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Combined Proton and Photon Conformal Radiotherapy for Intracranial Atypical and Malignant Meningioma
Int. J. Radiation Oncology Biol. Phys., Vol. 75, No. 2, pp. 399–406, 2009 Copyright Ó 2009 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/09/$–see front matter
doi:10.1016/j.ijrobp.2008.10.053
CLINICAL INVESTIGATION
Brain
COMBINED PROTON AND PHOTON CONFORMAL RADIOTHERAPY FOR INTRACRANIAL ATYPICAL AND MALIGNANT MENINGIOMA CHRISTOS BOSKOS, M.D.,*y LOIC FEUVRET, M.D.,*z GEORGES NOEL, M.D., PH.D.,x JEAN-LOUIS HABRAND, M.D.,* PASCAL POMMIER, M.D., PH.D.,k CLAIRE ALAPETITE, M.D.,* HAMID MAMMAR, M.D.,{ REGIS FERRAND, PH.D.,* GILBERT BOISSERIE, PH.D.,z AND JEAN-JACQUES MAZERON, M.D., PH.D.z * Institut Curie, Centre de Protonthe´rapie d’Orsay, Campus Universitaire, Orsay, France; y 251 General Hospital of Airforce, Athens, Greece; z Hoˆpital Pitie´ Salpeˆtrie`re, Paris, France; x Centre Paul Strauss, Strasbourg, France; k Centre Le´on Be´rard, Lyon, France; and { Centre Antoine Lacassagne, Nice, France Purpose: To evaluate retrospectively the efficacy of conformal fractionated radiotherapy combining proton and photon beams after primary surgery for treatment of atypical and malignant meningiomas. Patients and Methods: Between September 1999 and October 2006, 24 patients (12 male, 12 female) with histopathologically proven meningioma (atypical 19, malignant 5) received postoperative combined radiotherapy with a 201-MeV proton beam at the Centre Protontherapie d’Orsay and a high-energy photon beam. Six patients underwent gross total resection and 18 a subtotal resection. Median gross tumor volume and clinical target volume were 44.7 cm3 and 153.3 cm3, respectively. Mean total irradiation dose was 65.01 CGE (cobalt gray equivalent), with a mean proton total dose of 34.05 CGE and a mean photon total dose 30.96 CGE. Results: The median (range) follow-up interval was 32.2 (1–72) months. The overall mean local relapse-free interval was 27.2 (10–50) months, 28.3 (10–50) months for atypical meningioma and 23 (13–33) months for malignant meningioma. Ten tumors recurred locally. One-, 2-, 3-, 4-, 5-, and 8- year local control rates for the entire group of patients were 82.9% ± 7.8%, 82.9% ± 7.8%, 61.3% ± 11%, 61.3% ± 11%, 46.7% ± 12.3%, and 46.7% ± 12.3%, respectively. One-, 2-, 3-, 4-, 5-, and 8- year overall survival rates were 100%, 95.5% ± 4.4%, 80.4% ± 8.8%, 65.3% ± 10.6%, 53.2% ± 11.6%, and 42.6% ± 13%, respectively. Survival was significantly associated with total dose. There was no acute morbidity of radiotherapy. One patient developed radiation necrosis 16 months after treatment. Conclusions: Postoperative combination of conformal radiotherapy with protons and photons for atypical and malignant meningiomas is a well-tolerated treatment producing long-term tumor stabilization. Ó 2009 Elsevier Inc. Atypical meningioma, Malignant meningioma, Proton therapy, Proton beam, Radiotherapy.
Although the use of radiotherapy (RT) in benign meningiomas is controversial, most investigators advocate postoperative RT for malignant and clinically aggressive atypical meningiomas (9, 10). Some investigators, however, believe that postoperative RT for atypical meningioma remains controversial and requires further investigation (11). Fractionated photon RT is used worldwide for atypical and malignant meningiomas. Whether photon RT is planned by conventional, conformal, or intensity-modulated RT techniques, total dose delivered to the target typically varies from 55 Gy to 61.2 Gy (7, 12, 13). Proximity of high-risk
INTRODUCTION Meningiomas are the most common non-glial brain tumors. They represent 15–25% of all primary brain tumors (1). They are typically benign, slow-growing lesions arising from the arachnoidal cap cells (2). Pathologic criteria for atypical and malignant meningiomas have been established by a 1993 World Health Organization classification (3). Atypical and malignant meningiomas represent the most aggressive subgroup and are characterized by a high rate of local recurrence after surgical resection (4–6). In contrast to benign meningiomas, they may grow rapidly and may metastasize (3, 6–8). Reprint requests to: Christos Boskos, M.D., Department of Clinical Oncology, 251 GNAirforce, Eirinis 73, Agia Paraskevi, Athens, Greece. Tel: (+33) 618389283; Fax: (+33) 169298719; E-mail: [email protected] Presented at the Annual Meeting of the American Society for Therapeutic Radiology and Oncology, October 28–November 1, 2007, Los Angeles, CA.
Conflict of interest: none. Acknowledgments—The authors thank M. Selch, M.D., radiation oncologist from the Radiation Therapy Department of the University of California, Los Angeles Hospital, for supervising the article. Received July 28, 2008, and in revised form Oct 25, 2008. Accepted for publication Oct 30, 2008. 399
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organs (optic chiasm, optic nerves, brainstem) to the target volume may mandate a decrease in the recommended total dose. Stereotactic photon RT and radiosurgery techniques permit reduction in the volume of irradiated normal tissues adjacent to an intracranial target. According to limited literature, stereotactic irradiation for treatment of atypical and malignant meningioma results in a low rate of morbidity (6, 14, 15). However, the local control of these tumors and the overall survival remain poor. Conformal proton RT takes advantage of high physical selectivity and high precision of the Bragg peak effect coupled with modern three-dimensional treatment planning. Proton beam irradiation results in a significant reduction in dose to normal tissue surrounding a tumor target compared with photon beams. Postoperative conformal proton beam RT, with or without additional photon irradiation, is established for the treatment of skull base chordomas and chondrosarcomas (16–18). We present our initial experience with 24 patients treated with proton and photon beams for atypical and malignant meningiomas at the Centre de Protontherapie d’Orsay (CPO).
