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Radiotherapy and radiosurgery for benign skull base meningiomas

Radiotherapy and radiosurgery for benign skull base meningiomas Meningiomas located in the region of the base of skull are difficult to access. Complex combined surgical approaches are more likely to achieve complete tumor removal, but frequently at a cost of treatment related high morbidity. Local control following subtotal excision of benign meningiomas can be improved with conventional fractionated external beam radiation therapy with a reported 5-year progression-free survival up to 95%. New radiation techniques, including stereotactic radiosurgery (SRS), fractionated stereotactic radiotherapy (FSRT), and intensity- modulated radiotherapy (IMRT) have been developed as a more accurate technique of irradiation with more precise tumor localization, and consequently a reduction in the volume of normal brain irradiated to high radiation doses. SRS achieves a high tumour control rate in the range of 85-97% at 5 years, although it should be recommended only for tumors less than 3 cm away more than 3 mm from the optic pathway because of high risk of long-term neurological deficits. Fractionated RT delivered as FSRT, IMRT and protons is useful for larger and irregularly or complex-shaped skull base meningiomas close to critical structures not suitable for single-fraction SRS. The reported results indicate a high tumour control rate in the range of 85-100% at 5 years with a low risk of significant incidence of long-term toxicity. Because of the long natural history of benign meningiomas, larger series and longer follow-up are necessary to compare results and toxicity of different techniques. fractionated external beam radiotherapy (RT) with a Introduction Surgical excision is the treatment of choice for accessible reported 10-year progression-free survival in the region of intracranial meningiomas. Following apparently com- 75-90% [11-13]. plete removal of benign meningiomas the reported con- trol rates are in the region of 95% at 5 years, 90% at 10 Advances in radiation oncology include intensity-modu- years and 70% at 15 years [1-10]. However, meningiomas lated radiotherapy (IMRT), fractionated stereotactic radio- located in the region of the base of skull are often difficult therapy (FSRT) and stereotactic radiosurgery (SRS) that to access and only subtotal or partial resection is possible, allow for more localised and precise irradiation. Recent with a high tendency for tumor regrowth. studies using these new techniques report apparently high local control rates and low morbidity for skull base Local control following incomplete excision of a benign benign tumors as pituitary adenomas, craniopharyngi- meningioma can be improved with conventional omas and meningiomas [14-18]. We performed a review Page 1 of 11 (page number not for citation purposes) Radiation Oncology 2009, 4:42 http://www.ro-journal.com/content/4/1/42 of the published literature of fractionated RT and SRS for up of 5 years reported a local control in 101 patients skull base meningiomas in an attempt to define reasona- treated with 3-D conformal RT of 95% at 5 years and 92% bly objective and comparative information on the safety at 10 and 15 years, with a respective cause-specific survival and efficacy of the individual techniques. rates of 97% and 92%, respectively. There were no differ- ence between patients who underwent surgery and post- Conventional radiotherapy operative RT and patients who had RT alone. Overall, the Post-operative conventional RT has been reported effec- actuarial 5-year and 10-year control rates reported in 5 tive both following subtotal surgical resection of benign publications (11-13,25,29) for a total of 359 patients were meningiomas and at the time of recurrence. Using a dose 90% (> 90% when a 3-D planning was used) and 83%, of 50-55 Gy in 30-33 fractions the 10-year and 20-year respectively. local control rates are 70-80% (Table 1) [11-13,19-30]. Some tumor shrinkage after conventional RT has been In a series of 82 patients with skull base meningiomas reported in 10%-25% of patients. Local control after sur- treated at the Royal Marsden Hospital between 1962 and gery implies complete removal of the tumor without evi- 1992 using a dose of 55-60 Gy in 30-33 fractions, the 5- dence of regrowth on follow-up. In contrast, local control year and 10-year local tumor control rates were 92% and after radiation implies no evidence of progression on 83%, respectively [12]. Tumor site was the only significant imaging. Benign tumors may regress partially, but they predictor of local control, with a 10-year progression-free rarely disappear after successful irradiation. However, as survival rate of 69% for patients with sphenoid ridge men- long as there is no evidence of disease progression, the ingiomas as compared with 90% for those with tumors in tumor is cured as effectively as thought it had been the parasellar region. The overall 10-year survival rate for removed completely with surgery. The reported tumor the entire cohort of patients was 71%, with performance control is similar for patients receiving a dose up to 60 Gy. status and patient age found to be significant independent Most of published series show no significant difference on prognostic factors. Goldsmith et al. [11] reported on 117 tumor control with the use of doses ranging between 50 patients with benign meningiomas who were treated with and 60 Gy, however a dose <50 Gy is associated with conventional RT using a median dose of 54 Gy at