This analysis reports on outcome of 19 patients treated between 2010 and 2011 with proton beam therapy for LGG at the Heidelberg Ion Therapy Center. Proton beam therapy was applied to a median total dose of 54 GyE in single fractions of median 1.8GyE 5–6 times a week. Treatment was tolerated without high-grade side effects. Acute toxicity of the raster-scanning technique for these low-grade tumors is low. The patients will be followed prospectively. Due to the relatively long survival in patients with LGG, long-term side effects as impaired neurocognitive function become relevant. This issue was addressed by Brown et al. in a review on neurocognitive effects of radiotherapy in LGG [4
]. The authors concluded that by modern treatment techniques as MRI-based target volume delineation and the use of multiple overlapping conformal beams, the impact on neurocognitive function could be minimized. So, high conformal and normal brain tissue sparing radiation techniques provide us the potential to further minimize the risk of late neurocogintive impairment. A treatment option with a high potential for normal tissue sparing is e. g. proton beam therapy. Recently Beltran and his team reported on 14 pediatric patients with craniopharyngioma treated with 54 Gy photons. On this base different alternative treatment plans –including intensity-modulated radiotherapy, intensity-modulated proton beam therapy and double-scatter proton beam therapy- were calculated [5
]. The radiation dose to the whole-brain as well as –body was significantly decreased by proton beam therapy compared to intensity-modulated radiotherapy. Best treatment plans concerning conformal target coverage and sparing of normal tissue were achieved by intensity-modulated proton beam therapy while being very vulnerable to variations of the target volume on the other hand. Furthermore, not only in children but also adults the risk for secondary cancers after initial radiotherapy becomes crucial. A treatment plan comparison by Athar and Paganetti showed that scanned proton beam therapy had the lowest risk for out-of-field secondary cancers during lifetime compared to passive scattered proton therapy or intensity-modulated radiotherapy [6
]. Furthermore, the risk for developing secondary cancers after irradiation of the brain was retrospectively analyzed in 370 children with a median age of 8.1 years by Galloway et al.: In total, 18 secondary cancers were diagnosed in 16 patients median 18.9 years after the associated radiation therapy [7
]. The median time to diagnosis of secondary meningioma (n=10) was 22 years, while secondary glioma (n=4) were diagnosed after median 15 years. The incidence rates for secondary cancers at 10, 20 and 30 years after the associated irradiation in childhood were 3%, 8% and 24%, respectively. In conclusion, it seems justified to us, to perform radiation treatments especially in -but not only- children and young adults, if possible as a proton beam therapy, optimally with scanned protons. Clinical data on particle therapy in LGG is rare. In 2002 the colleagues from Loma Linda reported on the first 27 pediatric patients treated with proton beam therapy for LGG [8
]. The mean age at time of treatment was 8.7 years and treatment doses between 50.4 GyE and 63.0 GyE in single fractions of 1.8 GyE. The mean follow-up time was 3.3 years and 6 patents were reported to have in-field tumor recurrence. All children with local tumor control maintained their performance status. So the authors concluded that proton beam therapy is safe and efficacious, especially in situations, when high dose conformity is warranted due to central tumors or close relation to the optic pathway. The colleagues from Chiba recently published the results on 14 patients treated between 1994 and 2002 with carbon ions for WHO °II diffuse astrocytoma in a dose-escalation study [9
]. The patients were treated with 50.4 to 55.2 GyE carbon ions and for analysis divided into 2 groups according to the treatment dose. Patients in the high-dose group (55.2 GyE, n=5) showed a significantly longer median progression-free survival (91 months vs. 18 months) as well as median overall survival compared to the low-dose group (46.2-50.4 GyE, n=9). The median overall survival for all Patients was 53.4 months and the 5- and 10-year overall survival rates were 43% and 36%, respectively. Acute side effects were minor, while 2 patients of each group had MR-imaging based LENT-SOMA grade 3 late reactions of the brain. These grade 3 late reactions regressed ether spontaneously or after short course of steroids.
Considering MRI-based follow-up examinations, the differentiation of treatment related effects (including radiation necrosis) and tumor progression might be problematic. The rate of radiation induced brain necrosis in glioma patients treated with radiotherapy alone is up to 3.4%, while radiation induced brain necrosis seemed to be unlikely in radiation doses below 50 Gy in 25 fractions but increased with addition of concurrent chemotherapy [10
]. Meyzer et al. reported on a n asymptomatic 14 years old boy presenting with new contrast enhancement 6 months after proton therapy (54 GyE) for a low-grade oligodendroglioma located in the tectal region [11
]. The colleagues performed a dynamic susceptibility contrast MR-imaging as previously described for differentiation between post-treatment changes and high-grade glioma recurrence by Hu et al. [12
]. Meyzer et al. favoured the hypothesis of pseudo-progression, which was treated with weight-adapted oral steroids for one month. Follow-up MR-imaging showed gradual improvement and finally complete resolution of these changes in MR-imaging. Furthermore, MR-spectroscopy can help in differentiation between tumor recurrence and radiogenic changes [13
]. However, recently the colleagues from the German Cancer Research Center compared dynamic susceptibility-weighted contrast-enhanced (DSC), dynamic contrast-enhanced (DCE), and proton spectroscopic imaging ((1)H-MRSI) for treatment monitoring and concluded that DSC MR-imaging would be best for identification of tumor progression in glioma [14
]. Pseudo-progression occurred in our ladder in 11% of patients. Still, pseudo-progression is a challenging problem during follow-up examinations and could cause emotional stress not only in the affected patients. Radiobiological effects on the skin were reviewed for example by Malkinson et al. in 1981 and described as injure to the cutaneous vasculature and germinative cells causing for example reproductive failure [15
]. Radiogenic effects in the hair matrix cells could cause alopecia, which might be permanently in dosages of 7–8 Gy or more. The relatively high rate of alopecia within the proton beam portal of entry in our cohort seems to be related to the anatomical situation and the localization of the target volumes with isodose levels of up to 90% within the scalp. In an upcoming study at our institution, the treatment of patients with LGG will be evaluated prospectively including neuropsychological testing to further improve the knowledge on proton beam therapy in LGG and its effects on quality of life and neuropsychological function.