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Table 1. Characteristics and treatment parameters in 24 patients undergoing combined proton and photon radiotherapy for atypical and malignant meningiomas Age (y)* Sex (n) Male Female Histologic type (n) Atypical Malignant Resections before RT (n) 1 resection 2 resections 3 resections Type of surgery (n) Complete Incomplete Follow-up (mo)* Delay of RT (mo)* Duration of RT (mo)* RT dose* Total (CGE) Protons (CGE) Photons (Gy) Gross target volume (cm3)* Clinical target volume (cm3)*
48.3/52.5 (11–72) 12 12 19 5 8 12 4 6 18 42.3/45.5 (11–87) 10.3/5 (2–51) 49.5/50 (32–58) 65/68 34.1/34 31/34 48.3/32.5 (0–120) 156.5/151.3 (30–325)
PATIENTS AND METHODS Between September 1999 and October 2006, 25 patients underwent conformal postoperative adjuvant combined proton and photon RT (Table 1). One patient without follow-up was excluded from the study. There were 12 male and 12 female patients in the study population. Nineteen patients had atypical meningioma, and 5 had malignant meningioma. Median and mean age were 52.5 (range, 11–72) and 48.3 years, respectively. Six patients underwent macroscopic total resection and 18 subtotal resection. The number of resections before RT was variable. Eight patients had been operated once, 12 underwent two procedures, and 4 had three procedures. The mean delay between operation and irradiation was 10.3 months (range, 2–51 months) and the median 5 months. Tumor location was as follows: 2 temporal, 2 temporoparietal, 3 frontal, 2 frontoparietal, 2 frontotemporal, 2 parietal, 2 parietooccipital, 1 occipital, 3 cavernous sinus, 2 convexity, 2 petroclival, 1 cerebellar. Seven lesions were located at the base of the skull. All patients underwent combined RT with protons and photons, except one who underwent proton therapy. The reasons for combining protons and photons were unavailability of protons due to a single treatment room at CPO and the financial constraints due to the higher cost of proton sessions. Precise patient immobilization and daily repositioning accuracy were ensured using a custom-fitted thermoplastic face mask and five radio-opaque fiducial markers implanted under local anesthesia into the outer table of the skull. Orthogonal X-ray films were requested daily to check stereotactic alignment of each proton field. Digitally reconstructed radiographs were created to display the target volume in relation to the fiducial markers and the bony anatomic landmarks. The fiducial markers were used for the proton part to secure precise repositioning of the patient. According to their position, appropriate corrections, transactional and angular, were made using an original computer program developed at CPO (Rotaplus). Proton session time for one beam averaged 20 min, including 15 min for setup. Treatment planning involved three-dimensional virtual simulation based on a contrast CT scan with 3-mm-thick slices and contrast
Abbreviation: RT = radiotherapy. * Values are for mean/median, with range in parentheses.
MRI with 1.5-mm-thick slices performed with the patient in a supine position. The gross tumour volume (GTV) was defined as the macroscopic disease present on MRI. The clinical target volume (CTV) included a safety margin of 5–20 mm along the adjacent meninges and 5 mm toward the cerebral parenchyma. Median GTV was 32.8 mL (range, 0–120.5 mL), and median CTV was 151.3 mL (30–255 mL). Critical normal structures defined included the brainstem, upper spinal cord, pituitary gland, optic nerves, optic chiasm, pituitary, and internal auditory apparatus (cochlea and eighth cranial nerve). Treatment plans were generated using the ISIS three-dimensional treatment-planning system. Appropriate modulators and compensators were designed for each beam. Beam shaping was performed for each field using Cerrobend blocks. Dose–volume histograms were generated for all the organs at risk. Proton dose was reported in cobalt gray equivalents (CGE), defined as the physical proton dose multiplied by 1.1, the estimated relative biologic effectiveness in the mid–spread-out Bragg peak. Median total dose for all patients was 68 CGE. Median total photon dose for all patients was 34 Gy (range, 0–34.2 Gy), with 1.8–2 Gy per fraction. Median total proton dose for all patients was 34 CGE (28.8–68), with 1.8–2 CGE per fraction. Median total photon dose, proton dose, and total dose for the atypical meningioma patients were 31.95, 32.28, and 64.24 CGE, respectively. Median photon dose, proton dose, and total dose for the malignant meningioma patients were 27.2, 40.8, and 68 CGE, respectively. Dose levels to the optic nerves and optic chiasm were kept at <55 CGE, to the anterior surface of brainstem <64 CGE, and to the center of brainstem <53 CGE. Proton therapy was performed at CPO with a synchrocyclotron generating a 201-MeV proton beam. One fixed horizontal beam line is available. All patients are treated in a seated position with noncoplanar fields. Photon therapy was performed in one of two
Combined photon–proton RT for atypical and malignant meningioma d C. BOSKOS et al.
Table 2. Results of treatment in 24 patients undergoing combined proton and photon radiotherapy for atypical and malignant meningiomas Atypical
,8
Malignant Overall survival
Local control (%) 1y 2y 3y 4y 5y 8y Survival Alive (n) Dead (n) Primary* (n) Not primary* (n) Dead experienced local failure (%) Overall survival (%) 1y 2y 3y 4y 5y 8y
Total
1
82.9 7.8 82.9 7.8 61.3 11 61.3 11 46.7 12.3 46.7 12.3
,6 ,4 ,2
14 10 7 3
10 8 6 2
4 2 1 1
100
100
100
100 95.5 4.4 80.4 8.8 65.3 10.6 53.2 11.6 42.6 13
Values are number or percentage (mean SD). * Cause of death: primary disease vs. not. radiation oncology departments (Pitie Salpetriere Hospital and Institute Gustave Roussy) affiliated with CPO. Six- to 20-MV linear accelerator photons were used. Five noncoplanar beams were generally used. All patients except one received treatment with photons and protons, each delivered once per day, 5 days per week. One patient was irradiated with protons alone 3 days per week at 3.8 CGE per fraction to a total dose of 28.8 CGE. The median duration of the therapy was 50 days (range, 38–58 days). After treatment, follow-up was performed every 6 months for the first 2 years and annually thereafter. Magnetic resonance imaging or CT scans were performed systematically, and endocrine, auditory, and ophthalmologic status were assessed once per year. Survival curves were plotted from the first day of RT using the Kaplan-Meier method and compared using a log–rank test with a p value of <0.05. Local tumor control was defined as the absence of radiologic and/or clinical evidence of tumor progression. Uniand multivariate analysis were performed using StatView 4.5 (SAS Institute, Cary, NC) to evaluate the possible effect of pretreatment factors on local control (LC) and overall survival (OS).
RESULTS The median follow-up period for the study patients was 48 months (range, 1–87 months). Statistical data are shown in Table 2. One-, 2-, 3-, 4-, 5-, and 8-year OS rates (mean SD) for the study group were 100%, 95.5% 4.4%, 80.4% 8.8%, 65.3% 10.6%, 53.2% 11.6%, and 42.6% 13%, respectively (Fig. 1). One-, 2-, 3-, 4-, 5-, and 8-year LC rates for the entire group of patients were 82.9% 7.8%, 82.9% 7.8%, 61.3% 11%, 61.3% 11%, 46.7% 12.3%, and 46.7%
0
0
12
24
36
48
60
72
84
Time (months)
Fig. 1. Overall survival curve in 24 patients undergoing combined proton and photon radiotherapy for atypical and malignant meningiomas.
12.3%, respectively. There was no significant impact of any analyzed patient or treatment factor on LC (Fig. 2). No reduction in tumor size was noted on follow-up imaging. Stable disease seemed to be the best response for the entire group of irradiated patients. Ten patients relapsed locally. The mean local relapse-free interval was 27.2 months (range, 10–50 months) for the entire group of patients. Mean relapse-free intervals for the atypical and malignant meningioma were 28.3 (10–50) months and 23 (13–33) months, respectively. Three patients (2 with atypical and 1 with malignant meningioma) experienced intracranial metastatic disease. At the time of analysis, 10 patients were dead. Seven patients died as a result of primary tumor progression. Six had atypical meningioma and 1 a malignant meningioma. Median survival after local relapse in this group was 14 (1– 22) months (mean, 14.3 months). Primary tumors in this group were located in parietal lobe (3 patients), temporal lobe (2), cavernous sinus (1), and convexity (1).
