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Treatment of grade II–III intracranial meningioma with helical tomotherapy
Journal of Clinical Neuroscience 59 (2019) 190–196
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Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical study
Treatment of grade II–III intracranial meningioma with helical tomotherapy Geoffroy Boulle a, Stefano Bracci b, Kathryn Hitchcock c, Julian Jacob a, Emmanuelle Clausse a, Amandine Halley a, Bacem Belghith a, Leopold Kamsu Kom a, Charles-Henri Canova a, Franck Bielle d, Antoine Chevalier a, Matthieu Peyre e, Jean-Jacques Mazeron a, Philippe Maingon a, Loïc Feuvret a,⇑ a
Department of Radiation Oncology, Hôpital Pitié-Salpêtrière Charles Foix, APHP, Paris, France Institute of Radiation Oncology, Sapienza University, Sant’Andrea Hospital, Roma, Italy c Department of Radiation Oncology, University of Florida, Gainesville, FL, USA d Département of Neuropathology, Hôpital Pitié-Salpêtrière Charles Foix, APHP, Paris, France e Department of Neurosurgery, Hôpital Pitié-Salpêtrière Charles Foix, APHP, Paris, France b
a r t i c l e
i n f o
Article history: Received 3 June 2018 Accepted 14 October 2018
Keywords: Meningioma Intracranial tumors Helical tomotherapy
a b s t r a c t Meningiomas account for 30–35% of intracranial tumors. Grade I meningiomas are most common and carry the best prognosis. Grade II and III meningiomas are more aggressive and the outcomes after surgical resection alone remain unsatisfactory. The main objective of this retrospective, single-center study was to assess our results of treatment of grade II–III intracranial meningioma with helical tomotherapy (HT). We retrospectively reviewed patients with histologically proven (WHO 2007) grade II–III meningioma irradiated with HT. Patients were treated one session a day, 5 days a week, to a total dose of 59.4 Gy and 68.4 Gy delivered in 33 and 38 fractions of 1.8 Gy each to the LR PTV and HR PTV, with or without simultaneous integrated boost. From May 2011 to January 2015, 19 patients (15 with grade II and 4 with grade III meningiomas) were treated. Median follow-up for patients with Grade II or Grade III meningiomas, was 29.2 months (range, 10.7–52.4) and 21.3 months (range, 2.4–51.3), respectively. Disease free survival at 1, 2 and 3 years was 89.2%, 83.6% and 56.3% respectively. Overall survival at 1, 2 and 3 years was 94.7%, 94.7% and 78.9%, respectively. No patient had neurological toxicity greater than grade 2 in the acute period. During follow-up, only one patient had neurological toxicity greater than or equal to grade 3. The management of grade II to III meningiomas using HT with doses exceeding 60 Gy is associated with good local control and acceptable survival results. Ó 2018 Elsevier Ltd. All rights reserved.
1. Introduction Meningiomas account for 30–35% of intracranial tumors [1]. Grade I meningiomas are the most frequent and are associated with excellent results. According to the WHO classification, grade II and III meningiomas account for between 5–34% and 1–3% of tumors of the central nervous system, respectively [2]. These meningiomas are aggressive forms for which the surgical results, even after complete resection, remain unsatisfactory [3,4]. Several authors have suggested that the addition of postoperative radio-
⇑ Corresponding author at: Department of Radiation Oncology, groupe hospitalier La Pitié Salpêtrière – Charles Foix (Assistance Publique – Hôpitaux de Paris), 47-83, boulevard de l’hôpital, 75651 Paris cedex 13, France. E-mail address: [email protected] (L. Feuvret). https://doi.org/10.1016/j.jocn.2018.10.073 0967-5868/Ó 2018 Elsevier Ltd. All rights reserved.
therapy could improve local control. Goldsmith et al. reported a significant increase in the 5 year progression free survival (PFS) in patients with malignant meningioma who received higher dose radiotherapy (RT) after subtotal resections [5]. More recently, Cain et al reported identical results, describing a PFS improvement in 23% of patients but no change in overall survival (OS) [6]. For grade II–III meningiomas, several radiotherapy series have described an improvement in local control when delivering doses above 60 Gy [7–10]. However, the use of three-dimensional conformal radiotherapy for such a high dose exposes patients to risk of neurological side effects in mid- and long-term follow-up [11]. New photon irradiation techniques such as intensity modulated radiotherapy optimize treatment plans for these complex tumors located in a sensitive area [12,13].
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The main objective of this retrospective, single-center study was to assess our results in terms of efficiency and tolerance of intracranial meningioma grades II–III treatment with helical tomotherapy (HT). 2. Methods and materials Institutional review board approval was obtained for this retrospective study. The present series included 19 patients with histologically proven (WHO 2007) grade II–III meningiomas irradiated with HT from May 2011 to January 2015. No patient was excluded from the study. Magnetic resonance imaging (MRI) and clinical information were available up until the time of analysis or the patient’s death. The patient’s medical records were reviewed for clinical data, treatment details, and outcomes. All patients were treated with surgery followed by radiation therapy regardless of the extent of resection. Before treatment, all patients were discussed and considered suitable for the treatment by a multidisciplinary team. Quality of resection was assessed on the basis of surgical and pathological reports. The final database was locked for analysis in May 2017. Meningioma involving a venous sinus was present in 11 patients (57.9%): upper longitudinal in 8 patients (42.1%), and superior sagittal in 3 patients (15.8%). Before radiation therapy, single- and multi-procedure resections were performed in 8 patients (42.1%) and 11 patients (57.9%), respectively. Ten patients (52.6%) were referred at the time of the initial diagnosis (primary disease): 7 patients after gross tumor resection (Simpson class 1– 3), 2 patients after partial resection (Simpson class 4) and 1 patient after biopsy (Simpson class 5). Nine patients were treated exclusively with radiotherapy after recurrence. The median interval between last surgery and irradiation was 4 months (1–98 months).
Planning goal for target coverage respected ICRU 83 recommendations with for GTV: total and minimum dose, absolute dose delivered to 90% and 95%, dose delivered to 2%). Organs at risk dose constraints were: D2% < 54 Gy for optic tract, brainstem; D2% < 50 Gy for retina; D2% < 5% for eye lens; D2% < 45 Gy for spinal cord and D40% < 7,4 Gy for hippocampus.
2.3. Dose protocols Ten patients were treated one session a day, 5 days a week, to a total dose of 59.4 Gy and 68.4 Gy delivered in 33 and 38 fractions of 1.8 Gy each to the LR PTV and HR PTV, respectively. A simultaneous integrated boost was used for 9 patients, giving 59.4 Gy to the LR PTV (1.8 Gy per fraction) and 68.4 Gy simultaneously to the HR PTV (2.07 Gy per fraction) in 33 fractions. All patients received a dose equal or greater than 59.4 Gy of radiation. Dosimetric characteristics are summarized in Table 1.
2.4. Follow-up and toxicities All patients were seen once a week during treatment to assess acute reactions. Then after treatment, follow-up consisted of regular visits with brain MRI performed every 3 months for 2 years then every 6 months for 5 years. Tumor response was assessed according to Response Assessment in Neuro-Oncology criteria. Endocrine blood tests were performed annually to monitor for changes in the hypothalamus-pituitaryadrenal axis, and audiometric and visual examinations were performed annually. Early (before 90 days) and late (after 90 days) side effects were graded according to the Common Terminology Criteria for Adverse Events v.3.0 grading system.
