Treatment of Myelosuppression Clinical Usage of Myeloid Growth Factors

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 adult guidelines suggest 24–72 h Schaison et al. 1998 ; Lehrnbecher and Welte 2002 ; Smith et al. 2006 ; ESMO 2007 ; Aapro et al. 2011 . Limited adult and pediatric data have both shown that delay in CSF initiation does not lead to signifi - cant difference in mean duration of neutropenia, number of hospital days on parenteral antibiotics or number of febrile neutropenic episodes Ciernik et al. 1999 ; Hägglund et al. 1999 ; Lee et al. 1999 ; Rahiala et al. 1999 ; Hofmann et al. 2002 . Optimal timing for stoppage of CSFs is also poorly studied. Both pediatric and adult guidelines recommend continuing CSFs through the neutrophil nadir, approximately 7–10 days after chemotherapy Aapro et al. 2011 . The ideal ANC threshold for discontinuation of CSFs is unknown with guidelines recommending ANC 0.5–5 × 10 9 L as a potential stopping point Schaison et al. 1998 ; Lehrnbecher and Welte 2002 ; Smith et al. 2006 . ESMO guidelines sug- gest a suffi cient and stable recovery with no ANC threshold, although they do state the historical practice of continuing until ANC 10 × 10 9 L is unnecessary ESMO 2007 . The necessity of a daily dosing schedule i.e., versus every other day or other potential schedules has not been well studied in the literature and alternative schedules may potentially be equally effi cacious at a reduced cost Djulbegovic et al. 2005 . CSFs should be discontinued at least 24 h prior to the initiation of the subsequent chemotherapy cycle due to risk for enhanced myelosuppression by destruction of CSF-stimulated precursors by cell- cycle- specifi c chemotherapy Meropol et al. 1992 .

15.3 Erythropoietin

Erythropoietin EPO is a sialoglycoprotein pro- duced primarily in the cortical region of the kid- neys. EPO stimulates the proliferation and terminal differentiation of erythroid precursors in the bone marrow and is specifi cally stimulated by hypoxic conditions Krantz 1991 ; Jelkmann 1992 . In addition to effects on proliferation and differentiation, EPO has been shown to modulate apoptosis and increase erythrocyte survival time Masuda et al. 1999 . Additional studies have shown that EPO stimulates the proliferation and migration of endothelial cells in vitro and stimu- lates the expression of other angiogenic growth factors including vascular endothelial growth factor VEGF and placental growth factor Batra et al. 2003 . Recombinant human erythropoietin rhEPO was fi rst approved in 1989 for the treat- ment of anemia associated with chronic kidney disease and subsequently approved for the treat- ment of chemotherapy-induced anemia in patients with nonmyeloid malignancies. A second EPO-stimulating agent ESA, darbepoetin alfa, which has a 2–3-fold half-life compared with rhEPO, is also approved by the FDA for adult patients Zamboni and Stewart 2002 . Darbepoetin has undergone a phase I trial in pediatric patients with chemotherapy-induced anemia but is not approved in this population Blumer et al. 2007 . Multiple adult randomized controlled trials have shown that ESAs increase hemoglobin, reduce red blood cell transfusion requirements and improve quality of life in patients with che- motherapy- or radiation therapy-associated ane- mia Bokemeyer 2004 ; Bohlius et al. 2006 . Very limited data exist for pediatric oncology patients and has most recently been summarized by Shankar 2008 Porter et al. 1996 ; Csáki et al. 1998 ; Büyükpamukçu et al 2002 ; Wagner et al. 2004 ; Yilmaz et al. 2004 ; Razzouk et al. 2006 ; Abdelrazik and Fouda 2007 ; Çorapcioglu et al. 2008 ; Durmaz et al. 2011 . These studies are gen- erally with small cohorts of patients with a mix- ture of different pediatric malignancies and utilize variable doses, dose schedules, and routes of administration for rhEPO. The studies all show increased hemoglobin and decreased transfusion requirement as compared to controls. Quality of life data are limited, with only a subset of patients in the largest study showing signifi cant improve- ment Razzouk et al. 2006 . Data of effect on overall survival between the two groups are not ascertainable due to the small cohorts studied and was only reported in two studies Wagner et al. 2004 ; Durmaz et al. 2011 . Two adult trials of rhEPO in breast and head and neck cancer reported in 2003 were concerning