1 ,8
local control
Parameter/result
401
,6 ,4 ,2 0 0
12
24
36
48
60
72
time (months)
Fig. 2. Local control curve in 24 patients undergoing combined proton and photon radiotherapy for atypical and malignant meningiomas.
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Table 3. Univariate and multivariate analysis for local control, overall survival, and causespecific survival Univariate analysis Variable Age Histologic subtype Gross tumor volume Gender Total dose >60 Gy Total dose >65 Gy Locally controlled disease
Local Overall control (p) survival (p) 0.22 0.55 0.17 0.98 0.16 0.96 —
0.21 0.42 0.17 0.81 0.03* 0.06 0.001*
Overall survival (multivariate analysis) CSS
RR
p
— — — — 0.01* 0.27 —
— — — — 8.3 (1.2–57) — 6.7 (1.21–37)
NA NA NA NA 0.029* NA 0.029*
Abbreviations: CSS = cause-specific survival; RR = relative risk; NA = not applicable to multivariate analysis (not significant by univariate analysis). Values in parentheses are ranges. * p < 0.05.
Transformation to more aggressive tumors at the time of local relapse occurred in 2 patients with atypical meningioma. Tumor in 1 patient transformed to malignant meningioma and to meningiosarcoma in a second patient. Mean GTV of this group was 29.7 mL (range, 0–120.5 mL). Mean CTV was 128.3 mL and median CTV 128 mL (range, 30–242 mL). The median total dose received in this group of patients was 68 CGE (range, 56–68 CGE). Median time to local failure of the group was 30 months (range, 13–50 months) (mean, 28.4 months). Cause of death was unrelated to the primary disease in 3 patients. Two died from metastatic disease. The third patient of this group died from a second cancer located in the piriform sinus. None of these patients relapsed locally. Table 3 shows selected prognostic factors. According to multivariate analysis, two independent favorable factors for OS were total dose >60 Gy and locally controlled disease (Figs. 3–5). Histologic subtype, age, complete resection, and gender did not demonstrate statistical significance. There
Fig. 3. Overall survival curves for 24 patients undergoing combined proton and photon radiotherapy for atypical and malignant meningiomas for controlled vs. not-controlled disease. Overall survival is prolonged for the locally controlled patient group (p = 0.001).
was a trend toward improved survival with total dose >65 Gy by univariate analysis only. There was no acute morbidity associated with proton/photon irradiation. One patient developed seizures in the first 3 months after treatment. Two patients developed alopecia 9 and 13 months after treatment. One patient experienced radiation necrosis 16 months after 68 CGE (34 with protons and 34 with photons). DISCUSSION Surgery Surgery represents the primary treatment modality for meningioma, regardless of subtype. Surgical resection of the meningioma, with the involved dura, is considered the treatment of choice whenever this is accomplished with acceptable morbidity. Complete tumor removal is not a guarantee for tumor LC (6). For malignant meningiomas, in contrast
Fig. 4. Cause-specific survival curves for 24 patients undergoing combined proton and photon radiotherapy for atypical and malignant meningiomas, divided according to the delivered total dose. Cause-specific survival is prolonged in patients receiving a total dose of >60 Gy (p = 0.01).
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According some investigators, increase in LC positively affects OS in malignant meningioma and progression-free survival in atypical and malignant meningioma (30, 31). There is also evidence that LC increased with proton therapy compared with irradiation with photons (30). Local control of atypical meningioma correlated to benign meningioma is lower (32). Local control in malignant meningioma is lower than in benign meningioma, and this results in a higher possibility of regrowth and recurrence (8). We conclude that there is no correlation between age, gender, and pathologic subtype and LC or OS. Results from the international literature are shown in Table 4.
Fig. 5. Overall survivall curves for 24 patients undergoing combined proton and photon radiotherapy for atypical and malignant meningiomas, divided according to the delivered total dose. Overall survival is prolonged in patients receiving a total dose of >60 Gy (p = 0.03).
to benign meningioma, surgery does not seem to be a sufficient treatment as monotherapy. Local failure is increased 65–100% and progression-free survival is decreased in malignant meningioma compared with benign meningioma, independent of the quality of surgery (19–22). Complete resection was found to increase LC in atypical meningioma (11); this was achieved in a wide range of patients (20–96%) according to the localization of the lesion (23–25). In the skull base, total resection was accomplished in approximately half of cases (26). Skull base meningioma surgery is limited by the anatomic situation and the extension of the tumor. The most challenging parts are the cavernous sinus and petroclival sites (27). The likelihood of complete resection is inversely related to preoperative factors, such as prior irradiation, vessel encasement, multiple fossa involvement, and cranial nerve palsies (26, 28). Surgery in the skull base has become much safer, but as it becomes more aggressive the price is frequently translated to more nerve injuries (27) and a higher morbidity rate (24). Radiotherapy Radiotherapy could be a precious therapeutic possibility to minimize the risk of relapse. There is no randomized, controlled trial of RT and postoperative follow-up for atypical and malignant meningiomas. According to some investigators, regardless of the type of surgical resection (total or subtotal), radiation therapy is required (29). Local control and overall survival All patients died from the primary disease, experiencing local relapse before death. We conclude that improved LC positively affects OS for both atypical and malignant meningiomas (p = 0.001) (Fig. 3).
