Radiation therapy increases long-term risk of gonadotropin deficiency, hypothalamic pituitary dysfunction and brainstem necrosis in pediatric patients with brain tumor: A nationwide cohort study

Radiation therapy increases long-term risk of gonadotropin deficiency, hypothalamic pituitary dysfunction and brainstem necrosis in pediatric patients with brain tumor: A nationwide cohort study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Radiation therapy increases long-term risk of gonadotropin deficiency, hypothalamic pituitary dysfunction and brainstem necrosis in pediatric patients with brain tumor: A nationwide cohort study Feng-Chin Lee, Chi-Hsiang Chung, Sheng-Feng Lin, Wei-Fong Kao, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3855527/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: We evaluated associations between radiation therapy (RT) and late side effects (long-term endocrine, cognitive and cerebrovascular complications) in pediatric patients with brain tumor in a nationwide population. Methods: Data of pediatric patients with brain tumor were extracted from the National Health Insurance Research Database (NHIRD) of Taiwan. The RT cohort included 815 patients, randomly matched by age, gender, and index year with non-RT controls. Multivariable Cox proportional hazards regression was used to calculate adjusted hazard ratios (aHR) of developing late side effects in RT patients versus non-RT controls. Results: The risk of late side effects in RT group was 1.173-fold (aHR =1.173, 95%CI 1.063-1.430) higher than did non-RT group. RT patients exhibited 1.172-fold and 1.796-fold higher risk of long-term endocrinopathies and late-delayed complications, respectively, than did non-RT patients. For long-term endocrinopathies, patients with RT had 1.602-fold and 1.120-fold higher risk for gonadotropin deficiency and hypothalamic pituitary dysfunction, respectively, than did non-RT patients. For late-delayed complications, patients with RT had 3.208-fold higher risk for necrosis of brain stem than did non-RT patients. Conclusion: Gonadotropin deficiency, hypothalamic pituitary dysfunction and brainstem necrosis are dominant RT-related late side effects in pediatric patients. Frequency of these deficits increases with time, warranting long-term surveillance. brain tumor pediatric radiation therapy late effects Figures Figure 1 Figure 2 Background Radiation therapy is widely used to effectively treat primary and metastatic brain tumors in adult and pediatric patients [ 1 ]. The clinical difference between brain tumors in adults and children is striking. Compared with adults, pediatric tumor types (mostly glial and neuronal) are more sensitive to RT [ 2 ]. RT is the most effective nonsurgical treatment for pediatric with glioma, as 5-year progression-free survival estimates exceed 80% [ 3 ]. To maximize the therapeutic efficacy, RT has undergone revolutionary changes in recent decades like the development of intensity modulated radiation therapy, volumetric modulated arc therapy, and proton beam radiation therapy. Improved radiation therapies have also resulted in increased long-term brain tumor patient survival [ 4 ]. However, this leads the increased of RT-related late effects in pediatric patients with glioma, including neurocognitive, neuroendocrine dysfunction, and cerebrovascular complications, as well as hearing deficits [ 5 – 8 ]. Late-delayed treatment-induced brain complications frequently result in permanent neurologic disability [ 9 ]. Consequently, alteration or discontinuation of the overall antineoplastic treatment plan is frequently necessary to prevent further neurologic injury. Better identification of patients at high risk for developing late brain injury, neuroprotective strategies that modify existing antineoplastic treatment regimens, and research efforts directed at earlier recognition and improved treatment of neurologic complications are paramount. However, to date, no study has evaluated RT-related long-term gonadotropin deficiency, hypothalamic pituitary dysfunction and brainstem necrosis in pediatric patients with brain tumors using in a nationwide cohort. Therefore, the present study aimed to determine associations between radiation therapy and these late effects in pediatric patients with brain tumors in a nationwide population. Methods Data source All data for the present study were extracted from the National Health Insurance Research Database (NHIRD) in Taiwan, which currently covers more than 99% of the 23 million Taiwanese population [ 10 ]. The National Health Insurance Research Database (NHIRD) contains comprehensive demographic and clinical data for outpatient and inpatient claims data, where all clinical diagnoses and procedures are recorded based on the International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) codes. Additionally, the NHIRD was subjected to periodic quality control audits, and was also overseen by an advisory board run by the National Public Health Association. Ethical considerations To protect patient privacy, all personal patient information from the NHIRD is encrypted before being released to the public, including researchers. Therefore, all data for the present study were confirmed to be de-identified and were analyzed anonymously, precluding signed informed consent. The study protocol was approved by the Ethics Review Board of Tri-Service General Hospital (No. TSGHIRB. B-109-27). Study design and sample As illustrated in Fig. 1 , patients aged > 18 years; brain tumor diagnosed before index date; late effects before tracking; patients without tracking; and those with gender unknown were excluded. After exclusions, a cohort of pediatric patients with brain tumor (n = 3,292) identified by ICD-9-CM 191 (malignant neoplasm of brain), 192.0 (malignant cranial nerve tumor), 192.1 (malignant cerebral meninges tumor), 194 (malignant neoplasm of other endocrine glands and related structures), or 239.6 (neoplasm of unspecified nature of brain) from 2000 to 2015 was established. Among included patients, 815 cases received RT (ICD-9-CM V58.0) and 1,630 cases did not receive RT (who matched to age, gender, and the year of the index date with a RT:non-RT ratio of 1:2). For all hospitals and medical centers in Taiwan, the brain tumor was diagnosed according to the guideline of the Taiwan Society of Neuro-Oncology, while the RT (included exposure procedure, exposure dose and exposure location) was based on the guidelines of the Taiwan Society of Therapeutic Radiology and Oncology. Main outcomes The principal study outcome was overall late effects, including endocrinopathies (hypothyroidism, ICD-9-CM 244; hypothalamic pituitary dysfunction, ICD-9-CM 253; growth hormone deficiency, ICD-9-CM 259.4 and 259.8, cortisol deficiency, ICD-9-CM 255.4 and 255.5; gonadotropin deficiency, ICD-9-CM 259.0, 259.1, 259.4 and 259.8; delay milestone, ICD-9-CM 783.42; short stature, ICD-9-CM 783.43), late-delayed complications (late effect of radiation, ICD-9-CM 909.2; sensorineural hearing loss, ICD-9-CM 389.10; stroke, ICD-9-CM 437; post-RT necrosis of brain stem, ICD-9-CM OP31.1 and OP31.2; visual field defects, ICD-9-CM 368.4; myopia, ICD-9-CM 367.1; astigmatism, ICD-9-CM 367.2; RT-induced nonsenile cataract, ICD-9-CM 366.0; nasogastic tube insertion, ICD-9-CM OP44.99; gastrostomy, ICD-9-CM OP44.19), and late cerebrovascular complications (cavernous/arteriovenous malformation, ICD-9-CM 747.81; stroke, ICD-9-CM 434, 436, 437; cerebral atropy, ICD-9-CM 331.7, 331.89, 331.9; transient cerebral ischemia, ICD-9-CM 437.5). For all hospitals and medical centers in Taiwan, these late effects were assessed and diagnosed according to the follow-up of regular outpatient, regular blood test, regular imaging (CT/MRI) examination, clinically (neurological symptoms), histopathology, or assessment of growth and development, which were based on the guidelines of the major Medical Societies in Taiwan. The independent variables were age, gender, salary-based insured premium, prior chemotherapy (ICD-9-CM V58.1), prior brain surgery (ICD-9-CM OP01, OP02, OP04), location of residence, urbanization level, hospital care level, and the revised Charlson comorbidity index (CCI_R). CCI_R was defined as "CCI without brain tumor excision and stroke." The Charlson Comorbidity Index (CCI), as adapted by Deyo et al. [ 11 ], was used to assess the level of general comorbid conditions. Statistical Analysis Categorical variables were compared using the Chi-squared test, and continuous variables were compared using the Student's t-test. Possible confounding variables (p < 0.05) among baseline variables listed in each Table were adjusted for subsequent statistical analyses. Multivariable Cox proportional hazards regression analysis was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of late effects in the RT cohort compared with the non-RT cohort. Kaplan–Meier analysis was used to measure the cumulative incidence of late effects for both study cohorts, and the log-rank test was used to evaluate differences between the two cumulative incidence curves. All statistical analyses were carried out using IBM SPSS statistical software version 22 for Windows (IBM Corp., Armonk, New York, USA). A p-value of less than 0.05 in 2-tailed tests was considered to be statistically significant. Results Patients’ characteristics A total of 2,445 pediatric patients with brain tumors were included in this study, including 815 patients with RT and 1,630 patients without RT (Fig. 1 and Supplementary Table 1 ). No differences were found in age, gender, salary-based insured premium, and location of residence between the two groups at baseline and endpoint (all p > 0.05); however, the revised Charlson comorbidity index (CCI_R), prior chemotherapy (CT), prior brain surgery, urbanization level at baseline and the hospital level of medical care were different between the two group (all p < 0.05, Supplementary Table 1 and Table 1 ). Table 1 Characteristics of study population at endpoint. Total (n = 2,445) RT (n = 815) Non-RT (n = 1,630) p- value Late effects , n (%) 0.001* Without 2,000 (81.80) 636 (78.04) 1,364 (83.68) With 445 (18.20) 179 (21.96) 266 (16.32) Gender , n (%) 0.999 Male 1,475 (60.12) 490 (60.12) 980 (60.12) Female 970 (39.88) 325 (39.88) 650 (39.88) Age (years) , mean (SD) 10.83 ± 5.94 10.95 ± 5.32 10.77 ± 6.22 0.489 Age groups (years) , n (%) 0.007* < 1 15 (0.61) 3 (0.37) 12 (0.74) 1–6 695 (28.43) 202 (24.79) 493 (30.25) 7–12 924 (37.79) 341 (41.84) 583 (35.77) 13–18 811 (33.17) 269 (33.01) 542 (33.25) Insured premium (NT$) , n (%) 0.462 < 18,000 2,431 (99.43) 811 (99.51) 1,620 (99.39) 18,000–34,999 11 (0.45) 4 (0.49) 7 (0.43) ≧ 35,000 3 (0.12) 0 (0) 3 (0.18) CCI_R , mean (SD) 0.54 ± 1.06 1.50 ± 1.21 0.06 ± 0.89 < 0.001* Prior CT , n (%) < 0.001* Without 1,487 (60.82) 333 (40.86) 1,154 (70.80) With 958 (39.18) 482 (59.14) 476 (29.20) Prior brain surgery , n (%) < 0.001* Without 1,928 (78.85) 704 (86.38) 1,224 (75.09) With 517 (21.15) 111 (13.62) 406 (24.91) Location , n (%) 0.126 Northern Taiwan 1,359 (55.58) 476 (58.40) 883 (54.17) Middle Taiwan 495 (20.25) 148 (18.16) 347 (21.29) Southern Taiwan 487 (19.92) 155 (19.02) 332 (20.37) Eastern Taiwan 100 (4.09) 36 (4.42) 64 (3.93) Outlets islands 4 (0.16) 0 (0) 4 (0.25) Urbanization level , n (%) 0.053 1 (The highest) 1,038 (42.45) 321 (39.39) 717 (43.99) 2 1,209 (49.45) 435 (53.37) 774 (47.48) 3 52 (2.13) 16 (1.96) 36 (2.21) 4 (The lowest) 146 (5.97) 43 (5.28) 103 (6.32) Level of care , n (%) 0.036* Medical center 1,932 (79.02) 668 (81.96) 1,264 (77.55) Regional hospital 426 (17.42) 124 (15.21) 302 (18.53) Local hospital 87 (3.56) 23 (2.82) 64 (3.93) RT, radiation therapy; CCI_R, revised Charlson comorbidity index; SD, standard deviation. * p < 0.05 Associations between patients’ characteristics and incidence of RT-related late effects The incidence of late effects increased significantly in RT group compared with that in non-RT group (p < 0.05, Table 1 ). In multivariable Cox regression analysis adjusting for possible confounding variables, the risk of late effects in RT group was approximately 1.173-fold (adjusted HR [aHR] = 1.173, 95%CI 1.063–1.430, p < 0.05, Table 2 ) higher than that in non-RT group. In addition, high CCI_R, prior CT, prior brain surgery, and high level of care also were associated with an increased risk of late effects, while older age (> 6 years) was associated with a decreased risk of late effects (all p < 0.05, Table 2 ). After stratifying by the variables listed in Table 2 and analyzing using multivariable Cox regression adjusted for these variables, each subgroup among patients with RT had a higher risk of late effects than did subgroups among patients without RT (all p < 0.05, Supplementary Table 2 ), except for the older age subgroup, suggesting interactions between age and RT-related late effects. Table 2 Cox-regression analysis of factors associated with RT-related late effects. Variables Crude HR (95%CI) p -value aHR (95%CI) p -value RT Without Reference Reference With 1.260 (1.059, 1.504) 0.006* 1.173 (1.063, 1.430) 0.003* Gender Male 0.987 (0.817, 1.193) 0.894 1.002 (0.794, 1.165) 0.692 Female Reference Reference Age groups (years) < 1 Reference Reference 1–6 0.315 (0.100, 0.990) 0.048* 0.355 (0.113, 1.120) 0.077 7–12 0.236 (0.074, 0.749) 0.014* 0.270 (0.085, 0.860) 0.027* 13–18 0.208 (0.066, 0.657) 0.007* 0.248 (0.078, 0.784) 0.018* Insured premium (NT$) < 18,000 Reference Reference 18,000–34,999 1.423 (0.457, 0.434) 0.543 1.369 (0.431, 4.348) 0.594 ≧ 35,000 — — — — CCI_R 1.069 (1.046, 1.094) 0.014* 1.032 (1.004, 1.060) < 0.001* Prior CT Without Reference Reference With 1.633 (1.283, 2.079) < 0.001* 1.679 (1.299, 2.170) < 0.001* Prior brain surgery Without Reference Reference With 1.971 (1.570, 2.473) < 0.001* 1.856 (1.466, 2.350) < 0.001* Location Northern Taiwan Reference Multicollinearity with urbanization level Middle Taiwan 0.772 (0.603, 0.989) 0.040* Multicollinearity with urbanization level Southern Taiwan 1.009 (0.795, 1.281) 0.943 Multicollinearity with urbanization level Eastern Taiwan 0.681 (0.411, 1.129) 0.136 Multicollinearity with urbanization level Outlets islands — — Multicollinearity with urbanization level Urbanization level 1 (The highest) 2.320 (1.393, 3.861) 0.001* 0.787 (0.426, 1.456) 0.445 2 1.966 (1.183, 3.267) 0.009* 0.808 (0.268, 2.441) 0.706 3 0.706 (0.236, 2.113) 0.534 0.862 (0.459, 1.619) 0.644 4 (The lowest) Reference Reference Level of care Medical center 9.084 (2.915, 28.310) < 0.001* 8.889 (2.721, 29.040) < 0.001* Regional hospital 3.496 (1.087, 11.241) 0.036* 3.506 (1.080, 11.379) 0.037* Local hospital Reference Reference RT, radiation therapy; aHR, adjusted hazard ratio; CI, confidence interval; DM, diabetes mellitus; CCI_R, revised Charlson comorbidity index; SD, standard derivation. Adjusted HR: Adjusted for variables listed in the table. * p < 0.05. Kaplan-Meier plot and log-rank tests showed that RT group also had a high risk of late effects compared with risk in non-RT group across ≧ 7 years of tracking (all p < 0.05, Fig. 2 A and Supplementary Table 3 ). In addition, high insured premium, high urbanization level, and high hospital level of care also were associated with incident RT-related late effects (all p < 0.05, Table 2 ). Associations between RT and specific late effects After adjusting for the variables listed in Table 2 , RT group exhibited 1.172-fold (95% CI 1.020–1.398) and 1.796-fold (95% CI 1.250–2.578) higher risk of long-term endocrinopathies and late-delayed complications, respectively, than did non-RT group (all p < 0.05, Table 3 ). However, no significant differences were found in late cerebrovascular complications between the two groups. For long-term endocrinopathies, RT group had 1.602 (1.010–3.718)-fold and 1.120 (1.005–1.548)-fold higher risk for gonadotropin deficiency and hypothalamic pituitary dysfunction, respectively, than did non-RT group (all p < 0.05). For late-delayed complications, RT group had 3.208 (1.953–5.297)-fold higher risk for post-RT necrosis of the brain stem than did non-RT group (p < 0.05). Table 3 Multivariable Cox-regression analysis of RT-related late effects subgroup. Subgroup RT vs. Non-RT aHR (95%CI) p -value Long-term endocrinopathies 1.172 (1.020, 1.398) 0.018* Hypothyroidism 1.434 (0.635, 3.248) 0.364 Hypothalamic pituitary dysfunction 1.120 (1.005, 1.548) 0.045* Growth hormone deficiency Cortisol deficiency 0.667 (0.261, 1.699) 0.423 Gonadotropin deficiency 1.602 (1.010, 3.718) 0.031* Delay milestone Short stature 1.055 (0.348, 2.124) 0.789 Late-delayed complications 1.796 (1.250, 2.578) 0.002* Late effect of radiation — — Sensorineural hearing loss — — Stroke 2.785 (0.906, 8.589) 0.077 Post-RT necrosis of brain stem 3.208 (1.953, 5.297) < 0.001* Visual field defects 0.903 (0.387, 2.104) 0.853 Myopia 0.394 (0.139, 1.121) 0.094 Astigmatism 1.446 (0.270, 7.726) 0.655 RT-induced nonsenile cataract — — Nasogastic tube insertion — — Gastrostomy — — Late cerebrovascular complications 0.817 (0.454, 1.471) 0.553 Cavernous/Arteriovenous malformation 0.494 (0.104, 2.348) 0.403 Stroke 1.018 (0.492, 2.114) 0.928 Cerebral atropy 1.374 (0.240, 7.849) 0.714 Moyamoya disease 0.982 (0.048, 20.089) 0.998 RT, radiation therapy; aHR, adjusted hazard ratio; CI, confidence interval. Adjusted for variables listed in Table 3 . * p < 0.05 Kaplan-Meier plot and log-rank tests showed that RT group also had a higher risk of long-term endocrinopathies and late-delayed complications, respectively, than did non-RT group across ≧ 8 years of tracking (all p 0.05, Fig. 2 D and Supplementary Table 6 ). Discussion The present study is the first to evaluate associations between RT and the incidence of long-term specific late effects in pediatric patients with brain tumors in a national population. Results of the present study showed that RT group have higher risk of long-term side effects, long-term endocrinopathies and late-delayed complications compared to non-RT group. However, no significant differences were found in the risk of late cerebrovascular complications between the two groups. An interaction was noted between age and the risk or presence of RT-related late effects. For long-term endocrinopathies, RT group had higher risk for gonadotropin deficiency and hypothalamic pituitary dysfunction than did non-RT group. For late-delayed complications, RT group had higher risk for post-RT necrosis of brain stem than did non-RT group. Previous studies have reported that younger children are more sensitive to RT, which may compound their risk for late effects such as neurocognitive decline [ 7 , 12 ]. The effects of age also exceeded those of the radiation dose; patients younger than 5 years experienced the greatest decline in cognition [ 7 ]. Shalitin et al. [ 8 ] also revealed that pediatric patients with brain tumors who received RT are at increased risk of late endocrine effects, particularly those treated with cranial radiation and diagnosed at a younger age. Avadiappan et al. [ 13 ] also suggested that younger patients who were treated with RT are at greater risk of developing cerebrovascular complications. Our findings add further evidence that the most types among pediatric patients with young age who received RT are at increased risk of long-term side effects. In the present study, pediatric patients who were older at tumor diagnosis (> 6 years) had a decreased risk of long-term side effects compared to risk in pediatric patients who were younger ( ≦ 6 years) at tumor diagnosis. After stratifying by age, a high risk of RT-related long-term side effects was observed only in the younger subgroups, and was not observed in the older subgroups. These results appear to indicate an interaction between age and RT-related long-term side effects, with a cut-off value of 6-year-old. Thus, pediatric patients with brain tumors who are treated with RT need regular monitoring, including undergoing frequent neurologic evaluations to ensure normal development and additional educational and school support as needed. Cerebral radiation necrosis is a well-characterized toxicity of RT, first described in adult patients [ 14 ]. However, little data are available regarding the incidence and risk of radiation necrosis in pediatric patients. Plimpton et al. [ 15 ] reported that experience with pediatric patients undergoing RT for brain tumors suggests that children may have an increased likelihood to develop radiation necrosis compared to adults. Additional evidence revealed that brainstem injury is a rare complication of photon therapy [ 16 , 17 ]. The present study expanded these findings, showing further that pediatric patients (the most types of brain tumor) receiving RT had higher (3.208-fold) risk for post-RT necrosis of the brain stem than did non-RT patients. This may occur as a primary effect of cerebral cellular injury and vascular damage leading to tissue hypoxia. It has been reported that radiation necrosis begins as acute cellular injury in which endothelial cell death results in platelet aggregation and thrombus formation, finally leading to occlusion of micro-vessels [ 14 , 18 ]. Thus, we further speculated that RT-related brainstem necrosis may also be caused by the above mechanism in pediatric patients with brain tumors. These changes may further lead to cerebral atrophy, or focally, may cause development of mass lesions, resulting in confusion, seizures, and other significant neurologic effects [ 19 ]. Helton et al. [ 20 ] indicates that late-delayed cerebral radiation necrosis occurs between 6 and 12 months to years after therapy. Therefore, our recommendation is to routinely perform MRI monitoring for post-RT brain stem in pediatric patients within this time period. Such varied approaches as corticosteroids [ 21 ], bevacizumab [ 22 ], hyperbaric oxygen therapy [ 23 ], anticoagulation [ 24 ], and oral vitamin E [ 25 ] may be recommended for treatment of these cerebral radiation necrosis. Late endocrine effects also occur frequently and are often severe in pediatric patients with brain tumors [ 8 ]. The most common late endocrine effects is growth hormone (GH) deficiency, which may occur as soon as the first year after beginning RT [ 5 ]. Laughton et al. [ 26 ] reported that 84% of patients with embryonal brain tumors who received RT were diagnosed with GH deficiency at a median age of 1.8 years after RT, and 10% of patients developed thyroid-stimulating hormone (TSH) deficiency. The 4-year cumulative incidence rates for GH and TSH deficiency were 93% and 23%, respectively. In the study by Bahl et al. [ 27 ], the 5-year cumulative incidence rate was 68% for GH deficiency and 52% for hypothyroidism in patients with medulloblastomas (MB) who received RT. In the present study, showing further through up to 16 years of tracking, the most of pediatric patients with brain tumors (diagnosed as malignant neoplasm of brain, malignant neoplasm of cerebral meninges, malignant neoplasm of other endocrine glands and related structures, or neoplasm of unspecified nature of brain) who received RT had 1.120-fold higher risk for hypothalamic pituitary dysfunction than did non-RT patients. According to these findings, we suggest that the challenge here is not to reduce the