Molecular Mechanism and Cellular Endpoints

Radiation principally acts by ionizing molecules in irradiated tissues to cause DNA damage. Although radiation damage can be directly ionizing, in clinical therapy damage is most commonly caused indirectly, via the induction of highly reactive free radicals. The principal radiation-induced DNA damage is in the form of single- and double-strand breaks, the latter of which are generally considered the lethal event, leading to cell death.¹ The majority of radiation-induced DNA lesions, particularly single-strand breaks, are effectively repaired via a number of complex repair mechanisms.^2,3 It is assumed that DNA damage is responsible for radiation-induced inhibition of tumor growth in benign as well as in malignant tumors, and although likely, in benign tumors it remains unproven.

The end result of radiation damage after therapeutic radiation of malignant tumors is cell death, which is measured experimentally as clonogenic cell survival. Repeated small doses of radiation are less damaging to cells than an equivalent total dose given in a single fraction. Different dose fractionation schemes can be compared via a mathematical model (the linear quadratic [LQ] model), which compares different dose fractionation schemes through the concept of a biologically equivalent dose. The LQ model, which takes into account the total dose and the dose per fraction (and hence the number of doses/fractions), contains constants α and β, and it is the α/β ratio that distinguishes the responses of different tissues to radiation.^1,4

Acute reacting tissues such as epithelium have a high α/β ratio generally in the range of 8 to 10 Gy (ranging from 7 to 20 Gy), and late-reacting tissues, exemplified by the normal central nervous system (CNS), have a low α/β ratio, usually 1 to 3 Gy (ranging from 0.5 to 6 Gy). The slow growth and presumed limited dividing capacity of benign tumors such as meningiomas has led to the assumption they have a low α/β ratio, but this remains unproven. Late-responding tissues are more spared by fractionation than early-responding tissues, and this is the principle of fractionated radiotherapy, particularly as applied to the CNS which has an α/β ratio of 1 to 2 Gy where fractionation preferentially spares normal brain compared to a high α/β ratio tumor.¹

Radiotherapy Fractionation

External beam radiotherapy to tumors in the CNS is traditionally delivered in daily fractions of 1.6 to 2.0 Gy, 5 days per week for 5 to 7 weeks. Hyperfractionated schedules use smaller doses per fraction given two or three times per day separated by a time interval to allow for repair of sublethal damage of late-responding tissues (generally 6 hours). The rationale is to deliver higher total doses, causing more pronounced acute reactions including damage to tumors while maintaining an acceptable level of late normal tissue damage. In accelerated treatment the overall treatment time is shortened by giving the same dose per fraction two or three times a day. The rationale is to minimize the potential for tumor growth or regeneration over a protracted time. Hyperfractionated and accelerated radiotherapy have not been tested in the treatment of meningioma.

Hypofractionated radiotherapy, giving the treatment in fewer (down to one) fractions, is considered of value in brain tumors with an α/β ratio equivalent to that of the normal surrounding CNS where fractionation is believed not to lead to any differential sparing of normal tissue. Localized irradiation with a steep dose gradient between normal tissue and tumor is perceived to be primarily responsible for the differential damage to the tumor. This also presumes the absence of normal functional CNS within the treated tumor (which is not the case, for example, in cavernous meningioma) and the knowledge of the α/β ratio of the tumor, which is not known for meningioma of any grades. Nevertheless, hypofractionation is empirically administered to patients with benign tumors, including meningiomas.

Technical Aspects of Radiotherapy

The aim of modern radiotherapy is to give a maximum radiation dose to the tumor with the least dose to the normal brain. This is achieved by accurate localization of the tumor via computed tomography (CT) and magnetic resonance imaging (MRI) and techniques of localized delivery of radiation that employ precise and repeatable immobilization, coregistered imaging, and three-dimensional (3D) treatment planning.

Patients are typically immobilized in a custom-made plastic mask with movement limited to 2 to 5 mm. For localization of the meningioma, it is essential to use both CT and MRI. The extent of the soft tissue component of the meningioma and its relationship to critical structures is best seen with MRI, while the bony involvement is best assessed on a coregistered CT scan, which also provides the appropriate X-ray absorption characteristics necessary for radiotherapy treatment planning.