Total dose The use of protons in the treatment of intracranial and especially skull base meningiomas gives the advantage of increasing the total dose and provides the highest coverage of the target volume, despite the proximity to critical normal structures. Importantly, proton RT is not limited by the huge size or the abnormal shape of the tumor, as in conventional and conformal photon RT techniques. We conclude that the increase of the total dose to >60 Gy results in a better prognosis in cause-specific survival (p = 0.01; Fig. 4) and OS (p = 0.03; Fig. 5). A possible increase of the total dose to >65 Gy led to an additional shift of OS (p = 0.06). This last conclusion failed to be statistically significant marginally, probably because of the limited number of patients that were included in this study. It is remarkable that in the group of patients irradiated to >65 Gy, all patients had malignant meningioma, something that may have negatively affected the percentage of the nonrelapsed subgroup. The increase of total dose and the impact on LC is a controversial matter. According to DeVries et al. (33) when the TD is >60 Gy there is a remarkable increase in LC and OS for malignant meningioma. In this study the investigators reviewed the cases of 16 patients with malignant meningioma treated with conventional photons or combined proton irradiation with a mean delivered total dose of 40–70 Gy/CGE (median, 58 Gy/CGE) (33). In 2000, Hug et al. (30) reported results from a mixed group of 31 patients (15 atypical meningioma patients and 16 malignant meningioma patients) who were treated with conventional photons or combined proton irradiation. They conclude that when total dose is >60 Gy there is an increase of LC in atypical meningioma and malignant meningioma. The mean delivered target total dose for atypical meningioma and malignant meningioma was 62 Gy/CGE (range, 50–68 Gy/CGE) and 58 Gy/CGE (range, 40–72 Gy/CGE), respectively. According to other investigators there is no clear correlation between total dose and LC (6, 10). Tumor size A body of literature predicts that the use of protons provides substantial improvements in dose conformation for certain tumors, when compared with photon stereotactic or nonstereotactic RT, with or without intensity modulation (2, 34–39). These studies always compared photon beams
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Table 4. Results of retrospective studies from the international literature reporting LC, OS, and PFS for patients undergoing postoperative radiotherapy for atypical and/or malignant meningiomas Study (reference)
LC
OS
Hug et al. 2000 (30) (protons) Malignant (n = 16) 5 y: 52%; 8 y: 17% Atypical (n = 15) 5 y: 38%; 8 y: 19% Ojeman et al. 2000 (15) (Gamma knife) Malignant (n = 22) Goldsmith et al. 1994 (12) Malignant (n = 23) Milker-Zabel et al. 2006 (41) (fractionated stereotactic RT) Atypical (n = 26) Milosevic et al. 1996 (42) (conventional) Malignant (n = 42); atypical (n = 17) Hakim et al. 1998 (14) (X-knife) Malignant (n = 26)
5 y: 51%; 8 y: 51% 5 y: 89%; 8 y: 89% 2 y: 75%; 5 y: 40%
2 y: 32%; 5 y: 26%
5 y: 58%
5 y: 49%
5 y: 0 5 y: 68%
Total: Median: 32; 5 y: 28% Median: 1 y: 92.3%; 2 y: 64.6%; 3 y: 43.1%; 4 y: 21.5% 1 y: 91.7%; 2 y: 83.3%; 3 y: 83.3%; 4 y: 83.3% Median: 27mo 5 y: 0 5 y: 76%
1 y: 82.9% 7.8%; 2 y: 82.9% 7.8%; 3 y: 61.3% 11%; 4 y: 61.3% 11%; 5 y: 46.7% 12.3%; 8 y: 46.7% 12.3%
1 y: 100%; 2 y: 95.5% 4.4%; 3 y: 80.4% 8.8%; 4 y: 65.3% 10.6%; 5 y: 53.2% 11.6%; 8 y: 42.6% 13%
Atypical (n = 18) Stafford et al. 2001 (6) (Gamma knife) Malignant (n = 9) Atypical (n = 13) Present study (protons) Malignant (n = 5); atypical (n = 19)
PFS
3 y: 96%; 5 y: 89%; 10 y: 67% Total: Median: 32; 5 y: 34% Median time: 13.9 mo 24.4 mo SDS 5 y: 0 5 y: 76%
Abbreviations: LC = local control; OS = overall survival; PFS = progression-free survival; SDS = specific disease survival.
vs. proton beams or photon beams vs. photon and proton beams (2, 27, 40). It was not the purpose or the goal of our study to evaluate and compare dose conformation between the techniques, but this is a factor that we always have to take into account, especially when referring to the treatment of gross and complicated-shaped tumors. In our study we did not conclude that a correlation exists between the size of the tumor and LC or OS. Ojeman et al. (15) observed that small tumors (>8 cm3) with low GTV are more sensitive to radiation with the Gamma knife. According to other investigators, small tumors (GTV <60 cm3) are correlated with increased LC in atypical meningiomas treated with fractionated stereotactic RT (32, 41). Side effects The most common possible complications induced by RT are neuropathy, radiation necrosis, and insufficiency of the pituitary gland. According to the international literature, the main late high-grade complications reported after a variety of RT procedures for atypical and malignant meningiomas are reduced vision, trigeminal neuralgia, and tinnitus with fractionated stereotactic RT (41). Optic atrophy was reported in 1 patient after 60 Gy were delivered, and hypogonadotropic hypogonadism in 1 patient after 50 Gy were delivered with conventional RT (42). Radiation necrosis was induced in 2 patients after RT with protons and photons. The delivered total dose ranged be-
tween 59 and 72 Gy. One patient experienced visual field deficits, although maximum total dose to the optic nerve and optic chiasm was restricted to <60 and <55.8 Gy, respectively (30). Radiation necrosis was also reported in 5 patients treated with the Gamma knife. Three of the patients underwent retreatment of the same lesion at recurrence (15). Death for 2 patients and blindness for another were reported for treatment with the X-knife (14). The same article also reported hearing loss, hypesthesia, and hemiparesis. Increase of the radiation necrosis rate at 27% was reported with brachytherapy (43). Internal carotid stenosis was also reported in 2 patients and neuropathy (e.g., optic, trigeminal) in other patients who were treated with the Gamma knife (6). In our series, as noted earlier, only 1 patient experienced radiation necrosis. CONCLUSION Postoperative conformal combined RT with protons and photons for subtotal resected atypical and malignant meningiomas is a well-tolerated treatment with considerable OS. Increase of the total dose to >60 Gy results in a better prognosis in terms of cause-specific survival and OS. A possible increase of the total dose to >65 Gy leads to a trend for a possible additional shift in OS. Long-term, radiologically proven stabilization of disease increases OS. This results in an encouraging 8-year survival rate, comparable to the best survival reported in the literature.
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22. Maguire PD, Clough R, Friedman AH, et al. Fractionated external-beam radiation therapy for meningiomas of the cavernous sinus. Int J Radiat Oncol Biol Phys 1999;44:75–79. 23. Jung HW, Yoo H, Paek SH, et al. Long-term outcome and growth rate of subtotally resected petroclival meningiomas: Experience with 38 cases. Neurosurgery 2000;46:567–574. 24. O’Sullivan MG, van Loveren HR, Tew JM Jr. The surgical resectability of meningiomas of the cavernous sinus. Neurosurgery 1997;40:238–244. 25. Sekhar LN, Jannetta PJ, Burkhart LE, et al. Meningiomas involving the clivus: A six-year experience with 41 patients. Neurosurgery 1990;27:764–781. 26. Mirimanoff RO, Dosoretz DE, Linggood RM, et al. Meningioma: Analysis of recurrence and progression following neurosurgical resection. J Neurosurg 1985;62:18–24. 27. Noel G, Boisserie G, Dessard-Diana B, et al. [Comparison with dose-volume histograms of two conformal irradiation techniques used for the treatment of T2N0M0 nasopharyngeal cancer, one with association of photons and protons and another with photons alone]. Cancer Radiother 2002; 6:337–348. 28. Levine ZT, Buchanan RI, Sekhar LN, et al. Proposed grading system to predict the extent of resection and outcomes for cranial base meningiomas. Neurosurgery 1999;45: 221–230. 29. Carella RJ, Ransohoff J, Newall J. Role of radiation therapy in the management of meningioma. Neurosurgery 1982;10: 332–339. 30. Hug EB, Devries A, Thornton AF, et al. Management of atypical and malignant meningiomas: Role of high-dose, 3D-conformal radiation therapy. J Neurooncol 2000;48: 151–160. 31. Marks SM, Whitwell HL, Lye RH. Recurrence of meningiomas after operation. Surg Neurol 1986;25:436–440. 32. Milker-Zabel S, Zabel-du BA, Henze M, et al. Improved target volume definition for fractionated stereotactic radiotherapy in patients with intracranial meningiomas by correlation of CT, MRI, and [68Ga]-DOTATOC-PET. Int J Radiat Oncol Biol Phys 2006;65:222–227. 33. DeVries A, Munzenrider JE, Hedley-Whyte T, et al. [The role of radiotherapy in the treatment of malignant meningiomas]. Strahlenther Onkol 1999;175:62–67. 34. Lee M, Wynne C, Webb S, et al. A comparison of proton and megavoltage X-ray treatment planning for prostate cancer. Radiother Oncol 1994;33:239–253. 35. Miralbell R, Urie M. Potential improvement of three dimension treatment planning and proton beams in fractionated radiotherapy of large cerebral arteriovenous malformations. Int J Radiat Oncol Biol Phys 1993;25:353–358. 36. Miralbell R, Lomax A, Bortfeld T, et al. Potential role of proton therapy in the treatment of pediatric medulloblastoma/primitive neuroectodermal tumors: Reduction of the supratentorial target volume. Int J Radiat Oncol Biol Phys 1997;38:477–484. 37. Miralbell R, Lomax A, Russo M. Potential role of proton therapy in the treatment of pediatric medulloblastoma/primitive neuro-ectodermal tumors: Spinal theca irradiation. Int J Radiat Oncol Biol Phys 1997;38:805–811. 38. Tatsuzaki H, Urie MM, Willett CG. 3-D comparative study of proton vs. x-ray radiation therapy for rectal cancer. Int J Radiat Oncol Biol Phys 1992;22:369–374. 39. Tatsuzaki H, Urie MM, Linggood R. Comparative treatment planning: Proton vs. x-ray beams against glioblastoma multiforme. Int J Radiat Oncol Biol Phys 1992;22:265–273. 40. Weber DC, Trofimov AV, Delaney TF, et al. A treatment planning comparison of intensity modulated photon and proton
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therapy for paraspinal sarcomas. Int J Radiat Oncol Biol Phys 2004;58:1596–1606. 41. Milker-Zabel S, Zabel-du BA, Huber P, et al. Fractionated stereotactic radiation therapy in the management of benign cavernous sinus meningiomas: Long-term experience and review of the literature. Strahlenther Onkol 2006;182:635–640.
