Surgery

There is general agreement that the optimal treatment for these lesions, whenever feasible, should be a Simpson grade I resection of the tumor—carefully pre-embolyzed if necessary—providing definitive diagnosis, reducing immediately any mass effect, and alleviating clinical signs and symptoms.^2,57,59,60 Such a golden therapeutic standard is still the dominant option in the vast majority of convexity meningiomas in fronto-orbital and spinal locations, whereas surgical results are less satisfactory in intraparenchymal or cranial base lesions^2,59–62 and particularly grim in grades 2 and 3.³ Unfortunately, despite surgical advances, when these tumors are infiltrating the skull base, cranial nerves, or vascular structures, complete resection may not be feasible without unacceptable morbidity rates. Considering more recently published series, gross removal of basal meningiomas was achieved in 60% to 87.5% of the patients,^59–65 with 30% to 56% of severe complications,^{58,60,65–67} mostly represented by newer or deteriorated pre-existing cranial nerve deficit, occurring temporarily in 20% to 44%, and permanently in 16% to 56% of the cases. Median postoperative mortality rate was 3.6% (range 0%–9%).^59–68 Moreover, local recurrence rates are strictly dependent on Simpson’s grade⁶⁹: at 10-year follow-up, 10% to 33% (average 20% to 25%) after complete resection (Simpson 1–2); and 55% to 75% (average 60%–62%) after partial resection, that is, Simpson >2 (Table 104-2).^{20,32,70–74} The relevance of these findings may probably explain why, particularly in atypical-anaplastic varieties, adjuvant therapies and sometimes preplanned, combined multidisciplinary approaches may be advocated, to avoid early recurrences and repeat surgery, thereby reducing morbidity.^2,12,35

Fractionated Radiotherapy

External beam radiation therapy (EBRT) has been used for decades, either as a primary or as an adjuvant treatment, with documented improvement in local control and rarely in recurrences (see Table 104-2).^{12,41,42,75–80} In more aggressive cytotypes, most authors seem to favor administering EBRT—mostly Fractionated Stereotactic Radiotherapy (FSRT) early to patients who have undergone subtotal and even total resections.^{2,3,12,42,43,45,81} FSRT has proven to be successful in primary (imaging defined) meningiomas,^12,82–87 particularly in all cases with crucial exposure of extremely radiosensitive structures such as the optic pathways.^12,88–91 Series reports comparing progression-free survival (PFS) for patients treated with gross/total removal and subtotal removal (STR), with or without EBRT, have consistently shown the best results with the radical surgery or STR plus radiation, whereas STR alone turned out to be less valuable.^{3,32,33,41,42,45,70,71,76–78,85,92–107}

Stereotactic Radiosurgery

According to the historical definition by Lars Leksell stereotactic radiosurgery (SRS) is “a technique of closed skull destruction of a predetermined intracranial target by a single-fraction high dose of ionizing radiation using a precision stereotactic apparatus”.¹⁰⁸ In contrast with spatially less accurate conventional radiotherapy, radiosurgery has the capacity to maximize/optimize the dose exposure on the target volume, while minimizing the irradiation of surrounding critical structures, thereby reducing collateral damages. The concept of delivering a high dose of radiation energy to treat focal pathologic lesions fits all criteria for minimal invasiveness and has gradually become a powerful and attractive therapeutic strategy for many neurosurgical disorders. Recently the impressive advances in neuroimaging, stereotactic techniques, and robotic technology have further improved results, expanding the spectrum of applications. This approach may be increasingly considered not only as potentially adjuvant to microsurgery but also as a valuable alternative option.

