Optimal Timing Optimal Administration of Colony-Stimulating Factors

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 for increased mortality rates and increased dis- ease recurrence in the rhEPO treatment arm as compared to controls Henke et al. 2003 ; Leyland-Jones 2003 . Since that time, multiple meta-analyses have shown that survival may be worsened by utilization of ESAs, possibly sec- ondary to an increased risk of thromboembolic events which may be related to a high hemoglo- bin goal with rhEPO therapy Bohlius et al. 2006 ; Bennett et al. 2008 ; Bohlius et al. 2009 , 2010 ; Glasby et al. 2010 . No pediatric study has reported any case of venous thromboembolism secondary to rhEPO. Concern has also been raised due to the promotion of angiogenic growth factors and expression of antiapoptotic genes by EPO and potential effect on tumor cell growth Batra et al. 2003 ; Yasuda et al. 2003 . Batra et al. 2003 additionally reported the presence of EPO receptors and expression of EPO on pediatric tumor cells including neuroblastoma, Ewing sar- coma, Wilms tumor, rhabdomyosarcoma, hepato- blastoma, medulloblastoma, ependymoma and astrocytoma. Sartelet et al. 2007 similarly reported increased EPO-R expression on neuro- blastoma cell lines, although in vitro they were unable to show increased tumor cell proliferation with exogenous EPO. No study has shown an in vivo effect of ESAs on tumor proliferation and in a recent review Aapro et al. 2012 conclude that current clinical and preclinical data have not shown that ESAs have an effect on disease progression. Updated 2010 ASHASCO guidelines as well as the 2010 ESMO guidelines on the use of ESAs in adult oncology patients recommend a careful weighing of the risks and potential benefi ts of ESA therapy in patients with hemoglobin 10 g dL and nonmyeloid malignancies Rizzo et al. 2010 ; Schrijvers et al. 2010 . Concerns remain in regard to the stimulation of the leukemic clone and therefore ESAs are not recommended in leu- kemia, especially acute myelogenous leukemia Takeshita et al. 2000 . The combined guidelines recommend that ESAs should be used only in patients currently undergoing chemotherapy and should be used cautiously in patients undergoing therapy with curative intent and in those with risk for thromboembolism Rizzo et al. 2010 ; Schrijvers et al. 2010 . Additionally, patients should be monitored and treated for other etiolo- gies of anemia such as iron defi ciency and also monitored to ensure that hemoglobin does not increase over 12 gdL Glaspy and Cavill 1999 ; Rizzo et al. 2010 ; Schrijvers et al. 2010 . With the paucity of reported data, similar such guidelines are unavailable in the pediatric literature. For pediatric patients, the French National Cancer Institute concluded that: 1 systematic adminis- tration of ESAs is not recommended in pediatric cancer patients with anemia, 2 ESAs can be con- sidered on a case-by-case basis in those patients with a contraindication to red blood cell transfu- sion, and 3 intravenous ESA use is the preferred method of administration Marec-Berard et al. 2009 . From the adult oncology literature it is unclear if there is potency difference between subcutaneous and intravenous rhEPO administra- tion although studies in adult hemodialysis patients have shown that subcutaneous injection is approximately 30 more effective Kaufman et al. 1998 ; Galliford et al. 2005 ; Vercaigne et al. 2005 . In his editorial response to the French guidelines, Feusner 2009 concurs that evidence is lacking to support ESA use in pediatric oncol- ogy patients as their benefi t in quality of life and cost-effectiveness in this patient population as well as their potential risks in regard to tumor pro- gression, overall survival and thromboembolism are unclear.

15.4 Platelet Growth Factors

Platelet transfusion remains the only method for treatment of clinically signifi cant thrombocytope- nia in pediatric oncology patients. Multiple growth factors have in vitro stimulatory effects on platelet production, but only IL-11, stem cell fac- tor and thrombopoietin TPO have shown in vivo benefi t Broudy et al. 1995 ; Kuter et al. 1999 ; Kaushansky 2005 ; Bhatia et al. 2007 ; Zeuner et al. 2007 . Only IL-11 is approved for chemotherapy-induced thrombocytopenia and only in adult patients. TPO-receptor antagonists have been approved for the treatment of adult immune thrombocytopenic purpura ITP but as