Management of Neutropenia Hematologic Toxicity

2009 recommending primary prophylaxis with CSFs in high- risk situations including ANC 1.5 × 10 9 L due to radiotherapy of 20 of the bone marrow Crawford et al. 2009 . Small adult studies have shown a decrease in RT treatment interruption secondary to neutropenia with the use of G-CSF; yet, what effect, if any, this had on local control and outcome are unclear MacManus et al. 1993 , 1995 ; Fyles et al. 1998a ; Su et al. 2006 ; Kalaghchi et al. 2010 . Larger meta- analyses on the use of G-CSF after chemotherapeu- tic regimens and hematopoietic stem cell transplant HSCT have failed to show an improvement in overall survival and transplant- related mortality Dekker et al. 2006 ; Sung et al. 2007a ; Center for International Blood and Marrow Transplant Research et al. 2009 . A potential benefi t in mor- bidity from radiation- induced neutropenia is unclear although no study has shown any signifi - cant risk or toxicity with the use of CSFs beyond bone pain and local reactions. Similarly, there are no data in regard to the timing of CSF delivery; for instance, CSFs could be used as primary prophy- laxis to prevent the development of neutropenia in high-risk cases or secondarily to treat neutropenia once it has occurred. Current pediatric treatment protocols suggest the use of CSFs in both such cases. See Chap. 15 for more detail on CSF usage. Table 13.1 Summary of management strategies and level of evidence for common acute and subacute pediatric radiation- induced toxicities a Organ RT side effect Treatment Level of evidence b Hematologic Neutropenia Consider G-CSF see Chap. 15 for more detail 1C Thrombocytopenia Platelet transfusion 1C Anemia Red blood cell transfusion; erythropoietin EPO- stimulating agents should not be utilized 1C Skin Dermatitis Lotion, topical steroid 0.1 mometasone furoate to preventtreat irritationpruritus; other treatments or no therapy may be equally effi cacious 2C Moist desquamation Hydrocolloidhydrogel dressings for comfort 2C Ulcerationnecrosis Referral to wound care specialist 1C CNS Somnolence syndrome Dexamethasone 4 mgm 2 day until improvement in symptoms 1C Head and neck Oral mucositis Pain management with morphine PCA, fl uid and nutritional assessment; benzydamine, LLLT, and palifermin not yet recommended see Chap. 11 for more detail 1C Xerostomia IMRT for salivary gland sparing; oral mucosal lubricants salivary substitutes; consider pilocarpine, acupuncture 1C Gastrointestinal Esophagitis Supportive care with nutritional assessment and H 2 blocker or PPI for GER; consider promotility agent, rule out infectious etiologies 1C Nauseavomiting Supportive care with nutritional assessment; 5-HT 3 receptor antagonist ± dexamethasone see Chap. 10 for more detail 1C GI mucositis Bowel care and nutritional assessment; loperamide for diarrhea; atropine or octreotide for refractory cases; Lactobacillus spp. or sulfasalazine not yet recommended 1C Lung Pneumonitis Antitussive; prednisone 1–2 mgkgday 2C Bladder Cystitis Anesthetic agents e.g., pyridium and antispasmodics e.g., oxybutynin; copious bladder irrigation for hemorrhagic cystitis, consider HBO or intravesical therapy 1C RT radiation therapy, GCSF granulocyte colony-stimulating factor, CNS central nervous system, PCA patient-controlled analgesia, LLLT low-level laser therapy, IMRT intensity-modulated radiation therapy, PPI proton pump inhibitor, GER gastroesophageal refl ux, GI gastrointestinal, HBO hyperbaric oxygen a See text for full detail b Per Guyatt et al. 2006 ; see Preface 13 Management of Acute Radiation Side Effects

