Symptoms and General Pathology

All Conditions

Neoplasms

Nervous System Diseases

Rare Diseases

Recurrence

Meningioma

Neoplasms, Nerve Tissue

Neoplasms by Histologic Type

Neoplasms, Vascular Tissue

Meningeal Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Multisession radiosurgery (hypofractionated radiotherapy) with Cyberknife

Radiosurgery

Renato Mantegazza, MD

Laura Fariselli, MD

Fractionated radiosurgery will be delivered to atypical meningioma lesions in salvage setting for patients who present post-surgical residual lesion or develop recurrence.

Meningioma is the most common intracranial tumor (1). World Health Organization (WHO) grade II (atypical) meningioma recurs more frequently than WHO grade I (benign) meningioma, and patients with subtotally resected atypical meningioma should be treated with adjuvant radiation therapy (2). However, many atypical meningiomas can be gross totally resected, and whether to administer radiation to this population remains unclear. Apart from extent of resection, clinical characteristics such as age and gender and tumor-related characteristics such as tumor size and location have poor predictive capacity to determine which lesions will recur.

The lack of professional consensus on the role of adjuvant radiation therapy (RT) derived from the heterogeneity and retrospective nature of the published data: standard fractionation fails to demonstrate a benefit in term of local control and survival.

Recent advances in radiotherapy technology (staged radiosurgery) give the possibility to reach high dose levels only in tumor volume and in the same time to save the surrounding healthy tissues.

The purpose of this study is to verify the related toxicity of a new radiotherapy protocol and as second end point to evaluate the efficacy on disease local control at 3 years.

Multisession Radiosurgery in Residual/Recurrent Grade II Meningiomas.

Hypofractionated Stereotactic Radiotherapy (Multisession Radiosurgery) in Residual/Recurrent Grade II Meningiomas: Feasibility Study.

Frequency of neurological side effects related to the radiosurgical treatment, evaluated according with CTCAE scale at every follow-up (4 months post-treatment, then every 6 months).

The rate of tumor response defined as follow on the basis of modification of MRI imaging evaluated also with advanced RM techniques:Partial response (PR) is defined as 20%, decrease in the volumetric size of the lesion on MRI; stable disease (SD) as no change in the size of the lesion; progressive disease (PD) increase in any volumetric size of the lesion, confirmed at least a the following two consecutive MR

Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta

Radiotherapy

This is a prospective observational trial consisting of robotic multisession radiosurgery (CyberKnife ®) for large and medium size and/or located at critical site benign intracranial meningiomas.

To date, the treatment of choice for intracranial meningiomas is surgical removal.

Radiotherapy, especially the radiosurgery (SRS), in exclusive, adjuvant or salvage setting represents an alternative or complementary viable treatment to the neurosurgery. Despite being a well-established treatment for intracranial meningiomas, SRS might be associated with significant morbidity when large volumes or critical sites are treated. Hypofractionated stereotactic radiotherapy has the potential to deliver sharply focused high doses per fraction without increasing the risk of toxicity.

The aims of our study are toxicity and symptom control evaluation of radiosurgery treatment delivered in multisession, for large or medium size intracranial meningiomas and/or for intracranial meningioma located at the critical sites (perichiasmatic area, perioptic area, PCA). We will evaluate also the efficacy of the treatment by volumetric analysis of treated meningiomas carrying out a volumetric comparison between pre- and post-radiosurgery treatment (every 6 month after treatment).

The neurological and clinical assessment before and after s-SRS will be based on CTCAE v4.0 and BPN BSN House-Brackman and sensorineural internation scale assessment.

Multisession Radiosurgery in Large Meningiomas

evaluation every 6 months, up to 3 years. Afterwards, every year up to 5 years based on CTCAE v4.0

Evaluation based on 1-3 mm thickness T1 weighted (or volumetric FAT saturation weighted) brain gadolinium-MRI images

Evaluation based on sensorineural international scale

Evaluation based on ophthalmological evaluation

Eye Diseases

Nerve Sheath Neoplasms

Optic Nerve Neoplasms

Peripheral Nervous System Neoplasms

Peripheral Nervous System Diseases

Neuromuscular Diseases

Cranial Nerve Diseases

Optic Nerve Diseases

Patients will undergo multisession radiosurgery as clinical practice.

Multisession Radiosurgery

Traditional treatment options for optic nerve sheath meningiomas (ONSM) include observation, surgery and radiotherapy, but to date none of these has become the clear treatment of choice.

The role of the radiotherapy remained uncertain because of the concern about radiation related optic neuropathy In the recent past two large series of patients treated with a fractionated stereotactic radiotherapy confirmed these positive experiences in tumour control and greatly reduced the concern about the treatment related toxicity.

Under the light of successful meningiomas treatment, radiosurgery, had proposed as a treatment option. Single session, high conformality, frame based radiosurgery systems are seldom if ever proposed as ONSMs treatment due to the known dose tolerance of the optic nerve.

