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Pediatric Radiotherapy: Surgical Considerations, Sequelae, and Future Directions

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Textbook of Pediatric Neurosurgery

Abstract

Radiation therapy is a critical component in the treatment of children with central nervous system tumors. As the use of this modality continues to increase in complexity and sophistication, it is imperative for the neurosurgeon to understand the additional challenges that the use of radiotherapy may pose in both surgical and nonsurgical management. Operating after radiation to the surgical site may increase infection rate, decrease probability of wound healing, increase rate of intraoperative complications, distort typical anatomy, and alter operative approach. Radiation therapy can also result in many long-term sequelae, including radiation necrosis, vasculopathy, neurocognitive deficits, and secondary malignancies, many of which may require additional workup and surgical intervention. Such risks must be understood by all members of the team when developing management strategies in these patients, and a multidisciplinary approach is vital. This chapter discusses these topics and also reviews future directions for radiation therapy, including technologic advances, image guidance, and large-scale informatics efforts. Also promising is the role of next-generation sequencing in better understanding nuances in tumor biology and thus radiation sensitivity. Advanced sequencing efforts may also help predict susceptibility to sequelae of radiotherapy in individual patients.

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References

  • Ahmed KA, Chinnaiyan P, Fulp WJ, Eschrich S, Torres-Roca JF, Caudell JJ (2015) The radiosensitivity index predicts for overall survival in glioblastoma. Oncotarget 6:34414–34422

    PubMed  PubMed Central  Google Scholar 

  • Armstrong GT, Liu Q, Yasui Y, Huang S, Ness KK, Leisenring W et al (2009a) Long-term outcomes among adult survivors of childhood central nervous system malignancies in the childhood cancer Survivor study. J Natl Cancer Inst 101:946–958

    Article  PubMed  PubMed Central  Google Scholar 

  • Armstrong GT, Liu Q, Yasui Y, Neglia JP, Leisenring W, Robison LL et al (2009b) Late mortality among 5-year survivors of childhood cancer: a summary from the childhood cancer Survivor study. J Clin Oncol 27:2328–2338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baker GA, Cizik AM, Bransford RJ, Bellabarba C, Konodi MA, Chapman JR et al (2012) Risk factors for unintended durotomy during spine surgery: a multivariate analysis. Spine J 12:121–126

    Article  PubMed  PubMed Central  Google Scholar 

  • Ball WS Jr, Prenger EC, Ballard ET (1992) Neurotoxicity of radio/chemotherapy in children: pathologic and MR correlation. AJNR Am J Neuroradiol 13:761–776

    PubMed  Google Scholar 

  • Bouchard JA, Koka A, Bensusan JS, Stevenson S, Emery SE (1994) Effects of irradiation on posterior spinal fusions. A rabbit model. Spine (Phila Pa 1976) 19:1836–1841

    Article  CAS  Google Scholar 

  • Bowers DC, Mulne AF, Reisch JS, Elterman RD, Munoz L, Booth T et al (2002) Nonperioperative strokes in children with central nervous system tumors. Cancer 94:1094–1101

    Article  PubMed  Google Scholar 

  • Bowers DC, Liu Y, Leisenring W, McNeil E, Stovall M, Gurney JG et al (2006) Late-occurring stroke among long-term survivors of childhood leukemia and brain tumors: a report from the childhood cancer survivor study. J Clin Oncol 24:5277–5282

    Article  PubMed  Google Scholar 

  • Brinkman TM, Krasin MJ, Liu W, Armstrong GT, Ojha RP, Sadighi ZS et al (2016) Long-term neurocognitive functioning and social attainment in adult survivors of pediatric CNS tumors: results from the St Jude lifetime cohort study. J Clin Oncol 34:1358–1367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burgess L, Pulsifer M, Yeap BY, Grieco J, Weinstein ER, MacDonald S et al (2016) Estimated IQ (EIQ) systematically overestimates full-scale IQ (FSIQ) in survivors irradiated for pediatric brain tumors. Int J Radiat Oncol Biol Phys 96:S232

