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Title: Neuroplastic Response After Radiation Therapy for Pediatric Brain Tumors: A Pilot Study

Abstract

Purpose: Clinically effective measurement of cognitive toxicity from photon radiation therapy (XRT) should be accurate, sensitive, and specific. This pilot study tested translational findings on phasic changes in children's memory systems that are sensitive and insensitive to toxic XRT effects to identify a possible neuroplastic effect. Methods and Materials: Memory processes were prospectively tested before XRT and at 3 later time points up to 2 years in 35 children with mixed primary brain tumors who had not experienced recurrence. Memory processes were verbal-semantic, visual-semantic, and visual-perceptual, including accuracy, speed to recall, encoding, retrieval, and recognition. The mixed-effects model included time (to estimate slope), covariates (age, tumor locus, XRT field, and medications) as fixed effects, and individual random intercepts. A sensitivity analysis examined the influence of XRT dose to the hippocampi on memory. Results: Retrieval from long-term verbal-semantic memory declined 2 months after completing XRT, as seen in adults, and was lowest at 1 year, which was delayed in comparison with adults. Double dissociation from visual-perceptual memory at baseline and 2 months was found, consistent with adults. Recovery was demonstrated 2 years after XRT. Patterns were unchanged when dose to hippocampus was included in the model. Conclusions: Verbal and semantic long-term retrieval is specifically sensitive tomore » XRT-related cognitive dysfunction, without effect on visual-perceptual memory. Children reached nadir in XRT-sensitive memory 1 year after XRT and recovered by 2 years, which is later than that observed in adults. The protracted period of post-XRT injury may represent the maturation of the human hippocampus and white matter into late adolescence.« less

Authors:
 [1];  [1];  [2];  [3]; ;  [1]; ;  [3];  [1]
  1. Neuro-Oncology Section, Children's Hospital of Philadelphia, and Department of Pediatrics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania (United States)
  2. Oncology Division, Children's Hospital of Philadelphia, and Department of Biostatistics and Epidemiology, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania (United States)
  3. Department of Radiation Oncology, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania (United States)
Publication Date:
OSTI Identifier:
22648712
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 95; Journal Issue: 3; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; ADULTS; BRAIN; CHILDREN; NEOPLASMS; RADIOSENSITIVITY; RADIOTHERAPY; SENSITIVITY ANALYSIS; SURVIVAL TIME

