Meningiomas - Brain Workshop Discussion
Best Current Treatment
Meningiomas are generally well-managed with surgical resection or stereotactic radiosurgery. Skull base meningiomas, especially those with intimate associations with cranial nerves, continue to vex neurosurgeons dealing with them. Microneurosurgery and stereotactic radiosurgery, often combined, have allowed for improved management of challenging skull base meningiomas adjacent to cranial nerves in the last few decades, but there remains a cadre of very difficult cases.
Stereotactic radiotherapy (SRT) offers a gold standard in the treatment of meningiomas that are intimately involved with cranial nerves. SRT differs from SRS in that it utilizes the biological advantage of fractionation, or giving radiation in discrete doses separated by intervals that allow differential recovery of normal tissue more so than target tissue. One caveat of SRT is that, in general, it cannot be readily repeated because any normal tissue one is trying to protect within the target volume neighboring the lesion has been taken to a near-maximum dose during the course of the initial treatment. MRgFUS may have some advantage in that it can be repeated as often as is necessary or practical. There is no cumulative build up of thermal dose, as there is with ionizing radiation. Based on these properties, this modality may have significant potential benefit to this patient population, particularly to those who recur after standard treatment. However, thermal lesioning will not allow any preferential protection of normal tissue within the target zone. More elegant application of non-thermal FUS techniques may be required to safely treat lesions intimately associated with critical neural structures at a microscopic level (eg. nanoparticle drug release, modulation of inflammatory or apoptotic pathways, control of heat-shock proteins or immune response, etc.). Investigation into these effects is still very preliminary.
Thermal ablation with MRgFUS may also prove useful in eradicating or controlling growth of convexity meningiomas, as well as falcine and intraventricular lesions. It resembles stereotactic radiosurgery (SRS) in being noninvasive and exceptionally effective within a defined “kill zone” that has a very sharp gradient at the edge, allowing for the protection of adjacent normal structures. It has advantages over SRS in that it does not involve ionizing radiation, there is no cumulative dose and therefore it is repeatable without limitation. It also allows for real time visualization of energy location, and real time monitoring of energy delivery, through MR thermometry.
Certain features common to meningiomas have a significant influence on FUS treatment, especially the degree of vascularity, proximity to bone, and involvement with cranial nerves (in the case of skull base lesions) and blood vessels (internal carotid, cavernous sinus). In addition to the heat sink effect of vascularity within a tumor, initial studies will need to assess thermal effects on cerebral arteries and veins along the surface of the tumor, and take care to avoid the possibility of venous thrombosis and subsequent infarction. Bone heating adjacent to the sagittal sinus and other sinuses or large cortical veins will also require careful temperature monitoring so as to avoid the risks of sinus or cortical vein thrombosis with resultant venous infarction. Bone heating is also an important consideration in the skull base tumors, as well as in convexity lesions. However, the cranium has a very effective cooling mechanism which prevents the heating of the brain from heat sources outside the skull (like being in the sun). This mechanism assures the constant temperature of the brain despite the higher tissue temperature outside the skull. This mechanism does not exist at the skull base.
There is another big difference between convexity and skull base meningiomas when they are treated with FUS. In order to be able to focus on convexity meningiomas lower frequency is required while skull base tumor treatment is possible with higher frequency phased array transducers. In both cases the hemispheric phased array is necessary.
Animal studies in a porcine model have shown no histological damage of the optic nerve or chiasm after 52 deg C thermal exposure with FUS. The sonication target volume is surrounded by a 2-3 mm zone of steep temperature gradient, outside of which there is no significant temperature elevation. In these experiments, however, no functional ing was performed.
Studies in peripheral nerves suggest that increased myelin offers protection against thermal lesioning. Nerves with a significant proportion of unmyelinated c-fibers are at higher risk for damage from heating. FUS animal studies indicate that thermal tissue ablation can be accomplished safely within 2-3 mm of neural tissue. Tolerance of neurovascular bundles adjacent to the prostate has been investigated in a canine model of prostate ablation with MRgFUS. Despite these findings the issue of the nerves thermal sensitivity is not well known. Specifically there is not enough information about the thermal sensitivity and temperature tolerance of the optic nerve. Because the size of the nerve is also a significant factor, animal models may not sufficient to resolve this issue.
