Potential Impact of Selection Bias Related to the SRS Era
We compared potential selection bias variables in patients who underwent SRS in the era from 1987 to 1996 (the early era) and those who underwent SRS after 1996. In the group of patients who underwent SRS in the early era, there were 46 patients with prior microsurgery and 39 without prior microsurgery. In the group of patients who underwent SRS after 1996 (the recent era), there were 53 patients with prior microsurgery and 134 without prior microsurgery. Patients who underwent SRS in the early era received higher tumor margin doses (P < .001), more often had undergone prior microsurgery (P < .001), and more often had preexisting cranial nerve deficits (P = .002; Table 2). The 5-year improvement rate of preexisting cranial nerve deficits in patients who underwent SRS in the early era was 39% in patients without prior microsurgery and 12% in those with prior microsurgery (P = .01). The 5-year improvement rate of preexisting cranial nerve deficits in patients who underwent SRS in the recent era was 39% in patients without prior microsurgery and 15% in those with prior microsurgery (P = .008). In both groups of patients, prior microsurgery was significantly associated with lower improvement rates of preexisting cranial nerve deficits regardless of differences in margin dose. Before 1997, patients were more likely to have microsurgery recommended as the initial option by the initial consulting neurosurgeon.
Patient Survival and Tumor Control
Based on Kaplan-Meier analysis, the overall survival after SRS was 99.6% at 1 year, 98.1% at 2 years, 97.6% at 3 years, 94.3% at 5 years, and 83.4% at 10 years. Six patients died within 3 years after SRS. Three patients died of cardiovascular disease, 2 died of breast cancer, and 1 died of unknown causes. Serial follow-up imaging studies demonstrated tumor volume reduction in 164 (60%) and unchanged volumes in 87 (32%). Twenty-one (8%) had delayed growth of their tumors. On the basis of Kaplan-Meier analysis, the tumor PFS rate after SRS was 96% at 3 years, 94% at 5 years, and 86% at 10 years. Prior microsurgery was not associated with either improvement or worsening of the PFS (P = 0.49).
Improvement of Preexisting Cranial Nerve Deficits After Radiosurgery
Ninety-one patients (92%) who had prior microsurgery also had cranial nerve symptoms or signs at the time of SRS. One hundred forty-five patients (84%) without prior microsurgery had cranial nerve symptoms or signs at the time of SRS. Prior microsurgery was significantly associated with a higher rate of cranial nerve symptoms or signs (P = .02) before SRS. Other factors such as tumor volume, margin dose, age, sex, and tumor regression were not associated with an improvement of preexisting cranial nerve deficits. The tumor volumes before SRS in both groups were similar. The responses of cranial nerves to SRS are shown in Table 3.
After SRS, 13 of 91 patients (14%) who underwent prior microsurgery had improvement of preexisting cranial nerve symptoms or signs at a median follow-up of 79 months (range, 6-209 months). In contrast, 54 of 145 patients (37%) who had not undergone prior microsurgery had improvement in cranial nerve symptoms or signs at a median follow-up of 61 months (range, 6-185 months). On the basis of Kaplan-Meier analysis, the improvement rate of cranial nerve disorders after SRS in prior microsurgery patients was 8% at 1 year, 12% at 2 years, 12% at 3 years, and 14% at 5 years. In comparison, the improvement rate of cranial nerve disorders in patients without prior microsurgery was 20% at 1 year, 34% at 2 years, 36% at 3 years, and 39% at 5 years. Patients without prior microsurgery had a significantly higher likelihood of improvement of cranial nerve symptoms and signs (log-rank test, P = .001; Cox proportional-hazards analysis, P = .001; hazard ratio, 3.06, 95% confidence interval [CI], 1.66-5.62; Figure 2).
