- Email: [email protected]
Atypical and Malignant Meningioma: Outcome and Prognostic Factors in 119 Irradiated Patients. A Multicenter, Retrospective Study of the Rare Cancer Network
Int. J. Radiation Oncology Biol. Phys., Vol. 71, No. 5, pp. 1388–1393, 2008 Copyright Ó 2008 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/08/$–see front matter
doi:10.1016/j.ijrobp.2007.12.020
CLINICAL INVESTIGATION
Brain
ATYPICAL AND MALIGNANT MENINGIOMA: OUTCOME AND PROGNOSTIC FACTORS IN 119 IRRADIATED PATIENTS. A MULTICENTER, RETROSPECTIVE STUDY OF THE RARE CANCER NETWORK DAVID PASQUIER, M.D., PH.D.,* STEFAN BIJMOLT, M.D.,y THEO VENINGA, M.D.,y NICOLAS REZVOY, M.D.,* SALVADOR VILLA, M.D.,z MARCO KRENGLI, M.D.,x DAMIEN C. WEBER, M.D.,k BRIGITTA G. BAUMERT, M.D., PH.D.,{ EMINE CANYILMAZ, M.D.,# DENIZ YALMAN, M.D.,** EWA SZUTOWICZ, M.D.,yy TZAHALA TZUK-SHINA, M.D.,zz AND RENE´ O. MIRIMANOFF, M.D.xx; RARE CANCER NETWORK * Department of Radiation Oncology, Centre O. Lambret and University Lille II, Lille, France; y Department of Radiation Oncology, Dr. Bernard Verbeeten Instituut, Tilburg, The Netherlands; z Department of Radiation Oncology, H.U. Germans Trı´as, ICO-Badalona, Barcelona, Spain; x Department of Radiotherapy, University of Piemonte Orientale, Hospital Maggiore della Carita, Novara, Italy; k Department of Radiation Oncology, University Hospital, Geneva, Switzerland; { Department of Radiation Oncology (MAASTRO), GROW, University Hospital Maastricht, The Netherlands; # Department of Radiation Oncology, Karadeniz Technical University Faculty of Medicine, Trabzon, Turkey; ** Department of Radiation Oncology, Ege University Faculty of Medicine, Izmir, Turkey; yy Department of Radiation Oncology, Medical University of Gdansk, Gdansk, Poland; zz Northern Israel Oncology Centre, Rambam Medical Centre, Haifa, Israel; and xx Department of Radiation Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland Purpose: To retrospectively analyze and assess the outcomes and prognostic factors in a large number of patients with atypical and malignant meningiomas. Methods and Materials: Ten academic medical centers participating in this Rare Cancer Network contributed 119 cases of patients with atypical or malignant meningiomas treated with external beam radiotherapy (EBRT) after surgery or for recurrence. Eligibility criteria were histologically proven atypical or anaplastic (malignant) meningioma (World Health Organization Grade 2 and 3) treated with fractionated EBRT after initial resection or for recurrence, and age >18 years. Sex ratio (male/female) was 1.3, and mean (±SD) age was 57.6 ± 12 years. Surgery was macroscopically complete (Simpson Grades 1–3) in 71% of patients; histology was atypical and malignant in 69% and 31%, respectively. Mean dose of EBRT was 54.6 ± 5.1 Gy (range, 40–66 Gy). Median follow-up was 4.1 years. Results: The 5- and 10-year actuarial overall survival rates were 65% and 51%, respectively, and were significantly influenced by age >60 years (p = 0.005), Karnofsky performance status (KPS) (p = 0.01), and high mitotic rate (p = 0.047) on univariate analysis. On multivariate analysis age >60 years (p = 0.001) and high mitotic rate (p = 0.02) remained significant adverse prognostic factors. The 5- and 10-year disease-free survival rates were 58% and 48%, respectively, and were significantly influenced by KPS (p = 0.04) and high mitotic rate (p = 0.003) on univariate analysis. On multivariate analysis only high mitotic rate (p = 0.003) remained a significant prognostic factor. Conclusions: In this multicenter retrospective study, age, KPS, and mitotic rate influenced outcome. Multicenter prospective studies are necessary to clarify the management and prognostic factors of such a rare disease. Ó 2008 Elsevier Inc. Meningioma, Atypical meningioma, Malignant meningioma, Anaplastic meningioma, Radiotherapy.
Meningiomas are neoplasms that arise from meninges of the brain and spinal cord. Their annual incidence is approximately 6 per 100,000 (1). These tumors occur preferentially in middle-aged or elderly patients but can also occur in youn-
ger patients, typically with neurofibromatosis Type 2. Meningiomas constitute approximately 20% of all brain tumors, and at least 90% are histologically benign. A minority of these tumors present with clinical and histologic features suggesting aggressive potential (atypical and malignant meningiomas).
Reprint requests to: David Pasquier, M.D., Ph.D., Department of Radiation Oncology, Centre O. Lambret, University Lille II, 3 rue F. Combemale, 59020 Lille, France. Tel: (+33) 3-20-29-59-11; Fax: (+33) 3-20-29-59-72; E-mail: [email protected] Presented at the 49th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO), October
28–November 1, 2007, Los Angeles, CA. Conflict of interest: none. Acknowledgments—The authors thank Charles Fournier of the Biostatistics Unit at the Centre Oscar Lambret. Received June 29, 2007, and in revised form Dec 3, 2007. Accepted for publication Dec 5, 2007.
INTRODUCTION
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Atypical and malignant meningioma d D. PASQUIER et al.