    Article  Google Scholar 

  • Butler RW, Copeland DR, Fairclough DL, Mulhern RK, Katz ER, Kazak AE et al (2008) A multicenter, randomized clinical trial of a cognitive remediation program for childhood survivors of a pediatric malignancy. J Consult Clin Psychol 76:367–378

    Article  PubMed  PubMed Central  Google Scholar 

  • Carangelo B, Cerillo A, Mariottini A, Peri G, Rubino G, Mourmouras V et al (2010) Therapeutic strategy of late cerebral radionecrosis. A retrospective study of 21 cases. J Neurosurg Sci 54:21–28

    CAS  PubMed  Google Scholar 

  • Chen JR, Xu HZ, Ding JB, Qin ZY (2015) RT after hyperbaric oxygenation in malignant gliomas. Curr Med Res Opin 31:1977–1984

    Article  CAS  PubMed  Google Scholar 

  • Chetty IJ, Martel MK, Jaffray DA, Benedict SH, Hahn SM, Berbeco R et al (2015) Technology for innovation in radiation oncology. Int J Radiat Oncol Biol Phys 93:485–492

    Article  PubMed  PubMed Central  Google Scholar 

  • Cole PD, Finkelstein Y, Stevenson KE, Blonquist TM, Vijayanathan V, Silverman LB et al (2015) Polymorphisms in genes related to oxidative stress are associated with inferior cognitive function after therapy for childhood acute lymphoblastic leukemia. J Clin Oncol 33:2205–2211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Compas BE (2014) Neuroplasticity-based cognitive remediation for pediatric brain tumor survivors (CRPBT). ClinicalTrials.gov Identifier: NCT02129712. https://clinicaltrials.gov/ct2/show/NCT02129712?term=NCT02129712&rank=1

  • Compter I, Leijenaar R (2016) Radiomics for prediction of survival in GBM (radiomics). ClinicalTrials.gov Identifier: NCT02666066. Sponsor: Maastricht Radiation Oncology. https://clinicaltrials.gov/ct2/show/NCT02666066?term=NCT02666066&rank=1

  • de Jonge T, Slullitel H, Dubousset J, Miladi L, Wicart P, Illes T (2005) Late-onset spinal deformities in children treated by laminectomy and RT for malignant tumours. Eur Spine J 14:765–771

    Article  PubMed  PubMed Central  Google Scholar 

  • Demura S, Kawahara N, Murakami H, Nambu K, Kato S, Yoshioka K et al (2009) Surgical site infection in spinal metastasis: risk factors and countermeasures. Spine (Phila Pa 1976) 34:635–639

    Article  Google Scholar 

  • Drezner N, Hardy KK, Wells E, Vezina G, Ho CY, Packer RJ et al (2016) Treatment of pediatric cerebral radiation necrosis: a systematic review. J Neurooncol 130:141–148

    Article  CAS  PubMed  Google Scholar 

  • Fager M, Toma-Dasu I, Kirk M, Dolney D, Diffenderfer ES, Vapiwala N et al (2015) Linear energy transfer painting with proton therapy: a means of reducing radiation doses with equivalent clinical effectiveness. Int J Radiat Oncol Biol Phys 91:1057–1064

    Article  PubMed  Google Scholar 

  • Fajardo LF (1993) Basic mechanisms and general morphology of radiation injury. Semin Roentgenol 28:297–302

    Article  CAS  PubMed  Google Scholar 

  • Fouladi M, Langston J, Mulhern R, Jones D, Xiong X, Yang J et al (2000) Silent lacunar lesions detected by magnetic resonance imaging of children with brain tumors: a late sequela of therapy. J Clin Oncol 18:824–831

    Article  CAS  PubMed  Google Scholar 

  • Gagiano CA, Muller PG, Fourie J, Le Roux JF (1989) The therapeutic efficacy of paroxetine: (a) an open study in patients with major depression not responding to antidepressants; a double-blind comparison with amitriptyline in depressed outpatients. Acta Psychiatr Scand Suppl 350:130–131

