بسم الله الرحمن الرحيم

بسم الله الرحمن الرحيم

A COMPARATIVE STUDY FORTHE MANAGEMENT OFLOW RISK FEBRILE NEUTROPENICPEDIATRIC ONCOLOGY PATIENTSAT THE NATIONAL CANCERINSTITUTE (NCI) – EGYPT

INTRODUCTION & AIM OF WORK • Neutropenia is common after intensive • chemotherapy. Hospitalization and • intravenous broad spectrum antibiotics • are the standard of care for febrile • neutropenic pediatric oncology patients • because of the risk of serious complications • and associated mortality.

INTRODUCTION & AIM OF WORK • However, subgroups of patients are not necessarily the same, i.e. there are low risk patients and high risk patients. The latter group have a potential for high mortality and are considered of critical importance. • Low risk patients may not be hospitalized and can be • safely treated with parenteral or oral antibiotics. • Careful risk assessment and patient selection, appropriate • antimicrobial regimens and meticulous monitoring for • response or the development of complications or toxicity • are essential for the success of risk-based therapy.

INTRODUCTION & AIM OF WORK • The Aim of this Work is to assess :- • The safety and cost-effectiveness of outpatient • treatment with oral antibiotics in low risk • febrile neutropenic pediatric oncology • patients. • The correlation between various hematological • parameters (blood cultures and sensitivity, • CRP, IL6, IL8) as prognostic factors and to • detect type of infection in low risk febrile • neutropenic pediatric oncology patients.

PATIENTS & METHODS • This study was conducted on 160 episodes of 160 patients, who were randomly allocated from the pediatric oncology section of the National Cancer Institute , Cairo University, during the period from May 2001 to September 2003. • All patients were essentially chosen in a state of remission, with regards to their malignancies, and they were not receiving myeloablative therapy.

PATIENTS AND METHODS • They were randomized into two groups: Investigational (outpatient) Standardized (Inpatient) The sample size was determined assuming a minimum of 20% difference in cure rate, with a significant level not less than 0.05 and a power not less than 0.8.

PATIENTS AND METHODS INCLUSION CRITERIA • Age not more than two years (and not above sixteen). • Any Sex. • Monocyte count > 0.1 X 10 (9)/L. • Granulocyte count < 500/mm3 (but not less than 100 /mm3) • Both hematological and solid malignancies. • Expected duration of fever and neutropenia less than seven days. • Patients should be presenting without concurrent serious medical morbidity, and a stable cancer disease. • Compliant patients. • Travel distance from patient’s domicile to the hospital should not take more than an hour. • No organ failure.

PATIENTS AND METHODS EXCLUSION CRITERIA • Age less than two years (and above sixteen). • Monocyte count < 0.1 X 10 (9)/L. • Granulocyte count > 500/mm3 . • Expected duration of fever and neutropenia more than seven days. • Patients presenting with concurrent serious medical morbidity, and resistant or replacing cancer disease. • Non compliant patients. • Travel distance from patient’s domicile to the hospital exceeds • an hour. • Organ failure or hypotension. • Patient presenting with Mucositis or diarrhea or having a central line.

PATIENTS & METHODS Both the investigational and the standardized groups were thoroughly examined and underwent the following investigations :- - Complete blood picture. - Liver and kidney function tests. - Assessment of disease status. - Chest X-ray. - Blood culture ± other cultures according to the situation. - C-Reactive protein. - IL6 and IL 8.

METHODOLOGYa) Investigational Group This was an out-patient management. Patients received Amoxycillin – Clavulantic acid, and Quinlones (Ciprofloxacin) orally for seven days, during which the patient was followed by thorough clinical examination, complete blood count, and any other necessary investigations according to the situation, till granulocyte recovery (> 500/mm3), rising monocyte count, afebrible (more than two days) and stable patient situation.

METHODOLOGYa) Investigational Group • Patients received Amoxycillin – Clavulantic divided • doses every eight hours. • Patients also received Quinolones (Ciprofloxacin) • orally at 20-25 mg/Kg/day in two divided doses every • twelve hours. • Two blood cultures were taken from the patient from two different venipunctures on both day 1 and day 2. • After the end of day 3, if the patient was still febrile and neutropenic, a re-culture from the patient was done again and he was admitted to be treated as in-patient.