Atypical and malignant meningiomas constitute approximately 5–7% and 1–3% of meningiomas, respectively (2–4). A large range of prevalence data for these aggressive forms has been reported, owing to the use of different classification systems in the literature (see Discussion). Benign meningiomas occur most often in women, whereas atypical and malignant forms seem to be more frequent in men and more common in cerebral convexities (5). Because of the rarity of this disease, optimal management is difficult to establish. The aim of this retrospective analysis from the Rare Cancer Network was to analyze a sufficiently large number of patients to characterize the prognosis of this disease and to define prognostic factors for patients undergoing radiotherapy. METHODS AND MATERIALS Ten academic medical centers participating in this Rare Cancer Network contributed 119 cases of patients with atypical or malignant meningiomas treated with external beam radiotherapy (EBRT) after surgery or for recurrence. Eligibility criteria were histologically proven atypical or anaplastic (malignant) meningioma (World Health Organization [WHO] Grade 2 and 3) treated with fractionated EBRT after initial resection or for recurrence, and age >18 years. A previous benign histology was accepted, providing that radiotherapy was delivered for a non-benign recurrence. All patient data were collected through retrospective chart review from 1971 to 2005 (16 patients before 1990, 103 after 1990). Histologic slides were not centrally reviewed.
Patient characteristics Sex ratio (male/female) was 1.3, and mean (SD) age was 57.6 12 years. Sixteen patients (13.4%) presented first with benign meningioma; the median interval between benign and atypical or malignant histology was 2.8 5 years. Karnofsky performance status (KPS) was at least 80 in 86 of 119 patients (range, 40–100). Median neurologic functional status was 1 (range, 0–4). Patients presented with headaches, pyramidal tract dysfunction, cognitive disturbance, and seizure in 40%, 35%, 27%, and 25%, respectively. Location of meningioma was most commonly in the cerebral convexity. Surgery was macroscopically complete (Simpson Grades 1–3) in 71% of the patients. Histology was atypical and malignant in 69% and 31%, respectively.
Treatment characteristics Radiotherapy was administered after initial resection in 94 patients and for recurrence with or without resection in 25 patients. The technique was conventional, three-dimensional conformal, and unknown in 30.4%, 68.8%, and 0.8% of the patients, respectively; 20.2% and 79.8% of the patients were treated with cobalt and a linear accelerator, respectively. Mean dose was 54.6 5.1 Gy (range, 40–66 Gy). Five patients received a second course of radiotherapy; median interval between the two courses was 2 years (range, 1–8 years), and median dose of the second course was 47.5 Gy (range, 40–56 Gy). Median follow-up was 4.1 years. Late toxicity was assessed according to the Common Terminology Criteria for Adverse Events v3.0 score (http://ctep.cancer.gov/forms/CTCAEv3.pdf). Patients and treatment characteristics are summarized in Table 1.
Statistics Overall survival and disease-free survival were calculated from the date of surgery for atypical or malignant meningioma by the
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Table 1. Patient and treatment characteristics Age (y), mean SD Sex KPS, median (range) NFS, median (range) Location Convexity Falx and parasagittal Sphenoid ridge Other Histology Atypical (Grade 2) Malignant (Grade 3) Presence of high mitotic rate Nuclear atypia Necrosis Brain invasion Radiotherapy dose (Gy), mean SD (range) Dose per fraction 1.8 Gy 2 Gy
57.6 12 51 female; 68 male 90 (40–100) 1 (0–4) 60/119 (50.4) 32/119 (26.9) 16/119 (13.4) 11/119 (9.3) 82/119 (68.9) 37/119 (31.1) 41/84 74/86 44/94 15/80 54.6 5.1 (40–66) 39/119 (33) 80/119 (67)
Abbreviations: KPS = Karnofsky performance status; NFS = neurologic functional status. Values are number (percentage) unless otherwise noted. Kaplan-Meier method. The log–rank test was used to compare different survival functions according to clinical (age, KPS, neurologic functional status, benign meningioma at first presentation, grade, high mitotic rate, necrosis brain invasion) and therapeutic factors (extent of resection, radiotherapy dose, type of radiotherapy); Cox model was used for continuous variables. Multivariate analysis was performed by Cox stepwise regression analysis to define the independent contribution of each factor. Missing data in more than 33% of the patients (number of mitotic figures in 10 high-power fields [HPF], presence of increased cellularity, presence of high ratio of nucleus to cytoplasm, presence of prominent nucleoli, presence of sheet-like growth pattern, presence of frank anaplasia, Ki67 proliferative index) were excluded from statistical analysis. All p values were derived from log–rank tests; a p value of #0.05 was considered to indicate statistical significance.
RESULTS At last follow-up, 50 patients presented with relapse; this relapse was intracerebral in 46 patients, extracerebral in 1 case, and both in 3 cases. Among these 50 patients, 30 presented first with a Grade 2 meningioma, and 9 of them presented with Grade 3 at relapse. Treatment of relapse was surgery followed by EBRT, EBRT alone, and surgery alone in 20, 5, and 18 patients, respectively. From relapse, overall survival of these 50 patients was 54% and 36% at 3 and 5 years, respectively; their median overall survival was 3.7 years. The actuarial overall survival rate was 65% and 51% at 5 and 10 years, respectively (median 10.5 years) (Fig. 1) and was significantly influenced by age >60 years (p = 0.005), KPS (p = 0.01), and high mitotic rate (p = 0.047) on univariate analysis (Table 2). On multivariate analysis age >60 years (p = 0.001) and high mitotic rate (p = 0.02) remained significant adverse prognostic factors (Table 2, Figs. 2 and 3).
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were found to have histologically proven (biopsy and autopsy) liver metastasis and bone and liver metastasis. These two patients died from progressive disease 15 and 20 months after the diagnosis of distant metastasis. A patient with liver metastasis received chemotherapy (dacarbazine) without evidence of clinical benefit. Late toxicity occurred in 15 patients (12.6%); the most common symptom was cognitive disturbance (7 patients). Grade 2 and 3 complications were found in 4 and 6 patients, respectively (Table 3). DISCUSSION To the best of our knowledge the present series is one with the most important strength of atypical and malignant meningiomas ever published. The limits of this series are its retrospective character and the absence of second review of the histologic slides. All patients were treated with radiotherapy after surgery of for recurrence; as such, this analysis could not address the value of adjuvant radiotherapy. Despite these limits this large series confirmed a different sex ratio and tumor localization than in benign forms and allowed the characterization of certain prognostic factors, such as age, KPS, and mitotic rate. In our series 57.1% of patients were men, in accord with data in the literature suggesting that the gender ratio of atypical and malignant meningioma is different from that of benign forms, which are more frequent in women (1, 2, 5). Similarly, in our patients atypical and malignant forms were more frequent in the cerebral convexity, as previously described (5, 6). In our study age >60 years was an adverse prognostic factor for overall survival on multivariate analysis (p = 0.001). In a series reported by Milosevic et al. (8), age <40 years was associated with a favorable outcome. In our series the completion of resection was not a significant prognostic factor, probably because of the difficulty to retrospectively assess the completion of resection. Indeed, completion
Fig. 1. Overall and relapse-free survival in 119 patients with atypical and malignant meningioma.