Univer- higher recurrence rates [13,22,28]. So far, in most centers, sity of California between 1967 and 1990. The 5-year and the standard dose for a benign meningioma is 55 Gy, 10-year progression-free survival rates were 89% and whereas lower doses of 50-52 Gy are reserved for large 77%, and the respective survival 85% and 77%. A signifi- meningiomas involving the optic pathways. cant better progression-free survival was associated with a younger age and improvement of technologies. The 5-year Analysis of treatment outcome after RT has lead to con- progression-free survival rate for patients with benign flicting results. Size and tumor site have been reported as meningioma treated after 1980 with three-dimensional a predictor of tumor control. Connell et al [26] reported a (3-D) conformal RT was 98%, as compared with 77% for 5-year control of 93% for 54 patients with skull base men- patients treated before 1980, with two-dimensional (2-D) ingiomas less than 5 centimeters in greatest dimension RT. Similarly, Mendenhall et al [13] at a median follow- and 40% for tumors more than 5 centimeters, and similar Table 1: Summary of results on published studies on the conventional radiotherapy of skull base meningiomas authors Patients S + RT RT Volume Dose Follow-up Local control Late toxicity (n) (%) (%) (ml) (Gy) (months) (%) (%) Carella et al.,1982 57 84 16 NA 55 - 60 NA 95 NA Forbes et al., 1984 31 100 0 NA 53 45 72 at 4 years 13 Barbaro et al., 1987 54 100 0 NA 52.5 78 68 0 Miralbell et al., 1992 36 100 0 NA 45-64 88 84 at 8 years 16 Goldsmith et al., 1994 117 100 0 NA 54 40 89 at 5 and 77 at 10 years 3.6 Maire et al., 1995 91 52 48 NA 52 40 94 6.5 Peele et al., 1996 42 100 0 NA 55 48 100 5 Condra et al.,1997 28 75 25 NA 53.3 98 87 at 15 years 24 Connell et al., 1999 54 80 20 NA 54 55 76 at 5 years 19 Maguire et al., 1999 26 78 22 NA 53 41 8 at 8 years 8 Nutting et al., 1999 82 100 0 NA 55-60 41 92 at 5 and 83 at 10 years 14 Vendrely et al., 1999 156 51 49 NA 50 40 79 at 5 years 11.5 Dufour et al., 2001 31 55 45 NA 52 73 93 at 5 and 10 years 3.2 Pourel et al., 2001 28 80 20 NA 56 30 95 at 5 years 4 Mendenhall et al., 2003 101 35 65 NA 54 64 95 at 5, 92 at 10 and 15 years 8 Page 2 of 11 (page number not for citation purposes) Radiation Oncology 2009, 4:42 http://www.ro-journal.com/content/4/1/42 findings have been reported by others [11,23]. Nutting et Certainly, patients with large parasellar meningiomas are al [12] found that patients with sphenoid ridge tumors at risk to develop late hypopituitarism and should be care- had worse local control than other skull base meningi- fully assessed long-life after RT. Neurocognitive dysfunc- omas, and this was independent of the extent of surgery. tion is a recognized consequence of large volume RT for Age and gender have not been a generally accepted prog- brain tumors [32] and has been occasionally reported in nostic factors for benign meningiomas, however younger irradiated patients with meningiomas, especially impair- age may be associated with better outcome in some series ment of short-term memory [23,27,29]. High dose radia- [11,12]. The reported local control and survival rates are tion may be associated with the development of a second similar for patients treated with RT as a part of their pri- brain tumours. In a large series of 426 patients with pitu- mary treatment or at the time of recurrence in most series itary adenomas who received conventional RT at the [11-13,28]. However, only a prospective randomized trial Royal Marsden Hospital between 1962 and 1994, the risk can adequately determine whether the long-term control of second brain tumors was 2.0% at 10 yr and 2.4% at 20 is influenced by timing of RT (early treatment versus yr, measured from the date of RT [33]. The relative risk of delayed treatment after evidence of progression). second brain tumor compared with the incidence in the normal population was 10.5 (95% CI, 4.3-16.7), being An important clinical endpoint of treatment is the 7.0 for neuroepithelial and 24.3 for meningeal tumors. improvement or the preservation of neurological func- tion. Neurological deficits are usually present in up to In summary, conventional external beam radiation seems 70% of patients with skull base meningiomas as conse- to be an efficient and safe initial or adjuvant treatment of quence of tumor growth or previous surgery, and are benign meningiomas with a reported 10-year control rates mainly represented by deficits or II, III, IV, V and VI cranial more than 80% in most series, and compares favorably nerves. An improvement or stabilization of neurological with tumor control rates reported after surgery alone, even deficits are seen in up to 69% and 100% after conven- after complete resection, suggesting that fractionated irra- tional RT [12,13,23,28,29]. However most of the pub- diation may produce at least a temporary tumor growth lished series do not show any clinical result and clear arrest. Neurological improvement has been reported in a figures about the functional outcome after conventional significant number of patients with low toxicity in most RT are lacking. cases. The toxicity of external beam RT is relatively low, ranging Fractionated stereotactic conformal from 0 to 24% (Table 1), and includes the risk of develop- radiotherapy (FSRT) ing neurological deficits, especially optic neuropathy, Assuming that fractionated RT is of value in achieving brain necrosis, cognitive deficits, and pituitary deficits. tumor control more sophisticated fractionated stereotac- Cerebral necrosis with associated