2.1. Radiation treatment planning All patients were immobilized with a customized thermoplastic mask. A 2.5 mm slice-thickness simulation CT scan in supine position was performed. This CT was then fused with the pre-surgery and the pre-RT MRIs to delineate the target volumes as well as the organs at risk (OARs) including eyes, lenses, retinas, optic pathways, normal brain, brainstem, spinal cord, and cochleas. HT plans were created using the HiArt II treatment planning platform (version 4.2.0.87, tomotherapy Inc., Madison, WI, USA) using 6 MV photons. For beam modulation, a 64-leaf binary multi-leaf collimator was used with a leaf width of 6.25 mm projected at isocenter. A longitudinal aperture size of 2.5 cm, a pitch of 0.287, and a modulation factor of 2.4 were used. Once initial parameters were set for each plan, a full beamlet dose calculation was run followed by 350 optimization iterations allowing for full convergence of the cost function. For the final dose calculation, a collapsed convolution superposition dose calculation algorithm was used. 2.2. Target volumes Target volumes were defined according to International Commission for Radiation Units and Measurements report 62 definitions [13]. Gross target volume (GTV) was generated using the T1 weighted MRI with gadolinium contrast. The Low Risk Clinical Target Volume (LR CTV) was created by adding to the GTV 3–10 mm (grade II) [14,15] and 3–20 mm (grade III) safety margins, taking into account barriers to tumor spread such as bone structures, if not invaded. The High Risk Clinical Target Volume (HR CTV) was created by adding to the GTV 3 mm safety margins, again editing for barriers to tumor spread. The Planning Target Volume (PTV) was defined by adding a 3 mm isotropic expansion to the CTV.
2.5. Statistical analysis All statistics were performed using IBM SPSS v.24. Overall survival (OS) and progression-free survival (PFS) were calculated from the beginning of RT until death for any cause for OS, local and/or distant progression and/or death from any cause for PFS or the last follow-up if no event occurred. Local Control Rate (LCR) was defined as the absence of radiologic and clinical evidence of tumor progression. Univariate analysis was performed using the log-rank test to identify significant predictors of OS and PFS. A p-value of 0.05 or less was considered statistically significant. Potential prognostic factors were analyzed: age, gender, tumor grade, Simpson grade, type of resection, veinous involvement, cerebral oedema, number of surgeries, Ki67%, KPS status, corticosteroids.
Table 1 Dosimetric characteristics. Characteristics
Values (median)
Range
GTV (cc) LR CTV (cc) HR CTV (cc) LR PTV (cc) HR PTV (cc) LR PTV dose (Gy) HR PTV dose (Gy) Duration of radiation therapy (days) Irradiation Integrated boost No integrated boost
21.91 144.9 78.3 233.94 110.76 D50% = 59.4 D50% = 68.4 49
0–183.1 59.96–276.34 6.5–260.5 153.56–504 15.07–375.5 51.02–68.3 53.98–68.43 22–58
9 (47%) 10 (53%)
Abbreviations: GTV = gross tumor volume; LR = low-risk; CTV = clinical target volume; HR = high-risk; PTV = planning target volume, Gy = Gray.
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3. Results The median age of the patients was 63 years (range, 43–76), and the sex ratio (M/F) was 2.8 (14/5). Fifteen (79%) of the 19 patients had a diagnosis of grade II meningioma and 4 (21%) had a diagnosis of grade III meningioma. The median follow-up time was 29.2 months (range, 1.6–39.7). Median clinical follow-up for patients with Grade II or Grade III meningiomas, after completing treatment, was 29.2 months (range, 10.7–52.4) and 21.3 months (range, 2.4–51.3), respectively. Patient, tumor characteristics and details are presented in Tables 2 and 3. 3.1. Local control The 1-, 2- and 3-year PFS rates were 89.2% (95%CI = 76%–100%), 83.6% (95%CI = 68.2%–100%) and 56.3% (95%CI = 33.9%–93.5%), respectively. The 1-, 2- and 3-year LCR rates were 84.2% (95% CI = 69.3%–100%), 78.9% (95%CI = 62.6%–99.6%) and 67.7% (95% CI = 49.4%–92.8%) respectively. Six patients developed an in-field local recurrence, all in the high dose CTV. No patient developed out filed or metastatic recurrence. The median time to local recur-
Table 2 Patient characteristics and tumor characteristics. GRADE II
GRADE III
15 (79%)
4 (21%)
63 [43–78]
71 [49–74]
11 4
3 1
KPS 100 90 80 70
1 9 3 2
0 3 0 1
Histology Clear cell meningioma Atypical meningioma Anaplasic Unknown
2 (11%) 8 (42%) – 5 (26%)
– – 4 (21%) –
Locations Frontal Occipital Sphenoid wing Parietal Foramen magnum Cavernous sinus Venous Sinus invasion
8 (42%) 3 (16%) 1 (5%) 2 (11%) 1 (5%) 1 (5%) 10 (53%)
2 (11%) 0 0 1 (5%) 0 0 1 (5%)
7 (37%) 4 (21%) 4 (21%) 4.5 [2–26]
1 2 1 5
Radiotherapy indication Radiotherapy alone after recurrence After incomplete resection After complete resection
9 (47%) 5 (26%) 1 (5%)*
0 3 (16%) 1 (5%)
Simpson Class I II III IV V
1 3 2 8 1
0 1 (5%) 0 3 (16%) 0
Patient N (%) Age (years) Median Range Gender Male Female
Number of resections before RT 1 2 3 or more Median interval between last surgery and RT (months)
(5%) (16%) (11%) (42%) (5%)
(5%) (11%) (5%) [1–5]
* One patient was treated after complete resection but because of multiple previous surgeries, the indication of adjuvant radiotherapy was retained. Usually, about totally resected grade II meningioma, indication of irradiation depends on neurosurgeon preference.
rence was 19.1 months (range, 8.4–32.3). For patients with grade II meningioma, the 1-, 2-PFS rate were 93.3% (95%CI = 81.5%–100%) and 3-year PFS rates was 58.3% (95%CI = 33.5%–100%), LCR rates were 100% (95%CI = 100%–100%) at 1 and 2 years, and 71.4% (95% CI = 44.7%–100%) at 3 years. All of the patients with grade III meningioma showed a progression during follow up with a disease median control of 20 months (range 8.4–20). 3.1.1. Survival The 1-, 2- and 3-year OS rates were 94.7% (95%CI = 85.2%– 100%), 94.7% (95%CI = 85.2%–100%), and 78.9% (95%CI = 59.4%– 100%) respectively. Three patients died, 2 due to intercurrent disease and one from disease progression. 3.1.2. Prognosis factors At 3 years, age > 70 years old, Grade III meningioma and a Ki67% > 15% were identified as significant pejorative factors for PFS. At 3 years, significant pejorative factors for OS were notion of hospitalization and the Simpson score. Prognosis factors are summarized in Table 4. 3.1.3. Early side effects Treatment with radiotherapy was well tolerated with a median KPS of 90% (70–100) before treatment and 80% (50–90) after treatment. The most common Grade I–II side effects were alopecia for 18 patients (95%), radiodermatitis in 12 patients (63%) and headache in 5 patients (26%). One patient developed grade 3 ataxia during treatment. Two patients (11%) required hospitalization during treatment: one for a decline in general condition and one for ataxia. No treatment was interrupted. Early side effects are summarized in Table 5. Due to radiotherapy, symptomatic treatment with corticosteroids was initiated in 10 patients (53%), with a median methylprednisolone dose equivalent of 34.5 mg (range 75–16 mg). 3.1.4. Late side effects During long-term follow-up, only one patient experienced Grade 3 or higher toxicities (Table 5). These toxicities were associated with a progression of the disease and significant cerebral edema which later led to the patient’s death. Four patients were still dependent on corticosteroid 90 days after the end of treatment, with a median duration of use in this group of 19.4 months (range 12.6–23.2 months): 2 patients due to cerebral oedema, 1 patient due to local recurrence and 1 patient due to local recurrence associated with oedema. During radiological follow-up, there was no evidence of edema or suspicious contrast enhancement of radionecrosis, so no multimodal imaging was performed. 4. Discussion The aim of our study is to evaluate our treatment results of grade II and III meningiomas, operated or not, and irradiated by HT, in terms of efficiency and tolerance. We present the results after a median follow-up of 29.2 months with 1-, 2- and 3 year DFS of 89.2%, 83.6% and 56.3% respectively, LCR of 84.2%, 78.9% and 67.7% respectively and OS of 94.7%, 94, 7% and 78.9%, respectively. Other major series evaluated local control and survival outcomes for grade II and III meningiomas. In 2000, Hug et al studied the role of conformal radiotherapy in 31 patients with grade II and grade III meningiomas. Target doses ranged from 50 to 68 Gy for grade II and from 40 to 72 Gy for grade III. Sixteen patients received additional proton therapy boost, after surgery for 29 patients: 8 patients (26%) after total resection, 21 patients (67%) after subtotal resection. Two other patients (7%) underwent biopsy only. Rates of
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G. Boulle et al. / Journal of Clinical Neuroscience 59 (2019) 190–196 Table 3 Individual patient details. Meningioma grade
Age (y)
Sex
Simpson grade
Time period surgeryradiotherapy (m)
Relapse
time to relapse (m)
Status to analysis
Cause of death
Higher late toxicities (CTCAE grade)
II II II II II II II II III II II II II II III II III II III
70 72 57 71 56 69 49 45 50 46 49 67 53 64 78 66 72 79 75
M W M M W W M M M M W M M M W M M M M
5 4 4 4 4 3 4 1 4 4 3 2 4 4 4 2 4 2 2
2 4 3 28 7 4 2 5 2 4 14 98 8 4 2 26 5 6 1
No No No Yes No No No No Yes No No No No No Yes No Yes Yes Yes
– – – 25,6 – – – – 20,0 – – – – – 10,7 – 8,4 28,1 12,6
Alive Alive Alive Alive Alive Dead Alive Alive Alive Alive Dead Alive Alive Alive Alive Alive Alive Alive Dead
– – – – – NA – – – – NA – – – – – – – Progression disease
– Headache (II) – Concentration (II) Ataxia (II) NA – – Memory loss (I) – Vision change (I) – – – – Epilepsy (II) – – Epilepsy (VI), Ataxia (IV), Dysarthria (III), concentration (III)
Abbreviations: M = Man, W = Woman, y = years, m = months, NA = data Not Available.
