Multimodality management of cavernous sinus meningiomas with less extensive surgery followed by subsequent irradiation: Implications for an improved toxicity profile

Meningiomas comprise the most frequent intracranial benign tumors accounting for approximately one third of all intracranial neoplasms, and generally follow an indolent disease course with a typically benign nature and slow-growing behaviour. Although majority of meningiomas may follow an indolent disease course, affected patients may suffer from a plethora of symptoms with regard to lesion location. Symptoms typically occur as a result of the mass effect leading to compression of critical neurovascular structures. Headache, focal seizures, weakness in the limbs, visual disturbances, loss of smell, impaired memory or hearing functions may be observed. Advances in neurosurgery may allow for an improved toxicity profile following surgical resection as the traditional and a leading mode of management for meningiomas located at accessible brain areas. Nevertheless, vigilance is required given the morbidity and mortality risks associated with meningioma surgery particularly for elderly patients. In this context, radiation therapy (RT) may offer a viable alternative or adjunctive modality of management for meningiomas. Management of cavernous sinus meningiomas in intricate association with critical neurovascular structures pose a formidable challenge to the treating physicians. Attempting at extensive surgical procedures may be associated with substantial morbidity and even mortality. In this context, selected patients may benefit from a tailored multimodality approach including less extensive surgical resection followed by subsequent irradiation. Primary advantages of this refined therapeutic strategy may include improved toxicity profile along with improved functionality and quality of life. Herein, we assess multimodality management of cavernous sinus meningiomas with less extensive surgery followed by subsequent irradiation.Introduction

Introduction

Meningiomas comprise the most frequent intracranial benign tumors accounting for approximately one third of all intracranial neoplasms, and generally follow an indolent disease course with a typically benign nature and slow-growing behaviour [1-5]. Incidence of meningiomas demonstrates an age dependency with the highest incidence in the elderly age group [4,5]. These dural based tumors are considered to arise from the arachnoid meningothelial cells due to unknown etiology, although exposure to ionizing radiation and background of neurofibromatosis type 2 have been suggested to be in association with meningiomas [3].

Three World Health Organization (WHO) grades with 15 histological subtypes have been included in the WHO classification scheme which underscores the heterogeneity in clinical and molecular characteristics of meningiomas [1,3,6]. The most prevalent type includes grade 1 meningiomas as per the WHO classification [6]. Nevertheless, meningiomas of higher WHO grades are typically associated with higher recurrence rates and lower survival durations [3]. Also, a preponderance for frequent relapses, malignant transformation an deven metastases may be of concern although not typical [3].

Diverse localization throughout the central nervous system (CNS) may be seen, nevertheless, the most frequent location for meningiomas includes the supratentorial region, followed by skull base and the posterior fossa [7]. Parasagittal meningiomas, parafalcine meningiomas, convexity meningiomas and intraventricular meningiomas are located at the supratentorial brain whereas sphenoid ridge meningiomas, tuberculum sellae meningiomas, olfactory groove meningiomas, petroclival meningiomas, cavernous sinus meningiomas, and intraorbital meningiomas are located at the skull base region, and jugular foramen meningiomas, peritorcular meningiomas. cerebellopontine angle meningiomas, and cerebellar convexity meningiomas are included in the group of posterior fossa meningiomas [7].

Principal imaging modality for meningiomas is magnetic resonance imaging (MRI). However, computed tomography (CT) imaging may have a role in detection of tumoral calcifications, bony changes such as hyperostosis or osteolysis, and intraosseous tumor growth and pneumosinus dilatans especially for skull base lesions [8,9]. Diagnostic features suggestive of meningioma may be present on CT imaging in a considerable proportion of the patients as a lobular and circumscribed lesion with dural attachment [8,9]. Visualization is typically homogeneous on unhanced CT as a hyperdense extraaxial lesion with homogeneous contrast enhancement after administration of the contrast media [8,9]. MRI may be used in detection of the dural tail in some patients visualized as a post-contrast linear thickening of the duramater close to the lesion. Meningiomas are typically visualized as hypointense or isointense lesions on T1-weighted MRI and as hyperintense lesions on T2-weighted MRI usually with well defined borders [8,9]. While areas of calcification or necrosis may not demonstrate enhancement, homogeneous contrast enhancement is typical on MRI, and MRI may provide improved contrast differentiation to be utilized for differentiation of intraaxial and extraaxial meningioma lesions. Presence of dural tail may be suggestive of reactive dural changes whereas dural tails may also be infiltrated by the tumor in some cases. While not specific to meningiomas only, presence of the dural tail may facilitate differentiation of some meningioma lesions from other tumors not exhibiting dural tail such as pituitary adenomas or schwannomas [8,9].