clinical neurological tic radiation technique has been employed in patients decline is a severe and sometimes fatal complication of with residual and recurrent meningiomas (Table 2) [34- RT, however remains exceptional when doses less than 60 43]. FSRT leads to a reduction in the volume of normal Gy and 3-D planning system are used. Radiation injury to brain irradiated at high doses. Thus, the principal aim of the optic apparatus may be manifest as decreased visual radiosensitive structures sparing is to reduce the long-term acuity or visual field defects and it is reported in 0-3% of toxicity of radiotherapy, and to increase the precision of irradiated patients with meningiomas. Amongst 82 treatment maintaining or possibly increasing its effective- patients with benign skull base meningiomas who were ness. treated with conventional RT no cases of post-treatment optic nerve chiasm or other cranial nerve neuropathy were In a series of 41 patients with benign residual or recurrent recorded [12]. Goldsmith et al [11] found a low incidence meningiomas treated at the Royal Marsden Hospital with of radiation-induced optic neuropathy for dose less 55 Gy FSRT between 1994 and 1999 [35] at a median follow-up delivered to the optic pathways at conventional fractiona- of 21 months (range 2-62 months) none of patients have tion of 1,8-2 Gy per fraction. Parsons et al [31] observed recurred. Using a dose of 55 Gy in 33 fractions the actuar- no injuries in 106 optic nerves that received a total dose ial survival rates were 100% at 2 years and 91% at 3 and 5 less than 59 Gy, whereas the 15-year actuarial risk of radi- years. Tumor control was similar between patients treated ation-induced optic neuropathy was up to 47% in post-operatively and patients treated with FSRT alone, patients receiving a dose of 60 Gy or more using more regardless the sex, age, tumor site and irradiated volume. than 1,9 Gy per fraction. Other cranial deficits are Debus et al [34] reported on 189 patients with large reported in less than 1-3% of patients. Hypopituitarism is benign skull base meningiomas treated with FSRT with a reported in less than 5% of irradiated patients with skull mean radiation dose of 56.8 Gy at University of Heidel- base meningiomas, however hormone deficits are not sys- berg. At a median follow-up of 35 months (range, 3 tematically evaluated in the follow-up. months to 12 years) they reported a 5-year tumor control Page 3 of 11 (page number not for citation purposes) Radiation Oncology 2009, 4:42 http://www.ro-journal.com/content/4/1/42 Table 2: Summary of results on main published studies on the FSRT, IMRT, and proton radiotherapy of skull base meningiomas Authors Technique Patients S + SCRT SCRT Volume Dose Follow-up Control rate Late toxicity (n) (%) (%) (ml) (Gy) (months) (%) (%) Debus et al., 2001 FSRT 189 69 31 52.5 56.8 35 97 at 5 and 96 at 10 12 years Jalali et al., 2002 FSRT 41* 63 37 17.9 55 21 100 12.1 Lo et al., 2002 FSRT 18* 60 40 8.8 54 30.5 93.3 5 Torres et al., 2003 FSRT 77* 65 35 16.1 48.4 24 97.2 5.2 Selch et al., 2004 FSRT 45 64 36 14.5 56 36 100 at 3 years 0 Metellus et al., 2005 FSRT 38 20 18 12.7 53 88.6 94.7 2.6 Milker-Zabel et al., FSRT 317* 67 43 33.6 57.6 67 90.5 at 5 and 89 at 10 8.2 2005 years Henzel et al., 2006 FSRT 84 60 40 11.1 56 30 100 NA Brell et al., 2006 FSRT 30 57 43 11.3 52 50 93 at 4 years 6.6 Hamm et al., 2008 FSRT 183* 70 30 27.4 56 36 97 at 5 years 8.2 Uy et al., 2002 IMRT 40* 62.5 27.5 20.2 50.4 30 93 at 5 years 5 Pirzkall et al., 2003 IMRT 20 80 20 108 57 36 100 0 Saja et al., 2005 IMRT 35* 54 46 NA 50.4 19.1 97 at 3 years 0 Milker-Zabel et al., IMRT 94** 72 28 81.4 57.6 52 93.6 4 Wenkel et al, 2000 Ph + protons 46* 83 17 76 59 53 100 at 5 and 88 at 10 16 years Vernimmen et al, protons 23* 65 35 23.3° 20,6* 38° 87 13 Weber et al., 2004 protons 16* 81 19 17.5 56 34.1 91.7 at 3 years 24 Noel et al, 2005 Ph + protons 51* 86 14 17 60.6 21 98 at 4 years 4 S, surgery; FSRT, stereotactic conformal radiotherapy; IMRT, intensive modulated radiotherapy; Ph, photons *series includes some intracranial meningiomas **series includes some atypical/malignant meningiomas ° mean and survival of 94% and 97%, respectively. A volume A clinical neurological improvement is reported in 14- reduction of more than 50% was observed in 14% of 44% of patients after FSRT [34,39,41,43]. A late signifi- patients. A recent up-date of 317 patients treated at the cant toxicity is reported in less than 5% of patients, same Institution showed, at a median follow-up of 5.7 including cranial deficits (leading especially to visual years, a 5-year and 10-year tumor control of 90.5% and problems), hypopituarism and impairment for neurocog- 89%, and respective survival of 95% and 90% [40]. nitive function (Table 2). However, the evaluation of Patients treated for recurrent meningioma showed a trend complications is often subjective and unsatisfactory, so toward decreased progression-free survival compared that well designed prospective studies are needed to better with patients treated with primary therapy after subtotal evaluate the true incidence of long-term side effects com- resection. Patients with a tumor volume more than 60 paring the different techniques. No cases of second tumor cm had a significant recurrence rate of 15.5% vs. 4.3% for after FSRT for meningiomas have been reported to date. those with a tumor volume of 60 cm or less (p < 0.001). On theoretical grounds, the reduction of the volume of Hamm et al [43] at a median follow-up of 36 months normal brain receiving high radiation doses using FSRT