The rates of 5- and 10-year disease-free survival were 58% and 48%, respectively; the median time to recurrence was 2.1 years (range, 0.1–19.6 years) (Fig. 1). Disease-free survival was significantly influenced by KPS (p = 0.04) and high mitotic rate (p = 0.003) on univariate analysis. On multivariate analysis high mitotic rate (p = 0.003) remained a significant prognostic factor (Fig. 4). Extent of resection, brain invasion, and EBRT dose were not significant prognostic factors, neither for overall survival nor for disease-free survival (Table 2). Meningioma grade did not significantly influence overall survival or disease-free survival. The 5-year overall survival rate was 67.5% and 60% for patients with Grade 2 and 3 meningiomas, respectively (p = 0.6). The 5-year disease-free survival rate was 62% and 48% for patients with Grade 2 and 3 meningiomas, respectively (p = 0.18). Overall survival and disease-free survival according to grade is represented in Fig. 5. In this series 6 patients presented with skin or other distant metastasis. Four patients (2 patients with Grade 2 and 2 patients with Grade 3) presented skin metastasis near the surgical incision. Two patients with Grade 3 meningiomas
Table 2. Prognostic factors for overall and disease-free survival Overall survival (p)
Disease-free survival (p)
Prognostic factor
Univariate analysis
Multivariate analysis
Univariate analysis
Age <60 or >60 y Sex KPS (continuous variable) NFS Completion of resection (complete vs. incomplete) Simpson grade Grade (2 vs. 3) High mitotic rate Benign meningioma at first presentation Necrosis Brain invasion EBRT dose Type of radiotherapy (cobalt vs. linear accelerator)
0.005* 0.6 0.01* 0.08 0.19 0.09 0.6 0.047* 0.09 0.18 0.56 0.28 0.41
0.001*
0.95 0.2 0.04* 0.12 0.36 0.16 0.18 0.03* 0.82 0.18 0.23 > 0.05 0.43
0.25
0.02*
Abbreviations: EBRT = external beam radiotherapy. Other abbreviations as in Table 1. * p < 0.05.
Multivariate analysis
0.95
0.003*
Atypical and malignant meningioma d D. PASQUIER et al.
Fig. 2. Overall survival in 119 patients with atypical and malignant meningioma according to age >60 or <60 years (p = 0.001 on multivariate analysis).
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Fig. 4. Relapse-free survival in 84 patients with atypical and malignant meningioma according to mitotic rate (p = 0.003 on multivariate analysis).
of resection was associated with outcome in several series. Goyal et al. (2) reported that 8 of 22 patients with atypical meningiomas received adjuvant radiotherapy or radiotherapy for relapse. The overall 5- and 10-year survival rates were 91% and 76%, respectively. Patients with gross total resection had 5- and 10-year control rates of 87% and 87%, whereas patients with either subtotal resection or resection of unknown extent had local control rates of 51% and 17%, respectively (p = 0.02). In a series reported by Palma et al. (9), radical excision was significantly related to prolonged survival on multivariate analysis (p < 0.0003). Considering patients with incomplete resection, the survival curve of atypical meningioma was not significantly different from that of malignant meningioma (9). Ja¨a¨skelainen et al. (1) regarded Simpson Grades 1 and 2 as ‘‘complete resection,’’ but in a later study Ja¨a¨skelainen (10) found that simple coagulation of the dura mater (Grade 2) vs. excision (Grade 1) doubled the recurrence rate in that series of benign meningiomas. In our series actuarial overall survival and disease-free survival rates were 51% and 48% at 10 years, respectively, and were not influenced by the meningioma grade as in the Milosevic et al. series (8), in which 5-year specific survival was 34%. This is probably related to a default of reproducibility of grading between institutions and over the duration of the
study; the groups of patients with Grade 2 or 3 meningiomas were comparable in terms of completion of excision and adjuvant EBRT. Conversely, in Palma et al. (9) and a Mayo clinic series (7) the outcome was influenced by grade. In the Palma et al. series (9), 71 patients (42 Grade 2 and 29 Grade 3) received adjuvant radiotherapy or radiotherapy for relapse. The overall survival rate at 10 years was 79% and 34% in atypical and malignant meningiomas, respectively (p = 0.001); median recurrence-free survival was 11.9 and 2 years, respectively (p = 0.001). In the Mayo Clinic series (7), 32 of the 104 patients received external beam therapy and/or radiosurgery after their first malignant diagnosis. Median follow-up was 3.7 years. Rates of 5- and 10-year mortality were 38% and 53%, respectively, with a median survival of 7.5 years. Estimated 5-year mortality rates in benign, atypical, and ‘‘frankly’’ anaplastic brain invasive meningiomas were 27%, 25%, and 83%, respectively. Median survival was 14.9 years, 10.4 years, and 1.4 years, respectively. Survival was significantly shorter in the anaplastic group (p < 0.0001) (7). Mitotic rate was a significant prognostic factor for overall and relapse-free survival in our study, but we were not able to determine a significant threshold. Mitotic rate is a wellknown prognostic factor in the literature. In two studies Perry et al. attempted to develop a reproducible grading for
Fig. 3. Overall survival in 84 patients with atypical and malignant meningioma according to mitotic rate (p = 0.02 on multivariate analysis).
Fig. 5. Overall survival and disease-free survival in 119 patients with atypical and malignant meningioma according to grade.