13.2.2 Management of Thrombocytopenia

Platelet transfusion remains the mainstay of treatment for radiation-induced thrombocytope- nia. Guidelines are lacking in both the adult and pediatric literature as to what the appropriate threshold for platelet transfusion should be and thus transfusion criteria are variable between pediatric institutions, clinicians, and chemothera- peutic protocols Wong et al. 2005 . Clinicians should take into account potential risk factors which will help aid in the determination of an appropriate platelet threshold. For instance, fever, minor bleeding, coagulopathy and mucositis are potential clinical complaints which might increase the platelet transfusion threshold from 10 × 10 9 L to 20–50 × 10 9 L though evidence- based data are lacking. From a radiation stand- point, radiation fi elds with a high degree of marrow involvement such as a pelvic or cranio- spinal fi eld or those fi elds potentiating the risk of mucositis should also increase platelet transfusion thresholds from 10 × 10 9 L to 30–50 × 10 9 L though evidence-based data are lacking. Close monitoring and clinical judgment are warranted. Thrombopoietin receptor agonists TPO-RAs including eltrombopag and romiplostim have recently been approved in adults for multiple indi- cations including chemotherapy-induced throm- bocytopenia Bussel et al. 2006 . As yet, very limited data are available on their effi cacy for chemotherapy-induced thrombocytopenia and no pediatric data are available Basciano and Bussel 2012 . It is unclear if TPO-RAs will prove benefi - cial after chemotherapy- and secondarily after RT-induced thrombocytopenia. Additionally, con- cerns remain in regard to the safety of these agents specifi cally in pediatric patients due to reports of thrombocytosis, thrombosis, tumorleukemia cell growth and bone marrow fi brosis Kuter 2007 ; Gernsheimer 2008 ; Basciano and Bussel 2012 .

13.2.3 Management of Anemia

Hypoxia in solid tumors, especially head and neck, uterine cervix, and bladder cancers, and possibly soft tissue sarcomas, has been shown to be an important component in the decreased effectiveness of RT to promote tumor cell death Dische et al. 1983 ; Overgaard and Horsman 1996 ; Fyles et al. 1998b ; Brizel et al. 1999 ; Vaupel et al. 2001 ; Dunst et al. 2003 ; Pinel et al. 2003 ; Harrison and Blackwell 2004 ; Nordsmark and Overgaard 2004 ; Nordsmark et al. 2005 ; Overgaard 2007 . Causes for tumor hypoxia are multifactorial and include abnor- malities in tumor microvasculature, increased diffusion distances and underlying anemia Vaupel et al. 2001 ; Vaupel and Harrison 2004 . In normal cells, tissue hypoxia eventu- ally leads to cell death while tumor cells have adapted cellular pathways, such as by upregu- lation of hypoxia-inducible factor 1 HIF1, to allow for survival and growth in such condi- tions Harris 2002 ; Dewhirst et al. 2008 . Tumor hypoxia has independently been shown to be a poor prognostic factor representing an aggressive phenotype Brizel et al. 1999 ; Harris 2002 ; Harrison and Blackwell 2004 ; Vaupel and Harrison 2004 ; Nordsmark et al. 2005 ; Vaupel 2008 . Determining what role underlying anemia has in tumor tissue hypoxia is as yet to be fully understood. Brizel et al. 1999 showed that even in non-anemic patients, 50 of tumors were still poorly oxygenated. Studies in patients with head and neck and uterine cervix cancers under- going radiation therapy have shown that patient outcomes are worse with underlying anemia Grogan et al. 1999 ; Thomas 2001 ; Dunst et al. 2003 ; Prosnitz et al. 2005 ; Hoff et al. 2011 . Yet, it is not well understood whether anemia causes poor outcomes secondary to the ineffectiveness of therapy or, plausibly, is a marker of tumor aggressiveness and the severity of the underlying disease Harrison and Blackwell 2004 ; Prosnitz et al. 2005 ; Hoff et al. 2011 . Effectiveness of transfusion was mixed with Grogan et al. 1999 and Thomas 2001 showing that transfusion could overcome negative pretreatment and aver- age weekly nadir hemoglobin during radiother- apy for cervical cancer, while Hoff et al. 2011 showed no improvement in outcomes based on transfusion for patients with head and neck 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 .