J Neurooncol DOI 10.1007/s11060-015-1838-6
CLINICAL STUDY
Hypofractionated stereotactic radiation therapy in skull base meningiomas Pierina Navarria1 • Federico Pessina2 • Luca Cozzi1 • Elena Clerici1 • Elisa Villa1 • Anna Maria Ascolese1 • Fiorenza De Rose1 • Tiziana Comito1 • Ciro Franzese1 • Giuseppe D’Agostino1 • Francesca Lobefalo1 • Antonella Fogliata1 Giacomo Reggiori1 • Maurizio Fornari2 • Stefano Tomatis1 • Lorenzo Bello2 • Marta Scorsetti1
•
Received: 6 March 2015 / Accepted: 30 May 2015 Ó Springer Science+Business Media New York 2015
Abstract To investigate the role of hypo-fractionated stereotactic radiation treatment (HSRT) in the management of skull base meningioma. Twenty-six patients were included in the study and treated with a dose of 30 Gy in 5 fractions with volumetric modulated arc therapy (RapidArc). Eighteen patients were symptomatic before treatment. Endpoints were local toxicity and relief from symptoms. Tumors were located in anterior skull base in 4/27 cases, in middle skull base in 12/27 and in posterior skull base in 11/27. HSRT was performed as first treatment in 17 (65 %) patients, in 9 (35 %) patients it followed a previous partial resection. Median follow up was 24.5 months (range 5–57 months). clinical remission of symptoms, complete or partial, was obtained in the vast majority of patients after treatment. Out of the 18 symptomatic patients, partial remission occurred in 9 (50 %) patients and complete remission in 9 (50 %). All asymptomatic patients retained their status after treatment. No severe neurologic toxicity grade III–IV was recorded. No increase of meningioma in the same site of treatment occurred; 16 (62 %) patients had stable disease and 9 (38 %) patients had tumor reduction. The mean tumor volume after treatment was 10.8 ± 17.8 cm3 compared with 13.0 ± 19.1 cm3 before treatment (p = 0.02). The mean actuarial OS was 54.4 ± 2.8 months. The 1- and 2-years OS was 92.9 ± 0.7 %. HSRT proved to be feasible
& Luca Cozzi [email protected] 1
Radiosurgery and Radiotherapy Department, Istituto Clinico Humanitas Cancer Center Rozzano Milano, Via Manzoni 56, 20089 Rozzano, Milano, Italy
2
Neurosurgery Department, Humanitas Research Hospital, Milan, Italy
for these patients not eligible to full surgery or to ablative radiation therapy. Local control and durability of results suggest for a routine application of this approach in properly selected cases. Keywords Meningioma Hypofractionation Stereotactic radiation therapy RapidArc
Introduction Meningiomas are the most common primary intracranial tumor, accounting for approximately 13–30 % of primary brain lesions. The majority (*80 %) are benign slowgrowing lesions, (WHO grade I), 20 % are atypical (grade II WHO) and less than 5 % are anaplastic, aggressive, malignant tumors (WHO grade III) [1–3]. Regardless of grade the standard of care for meningioma is surgical resection with the goal of the complete removal of the lesion, including the dural attachment and the possible infiltrated bone. After gross total resection, as for Simpson’s definition Grade I and II, the reported 5 years control rate is about 88–95 % for grade I meningiomas, and 60–80 % for grade II. Unfortunately, not all tumors can be completely resected, due to their extension, site of origin, nerve and vessel involvement. In these cases the rate of local control is 50 % on the average. Skull base meningiomas, represent a subgroup of tumors in which a complete surgical removal is rarely achieved. In this subset, surgical resection has been associated with significant morbidity and mortality, high rate of incomplete resection, and delayed progression [4–9]. In case of incomplete resection (Simpson grade C III) the reported 5, 10 and 15 years progression rate is 30, 60 and 90 % respectively [10–12].
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Stereotactic radiotherapy, either as fractionated stereotactic radiotherapy (FSRT) or single dose radiosurgery (SRS) has emerged as a valuable first option in selected patients, or after incomplete surgical resection. In case of large residual tumors or progressive growing mass, conventional radiotherapy is associated with a 10-years control rates of more than 80 %, a good profile of toxicity and an improvement of neurological symptoms in a significant number of patients [13–15]. Radiosurgery is used for small lesions away from critical structures. The local control rate is similar to that of complete resection with minimal toxicity [16, 17]. Limitations are represented from large meningioma, close to critical structures for the high risk of late toxicity and radionecrosis. To date few date are published about hypo-fractionated stereotactic radiotherapy (HSRT). Those studies are frequently heterogeneous in relation to origin site, different schedules of radiation therapy (conventional, radiosurgery or HSRT) or in regard to the histology (including different sull base benign tumors as all meningiomas and schwannomas). The major issue, is the risk of toxicity to the normal tissues. So the new techniques, that allow a steep dose gradients and a better definition of real cancer volume and identification of so-called organs at risk, in association to the increase of dose for fraction, improve the therapeutic ratio decreasing the possibility of geographic missing of the target and minimizing the normal tissue toxicity. Based on this background patients with large skull base meningioma has been consecutively treated with HSRT in our Institution since 2009. In this study we reported the impact of HSRT in term of local toxicity and patients symptoms relief. The principles of HSRT are not new but the model have been applied here to an homogeneous (although small) cohort of patients. Primary scope of the study was the analysis of symptoms relief and preliminary results about (acute) toxicity.
