Current Surgical Management of High-Grade Gliomas

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Chapter 8 Current Surgical Management of High-Grade Gliomas

The malignant glioma has been the neurosurgeon’s eternal hydra, continually growing despite treatment. The category “high-grade glioma” (HGG) is heterogeneous, including mainly anaplastic astrocytoma (AA), glioblastoma multiforme (GBM), gliosarcoma, and anaplastic oligodendroglioma (AO). The incidence of new primary brain tumors in the United States is estimated to be 18 per 100,000, resulting in approximately 40,000 new primary brain tumors per year, 22,000 of which are high grade.¹ A total of 12,920 deaths in 2008 were attributed to primary malignant brain tumors.² Despite continually renewed efforts at treating HGGs, the odds of significant long-term survival have remained poor and stable for the past three decades with 2% to 4% of patients with GBM surviving to the 5-year point.³

Preoperative Workup

Magnetic resonance imaging (MRI) with and without gadolinium is essential for preliminary differential diagnosis, decision for surgery, and operative planning. Thallium SPECT scan, PET scan, or MR spectroscopy may help in determination of high grade versus low grade tumor, although none of these studies is definitive, and differentiation between HGGs and metastases is difficult.⁴ These studies are more helpful in cases with previous surgery and radiation in determining recurrent tumor vs. radiation effect, especially MR spectroscopy and MR perfusion. For selected patients who cannot undergo MRI (e.g., patients with a cardiac pacemaker), CT with and without contrast provides similar, albeit less detailed information. CT perfusion may be an aid in better defining the tumor from cerebral edema as well as help with the potential for post-treatment radiation effects.

A Wada (intracarotid amobarbital) test is the definitive, albeit invasive, method to establish cerebral hemispheric dominance for language and memory. It is required for procedures in patients with a seizure disorder with tumor in whom a formal temporal lobectomy is planned. A Wada may be useful in selected other patients, such as patients with a dominant hemisphere temporal lobe tumor in whom tumor resection without temporal lobectomy is planned. Although both functional MRI and a Wada test offer similar information about cerebral dominance,^5,⁶ a Wada test does not offer anatomic localization of critical areas for language as MRI does nor truly investigates the potential bilaterality of language.^7,⁸ Functional MRI is more useful than a Wada test for lesions of the dominant hemisphere near the motor cortex, frontal lobe pars triangularis and opercularis (Broca’s area), or Wernicke’s area. With changes in metabolic activity and blood flow demand, an active area of the brain during a silent speech or motor task becomes infused with more oxygenated blood; this change can be detected since oxygenated blood carries a different paramagnetic signal than deoxygenated (blood oxygen level–dependent or BOLD signal) (Fig. 8-1).^9,¹⁰ One limitation of functional MRI is that it becomes less useful in patients with a recurrent tumor because of altered vascular patterns and MR artifacts from the previous surgery. Some patients require both a Wada and a functional MRI as part of preoperative planning.

FIGURE 8-1 Functional MRI during a silent speech task in a patient with a glioblastoma of the left temporal glioblastoma (left and right are reversed).

Cytoreduction

Although decompression of mass effect is a surgical goal and influences symptomatic survival, controversy exists over whether the extent of resection influences survival or time to progression for HGGs. Dandy originally proposed hemispherectomy for selected patients with malignant tumors, but there was no significant effect on mortality.¹¹ Next, there were data suggesting that for GBMs, biopsy and resection were equivalent in terms of survival, and that it was really postoperative radiation that had a meaningful effect on survival. More recently, the Glioma Outcomes Project reported a statistically significant extension of survival for patients with HGGs who undergo resection over biopsy (median survival 51.6 weeks vs. 27.1 weeks, respectively).¹² This study was limited by lack of central pathologic review, lack of quantification of amount of resection, sampling error from a biopsy, and selection bias in biopsy vs. resection. Other surgeons have also reported extension of survival for patients with 90% or better resection; resection better than 98% was associated with a median survival of 13 months versus 8.8 months with less than 98% in one study.¹³ In a recent series focused on the GBM population for patients given aggressive (but not always gross total) resection, Gliadel chemotherapy wafers, radiation, and Temodar, median survival was 20.7 months, and the 2-year survival rate was 36%.¹⁴ Additionally, subtotal resection, the volume of residual tumor at the time of first recurrence, may negatively influence response to chemotherapy in terms of time to progression and overall survival.¹⁵ Thus, it is not clear that only a biopsy should be performed if a surgeon is facing a tumor that cannot totally be resected. However, even gross total resection does not truly address the diffuse nature of malignant gliomas.