Table 4 Prognosis factors. Prognostic factors Age <70 70 Gender M F Grade II III Venous sinus involvement Thrombosis Invasion No invasion Cerebral edema Yes No Number of surgeries 1 >1 Type of resection Complete Incomplete Biopsy Simpson score 1-2-3 4-5 * Ki67% <15% 15% KPS before RT 90 <90 Corticosteroids prescribed Yes No
n
3y-OS(%)
p-value
3y-PFS(%)
p-value
13 6
79 80
0.85
75 0
<0.001
14 5
91 53
0.14
49 75
0.68
15 4
80 75
0.66
79 0
<0.001
2 8 9
100 100 51
0.12
0 62 63
0.59
13 6
42 91
0.11
41 100
0.09
8 11
57 91
0.34
87 36
0.14
7 11 1
48 100 100
0.07
62 52 100
0.88
7 12
48 100
0.02
63 54
0.84
9 9
89 74
0.85
100 27.8
0.02
13 6
86 62
0.11
59 40
0.54
10 9
63 100
0.10 0.10
52 53
0.99 0.99
Bold p-values considered statistically significant. Abbreviations: OS = overall survival, PFS = progression-free survival, KPS = Karnofsky performance status. * Data not available in 1 patient.
recurrence were similar in grade II and III meningiomas with 5and 8-year local control rates of 38% and 19% for grade II and 52% and 17% for grade III, respectively. Boskos et al, reported in 2009 a cohort of 24 patients with grade II and III meningiomas treated with combined proton and photon conformal radiotherapy.
The overall mean local relapse-free intervals were 28.3 months for grade II and 23 months for grade III. The local control rate at 1, 2 and 3 years was 82.9%, 82.9% and 61.3%, respectively. Milosevic et al, with 60 patients, reported an overall survival at 1, 2 and 3 years of 75%, 60% and 50%, respectively, in a similar population
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Table 5 Side effects CATCAE v3.0.
*
Acute toxicities
G1
G2
G3
G4
Total (%)
Nausea Alopecia Headaches Dermatitis Ataxia
3 (16%) 7 (37%) 4 (21%) 10 (53%) 0
1 (5%) 11 (58%) 1 (5%) 2 (10%) 0
0 0 0 0 1 (5%)
0 0 0 0 0
4 (21%) 18 (95%) 5 (26%) 12 (63%) 1 (5%)
Late toxicities Memory loss Concentration Headache Ataxia Epilepsy Vision changes Dysarthria Alopecia
G1 1 (5%) 0 0 0 0 1 (5%) 0 3 (16%)
G2 0 1 (5%) 1 (5%) 1 (5%) 1 (5%) 0 0 4 (21%)*
G3 0 1 (5%)* 0 0 2 (10%)* 0 1 (5%)* 0
G4 0 0 0 1 (5%)* 1 (5%)* 0 0 0
Total (%) 1 (5%) 2 (11%) 1 (5%) 2 (11%) 4 (21%) 1 (5%) 1 (5%) 7 (37%)
Events occurred in the same patient.
[16]. Dziuk et al, reviewing 38 malignant meningiomas, showed a 1-year PFS of 94% [17]. Pasquier et al, with 39 patients had a 3-years PFS and OS of 65% and 76% respectively [18]. Recently, Cain et al reported a 1- and 3-year PFS of 100% and 63% and a 1- and 3-year of 75% OS, respectively [6]. Our results seem to be at least equivalent to those in the published literature (Table 6) [19]. There is no randomized data available assessing the role of radiotherapy in management of grade II or III meningiomas. Currently the ROAM/EORTC-1308 trial, which compares radiation therapy and observation following surgical resection of atypical meningiomas, may provide evidence in support of radiotherapy in the management of this pathology [20,21]. Several authors have suggested that the addition of postoperative radiotherapy to surgical resection would improve local control, especially in malignant meningiomas [22]. Goldsmith et al., in a retrospective analysis, reported a significant increase in the 5 year PFS in patients with malignant meningiomas after subtotal resections [5]. A study recently highlighted a new track for the identification of patients
with high risk of recurrence. Sahm et al, in a multicenter retrospective study, analyzed genome-wide DNA methylation patterns of 497 meningiomas. This study made it possible to stratify patients more precisely according to their risk of recurrence, especially for grade II [23]. Several studies of radiotherapy for meningioma have shown an improvement in clinical outcomes for higher doses. Milosevic et al observed an improvement in cause-specific survival for doses > 50 Gy on multivariate analysis [16]. Boskos et al, reported an improvement in OS and PFS for doses > 60 Gy in univariate analysis (p < 0.05) but in OS only on multivariate analysis (p = 0.029). There was a trend in OS improvement for doses > 65 Gy on univariate analysis [8]. Similarly, Hug et al, reported better DFS and OS with doses > 60 Gy at 5 and 8 years [7]. Two recent prospective studies, RTOG 0539 and EORTC 22042–26042, evaluated the interest of irradiation at doses greater than 60 Gy [24,25]. Weber et al, showed a 3-year PFS rate of 88.7% for grade II meningiomas with complete resection (Simpson 1–3) treated with a dose of 60 Gy.
Table 6 Comparison of our results with previous series. Year of publication
First Author
N
Grade
Treatment technique
Treatment dates
LCR or PFS (%)
1996
Milosevic et al [16]
59
Photons (2D and 3D)
1966–1990
1998
Dziuk et al [17]
48
I (7/59) II (18/59) III (30/59) Unclassified (4/59) III (48/48)
Photons (3D)
1984–1992
2002
Uy et al [19]
40
Grade II/III (10/40)
Photons (IMRT)
1994–1999
2008
Pasquier et al [18]
119
II (82/119) III (37/119)
Photons (2D and 3D)
1971–2005
2009
Boskos et al [8]
24
II (19/24) III (5/24)
Protons and photons (3D)
1999–2006
2011
Combs et al [12]
12
HT
2007–2009
2015
Cain et al [6]
58
Photons (3D)
2009–2012
2018
Our Study
19
I (5/12) II (5/12) III (2/12) I (7/58) II (45/58) III (6/58) II (15/19) III (4/19)
PFS : 75% -12 months 60% - 24 months 50% - 36 months LCR : 94% - 12 months LCR : 93% - 60 months LCR : 58% - 60 months 48% - 144 months LCR : 82.9% - 12 months 82.9% - 24 months 61.3% - 36 months LCR : 66% - 29 months
HT
2011–2015
LCR : 100% - 12 months 63% - 36 months PFS : 89.2% - 12 months 83.6% - 24 months 56.3% - 36 months LCR : 84.2% - 12 months 78.9% - 24 months 67.7% - 36 months
Abbreviations: HT: Helical tomotherapy, IMRT: Intensity Modulated Radiation Therapy; 2D: Two-dimensional; 3D: Three-dimensional, LCR: Local Control Rate, PFS: Progression Free Survival.