Incidental detection may account for a considerable proportion of newly diagnosed meningiomas thanks to increased availability and use of modernized diagnostic imaging modalities [10-12]. Nevertheless, affected meningioma patients may also present with a plethora of symptoms with regard to lesion location. Symptoms typically occur as a result of the mass effect leading to compression of critical neurovascular structures. Headache, focal seizures, weakness in the limbs, visual disturbances, loss of smell, impaired memory or hearing functions may be observed.

Active surveillance by use of periodical neurological assessment with incorporation of advanced neuroimaging techniques may be an option for selected patients given the non-negligible risk of morbidity and quality of life impairment following treatment of particularly incidental intracranial meningiomas [10-15]. In the context of cavernous sinus meningiomas, understanding of the natural history may play an integral role in decision making for management. However, limited data exist in the literature regarding the natural history of cavernous sinus meningiomas [16]. Growth of meningiomas within the cavernous sinus has been a less addressed issue, and series of radiation treatment typically focused on tumor growth under therapy without a control group of untreated cavernous sinüs meningiomas. In the comprehensive study by Amelot et al. focusing on this less addressed perspective, the evolution of cavernous sinus meningiomas were reported as unpredictable and irregular [16]. In contrast with meningiomas at other locations, modelling of growth rate profiles may be challenging for cavernous sinus meningiomas [16]. While some lesions may remain indolent for longer periods, gradual upsizing or abrupt manifestation with rapid progression may occur. It appears that thorough neuroimaging follow up is an indispensable component of conservative management of cavernous sinus meningiomas given the unpredictable natural history in a considerable proportion of lesions. Nevertheless, advances in neurosurgery may allow for an improved toxicity profile following surgical resection as the traditional and a leading mode of management for meningiomas located at accessible brain areas. Nevertheless, vigilance is required given the morbidity and mortality risks associated with meningioma surgery particularly for elderly patients [15,17-19]. Specific complications of surgery may include venous bleeding, intratumoral hemorrhages, damage to vital neurovascular structures such as the internal carotid artery, oculomotor nerve or the trigeminal nerve [16].

In this context, radiation therapy (RT) with conventional fractionation of radiosurgery delivered in a single or few treatment fractions may offer a viable alternative or adjunctive modality of management for meningiomas. Herein, we assess multimodality management of cavernous sinus meningiomas with less extensive surgery followed by subsequent irradiation.

Irradiation as adjunct to incomplete surgery for cavernous sinus meningiomas

Combined modality management may be considered as a valuable strategy for selected patients with cavernous sinus meningiomas to avoid the potential risks of aggressive surgical resection and improve local control rates by incorporation of subsequent irradiation after limited surgery. Rationale of RT in this setting is to control progression of meningiomas after incomplete surgery. When the risk of radical resection as the principal mode of management is considered excessive, a tailored therapeutic approach may be utilized with incorporation of RT to achieve an improved toxicity profile with avoidance of the associated risks of aggressive surgery for selected patients harbouring lesions at eloquent brain regions such as the cavernous sinus [20-26].

Patients undergoing intended subtotal resection followed by radiosurgery as a deliberate valuable strategy were assessed in a comprehensive study [22]. Treatment approach consisted of single session radiosurgery with a mean margin dose of 14.5 Gray subsequent to limited surgery [22]. The authors concluded that surgery with subsequent radiosurgery provided safe and effective management of intracranial meningiomas located in close vicinity of critical structures [22].