Materials and methods Patients and procedures This prospective observational study includes patients with MRI presumptive diagnosis of skull base meningioma. The study received the approval of the institutional review cancer center board. In order to define the most appropriate treatment, each patients was evaluated by a multidisciplinary team including radiation oncologists, neurosurgeons and a neuroradiologist. Criteria for treatment selection were the patients general condition (age, performance status, symptoms) and the disease features (location and size of meningioma). HSRT was chosen as treatment modality in case of
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one or more of the following: (1) large skull base meningioma, (2) proximity of critical structures, (3) growing residual tumor after surgery, (4) symptomatic patients (with stable and impairing symptoms since more than 3 months and requiring medications for their control), (5) contraindication to surgical resection. Conventional fractionation was also not chosen because of patient compliance, department workflow and the fact that the dosimetric quality of the plans allowed for the hypofractionation model. The choice of this total dose and fractionation was based on the similarity with data published in literature, the similar biological effective dose (BED) to conventional treatment assuming an alpha/beta ratio of 2 and the impossibility of prescribing a regimen with an higher BED (like in radiosurgery) because of the large target volumes involved. Aim of the study was to assess local acute and sub-acute toxicity and durability of clinical remission of the symptoms. Although local control rate and overall survival were not the primary objective of this study due to the short follow-up, they were evaluated as well. From September 2009 to July 2014, among consecutive patients referred at our institution for meningioma, 26 patients for 27 lesions received HSRT and were included in the present evaluation. Eight (31 %) were male and 18 (69 %) female with a median age of 67 years (range 33–89 years). HSRT was performed as first treatment in progressive tumors in 17 (65 %) patients while in 9 (35 %) patients it followed a previous surgery. All patients were treated with a total dose of 30 Gy in 5 fractions. Patients’ characteristics and treatments are shown in Table 1. HSRT treatment To precisely define the tumor extension, post GD T1-MRI, FLAIR-MRI sequences were acquired. The procedure for target definition included also post contrast CT scans. Patients were placed in supine position with arms close to the body. A personalized thermoplastic mask was used for a better patient immobilization and repositioning. All scans, extending from the top of the skull to the third cervical vertebrae, were acquired with 1–3 mm slice thickness. Automatic rigid co-registration, eventually manually corrected, was performed. The gross tumor volume (GTV) was defined as the enhanced contrast lesion on T1MRI. The planning target volume (PTV) was defined as an isotropic 3 mm expansion from the GTV. Organs at risk (OARs) considered were: brain stem, chiasm, optic nerves, lenses and cochlea. All treatments were optimized for Volumetric Modulated Arc therapy in the RapidArc form with the Eclipse planning system (Varian Medical Systems, Palo Alto, US versions 10 and 11). Dose calculations were performed with the Anisotropic Analytical Algorithm with a dose matric of 1.25 mm. Delivery was performed on
J Neurooncol Table 1 Patients characteristics and treatment
Patients Patients
26 (100 %)
Lesions treated with HSRT
27 (100 %)
Gender Males
8 (31 %)
Females
18 (69 %)
Median age
67 years (range 33–89 years)
Site Anterior skull base
4 (15 %)
Ethmoidal region
2 (8 %)
Olfactory groove region
2 (8 %)
Middle skull base
12 (44 %)
Tuberculum sella
2 (8 %)
Anterior clinoide
1 (4 %)
Cavernous sinus
9 (35 %)
Posterior skull base Foramen magnum
11 (41 %) 1 (4 %)
Tentorial
2 (8 %)
Petroclival
8 (15 %)
Mean volume of treated lesions
13.00 ± 19.1 cm3 (range 1.8–93.4 cm3)
Dose prescription
30 Gy in 5 fractions
Varian linear accelerators (Varian Medical Systems, Palo Alto, US). ExacTrac X-Ray 6D system and Cone-Beam CT (CBCT) images were used for daily patient set-up and isocenter positioning. Outcome evaluation Clinical outcome was evaluated by clinical neurological examination and brain MRI 3 months after treatment and then every 6 months at follow up for the first 3 years, then annually. The Response was defined as a reduction of tumor volume (Partial Remission, PR) or no change in tumor volume (Stable Disease, SD) compared to the volume at RT treatment; any increase greater than 10 % was defined as tumor progression. Dosimetric quality of the treatment plans was investigated by quantitative analysis of the dose volume histograms from each approved clinical plan. Standard descriptive statistics (mean standard deviation and cross tabulation analysis) was used to describe the data general behaviour. Overall survival (OS) was computed by means of Kaplan– Meier analysis, starting from the date of treatment.
