Treatment of meningiomas 1.10
INTRODUCTION — Meningiomas are among the most frequent primary brain tumors.
Although most meningiomas are benign, their location in the central nervous system can cause serious morbidity or mortality. The approach to patients with meningioma and the prognosis following treatment depend upon the anatomic location of the lesion and tumor pathology.
OVERVIEW OF MANAGEMENT — The management of patients with meningioma requires a balance between definitive treatment of the tumor and avoidance of neurologic damage from the treatment. Patient-related factors (eg, presence or absence of symptoms, age, comorbidity), the location of the meningioma in relation to critical brain structures and regions, and the degree of atypia or malignancy of the tumor all are important factors in determining the optimal treatment.
With the widespread availability of magnetic resonance imaging (MRI) and computed tomography (CT), meningiomas are frequently being diagnosed while relatively small or as an incidental diagnosis with no associated symptoms. The natural history of such lesions may be very prolonged, and some tumors do not exhibit evidence of growth. Thus, active surveillance, with deferred treatment, may be an appropriate option.
For patients in whom active intervention is indicated, complete surgical resection is preferred when a meningioma is in an accessible location, since complete resection of the tumor and its dural attachment can be curative. Multiple advances in neurosurgery, including microsurgery, improved preoperative imaging, and intraoperative image-guided approaches, have extended the neurosurgeon's ability to resect lesions that were previously considered only partially resectable or unresectable, while minimizing damage to normal brain.
Subtotal resection can be combined with radiation therapy (RT) for less accessible lesions and for atypical and malignant meningiomas where the risk of recurrence is much higher. RT is used alone as the primary treatment for inaccessible lesions, when the risks of neurologic damage from surgery are too high. Newer conformal RT techniques, including stereotactic radiosurgery (SRS), fractionated stereotactic radiotherapy (SRT), intensity-modulated radiation therapy (IMRT), and proton radiotherapy, are important for the delivery of radiation to meningiomas that are in close proximity to critical structures such as the optic nerve, while minimizing radiation to normal brain structures.
ACTIVE SURVEILLANCE — Many meningiomas are discovered on a neuroimaging study (MRI, CT) obtained for minimal symptoms that or may not be related to the tumor. Such tumors may remain unchanged in size or grow only very slowly over prolonged periods. As a result, most patients with small asymptomatic meningiomas can be observed and resected or irradiated only if the tumors enlarge significantly or become symptomatic
The role of active surveillance was illustrated by a retrospective Japanese study of 1434 patients with meningioma, who were diagnosed between 1989 and 2003. In this series, 603 patients (42 percent) were asymptomatic and 351 of these were managed with observation. Of the 171 patients followed for more than one year, 31 were subsequently treated with either surgery or stereotactic radiosurgery (SRS), in most cases due to tumor growth. Among the 67 asymptomatic patients with follow-up of more than five years, 63 percent did not have evidence of tumor growth. Among the 213 asymptomatic patients treated surgically, morbidity occurred in 4 percent of those less than 70 years of age and in 9 percent of those ≥70 years. These data suggest that a large proportion of asymptomatic patients do not become symptomatic in the short-term, providing a rationale for active surveillance.
Our approach to the management of small, asymptomatic meningiomas is to reassess the patient with MRI or CT after three to six months. If the patient remains asymptomatic and there is no evidence of tumor growth, the patient can then be monitored with neuroimaging on an annual basis.
This approach is particularly suitable for older patients and those with significant comorbidity. For relatively healthy younger patients, there is a lower threshold for surgical intervention because of the expectation that tumor progression will inevitably require active intervention
SURGERY — Symptomatic meningiomas and asymptomatic tumors that are expanding, infiltrating, or associated with surrounding edema should be surgically resected if feasible. Surgery is also often recommended for asymptomatic meningiomas in younger patients who have accessible lesions. In this setting, early surgery may be preferred because surgical morbidity is lower than in an older population and there is an assumption that lesions will eventually progress.
