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Title: Cerebrovascular Diseases in Childhood Cancer Survivors: Role of the Radiation Dose to Willis Circle Arteries

Abstract

Background and Purpose: The aim of this study was to investigate the role of radiation dose received to the circle of Willis (WC) during radiation therapy (RT) and of potential dose-response modifiers on the risk of stroke after treatment of childhood cancer. Methods: We evaluated the risk factors for stroke in a cohort of 3172 5-year survivors of childhood cancer who were followed up for a median time of 26 years. Radiation doses to the WC and brain structures were estimated for each of the 2202 children who received RT. Results: Fifty-four patients experienced a confirmed stroke; 39 were ischemic. Patients not receiving RT had a stroke risk similar to that of the general population, whereas those who received RT had an 8.5-fold increased risk (95% confidence interval [CI]: 6.3-11.0). The excess of incidence of stroke increased yearly. The dose of radiation to the WC, rather than to other brain structures, was found to be the best predictor of stroke. The relative risk was 15.7 (95% CI: 4.9-50.2) for doses of 40 Gy or more. At 45 years of age, the cumulative stroke incidence was 11.3% (95% CI: 7.1%-17.7%) in patients who received 10 Gy or more to the WC, compared with 1% expectedmore » from general population data. Radiation doses received to the heart and neck also increased the risk. Surgery for childhood brain cancer was linked to hemorrhagic strokes in these patients. Conclusion: The WC should be considered as a major organ at risk during RT for childhood brain cancers. The incidence of radiation-induced ischemic stroke strongly increases with long-term follow-up.« less

Authors:
; ; ; ; ; ; ; ; ;  [1];  [2];  [2];  [3];  [4];  [1];  [2];  [1]; ;  [4]; more »;  [5];  [6];  [7]; « less
  1. Inserm U1018, Villejuif (France)
  2. (France)
  3. Institut Curie, Paris (France)
  4. Gustave Roussy, Villejuif (France)
  5. Registre Dijonnais des accidents vasculaires cérébraux, Dijon (France)
  6. Centre Alexis Vautrin, Vandoeuvre-lès-Nancy (France)
  7. Centre Léon Bérard, Lyon (France)
Publication Date:
OSTI Identifier:
22645764
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 97; Journal Issue: 2; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; BRAIN; GY RANGE 01-10; GY RANGE 10-100; NEOPLASMS; PATIENTS; RADIATION DOSES; RADIATION HAZARDS; RADIOTHERAPY

Citation Formats

El-Fayech, Chiraz, Haddy, Nadia, Allodji, Rodrigue Sètchéou, Veres, Cristina, Diop, Fara, Kahlouche, Amar, Llanas, Damien, Jackson, Angela, Rubino, Carole, Guibout, Catherine, Gustave Roussy, Villejuif, University of Paris XI, Villejuif, Pacquement, Hélène, Oberlin, Odile, Thomas-Teinturier, Cécile, Hôpital Bicêtre, Le Kremlin Bicêtre, Scarabin, Pierre-Yves, Chavaudra, Jean, Lefkopoulos, Dimitry, Giroud, Maurice, Bejot, Yannick, Bernier, Valérie, Carrie, Christian, and and others. Cerebrovascular Diseases in Childhood Cancer Survivors: Role of the Radiation Dose to Willis Circle Arteries. United States: N. p., 2017. Web. doi:10.1016/J.IJROBP.2016.10.015.
El-Fayech, Chiraz, Haddy, Nadia, Allodji, Rodrigue Sètchéou, Veres, Cristina, Diop, Fara, Kahlouche, Amar, Llanas, Damien, Jackson, Angela, Rubino, Carole, Guibout, Catherine, Gustave Roussy, Villejuif, University of Paris XI, Villejuif, Pacquement, Hélène, Oberlin, Odile, Thomas-Teinturier, Cécile, Hôpital Bicêtre, Le Kremlin Bicêtre, Scarabin, Pierre-Yves, Chavaudra, Jean, Lefkopoulos, Dimitry, Giroud, Maurice, Bejot, Yannick, Bernier, Valérie, Carrie, Christian, & and others. Cerebrovascular Diseases in Childhood Cancer Survivors: Role of the Radiation Dose to Willis Circle Arteries. United States. doi:10.1016/J.IJROBP.2016.10.015.