Results Clinical presentation and treatment Tumors were located in anterior skull base in 4/27 cases, in middle skull base in 12/27 and in posterior skull base in
11/27. At HSRT treatment time, 18 (69 %) patients were symptomatic, with various presentation in relation to the tumor location, while 8 (31 %) patients were asymptomatic but with radiological evidence of tumor progression. One patient received two HSRT treatment. HSRT was performed as first treatment in 17 (65 %) patients, while in 9 (35 %) patients it followed a previous partial surgical resection. The median tumour volume treated was 13 ± 19.1 cm3 (range 1.8–93.4 cm3) and the total dose prescribed was 30 Gy in 5 fractions. Table 2 illustrates the summary of the quantitative analysis of the treatment plans for the target volumes and the organs at risk. All planning objectives were met in average. Outcome of patients With a median follow up from HSRT of 24.5 months (range 5–57 months), clinical remission of symptoms, complete or partial, was obtained in the vast majority of patients after treatment. Table 3 reports the summary of the clinical analysis on the patients cohort. Table 4 details the patterns of symptoms before and after treatment. Specifically, out of 18 symptomatic patients, a partial remission occurred in 9 (50 %) patients and a complete remission in 9 (50 %). The median time of clinical remission was 14 months. All asymptomatic patients retained their status after treatment. No severe neurologic acute toxicity grade III–IV was recorded. No increased of meningioma in the same site of
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J Neurooncol Table 2 Summary of the DVH analysis for the GTV, the PTV and the OARs. Data are reported as average values plus or minus one standard deviation and range
ORGAN
Parameter
GTV
Mean (Gy) (D5 D1
Whole brain
[20.1–40.0] [2.0–8.0] [20.5–40.7] [19.8–39.4]
Mean (Gy)
–
29.5 ± 3.9
[20.1–40.0]
(D5 %- D95 %)/mean
Minimise
7.8 ± 4.4
[3.6–19.7]
D1
Minimise
30.6 ± 3.9
[20.5–40.9]
Maximise
26.5 ± 4.1
[17.1–38.5]
%
%
(Gy)
%
(Gy)
Mean (Gy)
–
2.7 ± 1.6
[0.8–7.4]
V10Gy (%)
–
7.4 ± 6.1
[0.3–12.9]
3 cm
Chiasm
3 cm D0.1 cm3 D0.1 cm3 D0.1 cm3
Ipsilateral cochlea
3.6 ± 1.6 30.4 ± 3.9
D1
Ipsilateral optic nerve
29.7 ± 3.8
28.9 ± 3.7
(Gy)
Brain stem Ipsilateral lens
– \5 %
Range
Minimise
D99
(Gy)
Mean ± SD
Maximise
%
D99 PTV
D95 %)/mean (%)
%
Objective
D0.1
\20Gy
8.9 ± 9.1
[0.1–29.8]
(Gy)
\12 Gy
6.4 ± 8.3
[0.1–26.5]
(Gy)
\8 Gy
1.3 ± 1.7
[0.1–6.2]
(Gy)
\15 Gy
7.6 ± 8.3
[0.1–20.6]
(Gy)
\15 Gy
8.4 ± 8.9
[0.0–25.8]
(Gy)
SD standard deviation, Dx% dose received by at least x% of the volume, Vx% volume receiving at least x% of the dose
treatment occurred; 16 (62 %) patients had stable disease and 9 (38 %) patients had tumor reduction. An example of tumour response is shown in Fig. 1. The mean tumor volume after treatment was 10.8 ± 17.8 cm3 compared with 13.0 ± 19.1 cm3 before treatment (p = 0.02). Twenty-five patients (96 %) were alive at time of analysis and 1 (4 %) died for tumor unrelated cause. The mean actuarial OS was 54.4 ± 2.8 months. The 1- and 2-years OS was 92.9 ± 0.7 %. These data refer to a dataset with a very short follow-up time of 24.5 months.
Discussion The natural history of skull base meningiomas is still not defined and data from the literature are not conclusive on this matter. A recent review of 22 studies covering the natural history of meningiomas underlines that cavernous sinus lesions induced new or progressive symptoms in 61 % of the cases in a median follow-up of 4.6 years. In addition, patients with larger lesions (2–2.5 cm) have a 10 % chance of tumor grow per year and a 42.4 % chance of symptoms development in comparison to patients with lesions smaller than 2 cm, in which the chance is 0 %. In contrast, Bindal [21], described the outcome of 40 untreated meningiomas located in the cavernous sinus, petroclival region, or anterior clinoidal region. Over a mean follow up time of about 7 years only 27.5 % of patients experienced new or worsening CN deficits and only 17.5 % of patients tumor growth. There is also no clear consensus on which is the best treatment to treat a skull base meningioma. In this study, the decision to treat
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patients was the evidence of tumor progression on MRI or the occurrence of neurological symptoms. Surgery is the most effective treatment modality for meningioma, but it is rarely achieved in this region and it is frequently associated with a significant morbidity. Complication rates for grosstotal resection of skull base meningiomas vary widely, and adverse events have been reported to occur in 0–60 % of patients [4, 21–25]. The HSRT treatment of the patients was chosen when one or more of the following reasons were present: (i) previous partial surgical resection with MRI evidence of growing residual tumor (ii) elderly patients not eligible for surgical resection in relation to performance status and/or presence of comorbidity (iii) high risk of incomplete surgery (iv) high risk of adverse events. Recently, stereotactic radiation techniques emerged as a feasible treatment for skull base meningioma. Compared with conventional RT, stereotactic techniques, given as single fraction radiosurgery (SRS) or as fractionated stereotactic RT (FSRT), deliver more localized irradiation with a steeper dose gradient between tumor and the surrounding normal tissue reducing the risk of radiation induced complications. Fractionated techniques take additional advantage of the biological benefit of fractionation with regards to tumor control and toxicity. Hypo-fractionated SRT use the same principles but in addition, it is able to deliver treatment over 1 week versus 4–5 weeks of standard fractionation schemes, increasing patients quality of life. In our series patients with skull base meningioma underwent hypo-fractionated stereotactic radiation therapy. By use of this approach, an early and durable remission of neurological symptoms were obtained in all patients with