radiation dose, but to avoid radiation-induced hyposuppression of the hypothalamic-pituitary axis. Because radiation-induced toxicity in the hypothalamic-pituitary-thyroid axis was not reduced by the introduction of lower RT doses for low-risk MB patients [ 28 ]. The correlation between RT and developing endocrine dysfunction such as gonadotropin deficiency in pediatric and young adult patients with brain tumor was examined by Vatner et al. [ 29 ], with the 4-year actuarial rate for gonadotropin deficiencies was 4.1%. The largest cohort of pediatric brain tumors treated with RT and chemotherapy demonstrated an estimated 40-year cumulative incidence of gonadotropin deficiency of 24.4% [ 30 ]. Further, the present study demonstrated that pediatric patients with RT had a 1.602-fold higher risk for gonadotropin deficiency than that in pediatric patients without RT. These findings indicate that the risk of gonadotropin deficiencies is continuously increasing after RT in pediatric patients with brain tumors. Consequently, as long-term survival outcomes for these children improve, these RT-related gonadotropin deficiency may become increasingly important determinants of their quality of life and medical expenditures [ 31 ]. Both short and long-term cerebrovascular complications may arise following RT. While cerebral microbleeds can be detected as early as eight months after RT, cavernous malformations and atherosclerosis can present decades later [ 6 , 32 ]. In the present study, with up to 16 years tracking, no significant differences were found in late cerebrovascular complications between the RT and non-RT groups, including cavernous/arteriovenous malformation, stroke, cerebral atropy and moyamoya disease. Nevertheless, we still recommend that clinicians must pay continuous attention to these potential late cerebrovascular complications when using RT to treat pediatric patients with brain tumor, although cerebral microbleeds are RT-induced small vessel vasculopathies that are associated with poorer executive function, poor working memory, cognitive decline and stroke in pediatric patients with brain tumors [ 33 , 34 ]. Strengths and Limitations The present study was strengthened by the use of the longitudinal NHIRD, which represents a nationwide population in Taiwan. Therefore, participants in the present study displayed a wide range of demographic characteristics, which allowed us to perform stratified analyses according to age, sex, occupation, and urbanization level. However, several limitations of the present study also must be considered when interpreting the findings. First, the data were extracted from an administrative database and analyzed retrospectively, which does not rule out selection bias or allow inferences of causation, and limits patient follow-up time to that supported by insurance claims. ICD-9-CM code does not have an appropriate classification to present the neurocognitive decline, hence it did not be assessed in the present study. Also, the NHIRD does not provide detailed information on possible brain tumor- or RT-related risk factors such as smoking, diet, genetic variants, structural birth defects, types of tumors, location of tumors, brain surgery, radiation dose, treatment volume, fraction size, and image guidance, which could be potential confounding factors. However, the present study included the most of pediatric patients with brain tumor before index date, hence the two groups may have a similar distribution in types and location of tumors. For all hospitals and medical centers in Taiwan, the RT (included exposure procedure, exposure dose and exposure location) was based on the guidelines of the Taiwan Society of Therapeutic Radiology and Oncology, thereby reducing the effect of these RT-related factors. Moreover, the common treatments (prior chemotherapy and prior brain surgery), comorbidities (CCI_R) and demographics (age, gender, salary-based insured premium, location of residence, urbanization level, hospital care level) were also presented in this study, and further adjusted for these possible confounding factors in the Cox regression analysis. Nevertheless, prospective multicenter studies are needed to further confirm results of the present study. Conclusions Pediatric patients with brain tumor had an increased risk of RT-related late effects, particularly in patients who are younger at tumor diagnosis. RT-related late effects increased over time. Gonadotropin deficiency, hypothalamic pituitary dysfunction and brainstem necrosis are the major RT-related late effects. Lifelong medical surveillance and close follow-up for potential RT-related late effects are essential in unique patient population because early diagnosis of late effects may help to reduce morbidity and mortality. Abbreviations RT radiation therapy CCI_R revised Charlson comorbidity index GH growth hormone TSH thyroid-stimulating hormone MB medulloblastomas Declarations Ethics approval and consent to participate To protect patient privacy, all personal patient information from the NHIRD is encrypted before being released to the public, including researchers. Therefore, all data for the present study were confirmed to be de-identified and were analyzed anonymously, precluding signed informed consent. The study protocol was approved by the Ethics Review Board of Tri-Service General Hospital (No. TSGHIRB. B-109-27). Consent for publication Not applicable Competing interests The authors declare that they have no competing interests Funding This study was supported by the Tri-Service General Hospital Research Foundation (TSGH-B-111018), and the sponsor has no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Author Contribution Conceptualization, Feng-Chin Lee, Wu-Chien Chien, and Chun-Chieh Chao; Methodology, Sen-Kuang Hou; Data Curation; Feng-Chin Lee, Chi-Hsiang Chung, Sheng-Feng Lin, and Wu-Chien Chien Formal analysis, Chi-Hsiang Chung, Sheng-Feng Lin, Wu-Chien Chien, and Chun-Chieh Chao; Writing – Original Draft Preparation, Feng-Chin Lee, Wu-Chien Chien, and Chun-Chieh Chao; Writing – Review & Editing, Feng-Chin Lee, Chi-Hsiang Chung, Sheng-Feng Lin, Wei-Fong Kao, Sen-Kuang Hou, Hsi Chang, Peter C. Hou, Wu-Chien Chien, and Chun-Chieh Chao; all authors read and approved the final version for submission. Acknowledgements We appreciate the Health and Welfare Data Science Center, Ministry of Health and Welfare (HWDC, MOHW), Taiwan, for providing the National Health Insurance Research Database (NHIRD). Availability of data and materials The data used to support the findings of this study are included within the article and its supplementary information files. 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Lupo JM, Molinaro AM, Essock-Burns E, Butowski N, Chang SM, Cha S, et al. The effects of anti-angiogenic therapy on the formation of radiation-induced microbleeds in normal brain tissue of patients with glioma. Neuro Oncol. 2016;18(1):87–95. Merchant TE, Conklin HM, Wu S, Lustig RH, Xiong X. Late effects of conformal radiation therapy for pediatric patients with low-grade glioma: prospective evaluation of cognitive, endocrine, and hearing deficits. J Clin Oncol. 2009;27(22):3691–7. Shalitin S, Gal M, Goshen Y, Cohen I, Yaniv I, Phillip M. Endocrine outcome in long-term survivors of childhood brain tumors. Horm Res Paediatr. 2011;76(2):113–22. Winter SF, Jo J, Schiff D, Dietrich J. Central Nervous System Complications Among Oncology Patients. Hematol Oncol Clin North Am. 2022;36(1):217–36. Wu TY, Majeed A, Kuo KN. An overview of the healthcare system in Taiwan. Lond J Prim Care (Abingdon). 2010;3(2):115–9. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol. 1992;45(6):613–9. Reimers TS, Ehrenfels S, Mortensen EL, Schmiegelow M, Sonderkaer S, Carstensen H, et al. Cognitive deficits in long-term survivors of childhood brain tumors: Identification of predictive factors. Med Pediatr Oncol. 2003;40(1):26–34. Avadiappan S, Morrison MA, Jakary A, Felton E, Stoller S, Hess CP, et al. Relationship between 7T MR-angiography features of vascular injury and cognitive decline in young brain tumor patients treated with radiation therapy. J Neurooncol. 2021;153(1):143–52. Greene-Schloesser D, Robbins ME, Peiffer AM, Shaw EG, Wheeler KT, Chan MD. Radiation-induced brain injury: A review. Front Oncol. 2012;2:73. Plimpton SR, Stence N, Hemenway M, Hankinson TC, Foreman N, Liu AK. Cerebral radiation necrosis in pediatric patients. Pediatr Hematol Oncol. 2015;32(1):78–83. Haas-Kogan D, Indelicato D, Paganetti H, Esiashvili N, Mahajan A, Yock T, et al. National Cancer Institute Workshop on Proton Therapy for Children: Considerations Regarding Brainstem Injury. Int J Radiat Oncol Biol Phys. 2018;101(1):152–68. Vogel J, Grewal A, O'Reilly S, Lustig R, Kurtz G, Minturn JE, et al. Risk of brainstem necrosis in pediatric patients with central nervous system malignancies after pencil beam scanning proton therapy. Acta Oncol. 2019;58(12):1752–6. Sundgren PC, Cao Y. Brain irradiation: effects on normal brain parenchyma and radiation injury. Neuroimaging Clin N Am. 2009;19(4):657–68. Drezner N, Hardy KK, Wells E, Vezina G, Ho CY, Packer RJ, et al. Treatment of pediatric cerebral radiation necrosis: a systematic review. J Neurooncol. 2016;130(1):141–8. Helton KJ, Edwards M, Steen RG, Merchant TE, Sapp MV, Boop FA, et al. Neuroimaging-detected late transient treatment-induced lesions in pediatric patients with brain tumors. J Neurosurg. 2005;102(2 Suppl):179–86. Indelicato DJ, Flampouri S, Rotondo RL, Bradley JA, Morris CG, Aldana PR, et al. Incidence and dosimetric parameters of pediatric brainstem toxicity following proton therapy. Acta Oncol. 2014;53(10):1298–304. Sadraei NH, Dahiya S, Chao ST, Murphy ES, Osei-Boateng K, Xie H, et al. Treatment of cerebral radiation necrosis with bevacizumab: the Cleveland clinic experience. Am J Clin Oncol. 2015;38(3):304–10. Kuffler DP. Hyperbaric oxygen therapy: can it prevent irradiation-induced necrosis? Exp Neurol. 2012;235(2):517–27. Happold C, Ernemann U, Roth P, Wick W, Weller M, Schmidt F. Anticoagulation for radiation-induced neurotoxicity revisited. J Neurooncol. 2008;90(3):357–62. Williamson R, Kondziolka D, Kanaan H, Lunsford LD, Flickinger JC. Adverse radiation effects after radiosurgery may benefit from oral vitamin E and pentoxifylline therapy: a pilot study. Stereotact Funct Neurosurg. 2008;86(6):359–66. Laughton SJ, Merchant TE, Sklar CA, Kun LE, Fouladi M, Broniscer A, et al. Endocrine outcomes for children with embryonal brain tumors after risk-adapted craniospinal and conformal primary-site irradiation and high-dose chemotherapy with stem-cell rescue on the SJMB-96 trial. J Clin Oncol. 2008;26(7):1112–8. Bahl G, Urbach S, Bartels U, Hodgson DC, Millar B-AM, Parent A, et al. Endocrine complications in children treated for medulloblastoma or ependymoma using radiation therapy. Outcomes in the CT-planning era. J Clin Oncol. 2009;27(15suppl):100064. Paulino AC. Hypothyroidism in children with medulloblastoma: a comparison of 3600 and 2340 cGy craniospinal radiotherapy. Int J Radiat Oncol Biol Phys. 2002;53(3):543–7. Vatner RE, Niemierko A, Misra M, Weyman EA, Goebel CP, Ebb DH, et al. Endocrine Deficiency As a Function of Radiation Dose to the Hypothalamus and Pituitary in Pediatric and Young Adult Patients With Brain Tumors. J Clin Oncol. 2018;36(28):2854–62. Chemaitilly W, Li Z, Huang S, Ness KK, Clark KL, Green DM, et al. Anterior hypopituitarism in adult survivors of childhood cancers treated with cranial radiotherapy: a report from the St Jude Lifetime Cohort study. J Clin Oncol. 