    Article  CAS  PubMed  Google Scholar 

  • Gajjar A, Robinson G (2013) A clinical and molecular risk-directed therapy for newly diagnosed medulloblastoma. ClinicalTrials.gov Identifier: NCT01878617. https://clinicaltrials.gov/ct2/show/NCT01878617?term=NCT01878617&rank=1

  • Gajjar A, Pfister SM, Taylor MD, Gilbertson RJ (2014) Molecular insights into pediatric brain tumors have the potential to transform therapy. Clin Cancer Res 20:5630–5640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ghogawala Z, Mansfield FL, Borges LF (2001) Spinal radiation before surgical decompression adversely affects outcomes of surgery for symptomatic metastatic spinal cord compression. Spine (Phila Pa 1976) 26:818–824

    Article  CAS  Google Scholar 

  • Glover M, Smerdon GR, Andreyev HJ, Benton BE, Bothma P, Firth O et al (2016) Hyperbaric oxygen for patients with chronic bowel dysfunction after pelvic RT (HOT2): a randomised, double-blind, sham-controlled phase 3 trial. Lancet Oncol 17:224–233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grill J, Couanet D, Cappelli C, Habrand JL, Rodriguez D, Sainte-Rose C et al (1999) Radiation-induced cerebral vasculopathy in children with neurofibromatosis and optic pathway glioma. Ann Neurol 45:393–396

    Article  CAS  PubMed  Google Scholar 

  • Guan F, Bronk L, Titt U, Lin SH, Mirkovic D, Kerr MD et al (2015) Spatial mapping of the biologic effectiveness of scanned particle beams: towards biologically optimized particle therapy. Sci Rep 5:9850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gutin PH, Leibel SA, Sheline GE (1991) Radiation injury of the nervous system. Raven, New York

    Google Scholar 

  • Hardy KK, Willard VW, Allen TM, Bonner MJ (2013) Working memory training in survivors of pediatric cancer: a randomized pilot study. Psychooncology 22:1856–1865

    Article  PubMed  Google Scholar 

  • Harrod-Kim P, Kadkhodayan Y, Derdeyn CP, Cross DT 3rd, Moran CJ (2005) Outcomes of carotid angioplasty and stenting for radiation-associated stenosis. AJNR Am J Neuroradiol 26:1781–1788

    PubMed  Google Scholar 

  • Haubner F, Ohmann E, Pohl F, Strutz J, Gassner HG (2012) Wound healing after RT: review of the literature. Radiat Oncol 7:162

    Article  PubMed  PubMed Central  Google Scholar 

  • Herskind C, Bamberg M, Rodemann HP (1998) The role of cytokines in the development of normal-tissue reactions after RT. Strahlenther Onkol 174(Suppl 3):12–15

    PubMed  Google Scholar 

  • Hom DB, Adams G, Koreis M, Maisel R (1999) Choosing the optimal wound dressing for irradiated soft tissue wounds. Otolaryngol Head Neck Surg 121:591–598

    Article  CAS  PubMed  Google Scholar 

  • Hou J, Kshettry VR, Selman WR, Bambakidis NC (2013) Peritumoral brain edema in intracranial meningiomas: the emergence of vascular endothelial growth factor-directed therapy. Neurosurg Focus 35:E2

    Article  PubMed  Google Scholar 

  • Hsu F (2015) Neurocognitive outcome of conformal WBRT w/wo hippocampal avoidance for brain metastases. ClinicalTrials.gov Identifier: NCT02393131. https://clinicaltrials.gov/ct2/show/NCT02393131?term=NCT02393131&rank=1

  • Hunt TK, Thakral KK (1984) Cellular control of repair. In: Hunt T, Heppenstall RB, Pines E, Rovee D (eds) Soft and hard tissue repair: biological and clinical aspects. Praeger, New York, pp 3–19