reported a 5-year tumor control and survival of 93% and may decrease the risk of radiation-induced tumors, how- 97% in 183 patients with large skull base meningiomas. A ever to demonstrate a change in the incidence of second partial imaging response occurred in 23% of patients, and brain tumors will require large series of patients with in the 95% of patients the neurological symptoms appropriate follow-up of 10-20 years. improved or remained stable. In a series of 27 patients with large recurrent benign skull base meningiomas (> 4 In summary, FSRT is an effective and safe treatment cm) treated at our Institution with FSRT between 2005 modality for local control of skull base meningiomas and and 2009 at a median dose of 50 Gy in 30 daily fractions tumor control is comparable to the reported results of the 2-year local control and survival were 100% [44]. other fractionated radiation techniques and SRS for Eight patients (29%) showed a tumor shrinkage more benign skull base meningiomas. FSRT offers a more local- than 25% during the follow-up. Although majority of the ized irradiation compared with conventional RT and the tumors treated had irregular shape and compressed the reported data from literature indicate that radiation optic chiasm, no visual deficits have been recorded during induced morbidity is quite low. Although longer follow- the follow-up. up is necessary to clearly demonstrate the potential reduc- Page 4 of 11 (page number not for citation purposes) Radiation Oncology 2009, 4:42 http://www.ro-journal.com/content/4/1/42 tion of long term complications in comparison with con- protons in younger patients Moreover, proton therapy can ventional RT, currently FSRT should be preferred for the be delivered as stereotactic radiosurgery or as fractionated radiation treatment of large skull base tumors, especially stereotactic radiotherapy with the same used immobiliza- those in close proximity to the optic apparatus. tion systems and target accuracy of photon techniques. Intensity modulated radiotherapy (IMRT) Tumor control after proton beam RT is shown in Table IMRT represents an advanced form of 3-D conformal 2[50-53]. Noel et al [53] reported on 51 patients with which has been recently employed for the treatment of skull base meningiomas treated between 1994 and 2002 different brain tumors, especially large tumors with irreg- with a combination of photon and proton RT at Institute ular shapes close to critical structures [45]. IMRT for men- Curie in Orsay. At a median follow-up of 25.4 months the ingiomas results in a more conformality and better target 4-year local control and overall survival rates were 98% coverage than CRT and therefore able to spare more radi- and 100%, respectively. Neurological improvement was osensitive brain structures [46]. IMRT uses a series of mul- reported in 69% of patients and stabilization in 31%. tiple subfields created by MLC which move under Wenkel et al [50] reported on 46 patients with partially computer control creating modulated fields. IMRT treat- resected or recurrent meningiomas treated between 198 ment plans are generated using inverse planning system, and 1996 with combined photon and proton beam ther- which uses computer optimization techniques to modu- apy at the Massachusetts General Hospital (MGH). At a late intensities across the target volume and sensitive nor- median follow-up of 53 months overall survival at 5 and mal structures, starting from a specified dose distribution. 10 years was 93 and 77%, respectively, and the recurrence- free rate at 5 and 10 years was 100% and 88%, respec- Few series are available on the use of IMRT in patients tively. Three patients had local tumor recurrence at 61, 95, with meningiomas (Table 2) [16,47-49]. Milker-Zabel et and 125 months. Seventeen percent of patients developed al [16] reported on 94 patients with complex-shaped severe long-term toxicity from RT, including ophthalmo- meningiomas treated with IMRT at University of Heidem- logic, neurologic, and otologic complications. At a berg between 1998 and 2004. At a median follow-up of median follow-up of 40 months a tumor control of 89% 4.4 years, the reported tumor local control was 93.6%. has been reported by Vernimmen et al [51] in in 27 Recurrence-free survival in patients with WHO Grade 1 patients with large skull base meningiomas (median vol- meningiomas was 97.5% at 3 years and 93.6% at 5 years, ume 43.7 cm ) treated with stereotactic proton beam ther- and overall survival was 97%. Sixty-nine patients had sta- apy. Permanent neurological deficits were reported in 3 ble disease based on CT/MRI, whereas 19 had a tumor patients. volume reduction, and 6 patients showed tumor progres- sion after IMRT. A neurological improvement was noted In summary, proton irradiation alone or in combination in about 40% of patients and a worsening of preexisting with photons is effective in controlling meningiomas, neurologic symptoms was seen in 4% of patients. No sec- with a tumor control and toxicity in the range of photon ondary malignancies were seen after IMRT, however this therapy. On the basis of the dosimetric advantages of pro- may simply be a reflection of the lack of adequate long- tons, including better conformality and reduction of inte- term follow-up. Similar results have been reported by oth- gral radiation dose to normal tissue, fractionated proton ers in some small series, with a reported local control of irradiation may be considered in patients with large and/ 93-97% at median follow-up of 19-36 months and low or complex-shaped meningiomas or younger