Early intervention using high-precision radiotherapy preserved visual function for five consecutive patients with optic nerve sheath meningioma

Because of the extremely rare incidence of this disease, it is sometimes difficult to diagnose as primary ONSM. ONSMs comprise 2% of all orbital tumors and 1–2% of all meningiomas [8]. Furthermore, primary ONSM represents only 10% of all ONSM, all other (90%) being the secondary ONSM. In our previous report [3], patient #5 was initially diagnosed as Leber hereditary optic atrophy by the first ophthalmologist, because of the progressive visual loss with central scotoma. An ophthalmologist (O.M.) diagnosed this condition as intraocular lesion, which resulted in the compression of left optic nerve (ON) because of the absence of the family history and the presence of decreased light reflex. MRI showed a globular tumor on the left distal ON at precanalicular portion. Patient was consequently diagnosed with primary ONSM. Many kinds of tumors such as glioma, neurofibroma, schwannoma, fibrous histiocytoma, cavernous hemangioma and so on are the mimicking ONSM. Due to the considerable morbidities associated with biopsy, diagnosis of ONS tumors falls heavily on imaging findings, in addition to the clinical presentation. Unenhanced CT may demonstrate diffuse calcification within or along an ONS complex mass, which are highly suggestive of an ONSM. Gadolinium-based contrast enhanced fat-suppression T1W pulse sequences have made a significant contribution to the orbital imaging and gold standard for evaluation of the optic nerve disorders [9].

In this study, early improvement of VA and VFs was observed during the treatment courses among all 5 patients. However, many investigators have already recognized this phenomenon in other countries [1, 10‐12]. Most studies have reported that the underlying mechanism was not clear; however, we suggest that the early decompression of the optic nerve sheath, which resulted from the small reduction in the tumor size in the early stage of FSRT, was one of the main mechanisms. Jeremić et al. also supposed that the main reason for this observation might actually be a combination of a radiation-induced edema decrease and decompression of the functional nerve structures [1].

In the above FSRT studies, it was generally agreed that functional improvements were not followed by a significant decrease in the tumor size on imaging. Accordingly, Maclean et al. concluded that thorough ophthalmologic assessment was important because clinical responses often occurred in the absence of radiological change, based on their experience of meningiomas (including 3 ONSM) causing visual deficits [13]. Moreover, an improvement in visual function could occur even during the course of FSRT, as well as later in the follow-up period. However, there were controversial reports as to the extent of the tumor shrinkage observed after FSRT among large number of the patients with skull base meningioma [14, 15]. Becker et al. reported their experience of 39 patients with ONSM. All patients responded to the treatment. However, almost all patients experienced stable disease, i.e., no change on CT/MRI, and only 1 experienced a partial response [16]. Other investigators reported the same results in the same period [12, 17].

In this series, 1 patient developed retinal bleeding from the radiation retinopathy at 16 months after IMRT, probably because of a combination effect with the posterior retina dose and intercurrent diabetes mellitus. Baumert et al. reported that 1 patient developed radiation retinopathy complicated by a vitreous hemorrhage and cataract 4 years after FSRT [6]. A study by Sitathanee et al. described 12 patients treated with FSRT who received a mean dose of 55.5 Gy (range 51.6–59.1 Gy) delivered in 1.8 Gy daily; 1 patient with uncontrolled diabetes and hypertension developed vitreous hemorrhage 2 years after FSRT [17]. A previous case report described a patient with radiation retinopathy occurring 2 years after FSRT (optic nerve dose, 54 Gy in 30 fractions; optic nerve head dose, 48–54 Gy; posterior retina dose, 27.8–48 Gy) without pretreatment factors contributing to its occurrence. Therefore, it remains unclear why this patient developed retinopathy [18].