    Google Scholar 

  • Indelicato DJ, Flampouri S, Rotondo RL, Bradley JA, Morris CG, Aldana PR et al (2014) Incidence and dosimetric parameters of pediatric brainstem toxicity following proton therapy. Acta Oncol 53:1298–1304

    Article  CAS  PubMed  Google Scholar 

  • Kickingereder P, Burth S, Wick A, Gotz M, Eidel O, Schlemmer HP et al (2016) Radiomic profiling of glioblastoma: identifying an imaging predictor of patient survival with improved performance over established clinical and radiologic risk models. Radiology 280:880–889

    Article  PubMed  Google Scholar 

  • Kondziolka D, Kano H, Kanaan H, Madhok R, Mathieu D, Flickinger JC et al (2009) Stereotactic radiosurgery for radiation-induced meningiomas. Neurosurgery 64:463–469.; discussion 469–470

    Article  PubMed  Google Scholar 

  • Kupelian P, Sonke JJ (2014) Magnetic resonance-guided adaptive RT: a solution to the future. Semin Radiat Oncol 24:227–232

    Article  PubMed  Google Scholar 

  • Ladra MM, Edgington SK, Mahajan A, Grosshans D, Szymonifka J, Khan F et al (2014) A dosimetric comparison of proton and intensity modulated RT in pediatric rhabdomyosarcoma patients enrolled on a prospective phase II proton study. Radiother Oncol 113:77–83

    Article  PubMed  PubMed Central  Google Scholar 

  • Ladra MM, Wang KK, Terezakis SA (2016) Pencil-beam scanning for pediatric rhabdomyosarcoma: promise and precautions. Pediatr Blood Cancer 63:1698–1699

    Article  PubMed  Google Scholar 

  • Leibundgut K (2016) Efficacy of cognitive and physical trainings in pediatric cancer survivors. ClinicalTrials.gov Identifier: NCT02749877. https://clinicaltrials.gov/ct2/show/NCT02749877?term=NCT02749877&rank=1

  • Lew SM, Morgan JN, Psaty E, Lefton DR, Allen JC, Abbott R (2006) Cumulative incidence of radiation-induced cavernomas in long-term survivors of medulloblastoma. J Neurosurg 104:103–107

    PubMed  Google Scholar 

  • Maluf FC, DeAngelis LM, Raizer JJ, Abrey LE (2002) High-grade gliomas in patients with prior systemic malignancies. Cancer 94:3219–3224

    Article  PubMed  Google Scholar 

  • Marks JE, Baglan RJ, Prassad SC, Blank WF (1981) Cerebral radionecrosis: incidence and risk in relation to dose, time, fractionation and volume. Int J Radiat Oncol Biol Phys 7:243–252

    Article  CAS  PubMed  Google Scholar 

  • Mayer R, Sminia P (2008) Reirradiation tolerance of the human brain. Int J Radiat Oncol Biol Phys 70:1350–1360

    Article  CAS  PubMed  Google Scholar 

  • Merchant TE, Happersett L, Finlay JL, Leibel SA (1999) Preliminary results of conformal RT for medulloblastoma. Neuro-Oncology 1:177–187

    CAS  PubMed  PubMed Central  Google Scholar 

  • Merchant TE, Sharma S, Xiong X, Wu S, Conklin H (2014) Effect of cerebellum radiation dosimetry on cognitive outcomes in children with infratentorial ependymoma. Int J Radiat Oncol Biol Phys 90:547–553

    Article  PubMed  PubMed Central  Google Scholar 

  • Merchant TE, Hua CH, Sabin ND, Ezell SE, Madey MA, Wu S et al (2016) Necrosis, vasculopathy, and neurological complications after proton therapy for childhood craniopharyngioma: results from a prospective trial and a photon cohort comparison. Int J Radiat Oncol Biol Phys 96:S120–S121

    Article  Google Scholar 

  • Moore IM, Hockenberry MJ, Anhalt C, McCarthy K, Krull KR (2012) Mathematics intervention for prevention of neurocognitive deficits in childhood leukemia. Pediatr Blood Cancer 59:278–284

