Treatment of Myelosuppression with

recently analyzed G-CSF prophylaxis in pediat- ric acute myelogenous leukemia AML patients treated on the AAML0531 Children’s Oncology Group COG study and found a signifi cant reduction in bacterial infection; this contrasts with Lehrnbecher et al. 2007 who reported that although G-CSF signifi cantly reduced time of neutropenia in the AML-BFM 98 trial, there was no decrement in episodes of febrile neutropenia, documented infections, infection-related mortal- ity or 5-year event-free survival. A meta-analysis of AML patients similarly found no benefi t of CSF prophylaxis in the prevention of infection Gurion et al. 2012 .

15.2.1.2 Prevention of Febrile Neutropenia, Delay

in Chemotherapy Delivery, or Dose Reduction Adult guidelines recommend consideration for CSFs in patients in which delay in chemotherapy delivery or dose reduction is known to be poten- tially harmful in treatment outcome Smith et al. 2006 ; ESMO 2007 ; Aapro et al. 2011 . Early phase I and II studies in adult patients have shown that reduction in chemotherapy delay can be achieved with G-CSF and GM-CSF Antman et al. 1988 ; Bronchud et al. 1989 . Pediatric data are unclear although the recently published improved survival in localized Ewing sarcoma patients who received compressed every 2-week therapy with G-CSF support as compared to the standard every 3-week arm implies there are situ- ations in which G-CSF may be benefi cial Womer et al. 2012 . Further data are required to make more generalized pediatric recommendations. As a corollary, G-CSF has been analyzed as a method to increase dose intensity since chemotherapeutic effect is directly related to the dose delivered Bonadonna and Valagussa 1981 ; Kwak et al. 1990 . Multiple pediatric studies have evaluated increased dose intensity with G-CSF support, and although these studies have shown the safety of this method, benefi t on outcome has not been delineated Woods et al. 1993 ; Kushner et al. 1994 ; White et al. 1994 ; Jones et al. 1995 ; Kushner et al. 1995 ; Michon et al. 1998 ; Fernandez et al. 2000 ; Kushner et al. 2000 ; Michel et al. 2000 ; Saarinen-Pihkala et al. 2000 ; Alonzo et al. 2002 . In the meta-analysis by Sasse et al. 2005 in pediatric ALL patients, CSF usage had no effect on chemotherapy delays.

15.2.1.3 Treatment of Febrile Neutropenia

As described, adult consensus guidelines recom- mend utilization of CSFs in patients with high- risk neutropenia which is variably defi ned as neutropenia for 7–10 days, profound neutrope- nia with ANC 0.1 × 10 9 L, as well as clinical situations including pneumonia, hypotension, sepsis syndrome with multiorgan failure, uncon- trolled primary disease and invasive fungal infec- tion Smith et al. 2006 ; ESMO 2007 ; Aapro et al. 2011 . In a meta-analysis of randomized con- trolled trials, Clark et al. 2005 found that the use of CSFs in established febrile neutropenia reduced hospital stay and neutrophil recovery with potential marginal effect on infection- related mortality; no subgroup analysis on patients defi ned as high-risk could be performed. Limited data exist in pediatric patients: three ran- domized prospective trials have shown shortened median hospital stays, days of antibiotic use, cost of treatment and a reduction in duration of the febrile neutropenic episode Riikonen et al. 1994 ; Mitchell et al. 1997 ; Ozkaynak et al. 2005 . Pediatric consensus guidelines suggest similar parameters for utilization of CSFs in febrile neu- tropenia as adult guidelines, recommending usage in patients with pneumonia, hypotension, multiorgan dysfunction and fungal infection as well as, potentially, prolonged neutropenia i.e., 28 days, bacterial sepsis and age 12 months Schaison et al. 1998 ; Lehrnbecher and Welte 2002 . Although no pediatric study has demon- strated that CSF usage impacts infection- related mortality, reduction in hospital stay and therefore cost are reasonable parameters to support CSF utilization, especially in the high-risk patient.