J Neurooncol Table 3 Summary of the clinical analysis Patients
26
Clinical local control
Radiological local control
Initial volume (cm3) Final volume (cm3) Status at last FU Actuarial overall survival (monhts)
Progressive
0 (0 %)
Stable
15 (58 %)
Partial response
9 (35 %)
Complete response
2 (8 %)
Progressive
0 (0 %)
Stable
16 (62 %)
Partial response
10 (38 %)
Complete response
0 (0 %)
Mean
13.0 ± 19.1
Range
1.8 – 93.4
Mean
10.8 ± 17.8(*)
Range
1.1 – 93.0
Alive
25 (96 %)
Death
1 (4 %)(**)
Mean
54.4 ± 2.8(***)
95 % CI
48.8 – 59.9
Symptoms patterns Pre HSRT symptoms
Post HSRT symptoms Stable
Partial remission
Complete remission
Symptoms patterns Asymptomatic
8 (31 %)
–
–
–
Symptomatic
18 (69 %)
7 (27 %)
9 (35 %)
2 (8 %)
Haedache
4 (15 %)
Seizures
2 (8 %)
4 (15 %) 2 (8 %)
Cranial nerve deficit II cn
3 (12 %)
2 (8 %)
1 (4 %)
1 (4 %)
III cn
2 (8 %)
1 (4 %)
1 (4 %)
2 (8 %)
IV cn
1 (4 %)
1 (4 %)
1 (4 %)
V cn
5 (19 %)
VI cn
3 (12 %)
2 (8 %)
VIII cn
3 (12 %)
2 (8 %)
3 (12 %)
Cn cranial nerve; (*) statistical significant difference with p = 0.02; (**) death due to other cause not related to disease; (***) median not reached. 2 years OS—92.9 ± 0.7 %
Table 4 Summary of published clinical studies on stereotactic radiation therapy using unconventional dose fractionation schemes Authors
# Patients
Period
Hystology
Dose (Gy)
# Fractions 5 (3–27)
Vernimmen [26]
23
Since 1993
Meningiamas
Photons and protons
20–54
Pham [27]
34
1997–2001
Meningiomas and pituitary adenomas
Cyberknife
20 (15–30)
3 (2–5)
Gorman [28]
38
1997–2004
Meningiamas
Linac
37.5 (35–40)
15
Trippa [29]
35
2003–2007
Meningiamas
Linac
42–45
15
Morimoto [30]
31
1999–2008
Meningiamas
Cyberknife
27.8 (21–36)
3–5
Mahdevan [31]
26
Na
Meningiomas and neurinomas
Cyberknife
25–30
5
Conti [32]
25
2007–2010
Perioptic meningiomas
Cyberknife
25 (18–25)
5 (2–15)
no toxicity. At the last follow up, no progression of disease in site of treatment was recorded. Although biased by the small cohort of patients, a moderate correlation between volume reduction and improvement of symptoms was
observed. These results compare favorably with previous reports [13–17]. This study has some peculiar features and limitations. The limited sample size and the short follow up time are
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Fig. 1 An example of treatment response. Before HSRT (left panel) patient was affected by left ptosis and facial dysesthesia which were completely recovered after treatment (right panel, 24 months control MR). The dose distrivution in one axial plane is shown in the central panel
the primary limitations. Indeed 10 years would be needed for a proper assessment of tumor control. Longer follow up would be needed to warrant a broad adoption of this technique in the treatment of skull base meningioma, although the results shown here are encouraging. The study can be considered informative in terms of toxicity even in the presence of one single patient with less than 6 months FU). Table 4 summarises the main studies published for hypofractionated treatment of meningiomas. As it can be seen, most were conducted on Cyberknife or protons. The two conducted on linear accelerators were performed with a schedule of 15 fractions. The only one with a fixed schedule of 5 fractions (but variable total dose) was not on an homogeneous group of patients since mixed also Schwannomas. On the contrary, the present study, conducted on an homogeneous group and a single fractionation scheme. Concerning clinical outcome, despite the fact that patients in our series had large tumor, (mean tumor volume of 13 ± 19.1 cm3; range 1.8–93.4 cm3), and located in critical site, no severe acute/subacute toxicity or tissue damage were recorded. A rapid and durable remission of neurological symptoms was obtained and a radiological reduction of the lesions was visible at the early follow up (median tumor volume 10.8 ± 17.8 cm3; range 1.1–93 cm3) (p = 0.02).
Conclusion HSRT is a feasible treatment for patients with large, skull base meningiomas, associated with a high chance of neurological improvement. A longer follow up is needed to confirm these preliminary results in these selected series.
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Ethical standards All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Conflict of interest L. Cozzi acts as Scientific Advisor to Varian Medical Systems and is Clinical Research Scientist at Humanitas Cancer Center. All other co-authors have no conflicts of interest.