    Article  PubMed  Google Scholar 

  • Moteabbed M, Yock TI, Depauw N, Madden TM, Kooy HM, Paganetti H (2016) Impact of spot size and beam-shaping devices on the treatment plan quality for pencil beam scanning proton therapy. Int J Radiat Oncol Biol Phys 95:190–198

    Article  PubMed  Google Scholar 

  • Mulhern RK, Merchant TE, Gajjar A, Reddick WE, Kun LE (2004) Late neurocognitive sequelae in survivors of brain tumours in childhood. Lancet Oncol 5:399–408

    Article  PubMed  Google Scholar 

  • Murphy ES, Xie H, Merchant TE, Yu JS, Chao ST, Suh JH (2015) Review of cranial RT-induced vasculopathy. J Neurooncol 122:421–429

    Article  CAS  PubMed  Google Scholar 

  • Northcott PA, Shih DJ, Peacock J, Garzia L, Morrissy AS, Zichner T et al (2012) Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature 488:49–56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Otsuka NY, Hey L, Hall JE (1998) Postlaminectomy and postirradiation kyphosis in children and adolescents. Clin Orthop Relat Res 354:189–194

    Article  Google Scholar 

  • Packer RJ, Meadows AT, Rorke LB, Goldwein JL, D’Angio G (1987) Long-term sequelae of cancer treatment on the central nervous system in childhood. Med Pediatr Oncol 15:241–253

    Article  CAS  PubMed  Google Scholar 

  • Paganetti H (2012) Range uncertainties in proton therapy and the role of Monte Carlo simulations. Phys Med Biol 57:R99–117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perkins S (2015) Computer-based neurocognitive assessment in children with central nervous system tumors receiving proton beam RT. ClinicalTrials.gov Identifier: NCT02559752. https://clinicaltrials.gov/ct2/show/NCT02559752?term=NCT02559752&rank=1

  • Price RA, Birdwell DA (1978) The central nervous system in childhood leukemia. III. Mineralizing microangiopathy and dystrophic calcification. Cancer 42:717–728

    Article  CAS  PubMed  Google Scholar 

  • Rahmathulla G, Recinos PF, Valerio JE, Chao S, Barnett GH (2012) Laser interstitial thermal therapy for focal cerebral radiation necrosis: a case report and literature review. Stereotact Funct Neurosurg 90:192–200

    Article  PubMed  Google Scholar 

  • Rahmathulla G, Marko NF, Weil RJ (2013) Cerebral radiation necrosis: a review of the pathobiology, diagnosis and management considerations. J Clin Neurosci 20:485–502

    Article  PubMed  Google Scholar 

  • Resnick D (1995) Diangosis of bone and joint disorders, 3rd edn. Saunders, Philadelphia

    Google Scholar 

  • Reulen RC, Winter DL, Frobisher C, Lancashire ER, Stiller CA, Jenney ME et al (2010) Long-term cause-specific mortality among survivors of childhood cancer. JAMA 304:172–179

    Article  CAS  PubMed  Google Scholar 

  • Schaffer M, Weimer W, Wider S, Stulten C, Bongartz M, Budach W et al (2002) Differential expression of inflammatory mediators in radiation-impaired wound healing. J Surg Res 107:93–100

    Article  PubMed  Google Scholar 

  • Shi HP, Most D, Efron DT, Tantry U, Fischel MH, Barbul A (2001) The role of iNOS in wound healing. Surgery 130:225–229

    Article  CAS  PubMed  Google Scholar 

  • Squatrito M, Brennan CW, Helmy K, Huse JT, Petrini JH, Holland EC (2010) Loss of ATM/Chk2/p53 pathway components accelerates tumor development and contributes to radiation resistance in gliomas. Cancer Cell 18:619–629