Intraoperative Imaging

Even with continual improvements with operating microscopes, some form of intraoperative imaging or navigation is useful. A high-quality intraoperative ultrasound assists in many types of surgeries, but cannot aid in incision and craniotomy planning. Also, many tumors, especially lower-grade tumors, may not be dense enough compared to the normal brain to be visualized adequately by this method. Ultrasound is more helpful when the density difference is greater, such as if there is a hematoma to evacuate in addition to the tumor, if there is a cystic component, or if there is a need for ventricular access.

Frameless stereotactic navigation is very helpful in a craniotomy for tumor resection—some would say essential. This technology incorporates a preoperatively obtained MRI with fiducial markers that are left in place on the scalp. In the operating room, these markers or contours of the face can be registered in reference to a frame that is visualized by a computer via an optical apparatus, electromagnetic waves, or mechanical arms. This technology allows the surgeon to visualize points on the scalp and skull and compare them to the MRI, aiding in planning of a small, localized incision and craniotomy as well as ensuring that the exposure of the lesion is adequate. Surgical navigation can be performed intracranially with a localizing probe or with image fusion into the operating microscope based on focus depth. Because frameless navigation is based on a preoperative set of images without updating in the operating room, the surgeon needs to account for brain shift during the procedure. Brain shift up to 2 cm can occur, and is more common with increased patient age, cortical rather than subcortical structures, larger tumor volume, and lesions far from some point of tethering such as the skull base or falx.¹⁶ Once brain shift is taken into account, resection to the imaging abnormality borders (when safe) assists in the goal of cytoreduction.

Intraoperative MRI systems are available as well. Low-field (<0.5-T) systems allow most normal operating room equipment to be used throughout the case except right at the point of imaging.^17,¹⁸ Because the imaging can be updated, the surgeon does not need to account for brain shift. For craniotomies, once resection is deemed complete by the surgeon, an MRI can be performed to assess whether there is occult residual tumor, aiding in the aim of cytoreduction. These systems offer a smaller field of view, less detailed images, longer acquisition time, and fewer types of imaging options than conventional diagnostic MRIs.

High-field (1.5-T) systems exist, which offer all the imaging capabilities of a standard, diagnostic MRI.¹⁹ A biopsy needle can be watched in near–real time as it is passed to target and verified at the target before samples are taken. With craniotomies, intraoperative imaging can confirm completeness of tumor resection, which is especially helpful in cases of low-grade gliomas when the distinction between tumor and normal brain is less apparent. At closure, an MRI can be performed to exclude hemorrhage; for patients with a biopsy or simple craniotomy, excluding the hemorrhage may allow a patient to be transferred to a step-down unit instead of the ICU. These systems, however, require construction of an operating room suite specifically designed for an intraoperative MRI to provide adequate shielding and safety measures. The high-field strength requires a larger magnet than the low-field systems, limiting access to the patient. Normal operating room equipment can be used outside the 5-gauss line (several feet from the center of the bore of the magnet); inside that line, only MRI-compatible (titanium or surgical-grade stainless steel) instruments can be used.

Motor Strip Mapping

Surgery in the parietal lobe or the posterior frontal lobe may require motor strip mapping. Short-acting muscle relaxants are used during induction, and anesthetics are lightened for the mapping, but the patient does not need to emerge from anesthesia fully. Rather than identification of the motor cortex itself, this technique relies on identification of the sensory cortex by looking for somatosensory-evoked potentials (SSEPs). A 1 × 8 or other sized subdural electrode is used. By noting the electrodes with a positive (precentral) as opposed to a negative (postcentral) amplitude and noting the two electrodes between which there is phase reversal, the primary motor cortex can be identified and protected. This technique has good correlation to magnetoencephalography when integrated into the surgical navigation system.²⁰