2015;33(5):492–500. Chemaitilly W, Armstrong GT, Gajjar A, Hudson MM. Hypothalamic-Pituitary Axis Dysfunction in Survivors of Childhood CNS Tumors: Importance of Systematic Follow-Up and Early Endocrine Consultation. J Clin Oncol. 2016;34(36):4315–9. Gastelum E, Sear K, Hills N, Roddy E, Randazzo D, Chettout N, et al. Rates and characteristics of radiographically detected intracerebral cavernous malformations after cranial radiation therapy in pediatric cancer patients. J Child Neurol. 2015;30(7):842–9. Morrison MA, Payabvash S, Chen Y, Avadiappan S, Shah M, Zou X, et al. A user-guided tool for semi-automated cerebral microbleed detection and volume segmentation: Evaluating vascular injury and data labelling for machine learning. Neuroimage Clin. 2018;20:498–505. Roddy E, Sear K, Felton E, Tamrazi B, Gauvain K, Torkildson J, et al. Presence of cerebral microbleeds is associated with worse executive function in pediatric brain tumor survivors. Neuro Oncol. 2016;18(11):1548–58. Additional Declarations No competing interests reported. Supplementary Files SupplementaryMaterials.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3855527","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":274279031,"identity":"7f672cd3-02df-47bf-b656-8d96aab80e96","order_by":0,"name":"Feng-Chin Lee","email":"","orcid":"","institution":"Taipei Medical University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Feng-Chin","middleName":"","lastName":"Lee","suffix":""},{"id":274279032,"identity":"546e3581-a452-428f-89e1-895915c70222","order_by":1,"name":"Chi-Hsiang Chung","email":"","orcid":"","institution":"National Defense Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chi-Hsiang","middleName":"","lastName":"Chung","suffix":""},{"id":274279033,"identity":"936a0c6b-769c-4d7e-b641-91a8f0251940","order_by":2,"name":"Sheng-Feng Lin","email":"","orcid":"","institution":"Taipei Medical University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sheng-Feng","middleName":"","lastName":"Lin","suffix":""},{"id":274279034,"identity":"0236d407-3954-4ba0-ae8f-9bdafebda633","order_by":3,"name":"Wei-Fong Kao","email":"","orcid":"","institution":"Taipei Medical University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wei-Fong","middleName":"","lastName":"Kao","suffix":""},{"id":274279035,"identity":"50d68cd4-1a8e-4b2e-aeb6-a9ea025c8366","order_by":4,"name":"Sen-Kuang Hou","email":"","orcid":"","institution":"Taipei Medical University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sen-Kuang","middleName":"","lastName":"Hou","suffix":""},{"id":274279036,"identity":"3177b2e3-176d-46a4-a6af-cbcfbf13d631","order_by":5,"name":"Hsi Chang","email":"","orcid":"","institution":"Taipei Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hsi","middleName":"","lastName":"Chang","suffix":""},{"id":274279037,"identity":"f88155c6-58b0-4265-9734-1a63c30ae0fe","order_by":6,"name":"Peter C. Hou","email":"","orcid":"","institution":"Harvard Medical School","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Peter","middleName":"C.","lastName":"Hou","suffix":""},{"id":274279038,"identity":"41347e1e-6959-4517-8c24-ecd0e116ad36","order_by":7,"name":"Wu-Chien Chien","email":"","orcid":"","institution":"National Defense Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wu-Chien","middleName":"","lastName":"Chien","suffix":""},{"id":274279039,"identity":"d452dd92-742c-4b8e-bc6d-d42a3915ab60","order_by":8,"name":"Chun-Chieh Chao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3klEQVRIiWNgGAWjYDACCSBmbJBgMGDgAbIqQAwgeEC8ljNQLQmEtTBAtDC2MRDWwj+7x+zBzx0WcubsZw9++DjPIs+cvceAIbENjyV3zpgb9p6RMLbsyUuWnLlNotiy51gCXi0GEjlm0oxtEokbbvAYSPNuAzGSDzAknCGspR6oxfg37xyQlsQGorQkGNzgMZPmbYDZUoHHLzfSyiR72yQMN5zJMbOccUwicSfQLwfwaeGfkbxN4mdbnbzB8TPGNz7U1CVuZ+8xfPDBALcW7OAAqRpGwSgYBaNgFKACAA5qT2byevDLAAAAAElFTkSuQmCC","orcid":"","institution":"Taipei Medical University Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Chun-Chieh","middleName":"","lastName":"Chao","suffix":""}],"badges":[],"createdAt":"2024-01-12 03:44:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3855527/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3855527/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":51566313,"identity":"0666bf44-051b-47eb-aefa-2b1912777e10","added_by":"auto","created_at":"2024-02-23 19:11:55","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1363526,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart for selection of study population.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3855527/v1/6c396cf9632e61a85126b10c.png"},{"id":51566311,"identity":"38a54dac-314c-4e9a-a977-ef056bbacfe9","added_by":"auto","created_at":"2024-02-23 19:11:55","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":740772,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier plot for cumulative incidence of late effects in patients with (solid line) and without RT (dashed line). (A) Overall late effects. (B) Long-term endocrinopathies. (C) Late-delayed complications. (D) Late cerebrovascular complications. *\u003cem\u003ep\u003c/em\u003e\u0026lt;0.05\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-3855527/v1/f0bf78d67600eebb917fa86b.png"},{"id":63760323,"identity":"d40897cc-cb37-4f79-a8d4-02f897f08cb6","added_by":"auto","created_at":"2024-09-02 06:09:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3326928,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3855527/v1/f2a0a5d2-958c-4002-a451-4c32ad9fbf89.pdf"},{"id":51566556,"identity":"a9270b3f-cc06-43d0-a7e3-0251d5bed886","added_by":"auto","created_at":"2024-02-23 19:19:55","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":38202,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-3855527/v1/0951303cae9224edcc12a6bd.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Radiation therapy increases long-term risk of gonadotropin deficiency, hypothalamic pituitary dysfunction and brainstem necrosis in pediatric patients with brain tumor: A nationwide cohort study","fulltext":[{"header":"Background","content":"\u003cp\u003eRadiation therapy is widely used to effectively treat primary and metastatic brain tumors in adult and pediatric patients [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The clinical difference between brain tumors in adults and children is striking. Compared with adults, pediatric tumor types (mostly glial and neuronal) are more sensitive to RT [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. RT is the most effective nonsurgical treatment for pediatric with glioma, as 5-year progression-free survival estimates exceed 80% [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo maximize the therapeutic efficacy, RT has undergone revolutionary changes in recent decades like the development of intensity modulated radiation therapy, volumetric modulated arc therapy, and proton beam radiation therapy. Improved radiation therapies have also resulted in increased long-term brain tumor patient survival [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, this leads the increased of RT-related late effects in pediatric patients with glioma, including neurocognitive, neuroendocrine dysfunction, and cerebrovascular complications, as well as hearing deficits [\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLate-delayed treatment-induced brain complications frequently result in permanent neurologic disability [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Consequently, alteration or discontinuation of the overall antineoplastic treatment plan is frequently necessary to prevent further neurologic injury. Better identification of patients at high risk for developing late brain injury, neuroprotective strategies that modify existing antineoplastic treatment regimens, and research efforts directed at earlier recognition and improved treatment of neurologic complications are paramount. However, to date, no study has evaluated RT-related long-term gonadotropin deficiency, hypothalamic pituitary dysfunction and brainstem necrosis in pediatric patients with brain tumors using in a nationwide cohort. Therefore, the present study aimed to determine associations between radiation therapy and these late effects in pediatric patients with brain tumors in a nationwide population.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData source\u003c/h2\u003e \u003cp\u003eAll data for the present study were extracted from the National Health Insurance Research Database (NHIRD) in Taiwan, which currently covers more than 99% of the 23\u0026nbsp;million Taiwanese population [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The National Health Insurance Research Database (NHIRD) contains comprehensive demographic and clinical data for outpatient and inpatient claims data, where all clinical diagnoses and procedures are recorded based on the International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) codes. Additionally, the NHIRD was subjected to periodic quality control audits, and was also overseen by an advisory board run by the National Public Health Association.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eEthical considerations\u003c/h2\u003e \u003cp\u003eTo protect patient privacy, all personal patient information from the NHIRD is encrypted before being released to the public, including researchers. Therefore, all data for the present study were confirmed to be de-identified and were analyzed anonymously, precluding signed informed consent. The study protocol was approved by the Ethics Review Board of Tri-Service General Hospital (No. TSGHIRB. B-109-27).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and sample\u003c/h2\u003e \u003cp\u003eAs illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, patients aged\u0026thinsp;\u0026gt;\u0026thinsp;18 years; brain tumor diagnosed before index date; late effects before tracking; patients without tracking; and those with gender unknown were excluded. After exclusions, a cohort of pediatric patients with brain tumor (n\u0026thinsp;=\u0026thinsp;3,292) identified by ICD-9-CM 191 (malignant neoplasm of brain), 192.0 (malignant cranial nerve tumor), 192.1 (malignant cerebral meninges tumor), 194 (malignant neoplasm of other endocrine glands and related structures), or 239.6 (neoplasm of unspecified nature of brain) from 2000 to 2015 was established. Among included patients, 815 cases received RT (ICD-9-CM V58.0) and 1,630 cases did not receive RT (who matched to age, gender, and the year of the index date with a RT:non-RT ratio of 1:2). For all hospitals and medical centers in Taiwan, the brain tumor was diagnosed according to the guideline of the Taiwan Society of Neuro-Oncology, while the RT (included exposure procedure, exposure dose and exposure location) was based on the guidelines of the Taiwan Society of Therapeutic Radiology and Oncology.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eMain outcomes\u003c/h2\u003e \u003cp\u003eThe principal study outcome was overall late effects, including endocrinopathies (hypothyroidism, ICD-9-CM 244; hypothalamic pituitary dysfunction, ICD-9-CM 253; growth hormone deficiency, ICD-9-CM 259.4 and 259.8, cortisol deficiency, ICD-9-CM 255.4 and 255.5; gonadotropin deficiency, ICD-9-CM 259.0, 259.1, 259.4 and 259.8; delay milestone, ICD-9-CM 783.42; short stature, ICD-9-CM 783.43), late-delayed complications (late effect of radiation, ICD-9-CM 909.2; sensorineural hearing loss, ICD-9-CM 389.10; stroke, ICD-9-CM 437; post-RT necrosis of brain stem, ICD-9-CM OP31.1 and OP31.2; visual field defects, ICD-9-CM 368.4; myopia, ICD-9-CM 367.1; astigmatism, ICD-9-CM 367.2; RT-induced nonsenile cataract, ICD-9-CM 366.0; nasogastic tube insertion, ICD-9-CM OP44.99; gastrostomy, ICD-9-CM OP44.19), and late cerebrovascular complications (cavernous/arteriovenous malformation, ICD-9-CM 747.81; stroke, ICD-9-CM 434, 436, 437; cerebral atropy, ICD-9-CM 331.7, 331.89, 331.9; transient cerebral ischemia, ICD-9-CM 437.5). For all hospitals and medical centers in Taiwan, these late effects were assessed and diagnosed according to the follow-up of regular outpatient, regular blood test, regular imaging (CT/MRI) examination, clinically (neurological symptoms), histopathology, or assessment of growth and development, which were based on the guidelines of the major Medical Societies in Taiwan.