Lars Leksell designed the first arc centered device in 1948,¹⁰⁹ and in 1951 he introduced the term and concept of radiosurgery.^108,109 His first stereotactic instruments were suitable for replacing a probe (needle electrode) by cross firing intracerebral structures with narrow beams of radiant energy. X-rays were first tried, but both gamma rays and ultrasonic rays were included as alternatives. In close collaboration with Borje Larsson, a physicist at the synchrocyclotron unit in Uppsala, Leksell performed the original experiments with highly focused high-energy proton irradiation of human malignancies.¹¹⁰ As a rule, precise, well-limited lesions were produced, but the synchrocyclotron proved to be too complicated for widespread clinical use. This compelled Leksell to consider other radiation sources and he started designing a 179-source ⁶⁰Co gamma unit that was fully integrated into the stereotactic system; the first unit was inaugurated in 1967.¹¹⁰ Radiosurgery was initially developed with the aim to offer a bloodless and less risky method, essentially for functional treatments. However, within a few years the machine proved to be extremely effective in a variety of intracranial lesions, provided that the rationale of the approach, that is, the fundamentals of the technique, had been respected. Briefly, the latter are limited target volume, well-defined imaging, compatible site, and adequate cytology. As shown in the following reported experiences, to date it is possible or nearly possible to overcome each of the following constraints: tackling larger volumes with lower dosages,^111,112 crucial locations with staged procedures, and, perhaps in the near future, radioresistant oncotypes by means of radiosensitizers.

In recent decades, SRS techniques, particularly gamma knife radiosurgery (GKR), have progressively gained an unquestionable momentum in the therapeutic armamentarium for most brain tumors, particularly for well defined lesions, such as meningiomas. The main reasons for this growing role may be summarized as follows: (1) targeting update, with the advent of computerized and coregistered, morphofunctional neuroimaging; (2) the availability of newer, more powerful and precise irradiation devices; (3) the introduction of computer-guided dose planning; and (4) a deeper radiobiological experience. To date, an estimated half a million people have been treated by GKR worldwide at a continuously increasing annual rate (in 2009, roughly 50,000 patients were treated). In addition, approximately 200,000 patients worldwide have experienced SRS with other dedicated machines. Elective indications currently include metastatic brain tumors, benign endocranial tumors (meningiomas, neuromas, pituitary adenomas, etc.), low-grade neuro-ectodermal tumors, vascular malformations, and some types of functional neurosurgery (e.g., trigeminal neuralgia). Finally, it is generally accepted that the putative mechanism of action of SRS is intimately dependent on the main technical variables (dose–volume integral, timing, target cytology), as well as the goals that we are pursuing (tumor growth control [TGC], necrotic evolution, ephaptic block, etc.). Regarding meningiomas, routine protocols are focused on TGC, probably obtained through a combined mechanism, such as: 1, direct cytotoxicity, presumably promoting apoptosis; 2, damage to the vascular supply, mediated by inhibition of growth factors (vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), factor 8, etc.); and 3, inactivation/destruction of hormonal receptors (e.g., octreotide [OCT] receptor).^113,114

Proton Beam

High-energy protons represent an extremely important alternative option to photon and electron beams. In fact, proton beams offer the advantage to improve tumor control, especially for treating small volumes, where it is necessary to obtain a localized high-dose distribution in small deep-sited locations, while relatively sparing the surrounding normal tissue.^2,12 The tissue depth at which the Bragg ionization peak is maximal can be adjusted by cross-firing systems according to the target position.

Moreover, there is increasing evidence that a proton boost combined with more than 60-Gy photon therapy significantly improves mean survival and local tumor control (LTC) rates in atypical (5-year PFS, 89%) and anaplastic (5-year PFS, 51%) meningiomas. The drawbacks of this technique include the great expense of building and maintaining these sites; some compromise in spatial accuracy because instead of a frame attached to the skull, the patient wears an immobilizing plastic mask or bite block in the mouth to achieve fixation; relatively time-consuming treatment planning; and the need for beam-modifying devices that must be customized for each patient, thereby increasing the time and cost of treatments. The use of these charged particles has developed rapidly in recent decades. Currently there are 20 hadron-therapy facilities worldwide (half of them in Europe).