G. Boulle et al. / Journal of Clinical Neuroscience 59 (2019) 190–196
The results of the second arm of the high risk population (grade II meningiomas with Simpson grade 4–5) treated with a dose of 70 Gy has not been published yet [24]. Toxicities during treatment were generally minimal in our patient population and did not exceed grade 2 for neurological events. It should be noted, however, that our rate of hair loss is higher than in the rest of the literature with 58% grade 3 alopecia in the acute phase and 37% grade 3–4 during late follow-up. This may be explained by, first the use of HT irradiation, second, the lack of a strict constraint to preserve the scalp during the treatment-planning, and third, the close vicinity of the target volume to the scalp, which made compliance with even a modest scalp dose constraint difficult [21]. Aside from alopecia, only a few adverse effects were observed during follow-up with a rate not exceeding 21% for late neurological effects. Only one patient presented with several grade 4 toxicities and these were associated with disease progression. The use of HT makes it possible to guarantee better coverage of the target volumes, which are often complex, but also better protection of the organs at risk close to the target, when compared with conventional radiotherapy. This improved conformality has the potential to enable dose escalation within the target volumes. Previously, Combs et al studied the role of HT in the treatment of complex uni- or multifocal meningiomas of any grade. The treatment was well tolerated and the local control rate was 66% at 29 months: 50% of relapses occurring after first-line radiotherapy and 50% after re-irradiation [12]. In our study we identified several already known prognostic factors for survival and local control. Negative effect on 3-year survival was observed for any resection of Simpson grade 4 and 5 (p = 0.02), there was a negative tendency toward local control after incomplete resection, (p = 0.07) and for grade III histology (p < 0.001), as reported previously [26,27]. In the case of local control at 3 years, we found several negative prognostic factors such as age > 70 years (p < 0.001) and high mitotic index (Ki67 > 15%) (p = 0.02) but remain to be confirmed because of the small size of the population studied. We did not observe a correlation between the presence of thrombosis or invasion of the venous sinuses and local control, although this factor may indirectly cause an increased risk of recurrence due to its complication of complete resection [28–30]. Our study has several limitations, including the low number of patients and the retrospective setting. The majority of patients (79%) had grade II meningiomas, which likely influences control and survival parameters. There was no scale-based collection of data regarding neurological symptoms, cognitive effects, or quality of life during follow-up, although there was a low number of late neurological events. The duration of follow-up may be insufficient to detect all late recurrences and delayed side effects. The high rate of recurrence of high grade meningiomas should lead to a strengthening of the therapeutic strategy. Numerous ongoing trials are exploring different options like adding new molecules such as Vistusertib (NCT03071874), Nivolumab (NCT02648997), Prembrolizumab (NCT03279692), the use of innovative irradiation techniques such as proton dose escalation (NCT02978677) or the combination of both: neoadjuvant Avelumab and hypofractionated proton radiation therapy (NCT03267836). New imaging technologies such as DOTATOC PET/CT can also improve treatment planning, especially in complex cases [31,32].
5. Conclusion The management of grade II–III meningiomas with surgery followed by HT using doses exceeding 60 Gy is manageable, well
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tolerated, and associated with good local control and acceptable survival results. Several factors such as the quality of surgical resection and the histological characteristics remain paramount in the prognosis of treated patients. Large randomized trials are warranted to confirm this encouraging data. Acknowledgments The authors would like to thank Elizabeth Lecorre and Françoise Culot for having provided dosimetric calculations. Not previously published. Conflicts of interest notification No authors have direct or indirect financial interest in the subject matter. No funding. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jocn.2018.10.073. References [1] Ostrom QT, Gittleman H, Liao P, Vecchione-Koval T, Wolinsky Y, Kruchko C, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2010–2014. Neuro-Oncol 2017;19:v1–v88. https://doi.org/10.1093/neuonc/nox158. [2] Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol (Berl) 2016;131:803–20. https://doi.org/10.1007/s00401-016-1545-1. [3] Saraf S, McCarthy BJ, Villano JL. Update on meningiomas. Oncologist 2011;16:1604–13. https://doi.org/10.1634/theoncologist.2011-0193. [4] Goldbrunner R, Minniti G, Preusser M, Jenkinson MD, Sallabanda K, Houdart E, et al. EANO guidelines for the diagnosis and treatment of meningiomas. Lancet Oncol 2016;17:e383–91. https://doi.org/10.1016/S1470-2045(16)30321-7. [5] Goldsmith BJ, Wara WM, Wilson CB, Larson DA. Postoperative irradiation for subtotally resected meningiomas. A retrospective analysis of 140 patients treated from 1967 to 1990. J Neurosurg 1994;80:195–201. https://doi.org/ 10.3171/jns.1994.80.2.0195. [6] Cain SA, Smoll NR, Van Heerden J, Tsui A, Drummond KJ. Atypical and malignant meningiomas: considerations for treatment and efficacy of radiotherapy. J Clin Neurosci Off J Neurosurg Soc Australas 2015;22:1742–8. https://doi.org/10.1016/j.jocn.2015.03.054. [7] Hug EB, Devries A, Thornton AF, Munzenride JE, Pardo FS, Hedley-Whyte ET, et al. Management of atypical and malignant meningiomas: role of high-dose, 3D-conformal radiation therapy. J Neurooncol 2000;48:151–60. [8] Boskos C, Feuvret L, Noel G, Habrand J-L, Pommier P, Alapetite C, et al. Combined proton and photon conformal radiotherapy for intracranial atypical and malignant meningioma. Int J Radiat Oncol Biol Phys 2009;75:399–406. https://doi.org/10.1016/j.ijrobp.2008.10.053. [9] Glaholm J, Bloom HJ, Crow JH. The role of radiotherapy in the management of intracranial meningiomas: the Royal Marsden Hospital experience with 186 patients. Int J Radiat Oncol Biol Phys 1990;18:755–61. [10] Kokubo M, Shibamoto Y, Takahashi JA, Sasai K, Oya N, Hashimoto N, et al. Efficacy of conventional radiotherapy for recurrent meningioma. J Neurooncol 2000;48:51–5. [11] Hasan S, Young M, Albert T, Shah AH, Okoye C, Bregy A, et al. The role of adjuvant radiotherapy after gross total resection of atypical meningiomas. World Neurosurg 2015;83:808–15. https://doi.org/10.1016/j. wneu.2014.12.037. [12] Combs SE, Sterzing F, Uhl M, Habl G, Schubert K, Debus J, et al. Helical tomotherapy for meningiomas of the skull base and in paraspinal regions with complex anatomy and/or multiple lesions. Tumori 2011;97:484–91. https:// doi.org/10.1700/950.10402. [13] Gupta T, Wadasadawala T, Master Z, Phurailatpam R, Pai-Shetty R, Jalali R. Encouraging early clinical outcomes with helical tomotherapy-based imageguided intensity-modulated radiation therapy for residual, recurrent, and/or progressive benign/low-grade intracranial tumors: a comprehensive evaluation. Int J Radiat Oncol Biol Phys 2012;82:756–64. https://doi.org/ 10.1016/j.ijrobp.2010.12.044. [14] International Commission on Radiation Units and Measurements. ICRU report 50. Bethesda, MD: ICRU; 1993. n.d.. [15] Press RH, Prabhu RS, Appin CL, Brat DJ, Shu HKG, Hadjipanayis C, et al. Outcomes and patterns of failure for grade 2 meningioma treated with