\u003c/p\u003e \u003cp\u003eThe independent variables were age, gender, salary-based insured premium, prior chemotherapy (ICD-9-CM V58.1), prior brain surgery (ICD-9-CM OP01, OP02, OP04), location of residence, urbanization level, hospital care level, and the revised Charlson comorbidity index (CCI_R). CCI_R was defined as \"CCI without brain tumor excision and stroke.\" The Charlson Comorbidity Index (CCI), as adapted by Deyo et al. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], was used to assess the level of general comorbid conditions.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eCategorical variables were compared using the Chi-squared test, and continuous variables were compared using the Student's t-test. Possible confounding variables (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) among baseline variables listed in each Table were adjusted for subsequent statistical analyses. Multivariable Cox proportional hazards regression analysis was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of late effects in the RT cohort compared with the non-RT cohort. Kaplan\u0026ndash;Meier analysis was used to measure the cumulative incidence of late effects for both study cohorts, and the log-rank test was used to evaluate differences between the two cumulative incidence curves. All statistical analyses were carried out using IBM SPSS statistical software version 22 for Windows (IBM Corp., Armonk, New York, USA). A p-value of less than 0.05 in 2-tailed tests was considered to be statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u0026rsquo; characteristics\u003c/h2\u003e \u003cp\u003eA total of 2,445 pediatric patients with brain tumors were included in this study, including 815 patients with RT and 1,630 patients without RT (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003eand Supplementary Table\u0026nbsp;1\u003c/b\u003e). No differences were found in age, gender, salary-based insured premium, and location of residence between the two groups at baseline and endpoint (all p\u0026thinsp;\u0026gt;\u0026thinsp;0.05); however, the revised Charlson comorbidity index (CCI_R), prior chemotherapy (CT), prior brain surgery, urbanization level at baseline and the hospital level of medical care were different between the two group (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, \u003cb\u003eSupplementary Table\u0026nbsp;1 and\u003c/b\u003e Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of study population at endpoint.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;2,445)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eRT\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;815)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eNon-RT\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;1,630)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003ep-\u003c/em\u003evalue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLate effects\u003c/b\u003e, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWithout\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e2,000 (81.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e636 (78.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e1,364 (83.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWith\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e445 (18.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e179 (21.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e266 (16.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGender\u003c/b\u003e, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e1,475 (60.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e490 (60.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e980 (60.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e970 (39.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e325 (39.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e650 (39.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years)\u003c/b\u003e, mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e10.83\u0026thinsp;\u0026plusmn;\u0026thinsp;5.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e10.95\u0026thinsp;\u0026plusmn;\u0026thinsp;5.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e10.77\u0026thinsp;\u0026plusmn;\u0026thinsp;6.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.489\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge groups (years)\u003c/b\u003e, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.007*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e15 (0.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e3 (0.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e12 (0.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u0026ndash;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e695 (28.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e202 (24.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e493 (30.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u0026ndash;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e924 (37.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e341 (41.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e583 (35.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u0026ndash;18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e811 (33.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e269 (33.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e542 (33.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eInsured premium (NT$)\u003c/b\u003e, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.462\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;18,000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e2,431 (99.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e811 (99.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e1,620 (99.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18,000\u0026ndash;34,999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e11 (0.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e4 (0.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e7 (0.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e≧\u0026thinsp;35,000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e3 (0.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e3 (0.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCCI_R\u003c/b\u003e, mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e0.54\u0026thinsp;\u0026plusmn;\u0026thinsp;1.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e1.50\u0026thinsp;\u0026plusmn;\u0026thinsp;1.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e0.06\u0026thinsp;\u0026plusmn;\u0026thinsp;0.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrior CT\u003c/b\u003e, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWithout\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e1,487 (60.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e333 (40.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e1,154 (70.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWith\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e958 (39.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e482 (59.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e476 (29.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrior brain surgery\u003c/b\u003e, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWithout\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e1,928 (78.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e704 (86.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e1,224 (75.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWith\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e517 (21.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e111 (13.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e406 (24.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLocation\u003c/b\u003e, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.126\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNorthern Taiwan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e1,359 (55.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e476 (58.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e883 (54.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMiddle Taiwan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e495 (20.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e148 (18.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e347 (21.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSouthern Taiwan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e487 (19.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e155 (19.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e332 (20.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEastern Taiwan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e100 (4.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e36 (4.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e64 (3.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutlets islands\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e4 (0.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e4 (0.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUrbanization level\u003c/b\u003e, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.053\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1 (The highest)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e1,038 (42.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e321 (39.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e717 (43.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e1,209 (49.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e435 (53.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e774 (47.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e52 (2.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e16 (1.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e36 (2.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4 (The lowest)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e146 (5.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e43 (5.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e103 (6.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLevel of care\u003c/b\u003e, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.036*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedical center\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e1,932 (79.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e668 (81.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e1,264 (77.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegional hospital\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e426 (17.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e124 (15.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e302 (18.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocal hospital\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e87 (3.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e23 (2.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e64 (3.