The commonest preexisting cranial nerve symptom was diplopia. In prior microsurgery patients, 9 of 56 patients (16%) had improvement in diplopia at a median follow-up of 85 months (range, 6-209 months). In patients without prior microsurgery, 41 of 108 patients (38%) had improvement in diplopia at a median follow-up of 68 months (range, 6-167 months). Based on Kaplan-Meier analysis, the improvement rate of diplopia after SRS in prior microsurgery patients was 8% at 1 year, 14% at 2 years, 14% at 3 years, and 14% at 5 years. The improvement rate of diplopia after SRS in patients without prior microsurgery was 22% at 1 year, 35% at 2 years, 37% at 3 years, and 41% at 5 years. Patients without prior microsurgery had a significantly higher likelihood of improvement of diplopia (log rank test, P = .001; Cox proportional-hazards analysis, P = .002; hazard ratio, 3.17; 95% CI, 1.54-6.54; Figure 3).
The second commonest preexisting cranial nerve symptom or sign was trigeminal neuropathy. In prior microsurgery patients, 4 of 43 (9%) had improvement in trigeminal neuropathy at a median follow-up of 64 months (range, 8-199 months). In comparison, 13 of 55 patients (24%) without prior microsurgery had improvement at a median follow-up of 49 months (range, 17-185 months). On the basis of Kaplan-Meier analysis, the improvement rate of trigeminal neuropathy after SRS in prior microsurgery patients was 7% at 1 year, 9% at 2 years, 9% at 3 years, and 9% at 5 years. The improvement rate of trigeminal neuropathy after SRS in patients without prior microsurgery was 15% at 1 year, 26% at 2 years, 29% at 3 years, and 33% at 5 years. Patients without prior microsurgery had a significantly higher rate of improvement of preexisting trigeminal neuropathy (log-rank test, P = .02; Cox proportional-hazards analysis, P = .03; hazard ratio, 3.57; 95% CI, 1.16-10.96; Figure 3).
The third commonest preexisting cranial nerve symptom was optic neuropathy. Two of 25 patients (8%) without prior microsurgery had visual improvement at a median follow-up of 79 months (range, 22-127 months). Similarly, 2 of 15 patients (13%) who had undergone prior microsurgery had visual improvement at a median follow-up of 39 months (range, 6-149 months). Improved vision was noted within 18 months after SRS (Figure 3) in both series. Table 4 shows the response of cranial nerves after SRS.
Delayed Progression of Cranial Nerve Symptoms or Signs After SRS
After SRS, 29 patients (11%) had delayed onset of additional cranial nerve symptoms or signs. Four patients had tumor volume progression resulting in new cranial deficits between 1 and 10 years after SRS. One patient developed a partial oculomotor nerve palsy 125 months later; 1 patient suffered a new visual field deficit, diplopia, and facial numbness 118 months after SRS; 1 patient developed typical trigeminal neuralgia 14 months after SRS; and a final patient developed a facial neuropathy 24 months after SRS. Six patients had temporary symptomatic AREs that included facial sensory loss in 3, abducens nerve deficit in 2, and a facial palsy in 1 patient at a median of 12 months (range, 0.5-17 months). Nineteen patients developed new cranial nerve deficits without imaging evidence of tumor progression. Twelve of 19 patients who developed new cranial nerve deficits within 18 months after SRS (median, 5.3 months; range, 0.5-17 months) were considered to have symptomatic AREs. Seven additional patients developed new cranial nerve deficits > 3 years after SRS (median, 55 months; range, 39-85 months) without imaging evidence of tumor progression. In the absence of tumor progression, it was not possible to determine whether such signs represented late AREs or were caused by local tumor effects on cranial nerve function. The functional outcomes for affected cranial nerves after SRS are shown in Table 4.
On the basis of Kaplan-Meier analysis, the rate of development of new cranial nerve disorders was 5% at 1 year, 7% at 3 years, 10% at 5 years, and 16% at 10 years after SRS (Figure 4). Only confirmed tumor progression was associated with higher rate of delayed progression of cranial nerve disorders (P = .02). Other factors such as tumor volume, margin dose, age, prior microsurgery, and preexisting cranial nerve deficits were not associated with a delayed worsening of cranial nerve function.