Accurate and complete tumor delineation is a prerequisite for successful radiotherapy and requires detailed image interpretation skills. It is particularly challenging in patients with residual and recurrent disease after previous surgery where it may be difficult to distinguish residual meningioma from postoperative changes. While the target is outlined on imaging specifically performed for the purpose of treatment planning, the process of defining the full extent of disease should take into account all available preoperative imaging. During the process, it is also possible to outline critical surrounding structures such as the optic apparatus or the brain stem. However, fractionated irradiation is performed to doses below tolerance limits of normal CNS, and the definition of the tumor volume does not and should not be compromised by specific normal tissue avoidance. Such practice is of importance only when using doses beyond tolerance either in dose escalation studies or with high-dose hypofractionated protocols (e.g., single-fraction radiosurgery).

A 3D margin of 5 to 10 mm beyond the visible tumor is added to generate the planning target volume (PTV), and this account for the inaccuracy due to patient movement and setup variation between treatments. 3D treatment planning aims to achieve a uniform dose of radiation to the target, with a dose variation less than 10% and a minimum dose to the surrounding critical normal structures below the limits of radiation tolerance. This is achieved by using multiple intersecting spatially distributed beams of external beam radiotherapy wherein each beam is shaped to conform to the shape of the tumor and may be adjusted further with other means of optimization. The technique of shaping radiation beams, described as conformal radiotherapy, is standard practice for all intracranial tumors. Linear accelerator beams are routinely shaped with the use of a multileaf collimator (MLC). The leaves are automatically positioned to predefined shapes based on information transferred directly from the planning computer. Conventional external beam radiotherapy for meningioma uses three or four radiation beams.

MLC leaves can also be used to alter the intensity of radiation, and this is described as intensity-modulated radiotherapy (IMRT). IMRT allows for better conformation of radiation to complex shape targets, particularly with concave regions containing critical normal tissue. Planning studies of complex meningiomas have demonstrated that IMRT may improve sparing of normal brain tissue in selected^5,6 but not all cases.⁷

Stereotactic irradiation is a refinement of conformal radiotherapy. Increased accuracy of treatment delivery is achieved with the use of more precise patient immobilization and image coregistration which allow for accurate target definition and treatment planning. Relocatable frames and high-precision mask systems allow for smaller margins (1–3 mm), which is the principal gain in terms of avoiding normal neural structures, and this is combined with multiple (usually 4–6) fixed-shaped beams employing MLC with smaller leaves (mini or micro MLC). The additional gain of increasing the number of beams beyond 6 and reducing the width of MLC leaves below 5 mm is not clear.

Stereotactic irradiation can be given either as single fraction radiosurgery (SRS), which can be considered the extreme form of hypofractionated radiotherapy, or as fractionated stereotactic radiotherapy. SRS is delivered either with a multiheaded cobalt unit (Gamma Knife®) or a linear accelerator. Fractionated stereotactic conformal radiotherapy (SCRT) using either conventional or hypofractionated schedules is delivered via a linear accelerator.

Proton radiation has the appeal of more localized deposition of energy than can be achieved with photons (X-rays), therefore offering the potential for better sparing of normal tissue particularly beyond the principal target. The rationale for the use of protons in meningiomas is based solely on the theoretical benefit of more localized conformal delivery of radiation shown in some cases.^8,9

Tumor Control

Retrospective studies of conventional fractionated radiotherapy in patients with residual and recurrent meningiomas have demonstrated apparent benefit in local tumor control after radiotherapy^10–21 (Table 50-1). However, none of the studies are randomized or prospectively controlled and none have so far reported convincing survival gain with the early addition of irradiation. Nevertheless the reported progression-free survival (PFS) after radiotherapy of benign meningioma is in the region of 90% at 5 years and 80% to 90% at 10 years^{14,17,19,21,22} (see Table 50-1).

There is limited information on the appropriate dose of irradiation. The reported tumor control is similar for doses ranging from 50 to 60 Gy at less than or equal to 2 Gy per fraction. Doses less than 50 Gy were reported to be associated with worse disease control,^13,21,23 although this is based on retrospective studies. The recommended dose for benign meningiomas is generally 50 to 60 Gy (usually 54–56 Gy) at less than 2 Gy per fraction. Our practice is to limit the dose to 50 Gy for meningiomas involving the optic pathways.