The first experience in ONSMs treatment with multisession radiosurgery treatment was quite promising.

The aim of the present study is to prospectively evaluate the efficacy and safety of multisession radiosurgery in ONSMs treatment.

In order to evaluate multisession radiosurgery 50 patients will be enrolled in the present study.

All patients will be treated by using multisession radiosurgery, with 5 fractions of 5 Gy each to a total dose of 25 Gy prescribed to the 75-85% isodose line. Patients were evaluated both for tumor growth control and visual function.

Introduction Optic Nerve Sheath Meningiomas (ONSMs) are rare tumours. They represent approximately the 2% of all orbital tumours, 1-2% of intracranial meningiomas and one third of the optic nerve lesions (23, 32, 42, 43). Usually these tumour are monolateral but 5% have a bilateral development (33) On the base of the growth pattern these tumours can be classified in primary and secondary forms. The former type arise from the arachnoid cap cell of the fibrous dural capsule of the optic nerve and they usually growth circumferentially along the nerve. Primary ONSMs can be further subdivided in orbital and intracanalicular forms.

Secondary ONSMs usually arise from the sphenoid ridge or the tuberculum sellae and subsequently spread into the optic canal and the orbit (14, 42).

Often the pathological studies show meningotheliomatous or transitional histology.

Middle aged woman are the most often affected (4, 36, 44). The most frequent presentation symptom is a visual loss, both in acuity or visual field. This is nearly an expression of an optic nerve direct compression and of the vascular rearrangement.

Optic nerve atrophy is common. Optociliary shunts are a late and rare sign but they are the direct expression of compressive optic neuropathy and it can be pathognomonic for the diagnosis of ONSM (35, 43).

Traditionally treatment options include observation, surgery and radiotherapy but, until now, any of these had assumed as the treatment of choice.

Nevertheless, the development of the new technology improved the interest in radiotherapy application.

Conservative treatment can be considered due to the benign nature of the meningiomas and their slow growth pattern. Nevertheless this unavoidably leads to a visual deterioration or complete blindness (18, 33, 43, 44).

Surgery is advocate for tumour administration, particularly in case of a progressive visual loss or complete blindness, tumour progression and intracranial involvement. Anyway because of their intimate relationship to the optic nerve, ophthalmic artery and central retina artery ONSMs complete removal is extremely challenging. Moreover post-operative course is often characterized by symptoms worsening (4, 8, 9, 15).

In the recent past, the role of the radiotherapy remained uncertain: many author reported a positive experience, but the concern about complication and secondary effects strongly limited its acceptance (4, 5, 16, 21, 22, 26, 29, 31, 32). Radiation optic neuropathy has been described following conventional radiotherapy treatments (45 Gy, 2 Gy per fraction) (40).

More recently two large series of patients treated with a fractionated stereotactic radiotherapy confirmed these positive experiences in tumour control and greatly reduced the concern about the treatment related toxicity (6, 27).

Under the light of successful meningiomas treatment, radiosurgery had proposed as a treatment option. Single session, high conformality, frame based radiosurgery systems are seldom if ever proposed as ONSMs treatment due to the known dose tolerance of the optic nerve (22).

The development of the radiosurgery technology, starting in 1994, introduced a new and effective therapeutic option (3, 11, 12).

In this way it is possible to exploit the different recovery speed of normal and pathological tissues to optimize the tumour control and at the same time to spare the surrounding structure avoiding damage to the visual pathways.

In fact, the comparison between various fractionation regimens resulting in roughly equivalent biologically equivalent dose (BED) for tumour control and normal tissue late effects (assuming that tumour and normal tissue late effect have a similar α/β ratio). In this way the acute (early) reactions would be reduced with larger fractions size (19).

The first experience in ONSMs treatment with multisession radiosurgery treatment was quite promising (32).

The aim of the present study is to prospectively evaluate the efficacy and safety of multisession radiosurgery in ONSMs treatment.

The treatment will be evaluated both in terms of tumour growth control and sparing for vision.

PATIENTS AND METHODS Patient's population. XX patients affected by an Optic Nerve Sheath Meningioma (ONSM), both orbital and intra-canalicular will be considered for a multisession radiosurgery.

Eligibility:

Inclusions criteria are a significant visual impairment at presentation, progression of visual dysfunction during the observation period, disease progression.

Due to the histological diagnosis imply an invasive and hazardous procedure, no biopsies will be performed and the diagnosis will be exclusively radiological.

Pre-treatment evaluation. All patients, before treatment, will be collectively evaluated by Neurosurgeon, Radiation Oncologist and Neuro-Ophthalmologist.

Clinical investigation includes a full neurological examination. Particularly the I, III, IV, V and VI pair of cranial nerve will be investigated.

