Erythropoietin Supportive Care in Pediatric Oncology irantextbook.ir 93df

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 yet have not been found effective for the treatment of chemotherapy-induced thrombocytopenia. Multiple additional agents including IL-1, IL-3, IL-6 and GM-CSF have been attempted and found ineffective, to have unacceptable toxicity or lead to antibody development O’Shaughnessy et al. 1996 ; Jones et al. 1999 ; Miller et al. 1999 ; Demetri 2001 ; Farese et al. 2001 ; Vadhan-Raj et al. 2005 .

15.4.1 Interleukin-11

Interleukin-11 stimulates megakaryocyte matura- tion in addition to effects on bone, chondrocytes, neurons, adipocytes as well as gastrointestinal and bronchial epithelium Musashi et al. 1991 ; Teramura et al. 1992 ; Orazi et al. 1996 ; Du and Williams 1997 . Studies in adult solid tumor patients have shown benefi t in platelet count and subsequent need for platelet transfusion with no benefi t in patients with AML and no benefi t in overall survival Gordon et al. 1996 ; Tepler et al. 1996 ; Isaacs et al. 1997 ; Vredenburgh et al. 1998 ; Giles et al. 2005 ; Cripe et al. 2006 ; Usuki et al. 2007 . Only one study has been conducted in pediatric patients. Cairo et al. 2004 reported on 47 patients with solid tumors who received IL-11 after ifosfamide, carboplatin and etoposide che- motherapy. The study compared results to his- toric controls and found a decreased median time to platelet recovery and need for platelet transfu- sion although there were signifi cant noted side effects including the development of IL-11 anti- bodies, papilledema, periosteal bone changes, cardiomegaly, edema and tachycardia Cairo et al. 2004 .

15.4.2 Thrombopoietin Receptor Agonists

TPO is the primary regulator of megakaryopoie- sis and has shown both in vitro and in vivo effects with increase in platelet counts in 5–14 days in normal bone marrow Kaushansky et al. 1994 ; Kuter et al. 1994 ; Kaushansky 1998 . Although the original recombinant products, recombinant human TPO and recombinant human megakaryo- cyte growth and development factor, were shown to increase platelet counts, both were discontin- ued due to development of platelet- neutralizing antibodies Li et al. 2001 ; Basser et al. 2002 . Prior to discontinuation, both agents had shown benefi ts in children and adults with solid tumors with a trend toward decreased platelet transfusion and level of thrombocytopenia; benefi t on sur- vival was not reported and important side effects included risk for thromboembolism and dose- dependent thrombocytosis Basser et al. 1997 ; Fanucchi et al. 1997 ; Basser et al. 2000 ; Vadhan- Raj et al. 2000 , 2003 ; Angiolillo et al. 2005 ; Muskowitz et al. 2007 . Second-generation TPO-receptor antagonists, notably TPO peptide mimetic romiplostim and non-peptide mimetic eltrombopag, have shown dose-dependent increases in platelet count with- out the development of neutralizing antibodies and both drugs have been FDA approved for the treatment of ITP in adult patients Bussel et al. 2006 ; Andemariam et al. 2007 ; Bussel et al. 2007 ; Jenkins et al. 2007 ; Kuter et al. 2008 ; Bussel et al. 2009 . Two small, randomized, pla- cebo-controlled studies in pediatric patients with ITP have similarly shown benefi t with no signifi - cant short-term side effects Bussel et al. 2011 ; Elafy et al. 2011 . No study has been published using second-generation TPO-receptor antago- nists in chemotherapy-induced thrombocytope- nia Andemariam et al. 2007 . Although longer-term treatment in adult ITP patients has been shown safe, further study on the long-term effect of these agents in pediatric patients, espe- cially in regard to the potential for thrombosis, tumor or leukemic cell growth, development of neutralizing antibodies and increased bone mar- row reticulin or collagen deposition, is warranted Kuter 2007 ; Gernsheimer 2008 ; Kuter et al. 2013 .

15.5 Summary

Although several recombinant human hematopoi- etic growth factors are approved and in clinical use for adult patients, only G-CSF and GM-CSF are approved in children with cancer. Pediatric