The role of adjuvant radiotherapy in atypical meningioma
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The object of this study was to analyze treatment outcomes and to identify the prognostic factors, with a focus on the role of adjuvant radiotherapy (ART), predicting disease progression in atypical meningiomas. From 1997 to 2011, 83 patients with meningioma were included in this study. All patients were histologically confirmed as atypical meningioma and were treated with surgical resection with or without ART. As primary therapy, 27 patients received surgical resection followed by ART, and 56 received no adjuvant therapy. Of 83 evaluable patients, 55 (66.3 %) patients underwent complete resection. The median ART dose was 61.2 Gy and their median age was 52 years. The 5- and 10-year actuarial overall survival rates were 90.2 and 62.0 %, and the 5- and 10-year progression-free survival (PFS) rates were both 48.0 %, with a median follow-up of 43.0 months. Addition of ART (p = 0.016) and complete tumor resection (p = 0.002) were associated with superior PFS. When stratified to four groups according to resection status and ART, the groups of patient with incomplete resection without ART showed significantly worse PFS compared to other three groups (p < 0.001). In conclusion, surgical resection followed by ART led to lower local tumor progression in patients with atypical meningioma defined by the updated 2000/2007 WHO classification. Our results may contribute to the routine use of ART, especially after incomplete resection, until the outcomes of ongoing prospective trials are available.
KeywordsMeningioma Atypical meningioma Radiotherapy Postoperative radiotherapy Adjuvant radiotherapy
Meningiomas account for ~34 % of all primary intracranial tumors . The majority of these tumors are benign (World Health Organization (WHO) grade I, ~90 %). However, atypical (WHO grade II) and malignant (WHO grade III) meningiomas constitute approximately 5–7 and 1–3 % of meningiomas, respectively [2, 3]. Because of their high recurrence rate and poor prognosis, a combined-modality treatment approach using surgical resection followed by postoperative adjuvant radiotherapy (ART) has been commonly employed despite inconsistent reports regarding the benefit of ART.
The completeness of resection is a well known prognosticator for local recurrence of high risk meningiomas. Many advocate adjuvant radiotherapy for the treatment of malignant meningiomas regardless of the extent of surgery because of the extremely high rate of local recurrence [4, 5]. However, the optimal treatment for atypical meningiomas is still controversial. Atypical meningiomas are rare tumors and are often integrated with benign or malignant histology when analysis is performed. Few studies have reported the outcomes and prognostic factors for sole atypical meningiomas, but the results are inconsistent [6, 7, 8, 9, 10]. Some studies favor early addition of ART even after gross total resection (GTR) of tumors to achieve better local control [6, 7]. On the other hand, others argue that the role of ART remains unclear [9, 11]. Therefore, the existing data is insufficient to establish the indications for ART in patients with atypical meningioma.
In this study, we retrospectively analyzed the outcomes of atypical meningiomas in a relatively large series (n = 83) of patients after surgical resection with or without ART with a special focus on the benefit of ART at a single institution, and identified the prognostic factors predicting disease progression in these patients.
Patients and methods
After Institutional Review Board approval, our patient database was used to select patients referred between 1997 and 2011 who were pathologically diagnosed with atypical meningioma at Seoul National University Hospital, Korea. Histological slides were not centrally reviewed, but all pathologic reports were thoroughly examined to exclude patients who did not meet the definition of atypical meningioma (WHO grade II) according to the WHO 2000/2007 classification [12, 13]. Patients with recurrent atypical meningioma after treatment of previous benign meningioma were excluded. Patients with multiple intracranial meningiomas were excluded due to the difficulty in evaluating treatment response. However, we included one patient who had one benign lesion in the right convexity and another discrete atypical lesion in the left. Cases of spinal cord meningioma were also excluded. Considering the aim of our study, patients with preoperative radiotherapy or postoperative adjuvant radiosurgery, which did not target the whole surgical bed, were not included. Patients without resection were also excluded. Patients with <6 months follow-up period due to follow-up loss were excluded. The remaining 83 patients were analyzed in the present study.
Patient and tumor characteristics
Patient and treatment characteristics
Number of patients
62 (74.7 %)
21 (25.3 %)
33 (39.8 %)
50 (60.2 %)
43 (51.8 %)
20 (24.1 %)
Skull base/sphenoid ridge
10 (12.0 %)
6 (7.2 %)
4 (4.8 %)
Mitosis/10 high-power fields
51 (61.4 %)
31 (37.3 %)
1 (1.2 %)
59 (71.1 %)
8 (9.6 %)
16 (19.3 %)
55 (66.3 %)
25 (30.1 %)
3 (3.6 %)
27 (32.5 %)
56 (67.5 %)
Survival was calculated from the date of surgical resection. Statistical analysis was done using SPSS software (release version18; SPSS Inc. Chicago, IL, USA). Actuarial overall survival (OS) and progression-free survival (PFS) rates were calculated according to the Kaplan–Meier method, and comparisons between groups were performed using log-rank tests. A p value smaller than 0.05 was regarded statistically significant . For multivariate analysis, potentially confounding variables with a p value smaller than 0.1 on univariate analysis were incorporated into the Cox proportional hazard model, using the backward stepwise method. Variables with missing data more than 10 % were excluded from multivariate analysis.
