Proton Therapy for Low Grade Glioma: A Pilot Study

Reporter: Gita Suneja, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 30, 2012

Presenter: Helen Shih, MD MS MPH
Affiliation: Massachusetts General Hospital


  • Given the moderate long-term survival in LGG, many patients will live long enough to benefit from reduction in long-term radiation-associated toxicity.
  • For this reason, the reduction in excess dose to non-target tissues with proton therapy as compared to photon therapy may benefit patients with low grade glioma (LGG)
  • The pilot study was designed to evaluate the feasibility of proton therapy in the management of patients with LGG.


  • The pilot study enrolled 20 patients from 2007-2010.
  • Patients were adults > 18 years of age, with WHO grade 2 glioma and standard indication for radiation therapy, defined as either new diagnosis or progression of disease.
  • Exclusion criteria included prior history of cancer, existing neuro-psychiatric condition that would preclude accurate neuropsychological testing, and prior cranial radiation therapy.
  • Proton therapy was delivered to a volume of T2 hyper-intensity, contrast-enhancing regions, and surgical resection cavity with expansion of 1.5 cm. Total dose of 54 Gy/RBE in 30 fractions was delivered.
  • Additional medical therapies were optional.
  • Patients were evaluated at baseline (pre-radiation), and post-radiation at 3, 6, 12, 24, 36, 48, and 60 months.
    • Neuro-cognitive testing included assessment of intellectual/executive functioning, language skills, visuo-spatial relationships, motor functioning, and memory.
    • Neuro-endocrine and quality of life testing was also performed.
  • Primary endpoints were toxicity and progression-free survival.


  • The study cohort consisted of 13 men and 7 women with mean age 37.5 years.
  • Nine patients were newly diagnosed, and 11 were referred for progression following resection.
  • Nearly all patients had tumors in either frontal or temporal lobe location, and the presenting symptom was seizure in half the patients
  • Median follow-up was 3.2 years.
  • All patients completed treatment with proton radiation.
  • At the time of analysis, 14 patients were alive.
  • Progression-free survival was 100% at 1 year, and 58% at 4 years.
  • At baseline, patients scored average on measures of neuro-cognitive testing, except for memory where they were below average.
  • At 24 months, measures of neuro-cognitive testing were stable (intelligence, behavioral, attention, executive function) or improved (visuo-spatial, language, memory, motor). There was no reduction in neuro-cognitive testing measures.
  • Quality of life was stable from baseline to 24 months.
  • Neuro-endocrine functioning was decreased in the subset of patients that had tumor near the hypothalamus or pituitary.
  • No unexpected toxicities or grade 4-5 toxicities were observed.
  • Acute toxicities included fatigue, headache, alopecia, and erythema, at rates comparable to those reported for photon radiation therapy.

Author's conclusions

  • Early results of this pilot study demonstrate that LGG patients tolerated proton radiation therapy well, with no evidence of early decline in neuro-cognitive function.
  • No negative quality of life effects were observed.
  • A small subset of patients had neuro-endocrine deficiencies.
  • No atypical toxicities were observed, and progression-free survival was comparable to that reported with photon radiation therapy.

Clinical Implications

  • LGG accounts for about 10% of all primary central nervous system tumors and 25% of gliomas.
  • Although most LGG are generally slow-growing, they can be more aggressive and long-term outcomes vary widely.
  • Surgical resection is the mainstay of treatment, and the role of adjuvant radiation is not well-defined.
  • EORTC 22845 randomized LGG patients to adjuvant post-operative radiation vs. observation with salvage radiation at the time of progression. Upfront adjuvant radiation improved progression-free survival but not overall survival.
  • Additionally, radiation therapy to the brain may have considerable side effects, and treatment for LGG has been associated with impaired neuro-cognitive functioning.
  • The goal of management for LGG is to minimize toxicity, and one way to do this is to treat only patients at highest risk of progression following surgical resection. Numerous studies have attempted to identify high-risk features, however no consensus exists on which patients are truly at high risk of progression.
  • Another way to minimize toxicity to use a radiation technique that will spare as much normal tissue as possible. Proton therapy has the ability to provide this degree of normal tissue protection.
  • Although dosimetric studies of protons vs. photon therapy show substantial normal tissue sparing with protons, few studies document that the observed dosimetric advantages translate to a clinical benefit.
  • The authors of this study should be commended for compiling pilot data addressing this question, and their study suggests that proton therapy for LGG has a safety and efficacy profile similar to photon therapy in the acute setting, and potential for decreased neurocognitive toxicity in the long-term
  • The study was conducted with rigorous neuropsychiatric testing, and the outcomes of the cohort were well-characterized.
  • The study also paves the way for future potential studies of hypofractionation or dose escalation using proton therapy, techniques that could improve survival from LGG and may be more feasible with protons compared with photons.