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Clinical study
Treatment of grade II–III intracranial meningioma with helical tomotherapy Geoffroy Boulle a, Stefano Bracci b, Kathryn Hitchcock c, Julian Jacob a, Emmanuelle Clausse a, Amandine Halley a, Bacem Belghith a, Leopold Kamsu Kom a, Charles-Henri Canova a, Franck Bielle d, Antoine Chevalier a, Matthieu Peyre e, Jean-Jacques Mazeron a, Philippe Maingon a, Loïc Feuvret a,⇑ a
Department of Radiation Oncology, Hôpital Pitié-Salpêtrière Charles Foix, APHP, Paris, France Institute of Radiation Oncology, Sapienza University, Sant’Andrea Hospital, Roma, Italy c Department of Radiation Oncology, University of Florida, Gainesville, FL, USA d Département of Neuropathology, Hôpital Pitié-Salpêtrière Charles Foix, APHP, Paris, France e Department of Neurosurgery, Hôpital Pitié-Salpêtrière Charles Foix, APHP, Paris, France b
a r t i c l e
i n f o
Article history: Received 3 June 2018 Accepted 14 October 2018
Keywords: Meningioma Intracranial tumors Helical tomotherapy
a b s t r a c t Meningiomas account for 30–35% of intracranial tumors. Grade I meningiomas are most common and carry the best prognosis. Grade II and III meningiomas are more aggressive and the outcomes after surgical resection alone remain unsatisfactory. The main objective of this retrospective, single-center study was to assess our results of treatment of grade II–III intracranial meningioma with helical tomotherapy (HT). We retrospectively reviewed patients with histologically proven (WHO 2007) grade II–III meningioma irradiated with HT. Patients were treated one session a day, 5 days a week, to a total dose of 59.4 Gy and 68.4 Gy delivered in 33 and 38 fractions of 1.8 Gy each to the LR PTV and HR PTV, with or without simultaneous integrated boost. From May 2011 to January 2015, 19 patients (15 with grade II and 4 with grade III meningiomas) were treated. Median follow-up for patients with Grade II or Grade III meningiomas, was 29.2 months (range, 10.7–52.4) and 21.3 months (range, 2.4–51.3), respectively. Disease free survival at 1, 2 and 3 years was 89.2%, 83.6% and 56.3% respectively. Overall survival at 1, 2 and 3 years was 94.7%, 94.7% and 78.9%, respectively. No patient had neurological toxicity greater than grade 2 in the acute period. During follow-up, only one patient had neurological toxicity greater than or equal to grade 3. The management of grade II to III meningiomas using HT with doses exceeding 60 Gy is associated with good local control and acceptable survival results. Ó 2018 Elsevier Ltd. All rights reserved.
1. Introduction Meningiomas account for 30–35% of intracranial tumors [1]. Grade I meningiomas are the most frequent and are associated with excellent results. According to the WHO classification, grade II and III meningiomas account for between 5–34% and 1–3% of tumors of the central nervous system, respectively [2]. These meningiomas are aggressive forms for which the surgical results, even after complete resection, remain unsatisfactory [3,4]. Several authors have suggested that the addition of postoperative radio-
⇑ Corresponding author at: Department of Radiation Oncology, groupe hospitalier La Pitié Salpêtrière – Charles Foix (Assistance Publique – Hôpitaux de Paris), 47-83, boulevard de l’hôpital, 75651 Paris cedex 13, France. E-mail address: [email protected] (L. Feuvret). https://doi.org/10.1016/j.jocn.2018.10.073 0967-5868/Ó 2018 Elsevier Ltd. All rights reserved.
therapy could improve local control. Goldsmith et al. reported a significant increase in the 5 year progression free survival (PFS) in patients with malignant meningioma who received higher dose radiotherapy (RT) after subtotal resections [5]. More recently, Cain et al reported identical results, describing a PFS improvement in 23% of patients but no change in overall survival (OS) [6]. For grade II–III meningiomas, several radiotherapy series have described an improvement in local control when delivering doses above 60 Gy [7–10]. However, the use of three-dimensional conformal radiotherapy for such a high dose exposes patients to risk of neurological side effects in mid- and long-term follow-up [11]. New photon irradiation techniques such as intensity modulated radiotherapy optimize treatment plans for these complex tumors located in a sensitive area [12,13].
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The main objective of this retrospective, single-center study was to assess our results in terms of efficiency and tolerance of intracranial meningioma grades II–III treatment with helical tomotherapy (HT). 2. Methods and materials Institutional review board approval was obtained for this retrospective study. The present series included 19 patients with histologically proven (WHO 2007) grade II–III meningiomas irradiated with HT from May 2011 to January 2015. No patient was excluded from the study. Magnetic resonance imaging (MRI) and clinical information were available up until the time of analysis or the patient’s death. The patient’s medical records were reviewed for clinical data, treatment details, and outcomes. All patients were treated with surgery followed by radiation therapy regardless of the extent of resection. Before treatment, all patients were discussed and considered suitable for the treatment by a multidisciplinary team. Quality of resection was assessed on the basis of surgical and pathological reports. The final database was locked for analysis in May 2017. Meningioma involving a venous sinus was present in 11 patients (57.9%): upper longitudinal in 8 patients (42.1%), and superior sagittal in 3 patients (15.8%). Before radiation therapy, single- and multi-procedure resections were performed in 8 patients (42.1%) and 11 patients (57.9%), respectively. Ten patients (52.6%) were referred at the time of the initial diagnosis (primary disease): 7 patients after gross tumor resection (Simpson class 1– 3), 2 patients after partial resection (Simpson class 4) and 1 patient after biopsy (Simpson class 5). Nine patients were treated exclusively with radiotherapy after recurrence. The median interval between last surgery and irradiation was 4 months (1–98 months).
Planning goal for target coverage respected ICRU 83 recommendations with for GTV: total and minimum dose, absolute dose delivered to 90% and 95%, dose delivered to 2%). Organs at risk dose constraints were: D2% < 54 Gy for optic tract, brainstem; D2% < 50 Gy for retina; D2% < 5% for eye lens; D2% < 45 Gy for spinal cord and D40% < 7,4 Gy for hippocampus.
2.3. Dose protocols Ten patients were treated one session a day, 5 days a week, to a total dose of 59.4 Gy and 68.4 Gy delivered in 33 and 38 fractions of 1.8 Gy each to the LR PTV and HR PTV, respectively. A simultaneous integrated boost was used for 9 patients, giving 59.4 Gy to the LR PTV (1.8 Gy per fraction) and 68.4 Gy simultaneously to the HR PTV (2.07 Gy per fraction) in 33 fractions. All patients received a dose equal or greater than 59.4 Gy of radiation. Dosimetric characteristics are summarized in Table 1.
2.4. Follow-up and toxicities All patients were seen once a week during treatment to assess acute reactions. Then after treatment, follow-up consisted of regular visits with brain MRI performed every 3 months for 2 years then every 6 months for 5 years. Tumor response was assessed according to Response Assessment in Neuro-Oncology criteria. Endocrine blood tests were performed annually to monitor for changes in the hypothalamus-pituitaryadrenal axis, and audiometric and visual examinations were performed annually. Early (before 90 days) and late (after 90 days) side effects were graded according to the Common Terminology Criteria for Adverse Events v.3.0 grading system.