El-Fayech, Chiraz, Haddy, Nadia, Allodji, Rodrigue Sètchéou, Veres, Cristina, Diop, Fara, Kahlouche, Amar, Llanas, Damien, Jackson, Angela, Rubino, Carole, Guibout, Catherine, Gustave Roussy, Villejuif, University of Paris XI, Villejuif, Pacquement, Hélène, Oberlin, Odile, Thomas-Teinturier, Cécile, Hôpital Bicêtre, Le Kremlin Bicêtre, Scarabin, Pierre-Yves, Chavaudra, Jean, Lefkopoulos, Dimitry, Giroud, Maurice, Bejot, Yannick, Bernier, Valérie, Carrie, Christian, and and others. Wed . "Cerebrovascular Diseases in Childhood Cancer Survivors: Role of the Radiation Dose to Willis Circle Arteries". United States. doi:10.1016/J.IJROBP.2016.10.015.
@article{osti_22645764,
title = {Cerebrovascular Diseases in Childhood Cancer Survivors: Role of the Radiation Dose to Willis Circle Arteries},
author = {El-Fayech, Chiraz and Haddy, Nadia and Allodji, Rodrigue Sètchéou and Veres, Cristina and Diop, Fara and Kahlouche, Amar and Llanas, Damien and Jackson, Angela and Rubino, Carole and Guibout, Catherine and Gustave Roussy, Villejuif and University of Paris XI, Villejuif and Pacquement, Hélène and Oberlin, Odile and Thomas-Teinturier, Cécile and Hôpital Bicêtre, Le Kremlin Bicêtre and Scarabin, Pierre-Yves and Chavaudra, Jean and Lefkopoulos, Dimitry and Giroud, Maurice and Bejot, Yannick and Bernier, Valérie and Carrie, Christian and and others},
abstractNote = {Background and Purpose: The aim of this study was to investigate the role of radiation dose received to the circle of Willis (WC) during radiation therapy (RT) and of potential dose-response modifiers on the risk of stroke after treatment of childhood cancer. Methods: We evaluated the risk factors for stroke in a cohort of 3172 5-year survivors of childhood cancer who were followed up for a median time of 26 years. Radiation doses to the WC and brain structures were estimated for each of the 2202 children who received RT. Results: Fifty-four patients experienced a confirmed stroke; 39 were ischemic. Patients not receiving RT had a stroke risk similar to that of the general population, whereas those who received RT had an 8.5-fold increased risk (95% confidence interval [CI]: 6.3-11.0). The excess of incidence of stroke increased yearly. The dose of radiation to the WC, rather than to other brain structures, was found to be the best predictor of stroke. The relative risk was 15.7 (95% CI: 4.9-50.2) for doses of 40 Gy or more. At 45 years of age, the cumulative stroke incidence was 11.3% (95% CI: 7.1%-17.7%) in patients who received 10 Gy or more to the WC, compared with 1% expected from general population data. Radiation doses received to the heart and neck also increased the risk. Surgery for childhood brain cancer was linked to hemorrhagic strokes in these patients. Conclusion: The WC should be considered as a major organ at risk during RT for childhood brain cancers. The incidence of radiation-induced ischemic stroke strongly increases with long-term follow-up.},
doi = {10.1016/J.IJROBP.2016.10.015},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 2,
volume = 97,
place = {United States},
year = {Wed Feb 01 00:00:00 EST 2017},
month = {Wed Feb 01 00:00:00 EST 2017}
}
  • Purpose: To evaluate the prevalence and severity of clinical adverse events (AEs) and treatment-related risk factors in childhood cancer survivors treated with cranial radiation therapy (CRT), with the aim of assessing dose-effect relationships. Methods and Materials: The retrospective study cohort consisted of 1362 Dutch childhood cancer survivors, of whom 285 were treated with CRT delivered as brain irradiation (BI), as part of craniospinal irradiation (CSI), and as total body irradiation (TBI). Individual CRT doses were converted into the equivalent dose in 2-Gy fractions (EQD{sub 2}). Survivors had received their diagnoses between 1966 and 1996 and survived