• Daphne Haas-Kogan, Daniel Indelicato, Harald Paganetti, Natia Esiashvili, Anita Mahajan, Torunn Yock, Stella Flampouri, Shannon MacDonald, Maryam Fouladi, Kry Stephen, John Kalapurakal, Stephanie Terezakis, Hanne Kooy, David Grosshans, Mike Makrigiorgos, Kavita Mishra, Tina Young Poussaint, Kenneth Cohen, Thomas Fitzgerald, Vinai Gondi, Arthur Liu, Jeff Michalski, Dragan Mirkovic, Radhe Mohan, Stephanie Perkins, Kenneth Wong, Bhadrasain Vikram, Jeff Buchsbaum, and Larry Kun.
• Department of Radiation Oncology, Harvard Medical School and Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston Children's Hospital, Boston, Massachusetts.
• Int. J. Radiat. Oncol. Biol. Phys. 2018 May 1; 101 (1): 152-168.

PurposeProton therapy can allow for superior avoidance of normal tissues. A widespread consensus has been reached that proton therapy should be used for patients with curable pediatric brain tumor to avoid critical central nervous system structures. Brainstem necrosis is a potentially devastating, but rare, complication of radiation. Recent reports of brainstem necrosis after proton therapy have raised concerns over the potential biological differences among radiation modalities. We have summarized findings from the National Cancer Institute Workshop on Proton Therapy for Children convened in May 2016 to examine brainstem injury.Methods And MaterialsTwenty-seven physicians, physicists, and researchers from 17 institutions with expertise met to discuss this issue. The definition of brainstem injury, imaging of this entity, clinical experience with photons and photons, and potential biological differences among these radiation modalities were thoroughly discussed and reviewed. The 3 largest US pediatric proton therapy centers collectively summarized the incidence of symptomatic brainstem injury and physics details (planning, dosimetry, delivery) for 671 children with focal posterior fossa tumors treated with protons from 2006 to 2016.ResultsThe average rate of symptomatic brainstem toxicity from the 3 largest US pediatric proton centers was 2.38%. The actuarial rate of grade ≥2 brainstem toxicity was successfully reduced from 12.7% to 0% at 1 center after adopting modified radiation guidelines. Guidelines for treatment planning and current consensus brainstem constraints for proton therapy are presented. The current knowledge regarding linear energy transfer (LET) and its relationship to relative biological effectiveness (RBE) are defined. We review the current state of LET-based planning.ConclusionsBrainstem injury is a rare complication of radiation therapy for both photons and protons. Substantial dosimetric data have been collected for brainstem injury after proton therapy, and established guidelines to allow for safe delivery of proton radiation have been defined. Increased capability exists to incorporate LET optimization; however, further research is needed to fully explore the capabilities of LET- and RBE-based planning.Copyright © 2018 Elsevier Inc. All rights reserved.

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