2.1. Radiation treatment planning All patients were immobilized with a customized thermoplastic mask. A 2.5 mm slice-thickness simulation CT scan in supine position was performed. This CT was then fused with the pre-surgery and the pre-RT MRIs to delineate the target volumes as well as the organs at risk (OARs) including eyes, lenses, retinas, optic pathways, normal brain, brainstem, spinal cord, and cochleas. HT plans were created using the HiArt II treatment planning platform (version 4.2.0.87, tomotherapy Inc., Madison, WI, USA) using 6 MV photons. For beam modulation, a 64-leaf binary multi-leaf collimator was used with a leaf width of 6.25 mm projected at isocenter. A longitudinal aperture size of 2.5 cm, a pitch of 0.287, and a modulation factor of 2.4 were used. Once initial parameters were set for each plan, a full beamlet dose calculation was run followed by 350 optimization iterations allowing for full convergence of the cost function. For the final dose calculation, a collapsed convolution superposition dose calculation algorithm was used. 2.2. Target volumes Target volumes were defined according to International Commission for Radiation Units and Measurements report 62 definitions [13]. Gross target volume (GTV) was generated using the T1 weighted MRI with gadolinium contrast. The Low Risk Clinical Target Volume (LR CTV) was created by adding to the GTV 3–10 mm (grade II) [14,15] and 3–20 mm (grade III) safety margins, taking into account barriers to tumor spread such as bone structures, if not invaded. The High Risk Clinical Target Volume (HR CTV) was created by adding to the GTV 3 mm safety margins, again editing for barriers to tumor spread. The Planning Target Volume (PTV) was defined by adding a 3 mm isotropic expansion to the CTV.
2.5. Statistical analysis All statistics were performed using IBM SPSS v.24. Overall survival (OS) and progression-free survival (PFS) were calculated from the beginning of RT until death for any cause for OS, local and/or distant progression and/or death from any cause for PFS or the last follow-up if no event occurred. Local Control Rate (LCR) was defined as the absence of radiologic and clinical evidence of tumor progression. Univariate analysis was performed using the log-rank test to identify significant predictors of OS and PFS. A p-value of 0.05 or less was considered statistically significant. Potential prognostic factors were analyzed: age, gender, tumor grade, Simpson grade, type of resection, veinous involvement, cerebral oedema, number of surgeries, Ki67%, KPS status, corticosteroids.
Table 1 Dosimetric characteristics. Characteristics
Values (median)
Range
GTV (cc) LR CTV (cc) HR CTV (cc) LR PTV (cc) HR PTV (cc) LR PTV dose (Gy) HR PTV dose (Gy) Duration of radiation therapy (days) Irradiation Integrated boost No integrated boost
21.91 144.9 78.3 233.94 110.76 D50% = 59.4 D50% = 68.4 49
0–183.1 59.96–276.34 6.5–260.5 153.56–504 15.07–375.5 51.02–68.3 53.98–68.43 22–58
9 (47%) 10 (53%)
Abbreviations: GTV = gross tumor volume; LR = low-risk; CTV = clinical target volume; HR = high-risk; PTV = planning target volume, Gy = Gray.
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3. Results The median age of the patients was 63 years (range, 43–76), and the sex ratio (M/F) was 2.8 (14/5). Fifteen (79%) of the 19 patients had a diagnosis of grade II meningioma and 4 (21%) had a diagnosis of grade III meningioma. The median follow-up time was 29.2 months (range, 1.6–39.7). Median clinical follow-up for patients with Grade II or Grade III meningiomas, after completing treatment, was 29.2 months (range, 10.7–52.4) and 21.3 months (range, 2.4–51.3), respectively. Patient, tumor characteristics and details are presented in Tables 2 and 3. 3.1. Local control The 1-, 2- and 3-year PFS rates were 89.2% (95%CI = 76%–100%), 83.6% (95%CI = 68.2%–100%) and 56.3% (95%CI = 33.9%–93.5%), respectively. The 1-, 2- and 3-year LCR rates were 84.2% (95% CI = 69.3%–100%), 78.9% (95%CI = 62.6%–99.6%) and 67.7% (95% CI = 49.4%–92.8%) respectively. Six patients developed an in-field local recurrence, all in the high dose CTV. No patient developed out filed or metastatic recurrence. The median time to local recur-
Table 2 Patient characteristics and tumor characteristics. GRADE II
GRADE III
15 (79%)
4 (21%)
63 [43–78]
71 [49–74]
11 4
3 1
KPS 100 90 80 70
1 9 3 2
0 3 0 1
Histology Clear cell meningioma Atypical meningioma Anaplasic Unknown
2 (11%) 8 (42%) – 5 (26%)
– – 4 (21%) –
Locations Frontal Occipital Sphenoid wing Parietal Foramen magnum Cavernous sinus Venous Sinus invasion
8 (42%) 3 (16%) 1 (5%) 2 (11%) 1 (5%) 1 (5%) 10 (53%)
2 (11%) 0 0 1 (5%) 0 0 1 (5%)
7 (37%) 4 (21%) 4 (21%) 4.5 [2–26]
1 2 1 5
Radiotherapy indication Radiotherapy alone after recurrence After incomplete resection After complete resection
9 (47%) 5 (26%) 1 (5%)*
0 3 (16%) 1 (5%)
Simpson Class I II III IV V
1 3 2 8 1
0 1 (5%) 0 3 (16%) 0
Patient N (%) Age (years) Median Range Gender Male Female
Number of resections before RT 1 2 3 or more Median interval between last surgery and RT (months)
(5%) (16%) (11%) (42%) (5%)
(5%) (11%) (5%) [1–5]
* One patient was treated after complete resection but because of multiple previous surgeries, the indication of adjuvant radiotherapy was retained. Usually, about totally resected grade II meningioma, indication of irradiation depends on neurosurgeon preference.
rence was 19.1 months (range, 8.4–32.3). For patients with grade II meningioma, the 1-, 2-PFS rate were 93.3% (95%CI = 81.5%–100%) and 3-year PFS rates was 58.3% (95%CI = 33.5%–100%), LCR rates were 100% (95%CI = 100%–100%) at 1 and 2 years, and 71.4% (95% CI = 44.7%–100%) at 3 years. All of the patients with grade III meningioma showed a progression during follow up with a disease median control of 20 months (range 8.4–20). 3.1.1. Survival The 1-, 2- and 3-year OS rates were 94.7% (95%CI = 85.2%– 100%), 94.7% (95%CI = 85.2%–100%), and 78.9% (95%CI = 59.4%– 100%) respectively. Three patients died, 2 due to intercurrent disease and one from disease progression. 3.1.2. Prognosis factors At 3 years, age > 70 years old, Grade III meningioma and a Ki67% > 15% were identified as significant pejorative factors for PFS. At 3 years, significant pejorative factors for OS were notion of hospitalization and the Simpson score. Prognosis factors are summarized in Table 4. 3.1.3. Early side effects Treatment with radiotherapy was well tolerated with a median KPS of 90% (70–100) before treatment and 80% (50–90) after treatment. The most common Grade I–II side effects were alopecia for 18 patients (95%), radiodermatitis in 12 patients (63%) and headache in 5 patients (26%). One patient developed grade 3 ataxia during treatment. Two patients (11%) required hospitalization during treatment: one for a decline in general condition and one for ataxia. No treatment was interrupted. Early side effects are summarized in Table 5. Due to radiotherapy, symptomatic treatment with corticosteroids was initiated in 10 patients (53%), with a median methylprednisolone dose equivalent of 34.5 mg (range 75–16 mg). 3.1.4. Late side effects During long-term follow-up, only one patient experienced Grade 3 or higher toxicities (Table 5). These toxicities were associated with a progression of the disease and significant cerebral edema which later led to the patient’s death. Four patients were still dependent on corticosteroid 90 days after the end of treatment, with a median duration of use in this group of 19.4 months (range 12.6–23.2 months): 2 patients due to cerebral oedema, 1 patient due to local recurrence and 1 patient due to local recurrence associated with oedema. During radiological follow-up, there was no evidence of edema or suspicious contrast enhancement of radionecrosis, so no multimodal imaging was performed. 4. Discussion The aim of our study is to evaluate our treatment results of grade II and III meningiomas, operated or not, and irradiated by HT, in terms of efficiency and tolerance. We present the results after a median follow-up of 29.2 months with 1-, 2- and 3 year DFS of 89.2%, 83.6% and 56.3% respectively, LCR of 84.2%, 78.9% and 67.7% respectively and OS of 94.7%, 94, 7% and 78.9%, respectively. Other major series evaluated local control and survival outcomes for grade II and III meningiomas. In 2000, Hug et al studied the role of conformal radiotherapy in 31 patients with grade II and grade III meningiomas. Target doses ranged from 50 to 68 Gy for grade II and from 40 to 72 Gy for grade III. Sixteen patients received additional proton therapy boost, after surgery for 29 patients: 8 patients (26%) after total resection, 21 patients (67%) after subtotal resection. Two other patients (7%) underwent biopsy only. Rates of
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G. Boulle et al. / Journal of Clinical Neuroscience 59 (2019) 190–196 Table 3 Individual patient details. Meningioma grade
Age (y)
Sex
Simpson grade
Time period surgeryradiotherapy (m)
Relapse
time to relapse (m)
Status to analysis
Cause of death
Higher late toxicities (CTCAE grade)
II II II II II II II II III II II II II II III II III II III
70 72 57 71 56 69 49 45 50 46 49 67 53 64 78 66 72 79 75
M W M M W W M M M M W M M M W M M M M
5 4 4 4 4 3 4 1 4 4 3 2 4 4 4 2 4 2 2
2 4 3 28 7 4 2 5 2 4 14 98 8 4 2 26 5 6 1
No No No Yes No No No No Yes No No No No No Yes No Yes Yes Yes
– – – 25,6 – – – – 20,0 – – – – – 10,7 – 8,4 28,1 12,6
Alive Alive Alive Alive Alive Dead Alive Alive Alive Alive Dead Alive Alive Alive Alive Alive Alive Alive Dead
– – – – – NA – – – – NA – – – – – – – Progression disease
– Headache (II) – Concentration (II) Ataxia (II) NA – – Memory loss (I) – Vision change (I) – – – – Epilepsy (II) – – Epilepsy (VI), Ataxia (IV), Dysarthria (III), concentration (III)
Abbreviations: M = Man, W = Woman, y = years, m = months, NA = data Not Available.