patients, toxicity [47-49], suggesting that IMRT is a feasible treat- possibly limiting the long-term late effects of irradiation. ment modality for control of complex-shaped meningi- As more hospital-based proton treatment centers are oma. In summary, IMRT allows the delivery of a high dose becoming operational, prospective trials that assess the to such complex-shaped skull base tumors while sparing late toxicity of different radiation techniques are needed the surrounding radiosensitive structures, especially optic to confirm the expected reduction in long-term side effects chiasm and brainstem, although longer follow-up does with proton RT. needs to confirm the potential reduction of radiation- induced toxicity of IMRT in comparison with 3D confor- Stereotactic radiosurgery (SRS) mal RT in large skull base meningiomas. Since 1990, either Gamma Knife (GK) or Linear Accelera- tor (LINAC) have been extensively employed in the radi- Proton radiotherapy osurgical treatment of skull base meningiomas. A Proton irradiation can achieve better target-dose confor- summary of main recent published series of SRS in skull mality when compared to 3D-CRT and IMRT and the base meningiomas is shown in Table 3[36,37,39,54-84]. advantage becomes more apparent for large volumes. Dis- Differing from the earliest reports with short follow-ups, tribution of low and intermediate doses to portions of large recently published series report a more appropriate irradiated brain are significant lower with protons when 5-year and 10-year actuarial control rates. In a large series compared with photons and also could favor the use of of 972 patients mostly with skull base meningiomas, who Page 5 of 11 (page number not for citation purposes) Radiation Oncology 2009, 4:42 http://www.ro-journal.com/content/4/1/42 underwent Gamma GK SRS at the University of Pitts- base tumors that are - more than 3 cm; - in close proximity burgh, the reported actuarial tumor control rates were of the optic chiasm (less than 3-5 mm); compressing the 93% at 5 years and 87 at 10 and 15 years using a median brainstem and - with irregular margins. dose to the tumor margin of 13 Gy, with no differences between 384 patients who underwent postoperative SRS Radiosurgical doses between 12 and 18 Gy have been and 488 patients treated with primary SRS [18]. These used in the control of skull base meningiomas. Over the result confirm a previous study of 159 patients treated last years, SRS doses have been decreased with the aim to with GK SRS at the same Institution with a reported actu- minimize long-term toxicity while maintaining efficacy. arial tumor control rate for patients with typical meningi- Ganz et al [84] reported on 97 patients with meningiomas omas of about 93% at both 5 and 10 years [70]. Tumor with median volume of 15.9 cm treated with GK SRS volumes decreased in 3%, remained stable in 60%, and using a dose of 12 Gy. At A median follow-up of 54 increased in 6% of patients. Kreil et al [75] in 200 patients months the 2-year progression-free survival was 100%. with skull base meningiomas treated with GK SRS Twenty-seven were smaller and 72 unchanged in volume. reported a 5-year and 10-year local control of 98.5% and Three patients suffered adverse radiation effects. Overall, 97%, respectively, and similar results have been reported at median dose of 12-14 Gy the reported 5-year actuarial in some recent large series including more than 100 tumor control rate remains in the range of 90-95% as for patients [67,69,70,72,75,77,78,81,83]. Overall, eighteen higher doses [74,77,79-84]. studies including 2919 skull base meningiomas report a 5-year actuarial control of 91%; amongst them, 7 studies The rate of tumor shrinkage measured varied in all stud- including 1626 skull base meningiomas report a 10-year ies, ranging from 16% to 69% in the different series, and actuarial control of 87.6% (Table 3). Although in most tends to increase in patients with longer follow-up. Simi- series radiosurgical dose has been delivered using GK SRS, larly, a variable improvement of neurological functions a similar outcome has been reported with the use of has been shown in 10-60% of patients, however the eval- LINAC SRS. uation of neurological improvement is frequently retro- spective and the criteria used to evaluate the functional Only few studies have compared the outcome of SRS and improvement are subjective or not available in most FSRT in skull base meningiomas [36,37,39]. Metellus et al series. [39] found no differences in tumor control between 38 patients treated with fractionated RT and 36 patients Analysis of factors predicting local tumor control in most treated with SRS. Actuarial progression-free survival was series shows no significant differences between patients 94.7% in fractionated RT group and 94.4% in SRS group, underwent SRS as primary treatment and patients treated with permanent morbidity of 2.6% after FSRT and 0% for incomplete resected or recurrent meningioma. Age, after SRS. Torres et al [37] reported on 77 patients treated sex, site of meningioma, and neurological status did not with SRS and 51 patients treated with FSRT. Tumor con- affect significantly the outcome in most published series, trol was achieved in 90% of patients at a median follow- however larger meningiomas are associated with worse up of 40 months after SRS, and in 97% of patients at a long-term local control [18,72]. DiBiase et al [72] median follow-up of 24 months following FSRT. Late reported a significant higher 5-year tumor control in complications were recorded in 5% of