Mixed Proton and Photon Therapy for Benign Meningiomas: Long Term Results of a Prospective Randomized Dose Escalation Study
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: September 26, 2013
Presenting Author: Helen A. Shih, MD
Presenting Author Affiliation: Massachusetts General Hospital, Boston, MA
- Meningiomas can be classified according to WHO grade: I (benign), II (atypical), or III (anaplastic/malignant).
- Benign meningiomas can be treated with either surgery or radiation, and the radiation can be delivered either as fractionated external beam radiotherapy or stereotactic radiosurgery.
- In the setting of fractionated external beam radiotherapy, the optimal dose for management of benign meningiomas is unclear.
- The dosimetric properties of protons makes them attractive to use for meningiomas which are often in close proximity to critical structures such as the pituitary gland, optic nerves and chiasm, and brainstem.
- Proton therapy permits for consideration of safer dose escalation and reduced toxicities for normal tissue irradiation.
- The purpose of this prospective randomized trial was to assess outcomes of progression free survival (PFS), overall survival (OS), and treatment related toxicity at two dose levels.
Materials and Methods
- Study design was a prospective randomized trial.
- Eligible patients included patients with recurrent or subtotally resected benign meningiomas.
- Patients were treated with mixed proton and photon therapy with randomization to 55.8 Gy(RBE) versus 63 Gy(RBE) at 1.8 Gy (RBE) daily. All patients received 80% of their radiation with proton therapy.
- Photon radiation was delivered once weekly.
- Between 1991 and 2000, 47 patients were enrolled with 25 (53%) randomized to the 55.8 Gy(RBE) arm. 3 patients were removed for atypical histology.
- Median follow up is 13.2 years among 26 surviving patients.
- The median age was 60 in the low-dose arm and 50 in the high-dose arm. There were 65% females in the low dose and 67% females in the high dose arm. The most common site in both arms was the cavernous sinus/sella/parasella (39% low dose vs 43% high dose).
- The median volume in the low dose arm was 39.85 cc and 13.1 cc in the high dose arm (p=0.032).
- Most patients had one surgery pre-irradiation (52% low dose and 81% high dose, not significant).
- PFS was similar between 55.8 Gy (RBE) versus 63 Gy (RBE) arms at 5 years (87% vs 95%) and 10 years (82% vs 82%), but there was a suggestion of improved PFS with higher dose at 15 years (46% vs 73%), although the overall difference was not significant (p=0.202).
- Similarly, with the limited patient numbers, the OS at 5 years (87% vs 95%), 10 years (82% vs 85%) and 15 years (55% vs 78%) did not represent a significant difference (p=0.221). All patients completed the prescribed radiation therapy without complication.
- Acute toxicity within the first 6 months from treatment completion was predominantly grade 1-2 and transient–there were no acute toxicities prohibitive of treatment completion. One case of grade 3 weakness occurred in the 55.8 Gy(RBE) arm and one case of acute grade 3 fatigue occurred in the 63 Gy(RBE) arm.
- Late effects potentially attributable to radiation were also largely grade 1-2 but involved deficits in multiple domains including multiple cranial neuropathies, persistent headaches, ataxia, and persistent fatigue. There was no difference in the rate cerebral vascular accident or anti-convulsant medication use. There was no significant difference in new pituitary dysfunction between dose arms.
- One case of asymptomatic brain necrosis occurred in the 55.8 Gy(RBE) arm and two cases occurred in the 63 Gy(RBE) arm. There was no correlation of toxicities with treatment arm. There were no deaths secondary to radiation.
- Long-term data suggest higher doses achieve superior local control in benign meningiomas with gross residual disease.
- There was no difference in toxicities between the 55.8 and 64 Gy arms.
- Long-term data suggest that cranial irradiation in the setting of meningiomas is associated with increased risk of cerebral vascular accidents.
- Proton therapy may offer a means of safer dose escalation to achieve more durable long-term control.
- This is the first randomized trial of dose escalation for benign meningiomas. The standard dose for benign meningiomas is usually around 54 Gy, which was based solely on retrospective evidence (Goldsmith et al. 1994). This long-term data suggests that a higher dose is beneficial in terms of local control without increasing toxicity.
- There are several limitations of this study:
- It should be noted that the arms of this study were not balanced in terms of the size of the lesions treated- on average, the size of the high-dose arm lesions were smaller. Therefore, while there were no differences in toxicity found, there may in fact be differences in toxicity if the same volume were treated to the low and high dose.
- While the authors conclude based on the 15-year data that there is improved local control in the high-dose arm, there is no significant overall benefit and this should be taken into account in the analysis.
- The higher dose of 64 Gy may be more easily achievable for certain meningioma locations that are further away from the optic structures and brainstem, where we typically restrict the dose to 54 Gy.
- This study uses a mix of protons and photons; the likely rationale for doing this is to utilize the conformality of photon therapy combined with the Bragg peak of proton therapy. These patients were likely treated with double scatter proton therapy, and as pencil beam scanning is increasingly available, patients will be able to be treated with proton beam therapy alone.
- It is concerning to see an increased rate of cerebrovascular accidents in this patient population. This has also been validated in other studies of radiotherapy to the brain and head and neck. It suggests that these patients should be carefully managed for other risk factors that could lead to stroke (cholesterol, blood pressure).