Table 4 Prognosis factors. Prognostic factors Age <70 70 Gender M F Grade II III Venous sinus involvement Thrombosis Invasion No invasion Cerebral edema Yes No Number of surgeries 1 >1 Type of resection Complete Incomplete Biopsy Simpson score 1-2-3 4-5 * Ki67% <15% 15% KPS before RT 90 <90 Corticosteroids prescribed Yes No
n
3y-OS(%)
p-value
3y-PFS(%)
p-value
13 6
79 80
0.85
75 0
<0.001
14 5
91 53
0.14
49 75
0.68
15 4
80 75
0.66
79 0
<0.001
2 8 9
100 100 51
0.12
0 62 63
0.59
13 6
42 91
0.11
41 100
0.09
8 11
57 91
0.34
87 36
0.14
7 11 1
48 100 100
0.07
62 52 100
0.88
7 12
48 100
0.02
63 54
0.84
9 9
89 74
0.85
100 27.8
0.02
13 6
86 62
0.11
59 40
0.54
10 9
63 100
0.10 0.10
52 53
0.99 0.99
Bold p-values considered statistically significant. Abbreviations: OS = overall survival, PFS = progression-free survival, KPS = Karnofsky performance status. * Data not available in 1 patient.
recurrence were similar in grade II and III meningiomas with 5and 8-year local control rates of 38% and 19% for grade II and 52% and 17% for grade III, respectively. Boskos et al, reported in 2009 a cohort of 24 patients with grade II and III meningiomas treated with combined proton and photon conformal radiotherapy.
The overall mean local relapse-free intervals were 28.3 months for grade II and 23 months for grade III. The local control rate at 1, 2 and 3 years was 82.9%, 82.9% and 61.3%, respectively. Milosevic et al, with 60 patients, reported an overall survival at 1, 2 and 3 years of 75%, 60% and 50%, respectively, in a similar population
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Table 5 Side effects CATCAE v3.0.
*
Acute toxicities
G1
G2
G3
G4
Total (%)
Nausea Alopecia Headaches Dermatitis Ataxia
3 (16%) 7 (37%) 4 (21%) 10 (53%) 0
1 (5%) 11 (58%) 1 (5%) 2 (10%) 0
0 0 0 0 1 (5%)
0 0 0 0 0
4 (21%) 18 (95%) 5 (26%) 12 (63%) 1 (5%)
Late toxicities Memory loss Concentration Headache Ataxia Epilepsy Vision changes Dysarthria Alopecia
G1 1 (5%) 0 0 0 0 1 (5%) 0 3 (16%)
G2 0 1 (5%) 1 (5%) 1 (5%) 1 (5%) 0 0 4 (21%)*
G3 0 1 (5%)* 0 0 2 (10%)* 0 1 (5%)* 0
G4 0 0 0 1 (5%)* 1 (5%)* 0 0 0
Total (%) 1 (5%) 2 (11%) 1 (5%) 2 (11%) 4 (21%) 1 (5%) 1 (5%) 7 (37%)
Events occurred in the same patient.
[16]. Dziuk et al, reviewing 38 malignant meningiomas, showed a 1-year PFS of 94% [17]. Pasquier et al, with 39 patients had a 3-years PFS and OS of 65% and 76% respectively [18]. Recently, Cain et al reported a 1- and 3-year PFS of 100% and 63% and a 1- and 3-year of 75% OS, respectively [6]. Our results seem to be at least equivalent to those in the published literature (Table 6) [19]. There is no randomized data available assessing the role of radiotherapy in management of grade II or III meningiomas. Currently the ROAM/EORTC-1308 trial, which compares radiation therapy and observation following surgical resection of atypical meningiomas, may provide evidence in support of radiotherapy in the management of this pathology [20,21]. Several authors have suggested that the addition of postoperative radiotherapy to surgical resection would improve local control, especially in malignant meningiomas [22]. Goldsmith et al., in a retrospective analysis, reported a significant increase in the 5 year PFS in patients with malignant meningiomas after subtotal resections [5]. A study recently highlighted a new track for the identification of patients
with high risk of recurrence. Sahm et al, in a multicenter retrospective study, analyzed genome-wide DNA methylation patterns of 497 meningiomas. This study made it possible to stratify patients more precisely according to their risk of recurrence, especially for grade II [23]. Several studies of radiotherapy for meningioma have shown an improvement in clinical outcomes for higher doses. Milosevic et al observed an improvement in cause-specific survival for doses > 50 Gy on multivariate analysis [16]. Boskos et al, reported an improvement in OS and PFS for doses > 60 Gy in univariate analysis (p < 0.05) but in OS only on multivariate analysis (p = 0.029). There was a trend in OS improvement for doses > 65 Gy on univariate analysis [8]. Similarly, Hug et al, reported better DFS and OS with doses > 60 Gy at 5 and 8 years [7]. Two recent prospective studies, RTOG 0539 and EORTC 22042–26042, evaluated the interest of irradiation at doses greater than 60 Gy [24,25]. Weber et al, showed a 3-year PFS rate of 88.7% for grade II meningiomas with complete resection (Simpson 1–3) treated with a dose of 60 Gy.
Table 6 Comparison of our results with previous series. Year of publication
First Author
N
Grade
Treatment technique
Treatment dates
LCR or PFS (%)
1996
Milosevic et al [16]
59
Photons (2D and 3D)
1966–1990
1998
Dziuk et al [17]
48
I (7/59) II (18/59) III (30/59) Unclassified (4/59) III (48/48)
Photons (3D)
1984–1992
2002
Uy et al [19]
40
Grade II/III (10/40)
Photons (IMRT)
1994–1999
2008
Pasquier et al [18]
119
II (82/119) III (37/119)
Photons (2D and 3D)
1971–2005
2009
Boskos et al [8]
24
II (19/24) III (5/24)
Protons and photons (3D)
1999–2006
2011
Combs et al [12]
12
HT
2007–2009
2015
Cain et al [6]
58
Photons (3D)
2009–2012
2018
Our Study
19
I (5/12) II (5/12) III (2/12) I (7/58) II (45/58) III (6/58) II (15/19) III (4/19)
PFS : 75% -12 months 60% - 24 months 50% - 36 months LCR : 94% - 12 months LCR : 93% - 60 months LCR : 58% - 60 months 48% - 144 months LCR : 82.9% - 12 months 82.9% - 24 months 61.3% - 36 months LCR : 66% - 29 months
HT
2011–2015
LCR : 100% - 12 months 63% - 36 months PFS : 89.2% - 12 months 83.6% - 24 months 56.3% - 36 months LCR : 84.2% - 12 months 78.9% - 24 months 67.7% - 36 months
Abbreviations: HT: Helical tomotherapy, IMRT: Intensity Modulated Radiation Therapy; 2D: Two-dimensional; 3D: Three-dimensional, LCR: Local Control Rate, PFS: Progression Free Survival.