Linear Accelerator

Linear accelerator–based radiosurgery uses x-ray beams that are produced by the collision of accelerated electrons with a metal target (see Fig. 104-4). Multiple noncoplanar arcs converge at a single isocenter, where a nearly sphere-shaped dose distribution is created. These arcs are produced by gantry rotation during irradiation, and each is defined by a different couch angle. By adjusting the number, length, angles, and weights of individual arcs, irradiation of adjacent crucial structures can be reduced. Most LINAC radiosurgery units (e.g., Synergy and Axesse by Elekta, Stockholm; Trilogy by Varian, Palo Alto, CA; Novalis by Brain Lab, Feldkirchen, Germany) use tertiary circular collimators that further decrease beam divergence, thereby protecting normal tissues. For higher conformality while departing from a spherical shape, multiple isocenters are possible, at the cost of greater inhomogeneity and much longer treatment times. This technique has proved to be an effective, alternative radiosurgical option, particularly in cases of larger target volumes, or whenever fractionated radiosurgical procedures are required.^2,12,121 Comparative analyses of the literature concerning LINAC versus GK results in meningiomas, however, still show on one side similar tumor control indexes, and on the other, much higher complication rates with LINAC, with comparable or shorter follow-up periods (Table 104-3).^{9,29,42,58,63,122–159}

With the increasing use of SRS, the growing interest for highly sophisticated photon linear accelerators has led to micro-multileaf (MML) technology, potentially more competitive with GK and proton beam devices, and characterized by an easy patient setup and greater possibilities of reaching any irradiation position. Basic parameters that allow complex field shaping with the LINAC include the patient couch angle, gantry arc angle, isocenter position, and collimator size. Additional factors include beam weighting and the tissue depth through which various arc segments are delivered. Manipulation of these simple elements provides significant flexibility in the conformal three-dimensional dose distribution for a single isocenter. By using multiple isocenters, it is also possible to maximize the buffer exposure of the target, and of the adjacent critical structures.

CyberKnife

This extremely refined instrument was conceived in the mid-1980s and manufactured within a decade. In its 15-year history, the CyberKnife (Accuray, Sunnyvale, CA), has clearly shown basic pros and cons of the technique.^{121,155,160–163} Regarding the former, the main advantages include (1) easier fractionation, that is, increased protection of sensory cranial nerves,¹⁶² and so on; (2) no need of general anesthesia even in young patients; and (3) flexibility to treat lesions throughout the body. Regarding the latter, the absence of a stereotactic frame, as well as the mobility of the radiation source should somehow entail a slightly superior error margin if compared to the gamma knife. It is well known that CyberKnife operative programs are essentially based on CT scan imaging recognition. For certain targets, this might involve less sophisticated imaging.

The CyberKnife (see Fig. 104-4) combines a lightweight 6-MeV LINAC designed for radiosurgery and mounted onto a highly maneuverable robotic arm that can position and point the LINAC. Internally controlled real-time image guidance eliminates the need of skeletal fixation for either positioning or rigid immobilization of the target. This system acquires radiographs of skeletal features associated with the treatment site, uses image registration techniques to determine the target’s coordinates with respect to the LINAC and to the manipulator, which finally directs the beam to the planned point. Whenever the patient moves, internal controls detect the change, stop radiation, correct the trajectory of the beam, and start irradiating again nearly in the real time. Complex radiosurgical treatments may be performed, in which beams originate at arbitrary points in the workspace to target arbitrary points within the lesion. Even nonisocentric beams can be focused anywhere within a volume around the center. Total treatment time depends on the complexity of the plan and delivery paths but it is comparable to standard LINAC treatments.