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CLINICAL STUDY
Hypofractionated stereotactic radiation therapy in skull base meningiomas Pierina Navarria1 • Federico Pessina2 • Luca Cozzi1 • Elena Clerici1 • Elisa Villa1 • Anna Maria Ascolese1 • Fiorenza De Rose1 • Tiziana Comito1 • Ciro Franzese1 • Giuseppe D’Agostino1 • Francesca Lobefalo1 • Antonella Fogliata1 Giacomo Reggiori1 • Maurizio Fornari2 • Stefano Tomatis1 • Lorenzo Bello2 • Marta Scorsetti1
•
Received: 6 March 2015 / Accepted: 30 May 2015 Ó Springer Science+Business Media New York 2015
Abstract To investigate the role of hypo-fractionated stereotactic radiation treatment (HSRT) in the management of skull base meningioma. Twenty-six patients were included in the study and treated with a dose of 30 Gy in 5 fractions with volumetric modulated arc therapy (RapidArc). Eighteen patients were symptomatic before treatment. Endpoints were local toxicity and relief from symptoms. Tumors were located in anterior skull base in 4/27 cases, in middle skull base in 12/27 and in posterior skull base in 11/27. HSRT was performed as first treatment in 17 (65 %) patients, in 9 (35 %) patients it followed a previous partial resection. Median follow up was 24.5 months (range 5–57 months). clinical remission of symptoms, complete or partial, was obtained in the vast majority of patients after treatment. Out of the 18 symptomatic patients, partial remission occurred in 9 (50 %) patients and complete remission in 9 (50 %). All asymptomatic patients retained their status after treatment. No severe neurologic toxicity grade III–IV was recorded. No increase of meningioma in the same site of treatment occurred; 16 (62 %) patients had stable disease and 9 (38 %) patients had tumor reduction. The mean tumor volume after treatment was 10.8 ± 17.8 cm3 compared with 13.0 ± 19.1 cm3 before treatment (p = 0.02). The mean actuarial OS was 54.4 ± 2.8 months. The 1- and 2-years OS was 92.9 ± 0.7 %. HSRT proved to be feasible
& Luca Cozzi [email protected] 1
Radiosurgery and Radiotherapy Department, Istituto Clinico Humanitas Cancer Center Rozzano Milano, Via Manzoni 56, 20089 Rozzano, Milano, Italy
2
Neurosurgery Department, Humanitas Research Hospital, Milan, Italy
for these patients not eligible to full surgery or to ablative radiation therapy. Local control and durability of results suggest for a routine application of this approach in properly selected cases. Keywords Meningioma Hypofractionation Stereotactic radiation therapy RapidArc
Introduction Meningiomas are the most common primary intracranial tumor, accounting for approximately 13–30 % of primary brain lesions. The majority (*80 %) are benign slowgrowing lesions, (WHO grade I), 20 % are atypical (grade II WHO) and less than 5 % are anaplastic, aggressive, malignant tumors (WHO grade III) [1–3]. Regardless of grade the standard of care for meningioma is surgical resection with the goal of the complete removal of the lesion, including the dural attachment and the possible infiltrated bone. After gross total resection, as for Simpson’s definition Grade I and II, the reported 5 years control rate is about 88–95 % for grade I meningiomas, and 60–80 % for grade II. Unfortunately, not all tumors can be completely resected, due to their extension, site of origin, nerve and vessel involvement. In these cases the rate of local control is 50 % on the average. Skull base meningiomas, represent a subgroup of tumors in which a complete surgical removal is rarely achieved. In this subset, surgical resection has been associated with significant morbidity and mortality, high rate of incomplete resection, and delayed progression [4–9]. In case of incomplete resection (Simpson grade C III) the reported 5, 10 and 15 years progression rate is 30, 60 and 90 % respectively [10–12].
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Stereotactic radiotherapy, either as fractionated stereotactic radiotherapy (FSRT) or single dose radiosurgery (SRS) has emerged as a valuable first option in selected patients, or after incomplete surgical resection. In case of large residual tumors or progressive growing mass, conventional radiotherapy is associated with a 10-years control rates of more than 80 %, a good profile of toxicity and an improvement of neurological symptoms in a significant number of patients [13–15]. Radiosurgery is used for small lesions away from critical structures. The local control rate is similar to that of complete resection with minimal toxicity [16, 17]. Limitations are represented from large meningioma, close to critical structures for the high risk of late toxicity and radionecrosis. To date few date are published about hypo-fractionated stereotactic radiotherapy (HSRT). Those studies are frequently heterogeneous in relation to origin site, different schedules of radiation therapy (conventional, radiosurgery or HSRT) or in regard to the histology (including different sull base benign tumors as all meningiomas and schwannomas). The major issue, is the risk of toxicity to the normal tissues. So the new techniques, that allow a steep dose gradients and a better definition of real cancer volume and identification of so-called organs at risk, in association to the increase of dose for fraction, improve the therapeutic ratio decreasing the possibility of geographic missing of the target and minimizing the normal tissue toxicity. Based on this background patients with large skull base meningioma has been consecutively treated with HSRT in our Institution since 2009. In this study we reported the impact of HSRT in term of local toxicity and patients symptoms relief. The principles of HSRT are not new but the model have been applied here to an homogeneous (although small) cohort of patients. Primary scope of the study was the analysis of symptoms relief and preliminary results about (acute) toxicity.
