Management of Anemia Hematologic Toxicity

cancers. Nordsmark et al. 2005 showed that tumor hypoxia, independent of hemoglobin con- centration, was singularly associated with poor outcomes in adult patients with head and neck cancers. Multiple xenograft studies have shown a potential benefi t with the use of erythropoietin EPO-stimulating agents ESAs to increase tumor radiosensitivity and potentially improve patient outcomes Pinel et al. 2003 ; Stüben et al. 2003 ; Ning et al. 2005 . Yet, clinical studies with uterine cervix and head and neck cancers and a recent Cochrane review of adult patients with head and neck cancers have failed to show a ben- efi t in outcome with ESAs concurrent with RT Thomas et al. 2008 ; Hoskin et al. 2009 ; Lambin et al. 2009 . Additionally, meta-analyses of ESA usage in adult patients are troubling due to increased risk of thromboembolism and possible increased mortality Bohlius et al. 2006 ; Bennett et al. 2008 . Pediatric data are lacking. Recently updated American Society of Hematology ASH and ASCO guidelines by Rizzo et al. 2010 rec- ommend ESAs with caution for adult patients with chemotherapy-induced anemia and hemo- globin hgb 10 gdL. No mention is made of ESA usage for treatment of radiation-induced anemia. Pediatric consensus guidelines by the French National Cancer Institute recommend avoiding systematic administration of ESAs in pediatric cancer patients with anemia Marec- Berard et al. 2009 . Without any pediatric data, it is diffi cult to imply what potential benefi t transfusion may impart to solid tumor patients, such as patients with soft tissue sarcomas, undergoing radiother- apy. Patients with leukemia, lymphoma and germ cell tumors will likely not benefi t due to the inherent radiosensitivity of such tumor types. Additionally, it is unclear what level of hemoglo- bin would be optimal for radiosensitization. In the adult head and neck cancer studies, hgb 13 gdL was prognostic although again transfu- sion did not prove useful in altering outcomes Dunst et al. 2003 ; Prosnitz et al. 2005 . The cer- vical cancer studies, on the other hand, showed benefi t of transfusion, keeping the hgb ≥12 gdL Grogan et al. 1999 ; Thomas 2001 . Survey of pediatric oncologists’ blood transfusion practice with concurrent radiotherapy showed a bimodal distribution, with 47 of respondents transfus- ing for hgb 9 gdL Wong et al. 2005 . This again underscores the lack of clear evidence- based guidelines to provide for a more uniform treatment strategy, with data to date not support- ing transfusion.

13.3 Central Nervous System

Complications Risk factors for radiation-induced brain and spinal injury include higher total radiation dose, increased dose fractions e.g., 180–200 cGy dose, extended radiation fi eld volume and concomitant usage of central nervous system CNS toxic drugs such as intrathecal methotrex- ate New 2001 ; Butler et al. 2006 ; Chopra and Bogart 2009 ; Rinne et al. 2012 . The developed brain is able to tolerate high total RT doses with a 5 chance of radiation necrosis with daily frac- tionated doses to a total effective dose of 120 Gy Lawrence et al. 2010 . In comparison, the adult brain stem and spinal cord can tolerate effective doses of 54 Gy Kirkpatrick et al. 2010 ; Mayo et al. 2010 . Maximum standard of care doses are generally below these threshold levels. Acute neurologic complications include par- esthesias, seizures, encephalopathy, myelopathy, paralysis and coma and are most likely secondary to underlying brain and spinal pathology and the resulting alteration in the blood-brain barrier and tumor edema and potential mass effect which occurs with RT Keime-Guibert et al. 1998 ; Chopra and Bogart 2009 ; Soussain et al. 2009 ; Rinne et al. 2012 . Management of these symp- toms may require hospitalization as well as medi- cations such as anticonvulsants and steroids e.g., dexamethasone to reduce symptomatic edema. Unlike adults, radiation fatigue has not been reported in pediatric patients and is likely quite rare in this population. Methylphenidate can be used to treat fatigue as in adults if present Butler et al. 2006 . Somnolence syndrome, a subacute toxicity, has been reported in pediatric patients undergoing CNS irradiation Sect. 13.3.1 . Late complications include cerebral edema, radionecrosis, leukoencephalopathy, neuroen- docrine dysfunction, neurocognitive delay and secondary development of brain tumors; a discus- sion of these is beyond the scope of this chapter Keime-Guibert et al. 1998 ; Butler et al. 2006 ; Chopra and Bogart 2009 ; Soussain et al. 2009 ; Rinne et al. 2012 .

