Psychology scores were estimated by using linear mixed models through 5 years of follow-up. The parameter estimates for the battery of tests are listed in . Significant improvements were noted in the Child Behavior Checklist (CBCL) internalizing and behavioral problem scores and in the Woodcock Johnson—Revised visual auditory learning. Significant declines were noted for Wechsler Individual Achievement Test reading and spelling and for Vineland communication. Five years after CRT, only the decline in spelling scores was clinically significant. The average patient's score decreased from 98 to 90 points, but 90 still represented an average-range score (average score range, 85 to 115).
Models of Cognitive Effects After CRT for Pediatric Low-Grade Glioma
Thirteen of the 78 patients included in this research were diagnosed with NF-1. They had significantly lower baseline scores for intelligence quotient (IQ; −11.49 points; P = .0468), reading (−13.09 points; P = .0139), spelling (−12.33 points; P = .0485), and communication (−12.78 points; P = .0200). A significant decline was observed in the CBCL activities scores for patients with NF-1 (−0.1222 points/mo; P = .0484). After 5 years, the average score of a patient with NF-1 would decrease from 44.2139 to 36.8819, whereas the average score of a patient without NF-1 would be unchanged at 44.2806 (average score range, 40 to 60).
Age at CRT
Age impacted baseline scores and change over time. Lower CBCL school scores were observed at baseline for younger patients (0.6616 points/year of age; P = .0400). Each year of increasing age reduced the decline in IQ by 0.0256 points per month (P = .0025; ). When other factors were excluded, a 10-point decline in IQ 5 years after RT would be expected for a child age 5 years at the time of irradiation. Each year of increasing age resulted in lower (ie, improved) CBCL externalizing (−0.0275 points/mo; P = .0039) and internalizing (−0.0181 points/mo; P = .0362) scores.
Modeled intelligence quotient (IQ) scores after conformal radiation therapy (CRT) by age for pediatric low-grade glioma. Age is measured in years, and time is measured in months after the start of CRT.
The impact of surgery on psychology scores was determined by comparing patients on the basis of extent of resection (ie, no biopsy, biopsy, or subtotal resection). Psychology scores before CRT were significantly better for patients who underwent biopsy only compared with subtotal resection: the affected measures included California Verbal Learning Test (CVLT) (P = .0212), CBCL activities (P = .0152), behavior problems (P = .0377), and externalizing scores (P = .0055). Extent of resection influenced change over time; the biopsy group had worse scores in visual auditory learning (−0.2392 points/mo; P = .0052) compared with the subtotal resection group.
Hydrocephalus, Shunt, Pre-CRT Chemotherapy, and the Planning Target Volume
Patients who did not have hydrocephalus had higher CVLT scores at baseline (+5.70 points; P = .0804). Those who did not have hydrocephalus had higher CBCL externalizing scores at baseline (+4.3698 points; P = .0411). Pre-CRT chemotherapy had no impact on baseline psychology scores, although those not treated with chemotherapy showed a trend toward higher scores on visual auditory learning (+10.71 points; P = .0983). The size of the planning target volume affected baseline values of reading (−0.0479 points/mL; P = .0320), communication (−0.0720 points/mL; P = .0016), and daily living scores (−0.0409 points/mL; P = .0628).
Radiation Dose and Volume
Models that correlated cognitive effect with radiation dose were generated by using dose-volume data from the supratentorial, infratentorial, and total brain volumes. Models could not be generated with temporal lobe data. The relative volumes that received doses between 0 to 30 Gy and 30 to 60 Gy were the covariates. In most models, the parameter estimate for the percent volume that received a dose (ie, dose-volume interval) of 30 to 60 Gy (V30-60Gy) was statistically significant; whereas the significance of the dose-volume interval of 0 to 30 Gy (V0-30Gy) was inconsistent. Because of its importance and ease of use, age was included in the models. Age had the greatest impact on baseline values and increased the statistical significance of the longitudinal estimates. Psychology measures and the P values of significant dose-volume parameters are listed in to demonstrate the impact of high- and low-dose volumes across the range of measures.
Significant Parameter Estimates to Model Decline in Psychology Test Scores With Radiation Dose, Age, and Time After Conformal Radiation Therapy for Pediatric Low-Grade Glioma
Models of IQ and CBCL Externalizing Scores on the Basis of Radiation Dosimetry
Models that included IQ and the CBCL externalizing score had statistically significant parameter estimates for both of the dose-volume intervals, V0-30Gy and V30-60Gy.
The equation for IQ is represented by the following expression:
in which age at CRT was measured in years and time was measured in months after the start of CRT. V0-30Gy
were, respectively, the percent volume of the supratentorial brain that received a dose of 0 to 30 Gy and of 30 to 60 Gy. shows modeled differences in IQ during the first 5 years after CRT on the basis of age and radiation dosimetry. The ages of 4 and 12 years were chosen along with V0-30Gy
= 55.45% and V30-60Gy
= 44.55% and V0-30Gy
= 90.17% and V30-60Gy
= 9.83%. These values were chosen because they represented V30-60Gy
values of one standard deviation (17.36%) above and below the mean of 27.19%, respectively.
Fig 2. Modeled intelligence quotient (IQ) scores after conformal radiation therapy (CRT) by age and supratentorial brain dose-volume intervals for pediatric low-grade glioma. Age is measured in years, and time is measured in months after CRT. The dose-volume (more ...)