Materials and methods Patients and procedures This prospective observational study includes patients with MRI presumptive diagnosis of skull base meningioma. The study received the approval of the institutional review cancer center board. In order to define the most appropriate treatment, each patients was evaluated by a multidisciplinary team including radiation oncologists, neurosurgeons and a neuroradiologist. Criteria for treatment selection were the patients general condition (age, performance status, symptoms) and the disease features (location and size of meningioma). HSRT was chosen as treatment modality in case of
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one or more of the following: (1) large skull base meningioma, (2) proximity of critical structures, (3) growing residual tumor after surgery, (4) symptomatic patients (with stable and impairing symptoms since more than 3 months and requiring medications for their control), (5) contraindication to surgical resection. Conventional fractionation was also not chosen because of patient compliance, department workflow and the fact that the dosimetric quality of the plans allowed for the hypofractionation model. The choice of this total dose and fractionation was based on the similarity with data published in literature, the similar biological effective dose (BED) to conventional treatment assuming an alpha/beta ratio of 2 and the impossibility of prescribing a regimen with an higher BED (like in radiosurgery) because of the large target volumes involved. Aim of the study was to assess local acute and sub-acute toxicity and durability of clinical remission of the symptoms. Although local control rate and overall survival were not the primary objective of this study due to the short follow-up, they were evaluated as well. From September 2009 to July 2014, among consecutive patients referred at our institution for meningioma, 26 patients for 27 lesions received HSRT and were included in the present evaluation. Eight (31 %) were male and 18 (69 %) female with a median age of 67 years (range 33–89 years). HSRT was performed as first treatment in progressive tumors in 17 (65 %) patients while in 9 (35 %) patients it followed a previous surgery. All patients were treated with a total dose of 30 Gy in 5 fractions. Patients’ characteristics and treatments are shown in Table 1. HSRT treatment To precisely define the tumor extension, post GD T1-MRI, FLAIR-MRI sequences were acquired. The procedure for target definition included also post contrast CT scans. Patients were placed in supine position with arms close to the body. A personalized thermoplastic mask was used for a better patient immobilization and repositioning. All scans, extending from the top of the skull to the third cervical vertebrae, were acquired with 1–3 mm slice thickness. Automatic rigid co-registration, eventually manually corrected, was performed. The gross tumor volume (GTV) was defined as the enhanced contrast lesion on T1MRI. The planning target volume (PTV) was defined as an isotropic 3 mm expansion from the GTV. Organs at risk (OARs) considered were: brain stem, chiasm, optic nerves, lenses and cochlea. All treatments were optimized for Volumetric Modulated Arc therapy in the RapidArc form with the Eclipse planning system (Varian Medical Systems, Palo Alto, US versions 10 and 11). Dose calculations were performed with the Anisotropic Analytical Algorithm with a dose matric of 1.25 mm. Delivery was performed on
J Neurooncol Table 1 Patients characteristics and treatment
Patients Patients
26 (100 %)
Lesions treated with HSRT
27 (100 %)
Gender Males
8 (31 %)
Females
18 (69 %)
Median age
67 years (range 33–89 years)
Site Anterior skull base
4 (15 %)
Ethmoidal region
2 (8 %)
Olfactory groove region
2 (8 %)
Middle skull base
12 (44 %)
Tuberculum sella
2 (8 %)
Anterior clinoide
1 (4 %)
Cavernous sinus
9 (35 %)
Posterior skull base Foramen magnum
11 (41 %) 1 (4 %)
Tentorial
2 (8 %)
Petroclival
8 (15 %)
Mean volume of treated lesions
13.00 ± 19.1 cm3 (range 1.8–93.4 cm3)
Dose prescription
30 Gy in 5 fractions
Varian linear accelerators (Varian Medical Systems, Palo Alto, US). ExacTrac X-Ray 6D system and Cone-Beam CT (CBCT) images were used for daily patient set-up and isocenter positioning. Outcome evaluation Clinical outcome was evaluated by clinical neurological examination and brain MRI 3 months after treatment and then every 6 months at follow up for the first 3 years, then annually. The Response was defined as a reduction of tumor volume (Partial Remission, PR) or no change in tumor volume (Stable Disease, SD) compared to the volume at RT treatment; any increase greater than 10 % was defined as tumor progression. Dosimetric quality of the treatment plans was investigated by quantitative analysis of the dose volume histograms from each approved clinical plan. Standard descriptive statistics (mean standard deviation and cross tabulation analysis) was used to describe the data general behaviour. Overall survival (OS) was computed by means of Kaplan– Meier analysis, starting from the date of treatment.