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Table 3. Late toxicity (CTCAE v3.0 score) Grade 1 2 3 4
Brain necrosis
Cognitive disturbance
Memory impairment
Mood alteration
1 1
1
1
2 2 2 1
Pyramidal dysfunction
1
Seizure
3
Total 3 4 6 2
Abbreviation: CTCAE = common terminology criteria for adverse events.
meningioma. In the first (11), 581 consecutive patients were analyzed. Brain invasion, sheeting, absence of nuclear atypia, and a maximal mitotic rate greater than 4 per 10 HPF were univariately associated with decreased recurrence-free survival. The investigators recommended that ‘‘atypical’’ meningiomas be defined by the presence of at least three of these features: sheeting, macronuclei, hypercellularity, small-cell formation, or a minimum of 4 mitoses per 10 HPF (11). In their second work (7), Perry et al. expanded their analysis to 116 patients diagnosed with ‘‘malignant’’ meningioma. On multivariate analysis, histologic parameters that remained significant were anaplasia, extent of resection, >20 mitoses per 10 HPF, and nuclear atypia. The median survival for ‘‘frankly’’ anaplastic meningioma was 1.5 years, and the 5-year mortality rate was 68% (7). In the last WHO classification (4), a mitotic rate >4 per 10 HPF was considered as the most important factor to define atypical meningioma. In patients with a lower mitotic rate, the presence of at least three of the following variables is necessary: increased cellularity, macronuclei, prominent nucleoli, sheet-like growth pattern, and necrosis. Malignant meningioma is defined as the presence of a mitotic rate >20 per 10 HPF or ‘‘obvious’’ malignant cytology, or both. The significance of brain invasion has been debated widely and is not one of the criteria used for grading tumors in the WHO classification, but it should always be considered because it is associated with a higher recurrence rate (11, 12). Ki67 (MIB-1) proliferative index was missing in more than one third of our patients and was excluded from statistical analysis. Ming-Tak Ho et al. (13) found MIB-1 to be a powerful prognostic marker, and a cutoff point of 10% discriminated tumors in patients with different prognoses. In the literature, although a poor prognosis may be associated with a high MIB-1 labeling index, significant overlap exists in the MIB-1 labeling ranges for benign, atypical, and anaplastic meningiomas. Furthermore, because of differences in staining and counting methods, a cutoff point identified in one laboratory may not be usable in others. Genetic alterations are often present in meningiomas. Weber et al. (14) identified different genomic alterations in benign, atypical, and malignant meningiomas. Murakami et al. (15) also suggested that 10q loss may contribute to malignant progression. As in Weber et al., 9p deletions were associated with malignant progression and poor prognosis in malignant meningiomas in Perry et al. (16). In the future,
genomic alterations could be useful to appraise prognosis and to propose adapted treatments. Our study does not allow consideration of the role of adjuvant radiotherapy. Adjuvant radiotherapy after incomplete resection (benign or aggressive meningioma) has not been evaluated in a prospective study to date (17). Some retrospective trials promote adjuvant radiotherapy after incomplete resection in patients with atypical meningioma, and independently of the status of resection in malignant meningioma (6). The role of adjuvant radiotherapy in completely resected (Simpson Grade 1) atypical meningioma is unclear. In our patients the outcome was not related to radiotherapy dose, whereas in certain series EBRT dose is a prognostic factor. In Milosevic et al. (8), dose >50 Gy and age <40 years were the two prognostic factors associated with a favorable outcome on multivariate analysis. The use of dose <50 Gy is not optimal in patients with meningioma, as in benign meningioma, in which a dose–response relationship for local control was shown up to 52 Gy in retrospective series but not beyond (17, 18). The roles of dose escalation (dose >55–60 Gy) and radiosurgery in aggressive meningioma have not been evaluated in a controlled, prospective study. Extracerebral metastasis can be encountered in patients with atypical or malignant meningiomas. In our study 6 patients (2 Grade 2 and 4 Grade 3) presented with skin metastasis near the surgical excision or histologically proven liver and bone metastasis. In the Mayo Clinic series (7), 3 of 27 patients with ‘‘frankly’’ anaplastic meningiomas presented with distant metastasis. In the Milosevic et al. series (8), 4 of 59 patients with atypical and malignant meningiomas presented pathologically distant bone metastases.
CONCLUSIONS Multicenter, prospective studies are necessary to clarify management and more relevant prognostic factors. The role of dose escalation and/or stereotactic radiotherapy (fractionated or not) could be prospectively evaluated. A European Organization for Research and Treatment of Cancer Phase II study (22042-26042) evaluating adjuvant postoperative high-dose radiotherapy for atypical and malignant meningioma recently opened. The determination of many relevant prognostic factors, such as genetic alterations, could allow the proposal of more tailored treatments.
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REFERENCES 1. Ja¨a¨skelainen J, Haltia M, Servo A. Atypical and anaplastic meningiomas: Radiology, surgery, radiotherapy and outcome. Surg Neurol 1986;25:233–242. 2. Goyal L, Suh J, Mohan D, et al. Local control and overall survival in atypical meningioma: A retrospective study. Int J Radiat Oncol Biol Phys 2000;46:57–61. 3. Pourel N, Auque J, Bracard S, et al. Efficacy of external fractionated radiation therapy in the treatment of meningiomas: A 20-year experience. Radiat Oncol 2001;61:65–70. 4. Kleihues P, Cavenee W, editors. World Health Organization classification of tumors: Pathology and genetics of tumors of the nervous system. Lyon, France: IARC Press; 2000. 5. Mahmood A, Caccamo D, Tomecek F, et al. Atypical and malignant meningiomas: A clinicopathological review. Neurosurgery 1993;33:955–963. 6. Modha A, Gutin P. Diagnosis and treatment of atypical and anaplastic meningiomas: A review. Neurosurgery 2005;57: 538–550. 7. Perry A, Scheithauer BW, Stafford SL, et al. ‘‘Malignancy’’ in meningiomas: A clinicopathologic study of 116 patients, with grading implications. Cancer 1999;85:2046–2056. 8. Milosevic MF, Frost PJ, Lapierre NJ, et al. Radiotherapy for atypical or malignant intracranial meningioma. Int J Radiat Oncol Biol Phys 1996;34:817–822. 9. Palma L, Celli P, Franco C, et al. Long-term prognosis for atypical and malignant meningiomas: A study of 71 surgical cases. J Neurosurg 1997;86:793–800. 10. Ja¨a¨skelainen J. Seemingly complete removal of histologically benign intracranial meningioma: Late recurrence rate and factors predicting recurrence in 657 patients. A multivariate analysis. Surg Neurol 1986;26:461–469.