15.2.1.4 Treatment of Myelosuppression

with Radiation Therapy Adult guidelines recommend avoidance of CSFs during concomitant radiation therapy to the mediastinum due to a noted increased risk of mortality Smith et al. 2006 ; ESMO 2007 . The ASCO guidelines also warn against the use of CSFs when chemotherapy and radiation therapy are being administered jointly Smith et al. 2006 . No pediatric data are available to make recom- mendations for these clinical scenarios. The 2002 pediatric guidelines by Lehrnbecher and Welte recommend against G-CSF usage with concomi- tant chemotherapy and radiation therapy while no mention is made of utilization with radiation therapy alone.

15.2.2 Optimal Administration of Colony-Stimulating Factors

The optimal CSF formulation in pediatric oncol- ogy patients as well as the best dosing schedule, route of administration and timing of administra- tion must all be considered when administering CSFs.

15.2.2.1 Comparison of Granulocyte Colony-Stimulating Factor

and Granulocyte-Macrophage Colony-Stimulating Factor GM-CSF is not FDA approved for treating chemotherapy- induced myelosuppression or febrile neutropenia. A meta-analysis of G-CSF and GM-CSF trials for this purpose in adult oncology patients reported a signifi cantly increased rate of fever in patients receiving GM-CSF, a lack of head to head trials between GM-CSF and G-CSF, and GM-CSF being inef- fective in reducing febrile neutropenia compared with placebo Dubois et al. 2004 . EORTC adult guidelines recommend fi lgrastim, pegfi lgrastim or lenograstim not FDA approved with equipo- tency; ESMO recommends either fi lgrastim or pegfi lgrastim; and ASCO gives consideration for fi lgrastim, pegfi lgrastim and GM-CSF while cau- tioning that there is no long-term data with peg- fi lgrastim and no signifi cant comparative studies between G-CSF and GM-CSF Smith et al. 2006 ; ESMO 2007 ; Aapro et al. 2011 . Pediatric data are lacking. Lydaki et al. 1995 randomized a small cohort of pediatric oncology patients to G-CSF or GM-CSF and found a signifi cant delay in neutrophil recovery in those treated with GM-CSF although this had no bearing on antibi- otic usage or mean hospital stay.

15.2.2.2 Optimal Dosing Adult guidelines recommend dosing of 5 mcgkg

of fi lgrastim, 100 mcgkg of pegfi lgrastim max 6 mg and 250 mcgm 2 of sargramostim Smith et al. 2006 ; ESMO 2007 ; Aapro et al. 2011 . Few pediatric studies are available. Cairo et al. 2001 compared 5 and 10 mcgkg of G-CSF starting 24 h after intensive chemotherapy for 123 pediatric patients with relapsed or refractory solid tumors and found no signifi cant difference in time to ANC ≥1.0 × 10 9 L, incidence of infection, febrile days, incidence of hospitalization or overall sur- vival. A small pediatric study comparing 100 mcgm 2 vs. 250 mcgm 2 of GM-CSF showed that duration of neutropenia was signifi cantly shortened in the 250 mcgm 2 arm with a trend toward decreased duration of febrile neutropenia and no noted difference in side effects Kubota et al. 1995 .

15.2.2.3 Route of Administration

Although package inserts for CSFs consider intravenous and subcutaneous administration to be equipotent, adult data have found that 2–4 times dosing is required to achieve equivalent effect when either G-CSF or GM-CSF is given intravenous as compared to subcutaneous Eguchi et al. 1990 ; Kaneko et al. 1991 ; Stute et al. 1995 ; Honkoop et al. 1996 . Adult guide- lines all suggest subcutaneous administration for CSFs Smith et al. 2006 ; ESMO 2007 ; Aapro et al. 2011 . No pediatric data are available and no mention of route of administration is made in pediatric guidelines Schaison et al. 1998 ; Lehrnbecher and Welte 2002 . In the pediatric clinical setting, intravenous G-CSF is often used when the patient is admitted while subcutaneous dosing is given when at home with no dose adjustment.

15.2.2.4 Optimal Timing

Pediatric guidelines suggest initiation of CSFs 1–5 days after completion of chemotherapy while