Utility of conformal RT for cavernous sinus meningiomas was evaluated in another study in which patients were treated with conventionally fractionated radiation therapy (CFRT) as a definitive or complementary management modality [23]. Mean total RT dose was 52.9 Gray delivered over a period of 5 to 7 weeks with conventional fractionation using a median dose per fraction of 1.8 Gray [23]. The study reported satisfactory long term tumor control along with low treatment morbidity [23].

A technique utilizing combination of radiosurgery and microsurgery was reported as a viable bimodal approach to achieve improved cranial nerve functions in selected patients in a study for cavernous sinus meningiomas [24].

Management of 38 patients with sphenocavernous, clinoidocavernous, and sphenoclinoidocavernous meningiomas treated with surgery was assessed in a comprehensive study [25]. Twenty patients received irradiation after resection. Reduction in tumor size or tumor control was achieved in 18 patients (90%) out of the 20 patients receiving irradiation [25].

Long term follow-up outcomes of 31 patients undergoing RT with or without surgery for cavernous sinus meningiomas were reported by Dufour et al. [26]. Seventeen patients in the study were treated using a combined modality approach, and the results revealed a high rate of tumor control with a low risk of complications [26]. The authors concluded that RT could serve as a safe and effective treatment modality for initial or adjuvant management of cavernous sinus meningiomas considering the associated risks of complete aggressive surgical resection [26].

While the toxicity profile of RT may be more favorable than surgical resection for treatment of cavernous sinus meningiomas, adverse effects of irradiation also deserve consideration. Unlike surgical complications, toxicity of irradiation may also be observed as late effects in some patients. Deterioration in quality of life may occur due to untowards toxicity of irradiation such as edema, optic neuropathies, pituitary dysfunction. Ophthalmoplegia may also lead to emotional distress in some patients in addition to related visual disturbances. In this context, toxicity profile of a given treatment modality should be strongly considered in decision making for management of cavernous sinus meningiomas. Given the unpredictable behaviour in selected patients, a strict follow up strategy with periodical neuroimaging may be considered for active surveillance.

Recent Advances in the discipline of radiation oncology

There have been substantial improvements in irradiation techniques and technology in the millennium era. State of the art RT approaches have been introduced such as Intensity Modulated Radiation Therapy (IMRT), Adaptive Radiation Therapy (ART), and Image Guided Radiation Therapy (IGRT) [27-33]. Radiosurgical applications including Stereotactic Radiosurgery (SRS), Fractionated Stereotactic Radiation Therapy (FSRT), and Stereotactic Body Radiation Therapy (SBRT) have emerged as excellent therapeutic modalities for focused irradiation of many central nervous system disorders and a variety of distinct tumors located in the human body with stereotactic precise localization, excellent immobilization, and highly steep dose gradients around the target.allowing improved normal tissue sparing [34-66]. Radiosurgery is used to deliver extremely focused, high doses of radiation to relatively small, well defined targets under image guidance. There may be several radiobiological aspects of acquired results through the delivery of very high doses in a single fraction or a few fractions including induction of apoptosis and endothelial damage by ablative stereotactic irradiation [67-70].

Conclusions and future perspectives

Meningiomas are most common intracranial benign tumors. Although majority of meningiomas may follow an indolent disease course, affected patients may suffer from several symptoms due to the mass effect leading to compression of critical neurovascular structures. Management of cavernous sinus meningiomas in intricate association with critical neurovascular structures pose a formidable challenge to the treating physicians. Attempting at extensive surgical procedures may be associated with substantial morbidity and even mortality. In this context, selected patients may benefit from a tailored multimodality approach including less extensive surgical resection followed by subsequent irradiation. Primary advantages of this refined therapeutic strategy may include improved toxicity profile along with improved functionality and quality of life. Clearly, future studies may shed light on the role of this treatment approach in the management of cavernous sinus meningiomas.

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