Four patients (4%) who had undergone microsurgery had partial endocrine loss noted at the time of SRS. Nine (5%) who had not undergone microsurgery had partial endocrine loss. After SRS, 2 additional prior microsurgery patients developed endocrine dysfunction (1 patient developed hypothyroidism 42 months after SRS and 1 patient had reduced growth hormone levels detected 6 months after SRS). Two patients without prior microsurgery developed hyperprolactinemia 17 and 49 months after SRS. All 4 patients who developed new endocrine dysfunction did not have tumor progression. Maximum doses to the pituitary gland ranged from 8.8 to 15 Gy. The number of patients who developed new endocrinopathy was too small to assess any relationship to dose or volume delivered to the pituitary gland or stalk.
Nine patients underwent repeat SRS for treated tumor progression at a median of 54 months (range, 11-118 months) after SRS. Seven patients underwent surgical resection for tumor progression at a median of 62 months (range, 20-104 months) after SRS. Three patients required additional SRS for marginal tumor recurrence 12, 77, and 85 months after SRS. Two patients underwent surgical resection for marginal tumor recurrence 16 and 45 months after SRS. One patient underwent intensity-modulated RT for marginal recurrence 189 months after SRS.
The cavernous sinus is composed of a large collection of thin-walled veins on both sides of the sella, closely adjacent to the optic chiasm and optic nerves. In the cavernous sinus, the carotid siphon of the internal carotid artery and cranial nerves III, IV, V (branches V1 and V2), and VI all pass through this blood-filled space.
Recent advances in microsurgery have improved the ability to perform surgery for cavernous sinus meningiomas. Total tumor resection is not possible in most patients because the tumor compresses or envelopes critical neurovascular structures in the cavernous sinus. De Jesús et al5 studied 119 cavernous sinus meningioma patients and reported recurrence rates of 9.6% after “complete resection” and 15.2% after subtotal resection at a mean follow-up period of 39 months. Additional reports indicate tumor recurrence rates ranging from 9.6% to 25%.16-18 Initial microsurgery is associated with mortality rates that range from 0% to 9.5% of patients and morbidity in 17.9% to 74% of patients. DeMonte et al17 reported that the clinical improvement rate after microsurgery for 41 cavernous sinus meningiomas was 14% and permanent morbidity rate was 19.5%. Postsurgical morbidity includes new cranial nerve disorders, pituitary insufficiency, and injury to vascular structures.17-21 In a meta-analysis study, Sughrue et al22 reported 17 series (> 36 months of follow-up) of gross total resection for 217 cavernous sinus meningioma patients. Six series (218 patients) had > 36 months of follow-up after subtotal resection that was not followed by adjuvant radiotherapy or radiosurgery. They also reported a series of 1309 patients who underwent SRS alone and were reevaluated at intervals of > 36 months. SRS was significantly associated with lower rate of tumor recurrence (3.2%; 95% CI, 1.9-4.5) compared with either gross total resection (11.8%; 95% CI, 7.4-16.1) or subtotal resection alone (11.1%; 95% CI, 6.6-15.7; P < .01). The rate of postsurgical cranial neuropathy for patients who underwent microsurgery, including total and subtotal resections (59.6%; 95% CI, 7.4-16.1), was significantly higher than the rate of cranial neuropathy found in patients who underwent SRS alone (25.7%; 95% CI, 11.5-38.9%; P < .05).
Prior studies have indicated that the 5-year PFS after SRS ranged from 80% to 100% during follow-up intervals that ranged from 35 to 87 months.8-12,15,23-25 The 10-year PFS ranged between 73% and 98% during average follow-ups that ranged from 60 to 87 months.12,15,23 In the present study, PFS was 94% at 5 years and 86% at 10 years with a median follow-up of 62 months.
In published series of patients treated by fractionated RT and fractionated stereotactic RT for cavernous sinus meningiomas, 10-year PFS ranged from 81% to 96% with a mean follow-up ranging from 3.4 to 9.0 years.7,26,27 The tumor volumes in reports of cavernous sinus meningiomas treated by fractionated RT are often much larger than the tumor volumes that undergo SRS (range: RT, 11.3-35.2 cm3 vs SRS, 4.3-14.7 cm3). A limitation of SRS is the volume of the tumor that is immediately adjacent to the optic apparatus. With the use of highly conformal and selective SRS, tumor-controlling doses can be delivered safely. In our series, the dose limitation for the optic apparatus was ≤ 10 Gy.