Tomotherapy

Helical tomotherapy unit is a new modality for radiation treatments, the first dedicated to intensity-modulated irradiation using a fully integrated image-guided radiotherapy machine with on-board megavoltage CT capability. The tomotherapy system (see Fig. 104-4) uses a 6-megavoltage accelerator, and a 64-leaf binary multileaf collimator and xenon image detector array mounted on a rotating gantry. Radiation is delivered in a helical way, obtained by concurrent gantry rotation and couch/patient movements. Altogether, these components allow continuous, intensity-modulated rotational irradiation with fan beam entry from 360 degrees. A megavoltage CT scan before the treatment (nominal energy of 3.5 megavoltages) can be fused with a planning CT scan to determine the correct patient setup every time that the radiotherapist needs to check it. Finally, ultimate dose calculation is refined by means of convolution/superimposition. Tomotherapy has been used for the treatment of benign brain tumors (meningiomas and neurinomas), resulting in good target coverage with high-dose homogeneity and respecting organs-at-risk constraints.¹⁶⁴ In addition, this technique allows treatment of larger brain lesions than GKS. Once again the most important difference seems to be that the latter still maintains a better conformity index, and non-negligible advantages in terms of the integral dose to the brain.

Gamma Knife

Depending on the model, the gamma knife (GK) (Elekta, Sweden) contains an array of 201 (Model B or C) or 192 (Perfexion) (see Fig. 104-4) individual ⁶⁰Co sources aligned with a collimation system that directs each of the radiation beams to a very precise focal point. As a consequence, even very small targets can be treated by a high radiation dosage, whereas peripheral dose levels remain low. GK treatments are therefore quite heterogeneous in terms of dose distribution inside and outside of the target; tumor control and tissue sparing is achieved via the steep dose gradient at the periphery rather than exploiting the radiobiological differential between normal and pathologic tissue as in fractionated radiotherapy. At installation, GK units have an initial dose rate of approximately 4 Gy/min. Given that the ⁶⁰Co half-life of 5.28 years, the primary sources must be replaced every 6 to 7 years. Due to the low energy of the isotope sources, most treatments are referred to a normalization of 50%. With the multiple isocenters routinely used, GK plans tend to be more conformal but less homogeneous than LINAC-based plans. Due to the typically steep dose gradients of radiosurgery, an accurate alignment of the plan’s isocenter with the physical isocenter of the machine is a quite challenging issue.¹² Details of the structure and operation of the central body and collimation system are among the biggest differences between the Perfexion Gamma Knife (GKPx) and earlier B and C models. While the external hemispheric helmet in the B and C models is fundamental in providing the final beam collimation, in the Perfexion model the central body and collimation system are somewhat more complex because the ⁶⁰Co sources are mobile and the conical collimator body is entirely internal to the unit, so that there are no external helmets (Fig. 104-5). Moreover the surgeon can modify the shooting collimator size using the sector drive motors that move the sources along their bushing to the correct position; the localization of each sector is monitored by linear and rotational encoders characterized by a positioning repeatability of less than 0.01 mm.^165,166 Critical structures such as optic pathways and cranial nerves may be shielded through the application of beam blocking patterns that minimize the contribution of possibly dangerous shots.

FIGURE 104-5 Schematic drawing of the original gamma knife “model C” helmet (A) and the new Perfexion helmet (B). The latter evidently covers a much wider volume allowing easier treatment of skull base lesions, reaching C1–C2 level.