11. Perry A, Stafford SL, Scheithauer BW, et al. Meningioma grading: An analysis of histologic parameters. Am J Surg Pathol 1997;21:1455–1465. 12. Whittle I, Smith C, Navoo P, et al. Meningiomas. Lancet 2004; 363:1535–1543. 13. Ming-Tak Ho D, Hsu C, Ting L, et al. Histopathology and MIB-1 labeling index predicted recurrence of meningiomas. A proposal of diagnostic criteria for patients with atypical meningioma. Cancer 2002;94:1538–1547. 14. Weber R, Bostrom J, Wolter M, et al. Analysis of genomic alterations in benign, atypical, and anaplastic meningiomas: Toward a genetic model of meningioma progression. Proc Natl Acad Sci U S A 1997;94:14719–14724. 15. Murakami M, Hashimoto N, Takahashi Y, et al. A consistent region of deletion on 1p36 in meningiomas: Identification and relation to malignant progression. Cancer Genet Cytogenet 2003; 140:99–106. 16. Perry A, Banerjee R, Lohse C, et al. A role for chromosome 9p21 deletions in the malignant progression of meningiomas and the prognosis of anaplastic meningiomas. Brain Pathol 2002;12:183–190. 17. Mirimanoff RO. New radiotherapy technologies for meningiomas: 3D conformal radiotherapy? Radiosurgery? Stereotactic radiotherapy? Intensity-modulated radiotherapy? Proton beam radiotherapy? Spot scanning proton radiation therapy. or nothing at all? Radiother Oncol 2004;71:247–249. 18. Goldsmith BJ, Wara WM, Wilson CB, et al. Postoperative irradiation for subtotally resected meningiomas. A retrospective analysis of 140 patients treated from 1967 to 1990. J Neurosurg 1994;80:195–201.
doi:10.1016/j.ijrobp.2007.12.020
CLINICAL INVESTIGATION
Brain
ATYPICAL AND MALIGNANT MENINGIOMA: OUTCOME AND PROGNOSTIC FACTORS IN 119 IRRADIATED PATIENTS. A MULTICENTER, RETROSPECTIVE STUDY OF THE RARE CANCER NETWORK DAVID PASQUIER, M.D., PH.D.,* STEFAN BIJMOLT, M.D.,y THEO VENINGA, M.D.,y NICOLAS REZVOY, M.D.,* SALVADOR VILLA, M.D.,z MARCO KRENGLI, M.D.,x DAMIEN C. WEBER, M.D.,k BRIGITTA G. BAUMERT, M.D., PH.D.,{ EMINE CANYILMAZ, M.D.,# DENIZ YALMAN, M.D.,** EWA SZUTOWICZ, M.D.,yy TZAHALA TZUK-SHINA, M.D.,zz AND RENE´ O. MIRIMANOFF, M.D.xx; RARE CANCER NETWORK * Department of Radiation Oncology, Centre O. Lambret and University Lille II, Lille, France; y Department of Radiation Oncology, Dr. Bernard Verbeeten Instituut, Tilburg, The Netherlands; z Department of Radiation Oncology, H.U. Germans Trı´as, ICO-Badalona, Barcelona, Spain; x Department of Radiotherapy, University of Piemonte Orientale, Hospital Maggiore della Carita, Novara, Italy; k Department of Radiation Oncology, University Hospital, Geneva, Switzerland; { Department of Radiation Oncology (MAASTRO), GROW, University Hospital Maastricht, The Netherlands; # Department of Radiation Oncology, Karadeniz Technical University Faculty of Medicine, Trabzon, Turkey; ** Department of Radiation Oncology, Ege University Faculty of Medicine, Izmir, Turkey; yy Department of Radiation Oncology, Medical University of Gdansk, Gdansk, Poland; zz Northern Israel Oncology Centre, Rambam Medical Centre, Haifa, Israel; and xx Department of Radiation Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland Purpose: To retrospectively analyze and assess the outcomes and prognostic factors in a large number of patients with atypical and malignant meningiomas. Methods and Materials: Ten academic medical centers participating in this Rare Cancer Network contributed 119 cases of patients with atypical or malignant meningiomas treated with external beam radiotherapy (EBRT) after surgery or for recurrence. Eligibility criteria were histologically proven atypical or anaplastic (malignant) meningioma (World Health Organization Grade 2 and 3) treated with fractionated EBRT after initial resection or for recurrence, and age >18 years. Sex ratio (male/female) was 1.3, and mean (±SD) age was 57.6 ± 12 years. Surgery was macroscopically complete (Simpson Grades 1–3) in 71% of patients; histology was atypical and malignant in 69% and 31%, respectively. Mean dose of EBRT was 54.6 ± 5.1 Gy (range, 40–66 Gy). Median follow-up was 4.1 years. Results: The 5- and 10-year actuarial overall survival rates were 65% and 51%, respectively, and were significantly influenced by age >60 years (p = 0.005), Karnofsky performance status (KPS) (p = 0.01), and high mitotic rate (p = 0.047) on univariate analysis. On multivariate analysis age >60 years (p = 0.001) and high mitotic rate (p = 0.02) remained significant adverse prognostic factors. The 5- and 10-year disease-free survival rates were 58% and 48%, respectively, and were significantly influenced by KPS (p = 0.04) and high mitotic rate (p = 0.003) on univariate analysis. On multivariate analysis only high mitotic rate (p = 0.003) remained a significant prognostic factor. Conclusions: In this multicenter retrospective study, age, KPS, and mitotic rate influenced outcome. Multicenter prospective studies are necessary to clarify the management and prognostic factors of such a rare disease. Ó 2008 Elsevier Inc. Meningioma, Atypical meningioma, Malignant meningioma, Anaplastic meningioma, Radiotherapy.