    Article  CAS  PubMed  Google Scholar 

  • Strenger V, Sovinz P, Lackner H, Dornbusch HJ, Lingitz H, Eder HG et al (2008) Intracerebral cavernous hemangioma after cranial irradiation in childhood. Incidence and risk factors. Strahlenther Onkol 184:276–280

    Article  PubMed  Google Scholar 

  • Tartaglino LM, Rao VM, Markiewicz DA (1994) Imaging of radiation changes in the head and neck. Semin Roentgenol 29:81–91

    Article  CAS  PubMed  Google Scholar 

  • Tirode F, Surdez D, Ma X, Parker M, Le Deley MC, Bahrami A et al (2014) Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations. Cancer Discov 4:1342–1353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Torres-Roca JF (2012) A molecular assay of tumor radiosensitivity: a roadmap towards biology-based personalized RT. Per Med 9:547–557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsui K, Gajjar A, Li C, Srivastava D, Broniscer A, Wetmore C et al (2015) Subsequent neoplasms in survivors of childhood central nervous system tumors: risk after modern multimodal therapy. Neuro-Oncology 17:448–456

    Article  PubMed  Google Scholar 

  • Umansky F, Shoshan Y, Rosenthal G, Fraifeld S, Spektor S (2008) Radiation-induced meningioma. Neurosurg Focus 24:E7

    Article  PubMed  Google Scholar 

  • Valk PE, Dillon WP (1991) Radiation injury of the brain. AJNR Am J Neuroradiol 12:45–62

    CAS  PubMed  Google Scholar 

  • Wen Q, Xiong W, He J, Zhang S, Du X, Liu S et al (2016) Fusion cytokine IL-2-GMCSF enhances anticancer immune responses through promoting cell-cell interactions. J Transl Med 14:41

    Article  PubMed  PubMed Central  Google Scholar 

  • Yard BD, Adams DJ, Chie EK, Tamayo P, Battaglia JS, Gopal P et al (2016) A genetic basis for the variation in the vulnerability of cancer to DNA damage. Nat Commun 7:11428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yock TI, Tarbell NJ, Yeap BY, Ebb DH, Weyman E, Eaton BR et al (2016) Proton beam therapy for medulloblastoma – author’s reply. Lancet Oncol 17:e174–e175

    Article  PubMed  Google Scholar 

  • Yokogawa N, Murakami H, Demura S, Kato S, Yoshioka K, Hayashi H et al (2014) Perioperative complications of total en bloc spondylectomy: adverse effects of preoperative irradiation. PLoS One 9:e98797

    Article  PubMed  PubMed Central  Google Scholar 

  • Yokogawa N, Murakami H, Demura S, Kato S, Yoshioka K, Yamamoto M et al (2015) Effects of radiation on spinal dura mater and surrounding tissue in mice. PLoS One 10:e0133806

    Article  PubMed  PubMed Central  Google Scholar 

  • Yu SC, Zou WX, Soo YO, Wang L, Hui JW, Chan AY et al (2014) Evaluation of carotid angioplasty and stenting for radiation-induced carotid stenosis. Stroke 45:1402–1407

    Article  PubMed  Google Scholar 

  • Zide BM, Wisoff JH, Epstein FJ (1987) Closure of extensive and complicated laminectomy wounds. Operative technique. J Neurosurg 67:59–64

    Article  CAS  PubMed  Google Scholar 

  • Zou P, Conklin HM, Scoggins MA, Li Y, Li X, Jones MM et al (2016) Functional MRI in medulloblastoma survivors supports prophylactic reading intervention during tumor treatment. Brain Imaging Behav 10:258–271

    Article  PubMed  PubMed Central  Google Scholar 

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Lee, R.P., Lucas, J.T., Tinkle, C.L., Merchant, T.E., Boop, F.A. (2017). Pediatric Radiotherapy: Surgical Considerations, Sequelae, and Future Directions. In: Di Rocco, C., Pang, D., Rutka, J. (eds) Textbook of Pediatric Neurosurgery. Springer, Cham. https://doi.org/10.1007/978-3-319-31512-6_152-1

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