Local control after radiotherapy given in more recent times is better than reported previously, and this has largely accompanied improvement in imaging and surgery and cannot be explained in terms of better techniques of treatment delivery alone. Nevertheless, the technique of treatment in terms of adequate tumor coverage is important, as partial treatment of meningioma to effective radiation doses is equivalent to partial excision with worse long-term disease control.

Tumor site and size have been reported as predictors of tumor control.^14,15 In skull-base tumors, the generally larger sphenoid ridge tumors fare worse than small cavernous sinus lesions.²² There is little evidence that timing of radiotherapy is important, as local control and survival rates are similar whether radiotherapy is given as part of primary treatment or at the time of recurrence.^14,21,22 Age and gender have little influence on long-term disease control.

Timing of Radiotherapy

On the basis of the available data, conventional fractionated radiotherapy achieves good disease control in surgically inaccessible or inoperable benign meningiomas such as tumors at the skull base or unresectable residual disease in venous sinuses. However, there is little information to suggest that long-term survival is influenced by timing of radiotherapy and it is therefore reasonable to offer irradiation either after incomplete excision or with delay after evidence of progression. Our usual practice is to offer a policy of surveillance to patients with asymptomatic, particularly small meningiomas, and consider treatment only at the time of either clear progression threatening neurologic deficit or early in the development of a new neurologic problem that can be ascribed to a progressive tumor. In patients with benign meningioma invading venous sinuses, the option lies between either early irradiation to reduce the risk of regrowth and hence the need for further surgery, or surveillance, which may allow spontaneous occlusion of the sinus and subsequently make it amenable to complete resection. However, only prospective randomized trials can determine whether radiotherapy and its timing alter survival and quality of life in patients with subtotally resected or inoperable benign meningiomas.

Neurologic Function

An important endpoint of treatment of benign meningiomas is the preservation or improvement of neurologic function. More than 70% of patients with skull-base meningiomas have a neurologic deficit that may be a consequence of tumor growth or previous surgery. An improvement or more often stabilization of neurologic deficits has been reported in up to two thirds of patients after conventional radiotherapy,^15,19,23 although this is generally in the absence of objective prospective recording of function. Our experience suggests that the majority of patients have stabilization of neurologic deficit for the duration of disease control.

Toxicity of Fractionated Radiotherapy

The risk of late normal CNS toxicity of external beam radiotherapy to doses less than 60 Gy at less than 2 Gy per fraction is low. Radiation injury to the optic apparatus (radiation optic neuropathy), manifest as decreased visual acuity or visual field defect, is reported in 0 to 2% of patients irradiated for meningiomas.^10,12–25 No injuries were noted in 106 optic nerves treated to doses less than 59 Gy, while the 15-year actuarial risk of radiation optic neuropathy was up to 47% in patients receiving a dose greater than or equal to 60 Gy.²⁶ Other cranial deficits have been reported in 1% to 3% of patients. Radiation-induced necrosis of brain parenchyma is rare, and remains an exceptional event (<1% risk) after modern conformal radiotherapy to doses less than or equal to 60 Gy.

Neurocognitive dysfunction is a recognized consequence of large-volume cranial irradiation, particularly using hypofractionated schedules.^27,28 There are no large prospective cognitive function studies in patients with benign meningiomas treated with radiation. Although impairment of short-term memory has been recorded, the cause is likely to be multifactorial, especially in the elderly patient population. There is little evidence that small-volume fractionated irradiation for meningioma is responsible for cognitive dysfunction beyond the deleterious effect of surgery and the tumor itself.²⁹

Hypopituitarism is reported in less than 4% of irradiated patients with meningiomas,^19,21–23 although endocrine function has not been systematically evaluated. Patients with large parasellar meningiomas involving the sella and suprasellar region are at risk of hypopituitarism due to the disease itself and as a consequence of irradiation of the hypothalamic–pituitary axis. Regular endocrine assessment should be standard practice in patients with parasellar meningiomas and any tumors where the hypothalamic–pituitary axis received significant doses of irradiation.

Although there is an increased incidence of cerebrovascular accidents and excess cerebrovascular mortality in patients with benign tumors treated with radiotherapy,^30,31 the risk in patients with meningioma treated with radiation has not been defined and the influence of radiation on its frequency is also not clear.