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"8\" nameend=\"c8\" namest=\"c1\"\u003e \u003cp\u003eRT, radiation therapy; CCI_R, revised Charlson comorbidity index; SD, standard deviation. \u003cb\u003e*\u003c/b\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eAssociations between patients\u0026rsquo; characteristics and incidence of RT-related late effects\u003c/h2\u003e \u003cp\u003eThe incidence of late effects increased significantly in RT group compared with that in non-RT group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). In multivariable Cox regression analysis adjusting for possible confounding variables, the risk of late effects in RT group was approximately 1.173-fold (adjusted HR [aHR]\u0026thinsp;=\u0026thinsp;1.173, 95%CI 1.063\u0026ndash;1.430, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) higher than that in non-RT group. In addition, high CCI_R, prior CT, prior brain surgery, and high level of care also were associated with an increased risk of late effects, while older age (\u0026gt;\u0026thinsp;6 years) was associated with a decreased risk of late effects (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). After stratifying by the variables listed in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and analyzing using multivariable Cox regression adjusted for these variables, each subgroup among patients with RT had a higher risk of late effects than did subgroups among patients without RT (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, \u003cb\u003eSupplementary Table\u0026nbsp;2\u003c/b\u003e), except for the older age subgroup, suggesting interactions between age and RT-related late effects.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCox-regression analysis of factors associated with RT-related late effects.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eCrude HR (95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003eaHR (95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWithout\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWith\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e1.260 (1.059, 1.504)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.006*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e1.173 (1.063, 1.430)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.003*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e0.987 (0.817, 1.193)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.894\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e1.002 (0.794, 1.165)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.692\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge groups (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u0026ndash;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e0.315 (0.100, 0.990)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.048*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e0.355 (0.113, 1.120)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.077\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u0026ndash;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e0.236 (0.074, 0.749)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.014*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e0.270 (0.085, 0.860)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.027*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u0026ndash;18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e0.208 (0.066, 0.657)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.007*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e0.248 (0.078, 0.784)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.018*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eInsured premium (NT$)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;18,000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18,000\u0026ndash;34,999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e1.423 (0.457, 0.434)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.543\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e1.369 (0.431, 4.348)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.594\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e≧\u0026thinsp;35,000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCCI_R\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e1.069 (1.046, 1.094)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.014*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e1.032 (1.004, 1.060)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrior CT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWithout\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWith\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e1.633 (1.283, 2.079)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e1.679 (1.299, 2.170)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrior brain surgery\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWithout\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWith\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e1.971 (1.570, 2.473)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e1.856 (1.466, 2.350)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLocation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNorthern Taiwan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e \u003cp\u003eMulticollinearity with urbanization level\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMiddle Taiwan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e0.772 (0.603, 0.989)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.040*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e \u003cp\u003eMulticollinearity with urbanization level\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSouthern Taiwan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e1.009 (0.795, 1.281)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.943\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e \u003cp\u003eMulticollinearity with urbanization level\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEastern Taiwan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e0.681 (0.411, 1.129)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.136\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e \u003cp\u003eMulticollinearity with urbanization level\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutlets islands\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e \u003cp\u003eMulticollinearity with urbanization level\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUrbanization level\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1 (The highest)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e2.320 (1.393, 3.861)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.001*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e0.787 (0.426, 1.456)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.445\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e1.966 (1.183, 3.267)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.009*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e0.808 (0.268, 2.441)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.706\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e0.706 (0.236, 2.113)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.534\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e0.862 (0.459, 1.619)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.644\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4 (The lowest)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLevel of care\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedical center\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e9.084 (2.915, 28.310)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e8.889 (2.721, 29.040)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegional hospital\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e3.496 (1.087, 11.241)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.036*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e3.506 (1.080, 11.379)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.037*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocal hospital\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"9\" nameend=\"c9\" namest=\"c1\"\u003e \u003cp\u003eRT, radiation therapy; aHR, adjusted hazard ratio; CI, confidence interval; DM, diabetes mellitus; CCI_R, revised Charlson comorbidity index; SD, standard derivation. Adjusted HR: Adjusted for variables listed in the table. *\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eKaplan-Meier plot and log-rank tests showed that RT group also had a high risk of late effects compared with risk in non-RT group across ≧\u0026thinsp;7 years of tracking (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA and \u003cb\u003eSupplementary Table\u0026nbsp;3\u003c/b\u003e). In addition, high insured premium, high urbanization level, and high hospital level of care also were associated with incident RT-related late effects (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eAssociations between RT and specific late effects\u003c/h2\u003e \u003cp\u003eAfter adjusting for the variables listed in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, RT group exhibited 1.172-fold (95% CI 1.020\u0026ndash;1.398) and 1.796-fold (95% CI 1.250\u0026ndash;2.578) higher risk of long-term endocrinopathies and late-delayed complications, respectively, than did non-RT group (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). However, no significant differences were found in late cerebrovascular complications between the two groups. For long-term endocrinopathies, RT group had 1.602 (1.010\u0026ndash;3.718)-fold and 1.120 (1.005\u0026ndash;1.548)-fold higher risk for gonadotropin deficiency and hypothalamic pituitary dysfunction, respectively, than did non-RT group (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). For late-delayed complications, RT group had 3.208 (1.953\u0026ndash;5.297)-fold higher risk for post-RT necrosis of the brain stem than did non-RT group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariable Cox-regression analysis of RT-related late effects subgroup.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSubgroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eRT \u003cem\u003evs.