at least 5 yearsmore » after diagnosis. A complete inventory of Common Terminology Criteria for Adverse Events grade 3.0 AEs was available from our hospital-based late-effect follow-up program. We used multivariable logistic and Cox regression analyses to examine the EQD{sub 2} in relation to the prevalence and severity of AEs, correcting for sex, age at diagnosis, follow-up time, and the treatment-related risk factors surgery and chemotherapy. Results: There was a high prevalence of AEs in the CRT group; over 80% of survivors had more than 1 AE, and almost half had at least 5 AEs, both representing significant increases in number of AEs compared with survivors not treated with CRT. Additionally, the proportion of severe, life-threatening, or disabling AEs was significantly higher in the CRT group. The most frequent AEs were alopecia and cognitive, endocrine, metabolic, and neurologic events. Using the EQD{sub 2}, we found significant dose-effect relationships for these and other AEs. Conclusion: Our results confirm that CRT increases the prevalence and severity of AEs in childhood cancer survivors. Furthermore, analyzing dose-effect relationships with the cumulative EQD{sub 2} instead of total physical dose connects the knowledge from radiation therapy and radiobiology with the clinical experience.« less
  • Purpose: To test the hypotheses that (1) the increased risk of stroke conferred by childhood cranial radiation therapy (CRT) persists into adulthood; and (2) atherosclerotic risk factors further increase the stroke risk in cancer survivors. Methods and Materials: The Childhood Cancer Survivor Study is a multi-institutional retrospective cohort study of 14,358 5-year survivors of childhood cancer and 4023 randomly selected sibling controls with longitudinal follow-up. Age-adjusted incidence rates of self-reported late-occurring (≥5 years after diagnosis) first stroke were calculated. Multivariable Cox proportional hazards models were used to identify independent stroke predictors. Results: During a mean follow-up of 23.3 years, 292more » survivors reported a late-occurring stroke. The age-adjusted stroke rate per 100,000 person-years was 77 (95% confidence interval [CI] 62-96), compared with 9.3 (95% CI 4-23) for siblings. Treatment with CRT increased stroke risk in a dose-dependent manner: hazard ratio 5.9 (95% CI 3.5-9.9) for 30-49 Gy CRT and 11.0 (7.4-17.0) for 50+ Gy CRT. The cumulative stroke incidence in survivors treated with 50+ Gy CRT was 1.1% (95% CI 0.4-1.8%) at 10 years after diagnosis and 12% (95% CI 8.9-15.0%) at 30 years. Hypertension increased stroke hazard by 4-fold (95% CI 2.8-5.5) and in black survivors by 16-fold (95% CI 6.9-36.6). Conclusion: Young adult pediatric cancer survivors have an increased stroke risk that is associated with CRT in a dose-dependent manner. Atherosclerotic risk factors enhanced this risk and should be treated aggressively.« less
  • Testicular function was evaluated in 60 long-term survivors of childhood acute lymphoblastic leukemia (ALL). All the patients were treated on two consecutive Children Cancer Study Group protocols and received identical chemotherapy and either 18 or 24 Gy radiation therapy (RT) to one of the following fields: craniospinal plus 12 Gy abdominal RT including the gonads (group 1); craniospinal (group 2); or cranial (group 3). The median age at the time of their last evaluation was 14.5 years (range, 10.5 to 25.7), which took place a median of 5.0 years (range, 1 to 10.3) after discontinuing therapy. The incidence of primarymore » germ cell dysfunction as judged by raised levels of follicle-stimulating hormone (FSH) and/or reduced testicular volume was significantly associated with field of RT; 55% of group 1, 17% of group 2, and 0% of group 3 were abnormal (P = .002). Leydig cell function, as assessed by plasma concentrations of luteinizing hormone (LH) and testosterone, and pubertal development, was unaffected in the majority of subjects regardless of RT field. These data indicate that in boys undergoing therapy for ALL, germ cell dysfunction is common following testicular irradiation and can occur following exposure to scattered irradiation from craniospinal RT. In contrast, Leydig cell function appears resistant to direct irradiation with doses as high as 12 Gy.« less