Meningiomas are neoplasms that arise from meninges of the brain and spinal cord. Their annual incidence is approximately 6 per 100,000 (1). These tumors occur preferentially in middle-aged or elderly patients but can also occur in youn-
ger patients, typically with neurofibromatosis Type 2. Meningiomas constitute approximately 20% of all brain tumors, and at least 90% are histologically benign. A minority of these tumors present with clinical and histologic features suggesting aggressive potential (atypical and malignant meningiomas).
Reprint requests to: David Pasquier, M.D., Ph.D., Department of Radiation Oncology, Centre O. Lambret, University Lille II, 3 rue F. Combemale, 59020 Lille, France. Tel: (+33) 3-20-29-59-11; Fax: (+33) 3-20-29-59-72; E-mail: [email protected] Presented at the 49th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO), October
28–November 1, 2007, Los Angeles, CA. Conflict of interest: none. Acknowledgments—The authors thank Charles Fournier of the Biostatistics Unit at the Centre Oscar Lambret. Received June 29, 2007, and in revised form Dec 3, 2007. Accepted for publication Dec 5, 2007.
INTRODUCTION
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Atypical and malignant meningioma d D. PASQUIER et al.
Atypical and malignant meningiomas constitute approximately 5–7% and 1–3% of meningiomas, respectively (2–4). A large range of prevalence data for these aggressive forms has been reported, owing to the use of different classification systems in the literature (see Discussion). Benign meningiomas occur most often in women, whereas atypical and malignant forms seem to be more frequent in men and more common in cerebral convexities (5). Because of the rarity of this disease, optimal management is difficult to establish. The aim of this retrospective analysis from the Rare Cancer Network was to analyze a sufficiently large number of patients to characterize the prognosis of this disease and to define prognostic factors for patients undergoing radiotherapy. METHODS AND MATERIALS Ten academic medical centers participating in this Rare Cancer Network contributed 119 cases of patients with atypical or malignant meningiomas treated with external beam radiotherapy (EBRT) after surgery or for recurrence. Eligibility criteria were histologically proven atypical or anaplastic (malignant) meningioma (World Health Organization [WHO] Grade 2 and 3) treated with fractionated EBRT after initial resection or for recurrence, and age >18 years. A previous benign histology was accepted, providing that radiotherapy was delivered for a non-benign recurrence. All patient data were collected through retrospective chart review from 1971 to 2005 (16 patients before 1990, 103 after 1990). Histologic slides were not centrally reviewed.
Patient characteristics Sex ratio (male/female) was 1.3, and mean (SD) age was 57.6 12 years. Sixteen patients (13.4%) presented first with benign meningioma; the median interval between benign and atypical or malignant histology was 2.8 5 years. Karnofsky performance status (KPS) was at least 80 in 86 of 119 patients (range, 40–100). Median neurologic functional status was 1 (range, 0–4). Patients presented with headaches, pyramidal tract dysfunction, cognitive disturbance, and seizure in 40%, 35%, 27%, and 25%, respectively. Location of meningioma was most commonly in the cerebral convexity. Surgery was macroscopically complete (Simpson Grades 1–3) in 71% of the patients. Histology was atypical and malignant in 69% and 31%, respectively.
Treatment characteristics Radiotherapy was administered after initial resection in 94 patients and for recurrence with or without resection in 25 patients. The technique was conventional, three-dimensional conformal, and unknown in 30.4%, 68.8%, and 0.8% of the patients, respectively; 20.2% and 79.8% of the patients were treated with cobalt and a linear accelerator, respectively. Mean dose was 54.6 5.1 Gy (range, 40–66 Gy). Five patients received a second course of radiotherapy; median interval between the two courses was 2 years (range, 1–8 years), and median dose of the second course was 47.5 Gy (range, 40–56 Gy). Median follow-up was 4.1 years. Late toxicity was assessed according to the Common Terminology Criteria for Adverse Events v3.0 score (http://ctep.cancer.gov/forms/CTCAEv3.pdf). Patients and treatment characteristics are summarized in Table 1.
Statistics Overall survival and disease-free survival were calculated from the date of surgery for atypical or malignant meningioma by the
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Table 1. Patient and treatment characteristics Age (y), mean SD Sex KPS, median (range) NFS, median (range) Location Convexity Falx and parasagittal Sphenoid ridge Other Histology Atypical (Grade 2) Malignant (Grade 3) Presence of high mitotic rate Nuclear atypia Necrosis Brain invasion Radiotherapy dose (Gy), mean SD (range) Dose per fraction 1.8 Gy 2 Gy
57.6 12 51 female; 68 male 90 (40–100) 1 (0–4) 60/119 (50.4) 32/119 (26.9) 16/119 (13.4) 11/119 (9.3) 82/119 (68.9) 37/119 (31.1) 41/84 74/86 44/94 15/80 54.6 5.1 (40–66) 39/119 (33) 80/119 (67)
Abbreviations: KPS = Karnofsky performance status; NFS = neurologic functional status. Values are number (percentage) unless otherwise noted. Kaplan-Meier method. The log–rank test was used to compare different survival functions according to clinical (age, KPS, neurologic functional status, benign meningioma at first presentation, grade, high mitotic rate, necrosis brain invasion) and therapeutic factors (extent of resection, radiotherapy dose, type of radiotherapy); Cox model was used for continuous variables. Multivariate analysis was performed by Cox stepwise regression analysis to define the independent contribution of each factor. Missing data in more than 33% of the patients (number of mitotic figures in 10 high-power fields [HPF], presence of increased cellularity, presence of high ratio of nucleus to cytoplasm, presence of prominent nucleoli, presence of sheet-like growth pattern, presence of frank anaplasia, Ki67 proliferative index) were excluded from statistical analysis. All p values were derived from log–rank tests; a p value of #0.05 was considered to indicate statistical significance.