patients treated patients with meningiomas < 10 ml than those with larger with SRS and 5.2% patients treated with FSRT. A similar 3- tumors (92% vs 68%, p = 0.038). In a recent series of 972 year local control of 94% has been reported by Lo et al patients with meningioma poorer local control was corre- [36] in 35 patients treated with SRS and in 18 patients lated with increasing volume (p = 0.01), and a similar with large tumors treated with FSRT. Permanent morbid- trend was observed with disease-specific survival (p = ity was 2.6% in SRS group and 0% in FSRT group. These 0.11) [18]. data suggests that either SRS or FSRT are safe and effective techniques in the treatment of skull base meningiomas, More recently the image-guided robotic radiosurgery sys- affording comparable satisfactory long-term tumor con- tem (Cyberknife) has been employed for frameless SRS in trol. The main differences between FSRT group and SRS patients with skull base meningiomas [85,86]. Patient group treated at the same Institution was the average position and motion are measured by two diagnostic x-ray diameter of meningiomas or the close proximity to sensi- cameras and communicated in real time to the robotic tive structures. Patients with tumors less than 3 cm and arm for beam targeting and patient motion tracking. more than 3-5 mm away from radiosensitive structures, Although patients are fixed in a thermoplastic mask, the such as optic chiasm or brainstem, were selected for SRS system achieves the same level of targeting precision as whereas FSRT was employed for all tumors that were not conventional frame-based RS. Colombo et al [86] in a amenable to SRS. In our Institution both stereotactic tech- series of 199 benign intracranial meningiomas (157 skull niques are available and the we recommend FSRT for skull base meningiomas) reported a 5-year control of 93.5%. Page 6 of 11 (page number not for citation purposes) Radiation Oncology 2009, 4:42 http://www.ro-journal.com/content/4/1/42 Table 3: Summary of results on main published studies on the radiosurgery of skull base meningiomas authors patients type S + RS RS tumor median follow-up local volume neurologi Toxicity % % volume dose median control reduction cal % median Gy (months) % (%) improve (ml) ment valentino et 72 LINAC 53 47 NA NA 44 93 69 50 6.7 al., 1993 Hudgins et 100* GK 91 9 14 15 NA 91 47 8 12 al., 1996 Kurita et al., 18 GK 83 17 NA 17 34.8 87.5 at 5 35 NA 49.9 1997 years Chang et al., 24 GK 66 34 6.8 17.7 45.6 100 37 42 33 Pan et al., 63 GK 54 46 NA NA 21 91 74 37.5 7.5 Morita et 88 GK 55 45 8.1 16 35 95 at 5 years 70 NA 14.8 al., 1999 Shafron et 50 LINAC 46 54 10 12.7 23 100 44 NA 3 al., 1999 Liscak et al., 67 GK 36 64 7.8 12 19 100 52 35.8 3.8 (1999) Aichholzer 46* GK 67 33 NA 15.9 48 97.5 52 33 13.2 et al., 2000 Roche et al., 80 GK 37 63 4.7 14 30.5 92.8 at 5 31 43 5 2000 years Villavicencio 56 LINAC 64 36 6 15 26 95 44 34 9 et al., 2001 Kobayashi 87 GK 56 44 NA 14 30° 89 at 7 years 23 48 13.8 et al., 2001 Shin et al., 40 GK 66 34 4.3 18 40 82.3 a 10 37 20 22.5 2001 years Stafford et 190* GK 59 41 8.2 16 47 93 at 5 years 56 8 13 al., 2001 Spiegelmann 42 LINAC 26 74 8.4 14 36 97.5 at 7 60 22 22.4 et al., 2002 years Nicolato et 111 GK 49 51 10 14.8 48.2 96 at 5 years 63 66 8 al., 2002 Lee et al., 155 GK 46 54 6.5 15 35 93 at 5 and 34 29 6.7 2002 10 years Lo et al., 35 LINAC 60 40 6.8 14 38 92.7 at 3 37.5 NA 6 2002 years Eustachio et 121 GK 49 51 6.8 13 82 97.8 60 44 6.7 al., 2002) Torres et 77* LINAC 65 35 12.7 15.6 40.6 92.1 35 35 5 al., 2003 DiBiase et 162 GK 38 62 4.5 14 54 86.2 at 5 28 NA 8.3 al., 2004 years Deinsberger 37 LINAC 22 78 5.9 14.6 66 97.2 32 NA 5.6 et al., 2004 Pollock et 49 GK 0 100 10.2 16 58 85 at 3 and 59 26 20 al., 2005 80 at 7 years Kreil et al., 200 GK 50.5 49.5 6.5 12 95 98.5 at 5 and 56.5 41 4.5 2005 97 at 10 years Zachenhofe 36 GK 70 30 NA 17 103 94 53 36 5 r et al., Kollova et 368 GK 30 70 4.4 12.5 60 98 at 5 years 69 62 15.9 al., 2007 Hasewaga 115 GK 57 43 14 13 62 87 at 5 and 51 46 12 et al., 2007 73 at 10 years Feigl et al., 214 GK 43 57 6.5° 13.6° 24° 86.3 at 4 74 19 6.7 2007 years Page 7 of 11 (page number not for citation purposes) Radiation Oncology 2009, 4:42 http://www.ro-journal.com/content/4/1/42 Table 3: Summary of results on main published studies on the radiosurgery of skull base meningiomas (Continued) Davidson et 36 GK 100 0 4.1 16 81 100 at 5 and 14 44 3 al., 2007 94.7 at 10 years Kondziolka 972* GK 49 51 7.4* 14° 48° 87 at 10 and 42 35 7.7 et al., 2008 15 years Iway et al., 108 GK NA NA 8.1 12 86.1 93 at 5 and 46 21 6 2008 83 at 10 years Han et al., 98 GK 36 64 6.3° 12.7 77° 90 at 5 years 44 45 16 Takanashi et 101 GK 24 76 7.1 13.2 52° 97% 44 45 0 al., 2009 Ganz et al., 97 GK NA NA 15.9° 12° 53° 100% at 2 31 NA 3 2009 years *series include skull base and intracranial meningiomas; °mean Tumors larger than 8 ml and/or situated close to critical of radiosurgical series. Other complications, as epilepsy, structures were treated with hypofractionated stereotactic internal carotid occlusion, and hypopituitarism have been RT (2 to 5 daily fractions). The tumor volume decreased rarely reported (less than 1-2%). in 36 patients, was unchanged in 148 patients, and increased in 7 patients. Clinical symptoms improved in The risk of clinically significant radiation optic neuropa- 30 patients. Tumor control in 63 patients with tumor vol- thy for patients receiving SRS for skull base meningiomas ume up 65 ml treated with hypofractionated RT was sim- is 1-2% following doses to optic chiasm below 10 Gy and ilar to that obtained