Meningiomas occur naturally in dogs and cats, which might offer a convenient animal model if necessary. Matching the design of the technology to the animal in a way that would give meaningful results that are applicable in humans is quite difficult, however. This is due to the size and shape of the human skull, which is much larger than that of the experimental animals. One might perform limited experiments to directly assess the thermal effect of FUS on bone and overlying scalp, meningioma, arteries, veins and venous sinuses. In general, the animal would require a craniotomy for treatment, although a piece of human calvarium might be placed in the beam path to simulate the process of treating a patient transcranially with an FUS brain unit.
Treatment of the prostate with FUS in a dog model also leads to edema within the target region. Thermal lesioning with laser also is often associated with edema, which can be partially mitigated with pre-treatment with dexamethasone.
The Exablate 4000 (Insightec, Inc., Haifa, Israel) has been evaluated in rabbit and dog models at the Brigham & Women's Hospital, which models will also be assessed in Toronto. The common model uses closed skull with a 2 cm distance from overlying bone to target. Future work will assess the cavitation threshold at varying frequencies.
Issues related to Pilot Studies
Meningiomas are quite similar to uterine fibroids in having different fundamental tissue types that may require different FUS energies to achieve the same temperature. The determinant of tissue ablation is the peak temperature and the time it is maintained. The amount of energy required to achieve that temperature can vary with different types of tumor, depending on the vascularity and other characteristics, even within meningiomas as a group. In general, a longer sonication is required to achieve the ablative temperature in certain tissue types.
Meningiomas may have responses to treatment similar to those seen in breast fibroadenomas. FUS in those lesions causes tumoral edema for 24-48 hours. Initially the tumor hardens, but it later softens.
Initial FUS protocols for brain cases stipulate that at least 2 cm distance be maintained between the target and the inner table of the skull, in order to minimize the amount of bone heating that might occur. In the case of convexity meningiomas, this bone heating can even be used to advantage in helping to create a thermal lesion within the tumor. Care must still be taken to avoid excessive bone heating, and any damage to the overlying skin. The scalp is very well equipped for cooling given its exquisite blood flow. In addition, the ExAblate brain unit has a very efficient liquid cooling system for the scalp.
Protocol option 1: FUS treatment prior to surgery
One option for a treatment protocol mimics a study requested by the FDA in the evaluation of MRgFUS for the treatment of uterine fibroids. MRgFUS treatment would be performed on the central core of the meningioma (subdosal, ie. full ablative dose but to only a fraction of the tumor volume). As above, patients would stop anticoagulants for two days before MRgFUS, until there is no evidence of increased risk of hemorrhage. The entire meningioma would then be removed via a standard craniotomy. This type of study could be used to assess the safety of the technique and gain significant information about the histopathology of MRgFUS in this particular tumor type.
Protocol option 2: FUS treatment in patients unsuitable for surgery
Another suggested protocol would recruit patients who are not candidates for surgical resection (due to age, concomitant illness, coagulopathy, etc). This study might include patients who have failed stereotactic radiosurgery, or as an alternative to radiosurgery in patients who cannot undergo surgery. Malignant meningiomas, well known for failing radiation, would not be good candidates for these initial feasibility and safety studies. In addition, prior radiation would be a contraindication to meaningful histopathological assessment. Since meningiomas can be quite stable in size over an extended time, tumor growth or progressive symptoms must be shown prior to a decision to treat the patient.
Tumor growth or progressive symptoms must be shown prior to a decision to treat the patient. Meningiomas can be quite stable over time, without obvious growth.
Given the relative success of surgery and/or radiation (either stereotactic radiosurgery [SRS] or stereotactic radiotherapy [SRT]) in managing benign meningiomas, it is important to define clear endpoints in a well-defined cohort. It may be that the phase 1 route followed for uterine fibroids and breast fibroadenomas may well apply to meningiomas: treat with FUS to establish safety, then surgically remove the tumor. A parallel study could be performed in patients who are not surgical candidates.
Currently, the following institutions are interested in pursuing the phase 1 safety study: the Brigham & Women's Hospital in Boston, the University of Virginia, and the University of Toronto.