Citation Formats

Armstrong, Carol L., E-mail: armstrongc@email.chop.edu, Fisher, Michael J., Li, Yimei, Lustig, Robert A., Belasco, Jean B., Minturn, Jane E., Hill-Kayser, Christine E., Batra, Sonny, and Phillips, Peter C. Neuroplastic Response After Radiation Therapy for Pediatric Brain Tumors: A Pilot Study. United States: N. p., 2016. Web. doi:10.1016/J.IJROBP.2016.01.013.
Armstrong, Carol L., E-mail: armstrongc@email.chop.edu, Fisher, Michael J., Li, Yimei, Lustig, Robert A., Belasco, Jean B., Minturn, Jane E., Hill-Kayser, Christine E., Batra, Sonny, & Phillips, Peter C. Neuroplastic Response After Radiation Therapy for Pediatric Brain Tumors: A Pilot Study. United States. doi:10.1016/J.IJROBP.2016.01.013.
Armstrong, Carol L., E-mail: armstrongc@email.chop.edu, Fisher, Michael J., Li, Yimei, Lustig, Robert A., Belasco, Jean B., Minturn, Jane E., Hill-Kayser, Christine E., Batra, Sonny, and Phillips, Peter C. 2016. "Neuroplastic Response After Radiation Therapy for Pediatric Brain Tumors: A Pilot Study". United States. doi:10.1016/J.IJROBP.2016.01.013.
@article{osti_22648712,
title = {Neuroplastic Response After Radiation Therapy for Pediatric Brain Tumors: A Pilot Study},
author = {Armstrong, Carol L., E-mail: armstrongc@email.chop.edu and Fisher, Michael J. and Li, Yimei and Lustig, Robert A. and Belasco, Jean B. and Minturn, Jane E. and Hill-Kayser, Christine E. and Batra, Sonny and Phillips, Peter C.},
abstractNote = {Purpose: Clinically effective measurement of cognitive toxicity from photon radiation therapy (XRT) should be accurate, sensitive, and specific. This pilot study tested translational findings on phasic changes in children's memory systems that are sensitive and insensitive to toxic XRT effects to identify a possible neuroplastic effect. Methods and Materials: Memory processes were prospectively tested before XRT and at 3 later time points up to 2 years in 35 children with mixed primary brain tumors who had not experienced recurrence. Memory processes were verbal-semantic, visual-semantic, and visual-perceptual, including accuracy, speed to recall, encoding, retrieval, and recognition. The mixed-effects model included time (to estimate slope), covariates (age, tumor locus, XRT field, and medications) as fixed effects, and individual random intercepts. A sensitivity analysis examined the influence of XRT dose to the hippocampi on memory. Results: Retrieval from long-term verbal-semantic memory declined 2 months after completing XRT, as seen in adults, and was lowest at 1 year, which was delayed in comparison with adults. Double dissociation from visual-perceptual memory at baseline and 2 months was found, consistent with adults. Recovery was demonstrated 2 years after XRT. Patterns were unchanged when dose to hippocampus was included in the model. Conclusions: Verbal and semantic long-term retrieval is specifically sensitive to XRT-related cognitive dysfunction, without effect on visual-perceptual memory. Children reached nadir in XRT-sensitive memory 1 year after XRT and recovered by 2 years, which is later than that observed in adults. The protracted period of post-XRT injury may represent the maturation of the human hippocampus and white matter into late adolescence.},
doi = {10.1016/J.IJROBP.2016.01.013},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 3,
volume = 95,
place = {United States},
year = 2016,
month = 7
}
  • Three children with malignant primary CNS tumors treated with craniospinal radiotherapy developed intraparenchymal hemorrhages a median of 5 years following therapy in sites distant from the primary tumor. Radical surgical procedures disclosed fresh and old hematoma, gliosis, and necrosis in all 3 patients and an aggregation of abnormal microscopic blood vessels in two. No tumor was found. All 3 patients remain in long-term (greater than 10 years) continuous remission.
  • The CT findings after interstitial radiation therapy for brain tumors have not been extensively described. We evaluated retrospectively the CT scans of 13 patients who were treated with brachytherapy for malignant glioma. We found no typical CT appearance that differentiates recurrent tumor from radiation effect. After undergoing brachytherapy, eight of the 13 patients scanned demonstrated enhancement of brain tissue beyond the margins of the original enhancing tumor mass. In most cases, the pattern of enhancement diminished and extended more peripherally from the central necrotic area with time. We also report a new CT finding of focal calcification developing at themore » site of the radioactive implant.« less
  • A Phase I/II trial was initiated in 1987 to determine the toxicity/efficacy of the perfluorochemical emulsion Fluosol[sup R]-DA 20% and 100% oxygen as an adjuvant to conventional radiation therapy for high-grade brain tumors. Three grade 3 and 15 grade 4 patients received 1 Fluosol[sup R] administration (8 mL/kg) per week with daily oxygen breathing prior to and during radiation therapy. Megavoltage radiation was delivered to the whole brain at 25 x 1.8 Gy, followed by 10 x 2 Gy to a boost volume, resulting in a total tumor bed dose of 65 Gy in 7 weeks. Of the 18 patients,more » 10 (nine grade 4, one grade 3) survived more than 1 year postsurgery, six (all grade 4) lived more than 2 years, four of these patients lived more than 3 years, and three patients are alive at times ranging from 250 to 276 weeks. The median survival of the Fluosol[sup R] group was 75 weeks, not statistically different from 54 weeks for a historical, matched control group. However, a Gehan-Wilcoxon test applied to those patients that survived >1 year revealed a significant difference in favor of the Fluosol[sup R] group. Periodic clinical evaluations showed no evidence of any functional or neurological defects that could be attributed to radiation therapy and/or Fluosol[sup R]. Radiographic studies (computed tomography and magnetic resonance imaging) revealed no structural alterations outside the original tumor volume. Changes within the tumor region were easily assignable to expected effects of tumor, surgery, or radiation alone. These results indicate that, although Fluosol[sup R]/oxygen added to conventional radiation therapy does not enhance survival of patients who succumb to their disease early, it does confer a significant benefit to patients that survive past 1 year. The minimal acute side effects and no long-term deleterious effects suggest that Fluosol[sup R]/oxygen sensitizes only hypoxic cells, with no effect on well-oxygenated normal tissues within the brain. 2 refs., 2 figs., 1 tab.« less
  • Negative Pi-mesons (pions) are applied at the Paul Scherrer Institute in the radiotherapy of highly malignant gliomas using a dose escalation program. The therapy effects of 7 randomly selected patients were followed up by 62 MRI examinations. The quantification of the effects is based on the relaxation times T1 and T2, which are acquired by a new designed multi-echo multiple saturation recovery imaging technique. As a summary of the results, roughly two reaction types are observed. For both types the relaxation times increase up to two to three months after the radiation therapy. Then in one type (two patients) themore » T1 and T2 values of the tumors, and of the edemas surrounding the tumors, further increase, indicating an unfavorable prognosis. In the other type (five patients) the relaxation times drop down towards, or even below, their initial values, reflecting the onset of the reparation processes in the tissue. This later behavior reflects an at least temporary control of the disease; that is, the short term prognosis for these patients is more favorable. It further can be concluded, with respect to our MR parameters, that the radiotolerance of healthy brain tissue is much higher than that of malignant glioma tissue, despite the fact that these tumors are very seldom definitively radiosensible.« less
  • Purpose: To determine the effect of cochlear dose on sensorineural hearing loss in pediatric patients with brain tumor treated by using conformal radiation therapy (CRT). Patients and Methods: We studied 78 pediatric patients (155 ears) with localized brain tumors treated in 1997-2001 who had not received platinum-based chemotherapy and were followed up for at least 48 months. They were evaluated prospectively by means of serial pure-tone audiograms (250 Hz-8 kHz) and/or auditory brainstem response before and every 6 months after CRT. Results: Hearing loss occurred in 14% (11 of 78) of patients and 11% (17 of 155) of cochleae, withmore » onset most often at 3-5 years after CRT. The incidence of hearing loss was low for a cochlear mean dose of 30 Gy or less and increased at greater than 40-45 Gy. Risk was greater at high frequencies (6-8 kHz). In children who tested abnormal for hearing, average hearing thresholds increased from a less than 25 decibel (dB) hearing level (HL) at baseline to a mean of 46 {+-} 13 (SD) dB HL for high frequencies, 41 {+-} 7 dB HL for low frequencies, and 38 {+-} 6 dB HL for intermediate frequencies. Conclusions: Sensorineural hearing loss is a late effect of CRT. In the absence of other factors, including ototoxic chemotherapy, increase in cochlear dose correlates positively with hearing loss in pediatric patients with brain tumor. To minimize the risk of hearing loss for children treated with radiation therapy, a cumulative cochlear dose less than 35 Gy is recommended for patients planned to receive 54-59.4 Gy in 30-33 treatment fractions.« less