RESULTS At last follow-up, 50 patients presented with relapse; this relapse was intracerebral in 46 patients, extracerebral in 1 case, and both in 3 cases. Among these 50 patients, 30 presented first with a Grade 2 meningioma, and 9 of them presented with Grade 3 at relapse. Treatment of relapse was surgery followed by EBRT, EBRT alone, and surgery alone in 20, 5, and 18 patients, respectively. From relapse, overall survival of these 50 patients was 54% and 36% at 3 and 5 years, respectively; their median overall survival was 3.7 years. The actuarial overall survival rate was 65% and 51% at 5 and 10 years, respectively (median 10.5 years) (Fig. 1) and was significantly influenced by age >60 years (p = 0.005), KPS (p = 0.01), and high mitotic rate (p = 0.047) on univariate analysis (Table 2). On multivariate analysis age >60 years (p = 0.001) and high mitotic rate (p = 0.02) remained significant adverse prognostic factors (Table 2, Figs. 2 and 3).
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were found to have histologically proven (biopsy and autopsy) liver metastasis and bone and liver metastasis. These two patients died from progressive disease 15 and 20 months after the diagnosis of distant metastasis. A patient with liver metastasis received chemotherapy (dacarbazine) without evidence of clinical benefit. Late toxicity occurred in 15 patients (12.6%); the most common symptom was cognitive disturbance (7 patients). Grade 2 and 3 complications were found in 4 and 6 patients, respectively (Table 3). DISCUSSION To the best of our knowledge the present series is one with the most important strength of atypical and malignant meningiomas ever published. The limits of this series are its retrospective character and the absence of second review of the histologic slides. All patients were treated with radiotherapy after surgery of for recurrence; as such, this analysis could not address the value of adjuvant radiotherapy. Despite these limits this large series confirmed a different sex ratio and tumor localization than in benign forms and allowed the characterization of certain prognostic factors, such as age, KPS, and mitotic rate. In our series 57.1% of patients were men, in accord with data in the literature suggesting that the gender ratio of atypical and malignant meningioma is different from that of benign forms, which are more frequent in women (1, 2, 5). Similarly, in our patients atypical and malignant forms were more frequent in the cerebral convexity, as previously described (5, 6). In our study age >60 years was an adverse prognostic factor for overall survival on multivariate analysis (p = 0.001). In a series reported by Milosevic et al. (8), age <40 years was associated with a favorable outcome. In our series the completion of resection was not a significant prognostic factor, probably because of the difficulty to retrospectively assess the completion of resection. Indeed, completion
Fig. 1. Overall and relapse-free survival in 119 patients with atypical and malignant meningioma.
The rates of 5- and 10-year disease-free survival were 58% and 48%, respectively; the median time to recurrence was 2.1 years (range, 0.1–19.6 years) (Fig. 1). Disease-free survival was significantly influenced by KPS (p = 0.04) and high mitotic rate (p = 0.003) on univariate analysis. On multivariate analysis high mitotic rate (p = 0.003) remained a significant prognostic factor (Fig. 4). Extent of resection, brain invasion, and EBRT dose were not significant prognostic factors, neither for overall survival nor for disease-free survival (Table 2). Meningioma grade did not significantly influence overall survival or disease-free survival. The 5-year overall survival rate was 67.5% and 60% for patients with Grade 2 and 3 meningiomas, respectively (p = 0.6). The 5-year disease-free survival rate was 62% and 48% for patients with Grade 2 and 3 meningiomas, respectively (p = 0.18). Overall survival and disease-free survival according to grade is represented in Fig. 5. In this series 6 patients presented with skin or other distant metastasis. Four patients (2 patients with Grade 2 and 2 patients with Grade 3) presented skin metastasis near the surgical incision. Two patients with Grade 3 meningiomas
Table 2. Prognostic factors for overall and disease-free survival Overall survival (p)
Disease-free survival (p)
Prognostic factor
Univariate analysis
Multivariate analysis
Univariate analysis
Age <60 or >60 y Sex KPS (continuous variable) NFS Completion of resection (complete vs. incomplete) Simpson grade Grade (2 vs. 3) High mitotic rate Benign meningioma at first presentation Necrosis Brain invasion EBRT dose Type of radiotherapy (cobalt vs. linear accelerator)
0.005* 0.6 0.01* 0.08 0.19 0.09 0.6 0.047* 0.09 0.18 0.56 0.28 0.41
0.001*
0.95 0.2 0.04* 0.12 0.36 0.16 0.18 0.03* 0.82 0.18 0.23 > 0.05 0.43
0.25
0.02*
Abbreviations: EBRT = external beam radiotherapy. Other abbreviations as in Table 1. * p < 0.05.
Multivariate analysis
0.95
0.003*
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Fig. 2. Overall survival in 119 patients with atypical and malignant meningioma according to age >60 or <60 years (p = 0.001 on multivariate analysis).
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Fig. 4. Relapse-free survival in 84 patients with atypical and malignant meningioma according to mitotic rate (p = 0.003 on multivariate analysis).
of resection was associated with outcome in several series. Goyal et al. (2) reported that 8 of 22 patients with atypical meningiomas received adjuvant radiotherapy or radiotherapy for relapse. The overall 5- and 10-year survival rates were 91% and 76%, respectively. Patients with gross total resection had 5- and 10-year control rates of 87% and 87%, whereas patients with either subtotal resection or resection of unknown extent had local control rates of 51% and 17%, respectively (p = 0.02). In a series reported by Palma et al. (9), radical excision was significantly related to prolonged survival on multivariate analysis (p < 0.0003). Considering patients with incomplete resection, the survival curve of atypical meningioma was not significantly different from that of malignant meningioma (9). Ja¨a¨skelainen et al. (1) regarded Simpson Grades 1 and 2 as ‘‘complete resection,’’ but in a later study Ja¨a¨skelainen (10) found that simple coagulation of the dura mater (Grade 2) vs. excision (Grade 1) doubled the recurrence rate in that series of benign meningiomas. In our series actuarial overall survival and disease-free survival rates were 51% and 48% at 10 years, respectively, and were not influenced by the meningioma grade as in the Milosevic et al. series (8), in which 5-year specific survival was 34%. This is probably related to a default of reproducibility of grading between institutions and over the duration of the
study; the groups of patients with Grade 2 or 3 meningiomas were comparable in terms of completion of excision and adjuvant EBRT. Conversely, in Palma et al. (9) and a Mayo clinic series (7) the outcome was influenced by grade. In the Palma et al. series (9), 71 patients (42 Grade 2 and 29 Grade 3) received adjuvant radiotherapy or radiotherapy for relapse. The overall survival rate at 10 years was 79% and 34% in atypical and malignant meningiomas, respectively (p = 0.001); median recurrence-free survival was 11.9 and 2 years, respectively (p = 0.001). In the Mayo Clinic series (7), 32 of the 104 patients received external beam therapy and/or radiosurgery after their first malignant diagnosis. Median follow-up was 3.7 years. Rates of 5- and 10-year mortality were 38% and 53%, respectively, with a median survival of 7.5 years. Estimated 5-year mortality rates in benign, atypical, and ‘‘frankly’’ anaplastic brain invasive meningiomas were 27%, 25%, and 83%, respectively. Median survival was 14.9 years, 10.4 years, and 1.4 years, respectively. Survival was significantly shorter in the anaplastic group (p < 0.0001) (7). Mitotic rate was a significant prognostic factor for overall and relapse-free survival in our study, but we were not able to determine a significant threshold. Mitotic rate is a wellknown prognostic factor in the literature. In two studies Perry et al. attempted to develop a reproducible grading for
Fig. 3. Overall survival in 84 patients with atypical and malignant meningioma according to mitotic rate (p = 0.02 on multivariate analysis).