Surgery is combined with radiation therapy (RT) for less accessible lesions and for atypical and malignant meningiomas (WHO grades II and III) where the risk of recurrence is high and negative surgical margins cannot be assured.
Extent of resection — Early observational studies demonstrated that complete resection, when feasible, was associated with significantly prolonged survival compared to partial resection. Complete surgical resection should include the dural attachment of the meningioma.
The Simpson grading system has been used to describe the extent of surgical resection
Studies demonstrating the survival advantage from complete resection generally antedate the adjuvant use of radiation therapy (RT) with contemporary conformal techniques for patients with residual disease or with atypical/anaplastic meningiomas. The use of modern adjuvant RT to treat residual disease appears to yield results comparable to more aggressive surgery.
In contemporary practice, the goal of surgery is to achieve as extensive a resection as possible while minimizing neurologic deficits. The extent of resection varies depending upon the location of the tumor, whether there is imaging evidence of invasion, and the presurgical status of the patient (neurologic deficits, comorbidity).
Because meningiomas are vascular tumors, preoperative embolization may be useful to increase resectability in carefully selected patients with skull base meningiomas. When indicated, this procedure can be performed the day prior to surgery.
Surgical morbidity — Postoperative neurologic deficits can be a direct complication of surgery. The reported incidence of such neurologic deficits ranges from 2 to 30 percent depending upon the location of the tumor and the extent of the resection. Cortical brain injury may occur if the arachnoid and pia are adherent to the tumor and there is disruption of the pial vasculature with subsequent cortical microinfarction. Cranial nerve deficits are a risk in surgery for skull base meningiomas, and intraoperative cranial nerve monitoring should be used for tumors located near the cranial nerves.
The reported overall surgical mortality has varied widely, reflecting differences in patient selection criteria as well as changes in surgical care. Factors associated with an increased mortality included poor preoperative clinical condition, brain compression from tumor, advanced age, incomplete tumor removal, and intracranial hematoma requiring evacuation
Older series indicated that the mortality was higher in elderly patients. More recent series, using contemporary neurosurgical techniques, have shown that surgery is feasible in carefully selected elderly patients. As an example, there was no perioperative mortality in a carefully selected series of 74 patients aged ≥80 years, and the incidence of postoperative complications was 9 percent
Perioperative medical management — In addition to neurologic deficits that are a direct consequence of surgery, common medical complications include seizures, deep venous thrombosis, pulmonary embolism, pneumonia, myocardial infarction, and arrhythmias.
Seizures — Seizures are a frequent presenting symptom of meningiomas and can also occur in the postoperative period.
Cerebral edema — Standard preoperative medications include corticosteroids to reduce brain edema. During the surgical procedure, mannitol and furosemide are administered and the arterial PCO2 is lowered to 30 mmHg to reduce intracranial pressure if the tumor is large or if significant brain retraction is anticipated. Corticosteroids are tapered postoperatively.
Deep venous thrombosis — Deep venous thrombosis (DVT) is especially problematic both because the thromboembolic risk in general is increased in patients undergoing brain surgery and because meningiomas can produce a hypercoagulable state. In one small series, for example, almost three-fourths of patients had evidence of postoperative DVT following surgery for intracranial meningioma' The hemostatic disorder in these patients resembles a chronic subclinical form of disseminated intravascular coagulation (DIC)
Prophylactic anticoagulation may lower the risk of thromboembolic events and should be considered in the postoperative period for all patients with brain tumors. Subcutaneous low-molecular-weight heparin is recommended postoperatively for patients requiring craniotomy for removal of a meningioma. In addition, pneumatic compression boots should be used until the patient is ambulatory.
RADIATION THERAPY — Radiation therapy (RT) has an important role in the management of meningiomas that have been subtotally resected or are unresectable because of their proximity to critical neurologic structures. RT is also used in some cases after presumed complete resection of atypical or malignant meningiomas, which otherwise have a high rate of local recurrence.