Results Clinical presentation and treatment Tumors were located in anterior skull base in 4/27 cases, in middle skull base in 12/27 and in posterior skull base in
11/27. At HSRT treatment time, 18 (69 %) patients were symptomatic, with various presentation in relation to the tumor location, while 8 (31 %) patients were asymptomatic but with radiological evidence of tumor progression. One patient received two HSRT treatment. HSRT was performed as first treatment in 17 (65 %) patients, while in 9 (35 %) patients it followed a previous partial surgical resection. The median tumour volume treated was 13 ± 19.1 cm3 (range 1.8–93.4 cm3) and the total dose prescribed was 30 Gy in 5 fractions. Table 2 illustrates the summary of the quantitative analysis of the treatment plans for the target volumes and the organs at risk. All planning objectives were met in average. Outcome of patients With a median follow up from HSRT of 24.5 months (range 5–57 months), clinical remission of symptoms, complete or partial, was obtained in the vast majority of patients after treatment. Table 3 reports the summary of the clinical analysis on the patients cohort. Table 4 details the patterns of symptoms before and after treatment. Specifically, out of 18 symptomatic patients, a partial remission occurred in 9 (50 %) patients and a complete remission in 9 (50 %). The median time of clinical remission was 14 months. All asymptomatic patients retained their status after treatment. No severe neurologic acute toxicity grade III–IV was recorded. No increased of meningioma in the same site of
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J Neurooncol Table 2 Summary of the DVH analysis for the GTV, the PTV and the OARs. Data are reported as average values plus or minus one standard deviation and range
ORGAN
Parameter
GTV
Mean (Gy) (D5 D1
Whole brain
[20.1–40.0] [2.0–8.0] [20.5–40.7] [19.8–39.4]
Mean (Gy)
–
29.5 ± 3.9
[20.1–40.0]
(D5 %- D95 %)/mean
Minimise
7.8 ± 4.4
[3.6–19.7]
D1
Minimise
30.6 ± 3.9
[20.5–40.9]
Maximise
26.5 ± 4.1
[17.1–38.5]
%
%
(Gy)
%
(Gy)
Mean (Gy)
–
2.7 ± 1.6
[0.8–7.4]
V10Gy (%)
–
7.4 ± 6.1
[0.3–12.9]
3 cm
Chiasm
3 cm D0.1 cm3 D0.1 cm3 D0.1 cm3
Ipsilateral cochlea
3.6 ± 1.6 30.4 ± 3.9
D1
Ipsilateral optic nerve
29.7 ± 3.8
28.9 ± 3.7
(Gy)
Brain stem Ipsilateral lens
– \5 %
Range
Minimise
D99
(Gy)
Mean ± SD
Maximise
%
D99 PTV
D95 %)/mean (%)
%
Objective
D0.1
\20Gy
8.9 ± 9.1
[0.1–29.8]
(Gy)
\12 Gy
6.4 ± 8.3
[0.1–26.5]
(Gy)
\8 Gy
1.3 ± 1.7
[0.1–6.2]
(Gy)
\15 Gy
7.6 ± 8.3
[0.1–20.6]
(Gy)
\15 Gy
8.4 ± 8.9
[0.0–25.8]
(Gy)
SD standard deviation, Dx% dose received by at least x% of the volume, Vx% volume receiving at least x% of the dose
treatment occurred; 16 (62 %) patients had stable disease and 9 (38 %) patients had tumor reduction. An example of tumour response is shown in Fig. 1. The mean tumor volume after treatment was 10.8 ± 17.8 cm3 compared with 13.0 ± 19.1 cm3 before treatment (p = 0.02). Twenty-five patients (96 %) were alive at time of analysis and 1 (4 %) died for tumor unrelated cause. The mean actuarial OS was 54.4 ± 2.8 months. The 1- and 2-years OS was 92.9 ± 0.7 %. These data refer to a dataset with a very short follow-up time of 24.5 months.
Discussion The natural history of skull base meningiomas is still not defined and data from the literature are not conclusive on this matter. A recent review of 22 studies covering the natural history of meningiomas underlines that cavernous sinus lesions induced new or progressive symptoms in 61 % of the cases in a median follow-up of 4.6 years. In addition, patients with larger lesions (2–2.5 cm) have a 10 % chance of tumor grow per year and a 42.4 % chance of symptoms development in comparison to patients with lesions smaller than 2 cm, in which the chance is 0 %. In contrast, Bindal [21], described the outcome of 40 untreated meningiomas located in the cavernous sinus, petroclival region, or anterior clinoidal region. Over a mean follow up time of about 7 years only 27.5 % of patients experienced new or worsening CN deficits and only 17.5 % of patients tumor growth. There is also no clear consensus on which is the best treatment to treat a skull base meningioma. In this study, the decision to treat
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patients was the evidence of tumor progression on MRI or the occurrence of neurological symptoms. Surgery is the most effective treatment modality for meningioma, but it is rarely achieved in this region and it is frequently associated with a significant morbidity. Complication rates for grosstotal resection of skull base meningiomas vary widely, and adverse events have been reported to occur in 0–60 % of patients [4, 21–25]. The HSRT treatment of the patients was chosen when one or more of the following reasons were present: (i) previous partial surgical resection with MRI evidence of growing residual tumor (ii) elderly patients not eligible for surgical resection in relation to performance status and/or presence of comorbidity (iii) high risk of incomplete surgery (iv) high risk of adverse events. Recently, stereotactic radiation techniques emerged as a feasible treatment for skull base meningioma. Compared with conventional RT, stereotactic techniques, given as single fraction radiosurgery (SRS) or as fractionated stereotactic RT (FSRT), deliver more localized irradiation with a steeper dose gradient between tumor and the surrounding normal tissue reducing the risk of radiation induced complications. Fractionated techniques take additional advantage of the biological benefit of fractionation with regards to tumor control and toxicity. Hypo-fractionated SRT use the same principles but in addition, it is able to deliver treatment over 1 week versus 4–5 weeks of standard fractionation schemes, increasing patients quality of life. In our series patients with skull base meningioma underwent hypo-fractionated stereotactic radiation therapy. By use of this approach, an early and durable remission of neurological symptoms were obtained in all patients with
