Evolution of Proton Radiation Therapy Brainstem Constraints on the Pediatric Proton/ Photon Consortium Registry

Purpose: Increasing concern that brainstem toxicity incidence after proton radiation therapy might be higher than with photons led to a 2014 University of Florida (UF) landmark paper identifying its risk factors and proposing more conservative dose constraints. We evaluated how practice patterns changed among the Pediatric Proton/Photon Consortium Registry (PPCR). Material and Methods: This prospective multicenter cohort study gathered data from patients under the age of 22 years enrolled on the PPCR, treated between 2002 and 2019 for primary posterior fossa brain tumors. After standardizing brainstem contours, we garnered dosimetry data and correlated those meeting the 2014 proton-specific brainstem constraint guidelines by treatment era, histology, and extent of surgical resection. Results: A total of 467 patients with evaluable proton radiation therapy plans were reviewed. Median age was 7.1 years (range: <1-21.9), 63.0% (n = 296) were men, 76.0% (n = 357) were White, and predominant histology was medulloblastoma (55.0%, n = 256), followed by ependymoma (27.0%, n = 125). Extent of resection was mainly gross total resection (GTR) (67.0%, n = 312), followed by subtotal resection (STR) or biopsy (20.0%, n = 92), and near total resection (NTR) (9.2%, n = 43). The UF brainstem constraint metrics most often exceeded were the goal D-50% of 52.4 gray relative biological equivalents (43.3%, n = 202) and maximal D-50% of 54 gray relative biological equivalents (12.6%, n = 59). The compliance rate increased after the new guidelines (2002-2014: 64.0% vs 2015-2019: 74.6%, P = .02), except for ependymoma (46.3% pre- vs 50.0% post-guidelines, P = .86), presenting lower compliance (48.8%) in comparison to medulloblastoma/ primitive neuroectodermal tumors/pineoblastoma (77.7%), glioma (89.1%), and atypical teratoid/rhabdoid tumors (90.9%) (P < .001). Degree of surgical resection did not affect compliance rates (GTR/NTR 71.0% vs STR/biopsy 72.8%, P = .45), even within the ependymoma subset (GTR/NTR 50.5% vs STR/biopsy 38.1%, P = .82). Conclusion: Since the publication of the UF guidelines, the pediatric proton community has implemented more conservative brainstem constraints in all patients except those with ependymoma, irrespective of residual disease after surgery. Future work will evaluate if this change in practice is associated with decreased rates of brainstem toxicity.