  • Sixty-eight long-term survivors of childhood cancer were evaluated for dental and maxillofacial abnormalities. Forty-five patients had received maxillofacial radiation for lymphoma, leukemia, rhabdomyosarcoma, and miscellaneous tumors. Forty-three of the 45 patients and the remaining 23 who had not received maxillofacial radiation also received chemotherapy. Dental and maxillofacial abnormalities were detected in 37 of the 45 (82%) radiated patients. Dental abnormalities comprised foreshortening and blunting of roots, incomplete calcification, premature closure of apices, delayed or arrested tooth development, and caries. Maxillofacial abnormalities comprised trismus, abnormal occlusal relationships, and facial deformities. The abnormalities were more severe in those patients who received radiationmore » at an earlier age and at higher dosages. Possible chemotherapeutic effects in five of 23 patients who received treatment for tumors located outside the head and neck region comprised acquired amelogenesis imperfecta, microdontia of bicuspid teeth, and a tendency toward thinning of roots with an enlarged pulp chamber. Dental and maxillofacial abnormalities should be recognized as a major consequence of maxillofacial radiation in long-term survivors of childhood cancer, and attempts to minimize or eliminate such sequelae should involve an effective interaction between radiation therapists, and medical and dental oncologists.« less
  • Purpose: To assess, in a retrospective cohort study, rates and predictors of first and recurrent stroke in patients treated with cranial irradiation (CRT) and/or cervical irradiation at ≤18 years of age. Methods and Materials: We performed chart abstraction (n=383) and phone interviews (n=104) to measure first and recurrent stroke in 383 patients who received CRT and/or cervical radiation at a single institution between 1980 and 2009. Stroke was defined as a physician diagnosis and symptoms consistent with stroke. Incidence of first stroke was number of first strokes per person-years of observation after radiation. We used survival analysis techniques to determinemore » cumulative incidence of first and recurrent stroke. Results: Among 325 subjects with sufficient follow-up data, we identified 19 first strokes (13 ischemic, 4 hemorrhagic, 2 unknown subtype) occurring at a median age of 24 years (interquartile range 17-33 years) in patients treated with CRT. Imaging was reviewed when available (n=13), and the stroke was confirmed in 12. Overall rate of first stroke was 625 (95% confidence interval [CI] 378-977) per 100,000 person-years. The cumulative incidence of first stroke was 2% (95% CI 0.01%-5.3%) at 5 years and 4% (95% CI 2.0%-8.4%) at 10 years after irradiation. With each 100-cGy increase in the radiation dose, the stroke hazard increased by 5% (hazard ratio 1.05; 95% CI 1.01-1.09; P=.02). We identified 6 recurrent strokes; 5 had available imaging that confirmed the stroke. Median time to recurrence was 15 months (interquartile range 6 months-3.2 years) after first stroke. The cumulative incidence of recurrent stroke was 38% (95% CI 17%-69%) at 5 years and 59% (95% CI 27%-92%) at 10 years after first stroke. Conclusion: Cranial irradiation puts childhood cancer survivors at high risk of both first and recurrent stroke. Stroke prevention strategies for these survivors are needed.« less