Journal of Neuro-Oncology

, Volume 115, Issue 2, pp 241–247 | Cite as

The role of adjuvant radiotherapy in atypical meningioma

  • Hae Jin Park
  • Hyun-Cheol Kang
  • Il Han Kim
  • Sung-Hye Park
  • Dong Gyu Kim
  • Chul-Kee Park
  • Sun Ha Paek
  • Hee-Won Jung
Clinical Study

Abstract

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.

Keywords

Meningioma Atypical meningioma Radiotherapy Postoperative radiotherapy Adjuvant radiotherapy 

Introduction

Meningiomas account for ~34 % of all primary intracranial tumors [1]. 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

Our study included 50 female and 33 male patients. The median age at diagnosis of atypical meningioma was 52 years (range, 24–78 years). Tumor locations were divided into the following 5 categories: (1) convexity (n = 43), (2) parasagittal/falx (n = 20), (3) skull base/sphenoid ridge (n = 10), (4) sella/parasella (n = 6), (5) and other (n = 4). Of the 83 patients, 77 (92.8 %) had clinical symptoms before diagnosis. Frequent symptoms at presentation were headache, visual deficits, gait disturbance, aphasia/dysphasia, seizures, and dizziness. One patient had neurofibromatosis type 2, and 2 patients had a history of leukemia. The median mitosis number per 10 high power fields was 5. The proliferation index Ki-67 was available in 67 patients. The details of the characteristics are summarized in Table 1.
Table 1

Patient and treatment characteristics

Characteristics

Total (%)

Number of patients

ART(+) group

ART(−) group

Age

 ≤60

62 (74.7 %)

16

46

 >60

21 (25.3 %)

11

10

Gender

 Male

33 (39.8 %)

13

20

 Female

50 (60.2 %)

14

36

Location

 Convexity

43 (51.8 %)

12

31

 Parasagittal/falx

20 (24.1 %)

10

10

 Skull base/sphenoid ridge

10 (12.0 %)

2

8

 Sella/parasella

6 (7.2 %)

1

5

 Other

4 (4.8 %)

2

2

Mitosis/10 high-power fields

 ≤5

51 (61.4 %)

21

30

 >5

31 (37.3 %)

6

25

 Unknown

1 (1.2 %)

0

1

Ki-67

 ≤10 %

59 (71.1 %)

15

44

 >10 %

8 (9.6 %)

2

6

 Unknown

16 (19.3 %)

10

6

Resection status

 Complete

55 (66.3 %)

  

 Subtotal

25 (30.1 %)

  

 Unknown

3 (3.6 %)

  

Adjuvant radiotherapy

 Yes

27 (32.5 %)

  

 No

56 (67.5 %)

  

Treatment characteristics

All 83 patients had surgical resection of the tumor with radical aim. Completeness of resection was evaluated based on surgical records. GTR or Simpson Grade I–II was regarded as complete resection, which was achieved in 55 patients (66.3 %). Information regarding resection status was unavailable in 3 patients. Twenty-seven out of 88 (32.5 %) patients received ART following surgical intervention, and 56 (67.5 %) were observed without adjuvant treatment. Seventeen patients were treated with ART even after complete resection, and 18 patients were not treated despite incomplete resection (Fig. 1). ART was given using a median dose was 61.2 Gy (range 40–61.2 Gy) over 7 weeks with photon. All the patients except one with poor performance status were treated with over 54 Gy. Conventional RT until 2002 and three-dimensional conformal RT thereafter were used in 9 and 27 patients, respectively. Neither fractionated stereotactic RT nor intensity-modulated RT was applied. Clinical target volume (CTV) encompassed residual enhancing lesions, if existed, and the entire resection cavity with a 1.5 cm margin for the large field and with a 0.5 cm margin for the cone-down field adhering to the anatomical borders. To account for setup inaccuracy, a 0.3 cm margin was added to CTV for planning target volume.
Fig. 1

Flow diagram of resection status and adjuvant treatment

Statistical analysis

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 [14]. 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.

Results

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

PFS was significantly higher in patients undergoing ART after surgical resection than those not undergoing ART (58.7 vs. 44.3 % at 5 years, p = 0.029) (Fig. 2a). Resection status had a significant impact on PFS (58.6 % in complete resection vs. 30.3 % in others at 5 years, p = 0.012) (Fig. 2b). Female patients showed marginally lower PFS (p = 0.068). A high Ki-67 proliferation index with a cutoff value of 10 % was also significantly correlated with lower PFS (p = 0.045), but it was excluded from multivariate analysis due to missing data. Other variables including age at diagnosis, and mitotic count did not have any influence on PFS. On multivariate analysis, addition of ART (p = 0.016) and complete tumor resection (p = 0.002) were associated with superior PFS, whereas gender was not (p = 0.085) (Table 2).
Fig. 2

Progression-free survival rate according to a adjuvant radiotherapy, b resection status of tumors, and c resection status of tumors and adjuvant radiotherapy

Table 2

Prognostic factors for progression-free survival and overall survival

 

PFS

OS

Univariate

Multivariate

Univariate

Multivariate

Age (≤60 vs. >60)

0.587

 

0.002

0.005

Gender

0.068

0.085

0.491

 