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42. Milosevic MF, Frost PJ, Laperriere NJ, et al. Radiotherapy for atypical or malignant intracranial meningioma. Int J Radiat Oncol Biol Phys 1996;34:817–822. 43. Ware ML, Larson DA, Sneed PK, et al. Surgical resection and permanent brachytherapy for recurrent atypical and malignant meningioma. Neurosurgery 2004;54:55–63.
doi:10.1016/j.ijrobp.2008.10.053
CLINICAL INVESTIGATION
Brain
COMBINED PROTON AND PHOTON CONFORMAL RADIOTHERAPY FOR INTRACRANIAL ATYPICAL AND MALIGNANT MENINGIOMA CHRISTOS BOSKOS, M.D.,*y LOIC FEUVRET, M.D.,*z GEORGES NOEL, M.D., PH.D.,x JEAN-LOUIS HABRAND, M.D.,* PASCAL POMMIER, M.D., PH.D.,k CLAIRE ALAPETITE, M.D.,* HAMID MAMMAR, M.D.,{ REGIS FERRAND, PH.D.,* GILBERT BOISSERIE, PH.D.,z AND JEAN-JACQUES MAZERON, M.D., PH.D.z * Institut Curie, Centre de Protonthe´rapie d’Orsay, Campus Universitaire, Orsay, France; y 251 General Hospital of Airforce, Athens, Greece; z Hoˆpital Pitie´ Salpeˆtrie`re, Paris, France; x Centre Paul Strauss, Strasbourg, France; k Centre Le´on Be´rard, Lyon, France; and { Centre Antoine Lacassagne, Nice, France Purpose: To evaluate retrospectively the efficacy of conformal fractionated radiotherapy combining proton and photon beams after primary surgery for treatment of atypical and malignant meningiomas. Patients and Methods: Between September 1999 and October 2006, 24 patients (12 male, 12 female) with histopathologically proven meningioma (atypical 19, malignant 5) received postoperative combined radiotherapy with a 201-MeV proton beam at the Centre Protontherapie d’Orsay and a high-energy photon beam. Six patients underwent gross total resection and 18 a subtotal resection. Median gross tumor volume and clinical target volume were 44.7 cm3 and 153.3 cm3, respectively. Mean total irradiation dose was 65.01 CGE (cobalt gray equivalent), with a mean proton total dose of 34.05 CGE and a mean photon total dose 30.96 CGE. Results: The median (range) follow-up interval was 32.2 (1–72) months. The overall mean local relapse-free interval was 27.2 (10–50) months, 28.3 (10–50) months for atypical meningioma and 23 (13–33) months for malignant meningioma. Ten tumors recurred locally. One-, 2-, 3-, 4-, 5-, and 8- year local control rates for the entire group of patients were 82.9% ± 7.8%, 82.9% ± 7.8%, 61.3% ± 11%, 61.3% ± 11%, 46.7% ± 12.3%, and 46.7% ± 12.3%, respectively. One-, 2-, 3-, 4-, 5-, and 8- year overall survival rates were 100%, 95.5% ± 4.4%, 80.4% ± 8.8%, 65.3% ± 10.6%, 53.2% ± 11.6%, and 42.6% ± 13%, respectively. Survival was significantly associated with total dose. There was no acute morbidity of radiotherapy. One patient developed radiation necrosis 16 months after treatment. Conclusions: Postoperative combination of conformal radiotherapy with protons and photons for atypical and malignant meningiomas is a well-tolerated treatment producing long-term tumor stabilization. Ó 2009 Elsevier Inc. Atypical meningioma, Malignant meningioma, Proton therapy, Proton beam, Radiotherapy.
Although the use of radiotherapy (RT) in benign meningiomas is controversial, most investigators advocate postoperative RT for malignant and clinically aggressive atypical meningiomas (9, 10). Some investigators, however, believe that postoperative RT for atypical meningioma remains controversial and requires further investigation (11). Fractionated photon RT is used worldwide for atypical and malignant meningiomas. Whether photon RT is planned by conventional, conformal, or intensity-modulated RT techniques, total dose delivered to the target typically varies from 55 Gy to 61.2 Gy (7, 12, 13). Proximity of high-risk
INTRODUCTION Meningiomas are the most common non-glial brain tumors. They represent 15–25% of all primary brain tumors (1). They are typically benign, slow-growing lesions arising from the arachnoidal cap cells (2). Pathologic criteria for atypical and malignant meningiomas have been established by a 1993 World Health Organization classification (3). Atypical and malignant meningiomas represent the most aggressive subgroup and are characterized by a high rate of local recurrence after surgical resection (4–6). In contrast to benign meningiomas, they may grow rapidly and may metastasize (3, 6–8). Reprint requests to: Christos Boskos, M.D., Department of Clinical Oncology, 251 GNAirforce, Eirinis 73, Agia Paraskevi, Athens, Greece. Tel: (+33) 618389283; Fax: (+33) 169298719; E-mail: [email protected] Presented at the Annual Meeting of the American Society for Therapeutic Radiology and Oncology, October 28–November 1, 2007, Los Angeles, CA.
