Low-Risk Fever and Neutropenia in Children With Cancer: Safety and Efficacy of Oral Antibiotics in an Outpatient Setting

Condition(s) targeted: Fever; Neutropenia; Cancer

Intervention: ciprofloxacin and amoxicillin (Drug); Outpatient management (Procedure)

Phase: Phase 3

Status: Terminated

Sponsored by: Swiss Pediatric Oncology Group

Official(s) and/or principal investigator(s):
Roland A Ammann, MD, Study Chair, Affiliation: Pediatric Hematology/Oncology, University Children's Hospital, Inselspital, CH-3010 Bern, Switzerland
Christoph Aebi, MD, Study Director, Affiliation: University Children's Hospital, Bern, Switzerland
Maja Beck-Popovic, MD, Principal Investigator, Affiliation: Pediatric Hematology/Oncology, University Children's Hospital, Lausanne, Switzerland
Eveline SJM de Bont, MD, Principal Investigator, Affiliation: Pediatric Hematology/Oncology, University Children's Hospital, Groningen, The Netherlands
Thomas Kuehne, MD, Principal Investigator, Affiliation: Pediatric Hematology/Oncology, University Children's Hospital, Basel, Switzerland
David Nadal, MD, Study Director, Affiliation: University Children's Hospital, Zurich, Switzerland
Felix Niggli, MD, Principal Investigator, Affiliation: Pediatric Hematology/Oncology, University Children's Hospital, Zurich, Switzerland
Arne Simon, MD, Principal Investigator, Affiliation: Pediatric Hematology/Oncology, University Children's Hospital, Bonn, Germany
Nicole Bodmer, MD, Study Director, Affiliation: Pediatric Hematology/Oncology, University Children's Hospital, Zurich, Switzerland
Hulya Ozsahin, MD, Principal Investigator, Affiliation: Pediatric Hematology/Oncology, University Children's Hospital, Geneva, Switzerland

The purpose of this study is to determine whether, in children with cancer presenting with fever in severe chemotherapy-induced neutropenia at low risk for medical complications, oral antibiotics in an outpatient setting after an initial phase of intravenous antibiotics and in-hospital observation for 8 to 22 hours, is not inferior as to safety and efficacy compared to continued intravenous antibiotics given in-hospital.

Official title: A Prospective Multi-Center Study on Pediatric Patients With Fever in Severe Chemotherapy Induced Neutropenia, Including a Randomized Comparison of Outpatient Management and Oral Antimicrobial Therapy Versus Inpatient Management and Intravenous Antimicrobial Therapy in a Subgroup With Low Risk of Adverse Events (Low-Risk Subgroup Study)

Study design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study

Primary outcome:

Safety: No serious medical complication due to infection (death, treatment in ICU [Intensive Care Unit], potentially life-threatening complication) (non-inferiority-design, limit 3.5%)

Efficacy: Response without rehospitalization or changing randomized antibiotics (non-inferiority design, limit 10%)

Secondary outcome:

Improved prediction of low-risk episodes of fever and neutropenia

Description of characteristics of low-risk episodes of fever and neutropenia

Description of characteristics of high-risk episodes of fever and neutropenia (observational study part)

Detailed description: Details on antimicrobial therapy

- At presentation with FN (fever and neutropenia) and during an initial inpatient

observation period of 8 to 22 hours, empirical intravenous broad-spectrum antibiotics are given. Type and dosage are chosen by the treating physician.

- Patients randomized to continued intravenous antibiotics continue with these

antibiotics.

- Patients randomized to oral antibiotics receive a combination of oral ciprofloxacin (25

to 30 mg/kg/day, top dose 1500 mg/day) plus oral amoxicillin (65 to 80 mg/kg/day, top dose 2250 mg/day), both given in two doses per day.

- In both groups, the study gives guidelines (for certain situations) and rules (for other

situations) when to change and when to stop antibiotics.

Details on clinical and laboratory controls

- During antibiotic therapy, patients are seen daily, either as inpatients or as

outpatients according to randomization. Complete blood counts are performed at least every second day.

- After stopping antibiotic therapy and until resolution of severe neutropenia (if

applicable), patients are seen every other day, with a complete blood count.

- Patients randomized to outpatient management have the possibility to contact at any time

of the day (and night) a pediatric oncologist in case of problems, in order to discuss necessity for emergency control and/or rehospitalization.

Minimum age: 1 Year. Maximum age: 18 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Chemotherapy because of malignancy

- Severe neutropenia (absolute neutrophil count ≤ 0. 5x10E9/L)

- Fever (axillary temperature ≥ 38. 5°C once or ≥ 38. 0°C during ≥ 2 hours)

- Able to swallow oral medication

- Written informed consent from patients and/or parents

Exclusion Criteria:

- Status post myeloablative chemotherapy

- Diagnosis: acute myeloid leukemia, B-cell acute lymphoblastic leukemia, or B-cell

Non-Hodgkin lymphoma

- Bone marrow involvement by malignancy ≥ 25%

- Any comorbidity requiring hospitalization: [1] mean arterial blood pressure < 50 mmHg

(up to 10 years) / < 60 mmHg (older than 10 years); [2] oxygen saturation < 94% at room air; [3] radiologically defined pneumonia; [4] focal bacterial infection; [5] blood cultures taken at presentation reported positive at reassessment; [6] need for inpatient treatment or observation due to any other reason, as judged by the physician in charge

- Ever shaking chills

- Ever axillary temperature ≥ 39. 5°C

- Antibacterial treatment before presentation with fever and neutropenia (except for

prevention against Pneumocystis jiroveci [formerly P. carinii] pneumonia)

- Modification or de novo institution of a prophylaxis against P. jiroveci pneumonia

- Modification or de novo institution of a therapy with G-CSF or GM-CSF.

- Allergy to ciprofloxacin and/or amoxicillin

- Serum creatinine level above the upper limit of normal range

Pediatric Hematology/Oncology, University Hospital St. Hedwig, Regensburg D-93049, Germany

Pediatric Hematology/Oncology, University Children's Hospital, Bonn D-53113, Germany

Pediatric Hematology/Oncology, University Children's Hospital, Duesseldorf D-40225, Germany

Pediatric Hematology/Oncology, University Children's Hospital, Freiburg D-79106, Germany

Pediatric Hematology/Oncology, University Children's Hospital von Hauner, Munich D-80337, Germany

Pediatric Hematology/Oncology, University Children's Hospital, Groningen NL-9700, Netherlands

Pediatric Hematology/Oncology, University Children's Hospital, Basel CH-4005, Switzerland

Pediatric Hematology/Oncology, University Children's Hospital, Bern CH-3010, Switzerland

Pediatric Hematology/Oncology, University Children's Hospital, Geneva CH-1205, Switzerland

Pediatric Hematology/Oncology, University Children's Hospital, Lausanne CH-1011, Switzerland

Pediatric Hematology/Oncology, Children's Hospital, Lucerne CH-6004, Switzerland

Pediatric Hematology/Oncology, University Children's Hospital, Zurich CH-8032, Switzerland

The Swiss Institute for Applied Cancer Research (SIAK) is the umbrella organization of patient-oriented cancer research in Switzerland. The Swiss Pediatric Oncology Group (SPOG) is one of its three member organizations.

Related publications:

Ammann RA, Simon A, de Bont ES. Low risk episodes of fever and neutropenia in pediatric oncology: Is outpatient oral antibiotic therapy the new gold standard of care? Pediatr Blood Cancer. 2005 Mar 3; [Epub ahead of print] No abstract available.

Starting date: January 2004
Ending date: December 2007
Last updated: January 12, 2008