There is a great discrepancy between the effective IMRT and/or FSRT dose producing early improvement (20–30 Gy) and definitive control of the disease (50 Gy). The lowest controlled dose might be estimated as 30–40 Gy. If a tumor were controlled with a lower dose, it would be better for patients who have a severe intercurrent disease and a high risk of adverse effects, such as radiation retinopathy and/or optic neuropathy. High-risk patients could refuse definitive radiotherapy for these reasons. However, such high-risk patients cannot undergo radical surgery either. Accordingly, it is important to investigate safer ways to perform precision IMRT or FSRT for these high-risk patients with severe intercurrent disease.

In this retrospective study, no patients developed radiation-induced optic neuropathy during the follow-up time from 18 to 54 months. Median D_2% and \({D_{0.1c{m^3}}}\) for optic nerve was 55.0 Gy (range 47.8–63.2 Gy) and 52.2 Gy (range 40.1–62.5 Gy), respectively.

Many previous studies have investigated radiation tolerance of the optic nerve. Without previous surgical damage to the optic pathways, with a single dose of < 2.0 Gy and a total dose ranging from 45 to 50 Gy, the risk of radiation optic neuropathy was below 2% [19, 20]. When the total dose increased to 54 Gy, the risk of optic neuropathy rose to 5% [21, 22]. However, in a study of head and neck cancer with a dose of < 59 Gy no injury was observed in 106 optic nerves. With a dose of ≥ 60Gy, the 15-year actuarial risk of developing optic neuropathy was 47% with a fraction size of ≥ 1.9 Gy, but this was only 11% with fractions < 1.9 Gy [2]. Zenda et al. reported that 4 head and neck tumor patients who received a proton dose from 53.2 GyE (Gy equivalent) to 65.3 GyE developed optic nerve disorders [23]. In a study of carbon therapy, 58% patients who received irradiation to the optic nerve with > 57 GyE (D_max) developed radiation optic neuropathy. In addition, a dose of 20% of the volume of the optic nerve (D₂₀) was significantly associated with visual loss [24].

Because the conventional tolerance dose proposed for the retina and optic nerve estimated from conventional fractionated radiotherapy does not apply to modern precision radiotherapy [7, 25], updated information is necessary to determine the relevant tolerance dose for advanced treatment strategies.

At this moment, there are three primary treatment options for patients with cavernous sinus meningiomas: observation, microsurgical resection, and stereotactic radiosurgery (SRS). SRS may complement surgery or can be only reserved for growing remnants [26]. SRS can be replaced with FSRT or IMRT fundamentally and safely. Advanced radiotherapy techniques with standard fractionation schedules (56 Gy/28 fractions) can be a good option. The reported local control reached 82–95% at 5 years and a radiological response rate of 29–31% was observed. Multisession radiosurgery (mRS) has been evaluated in meningiomas with CyberKnife. When a 25 Gy in 5 fractions scheme is adopted, the total dose is theoretically comparable to the doses delivered with conventional fractionated regimens (50.4–56 Gy). The indication for mRS was given by the proximity to optic nerve and chiasm or the dimension of the lesion (> 3 cm). The local control rate at 5 years was of 95%. Only 3.5% of patients experienced a deterioration of preexisting symptoms. Proton has been also advocated to obtain reduced complication in this specific site. High overall 5-year local control rate (96%) was observed using 57EGy without major toxicity in Loma Linda University [27].

Early intervention with IMRT as well as FSRT resulted in a rapid improvement and reestablishment of visual impairment in 5 patients with ONSM. One patient with diabetes mellitus developed radiation retinopathy 16 months after completion of IMRT. The remaining 4 patients have not experienced any late toxicity at the follow-up time from 34 to 54 months. Accordingly, we suggest that early intervention with IMRT as well as FSRT is an effective and standard treatment option for not only stabilizing but also improving the vision of patients with primary ONSM. There has been a substantial shift in the treatment for ONSM from surgery to FSRT in US and EU. While a comprehensive evaluation of radiotherapy is not yet at hand, due to the benign nature of ONSM, limited number of this disease and thus decades of follow-up needed, it seems that this treatment option with early intervention using IMRT and FSRT might in future represent the mainstay of therapy for ONSM in Japan.