13.3.1 Somnolence Syndrome

Somnolence syndrome was fi rst described in 1929 in children receiving scalp irradiation for the treatment of ringworm and has since become asso- ciated with prophylactic cranial irradiation in chil- dren with acute lymphoblastic leukemia ALL Freeman et al. 1973 . Freeman et al. 1973 noted that 39 of ALL patients developed pronounced symptoms including lethargy, excessive sleeping up to 20 h per day, anorexia, headache, irritability, fever, nausea and vomiting and transient cognitive dysfunction. An additional 39 had mild symp- toms. All patients received 24 Gy cranial irradiation spinal irradiation ranged from 10 to 24 Gy and there was no difference in frequency in somnolence between those children that received concomitant intrathecal methotrexate versus those who received RT alone. Mean onset of symptoms was 38 days after the completion of RT with symptoms resolv- ing spontaneously without neurologic sequelae in a median of 18.5 days. Electroencephalogram done in a small subset of patients showed rhythmic slow- ing which improved with resolution of symptoms. Somnolence syndrome has also been reported after total body irradiation TBI with HSCT and in adult patients with primary brain tumors Miyahara et al. 2000 ; Powell et al. 2011 . Follow-up studies have confi rmed the fi ndings of Freeman et al. 1973 , showing a frequency of symptoms ranging from 58–71 of patients Parker et al. 1978 ; Ch’ien et al. 1980 ; Littman et al. 1984 ; Vern and Salvi 2009 . Berg et al. 1983 performed neuropsychological testing on 48 chil- dren with ALL 1.5 and 3.75 years after somnolence syndrome and found no signifi cant difference in cognitive function compared to 31 children with ALL who had not experienced somnolence after RT. Littman et al. 1984 compared the daily frac- tionated dose of RT, giving 100 and 180 cGy to a total dose of 18 Gy, and found the same rate of somnolence syndrome in both groups. Symptoms of somnolence syndrome are thought due to demyelination injury of oligodendrocytes Butler et al. 2006 ; Rinne et al. 2012 . Two studies have looked at prophylactic administration of steroids during RT. Mandell et al. 1989 showed a 3 incidence of symp- toms in patients receiving daily prednisone ≥15 mgm 2 and Uzal et al. 1998 reported an incidence of 17.6 in patients receiving 4 mgm 2 of daily dexamethasone there was no signifi cant difference between studies due to small patient numbers. Current pediatric ALL protocols do not recommend prophylactic ste- roids during RT secondary to the lack of large multicenter prospective trials. Steroid treatment at the onset of symptoms has also shown benefi t in reducing the duration of illness Butler et al. 2006 ; Kelsey and Marks 2006 ; Rinne et al. 2012 .

13.3.2 Lhermitte’s Sign

Lhermitte’s sign is a transient spinal radiation myelopathy which occurs after cervical irradia- tion and presents with electric-like sensations in the spine and extremities with neck fl exion thought to be secondary to transient demyelin- ation of the cord Keime-Guibert et al. 1998 ; Chopra and Bogart 2009 ; Soussain et al. 2009 . It has not been specifi cally reported in pediatrics but could presumably occur with a spinal tumor, especially in adolescent patients considering their increased vulnerability to spinal cord injury with radiation or intrathecal chemotherapy Bleyer et al. 2009 . Spontaneous clinical improvement occurs in months Chopra and Bogart 2009 ; Soussain et al. 2009 .

13.4 Skin Complications

Acute radiation skin changes are seen in up to 85–95 of adult patients undergoing RT though may be decreased in incidence with IMRT and