Fig. 5. Overall survival and disease-free survival in 119 patients with atypical and malignant meningioma according to grade.
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Table 3. Late toxicity (CTCAE v3.0 score) Grade 1 2 3 4
Brain necrosis
Cognitive disturbance
Memory impairment
Mood alteration
1 1
1
1
2 2 2 1
Pyramidal dysfunction
1
Seizure
3
Total 3 4 6 2
Abbreviation: CTCAE = common terminology criteria for adverse events.
meningioma. In the first (11), 581 consecutive patients were analyzed. Brain invasion, sheeting, absence of nuclear atypia, and a maximal mitotic rate greater than 4 per 10 HPF were univariately associated with decreased recurrence-free survival. The investigators recommended that ‘‘atypical’’ meningiomas be defined by the presence of at least three of these features: sheeting, macronuclei, hypercellularity, small-cell formation, or a minimum of 4 mitoses per 10 HPF (11). In their second work (7), Perry et al. expanded their analysis to 116 patients diagnosed with ‘‘malignant’’ meningioma. On multivariate analysis, histologic parameters that remained significant were anaplasia, extent of resection, >20 mitoses per 10 HPF, and nuclear atypia. The median survival for ‘‘frankly’’ anaplastic meningioma was 1.5 years, and the 5-year mortality rate was 68% (7). In the last WHO classification (4), a mitotic rate >4 per 10 HPF was considered as the most important factor to define atypical meningioma. In patients with a lower mitotic rate, the presence of at least three of the following variables is necessary: increased cellularity, macronuclei, prominent nucleoli, sheet-like growth pattern, and necrosis. Malignant meningioma is defined as the presence of a mitotic rate >20 per 10 HPF or ‘‘obvious’’ malignant cytology, or both. The significance of brain invasion has been debated widely and is not one of the criteria used for grading tumors in the WHO classification, but it should always be considered because it is associated with a higher recurrence rate (11, 12). Ki67 (MIB-1) proliferative index was missing in more than one third of our patients and was excluded from statistical analysis. Ming-Tak Ho et al. (13) found MIB-1 to be a powerful prognostic marker, and a cutoff point of 10% discriminated tumors in patients with different prognoses. In the literature, although a poor prognosis may be associated with a high MIB-1 labeling index, significant overlap exists in the MIB-1 labeling ranges for benign, atypical, and anaplastic meningiomas. Furthermore, because of differences in staining and counting methods, a cutoff point identified in one laboratory may not be usable in others. Genetic alterations are often present in meningiomas. Weber et al. (14) identified different genomic alterations in benign, atypical, and malignant meningiomas. Murakami et al. (15) also suggested that 10q loss may contribute to malignant progression. As in Weber et al., 9p deletions were associated with malignant progression and poor prognosis in malignant meningiomas in Perry et al. (16). In the future,
genomic alterations could be useful to appraise prognosis and to propose adapted treatments. Our study does not allow consideration of the role of adjuvant radiotherapy. Adjuvant radiotherapy after incomplete resection (benign or aggressive meningioma) has not been evaluated in a prospective study to date (17). Some retrospective trials promote adjuvant radiotherapy after incomplete resection in patients with atypical meningioma, and independently of the status of resection in malignant meningioma (6). The role of adjuvant radiotherapy in completely resected (Simpson Grade 1) atypical meningioma is unclear. In our patients the outcome was not related to radiotherapy dose, whereas in certain series EBRT dose is a prognostic factor. In Milosevic et al. (8), dose >50 Gy and age <40 years were the two prognostic factors associated with a favorable outcome on multivariate analysis. The use of dose <50 Gy is not optimal in patients with meningioma, as in benign meningioma, in which a dose–response relationship for local control was shown up to 52 Gy in retrospective series but not beyond (17, 18). The roles of dose escalation (dose >55–60 Gy) and radiosurgery in aggressive meningioma have not been evaluated in a controlled, prospective study. Extracerebral metastasis can be encountered in patients with atypical or malignant meningiomas. In our study 6 patients (2 Grade 2 and 4 Grade 3) presented with skin metastasis near the surgical excision or histologically proven liver and bone metastasis. In the Mayo Clinic series (7), 3 of 27 patients with ‘‘frankly’’ anaplastic meningiomas presented with distant metastasis. In the Milosevic et al. series (8), 4 of 59 patients with atypical and malignant meningiomas presented pathologically distant bone metastases.
CONCLUSIONS Multicenter, prospective studies are necessary to clarify management and more relevant prognostic factors. The role of dose escalation and/or stereotactic radiotherapy (fractionated or not) could be prospectively evaluated. A European Organization for Research and Treatment of Cancer Phase II study (22042-26042) evaluating adjuvant postoperative high-dose radiotherapy for atypical and malignant meningioma recently opened. The determination of many relevant prognostic factors, such as genetic alterations, could allow the proposal of more tailored treatments.
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