Anita Mahajan1, Peter L Stavinoha2, Warissara Rongthong3, N Patrik Brodin4, Susan L McGovern5, Issam El Naqa6, Joshua D Palmer7, Sabina Vennarini8, Daniel J Indelicato9, Paul Aridgides10, Daniel C Bowers11, Leontien Kremer12, Cecile Ronckers13, Louis Constine14, Michele Avanzo15. 1. Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota. Electronic address: mahajan.anita@mayo.edu. 2. Division of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, Texas. 3. Division of Radiation Oncology, Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. 4. Department of Radiation Oncology, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York. 5. Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas. 6. Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan. 7. Department of Radiation Oncology, James Cancer Hospital at Ohio State University, Nationwide Children's Hospital, Columbus, Ohio. 8. Proton Therapy Center, Azienda Provinciale per I Servizi Sanitari, Trento, Italy. 9. Department of Radiation Oncology, University of Florida, Gainesville, Florida. 10. Department of Radiation Oncology, SUNY Upstate Medical University, Syracuse, New York. 11. Division of Pediatric Hematology and Oncology, University of Texas Southwestern Medical School, Dallas, Texas. 12. Department of Pediatrics, UMC Amsterdam, Location AMC, Amsterdam, the Netherlands; Department of Pediatric Oncology, Princess Máxima Center for Paediatric Oncology, Utrecht, the Netherlands. 13. Department of Pediatrics, UMC Amsterdam, Location AMC, Amsterdam, the Netherlands; Department of Pediatric Oncology, Princess Máxima Center for Paediatric Oncology, Utrecht, the Netherlands; Institute of Biostatistics and Registry Research, Medical University Brandenburg-Theodor Fontane, Neuruppin, Germany. 14. Department of Radiation Oncology, University of Rochester Medical Center, Rochester, New York. 15. Medical Physics Department, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.
Abstract
PURPOSE: A PENTEC review of childhood cancer survivors who received brain radiation therapy (RT) was performed to develop models that aid in developing dose constraints for RT-associated central nervous system (CNS) morbidities. METHODS AND MATERIALS: A comprehensive literature search, through the PENTEC initiative, was performed to identify published data pertaining to 6 specific CNS toxicities in children treated with brain RT. Treatment and outcome data on survivors were extracted and used to generate normal tissue complication probability (NTCP) models. RESULTS: The search identified investigations pertaining to 2 of the 6 predefined CNS outcomes: neurocognition and brain necrosis. For neurocognition, models for 2 post-RT outcomes were developed to (1) calculate the risk for a below-average intelligence quotient (IQ) (IQ <85) and (2) estimate the expected IQ value. The models suggest that there is a 5% risk of a subsequent IQ <85 when 10%, 20%, 50%, or 100% of the brain is irradiated to 35.7, 29.1, 22.2, or 18.1 Gy, respectively (all at 2 Gy/fraction and without methotrexate). Methotrexate (MTX) increased the risk for an IQ <85 similar to a generalized uniform brain dose of 5.9 Gy. The model for predicting expected IQ also includes the effect of dose, age, and MTX. Each of these factors has an independent, but probably cumulative effect on IQ. The necrosis model estimates a 5% risk of necrosis for children after 58.9 Gy or 59.9 Gy (2 Gy/fraction) to any part of the brain if delivered as primary RT or reirradiation, respectively. CONCLUSIONS: This PENTEC comprehensive review establishes objective relationships between patient age, RT dose, RT volume, and MTX to subsequent risks of neurocognitive injury and necrosis. A lack of consistent RT data and outcome reporting in the published literature hindered investigation of the other predefined CNS morbidity endpoints.
PURPOSE: A PENTEC review of childhood cancer survivors who received brain radiation therapy (RT) was performed to develop models that aid in developing dose constraints for RT-associated central nervous system (CNS) morbidities. METHODS AND MATERIALS: A comprehensive literature search, through the PENTEC initiative, was performed to identify published data pertaining to 6 specific CNS toxicities in children treated with brain RT. Treatment and outcome data on survivors were extracted and used to generate normal tissue complication probability (NTCP) models. RESULTS: The search identified investigations pertaining to 2 of the 6 predefined CNS outcomes: neurocognition and brain necrosis. For neurocognition, models for 2 post-RT outcomes were developed to (1) calculate the risk for a below-average intelligence quotient (IQ) (IQ <85) and (2) estimate the expected IQ value. The models suggest that there is a 5% risk of a subsequent IQ <85 when 10%, 20%, 50%, or 100% of the brain is irradiated to 35.7, 29.1, 22.2, or 18.1 Gy, respectively (all at 2 Gy/fraction and without methotrexate). Methotrexate (MTX) increased the risk for an IQ <85 similar to a generalized uniform brain dose of 5.9 Gy. The model for predicting expected IQ also includes the effect of dose, age, and MTX. Each of these factors has an independent, but probably cumulative effect on IQ. The necrosis model estimates a 5% risk of necrosis for children after 58.9 Gy or 59.9 Gy (2 Gy/fraction) to any part of the brain if delivered as primary RT or reirradiation, respectively. CONCLUSIONS: This PENTEC comprehensive review establishes objective relationships between patient age, RT dose, RT volume, and MTX to subsequent risks of neurocognitive injury and necrosis. A lack of consistent RT data and outcome reporting in the published literature hindered investigation of the other predefined CNS morbidity endpoints.
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