G. Boulle et al. / Journal of Clinical Neuroscience 59 (2019) 190–196
The results of the second arm of the high risk population (grade II meningiomas with Simpson grade 4–5) treated with a dose of 70 Gy has not been published yet [24]. Toxicities during treatment were generally minimal in our patient population and did not exceed grade 2 for neurological events. It should be noted, however, that our rate of hair loss is higher than in the rest of the literature with 58% grade 3 alopecia in the acute phase and 37% grade 3–4 during late follow-up. This may be explained by, first the use of HT irradiation, second, the lack of a strict constraint to preserve the scalp during the treatment-planning, and third, the close vicinity of the target volume to the scalp, which made compliance with even a modest scalp dose constraint difficult [21]. Aside from alopecia, only a few adverse effects were observed during follow-up with a rate not exceeding 21% for late neurological effects. Only one patient presented with several grade 4 toxicities and these were associated with disease progression. The use of HT makes it possible to guarantee better coverage of the target volumes, which are often complex, but also better protection of the organs at risk close to the target, when compared with conventional radiotherapy. This improved conformality has the potential to enable dose escalation within the target volumes. Previously, Combs et al studied the role of HT in the treatment of complex uni- or multifocal meningiomas of any grade. The treatment was well tolerated and the local control rate was 66% at 29 months: 50% of relapses occurring after first-line radiotherapy and 50% after re-irradiation [12]. In our study we identified several already known prognostic factors for survival and local control. Negative effect on 3-year survival was observed for any resection of Simpson grade 4 and 5 (p = 0.02), there was a negative tendency toward local control after incomplete resection, (p = 0.07) and for grade III histology (p < 0.001), as reported previously [26,27]. In the case of local control at 3 years, we found several negative prognostic factors such as age > 70 years (p < 0.001) and high mitotic index (Ki67 > 15%) (p = 0.02) but remain to be confirmed because of the small size of the population studied. We did not observe a correlation between the presence of thrombosis or invasion of the venous sinuses and local control, although this factor may indirectly cause an increased risk of recurrence due to its complication of complete resection [28–30]. Our study has several limitations, including the low number of patients and the retrospective setting. The majority of patients (79%) had grade II meningiomas, which likely influences control and survival parameters. There was no scale-based collection of data regarding neurological symptoms, cognitive effects, or quality of life during follow-up, although there was a low number of late neurological events. The duration of follow-up may be insufficient to detect all late recurrences and delayed side effects. The high rate of recurrence of high grade meningiomas should lead to a strengthening of the therapeutic strategy. Numerous ongoing trials are exploring different options like adding new molecules such as Vistusertib (NCT03071874), Nivolumab (NCT02648997), Prembrolizumab (NCT03279692), the use of innovative irradiation techniques such as proton dose escalation (NCT02978677) or the combination of both: neoadjuvant Avelumab and hypofractionated proton radiation therapy (NCT03267836). New imaging technologies such as DOTATOC PET/CT can also improve treatment planning, especially in complex cases [31,32].
5. Conclusion The management of grade II–III meningiomas with surgery followed by HT using doses exceeding 60 Gy is manageable, well
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tolerated, and associated with good local control and acceptable survival results. Several factors such as the quality of surgical resection and the histological characteristics remain paramount in the prognosis of treated patients. Large randomized trials are warranted to confirm this encouraging data. Acknowledgments The authors would like to thank Elizabeth Lecorre and Françoise Culot for having provided dosimetric calculations. Not previously published. Conflicts of interest notification No authors have direct or indirect financial interest in the subject matter. No funding. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jocn.2018.10.073. References [1] Ostrom QT, Gittleman H, Liao P, Vecchione-Koval T, Wolinsky Y, Kruchko C, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2010–2014. Neuro-Oncol 2017;19:v1–v88. https://doi.org/10.1093/neuonc/nox158. [2] Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol (Berl) 2016;131:803–20. https://doi.org/10.1007/s00401-016-1545-1. [3] Saraf S, McCarthy BJ, Villano JL. Update on meningiomas. Oncologist 2011;16:1604–13. https://doi.org/10.1634/theoncologist.2011-0193. [4] Goldbrunner R, Minniti G, Preusser M, Jenkinson MD, Sallabanda K, Houdart E, et al. EANO guidelines for the diagnosis and treatment of meningiomas. Lancet Oncol 2016;17:e383–91. https://doi.org/10.1016/S1470-2045(16)30321-7. [5] Goldsmith BJ, Wara WM, Wilson CB, Larson DA. Postoperative irradiation for subtotally resected meningiomas. A retrospective analysis of 140 patients treated from 1967 to 1990. J Neurosurg 1994;80:195–201. https://doi.org/ 10.3171/jns.1994.80.2.0195. [6] Cain SA, Smoll NR, Van Heerden J, Tsui A, Drummond KJ. Atypical and malignant meningiomas: considerations for treatment and efficacy of radiotherapy. J Clin Neurosci Off J Neurosurg Soc Australas 2015;22:1742–8. https://doi.org/10.1016/j.jocn.2015.03.054. [7] Hug EB, Devries A, Thornton AF, Munzenride JE, Pardo FS, Hedley-Whyte ET, et al. Management of atypical and malignant meningiomas: role of high-dose, 3D-conformal radiation therapy. J Neurooncol 2000;48:151–60. [8] Boskos C, Feuvret L, Noel G, Habrand J-L, Pommier P, Alapetite C, et al. Combined proton and photon conformal radiotherapy for intracranial atypical and malignant meningioma. Int J Radiat Oncol Biol Phys 2009;75:399–406. https://doi.org/10.1016/j.ijrobp.2008.10.053. [9] Glaholm J, Bloom HJ, Crow JH. The role of radiotherapy in the management of intracranial meningiomas: the Royal Marsden Hospital experience with 186 patients. Int J Radiat Oncol Biol Phys 1990;18:755–61. [10] Kokubo M, Shibamoto Y, Takahashi JA, Sasai K, Oya N, Hashimoto N, et al. Efficacy of conventional radiotherapy for recurrent meningioma. J Neurooncol 2000;48:51–5. [11] Hasan S, Young M, Albert T, Shah AH, Okoye C, Bregy A, et al. The role of adjuvant radiotherapy after gross total resection of atypical meningiomas. World Neurosurg 2015;83:808–15. https://doi.org/10.1016/j. wneu.2014.12.037. [12] Combs SE, Sterzing F, Uhl M, Habl G, Schubert K, Debus J, et al. Helical tomotherapy for meningiomas of the skull base and in paraspinal regions with complex anatomy and/or multiple lesions. Tumori 2011;97:484–91. https:// doi.org/10.1700/950.10402. [13] Gupta T, Wadasadawala T, Master Z, Phurailatpam R, Pai-Shetty R, Jalali R. Encouraging early clinical outcomes with helical tomotherapy-based imageguided intensity-modulated radiation therapy for residual, recurrent, and/or progressive benign/low-grade intracranial tumors: a comprehensive evaluation. Int J Radiat Oncol Biol Phys 2012;82:756–64. https://doi.org/ 10.1016/j.ijrobp.2010.12.044. [14] International Commission on Radiation Units and Measurements. ICRU report 50. Bethesda, MD: ICRU; 1993. n.d.. [15] Press RH, Prabhu RS, Appin CL, Brat DJ, Shu HKG, Hadjipanayis C, et al. Outcomes and patterns of failure for grade 2 meningioma treated with
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