Improvement of Cranial Nerve Deficits
Skeie et al28 reported that 58 of 60 patients (97%) who underwent craniotomy had cranial nerve deficits before SRS compared with 33 of 40 patients (83%) who had not undergone craniotomy. In their study, a prior craniotomy was significantly associated with cranial nerve injury before SRS (P = .003). In the present series, impaired cranial nerve function was noted more often in patients who had prior microsurgery (92%) compared with patients who had not undergone prior microsurgery (84%; P = .02).
In the present study, we wished to define the potential for improvement of preexisting cranial neuropathies. Using linear accelerator--based SRS, Spiegelmann et al29 reported that 39% of patients had neurological improvement or resolution after SRS. In their series, 35% of patients had undergone prior microsurgery. They also reported that cranial nerve neuropathies had significantly higher resolution rates when SRS was performed early (< 1 year) after their onset (53% vs 26%), even in patients with deficits after surgery (P < .03, χ2 test). In the present study, the interval between the onset of cranial neuropathies and SRS was not associated with the likelihood of improvement.
After SRS, neurological improvement has been reported in 20% to 29% of cavernous sinus meningioma patients.10,24,25,29 In the present study, 54 of 145 patients (37%) who had not undergone prior microsurgery had improvement of preexisting cranial nerve symptoms or signs. Surprisingly, Nicolato et al9 reported that 44 of 56 patients (78.5%) who underwent SRS as a primary treatment had improvement of preexisting clinical symptoms or signs.
The commonest preexisting cranial nerve symptom was diplopia in previous reports. Hasegawa et al23 reported that 11 of 38 patients (29%) with diplopia had improvement. Spiegelmann et al29 reported that 6 of 17 patients (35%) with oculomotor neuropathy, 0 of 7 patients with trochlear neuropathy, and 11 of 39 patients (28%) with abducens neuropathy had improvement or resolution. We found that 44% of patients with oculomotor neuropathy, 60% with trochlear neuropathy, and 37% with abducens neuropathy had improvement if the patient had not undergone prior microsurgery. In this same group of patients, we found that the improvement rate of diplopia was 22% at 1 year, 35% at 2 years, 37% at 3 years, and 41% at 5 years. After SRS, improvement of diplopia was noted within 2 years; further improvement beyond 5 years was not noted (Figure 3). We believe that the Kaplan-Meier method is a superior way to demonstrate the time course of potential cranial nerve symptom improvement after SRS.
After disorders of ocular motility, trigeminal neuropathy was the next commonest cranial nerve symptom. Hasegawa et al23 reported that 10 of 30 patients (30%) with facial sensory loss had improvement after SRS. Spiegelmann et al29reported that 4 of 11 patients (36%) had improvement of their trigeminal neuropathy. We found that 13 of 55 patients (24%) with trigeminal neuropathy had improvement if the patient had not undergone prior microsurgery. The improvement rate of trigeminal neuropathy in patients without prior microsurgery was 14.7% at 1 year, 26% at 2 years, 29% at 3 years, and 33% at 5 years. Preexisting optic neuropathy was the least likely cranial neuropathy to improve. We found that only 2 of 15 patients (13%) without prior microsurgery had improvement. Hasegawa et al23 reported that 3 of 28 patients (11%) had improvement if they had not undergone microsurgery.