Awake Craniotomy

Awake craniotomy with cortical mapping affords the ultimate protection for surgery in or near language areas. In one option, patients are never intubated—they are merely sedated with an agent like Propofol, which takes effect quickly and wears off quickly; proponents of this pattern espouse that patients’ airways are less irritated and that language testing is better quality. The other way to accomplish the anesthesia is for patients to be nasotracheally intubated so that the endotracheal tube can later be withdrawn out of the vocal cords and language tasks can be performed. In addition to a local anesthetic to the incision, a field block to the scalp in the area of the incision as well as the Mayfield pins is performed with a long-acting anesthetic such as bupivicaine. Muscle relaxants may be used at induction, but they must be short-acting. Draping is per routine except that the face needs to have an unobstructed view so visual naming and interaction with the neuropsychologist are possible, so one must be careful that the head frame and subsequent retractor bars do not obscure vision. Once the craniotomy is created, anesthetics are lightened, the endotracheal tube is withdrawn from the vocal cords, and a handheld bipolar stimulator is used to stimulate areas likely to have language function or areas of planned resection to determine the effect. Continuous language testing can be performed during resection to reconfirm safety. Once resection is complete, the endotracheal tube is replaced and general anesthesia is reinstated for closure.

Frontal Lobe

High-grade gliomas are most common in the frontal lobe, as it occupies one third of the surface of the brain and is the largest lobe.²¹ The frontal lobe tolerates unilateral surgical resection very well as long as the motor cortex and Broca’s area are respected. Frontal lobe tumors are often amenable to image-complete resection. For tumors with significant growth into the corpus callosum and across the midline, surgical resection is unlikely to provide significant cytoreduction, and therefore a biopsy may be the more prudent choice.

Motor Cortex

For lesions in the posterior frontal lobe, operative anatomy and imaging are not always sufficient to make adequate surgical plans. Functional MRI can reliably identify the motor strip, but even with modern neuronavigation systems, surgical resection is safer with some type of functional evaluation. Two current ways to identify motor cortex include intraoperative cortical stimulation mapping (discussed above) and placement of a subdural grid for mapping out of the operating room.

Proponents of subdural grid placement argue that electrocorticography out of the operating room and without sedation is superior. Time is not limited, and residual effects of anesthetics and narcotics can be minimized. Operating-room time at resection is minimized, but the patient requires two surgeries. The additional risks of the second surgery for grid removal and surgical resection are minimal. However, some surgeons prefer intraoperative testing to subdural grid placement. Intraoperative mapping may gain an extra margin of safety from continuous testing during surgical resection.

Broca’s Area

Approximately 95% of right-handed, 85% of ambidextrous, and 75% of left-handed persons will have left-sided cerebral dominance for language.²² Broca’s area encompasses the middle and posterior parts of the inferior frontal gyrus, that is, the pars opercularis and the pars triangularis. Protection of language area via awake craniotomy and intraoperative corticography or subdural electrode placement for cortical mapping is essential for tumors adjacent to Broca’s area (Fig. 8-2).

FIGURE 8-2 Preoperative (A) and postoperative (B) brain MRI in a patient with seizures, revealing a heterogeneous lesion of mixed signal on FLAIR that was nonenhancing (not shown). Surgery with awake craniotomy was performed; an image-complete resection was achieved. Pathology revealed an anaplastic oligodendroglioma, and the patient was referred for chemotherapy.

Premotor Area

Deficits from surgical resection in the premotor area generally recover over a period of weeks to months through reorganization. Premotor weakness generally shows a better response to stimulation than to voluntary initiation.

Supplementary Motor Area

The supplementary motor area (SMA) occupies the posterior one third of the superior frontal gyrus and is responsible for planning of complex movements of contralateral extremities but ipsilateral planning to a small effect.²³ The full “SMA syndrome” involves speech arrest, contralateral weakness, and near-total recovery in weeks to months. For tumors involving the SMA, functional MRI shows ipsilateral decreased SMA activity compensated by increased contralateral activity.²⁴ After resection in the SMA, the motor deficit is further compensated by recruitment of activity in the contralateral SMA and premotor cortex. Typically, leg weakness improves followed by the arm and then speech. There are patients who have reported even 6 months of significant speech trouble before returning to almost normal speech.

Temporal Lobe

Anterior temporal lobe lesions are amenable to surgical resection. Decompression of mass effect in this area is especially important due to proximity to the brainstem. Resection is generally safe back to 4 cm back from the temporal tip on the dominant hemisphere and 6 cm back on the nondominant side. Removal of temporal lobe back to 6 cm is often associated with at least a rim of visual defect in the contralateral superior quadrant, but this deficit is generally well tolerated. On the dominant side, resection at or behind 4 cm back from the tip of the middle cranial fossa requires either intraoperative electrocorticography or subdural grid placement for identification of Wernicke’s area (Fig. 8-3). When a lesion involves the hippocampus, it is most likely that the contralateral hippocampus is compensating for function, but for the dominant hemisphere, this is best proven with a Wada test before surgery.