\u003c/em\u003e Non-RT\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eaHR (95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLong-term endocrinopathies\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.172 (1.020, 1.398)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.018*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypothyroidism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.434 (0.635, 3.248)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.364\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypothalamic pituitary dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.120 (1.005, 1.548)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.045*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrowth hormone deficiency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCortisol deficiency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.667 (0.261, 1.699)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.423\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGonadotropin deficiency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.602 (1.010, 3.718)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.031*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelay milestone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eShort stature\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.055 (0.348, 2.124)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.789\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLate-delayed complications\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.796 (1.250, 2.578)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.002*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLate effect of radiation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSensorineural hearing loss\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStroke\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.785 (0.906, 8.589)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.077\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePost-RT necrosis of brain stem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.208 (1.953, 5.297)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVisual field defects\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.903 (0.387, 2.104)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.853\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMyopia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.394 (0.139, 1.121)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.094\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAstigmatism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.446 (0.270, 7.726)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.655\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRT-induced nonsenile cataract\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNasogastic tube insertion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGastrostomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLate cerebrovascular complications\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.817 (0.454, 1.471)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.553\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCavernous/Arteriovenous malformation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.494 (0.104, 2.348)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.403\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStroke\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.018 (0.492, 2.114)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.928\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCerebral atropy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.374 (0.240, 7.849)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.714\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMoyamoya disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.982 (0.048, 20.089)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.998\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eRT, radiation therapy; aHR, adjusted hazard ratio; CI, confidence interval. Adjusted for variables listed in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. *\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eKaplan-Meier plot and log-rank tests showed that RT group also had a higher risk of long-term endocrinopathies and late-delayed complications, respectively, than did non-RT group across ≧\u0026thinsp;8 years of tracking (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB-\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC and \u003cb\u003eSupplementary Table\u0026nbsp;4\u0026ndash;5\u003c/b\u003e). No significant differences were found in the risk of late cerebrovascular complications between the two groups across all years of tracking (all p\u0026thinsp;\u0026gt;\u0026thinsp;0.05, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD and \u003cb\u003eSupplementary Table\u0026nbsp;6\u003c/b\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe present study is the first to evaluate associations between RT and the incidence of long-term specific late effects in pediatric patients with brain tumors in a national population. Results of the present study showed that RT group have higher risk of long-term side effects, long-term endocrinopathies and late-delayed complications compared to non-RT group. However, no significant differences were found in the risk of late cerebrovascular complications between the two groups. An interaction was noted between age and the risk or presence of RT-related late effects. For long-term endocrinopathies, RT group had higher risk for gonadotropin deficiency and hypothalamic pituitary dysfunction than did non-RT group. For late-delayed complications, RT group had higher risk for post-RT necrosis of brain stem than did non-RT group.\u003c/p\u003e \u003cp\u003ePrevious studies have reported that younger children are more sensitive to RT, which may compound their risk for late effects such as neurocognitive decline [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The effects of age also exceeded those of the radiation dose; patients younger than 5 years experienced the greatest decline in cognition [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Shalitin et al. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] also revealed that pediatric patients with brain tumors who received RT are at increased risk of late endocrine effects, particularly those treated with cranial radiation and diagnosed at a younger age. Avadiappan et al. [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] also suggested that younger patients who were treated with RT are at greater risk of developing cerebrovascular complications. Our findings add further evidence that the most types among pediatric patients with young age who received RT are at increased risk of long-term side effects. In the present study, pediatric patients who were older at tumor diagnosis (\u0026gt;\u0026thinsp;6 years) had a decreased risk of long-term side effects compared to risk in pediatric patients who were younger (\u0026thinsp;≦\u0026thinsp;6 years) at tumor diagnosis. After stratifying by age, a high risk of RT-related long-term side effects was observed only in the younger subgroups, and was not observed in the older subgroups. These results appear to indicate an interaction between age and RT-related long-term side effects, with a cut-off value of 6-year-old. Thus, pediatric patients with brain tumors who are treated with RT need regular monitoring, including undergoing frequent neurologic evaluations to ensure normal development and additional educational and school support as needed.\u003c/p\u003e \u003cp\u003eCerebral radiation necrosis is a well-characterized toxicity of RT, first described in adult patients [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. However, little data are available regarding the incidence and risk of radiation necrosis in pediatric patients. Plimpton et al. [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] reported that experience with pediatric patients undergoing RT for brain tumors suggests that children may have an increased likelihood to develop radiation necrosis compared to adults. Additional evidence revealed that brainstem injury is a rare complication of photon therapy [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The present study expanded these findings, showing further that pediatric patients (the most types of brain tumor) receiving RT had higher (3.208-fold) risk for post-RT necrosis of the brain stem than did non-RT patients. This may occur as a primary effect of cerebral cellular injury and vascular damage leading to tissue hypoxia. It has been reported that radiation necrosis begins as acute cellular injury in which endothelial cell death results in platelet aggregation and thrombus formation, finally leading to occlusion of micro-vessels [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Thus, we further speculated that RT-related brainstem necrosis may also be caused by the above mechanism in pediatric patients with brain tumors. These changes may further lead to cerebral atrophy, or focally, may cause development of mass lesions, resulting in confusion, seizures, and other significant neurologic effects [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Helton et al. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] indicates that late-delayed cerebral radiation necrosis occurs between 6 and 12 months to years after therapy. Therefore, our recommendation is to routinely perform MRI monitoring for post-RT brain stem in pediatric patients within this time period. Such varied approaches as corticosteroids [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], bevacizumab [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], hyperbaric oxygen therapy [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], anticoagulation [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], and oral vitamin E [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] may be recommended for treatment of these cerebral radiation necrosis.\u003c/p\u003e \u003cp\u003eLate endocrine effects also occur frequently and are often severe in pediatric patients with brain tumors [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The most common late endocrine effects is growth hormone (GH) deficiency, which may occur as soon as the first year after beginning RT [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Laughton et al. [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] reported that 84% of patients with embryonal brain tumors who received RT were diagnosed with GH deficiency at a median age of 1.8 years after RT, and 10% of patients developed thyroid-stimulating hormone (TSH) deficiency. The 4-year cumulative incidence rates for GH and TSH deficiency were 93% and 23%, respectively. In the study by Bahl et al. [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], the 5-year cumulative incidence rate was 68% for GH deficiency and 52% for hypothyroidism in patients with medulloblastomas (MB) who received RT. In the present study, showing further through up to 16 years of tracking, the most of pediatric patients with brain tumors (diagnosed as malignant neoplasm of brain, malignant neoplasm of cerebral meninges, malignant neoplasm of other endocrine glands and related structures, or neoplasm of unspecified nature of brain) who received RT had 1.120-fold higher risk for hypothalamic pituitary dysfunction than did non-RT patients. According to these findings, we suggest that the challenge here is \u003cem\u003enot\u003c/em\u003e to reduce the radiation dose, but to avoid radiation-induced hyposuppression of the hypothalamic-pituitary axis. Because radiation-induced toxicity in the hypothalamic-pituitary-thyroid axis was not reduced by the introduction of lower RT doses for low-risk MB patients [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe correlation between RT and developing endocrine dysfunction such as gonadotropin deficiency in pediatric and young adult patients with brain tumor was examined by Vatner et al. [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], with the 4-year actuarial rate for gonadotropin deficiencies was 4.1%. The largest cohort of pediatric brain tumors treated with RT and chemotherapy demonstrated an estimated 40-year cumulative incidence of gonadotropin deficiency of 24.4% [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Further, the present study demonstrated that pediatric patients with RT had a 1.602-fold higher risk for gonadotropin deficiency than that in pediatric patients without RT. These findings indicate that the risk of gonadotropin deficiencies is continuously increasing after RT in pediatric patients with brain tumors. Consequently, as long-term survival outcomes for these children improve, these RT-related gonadotropin deficiency may become increasingly important determinants of their quality of life and medical expenditures [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBoth short and long-term cerebrovascular complications may arise following RT. While cerebral microbleeds can be detected as early as eight months after RT, cavernous malformations and atherosclerosis can present decades later [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. In the present study, with up to 16 years tracking, no significant differences were found in late cerebrovascular complications between the RT and non-RT groups, including cavernous/arteriovenous malformation, stroke, cerebral atropy and moyamoya disease. Nevertheless, we still recommend that clinicians must pay continuous attention to these potential late cerebrovascular complications when using RT to treat pediatric patients with brain tumor, although cerebral microbleeds are RT-induced small vessel vasculopathies that are associated with poorer executive function, poor working memory, cognitive decline and stroke in pediatric patients with brain tumors [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eStrengths and Limitations\u003c/h2\u003e \u003cp\u003eThe present study was strengthened by the use of the longitudinal NHIRD, which represents a nationwide population in Taiwan. Therefore, participants in the present study displayed a wide range of demographic characteristics, which allowed us to perform stratified analyses according to age, sex, occupation, and urbanization level. However, several limitations of the present study also must be considered when interpreting the findings. First, the data were extracted from an administrative database and analyzed retrospectively, which does not rule out selection bias or allow inferences of causation, and limits patient follow-up time to that supported by insurance claims. ICD-9-CM code does not have an appropriate classification to present the neurocognitive decline, hence it did not be assessed in the present study. Also, the NHIRD does not provide detailed information on possible brain tumor- or RT-related risk factors such as smoking, diet, genetic variants, structural birth defects, types of tumors, location of tumors, brain surgery, radiation dose, treatment volume, fraction size, and image guidance, which could be potential confounding factors. However, the present study included the most of pediatric patients with brain tumor before index date, hence the two groups may have a similar distribution in types and location of tumors. For all hospitals and medical centers in Taiwan, the RT (included exposure procedure, exposure dose and exposure location) was based on the guidelines of the Taiwan Society of Therapeutic Radiology and Oncology, thereby reducing the effect of these RT-related factors. Moreover, the common treatments (prior chemotherapy and prior brain surgery), comorbidities (CCI_R) and demographics (age, gender, salary-based insured premium, location of residence, urbanization level, hospital care level) were also presented in this study, and further adjusted for these possible confounding factors in the Cox regression analysis. Nevertheless, prospective multicenter studies are needed to further confirm results of the present study.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003ePediatric patients with brain tumor had an increased risk of RT-related late effects, particularly in patients who are younger at tumor diagnosis. RT-related late effects increased over time. Gonadotropin deficiency, hypothalamic pituitary dysfunction and brainstem necrosis are the major RT-related late effects. Lifelong medical surveillance and close follow-up for potential RT-related late effects are essential in unique patient population because early diagnosis of late effects may help to reduce morbidity and mortality.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eradiation therapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCCI_R\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003erevised Charlson comorbidity index\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003egrowth hormone\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTSH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ethyroid-stimulating hormone\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emedulloblastomas\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003eTo protect patient privacy, all personal patient information from the NHIRD is encrypted before being released to the public, including researchers. Therefore, all data for the present study were confirmed to be de-identified and were analyzed anonymously, precluding signed informed consent. The study protocol was approved by the Ethics Review Board of Tri-Service General Hospital (No. TSGHIRB. B-109-27).\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003eNot applicable\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis study was supported by the Tri-Service General Hospital Research Foundation (TSGH-B-111018), and the sponsor has no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eConceptualization, Feng-Chin Lee, Wu-Chien Chien, and Chun-Chieh Chao; Methodology, Sen-Kuang Hou; Data Curation; Feng-Chin Lee, Chi-Hsiang Chung, Sheng-Feng Lin, and Wu-Chien Chien Formal analysis, Chi-Hsiang Chung, Sheng-Feng Lin, Wu-Chien Chien, and Chun-Chieh Chao; Writing \u0026ndash; Original Draft Preparation, Feng-Chin Lee, Wu-Chien Chien, and Chun-Chieh Chao; Writing \u0026ndash; Review \u0026amp; Editing, Feng-Chin Lee, Chi-Hsiang Chung, Sheng-Feng Lin, Wei-Fong Kao, Sen-Kuang Hou, Hsi Chang, Peter C. Hou, Wu-Chien Chien, and Chun-Chieh Chao; all authors read and approved the final version for submission.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eWe appreciate the Health and Welfare Data Science Center, Ministry of Health and Welfare (HWDC, MOHW), Taiwan, for providing the National Health Insurance Research Database (NHIRD).\u003c/p\u003e\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e \u003cp\u003eThe data used to support the findings of this study are included within the article and its supplementary information files.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTurnquist C, Harris BT, Harris CC. Radiation-induced brain injury: current concepts and therapeutic strategies targeting neuroinflammation. Neurooncol Adv. 2020;2(1):vdaa057.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCowman S, Fan YN, Pizer B, See V. 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J Neurooncol. 2016;130(1):141\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHelton KJ, Edwards M, Steen RG, Merchant TE, Sapp MV, Boop FA, et al. Neuroimaging-detected late transient treatment-induced lesions in pediatric patients with brain tumors. J Neurosurg. 2005;102(2 Suppl):179\u0026ndash;86.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIndelicato DJ, Flampouri S, Rotondo RL, Bradley JA, Morris CG, Aldana PR, et al. Incidence and dosimetric parameters of pediatric brainstem toxicity following proton therapy. Acta Oncol. 2014;53(10):1298\u0026ndash;304.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSadraei NH, Dahiya S, Chao ST, Murphy ES, Osei-Boateng K, Xie H, et al. Treatment of cerebral radiation necrosis with bevacizumab: the Cleveland clinic experience. Am J Clin Oncol. 2015;38(3):304\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKuffler DP. 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J Clin Oncol. 2018;36(28):2854\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChemaitilly W, Li Z, Huang S, Ness KK, Clark KL, Green DM, et al. Anterior hypopituitarism in adult survivors of childhood cancers treated with cranial radiotherapy: a report from the St Jude Lifetime Cohort study. J Clin Oncol. 2015;33(5):492\u0026ndash;500.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChemaitilly W, Armstrong GT, Gajjar A, Hudson MM. Hypothalamic-Pituitary Axis Dysfunction in Survivors of Childhood CNS Tumors: Importance of Systematic Follow-Up and Early Endocrine Consultation. J Clin Oncol. 2016;34(36):4315\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGastelum E, Sear K, Hills N, Roddy E, Randazzo D, Chettout N, et al. Rates and characteristics of radiographically detected intracerebral cavernous malformations after cranial radiation therapy in pediatric cancer patients. J Child Neurol. 2015;30(7):842\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorrison MA, Payabvash S, Chen Y, Avadiappan S, Shah M, Zou X, et al. A user-guided tool for semi-automated cerebral microbleed detection and volume segmentation: Evaluating vascular injury and data labelling for machine learning. Neuroimage Clin. 2018;20:498\u0026ndash;505.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoddy E, Sear K, Felton E, Tamrazi B, Gauvain K, Torkildson J, et al. Presence of cerebral microbleeds is associated with worse executive function in pediatric brain tumor survivors. Neuro Oncol. 2016;18(11):1548\u0026ndash;58.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"brain tumor, pediatric, radiation therapy, late effects","lastPublishedDoi":"10.21203/rs.3.rs-3855527/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3855527/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eWe evaluated associations between radiation therapy (RT) and late side effects (long-term endocrine, cognitive and cerebrovascular complications) in pediatric patients with brain tumor in a nationwide population.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eData of pediatric patients with brain tumor were extracted from the National Health Insurance Research Database (NHIRD) of Taiwan. The RT cohort included 815 patients, randomly matched by age, gender, and index year with non-RT controls. Multivariable Cox proportional hazards regression was used to calculate adjusted hazard ratios (aHR) of developing late side effects in RT patients versus non-RT controls.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe risk of late side effects in RT group was 1.173-fold (aHR =1.173, 95%CI 1.063-1.430) higher than did non-RT group. RT patients exhibited 1.172-fold and 1.796-fold higher risk of long-term endocrinopathies and late-delayed complications, respectively, than did non-RT patients. For long-term endocrinopathies, patients with RT had 1.602-fold and 1.120-fold higher risk for gonadotropin deficiency and hypothalamic pituitary dysfunction, respectively, than did non-RT patients. For late-delayed complications, patients with RT had 3.208-fold higher risk for necrosis of brain stem than did non-RT patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eGonadotropin deficiency, hypothalamic pituitary dysfunction and brainstem necrosis are dominant RT-related late side effects in pediatric patients. Frequency of these deficits increases with time, warranting long-term surveillance.\u003c/p\u003e","manuscriptTitle":"Radiation therapy increases long-term risk of gonadotropin deficiency, hypothalamic pituitary dysfunction and brainstem necrosis in pediatric patients with brain tumor: A nationwide cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-23 19:11:50","doi":"10.21203/rs.3.rs-3855527/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7fe17880-1379-4fd2-862e-47635f0047ef","owner":[],"postedDate":"February 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-09-02T05:44:56+00:00","versionOfRecord":[],"versionCreatedAt":"2024-02-23 19:11:50","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3855527","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3855527","identity":"rs-3855527","version":["v1"]},"buildId":"zQwnuV7TCBrMSSSToR1PI","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}