Conflict of interest: none. Acknowledgments—The authors thank M. Selch, M.D., radiation oncologist from the Radiation Therapy Department of the University of California, Los Angeles Hospital, for supervising the article. Received July 28, 2008, and in revised form Oct 25, 2008. Accepted for publication Oct 30, 2008. 399
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organs (optic chiasm, optic nerves, brainstem) to the target volume may mandate a decrease in the recommended total dose. Stereotactic photon RT and radiosurgery techniques permit reduction in the volume of irradiated normal tissues adjacent to an intracranial target. According to limited literature, stereotactic irradiation for treatment of atypical and malignant meningioma results in a low rate of morbidity (6, 14, 15). However, the local control of these tumors and the overall survival remain poor. Conformal proton RT takes advantage of high physical selectivity and high precision of the Bragg peak effect coupled with modern three-dimensional treatment planning. Proton beam irradiation results in a significant reduction in dose to normal tissue surrounding a tumor target compared with photon beams. Postoperative conformal proton beam RT, with or without additional photon irradiation, is established for the treatment of skull base chordomas and chondrosarcomas (16–18). We present our initial experience with 24 patients treated with proton and photon beams for atypical and malignant meningiomas at the Centre de Protontherapie d’Orsay (CPO).
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Table 1. Characteristics and treatment parameters in 24 patients undergoing combined proton and photon radiotherapy for atypical and malignant meningiomas Age (y)* Sex (n) Male Female Histologic type (n) Atypical Malignant Resections before RT (n) 1 resection 2 resections 3 resections Type of surgery (n) Complete Incomplete Follow-up (mo)* Delay of RT (mo)* Duration of RT (mo)* RT dose* Total (CGE) Protons (CGE) Photons (Gy) Gross target volume (cm3)* Clinical target volume (cm3)*
48.3/52.5 (11–72) 12 12 19 5 8 12 4 6 18 42.3/45.5 (11–87) 10.3/5 (2–51) 49.5/50 (32–58) 65/68 34.1/34 31/34 48.3/32.5 (0–120) 156.5/151.3 (30–325)
PATIENTS AND METHODS Between September 1999 and October 2006, 25 patients underwent conformal postoperative adjuvant combined proton and photon RT (Table 1). One patient without follow-up was excluded from the study. There were 12 male and 12 female patients in the study population. Nineteen patients had atypical meningioma, and 5 had malignant meningioma. Median and mean age were 52.5 (range, 11–72) and 48.3 years, respectively. Six patients underwent macroscopic total resection and 18 subtotal resection. The number of resections before RT was variable. Eight patients had been operated once, 12 underwent two procedures, and 4 had three procedures. The mean delay between operation and irradiation was 10.3 months (range, 2–51 months) and the median 5 months. Tumor location was as follows: 2 temporal, 2 temporoparietal, 3 frontal, 2 frontoparietal, 2 frontotemporal, 2 parietal, 2 parietooccipital, 1 occipital, 3 cavernous sinus, 2 convexity, 2 petroclival, 1 cerebellar. Seven lesions were located at the base of the skull. All patients underwent combined RT with protons and photons, except one who underwent proton therapy. The reasons for combining protons and photons were unavailability of protons due to a single treatment room at CPO and the financial constraints due to the higher cost of proton sessions. Precise patient immobilization and daily repositioning accuracy were ensured using a custom-fitted thermoplastic face mask and five radio-opaque fiducial markers implanted under local anesthesia into the outer table of the skull. Orthogonal X-ray films were requested daily to check stereotactic alignment of each proton field. Digitally reconstructed radiographs were created to display the target volume in relation to the fiducial markers and the bony anatomic landmarks. The fiducial markers were used for the proton part to secure precise repositioning of the patient. According to their position, appropriate corrections, transactional and angular, were made using an original computer program developed at CPO (Rotaplus). Proton session time for one beam averaged 20 min, including 15 min for setup. Treatment planning involved three-dimensional virtual simulation based on a contrast CT scan with 3-mm-thick slices and contrast
Abbreviation: RT = radiotherapy. * Values are for mean/median, with range in parentheses.
MRI with 1.5-mm-thick slices performed with the patient in a supine position. The gross tumour volume (GTV) was defined as the macroscopic disease present on MRI. The clinical target volume (CTV) included a safety margin of 5–20 mm along the adjacent meninges and 5 mm toward the cerebral parenchyma. Median GTV was 32.8 mL (range, 0–120.5 mL), and median CTV was 151.3 mL (30–255 mL). Critical normal structures defined included the brainstem, upper spinal cord, pituitary gland, optic nerves, optic chiasm, pituitary, and internal auditory apparatus (cochlea and eighth cranial nerve). Treatment plans were generated using the ISIS three-dimensional treatment-planning system. Appropriate modulators and compensators were designed for each beam. Beam shaping was performed for each field using Cerrobend blocks. Dose–volume histograms were generated for all the organs at risk. Proton dose was reported in cobalt gray equivalents (CGE), defined as the physical proton dose multiplied by 1.1, the estimated relative biologic effectiveness in the mid–spread-out Bragg peak. Median total dose for all patients was 68 CGE. Median total photon dose for all patients was 34 Gy (range, 0–34.2 Gy), with 1.8–2 Gy per fraction. Median total proton dose for all patients was 34 CGE (28.8–68), with 1.8–2 CGE per fraction. Median total photon dose, proton dose, and total dose for the atypical meningioma patients were 31.95, 32.28, and 64.24 CGE, respectively. Median photon dose, proton dose, and total dose for the malignant meningioma patients were 27.2, 40.8, and 68 CGE, respectively. Dose levels to the optic nerves and optic chiasm were kept at <55 CGE, to the anterior surface of brainstem <64 CGE, and to the center of brainstem <53 CGE. Proton therapy was performed at CPO with a synchrocyclotron generating a 201-MeV proton beam. One fixed horizontal beam line is available. All patients are treated in a seated position with noncoplanar fields. Photon therapy was performed in one of two
Combined photon–proton RT for atypical and malignant meningioma d C. BOSKOS et al.
Table 2. Results of treatment in 24 patients undergoing combined proton and photon radiotherapy for atypical and malignant meningiomas Atypical
,8
Malignant Overall survival
Local control (%) 1y 2y 3y 4y 5y 8y Survival Alive (n) Dead (n) Primary* (n) Not primary* (n) Dead experienced local failure (%) Overall survival (%) 1y 2y 3y 4y 5y 8y
Total
1
82.9 7.8 82.9 7.8 61.3 11 61.3 11 46.7 12.3 46.7 12.3
,6 ,4 ,2
14 10 7 3
10 8 6 2
4 2 1 1
100
100
100
100 95.5 4.4 80.4 8.8 65.3 10.6 53.2 11.6 42.6 13
Values are number or percentage (mean SD). * Cause of death: primary disease vs. not. radiation oncology departments (Pitie Salpetriere Hospital and Institute Gustave Roussy) affiliated with CPO. Six- to 20-MV linear accelerator photons were used. Five noncoplanar beams were generally used. All patients except one received treatment with photons and protons, each delivered once per day, 5 days per week. One patient was irradiated with protons alone 3 days per week at 3.8 CGE per fraction to a total dose of 28.8 CGE. The median duration of the therapy was 50 days (range, 38–58 days). After treatment, follow-up was performed every 6 months for the first 2 years and annually thereafter. Magnetic resonance imaging or CT scans were performed systematically, and endocrine, auditory, and ophthalmologic status were assessed once per year. Survival curves were plotted from the first day of RT using the Kaplan-Meier method and compared using a log–rank test with a p value of <0.05. Local tumor control was defined as the absence of radiologic and/or clinical evidence of tumor progression. Uniand multivariate analysis were performed using StatView 4.5 (SAS Institute, Cary, NC) to evaluate the possible effect of pretreatment factors on local control (LC) and overall survival (OS).