in smaller meningiomas treated with this percentage may significantly increase for higher doses single fraction SRS. Neurological deterioration was [56,85,86]. Leber et al [92] reviewed 50 patients having observed in 4% of patients, represented mainly by visual SRS for benign skull base tumors in which the optic nerves deficits. Although the small numbers of fractions possible or chiasm were exposed to 4.5 Gy or more. For patients with the CyberKnife seems safer than SRS for large para- receiving 10 to 15 Gy and greater than 15 Gy, the risk of sellar meningiomas, further large series with appropriate radiation-induced optic neuropathy was 26.7% and follow-up should confirm the low risk of optic neuropa- 77.8%, respectively, however no optic neuropathy was thy in patients treated with hypofractionated regimens. observed when a dose less than 10 Gy was delivered to the Currently for large meningiomas close to the optic path- optic apparatus. Stafford et al [93] found that the risk of ways, in our opinion FSRT should be chosen based on its developing a clinically significant optic neuropathy was proven efficacy and safety. 1.1% for patients receiving a point maximum dose of 12 Gy or less, and similar results have been reported by oth- Complications of SRS are reported in 3 to 40% of cases ers [59]. Considering an effective dose of 13-16 Gy to (corrected mean 8%), being represented by either tran- achieve local control of a skull base meningioma and a sient (3.0%) or permanent complications (5.0%). recommended dose of 8 Gy as the maximum for the optic Although radionecrosis of the brain and delayed cranial chiasm, in clinical practice this means that a distance nerve deficits after SRS are of concern, the rate of signifi- between tumor margin and optic apparatus should be at cant complications at doses of 12-15 Gy as currently used least of 2-3 mm to avoid visual deterioration. In contrast in most centers is less than 6% (Table 3). Kondziolka et al motor cranial nerve deficits in the cavernous sinus rarely [18] reported a permanent neurological deficits of 9% at have been reported with doses less than 16 Gy. For men- 10 and 15 years in 972 patients treated with GK SRS for ingiomas involving the clivus and cerebellopontine angle intracranial meningiomas. The morbidity rate for cavern- the estimated tolerance dose for the brainstem is 15 Gy, ous sinus meningiomas was 6.3%, including visual dete- however facial nerve and acoustic injuries may occur at th rioration, 6 nerve palsy, and trigeminal neuropathy. In lower doses. the series of Nicolato et al [69] late complications occurred in 4.5% of patients, being transient in 80% of In summary, SRS may represents a convenient and safe them, and similar complication rates have been reported approach for patients with skull base meningiomas with a in all main published series (Table 3). Few cases of radia- tumor control at 5 and 10 years comparable to fraction- tion induced tumors, mainly glioblastoma, have been ated RT. Both SRS and FSRT are effective treatment reported in the literature [84,87-91], however the real options for benign skull base meningiomas and the incidence of second brain tumors cannot be clearly estab- choice of stereotactic technique is mainly based on the lished because of short follow-up reported in the majority characteristics of tumors. In most centers SRS is usually Page 8 of 11 (page number not for citation purposes) Radiation Oncology 2009, 4:42 http://www.ro-journal.com/content/4/1/42 3. Kallio M, Sankila R, Hakulinen T, Jääskeläinen J: Factors affecting reserved for tumors less than 3 cm away 3-5 mm from the operative and excess long-term mortality in 935 patients optic chiasm, whereas FSRT is employed for those tumors with intracranial meningioma. Neurosurgery 1992, 31:2-12. not amenable to SRS. The reported toxicity of SRS is low 4. DeMonte F, Smith HK, al-Mefty O: Outcome of aggressive removal of cavernous sinus meningiomas. 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Davidson L, Fishback D, Russin JJ, Weiss MH, Yu C, Pagnini PG, Zel- Publish with Bio Med Central and every man V, Apuzzo ML, Giannotta SL: Postoperative Gamma Knife scientist can read your work free of charge surgery for benign meningiomas of the cranial base. Neuro- surg Focus 2007, 23(4):E6. "BioMed Central will be the most significant development for 81. Iwai Y, Yamanaka K, Ikeda H: Gamma Knife radiosurgery for disseminating the results of biomedical researc h in our lifetime." skull base meningioma: long-term results of low-dose treat- Sir Paul Nurse, Cancer Research UK ment. J Neurosurg 2008, 109:804-810. 82. Han JH, Kim DG, Chung HT, Park CK, Paek SH, Kim CY, Jung HW: Your research papers will be: Gamma knife radiosurgery for skull base meningiomas: long- available free of charge to the entire biomedical community term radiologic and clinical outcome. Int J Radiat Oncol Biol Phys 2008, 72:1324-1332. peer reviewed and published immediately upon acceptance 83. Takanashi M, Fukuoka S, Hojyo A, Sasaki T, Nakagawara J, Nakamura cited in PubMed and archived on PubMed Central H: Gamma knife radiosurgery for skull-base meningiomas. Prog Neurol Surg 2009, 22:96-111. yours — you keep the copyright BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 11 of 11 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

Radiotherapy and radiosurgery for benign skull base meningiomas

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Springer Journals
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Copyright © 2009 by Minniti et al; licensee BioMed Central Ltd.