J Neurooncol Table 3 Summary of the clinical analysis Patients
26
Clinical local control
Radiological local control
Initial volume (cm3) Final volume (cm3) Status at last FU Actuarial overall survival (monhts)
Progressive
0 (0 %)
Stable
15 (58 %)
Partial response
9 (35 %)
Complete response
2 (8 %)
Progressive
0 (0 %)
Stable
16 (62 %)
Partial response
10 (38 %)
Complete response
0 (0 %)
Mean
13.0 ± 19.1
Range
1.8 – 93.4
Mean
10.8 ± 17.8(*)
Range
1.1 – 93.0
Alive
25 (96 %)
Death
1 (4 %)(**)
Mean
54.4 ± 2.8(***)
95 % CI
48.8 – 59.9
Symptoms patterns Pre HSRT symptoms
Post HSRT symptoms Stable
Partial remission
Complete remission
Symptoms patterns Asymptomatic
8 (31 %)
–
–
–
Symptomatic
18 (69 %)
7 (27 %)
9 (35 %)
2 (8 %)
Haedache
4 (15 %)
Seizures
2 (8 %)
4 (15 %) 2 (8 %)
Cranial nerve deficit II cn
3 (12 %)
2 (8 %)
1 (4 %)
1 (4 %)
III cn
2 (8 %)
1 (4 %)
1 (4 %)
2 (8 %)
IV cn
1 (4 %)
1 (4 %)
1 (4 %)
V cn
5 (19 %)
VI cn
3 (12 %)
2 (8 %)
VIII cn
3 (12 %)
2 (8 %)
3 (12 %)
Cn cranial nerve; (*) statistical significant difference with p = 0.02; (**) death due to other cause not related to disease; (***) median not reached. 2 years OS—92.9 ± 0.7 %
Table 4 Summary of published clinical studies on stereotactic radiation therapy using unconventional dose fractionation schemes Authors
# Patients
Period
Hystology
Dose (Gy)
# Fractions 5 (3–27)
Vernimmen [26]
23
Since 1993
Meningiamas
Photons and protons
20–54
Pham [27]
34
1997–2001
Meningiomas and pituitary adenomas
Cyberknife
20 (15–30)
3 (2–5)
Gorman [28]
38
1997–2004
Meningiamas
Linac
37.5 (35–40)
15
Trippa [29]
35
2003–2007
Meningiamas
Linac
42–45
15
Morimoto [30]
31
1999–2008
Meningiamas
Cyberknife
27.8 (21–36)
3–5
Mahdevan [31]
26
Na
Meningiomas and neurinomas
Cyberknife
25–30
5
Conti [32]
25
2007–2010
Perioptic meningiomas
Cyberknife
25 (18–25)
5 (2–15)
no toxicity. At the last follow up, no progression of disease in site of treatment was recorded. Although biased by the small cohort of patients, a moderate correlation between volume reduction and improvement of symptoms was
observed. These results compare favorably with previous reports [13–17]. This study has some peculiar features and limitations. The limited sample size and the short follow up time are
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Fig. 1 An example of treatment response. Before HSRT (left panel) patient was affected by left ptosis and facial dysesthesia which were completely recovered after treatment (right panel, 24 months control MR). The dose distrivution in one axial plane is shown in the central panel
the primary limitations. Indeed 10 years would be needed for a proper assessment of tumor control. Longer follow up would be needed to warrant a broad adoption of this technique in the treatment of skull base meningioma, although the results shown here are encouraging. The study can be considered informative in terms of toxicity even in the presence of one single patient with less than 6 months FU). Table 4 summarises the main studies published for hypofractionated treatment of meningiomas. As it can be seen, most were conducted on Cyberknife or protons. The two conducted on linear accelerators were performed with a schedule of 15 fractions. The only one with a fixed schedule of 5 fractions (but variable total dose) was not on an homogeneous group of patients since mixed also Schwannomas. On the contrary, the present study, conducted on an homogeneous group and a single fractionation scheme. Concerning clinical outcome, despite the fact that patients in our series had large tumor, (mean tumor volume of 13 ± 19.1 cm3; range 1.8–93.4 cm3), and located in critical site, no severe acute/subacute toxicity or tissue damage were recorded. A rapid and durable remission of neurological symptoms was obtained and a radiological reduction of the lesions was visible at the early follow up (median tumor volume 10.8 ± 17.8 cm3; range 1.1–93 cm3) (p = 0.02).
Conclusion HSRT is a feasible treatment for patients with large, skull base meningiomas, associated with a high chance of neurological improvement. A longer follow up is needed to confirm these preliminary results in these selected series.
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Ethical standards All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Conflict of interest L. Cozzi acts as Scientific Advisor to Varian Medical Systems and is Clinical Research Scientist at Humanitas Cancer Center. All other co-authors have no conflicts of interest.
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