The published incidence of delayed cranial neuropathies after SRS ranges from 0% to 25%.11,12,14,16,17,27-29 In the present study, 29 patients (11%) had worsening of cranial nerve symptoms and signs after SRS. Only 4 of these patients had tumor progression. Six patients (2%) developed symptomatic AREs (characterized by new neurological signs or symptoms in the absence of tumor growth with new changes in tumor contrast enhancement or reactive changes on MRI). Nineteen additional patients (7%) had further worsening of presenting cranial nerve symptoms and signs without evidence of tumor progression. Seven of 19 patients who developed new cranial nerve deficits > 3 years after SRS are suspected to have tumor-caused deficits perhaps related to growth below the resolution of surveillance imaging. Twelve of 19 patients (4%) who developed new cranial nerve deficits within 18 months after SRS were considered to have symptomatic AREs because we could detect no change in the tumor volume. In total, 18 patients (7%) developed signs or symptoms compatible with AREs. The rate of delayed progression of cranial nerve deficits was 5% at 1 year, 7% at 3 years, 10% at 5 years, and 16% at 10 years after SRS. Hasegawa et al23 reported that 12% of cavernous sinus meningioma patients who underwent SRS had exacerbation of preexisting cranial nerve deficits or developed new signs or symptoms. Williams et al13 reported that new or worsening cranial nerve deficits occurred in 10% of patients after SRS. They found that factors associated with new deficits included larger tumor volumes (P = .05), lower margin doses (P = .004), tumor progression (P < .001), and longer follow-up duration (P = .03). In the present study, only tumor progression was associated with a higher rate of delayed progression of cranial nerve deficit (P = .02).
Weaknesses of This Study
Although this study is one of the largest radiosurgery series with extended follow-up, we acknowledge that this is a single-center study. After the initial Gamma Knife was installed in 1987, the number of patients with cavernous sinus meningiomas who underwent initial SRS gradually increased, whereas the number of patients with prior microsurgery gradually decreased. This trend in patient management may affect our results. This study does not address the alternative strategy of observation of symptomatic cavernous sinus meningiomas. Large-volume symptomatic meningiomas in the region of the cavernous sinus may benefit from judicious microsurgical debulking followed by SRS to improve long-term tumor control rates.
In this series, SRS for newly diagnosed or residual cavernous sinus meningiomas was associated with high tumor control rates and a relatively low risk of developing new cranial nerve deficits. Patients who underwent prior microsurgery had higher rates of cranial nerve deficits before SRS and a reduced likelihood of improvement of such deficits after SRS. Improvement in preexisting cranial neuropathy was noted in one-third of patients who underwent SRS as the primary management.
The work described in this report was funded by a research grant to Dr Kano from AB Elekta, Stockholm, Sweden, and the Osaka Medical Research Foundation for Incurable Diseases. Drs Lunsford and Kondziolka are consultants for and Dr Lunsford is a stockholder of AB Elekta. The other authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.
This study was presented and awarded the Integra Foundation Award at the 2012 Annual Meeting of the Congress of Neurological Surgeons.
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This article is one of the largest series for cavernous sinus meningiomas treated with stereotactic radiosurgery with a median follow-up period of > 5 years and provides detailed information of cranial nerve symptoms or signs before and after radiosurgery. The authors documented in a large series of 272 cavernous sinus meningioma patients treated with Gamma Knife surgery with a median follow-up period of 62 months that stereotactic radiosurgery provided a high rate of long-term tumor control and a low risk of new cranial nerve deficits. They also found that 14% of patients with prior microsurgery had improved their preexisting symptoms or signs compared with 37% of patients without prior microsurgery. These findings are comparable to the results of our previous study1 showing that 64% of patients without prior microsurgery experienced some degree of functional improvement compared with 34% of patients who underwent prior microsurgery (P = .006). However, this is not surprising for several reasons. One reason is the inclusion of patients who had cranial nerve injury caused by microsurgical resection in the group of patients with prior microsurgery. If cranial nerves are sacrificed at the time of microsurgery, the cranial nerve function never recovers. Next, duration of cranial nerve symptoms is related to functional improvement after radiosurgery. The time interval from onset to tumor regression after radiosurgery in patients with prior microsurgery should be longer than in those who underwent radiosurgery as an initial treatment. Longer-term compression of cranial nerves would make functional improvement more difficult. The last reason is the difference of original tumor sizes. There is no doubt that the original tumor volume in patients who selected microsurgery first was larger than that in patients who underwent radiosurgery as an initial treatment. This indicates that patients with prior microsurgery are more likely to have a strong compression or tumor invasion to cranial nerves before intervention. In any case, it is almost infeasible to completely remove meningiomas in the cavernous sinus without any neurological deficits even for experienced neurosurgeons despite recent refinements of microsurgical techniques and neuromonitoring systems. Considering an excellent long-term tumor control rate and a low risk of complications in patients harboring cavernous sinus meningiomas treated with stereotactic radiosurgery as shown by the authors, meningiomas in the cavernous sinus should not be removed. That is why it is a current standard strategy to add radiosurgery to the residual meningioma in the cavernous sinus after maximal tumor resection outside the cavernous sinus when tumors are relatively large. In cases of small to medium cavernous sinus meningiomas, stereotactic radiosurgery can be a reasonable alternative to microsurgery to retain better functional outcomes.
