In the last decades, recurrences after radiotherapy in patients with meningioma are an evolving and challenging situation, but so far, their management is often driven by a local experience without the support of clinical randomized trials and strong evidence. In several cases the indication of re-irradiation is excluded for a number of reasons: radiotherapy has often fully exhausted the radiation tolerance of surrounding normal tissue, extension of meningioma, poor performance status of the patient; in this contest clinical reports of re-irradiation are limited and consequently, the evidence is moderate.
The physical dose distribution of protons (typical dose fall-off of the Bragg peak) makes the PT an attractive therapeutic option. In the last years it is well established from pre-clinical and plan comparison studies that PT can deliver higher dose conformity, reduce the mean and minimum dose to the surrounding tissue ultimately providing a better sparing of the organs at risk near the target [9-11]. However, the evidence that dosimetric advantage translates into a clinical superiority is not clear and clinical studies with a significative accrual are limited.
Previous published studies have shown a satisfying clinical outcome after re-irradiation for Grade I meningioma, but high-grade meningioma seem to have a poor prognosis, with a worse PFS comparing with benign lesions. [5,12-17]
Wojcieszynski et al. in their analysis of 19 patients re-irradiated with either fractionated-SRT (median dose = 50.4 Gy) or SRS (median Dose = 15 Gy) reported a median and 1-yr PFS of 57 months and 92% for grade 1 versus 8 months and 17% for grade II/III, respectively. Lin et al. reviewed 43 patients treated with SRS or EBRT showing a global 1-yr, 2-yr PFS of 73%, 63% and 1-yr, 2-yr OS of 93%, 80%, respectively. Their results confirmed the relatively poor results in terms of PFS for aggressive meningiomas (median for grade 2/3 and grade 1, respectively, 26 months vs 41 months; 2-year, 50% vs 92%). Furthermore, Kim et al. proved in 33 patients who repeated SRS with a median dose of 14 Gy, the benefit of re-irradiation for benign lesions and worse outcome for grade II-III (median PFS grade I vs grade II-III 60 months vs 12 months, respectively).
Consistent with above mentioned data, our results reported a similar or better outcome in terms of PFS (1-yr and 2-yr PFS: 89.4% and 74.5%, respectively) and OS (1-yr and 2-yr OS: 86.6% and 83%, respectively). Also in our population, histology appeared to be an important prognostic factor for progression-free survival as well as overall survival (median PFS not reached, 27.5 months and 14.1 months for grade I, II and III, respectively; median OS not reached and 47.5 months for grade I and II-III, respectively), but generally with better results compared with the historical data.
To our knowledge, this study represents the largest monocentric experience of re-irradiation with PT for recurrence meningioma, with at least similar outcome respect the other published researches. [7,17]
El Shafie et al. analyzed 42 patients re-irradiated with ions (only 19% treated with PT) with 1-yr and 2-yr PFS of 71% and 56,5% and a median PFS of 34,3 months. 1-yr OS after re-irradiation was 89,6% and 2-yr OS 71,4% with a median OS of 61 months. The authors confirmed the negative effect of histology on PFS (median PFS of 25,7 months for grade II-III, not reached for grade I) and OS (median OS not reached for grade I, 45.5 months for grade II-III). In addition, Imber at al. reported in their analysis of 16 patients irradiated with PT, 1-yr and 2-yr PFS of 80% and 43% and 1-yr and 2-yr OS of 94% and 73%, respectively. Also, their results were negative for aggressive meningiomas (grade II-III).
Even now, radiation oncologist community is unwilling to indicate re-irradiation for recurrence meningiomas because of concern of late radiation toxicity, in particular RN. Actually, these studies showed that re-irradiation is an acceptable treatment modality with a low-moderate risk of grade 2 or more RN, around 15-21% [5,7,12-15]. In some cases, this risk may increase above a cumulative EQD2 brain dose of 120 Gy [5].
The hesitation to propose re-irradiation is further accentuated with the possibility to use PT due to the historical concern about physical characteristics of proton (range uncertainties, RBE variable). However, several trials showed that PT was associated with significantly higher rates of MRI sequences T1c+T2 changes compared with photon therapy for brain tumors but the rates of symptomatic RN following PT was as uncommon as conventional photon-based group. [18,19]. In our series we reported a rate of RN of 14% (8.5% for RN grade 2 or more), with a median cumulative EQD2 brain dose of 122 GyRBE (range 111.7-123.2), in line with trials previously published, despite significant large irradiated volume (median GTV 43 cc, range 1.2-225.5 cc).
Due to lack of available data, the optimal choice of radiotherapy modality for reirradiation of recurrent meningiomas remains poorly defined. Based on results of the clinical studies discussed above SRS seems to be a safe and effective treatment for small grade I meningioma. For large recurrence and grade II-III meningioma, where probably larger margins are recommended, conventional fractionation (EBRT, fractionated-SRT, IMRT) and in particular PT should be the preferred options.
There were several limitations to our study including its retrospective nature, relatively small size of patients and the lack of quality-of-life analysis. Furthermore, the median follow-up of 27 months may still be short to assess late events of radiation toxicity and the durability of responses observed.