A prospective experience of proton therapy in low-grade gliomas

Reporting Author: Abigail T. Berman, MD
Last Modified: June 10, 2013

Presenting Author: Helen A. Shih MD
Presenting Author Affiliation: MGH, Radiation Oncology, Boston


  • Low-grade gliomas are treated by maximal safe resection followed by either observation or immediate radiotherapy. The role of adjuvant versus salvage radiotherapy was evaluated in the EORTC 22845 randomized trial, in whichthey authors found an improvement in symptom control and progression-free survival with immediate adjuvant radiotherapy, but no difference in overall survival.
  • Proton therapy markedly reduced excess dose to non-targeted tissues.
  • Low-grade glioma patients represent a population of modestly long-term survivors who are often young when they are diagnosed, and therefore may clinically benefit from protons by reduction in radiation-associated toxicity.
  • The purpose of this study was to evaluate proton therapy in the management of low-grade glioma patients with regard to toxicity and progression free survival (PFS).

Materials and Methods

  • This was a pilot study of 20 patients enrolled between 2007-2010.
  • WHO grade II glioma patients with indications for radiation therapy were enrolled in a prospective single arm trial
    • Patients were >18 yo, with standard indication for proton therapy (new diagnosis, progression), no other cancers, no other comorbidities to expect <5 year survival, no pre-existing cognitive deficits that would compromise neurocognitive assessments, no prior cranial irradiation.
  • Involved field proton therapy receiving a dose of 54 Gy (RBE) in 30 fractions.
    • Target was T2 hyperintensity, contrast enhancement, surgical cavity with 1 cm CTV expansion
    • Optional medical therapies were given per oncologist discretion
  • Comprehensive baseline and regular post treatment evaluations of neuroendocrine function, neurocognitive functions, quality of life (QOL)/emotional functioning, toxicity (CTCAE v3), and PFS were performed
    • Post-treatment at 3,6,12,24,36, 48, and 60 months
    • Exceptions: no neurocognitive testing was done at 3 months, and an abbreviated version was done at 6 months to minimize learned behavior.
  • Patients were removed from study at time of disease progression


  • All 20 patients (median age 37.5) enrolled tolerated treatment without difficulty.
  • Out of 20 pts, 13 were male, 11 were recurrent tumor (9 newly diagnosed), 9 mixed oligoastrocytoma, 7 astrocytoma, 4 oligodendroglioma.
  • MIB-1 index mean was 3.9% (0-10%)
  • Most common tumor site was frontal (11 pts), then temporal (8), and occipital (1). The most common presenting symptom was seizure (10).
  • Median follow up after proton therapy was 3.2 years among 14 patients without disease progression (range 2.1-5.1 years).
  • New endocrine dysfunction was detected in 8 patients and was not associated with direct irradiation to the hypothalamic-pituitary complex.
    • The most common deficits were corticosteroid axis (3 pts) and gonadal axis, men (2 pts).
  • Baseline level of intellectual functioning on a standardized IQ measure was slightly above the normative mean for the group and remained stable at last follow up.
  • QOL assessment showed no change at 3-year follow up. QOL was measured by the FACT scale and at 24 months, the FACT-brain increased by 2.7 pts and FACT-Fatigue by 0.6. At 36 mos, the mean increase was 7.5 and 5.0 pts, respectively.
  • Executive function defined by attention, working memory, behavior initiation and cognitive flexibility was also in the average range at baseline and improved slightly at 24 months.
  • Baseline memory was within normal limits and was slightly improved at last follow-up.
  • There were no grade 4 or 5 related toxicities. The most common grade 1, 2, or 3 acute toxicity was fatigue and late toxicity was headache.
  • PFS at 1, 2, 3, and 4 years was 100, 95, 82, and 52%, respectively.

Author’s Conclusions

  • Early results demonstrate that low-grade glioma patients tolerate proton therapy well, although a subset develops neuroendocrine deficiencies.
  • There is no evidence for early decline in neurocognitive function with regard to intellectual function, visuospatial skills, attention/executive function, or language, which may be partially attributable to limited integral dose to the brain by use of proton therapy.
  • No negative treatment-related effect on emotional function or QOL was seen in this population.
  • PFS is equivalent to that of photon based therapy.
  • No atypical or severe toxicities were experienced.

Clinical Implications

  • This is an excellent study of 20 patients all treated to 54 Gy(RBE) with proton therapy, and followed consistently with neuroendocrine, neurocognitive, and QOL/emotional functioning testing for up to 3 years after treatment.
  • This is the first publication of these long-term outcomes and it is reassuring to see what while some patients developed neuroendocrine changes, no decline in neurocognitive or emotional/QOL functioning was observed.
  • The authors have previously published their dosimetric experience showing improvement of the dose to surrounding normal tissues in low grade glioma patients treated with protons compared to IMRT; in addition they showed that IMRT should yield a twofold higher risk of secondary intracranial tumors as compared to proton therapy. The found that the benefit of proton therapy over IMRT may be more substantial in patients with tumors in proximity to critical structures (Dennis et al. Technol Cancer Res Treat 2013).
  • The University of Heidelberg recently published their experience of acute toxicity and feasibility of proton beam therapy and found high rates of mild alopecia but otherwise proton therapy was well-tolerated. This study did not investigate long-term functional outcomes (Hauswald et al. Radiat Oncol 2012).
  • Several questions remaining after this study include:
    • This study treated patients to 54 Gy, however, the optimal dose for low-grade glioma patients is still somewhat a debate, as the randomized trials of higher dose versus lower dose have not shown a benefit to higher dose. However, it is unclear if, in the setting of proton therapy, there may be a benefit to a higher dose.
    • Most patients in this study had frontal tumors, which are often farther away from critical organs at risk, and therefore it will be important to see the long-term toxicity and functional outcomes by disease site.
    • Lastly, the most common histology was mixed oligoastrocytoma, whereas the most common histology in general is astrocytoma. Therefore, it will be important to see the results of this subset in the final manuscript.


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