This is a retrospective study of 272 patients with benign primary cavernous sinus meningiomas that were treated with Gamma Knife radiosurgery. They had 6 to 209 months (median, 62 months) of follow-up. The median tumor volume was 7.9 cm3. The majority of the patients (173 patients) had no surgery before the SRS treatment. The diagnosis in the nonsurgical group was based on typical imaging characteristics. Although most of the patients had neurological findings, it is not mentioned how many of the tumors were documented to be growing before SRS. The tumors were treated with a marginal dose of 13 Gy. The optic nerve dose was kept < 10 Gy.
The authors reported that 60% of patients had reduction in tumor volume by > 50%, 32% of patients had stable tumors, and 8% of patients progressed. Delayed tumor progression was noted in only 4 patients, and delayed cranial neuropathies were noted in only 11% of patients. Progression-free survival was 96% at 3 years, 94% at 5 years, and 86% at 10 years. Thirty-one percent of patients with cranial nerve impairment but without prior surgery had improvement in function up to 5 years after SRS. This number was significantly lower in those patients who had prior surgery. Surgically traumatized cranial nerves would not be expected to improve after SRS. Table 3 illustrates this well. The rate of complications from the treatment (adverse radiation effects) is very low and consists of temporary cranial nerve dysfunctions. The rate of postradiation pituitary dysfunction is also low.
This well-documented article adds to the literature that stereotactic radiosurgery is the treatment of choice for most small, benign, symptomatic cavernous sinus meningiomas even without prior surgical confirmation. Observation with serial imaging studies of asymptomatic small tumors remains an option. Situations in which there is significant degree of optic nerve involvement or extracavernous extension would likely require surgical resection before radiosurgery.
New York, New York
The authors present a large series of patients with cavernous sinus meningiomas treated with stereotactic radiosurgery. The aim of the study was compare tumor control and cranial nerve outcomes in patients with or without microsurgery before SRS. The limitations of SRS for these tumors are large volumes and close proximity to the anterior visual pathways. To reduce the exposure of the optic apparatus, SRS treatment of these large tumors may result in suboptimal dose coverage and a compromise in tumor control rate. On the other hand, prior surgery may leave both multifocal and irregular lesions behind, and the exact differentiation between postoperative changes and tumor may sometimes be troublesome, making dose planning more difficult.
At the University of Pittsburgh, the number of patients treated with initial SRS gradually increased from 45.9% to 71.7% during the study period between 1987 and 2010. Patients treated in the early era (1987-1996) received significantly higher margin doses, more often had undergone prior microsurgery, and had preexisting cranial nerve deficits more often than patients treated after 1996, implying potential selection bias.
Progression-free survival for the total group was 94% at 5 years and 86% at 10 years. A reduced local control rate for meningiomas treated with prior surgery was not reported. Thus, large symptomatic tumors may benefit from microsurgical debulking before SRS. However, treatment-naïve patients had significantly higher improvement rates of preexisting cranial nerve function than patients treated for residual or recurrent tumor after microsurgery (37% vs 14%; P = .001). Improvement in cranial nerve symptoms was registered up to 5 years after SRS. Thus, the results of this study suggest that surgically traumatized cranial nerves have less potential of recovery after SRS and therefore that patients with cavernous sinus meningiomas would benefit from SRS treatment alone if possible.
Bente Sandvei Skeie
Keywords:Copyright © by the Congress of Neurological Surgeons
Cavernous sinus; Cranial nerve deficits; Gamma Knife; Meningioma; Stereotactic radiosurgery