METHODOLOGYb) Standardized Group • This was an in-patient management. • Patients received 3rd generation cephalosporins (Ceflazidime) 100 mg/Kg/day in 3 divided doses and Aminoglycosides (Amikacin) 15 mg/Kg/day in 2 divided doses. • Two blood cultures were taken from the patient from two different venipunctures on both day 1 and day 2. • Re-culture from the patients were done according to the situation and on day 5 if necessary. • Addition or modification of the regimen is according to the cultures and to the situation.

Table (1) Clinical Characteristics of Patients included in the Study

Figure 1 - Percentage of hematological vs. non-hematological patients

Table (2) Percentage of Growth Pattern in Investigational & Standardized Groups

Table (3) Growth Pattern in Investigational & Standardized Groups

Figure (2) Pattern of Microbiological Growth in both Investigational & Standardized Groups

Table (4A) The Primary Response to Oral Antibiotics & Percentage of Patients Requiring Hospitalization in the Investigational Group

Table (4B) The Response of Standardized Group to Treatment and Percentage of Patients Requiring Shift or Addition of Antimicrobials

Table (5) Shift and/or Addition of Antimicrobials in Investigational and Standardized Groups

Table (6) Assessment of CRP in both The Investigational and Standardized Groups

Table (7) Correlation Between CRP with Shift and/or Addition of Antimicrobials Within The Investigational Group

Table (8) Correlation Between CRP with Recovery Time Within The Standardized Group

Table (9) Correlation Between CRP and Blood Stream InfectionIn both Investigational & Standardized Groups

Table (10) Correlation Between IL6 & IL8In both Investigational and Standardized Groups

Table (11) Correlation of IL6 and IL8 With the Outcome in both Investigational &Standardized Groups

Figure (3) - Correlation of IL6 & IL8 with the Outcome in both Investigational & Standardized Groups

Figure (4) – ROC Curve for IL6 & IL8 For Predicting Outcome

Table (12) Correlation Between IL6 & IL8 with Microbiological Growth in both Investigational &Standardized Groups

Figure (5) Correlation between IL6 & IL8 with Microbiological Growth in Both Investigational & Standardized Groups

Figure (6) ROC Curve for IL6 & IL8 as Predictors of BSI

Table (13) Correlation of IL6 and IL8 With CRP in Both Investigational &Standardized Groups

Figure (7) Correlation Between IL6 & IL8 With CRP In Both Investigational & Standardized Groups 121.8 17.3 11.9 16 10.6 11 Negative Positive <50 mg/L Positive > 50mg/L IL 8 IL 6

Table (14) Success & Failure Outcome in Both The Investigational & Standardized Groups

Table (15) - Analysis of Failure

Table (16) Antimicrobial Management Cost in Both The Investigational & Standardized Groups

Figure (8) Antibiotic Cost of Management In Both Investigational & Standardized Groups

CONCLUSIONS • It is both safe and cost-effective to treat low risk febrile neutropenic pediatric oncology patients with oral outpatient antimicrobials. • CRP level > 50mg/L may be a useful determinant for patients with blood stream infections and patients requiring shift to inpatient treatment .

IL 8 can be used as a useful determinant for blood stream infections, and outcome with a cut-off level 100 and 140 pg/mL respectively. • IL6 may be used as a determinant for blood stream infection and outcome with a cut-off level of 14.5 and 24.5 pg/mL respectively.

RECOMMENDATIONS • We recommend treating low risk febrile neutropenic pediatric oncology patients with oral outpatient Amoxycillin Clavulanic acid at 40-50 mg/Kg/day in three divided doses every 8 hours and Ciprofloxacin at 20-25 mg/Kg/day in two divided doses every 12 hours being both safe and cost-effective alternative to inpatient treatment.

We recommend further use of CRP as a determinant of blood stream infection, and in patient who might shift to inpatient treatment with a cut-off level of > 50mg/L. • We recommend the use of IL8 for determination of blood stream infection and outcome with a cut-off point of 100 and 140 pg/mL respectively. • However, these recommendations need further larger studies to evaluate their usefulness.

Thank You

بسم الله الرحمن الرحيم