RT after subtotal resection — Although there are no randomized trials that assess the role of RT, observational studies have provided evidence that RT after a partial resection of a meningioma substantially improves progression-free survival compared to partial resection alone and may be as effective as complete resection. Whether this approach improves overall survival compared to using RT upon the development of a recurrence is unclear.
Accurate delineation of the residual tumor volume using contemporary imaging studies is important for optimal results with postoperative RT. This was illustrated by a retrospective analysis from the University of California at San Francisco, which included 140 patients who underwent a subtotal resection of an intracranial meningioma between 1967 and 1990 and were then treated with postoperative RT. For patients treated between 1967 and 1980, RT treatment volumes were based exclusively upon the surgeon's assessment of the site and volume of residual disease. From 1981 through 1990, RT treatment volumes incorporated information about residual tumor from CT and/or MRI. Among the 117 patients with benign meningiomas, the use of CT and/or MRI to plan the postoperative RT was associated with a significant improvement in the five-year progression-free survival (98 versus 77 percent).
Retrospective data from other groups also supports the role of RT in patients who have undergone subtotal resection of meningiomas
RT alone for nonresectable meningiomas — RT can also be effective in treating meningiomas that are not amenable to even a subtotal resection, providing excellent tumor control and avoiding the risks of surgery.
High-grade meningiomas — Atypical (WHO grade II, and malignant/anaplastic (WHO grade III) meningiomas have an increased frequency of recurrence even after gross total resection As an example, in a series of 936 intracranial meningiomas, the five-year recurrence rates after presumed complete resection for benign, atypical, and anaplastic meningiomas were 3, 38, and 78 percent, respectively
Although there are no randomized trials, the high risk of recurrence has led to the widespread use of postoperative RT in patients with WHO grade II or III meningiomas, even after a seemingly complete resection. In the largest series, the effectiveness of RT was assessed in 119 patients with atypical or malignant meningiomas treated at 10 European centers. RT (mean dose 55 Gy) was administered after the initial resection in 94 cases and for recurrence in the other 25. The overall and disease-free survival rates at 10 years were was 51 percent and 48 percent, respectively. On multivariate analysis a high mitotic rate was a poor prognostic factor.
Dosage and toxicity — When RT is used postoperatively to treat residual disease, a dose of 54 Gy in daily fractions of 1.8 to 2 Gy is generally used for benign meningiomas. Atypical and anaplastic meningiomas are treated with higher doses (typically 59.4 Gy).
The importance of the radiation dose is illustrated by a retrospective series of 140 patients with benign or malignant meningiomas, including an overlapping subset from the previously cited study. Among the 117 patients with benign meningiomas, those treated to doses >52 Gy had a better 10-year progression-free survival (93 versus 65 percent with ≤52 Gy). Similarly, among patients with malignant meningiomas, the five-year progression free survival was better with doses >54 Gy (63 versus 17 percent with doses ≤53 Gy).
Potential adverse effects of external beam radiation on the surrounding normal brain are rarely seen at fractionated doses of 54 Gy and are uncommon at doses up to 59.4 Gy.
RT technical advances — Technical advances that increase the dose of radiation to the meningioma while minimizing radiation to normal structures include stereotactic radiosurgery (SRS), stereotactic radiotherapy (SRT), and intensity-modulated radiation therapy (IMRT). Preliminary data indicate that proton beam therapy, where available, may also be useful in selected cases.
Stereotactic radiosurgery — Stereotactic radiosurgery (SRS) utilizes multiple convergent beams to deliver a high single dose of radiation to a radiographically discrete treatment volume, thereby minimizing injury to adjacent structures.
SRS is an alternative to surgery for small tumors in selected sites where complete excision is difficult or in patients at high risk for surgical resection. Although no randomized trials have been completed comparing SRS to surgery, the outcomes appear to be similar to surgery for small to medium-sized meningiomas. As an example, actuarial local control rates are 93 percent at five and 10 years for cavernous sinus meningiomas.