FIGURE 8-3 A 40-year-old, right-handed man presented with seizures. Preoperative brain MRI (A) was remarkable for a nonenhancing left temporal lesion. Functional imaging revealed language posterior to the lesion (not shown). Craniotomy for gross total resection was performed. Postoperative imaging (B) showed resection of the lesion with residual FLAIR abnormality posteriorly. Pathology showed mixed oligoastrocytoma.

Parietal Lobe

Complete lesions of the dominant parietal lobe can be characterized by Gerstmann’s syndrome, which consists of left/right confusion, digit agnosia, acalculia, and agraphia.²⁵ Even with a large parietal lobe neoplasm, the deficit is usually incomplete. Lesions of the dominant superior parietal lobule alone rarely cause the full syndrome; the angular gyrus has to be involved.²⁶ Low-grade gliomas are more likely than HGGs to have infiltrated into still functioning cortical areas; HGGs tend more to displace and destroy function. Restoration of a preoperative dominant parietal deficit is unlikely unless there is a cystic component, a hematoma to evacuate, or significant mass effect from edema that resolves with surgery and radiation (Fig. 8-4). Surgery within the nondominant parietal lobe is generally tolerated well as long as there is not a large parietal stroke that can lead to significant neglect of the contralateral side. Motor strip mapping adds an extra layer of safety as described above.

FIGURE 8-4 A 60-year-old, right-handed woman presented with increasing word-finding difficulty and right-sided hemiparesis. A brain MRI (A) revealed an enhancing left parietal mass with edema. At awake craniotomy, there was no involvement of the language area by tumor, and an image-complete resection was achieved (B). Pathology demonstrated glioblastoma, and the patient underwent radiation therapy and chemotherapy. Her speech improved after surgery, possibly because of resolution of mass effect and little direct involvement of the speech area by tumor.

Occipital Lobe

Occipital lobe surgery almost invariably results in some form of visual field cut, although most high-grade tumors that present in this location have already caused a visual defect. It is very difficult to improve visual symptoms with resection in this area. Some tumors that present more laterally may leave less visual field disturbance but may cause occipital association symptoms such as visual auras, color agnosia, or episodic blindness. Some researchers have described the use of visual-evoked potentials during occipital tumor resections, but the potentials are generally thought to be unreliable.

Prognosis

Outcome from diagnosis for an HGG depends on several factors. Precise pathologic diagnosis contributes a significant impact, as approximately 30% of patients with GBM survive to the 1-year point versus 60% of patients with anaplastic astrocytoma.²⁷ However, glioblastoma and the rare gliosarcoma do not differ significantly in behavior, response to therapy, or cytogenetics.²⁸ According to recently published data from the Glioma Outcomes Project, resection instead of biopsy, age less than or equal to 60, and Karnofsky Performance Scale of 70 or greater were all significantly correlated with outcome.¹²

New Directions

Certainly, surgery alone for HGGs will not provide a cure or have the largest long-term effect for patients with an HGG. Surgeons also have impact on radiation and chemotherapy delivery to the brain. Besides local chemotherapy with BCNU-impregnated wafers,²⁹ other avenues proposed to effect change in the local tumor environment include convection-enhanced delivery (CED) of chemotherapy or targeted toxins.³⁰ An option for increasing the local dose of radiation is an implantable balloon system for radioactive iodine,³¹ but it is unclear if this method of radiation delivery is clearly better than focused conventional radiation to the area. To date, there have been no convincing data that have driven an intracavity therapy to be widely accepted. Overall, these local delivery approaches to HGGs raise interesting questions but also battle with the notion over whether malignant glioma is a focal or diffuse disease.

An approach that attacks the diffuse nature of gliomas is immunotherapy. One option involves creation of a subcutaneous vaccine specific to the patient’s resected tumor using tumor lysate–pulsed dendritic cells.^32,³³ Vaccinated patients demonstrate an antigen-specific T-cell response and survival benefit as well as increased responsiveness to chemotherapy.³⁴ Other potential strategies include interleukin gene introduction via viral vectors,³⁵ vaccination with dendritic–glioma cell fusions using interleukin-12,³⁶ or scores of other targets to immunotherapy. What additional therapies will be useful over the next 10 years are unpredictable.