Evaluation of particle radiotherapy for the re-irradiation of recurrent intracranial meningioma

Intracranial meningiomas are among the most frequent primary brain tumors [1]. Although benign in principle, they can afflict severe damage on sensitive intracranial structures, causing substantial morbidity. Several different approaches to the treatment of meningiomas are established. For safely accessible tumors, neurosurgical resection is the treatment of choice, however, in critical locations, e.g. at the skull base, radiation therapy (RT) has been established as a safe and highly effective treatment modality [2‐4].

For asymptomatic low-grade lesions found incidentally, a wait-and-see strategy can be adapted and based on regular clinical and imaging follow-up [5]. Good long-term local control rates of up to 95% progression-free survival (PFS) at five years and 60–80% at 10 years in separate series can be achieved if the lesion is easily accessible for complete resection [6]. However, substantial post-operative morbidity can occur if sensitive vascular or neuronal structures are compromised by the resection, such as is the case with large tumors located at the skull base if complete resection is sought. On the other hand, postoperative RT can complement incomplete resection and achieve satisfactory results at low toxicity rates. It is strongly recommended for WHO grade II/III meningiomas and can be a suitable option for salvage treatment in case of recurrence after neurosurgical resection [6, 7]. Non-surgical treatment options include stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT), achieving local control rates similar to those of complete surgical resection for tumors located in regions not accessible to surgery [8]. In some cases, where the preservation of adjoining radiosensitive tissue is critical or tumor shapes are more complex, intensity modulated radiotherapy (IMRT) can deliver higher dose conformity than conventional SRS or FSRT, achieving excellent local control rates [9]. Particle therapy, such as proton or carbon ion irradiation, is characterized by distinct physical and biological properties. The reduction of integral dose to adjoining healthy tissue with particle therapy could contribute to the reduction of long-term toxicity and is of special interest where prolonged survival is potentially achievable, as applies to the treatment of meningiomas [6]. Furthermore, the higher biological doses that can be delivered by the use of heavy particles such as carbon ions could improve tumor control for high-risk histologies [10, 11]. To date, sparse clinical data is available on particle therapy for meningiomas. A significant prognostic factor for progression-free survival (PFS) as well as overall survival (OS) lies in the histological characteristics of the tumor, with benign WHO grade I meningiomas yielding significantly longer PFS and OS than atypical meningiomas (WHO grade II) and malignant/anaplastic tumors (WHO grade III) showing the lowest local control rates as well as shortest OS [12].

In cases of tumor progression after initial radiotherapy, treatment options are generally limited. Interdisciplinary treatment decisions are usually obtained. Re-irradiation can be indicated in selected cases, depending on the previous dose distribution, time between primary and re-irradiation, location and especially on the vicinity to organs at risk (OAR).

Re-irradiation is generally performed using high-precision techniques; the characteristics of particle therapy offer excellent sparing of normal tissue outside the defined target volume, thus promising a beneficial risk-benefit-profile. The current analysis was performed to evaluate toxicity as well as local control and survival after re-irradiation with protons and carbon ions for recurrent meningiomas.

The present analysis demonstrates that re-irradiation with particle therapy offers a low toxicity profile; in spite of the reduced doses in re-irradiation, local control is relatively high at 71% after 12 months and survival after re-irradiation is promising.

Recurrences after RT in patients with meningiomas generally represent a difficult clinical situation; previous radiotherapy has often fully exhausted the radiation tolerance of surrounding normal tissue; thus, any additional RT has to be performed using highly advanced RT modalities. Other treatment alternatives include surgery, however, especially in skull base lesions, the risk of neurosurgical intervention can be associated with high rates of treatment-related sequelae [6]. Systemic treatment offers only modest effect: Smaller series on chemotherapeutic substances such as Hydroxyurea and temozolomide offer only limited efficacy, however, can by associated with significant hematological toxicity [24, 25]. Molecularly targeted substances, such as VEGFR and EGFR inhibitors have been applied in individual patients after neuropathological evaluation of marker expression, however, overall results were poor and no larger series or randomized trials are available. Moderate results have been shown in small retrospective series for the angiogenesis inhibitor bevacizumab with a median PFS of 18 months although significant toxicity was reported, with one fifth of the included patients discontinuing therapy due to toxicity [26]. Comparable results were found for treatment with sunitinib, a small-molecule tyrosine kinase inhibitor targeting VEGFR with a reported six-months-PFS rate (PFS-6) of 42%. However, here again one third of the included patients required dose reduction and 22% were removed from the study due to increased toxicity including one fatal CNS hemorrhage [27]. An overview of the limited systemic treatment options for recurrent meningioma has been provided by Kaley and colleagues, who in 2014 reviewed forty-seven different publications on the subject and calculated a weighted average PFS-6 of 29% for WHO grade I meningioma and 26% for WHO grade II/III meningioma respectively [28].