Survival outcomes after primary treatment
The median follow-up time from the date of surgical intervention of atypical meningiomas was 43.0 months (range 6.2–160.0 months). At the time of survival analysis, 11 patients (13.3 %) died and 7 of them had progressed disease. The actuarial 5-year and 10-year OS were 90.0 and 62.0 %, respectively. At last follow-up, 37 patients (44.6 %) presented with local disease progression, and all of them had occurred within 5 years. The median time to progression was 25.4 months (range 0.8–157.2 months).The actuarial 5-year and 10-year PFS were both 48.0 %. Two patients showed distant metastasis accompanied by local disease progression. One patient had local disease progression and distant metastases to the lung, liver, and bone, concurrently. The other patient had lung metastases 2 years after local disease progression.
Prognostic factors affecting survivals
Prognostic factors for progression-free survival and overall survival
Age (≤60 vs. >60)
Completion of resection
High mitotic rate (≤5 vs. >5/10HPF)
Ki-67a (≤10 vs. >10 %)
OS was significantly inferior in patients over 60 years of age (94.4 vs. 77.2 % at 5 years, p = 0.002). Interestingly, surgical resection without postoperative ART showed a trend toward better OS (p = 0.082). On multivariate analysis, age at diagnosis was the only prognostic factor affecting OS (p = 0.005), whereas ART was not (p = 0.380) (Table 2).
In group of patients with GTR, the addition of ART did not influence PFS (p = 0.858). On the other hand, it significantly increased PFS in group of patients with incomplete resection (p < 0.001).
When stratified to four groups according to resection status and ART, the group which did not receive ART despite incomplete resection showed far worse PFS compared to the other three groups (Fig. 2c) (p < 0.001).
Salvage treatments after disease progression
Details of first-salvage treatment according to primary therapy
Resection only (n = 27)
ART addition (n = 10)
Resection + ART
Gamma knife radiosurgery
During the treatment period, no severe acute side effects were observed. Transient mild side effects, such as fatigue, headache, intermittent nausea, dizziness and skin irritation at portals were observed in most patients. Late toxicity was categorized according to the Common Terminology Criteria for Adverse Events v3.0 score. Cognitive disturbance and motor neuropathy were the most common late side effects. Others including memory disturbance, speech impairment, encephalopathy, seizures, and hemorrhage were also observed.
The purpose of this study was to analyze long-term treatment outcomes in patients with atypical meningioma treated with surgical resection with or without postoperative adjuvant radiotherapy at a single institution. To the best of our knowledge, the present work is one of the largest series ever published dealing with only atypical histology and with a focus on the usefulness of ART in this group of patients.
Summary of recent atypical meningioma studies
Atypical histology (%)
5Y PFS (%)
Progression ART (+) vs. (−)
Pasquier et al. 
Gabeau-Lacet et al. 
p = 0.83
Aghi et al. 
Mair et al. b
Komotar et al. 
p = 0.085
Adeberg et al. b
Hardesty et al. b
p = 0.029
The present study failed to demonstrate that improvement of local control obtained with the addition of ART could lead to an increase in the overall survival rate. Nevertheless, it is important to put efforts into preventing local tumor progression because recurrence causes additional treatment burden to patients, both emotionally and economically, and multiple re-treatments including craniotomies possibly give rise to morbidity.
Despite growing evidence that postoperative radiotherapy helps to lower local recurrence, some clinicians still advocate to offer salvage treatments only after local failure is evident. The main argument against early ART is the concern about possible late neurotoxicity. However, van Nieuwenhuizen et al.  demonstrated that radiotherapy following surgery did not have additional deleterious effects on impaired long-term neurocognitive functioning in meningioma patients. In the subsequent study, it was suggested that neurocognitive deficits could be partly attributed to the use of antiepileptic drugs and tumor location but not to the use of radiotherapy . Therefore, deferring ART for the fear of radiotherapy-induced neurotoxicity should not be done.
In the 2000/2007 WHO classification, a mitotic rate >4 per 10 high-power fields was considered as the most important factor defining atypical meningioma. In patients with a lower mitotic rate, the presence of at least three of the following variables is necessary: (1) increased cellularity, (2) macronuclei, (3) prominent nucleoli, (4) a sheet-like growth pattern, and (5) necrosis. The diagnosis of atypical meningioma in the present work was made according to this updated WHO criteria. Considering that most publications predated the 2000 WHO grading change and only three studies in Table 4 have adopted the new WHO classification [9, 10, 15], our study is valuable in that it can set up the indications for ART according to the newly defined atypical meningioma. Moreover, we are anticipating the results of two ongoing phase II trials (NCT00626730 and RTOG 0539), which are examining the role of radiotherapy following resection in the management of these patients. However, the results will not be available in the near future. We believe this makes the present study more relevant to current clinical practice for the time-being.
It is important to recognize the limitations of this study. Firstly, due to the retrospective nature, conclusions drawn from our study need further validation through prospective trials. Secondly, the decision to undergo postoperative ART was at the discretion of referring surgeons rather than objective parameters, such as the extent of residual disease, although close observation after tumor resection tends to be the choice for young patients or completely resected tumor in our institution. This may hamper appropriate evaluation of the efficacy of ART in local control. Thirdly, retrospective grading of treatment complications had its inborn limitations including difficulty in distinguishing disease related symptoms from treatment related symptoms.
Surgical resection followed by ART led to lower local tumor progression in patients with atypical meningioma defined by the updated 2000/2007 WHO classification. This result would contribute to a growing number of series that support routine ART as an adjuvant treatment for these lesions, especially after incomplete resection.
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