RESULTS The median follow-up period for the study patients was 48 months (range, 1–87 months). Statistical data are shown in Table 2. One-, 2-, 3-, 4-, 5-, and 8-year OS rates (mean SD) for the study group were 100%, 95.5% 4.4%, 80.4% 8.8%, 65.3% 10.6%, 53.2% 11.6%, and 42.6% 13%, respectively (Fig. 1). One-, 2-, 3-, 4-, 5-, and 8-year LC rates for the entire group of patients were 82.9% 7.8%, 82.9% 7.8%, 61.3% 11%, 61.3% 11%, 46.7% 12.3%, and 46.7%
0
0
12
24
36
48
60
72
84
Time (months)
Fig. 1. Overall survival curve in 24 patients undergoing combined proton and photon radiotherapy for atypical and malignant meningiomas.
12.3%, respectively. There was no significant impact of any analyzed patient or treatment factor on LC (Fig. 2). No reduction in tumor size was noted on follow-up imaging. Stable disease seemed to be the best response for the entire group of irradiated patients. Ten patients relapsed locally. The mean local relapse-free interval was 27.2 months (range, 10–50 months) for the entire group of patients. Mean relapse-free intervals for the atypical and malignant meningioma were 28.3 (10–50) months and 23 (13–33) months, respectively. Three patients (2 with atypical and 1 with malignant meningioma) experienced intracranial metastatic disease. At the time of analysis, 10 patients were dead. Seven patients died as a result of primary tumor progression. Six had atypical meningioma and 1 a malignant meningioma. Median survival after local relapse in this group was 14 (1– 22) months (mean, 14.3 months). Primary tumors in this group were located in parietal lobe (3 patients), temporal lobe (2), cavernous sinus (1), and convexity (1).
1 ,8
local control
Parameter/result
401
,6 ,4 ,2 0 0
12
24
36
48
60
72
time (months)
Fig. 2. Local control curve in 24 patients undergoing combined proton and photon radiotherapy for atypical and malignant meningiomas.
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Table 3. Univariate and multivariate analysis for local control, overall survival, and causespecific survival Univariate analysis Variable Age Histologic subtype Gross tumor volume Gender Total dose >60 Gy Total dose >65 Gy Locally controlled disease
Local Overall control (p) survival (p) 0.22 0.55 0.17 0.98 0.16 0.96 —
0.21 0.42 0.17 0.81 0.03* 0.06 0.001*
Overall survival (multivariate analysis) CSS
RR
p
— — — — 0.01* 0.27 —
— — — — 8.3 (1.2–57) — 6.7 (1.21–37)
NA NA NA NA 0.029* NA 0.029*
Abbreviations: CSS = cause-specific survival; RR = relative risk; NA = not applicable to multivariate analysis (not significant by univariate analysis). Values in parentheses are ranges. * p < 0.05.
Transformation to more aggressive tumors at the time of local relapse occurred in 2 patients with atypical meningioma. Tumor in 1 patient transformed to malignant meningioma and to meningiosarcoma in a second patient. Mean GTV of this group was 29.7 mL (range, 0–120.5 mL). Mean CTV was 128.3 mL and median CTV 128 mL (range, 30–242 mL). The median total dose received in this group of patients was 68 CGE (range, 56–68 CGE). Median time to local failure of the group was 30 months (range, 13–50 months) (mean, 28.4 months). Cause of death was unrelated to the primary disease in 3 patients. Two died from metastatic disease. The third patient of this group died from a second cancer located in the piriform sinus. None of these patients relapsed locally. Table 3 shows selected prognostic factors. According to multivariate analysis, two independent favorable factors for OS were total dose >60 Gy and locally controlled disease (Figs. 3–5). Histologic subtype, age, complete resection, and gender did not demonstrate statistical significance. There
Fig. 3. Overall survival curves for 24 patients undergoing combined proton and photon radiotherapy for atypical and malignant meningiomas for controlled vs. not-controlled disease. Overall survival is prolonged for the locally controlled patient group (p = 0.001).
was a trend toward improved survival with total dose >65 Gy by univariate analysis only. There was no acute morbidity associated with proton/photon irradiation. One patient developed seizures in the first 3 months after treatment. Two patients developed alopecia 9 and 13 months after treatment. One patient experienced radiation necrosis 16 months after 68 CGE (34 with protons and 34 with photons). DISCUSSION Surgery Surgery represents the primary treatment modality for meningioma, regardless of subtype. Surgical resection of the meningioma, with the involved dura, is considered the treatment of choice whenever this is accomplished with acceptable morbidity. Complete tumor removal is not a guarantee for tumor LC (6). For malignant meningiomas, in contrast
Fig. 4. Cause-specific survival curves for 24 patients undergoing combined proton and photon radiotherapy for atypical and malignant meningiomas, divided according to the delivered total dose. Cause-specific survival is prolonged in patients receiving a total dose of >60 Gy (p = 0.01).
Combined photon–proton RT for atypical and malignant meningioma d C. BOSKOS et al.
403
According some investigators, increase in LC positively affects OS in malignant meningioma and progression-free survival in atypical and malignant meningioma (30, 31). There is also evidence that LC increased with proton therapy compared with irradiation with photons (30). Local control of atypical meningioma correlated to benign meningioma is lower (32). Local control in malignant meningioma is lower than in benign meningioma, and this results in a higher possibility of regrowth and recurrence (8). We conclude that there is no correlation between age, gender, and pathologic subtype and LC or OS. Results from the international literature are shown in Table 4.
Fig. 5. Overall survivall curves for 24 patients undergoing combined proton and photon radiotherapy for atypical and malignant meningiomas, divided according to the delivered total dose. Overall survival is prolonged in patients receiving a total dose of >60 Gy (p = 0.03).
to benign meningioma, surgery does not seem to be a sufficient treatment as monotherapy. Local failure is increased 65–100% and progression-free survival is decreased in malignant meningioma compared with benign meningioma, independent of the quality of surgery (19–22). Complete resection was found to increase LC in atypical meningioma (11); this was achieved in a wide range of patients (20–96%) according to the localization of the lesion (23–25). In the skull base, total resection was accomplished in approximately half of cases (26). Skull base meningioma surgery is limited by the anatomic situation and the extension of the tumor. The most challenging parts are the cavernous sinus and petroclival sites (27). The likelihood of complete resection is inversely related to preoperative factors, such as prior irradiation, vessel encasement, multiple fossa involvement, and cranial nerve palsies (26, 28). Surgery in the skull base has become much safer, but as it becomes more aggressive the price is frequently translated to more nerve injuries (27) and a higher morbidity rate (24). Radiotherapy Radiotherapy could be a precious therapeutic possibility to minimize the risk of relapse. There is no randomized, controlled trial of RT and postoperative follow-up for atypical and malignant meningiomas. According to some investigators, regardless of the type of surgical resection (total or subtotal), radiation therapy is required (29). Local control and overall survival All patients died from the primary disease, experiencing local relapse before death. We conclude that improved LC positively affects OS for both atypical and malignant meningiomas (p = 0.001) (Fig. 3).
