Increase of pseudoprogression and other treatment related effects in low-grade glioma patients treated with proton radiation and temozolomide

J Neurooncol. 2019 Mar;142(1):69-77. doi: 10.1007/s11060-018-03063-1. Epub 2018 Nov 28.


Introduction: Concurrent radiotherapy and temozolomide (TMZ) is associated with radiographic pseudoprogression (PsP) in glioblastoma. The occurrence of PsP and other treatment effects is less well understood in low-grade gliomas (LGG). The purpose of this study is to evaluate whether the addition of TMZ to radiotherapy increases the incidence of PsP in adults with LGG treated with proton radiotherapy (PRT).

Methods: Chart review and volumetric MRI-analysis was performed on radiotherapy-naive adults with WHO grade II or IDH mutant WHO grade III gliomas treated with PRT between 2005 and 2015. Progression was defined by histology, new chemotherapy initiation, or progressive increase in lesion volume beyond 40% from baseline. Post treatment related effects (PTRE) were defined as new/increased T2/FLAIR or abnormal enhancement which eventually resolved or stabilized without evidence of progression for a period of 6-12 months. PsP was defined as the subset of PRTE suspicious for progression or volumetrically increased at least 40% from baseline. Pearson's chi-squared test and Cox-proportional hazards models were used for statistical analysis.

Results: There were 119 patients meeting inclusion criteria. There was an increased risk of PsP following PRT + TMZ versus PRT-alone (HR = 2.2, p = 0.006, on Cox univariate analysis). Presence of PsP was associated with improved OS (p = 0.02 with PsP as time-varying covariate).

Conclusions: TMZ use, when added to PRT, was associated with increased PsP in patients with LGG; however, patients with PsP tended to achieve longer survival.

Keywords: Low-grade gliomas; Proton radiotherapy; Pseudoprogression; Radiation necrosis; Toxicity.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antineoplastic Agents, Alkylating / therapeutic use*
  • Brain Neoplasms / diagnostic imaging
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / radiotherapy
  • Brain Neoplasms / therapy*
  • Combined Modality Therapy
  • Disease Progression
  • Female
  • Glioma / diagnostic imaging
  • Glioma / drug therapy
  • Glioma / radiotherapy
  • Glioma / therapy*
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Neoplasm Grading
  • Proton Therapy*
  • Temozolomide / therapeutic use*
  • Young Adult


  • Antineoplastic Agents, Alkylating
  • Temozolomide