Early stoppage versus continuation of antimicrobial therapy in low risk pediatric cancer patients with febrile neutropenia, before recovery of counts: a randomized controlled study

Febrile neutropenia is a common complication arising in paediatric cancer patients during course of chemotherapy. For long, in view of likely possibility of an adverse outcome, the approach in such cases has been to start empirical antimicrobials at the earliest. The choice of agents are modified as further investigations reveal any specific organism and, or depending on the clinical assessment of the patient. In a large number of cases, no definite focus of infection can be identified.  The optimal management approach (duration or inpatient /outpatient setting) is still debatable.

In adults, MASCC score (1) has long been followed to stratify febrile neutropenia patients into high risk and low risk category.  The high risk patients are should be managed on inpatient basis with empirical intravenous antibiotics in view of higher chances of complications. On the other hand, low risk group can be managed on outpatient basis with oral antibiotics. This criteria has been validated widely and has helped form various adult based febrile neutropenia guidelines. In paediatric patients, however, this criteria is not validated and has many limitations. The variables like COPD and age < 60 years are not applicable in children. Besides, presence of central venous catheter, a strong variable in adults might not be as major a variable in children, in view of its widespread use during chemotherapy and poor venous access

Various studies have been done in pediatric febrile neutropenia patients to stratifying them into risk groups (2-7). The criteria to divide patients into different risk groups have been variable. However, common criteria like hemodynamic stability, expected duration of resolution of neutropenia < 10days, no central venous catheter related infections, normal renal /hepatic functions, no pneumonia/ diarrhoea, and stable mental/neurological status, has largely been taken as surrogate for low risk patients (10,11).  Patients with signs of marrow recovery, defined variably by ANC ≥100 post nadir, AMC > 100 or a sustained rise in absolute phagocytic count  have been included in low risk group in some studies(5,). The antibiotics in high risk group have conventionally been continued till ANC > 500. This assumption is largely based on one small study by Pizzo et al (12), and thus the optimal duration is still not known.

In low risk patients, an oral antibiotics policy on outpatient basis has been proven to be equally efficacious (10, 11) and few studies, mostly retrospective (13,14)have shown that the duration of antibiotics can be shortened in this group. The basis of early discontinuation has largely been arbitrary.  The only randomized control trial done in pediatric patients with low risk of bacterial infections, based on clinical and laboratory parameters along with serial CRP values by Santolaya et al (14)showed a success rate of 94% vs 92% in continuation group versus stoppage group, in inpatient setting. In that study, bone marrow recovery was not an inclusion criteria. However, the study was very small and not adequately powered to answer the research question convincingly.  Lehrnbergs et al (15), recently, has inferred that antibiotics can be safely discontinued in low risk children with evidence of marrow recovery (Grade –IC), and also in children with no signs of marrow recovery, if intensive regular follow-up is ensured (Grade – 2B).

REFERENCES:

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SAMPLE SIZE: Presuming  95% success with or without continuing antibiotics and if we withdraw the antibiotics, this withdrawal is not inferior to continuing antibiotics with a non-inferiority margin of 5% and a power of 80%, with alpha - 5%, would require 235 patients in each arm.

the study started recruiting on 15/3/16.

However, post assessment of feasibility after an initial pilot study, a repeat calculation of sample size was done in Dec,2016 and another approval from ethics was taken for the new sample size of 71 patients in each arm ( non-inferiority margin-15%, power-80%, alpha-5%).