Thus, in cases of meningioma recurrence after RT treatment options are limited, and a second course of RT is discussed frequently when no other alternatives are available. Although high precision photon RT modalities such as SRS/FSRT and IMRT are widely available by now, particle therapy still offers several distinct advantages due to its unique physical characteristics that allow a local dose peak (Bragg Peak) at a variably definable depth level with very little dose deposition up to and beyond that point [29]. Over the past years, several planning studies have shown repeatedly that particle therapy can deliver higher dose conformity, with maximum dose applied to the tumor and reduction of medium and low dose to the surrounding tissue, thus reducing the overall integral dose and effectively sparing OAR [30‐32]. This has recently and comprehensively been reviewed by De Ruysscher and colleagues [33]. Particle therapy employing passive methods of beam delivery has been in use at several institutions for some time, however the method of active raster-scanning [13], with which beam delivery is being conducted at HIT is to date unique and has proven advantageous over passive beam delivery in different aspects, since no additional patient-specific hardware is required for the accurate shaping of dose distribution, significantly facilitating and accelerating planning as well as treatment processes [10].

In addition to the abovementioned physical advantages of particle therapy, heavy ions such as carbon offer biological benefits attributed to the increased relative biological effectiveness (RBE) of heavy ion irradiation [16] and decisively affecting treatment planning and effective dose calculation. In vitro experiments have proven the increased cytotoxic effect of carbon ion RT, yielding different values for the RBE depending on factors such as linear energy transfer (LET) value and cell line [34] and showing enhanced cytotoxicity even for relatively radioresistant cells such as pancreatic cancer cells with calculated RBE values of up to 4,5 compared to photon RT [11]. Clinical correlation for this data can be found in studies that have been conducted for several tumor entities such as chordoma, skull base chondrosarcoma as well as adenoid cystic carcinoma, showing improved local control after irradiation with carbon ions compared to photon RT [35‐37].

Altogether, the abovementioned aspects prove beneficial in treating a recurrent tumor that is in close vicinity to radiosensitive OAR, especially in a heavily pre-treated situation, as is the case for the patients in this analysis. There have been few studies to date that showed the feasibility and effectiveness of carbon ion RT in the setting of re-irradiation, showing local tumor control of up to 92% at 24 months and 64% at 36 months for different tumor entities of the skull base [20] and only moderate toxicity for recurrent head and neck cancers with different histologies [38].

For the treatment of meningioma, feasibility of particle therapy has been proven in past studies, however the available data focuses mainly on treatment in a primary or adjuvant setting with no prior course of RT, usually including only small groups of patients. Reported survival rates were up to 75% at 5 years and 63% at 7 years for high-risk meningiomas [39] and a more recent analysis employing additional DOTATOC-PET for target volume definition has shown 100% local control (follow-up 2–22 months) for WHO grade I meningiomas [10].

Taking into account those results, there is sparse clinical data available on particle therapy for patients with recurrent meningioma. The abovementioned studies have reported on smaller patient sub-groups receiving helical tomotherapy (n = 4) or particle therapy (n = 19) as re-irradiation yielding local control rates of up to 67% at 12 months for carbon ion RT [10, 40]. Furthermore, a series on nineteen patients receiving SRS or FSRT as re-irradiation for recurrent meningioma has yielded similar PFS rates and once more proven histology to be the most important prognostic factor for PFS [41]. Limitations of this present study include its retrospective character, limited number of patients, as well as relatively short follow-up. To date, however, there is no other dedicated analysis focusing primarily on the setting of re-irradiation and the use of particle therapy for recurrent meningioma and featuring a comparable cohort size.

Particle therapy applied as re-irradiation in recurrent meningiomas is a feasible method of achieving good local control at moderate toxicity. Improved dose conformity and thus the reduction of integral dose to OAR potentially leads to substantial clinical benefits. In addition, carbon ions provide an increased relative biological effectiveness, which could be beneficial to tumor control. A longer follow-up and prospective clinical studies on a larger number of patients are necessary to more accurately validate the real value of particle re-irradiation in recurrent meningiomas.