting fever4/19 (21 %). patients with medical reason4/42 (9 %). patients without medical reason2/38 (2%)J. Klastersky et al., 2005
23ConclusionsSimplified management of FN (oral and ambulatory) has great potential for quality of life and cost reductionOur study suggests that it is feasible and safe in a significant proportion (44 %) of patients predicted to be at low risk of complications using the MASCC scoreObservation for hours seems critical even if criteria for early discharge are fullfilled; 9 % of patients maintained hospitalized for« good » or « bad » reasons developed severe complicationsLow risk prediction and suitability for oral outpatient treatment are to some extent different issues; safe prediction of the feasibility of early discharge remains to be established.
24Mortality in 3190 patients with febrile neutropenia 30 days after entry (IATCG trials Vb, VIII, IX and XIBacteremia (%)No Bacteremia (%)No evaluable patients8052385Causes of DeathInfections Infections + other*other*48 (5.9)20 (205)29 (3.6)71 (2.9)35 (105)83 (3.5)P=0.001Total n° of deaths97 (12.0)189 (7.9)P=0.003(*) mainly hemorrhage and extensive cancer
26Outcome and distribution : complicated versus uncomplicated bacteremias Single gram positiveSingle gram negativePolymicrobialTotalComplicationsDeathsClinical site of infection12821 %5 %8223 %2516 %No clinical site of infection15519 %8624 %13 %2330 %9 %J. Klastersky et al., J. Antimicrob. Chemother., 2007
27Mortality rate in bacteremic patients stratified by classes of the MASCC score and type of bacteremiaMASCC scoreGram+Gram-Total (Nr.)Deaths (%)< 151828234315-2089664≥ 21176281Klastersky et al., J. Antimicrob. Chemother., 2007
28Factors predicting bacteremia* (multivariate analysis) High fever (> 39°C)P < 0.001Presence of shockClinical site of infectionP = 0.04Antifungal prophylaxisPlatelets > /ulDuration of granylocytopenia > 6 days* « when tested in the validation set, the model was poorly predictive »Adapted from Viscoli et al., Europ. J. Cancer, 1994
29ROC curves for predicting mortality in the test population (N = 1003) AUC :MASCC : 0.778, 95% CI :MASCC + B : 0.790, 95% CI :MASCC + GNB : 0.791, 95% CI :
30We can predict the high risk patients What can we do for improving the outcome of FN in that subset of patients ?
31Combination(cephalosporin + amikacin) Response to empiric combination antimicrobial therapy vs monotherapy in patients with leukemiaCombination(cephalosporin + amikacin)Monotherapy(cephalosporin)Klastersky et al. (1988)6/121/16Tamura et al. (2004)33/4524/4539/57 (68 %)25/61 (40 %)
32Therapeutic CSF: Infection-Related Mortality CitationEffectLUAnaissie0.3200.0323.184Aviles0.2740.0930.810Biesma3.7830.141Garcia-Carb1.4410.2368.809Lopez-Hern0.4250.0355.106Mayordomo1.6800.16916.664Ravaud0.3240.0138.229Combined0.5260.2691.0310.010.1110100Favours CSFFavours No CSF
34Description of patients with death within 2 weeks of Emergency Department presentation among a total of 48 admitted for neutropenic feverAgeGenderMalignancyPositive EDblood culturesICUMASCCscoreDescription of death55FAMLNoFrom ED8Improving 2 days prior to death suddenly with cardiac arrest35Group g strepFrom floor12Aspergillosis on lung biopsy, respiratory failure, DNR decided58MWaldenstrom’s21Bacteremia, intracranial bleed, respiratory failure, DNR decided57Was discharged recently but readmitted to palliative care, DNR decided80Enterobacter19Bacteremia, pneumonia, respiratory failure, DNR decided93MyelodysplasiaDNR decidedDM Courtney et al; The Oncologist, 2009
35Prevention (antibiotics or G-CSF’s) is essential; should the present indications be extended ? 2) Empirical therapy with broad spectrum antibiotics remains a basic rule; be adapted to the risk of complications !3) Occult fungal infection should be suspected early in patients with prolonged neutropenia; do we need empirical or pre-emptive treatment ?
36Randomized Studies Comparing Empirical Treatment with Antifungal Agents for Persisting Fever during NeutropeniaYEARSTUDYANTIFUNGAL AGENTS COMPARED198219891996199819992000200120022004Pizzo et alEORTCViscoli et al.Malik et al.White et al..Walsh et al.Winston et al.Wingard et al.Boogaerts et al.Conventional ampho B vs no antifungal therapyConventional ampho B vs fluconazoleConventional ampho B vs ampho B colloidaldispersionConventional ampho B vs liposomal ampho BLiposomal ampho B vs ampho B lipid complexConventional ampho B vs itraconazoleLiposomal ampho B vs voriconazoleLiposomal ampho B vs caspofungin3636
37FAILURES of Empirical Antifungal Therapy in Microbiologically Demonstrated Fungal Infections (FI) Liposomal ampho BVoriconazoleCaspofungin(961)(415)(556)Breakthrough FI45 (4.6)8 (1.9)29 (5.2)No cure of base line FI22 (2.2)7 (1.6)13 (2.3)Total failures*67 (6.9 %)15 (3.6 %)42 (7.7 %)*p = 0.03J. Klastersky, NEJM, 2004
38Prevalence of fungal infections in persistently neutropenic patients not receiving empirical therapy Pizzo et al. (1982)18EORTC (1989)28*Guiot et al. (1993)26*Corey and Boeckh (2002)45Maertens et al. (2005)21* Autopsy-based data
39Empirical vs pre-emptive approach (PE) Empirical versus preemptive therapy in febrile neutropenic patients not responding patients to empirical broad spectrum antibiotic therapyEmpirical vs pre-emptive approach (PE)ResultsEPE150 patients143 patientsDiagnosed IFI4 (2.6 %)13 (9.0 %)P < 0.02Overall survival147 (98 %)136 (95 %)NSIFI related mortality0 (0 %)3 (2.1 %)P = 0.12Mean cost (euros)3.5953.745C. Cordonnier et al., Blood, 2006
40What do we need beyond empiric of pre-emptive therapy of suspected fungal infections in febrile neutropenic cancer patients ?Predictive models of patients at risk of developing fungal infectionsEarly and specific tools for diagnosing fungal infection and monitoring therapyMore reliable antifungal therapies
41ConclusionsPrevention is essential : the indications for G-CSF should be extended to « low risk » patients with solid tumorsEmpirical antimicrobial therapy : should be supplemented with more pathophysiologically-oriented approaches and early intensive care in high risk patientsOccult fungal infections : require definition of high riskgroups and earlier specific diagnosis, in addition to empirical therapy
42The past two decades have witnessed major progress in the supportive management of cancer patients who develop fever and neutropenia. Morbidity and mortality have been dramatically reduced, and for many patients therapies are simplier, less toxic and more appropriately delineated according the patient’s risk status. Despite these progresses, however, numerous challenges remain to be addressed and important problems to be solved
43Thank you foryour kind attentionand« Au revoir »