High-dose radiation may be associated with the development of a second brain tumor, usually a meningioma or an astrocytoma, as reported after irradiation of a pituitary adenoma.³² The estimated risk after radiotherapy of pituitary adenoma is in the region of 2% at 20 years; the risk after localized radiotherapy of meningioma is not defined.

Conclusions

Modern radiotherapy using accurate tumor localization with coregistered MRI and CT imaging and localized conformal treatment delivery with adequate coverage of the target and sparing of adjacent normal tissue makes conformal radiotherapy of benign meningiomas a relatively safe treatment option with a low risk of treatment-related morbidity and good disease control defined at 5 and 10 years after treatment. The results of modern conformal radiotherapy serve as a basis for comparison with other techniques of irradiation such as radiosurgery, stereotactic conformal radiotherapy, and particle therapy.

Stereotactic Radiotherapy

Stereotactic radiotherapy in the form of fractionated stereotactic radiotherapy (SCRT) and single fraction radiosurgery (SRS) have been in regular use for the treatment of benign tumors for two to three decades, and although outcome data should be reasonably mature, long-term results are scarce. SCRT has been employed for meningiomas of all sizes, lying in close proximity to or involving, the cranial nerves and other sensitive structures such as the brain stem. High-dose SRS is generally used for smaller tumors, away from critical neural structures.

The reported control after SCRT is greater than 90% at 5 years (weighted mean 95% at a median follow-up of 40 months)^33–38 (Table 50-2). The largest series of 189 patients with benign skull-base meningioma treated with fractionated stereotactic conformal radiotherapy reported a 5-year local PFS and survival of 94% and 97%, respectively.³⁹ An update of 317 patients reported a 5-year and 10-year PFS of 91% and 89% and respective survival of 95% and 90% for Grade 1 meningiomas.³⁷ Tumor volume greater than 60 cm³ was associated with 16% recurrence rate compared to 4% for smaller tumors less than or equal to 60 cm³. The 5-year local PFS of 110 patients with benign skull-base meningioma treated with SCRT between 1994 and 2006 at the Royal Marsden Hospital is 89% and the 5-year survival is 96% (unpublished update). Patients with small cavernous and parasellar meningiomas had a local PFS of 100%.

Improvement in neurologic function, usually in the form of improvement or recovery of cranial nerve deficit, has been reported in 14% to 44% patients.^33,37 In the authors’ experience, pain due to meningiomas is rarely improved by fractionated irradiation. Late toxicity including cranial nerve deficit (e.g., visual problems), hypopituitarism, and impairment of neurocognitive function have been reported in fewer than 8% of patients treated with SCRT^33–38 (see Table 50-2). However, the evaluation of complications is frequently retrospective without defined objective severity scales and long-term prospective studies are needed.

Overall the efficacy and toxicity of fractionated stereotactic radiotherapy for benign meningiomas is comparable to the reported results of conventional external beam radiotherapy. At present it is not possible to assess the impact of SCRT on late morbidity.

IMRT

Based on reports of improved normal tissue sparing in comparison to conventional radiotherapy and SCRT in selected meningiomas, IMRT has been employed particularly in patients with complex shaped tumors. The reported local tumor control in the largest cohort of patients with benign meningiomas treated with IMRT was 94%, with improvement in neurologic function in approximately 40%.⁴⁰ Similar results have been reported in other smaller cohorts^41–43 (see Table 50-2). Although IMRT is a feasible technique of radiation delivery for complex shaped meningiomas, tumor and morbidity control are similar to those achieved with other means of photon irradiation without clear evidence of benefit.

Protons

Relatively few patients with meningioma received proton irradiation. Reported tumor control rates after proton therapy is shown in Table 50-3. The 3- to 5-year local PFS is 91% to 100%^44–47 and the only reported 10-year PFS is 88%.⁴⁴ The treatment as reported was associated with a relatively high incidence of late morbidity, with 16% actuarial risk at 2 years in one study⁴⁴ and a 13% to 24% risk in other smaller studies,^46,47 usually associated with doses greater than 60 GyE. In summary, although proton irradiation appears equally effective as photon radiotherapy in achieving local control of benign meningiomas, the reported morbidity of treatment, particularly when employing doses beyond tolerance of normal CNS, appears higher.