ART

0.029

0.016

0.082

0.380

Completion of resection

0.012

0.002

0.846

 

High mitotic rate (≤5 vs. >5/10HPF)

0.939

 

0.302

 

Ki-67a (≤10 vs. >10 %)

0.045

 

0.639

 

PFS progression-free survival, OS overall survival, ART adjuvant radiotherapy, HPF high-power fields

a67 Patients’ data available for analysis

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

Of 37 patients with disease progression, 30 (81.1 %) received at least one course of salvage therapy. Treatment of choice as the first-salvage treatment at our institution was radiosurgery using Gamma Knife irrespective of previous radiotherapy history, which constituted 70.0 % (21 out of 30 treatments) of first-salvage therapy. Twenty-four out of 56 (42.9 %) in the resection only group and 6 out of 27 (22.2 %) in the ART addition group received salvage therapy. The salvage treatment option related details are summarized in Table 3. Five patients had more than three courses of treatment after disease recurrence with various combinations of modalities. Chemotherapy was used in one patient.
Table 3

Details of first-salvage treatment according to primary therapy

Salvage options

Resection only (n = 27)

ART addition (n = 10)

Resection alone

2

2

Resection + ART

4

0

EBRT (IMRT)

1

0

Gamma knife radiosurgery

17

4

None

3

4

ART adjuvant radiotherapy, EBRT external radiotherapy, IMRT intensity modulated radiotherapy

Complications

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.

Discussion

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.

Survival outcomes of the current study are comparable to those of recent other atypical meningioma series (Table 4) [6, 7, 9, 15, 16, 17]. The results from the current study demonstrated a significant benefit of ART by showing reduced tumor progression following surgery, especially for the patients who underwent less than GTR, as these patients achieved similar PFS with the addition of postoperative radiotherapy covering gross residual disease and tumor bed. While the use of ART after incomplete resection in atypical meningiomas has been accepted as a standard treatment, the optimal treatment after complete tumor resection still remains uncertain. Studies shown in Table 4 have presented inconsistent outcomes in relation to the effects of ART. Mair et al. [9] represented that radiotherapy after first-time resection was beneficial only for patients who had undergone subtotal resection and favored radiosurgery after tumor progression rather than early ART after surgery. The most recent study by Hardesty et al. [10] reported neither ART nor adjuvant radiosurgery affected tumor recurrence rate. However, the group treated with GRT followed by adjuvant ART or radiosurgery showed 100 % PFS, even though 39 (17.1 %) and 32(14.0 %) patients had ART and adjuvant radiosurgery, respectively. On the contrary, Aghi et al. [6] reported high recurrence rates without postoperative radiation although all their patients underwent GTR. Nevertheless, they could not evaluate the influence of ART on tumor progression because only 7.4 % patients had ART. Komotar et al. [7] also included only GTR cases in their study and presented that there was no recurrence in 92 % patients who received postoperative radiotherapy whereas in 59 % patients who did not (p = 0.085), demonstrating a strong trend toward improved local control with ART. The virtue of postoperative radiotherapy, especially covering the entire tumor bed, could be reasonably inferred from these two studies, because they excluded the most powerful confounding factor, the completeness of resection.
Table 4

Summary of recent atypical meningioma studies

Authors

Years

Median f/u

Pts no.

Atypical histology (%)

GTR (%)

ART (%)

5Y PFS (%)

Progression ART (+) vs. (−)

Pasquier et al. [17]

2008

49 mo

119

68.9

NR

79.7

58a

NR

Gabeau-Lacet et al. [16]

2009

29 mo

47

100

74

23

48

p = 0.83

Aghi et al. [6]

2009

39 mo

108

100

100

7.4

59

Not significant

Mair et al. [9]b

2011

NR

114

100

57.9

26.3

47

Not significant

Komotar et al. [7]

2012

44 mo

45

100

100

28.9

65

p = 0.085

Adeberg et al. [15]b

2012

73 mo

85

72.9

41.2

60.0

50

NR

Hardesty et al. [10]b

2013

52 mo

228

100

58.0

17.1

NR

Not significant

Current study

2013

43 mo

83

100

66.3

32.5

48

p = 0.029

NR not reported, GTR gross total resection, ART adjuvant radiotherapy, 5YPFS 5-year progression-free survival

aAnalysis of atypical and malignant histology together

b2000/2007 updated WHO classification adopted

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. [18] 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 [19]. 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, 1015], 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.

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. 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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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Hae Jin Park
    • 1
    • 2
  • Hyun-Cheol Kang
    • 1
  • Il Han Kim
    • 1
  • Sung-Hye Park
    • 3
  • Dong Gyu Kim
    • 4
  • Chul-Kee Park
    • 4
  • Sun Ha Paek
    • 4
  • Hee-Won Jung
    • 4
  1. 1.Department of Radiation OncologySeoul National University Hospital, Seoul National University College of MedicineSeoulKorea
  2. 2.Department of Radiation Oncology and CyberKnife CenterSoonchunhyang University HospitalSeoulKorea
  3. 3.Department of PathologySeoul National University College of MedicineSeoulKorea
  4. 4.Department of NeurosurgerySeoul National University College of MedicineSeoulKorea

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