Stereotactic radiotherapy — Stereotactic radiotherapy (SRT) uses focused radiation in the same way as SRS but fractionates treatment over a series of sessions. Fractionation improves normal tissue tolerance of radiation, and SRT may be a reasonable alternative for patients with surgically inaccessible lesions, either as postoperative therapy following subtotal resection or to treat local recurrence
SRT may be particularly useful for patients with optic nerve sheath meningiomas, in whom surgery can cause postoperative blindness. In multiple small series, SRT resulted in preservation and/or improvement in vision in approximately 80 percent of cases. SRT also appears to be useful in those with small meningiomas of the skull base.
Intensity-modulated RT — Intensity-modulated RT (IMRT) is a technique that relies upon software and modification of standard linear accelerator output to vary the radiation intensity across each treatment field. IMRT may be particularly useful for patients with meningiomas when the target is juxtaposed to radiation-sensitive structures or has a particularly complex shape, such as those involving the skull base
ONCOLOGIC AND FUNCTIONAL OUTCOME — The results with surgery vary depending upon the location of the resected lesion, as well as the experience of the hospital and surgeon. Interpretation of results from large series also needs to consider the case mix.
Optimal therapy needs to be individualized, based upon the anatomic location of the tumor and patient-specific considerations. Results are discussed for two of the more common meningioma locations, convexity meningiomas, which usually can be managed with surgery alone, and skull base lesions, which often require a multidisciplinary approach.
Convexity meningiomas — Results with surgery primarily as a single modality are illustrated by a series of 163 patients with convexity meningiomas treated by a single surgeon over a 20-year period This cohort represented 22 percent of all meningiomas operated on during that period.
Skull base meningiomas — The management of patients with skull base meningiomas is difficult because these lesions generally have an indolent history with only mild symptoms At the same time, radical surgery is associated with substantial morbidity because of the involvement of critical structures (vascular structures, cranial nerves, brainstem) and the high frequency of local recurrence.
The results of a combined modality approach are illustrated by a single surgeon series of 100 consecutive patients. Patients with minimal or no symptoms were initially managed with observation. Aggressive surgical resection was indicated for patients with a symptomatic tumor, for those with edema and mass effect, or progressive tumor enlargement. Conformal RT or stereotactic radiosurgery (SRS) was used for treatment of residual tumor following surgery or in those patients for whom surgical resection was contraindicated or refused.
Treatment included surgery in 72 cases, including 27 in which surgery was followed by radiation. Radiation alone was used in 13 cases and 15 patients were managed with observation. At a median follow-up of five years, only one patient had evidence of tumor progression. There were no treatment-related deaths, and serious complications from surgery were limited to hemiparesis, new cranial nerve palsy, and osteomyelitis (2.8, 2.8, and 1.4 percent of surgical cases, respectively).
The overall impact of diagnosis and treatment was studied in a single-surgeon series of 200 patients operated on for intracranial meningioma . At a mean follow-up of 33 months, 36 patients had died within the first five years, including 18 due to the meningioma. Another eight patients died secondary to the meningioma after five years. Among the patients still living at the time of analysis, 80 percent were satisfied with their posttreatment quality of life, based upon a self-reported questionnaire.
The late impact of disease and treatment on neurocognitive function was studied at least one year after treatment in 89 patients who had been operated on for a grade I meningioma, including 22 who also received RT. Compared to matched healthy controls, patients had statistically significant impairment in several neurocognitive areas including executive functioning, verbal memory, information processing capacity, psychomotor speed, and working memory. Factors that appeared to partially account for these deficits include the use of anticonvulsants and the location of the tumor, but not the use of RT.
Neurocognitive impairment can be delayed after cranial irradiation and longer follow-up is required to definitively address this issue.
SURVEILLANCE AFTER INITIAL TREATMENT — Cranial imaging (preferably MRI) is used following initial treatment to monitor for evidence of recurrence or for progression of residual disease. There are no studies that define the optimal schedule for such imaging.