Dose Planning

The goal of dose planning is to create an extremely conformal and selective isodose configuration, with complete covering of the tumor, and minimal exposure of the surrounding tissues (Fig. 104-6). Using a combination of multiple isocenters of different sizes, differential weighting of the crucial shots, selective blocking of the collimated beams and—typical of the Perfexion Gamma Knife—using hybrid shots,¹⁶⁵ it is possible to produce dose plans that closely conform not only to the main shape of the meningioma, but also to all the MRI-documented dural attachments (Fig. 104-7), while sparing the neighboring neural structures. Probabilistic models, quadrature-sum analysis, and phantom studies have repeatedly confirmed the reliability of such operative models.^107,108,166 These newer approaches in treatment planning have consistently improved Paddick’s conformity index,¹⁶⁷ meanwhile reducing treatment times for both GKR and GKPx^88,165,169 and for MML LINAC.^88,168 To date, the recommended surface (SD), edge (ED), or peripheral (PD) doses for meningiomas range from 11 to 15 Gy at the 50% isodose; the higher levels are currently reserved for more aggressive histotypes.^2,3 The “ideal”—that is, the most biologically justified—planning target volume, is still a matter of debate, with a spectrum of options, ranging from including the gross, T1 contrast–enhancing image plus a supposedly infiltrated margin of a few millimeters,^{3,32,41,98,103,170} to the controversial inclusion of the “dural tail” that—according to studies of extremely refined doses—should be essentially composed of hypervascular dura with none of the expected tumor colonies.^3,92,171,172 Another deceptive variable in the definition of the target volume is represented by hyperostosis,^3,173,174 particularly after the studies of Pieper et al.¹⁷⁴ showing that (in a series of 26 consecutively operated patients) hyperostotic bone was almost constantly (25/26) present, even without any imaging evidence. In these cases, ablative radiosurgery on the hyperostotic bone might have the same meaning of Simpson’s grade 1 in surgical approaches. As mentioned previously, the novel and impressive advances in radiosurgical treatment strategies, particularly coregistration and fusion algorithms–dose-planning software, and automatic positioning systems are helping to overcome some of the major SRS, and specifically GKR, constraints. We can reasonably target unusually larger volumes, even in crucial sites, by using lower dosages or adopting “staged” SRS procedures, via means of dose and/or volume fractionation.^111,112

FIGURE 104-6 Gamma knife radiosurgery treatment of a left cavernous sinus meningioma. Note the highly conformal shape of the therapeutic isodose.

FIGURE 104-7 A multiple-isocenter conformal gamma plan for a Sylvian meningioma (red line) with dural attachment, the so-called “dural tail”; and bone reaction in the adjacent skull. The yellow line corresponds to the 55% isodose line and the green line indicates the 50% isodose curve.

Published results are interesting, and there is no evidence of increased adverse radiation effects (AREs).^111,112,152 In fact, the well-known relationship between the dose–volume integral and the risk of adverse radiation effects does not seem to apply at lower-dose regimens.^{135,152,175,176} Nonetheless, in meningioma treatments, relevant limits, pitfalls, and risks remain to be tackled. An instructive example is represented by dosimetry planning for cavernous sinus meningiomas (Fig. 104-8). The dose heterogeneity of these treatments usually requires an extremely careful evaluation of dose-distribution algorithms,^177–179 because of the occasional reported cases of radio-induced vascular injury to the carotid arteries,^177–179 the still observed morbidity of this technique on sensory nerves,¹⁵¹ and the sometimes disappointing results in atypical and anaplastic lesions.^2,151 Finally, a controversial issue in treatment planning pertains to the so-called “radiation-induced meningiomas.^180–182 These tumors usually appear at a variable interval from radiation exposure, depending on the dose and timing. They are non-infrequently deep seated, multifocal in 4.6% to 18.7% of the cases.^180,181 Surgical resection is considered to be the best therapeutic option. However, when dealing with frail patients or with particularly crucial locations, radical surgery may be too risky, opening the question on the SRS alternative. The published literature is rather scanty.^180,182 Eligibility criteria (limited volume, well-defined imaging, etc.) adopted in these cases do not differ from standard protocols. Clinical-radiologic results—particularly the LTC (75% to 78%) and the 5-year PFS (similar)—are satisfactory, and only slightly inferior to the published data regarding regular meningiomas. Morbidity remains low (5%) with no reported cases of newer carcinogenesis.^180–182

FIGURE 104-8 Gamma knife radiosurgery treatment of a left cavernous sinus meningioma. Paddick’s conformity index is extremely rewarding, although at the price of a pronounced in homogeneity, with a too large, potentially dangerous hot spot (75%) covering the carotid artery and not far from the left optic nerve-hemichiasm. The dose plan needs modification. The yellow line corresponds to the 50% isodose line and the blue line indicates the 20% isodose curve.