Total dose The use of protons in the treatment of intracranial and especially skull base meningiomas gives the advantage of increasing the total dose and provides the highest coverage of the target volume, despite the proximity to critical normal structures. Importantly, proton RT is not limited by the huge size or the abnormal shape of the tumor, as in conventional and conformal photon RT techniques. We conclude that the increase of the total dose to >60 Gy results in a better prognosis in cause-specific survival (p = 0.01; Fig. 4) and OS (p = 0.03; Fig. 5). A possible increase of the total dose to >65 Gy led to an additional shift of OS (p = 0.06). This last conclusion failed to be statistically significant marginally, probably because of the limited number of patients that were included in this study. It is remarkable that in the group of patients irradiated to >65 Gy, all patients had malignant meningioma, something that may have negatively affected the percentage of the nonrelapsed subgroup. The increase of total dose and the impact on LC is a controversial matter. According to DeVries et al. (33) when the TD is >60 Gy there is a remarkable increase in LC and OS for malignant meningioma. In this study the investigators reviewed the cases of 16 patients with malignant meningioma treated with conventional photons or combined proton irradiation with a mean delivered total dose of 40–70 Gy/CGE (median, 58 Gy/CGE) (33). In 2000, Hug et al. (30) reported results from a mixed group of 31 patients (15 atypical meningioma patients and 16 malignant meningioma patients) who were treated with conventional photons or combined proton irradiation. They conclude that when total dose is >60 Gy there is an increase of LC in atypical meningioma and malignant meningioma. The mean delivered target total dose for atypical meningioma and malignant meningioma was 62 Gy/CGE (range, 50–68 Gy/CGE) and 58 Gy/CGE (range, 40–72 Gy/CGE), respectively. According to other investigators there is no clear correlation between total dose and LC (6, 10). Tumor size A body of literature predicts that the use of protons provides substantial improvements in dose conformation for certain tumors, when compared with photon stereotactic or nonstereotactic RT, with or without intensity modulation (2, 34–39). These studies always compared photon beams
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Table 4. Results of retrospective studies from the international literature reporting LC, OS, and PFS for patients undergoing postoperative radiotherapy for atypical and/or malignant meningiomas Study (reference)
LC
OS
Hug et al. 2000 (30) (protons) Malignant (n = 16) 5 y: 52%; 8 y: 17% Atypical (n = 15) 5 y: 38%; 8 y: 19% Ojeman et al. 2000 (15) (Gamma knife) Malignant (n = 22) Goldsmith et al. 1994 (12) Malignant (n = 23) Milker-Zabel et al. 2006 (41) (fractionated stereotactic RT) Atypical (n = 26) Milosevic et al. 1996 (42) (conventional) Malignant (n = 42); atypical (n = 17) Hakim et al. 1998 (14) (X-knife) Malignant (n = 26)
5 y: 51%; 8 y: 51% 5 y: 89%; 8 y: 89% 2 y: 75%; 5 y: 40%
2 y: 32%; 5 y: 26%
5 y: 58%
5 y: 49%
5 y: 0 5 y: 68%
Total: Median: 32; 5 y: 28% Median: 1 y: 92.3%; 2 y: 64.6%; 3 y: 43.1%; 4 y: 21.5% 1 y: 91.7%; 2 y: 83.3%; 3 y: 83.3%; 4 y: 83.3% Median: 27mo 5 y: 0 5 y: 76%
1 y: 82.9% 7.8%; 2 y: 82.9% 7.8%; 3 y: 61.3% 11%; 4 y: 61.3% 11%; 5 y: 46.7% 12.3%; 8 y: 46.7% 12.3%
1 y: 100%; 2 y: 95.5% 4.4%; 3 y: 80.4% 8.8%; 4 y: 65.3% 10.6%; 5 y: 53.2% 11.6%; 8 y: 42.6% 13%
Atypical (n = 18) Stafford et al. 2001 (6) (Gamma knife) Malignant (n = 9) Atypical (n = 13) Present study (protons) Malignant (n = 5); atypical (n = 19)
PFS
3 y: 96%; 5 y: 89%; 10 y: 67% Total: Median: 32; 5 y: 34% Median time: 13.9 mo 24.4 mo SDS 5 y: 0 5 y: 76%
Abbreviations: LC = local control; OS = overall survival; PFS = progression-free survival; SDS = specific disease survival.
vs. proton beams or photon beams vs. photon and proton beams (2, 27, 40). It was not the purpose or the goal of our study to evaluate and compare dose conformation between the techniques, but this is a factor that we always have to take into account, especially when referring to the treatment of gross and complicated-shaped tumors. In our study we did not conclude that a correlation exists between the size of the tumor and LC or OS. Ojeman et al. (15) observed that small tumors (>8 cm3) with low GTV are more sensitive to radiation with the Gamma knife. According to other investigators, small tumors (GTV <60 cm3) are correlated with increased LC in atypical meningiomas treated with fractionated stereotactic RT (32, 41). Side effects The most common possible complications induced by RT are neuropathy, radiation necrosis, and insufficiency of the pituitary gland. According to the international literature, the main late high-grade complications reported after a variety of RT procedures for atypical and malignant meningiomas are reduced vision, trigeminal neuralgia, and tinnitus with fractionated stereotactic RT (41). Optic atrophy was reported in 1 patient after 60 Gy were delivered, and hypogonadotropic hypogonadism in 1 patient after 50 Gy were delivered with conventional RT (42). Radiation necrosis was induced in 2 patients after RT with protons and photons. The delivered total dose ranged be-
tween 59 and 72 Gy. One patient experienced visual field deficits, although maximum total dose to the optic nerve and optic chiasm was restricted to <60 and <55.8 Gy, respectively (30). Radiation necrosis was also reported in 5 patients treated with the Gamma knife. Three of the patients underwent retreatment of the same lesion at recurrence (15). Death for 2 patients and blindness for another were reported for treatment with the X-knife (14). The same article also reported hearing loss, hypesthesia, and hemiparesis. Increase of the radiation necrosis rate at 27% was reported with brachytherapy (43). Internal carotid stenosis was also reported in 2 patients and neuropathy (e.g., optic, trigeminal) in other patients who were treated with the Gamma knife (6). In our series, as noted earlier, only 1 patient experienced radiation necrosis. CONCLUSION Postoperative conformal combined RT with protons and photons for subtotal resected atypical and malignant meningiomas is a well-tolerated treatment with considerable OS. Increase of the total dose to >60 Gy results in a better prognosis in terms of cause-specific survival and OS. A possible increase of the total dose to >65 Gy leads to a trend for a possible additional shift in OS. Long-term, radiologically proven stabilization of disease increases OS. This results in an encouraging 8-year survival rate, comparable to the best survival reported in the literature.
Combined photon–proton RT for atypical and malignant meningioma d C. BOSKOS et al.
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