Incidence and Dosimetric Parameters of Brainstem Toxicity Following Proton Therapy

Reporter: Jacob E. Shabason, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: September 24, 2013

Presenting Author: Daniel J. Indelicato, MD
Presenting Author Affiliation: University of Florida Proton Therapy Institute, Jacksonville, FL


  • There are many critical organs at risk for radiation-induced toxicity when treating pediatric tumors of the brain and base of skull.
  • One of the most critical structures is the brainstem.
  • Proton therapy for pediatric brain and base of skull tumors may help spare critical normal structures in the brain, including the brainstem.
  • Although the low and intermediate dose distribution of proton therapy is typically improved with proton therapy, high dose areas immediately adjacent to a specific target may receive comparable doses to standard photon therapy.
  • As such the authors sought to investigate the tolerance of the pediatric brainstem to proton radiation.


  • The medical records of all patients ≤18 years old with tumors of the brain or skull base treated with proton therapy at the University of Florida Proton Therapy Institute (UFPTI) from 2006- 2013 were reviewed.
  • Patients who received <50.4 Cobalt Gray Equivalent (CGE) to the brainstem and those with intrinsic brainstem tumors were excluded from the study
  • Brainstem toxicity was defined by new or progressive symptoms following radiation involving cranial nerves V-VII or IX-XII, motor weakness or dysmetria, all in the absence of disease progression.


  • 563 patients from 2006-2013 were treated with proton therapy and 313 of these patients met the inclusion criteria.
  • The 3 most common histologies included ependymoma (n=73), craniopharyngioma (n=68), and low-grade glioma (n=66).
  • The median age of treatment was 5.9 years (range, 0.5-17.9 years).
  • 109 patients had a gross total or near total resection at the time of radiation.
  • 155 patients received chemotherapy, 48 of which were intrathecal or high dose methotrexate with good central nervous system penetration.
  • The median prescribed dose was 54 CGE (range, 48.6-75.6 CGE) using double scatter protons.
  • All patients were treated with daily image guidance and all plans utilized multiple beams to minimize the risk of distal range RBE uncertainty.
  • The brainstem doses were all within the Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) and Children's Oncology Group (COG) protocol guidelines predicting <5% rate of brainstem necrosis.
  • With 2 year median follow up data:
    • The 2-year actuarial survival was 90.5%.
    • 11 out of 313 patients experienced brainstem toxicity (7 Grade II, 1 Grade III, 2 Grade IV and 1 Grade V).
    • The 2-year cumulative incidence of any brainstem toxicity was 3.8% (+/- 1.1%) and the incidence of serious brain stem toxicity (³ Grade 3) was 2.1 % (+/-0.9%).
  • Clinical parameters that were associated with toxicity included, (a) age <5 years, (b) posterior fossa tumor location and (c) degree of resection (GTR or NTR).
  • In multivariate analysis the only dosimetric predictors for toxicity were the D50% and V60.

Author's Conclusions

  • This study encompasses a large population treated with proton therapy and reports brainstem toxicity by DVH data, rather then nominal prescription dose or tumor type.
  • Current QAUNTEC and COG guidelines predict a low risk of brainstem toxicity in pediatric patients treated with protons or photons.
  • However, for patients at higher risk of toxicity (young patients, with posteriori fossa tumors and GTR/NTR) it may be beneficial to use more conservative guidelines based on the V60 and D50%.
  • These variables need to be verified in a larger prospective database.

Clinical Implications

  • This is an important and well-performed study that helps to define predictors of radiation induced brainstem toxicity in pediatric patients.
  • The findings that the V60 and D50% of the brainstem may be important predictive factors have important clinical implications in constraints used for radiation planning in order to maximize patient safety.
  • In particular, in patients with a high risk of radiation induced toxicity it is certainly prudent to be more conservative with constraints and pay particular attention to the D50% and V60.
  • Limitations of this study are that it was retrospective single institution study. In addition, although one would expect the dosimetric predictors to also hold true for photon plans these were no included in the study.

As the authors indicate these variables need to be confirmed in larger prospective databases.


Survivorship Benefits of Proton Therapy
by OncoLink Editorial Team
June 17, 2015