Visual acuity, visual field will be also investigated by the same Neuro-ophthalmologist. Visual acuity will be investigated using best correct Snellen visual acuity. A standardized automated perimetry by humphrey Visual 30-2 field testing will be performed in order to define the presence of visual field deficits Dose selection and radiobiology considerations. The dose selection is based on previous experience with Radiosurgery and Stereotactical Radiotherapy (1, 2, 23, 28, 30), but also on the previous studies concerning the dose tolerance of the anterior visual pathways (38).

Assumed these considerations we plan multisession radiosurgery: all patients will be treated with a maximum dose of 25 Gy (5 Gy/fraction; 5 fractions).

The total dose plans in this study is comparable to the doses delivered with the conventional fractionated regimens (50,4 - 56 Gy). In fact, assumed that the meningioma's α/β ratio is approximately 3,7-3,8 Gy (34, 41).

According to the equivalent dose formula:

EQD2 = D \* \[(d + α/β)/(2 + α/β) = 38,2 Gy where D is the altered schedule total dose, d is the altered daily dose. Then, considering the differences between the overall treatment time between conventional fractionated and hypofractionated treatment (28 fractions, 5 fractions per week, 38 total days and 5 fractions, 5 days respectively), assumed Dprolif = 0,7 as for the most of the tumours (7, 17), where Dprolif is the dose recovered daily owning to proliferation: EQD2,T = EQD2,t - \[(T - t) \* Dprolif \] = 61 Gy Treatment planning. Patients will have a 1.25 mm thickness MRI, including fat suppression sequence, T1with Gadolinium sequence and a contrast-enhanced CT scans. The images will then merged in order to optimize the definition of the target volume and the intra-extraorbital segment of the optic nerve, and the organ at risk (i.e. retina) An inverse planning software will be adopted to optimize the target coverage and at the same time to achieve the maximum of conformality and homogeneity of the prescription dose. The treatment plan used for each treatment will be based on an analysis of the volumetric dose including dose-volume histogram (DVH) analyses of the PTV and critical normal structures. The number of paths and beams used for each patient will vary and will be determined by the selected individual treatment plan.

Target Volumes The target volume will consist of the tumor outlined in the treatment planning software seen on planning CT and/or MRI.

The planning target volume (PTV) is planned to encompasses the 75-85% isodose line. All organs at risk will be defined.

Follow-up. Following multisession radiosurgery, patients will be evaluated for tumour progression and visual function by a multidisciplinary team (Radiation Oncologist, Neurosurgeon; Neuro-Ophthalmologist). The patients will be evaluated 3 months after treatment, every 6 months during the first two years and then once per years.

Every follow-up includes Neurological, Radiological and neuro-ophthalmological evaluation.

Neuro-Ophthalmologic assessment includes a comprehensive evaluation of the visual acuity, visual field, extrinsic eyes movements, and proptosis. Visual acuity will be investigated by using the same tests at base line.

Post-treatment radiographic evaluation includes an MRI scan every 6 months. Primary end point Primary end points are local growth control and maintenance or improvement of visual acuity at base line Response criteria The partial response is defined as a tumour reduction more than 20 %. Progression disease is defined as any increase in the tumour dimensions.

Toxicity Ocular toxicity will be described with reference to CTCAE 3 version criteria. DATA COLLECTION Patients will be allocated a number and their data will be collected on a Case Report Forms. Data will include information from each protocol visit and will be completed on a timely manner.

STATISTICAL CONSIDERATIONS Analysis will be conducted to check if tumor control is correlated to clinical symptoms improvement by using short course radiotherapy treatment in relation to previous described radiobiological considerations.

Clinical improvement will be measured specific ophthalmological tests.

Multisession Radiosurgery for Optic Nerve Sheath Meningiomas

Observational Study on Multisession Radiosurgery for Optic Nerve Sheath Meningiomas

pre and post treatment visual acuity and visual field will be evaluated

Partial response: tumor reduction more than 20%. Progression disease: any increased

Toxicity evaluated according to NCI CTCAE v3.0

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Multisession Radiosurgery in Residual/Recurrent Grade II Meningiomas.	NCT05081908	Meningioma Atyp...	Radiosurgery	18 Years -	Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta
Multisession Radiosurgery in Residual/Recurrent Grade II Meningiomas.	NCT05081908	Meningioma Atyp...	Radiosurgery	18 Years -	Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta
Multisession Radiosurgery in Large Meningiomas	NCT02974127	Intracranial Me...	Radiotherapy	18 Years - 80 Years	Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta
Multisession Radiosurgery for Optic Nerve Sheath Meningiomas	NCT02594709	Optic Nerve She...	Multisession Ra...	18 Years -	Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta
Multisession Radiosurgery in Large Meningiomas	NCT02974127	Intracranial Me...	Radiotherapy	18 Years - 80 Years	Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta

Spots Global Cancer Trial Database for multisession radiosurgery