RECURRENT DISEASE — Most recurrences of meningioma are local or adjacent to a radiation treatment field. Metastases of cranial meningiomas to the spinal cord due to spreading through the cerebrospinal fluid are rare and are more frequently associated with atypical or malignant meningiomas. There are only isolated case reports of metastases outside the central nervous system
Surgery and RT for localized recurrences — Despite optimal therapy, some patients develop locally recurrent disease. For patients who recur locally after their initial treatment, additional surgery and/or RT (SRS, SRT, combined proton and photon RT) can sometimes provide effective therapy, and occasionally permit long-term overall and recurrence-free survival.
The principles underlying the use of surgery or radiation are similar to those for patients presenting de novo, but appropriate management requires a consideration of the effects of prior surgery and/or RT.
Systemic therapy — There is only limited experience with systemic therapy for the treatment of meningiomas, and most data are from observational studies. Systemic therapy has been used in small numbers of patients with recurrent, unresectable, and/or malignant meningiomas that are no longer controllable despite maximal surgery and RT.
Although a number of agents have been studied, none have an established role in prolonging progression-free or overall survival
Mifepristone — Epidemiologic evidence suggests that there is a link between progesterones and the progesterone receptor and the development or progression of meningiomas. Mifepristone is a progesterone and glucocorticoid receptor antagonist.
Preliminary studies indicated that mifepristone produced objective improvement in about 25 to 30 percent of patients with unresectable meningioma. However, a randomized, placebo-controlled trial conducted by the Eastern Cooperative Oncology Group (ECOG) in 160 patients with unresectable meningioma found there was no improvement in median time to progression with mifepristone compared to placebo (10 versus 12 months).
Hydroxyurea — Hydroxyurea induces apoptosis and inhibits meningioma cell growth in culture
Clinical experience with hydroxyurea consists of small series. In the two largest reports, there was only a modest degree of activity:
Interferon alfa-2b — In vitro, interferon alfa-2b (IFNa) inhibits the growth of meningioma cells exposed to mitotic stimuli, and preliminary reports suggested clinical activity.
The most extensive experience with IFNa comes from a prospective phase II study in which 35 patients with recurrent grade I intracranial meningiomas were treated with IFNa (10 million units subcutaneously every other day). All patients had received prior surgery and RT, and 34 had received prior systemic therapy. Although no objective responses were observed, 26 patients (74 percent) had stable disease for at least 12 weeks. Median overall survival was eight months.
The extent to which these results indicate clinical activity for IFNa is unclear, since grade I meningiomas are generally slow growing and multiple scans may be required to demonstrate significant changes in tumor size. Furthermore, the median overall survival of eight months suggests that this was a highly selected group of patients with a particularly poor prognosis.
Somatostatin analogs — Somatostatin receptors are present on most meningiomas. Case reports suggested that therapy targeted to this pathway might have therapeutic usefulness for patients with recurrent, unresectable meningiomas
A prospective pilot study treated 16 patients with a long-acting formulation of the somatostatin analog octreotide. All patients had recurrent, progressive meningioma and at least six months had passed since prior radiation therapy. All of the meningiomas expressed somatostatin receptors as demonstrated by a radiolabeled octreotide scan. Partial responses were observed in five patients (31 percent) and another five patients had stable disease. The median survival was eight months.
Another somatostatin analog, pasireotide (SOM230C), is currently being evaluated in a multicenter, phase II trial in patients with recurrent, progressive meningioma (NCT00859040).
SUMMARY AND RECOMMENDATIONS — The management of patients with meningioma requires a delicate balance between definitive treatment of the tumor and avoidance of neurologic damage from the treatment. Patient-related factors (eg, presence or absence of symptoms, age, comorbidity), the location of the meningioma in relation to critical brain structures and regions, and the degree of atypia or malignancy of the tumor all are important factors in determining the optimal approach to management.