The equation for CBCL externalizing score is represented by the following expression:
in which age at CRT was measured in years and time was measured in months after the start of CRT. V0-30Gy
were, respectively, the percent volume of the infratentorial brain that received a dose between 0 to 30 Gy and 30 to 60 Gy. Appendix Figure A1 (online only) shows modeled differences in IQ during the first 5 years after CRT on the basis of age and radiation dosimetry. The ages of 4 and 12 years were chosen along with V0-30Gy
= 34.28% and V30-60Gy
= 65.72% and V0-30Gy
= 92.14% and V30-60Gy
= 7.86%. These values were chosen because they represented V30-60Gy
values of one standard deviation (28.93%) above and below the mean of 36.79%, respectively.
Simplified models of dose and effect were developed by using mean dose. The mean dose to specific brain volumes was found to impact baseline and longitudinal reading and math scores. Age was included in these models. Reading and math scores were estimated by equations listed in .
Models of Academic Achievement at the Time of Conformal Radiation Therapy to Specific Volumes of the Brain
Pre-CRT HRT was noted and included thyroid hormone (n = 6), glucocorticoid (n = 3), desmopressin acetate (DDAVP) (n = 2), and gonadotropin-releasing hormone (GnRH) analog (n = 6). Provocative testing performed before CRT in 42 patients revealed that 43% had peak GH values less than 10 ng/mL and that 24% had peak GH values less than 7 ng/mL. The number of patients (of 50 patients total) on HRT at baseline, at 12 months, and at 24 months, respectively, were 14, 21, and 28 for thyroid hormone replacement; seven, nine, and 11 for glucocorticoid replacement; and six, eight, and 11 for GnRH analog. One patient required sex hormone replacement within 24 months of irradiation.
The CI (reported as mean ± SE) of HRT and treatment of precocious puberty was determined for the first 50 consecutive patients in the series. Treatment failure and HRT before CRT were considered competing risks. The 5- and 10-year CIs, respectively, (and the 10-year CI for 43 patients who had a mean hypothalamus dose ≥ 40 Gy) of growth hormone replacement were 46.0% ± 7.2% and 48.9% ± 7.4% (54.7%); of thyroid hormone replacement, 61.4% ± 7.5% and 64.0% ± 7.5% (69.1%); of glucocorticoid replacement, 19.2% ± 5.8% and 19.2% ± 5.8% (20.0%); of DDAVP replacement, 2.1% ± 2.1% and 5.2% ± 3.8% (6.2%); of sex hormone replacement, 8.0% ± 3.9% and 14.1% ± 5.0% (16.4%); and of GnRH analog therapy, 31.8% ± 7.1% and 34.2% ± 7.3% (35.3%). Two of the patients treated with GnRH analog therapy did not have documented precocious puberty but were treated at 38.5 and 49.5 months after CRT to increase time for growth promotion. ().
CI of hormone replacement therapy and therapy for precocious puberty after conformal radiation therapy (CRT) for pediatric low-grade glioma. CI, cumulative incidence; GnRH, gonadotropin-releasing hormone; DDAVP, desmopressin acetate.
Provocative testing performed before CRT in 42 corticosteroid-naïve patients revealed that 43% had peak GH values less than 10 ng/mL and that 24% had peak GH values less than 7 ng/mL. When the first 50 patients were considered, the number of patients on HRT at baseline, at 12 months, and at 24 months were 14, 21, and 28 for thyroid hormone replacement; seven, nine, and 11 for glucocorticoid replacement; and six, eight, and 11 for GnRH analog. One patient required GnRH replacement within 24 months of irradiation.
Hearing loss was estimated for 74 of 78 patients; four were excluded because of early treatment failure. The median (±SD) hearing follow-up was 61.4 ± 27.9 months (range, 5.6 to 124.5 months). Hearing loss at any frequency occurred in nine patients, transient values greater than 25 dB were noted in 17 patients, and 48 patients never exceeded the threshold value of 25 dB. The CI (reported as mean ± SE) of hearing loss differed by ear and did not exceed 5.7% ± 3.3% (ie, 2,000 Hz) in the right ear or 4.0% ± 2.8% (ie, 1000 Hz) in the left ear when estimated at 10 years (Appendix Table A2, online only). An analysis to determine the effect of cochlear dose on hearing loss showed that irradiation to dose levels that exceeded 45 Gy in 16 patients resulted in statistically significantly higher rates of increased hearing threshold in the right ear at the following frequencies (10-year CI < 45Gy v 10-year CI > 45 Gy; reported as mean ± SE): 1 kHz (0 v 15.6% ± 10.7%; P = .0156), 4 kHz (0 v 15.6% ± 10.7%; P = .0156), 6 kHz (0 v 19.2% ± 12.9%; P = .0192), and 8 kHz (0 v 19.2% ± 12.9%; P = .0226). There was not a similar effect on the left ear, which had a similar number of cochleae that received greater than 45 Gy. Among the 23 patients treated with chemotherapy, increased hearing thresholds were estimated at 10 years (no chemotherapy v chemotherapy; reported as mean ± SD) for 1 kHz (0 v 14.1% ± 10.1%; P = .0262) and 4kHz (0 v 14.1% ± 10.0%; P = .062). This effect was limited to the right ear.