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Medicine & Public Health; Oncology; Radiotherapy
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19828022
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Abstract

Meningiomas located in the region of the base of skull are difficult to access. Complex combined surgical approaches are more likely to achieve complete tumor removal, but frequently at a cost of treatment related high morbidity. Local control following subtotal excision of benign meningiomas can be improved with conventional fractionated external beam radiation therapy with a reported 5-year progression-free survival up to 95%. New radiation techniques, including stereotactic radiosurgery (SRS), fractionated stereotactic radiotherapy (FSRT), and intensity- modulated radiotherapy (IMRT) have been developed as a more accurate technique of irradiation with more precise tumor localization, and consequently a reduction in the volume of normal brain irradiated to high radiation doses. SRS achieves a high tumour control rate in the range of 85-97% at 5 years, although it should be recommended only for tumors less than 3 cm away more than 3 mm from the optic pathway because of high risk of long-term neurological deficits. Fractionated RT delivered as FSRT, IMRT and protons is useful for larger and irregularly or complex-shaped skull base meningiomas close to critical structures not suitable for single-fraction SRS. The reported results indicate a high tumour control rate in the range of 85-100% at 5 years with a low risk of significant incidence of long-term toxicity. Because of the long natural history of benign meningiomas, larger series and longer follow-up are necessary to compare results and toxicity of different techniques. fractionated external beam radiotherapy (RT) with a Introduction Surgical excision is the treatment of choice for accessible reported 10-year progression-free survival in the region of intracranial meningiomas. Following apparently com- 75-90% [11-13]. plete removal of benign meningiomas the reported con- trol rates are in the region of 95% at 5 years, 90% at 10 Advances in radiation oncology include intensity-modu- years and 70% at 15 years [1-10]. However, meningiomas lated radiotherapy (IMRT), fractionated stereotactic radio- located in the region of the base of skull are often difficult therapy (FSRT) and stereotactic radiosurgery (SRS) that to access and only subtotal or partial resection is possible, allow for more localised and precise irradiation. Recent with a high tendency for tumor regrowth. studies using these new techniques report apparently high local control rates and low morbidity for skull base Local control following incomplete excision of a benign benign tumors as pituitary adenomas, craniopharyngi- meningioma can be improved with conventional omas and meningiomas [14-18]. We performed a review Page 1 of 11 (page number not for citation purposes) Radiation Oncology 2009, 4:42 http://www.ro-journal.com/content/4/1/42 of the published literature of fractionated RT and SRS for up of 5 years reported a local control in 101 patients skull base meningiomas in an attempt to define reasona- treated with 3-D conformal RT of 95% at 5 years and 92% bly objective and comparative information on the safety at 10 and 15 years, with a respective cause-specific survival and efficacy of the individual techniques. rates of 97% and 92%, respectively. There were no differ- ence between patients who underwent surgery and post- Conventional radiotherapy operative RT and patients who had RT alone. Overall, the Post-operative conventional RT has been reported effec- actuarial 5-year and 10-year control rates reported in 5 tive both following subtotal surgical resection of benign publications (11-13,25,29) for a total of 359 patients were meningiomas and at the time of recurrence. Using a dose 90% (> 90% when a 3-D planning was used) and 83%, of 50-55 Gy in 30-33 fractions the 10-year and 20-year respectively. local control rates are 70-80% (Table 1) [11-13,19-30]. Some tumor shrinkage after conventional RT has been In a series of 82 patients with skull base meningiomas reported in 10%-25% of patients. Local control after sur- treated at the Royal Marsden Hospital between 1962 and gery implies complete removal of the tumor without evi- 1992 using a dose of 55-60 Gy in 30-33 fractions, the 5- dence of regrowth on follow-up. In contrast, local control year and 10-year local tumor control rates were 92% and after radiation implies no evidence of progression on 83%, respectively [12]. Tumor site was the only significant imaging. Benign tumors may regress partially, but they predictor of local control, with a 10-year progression-free rarely disappear after successful irradiation. However, as survival rate of 69% for patients with sphenoid ridge men- long as there is no evidence of disease progression, the ingiomas as compared with 90% for those with tumors in tumor is cured as effectively as thought it had been the parasellar region. The overall 10-year survival rate for removed completely with surgery. The reported tumor the entire cohort of patients was 71%, with performance control is similar for patients receiving a dose up to 60 Gy. status and patient age found to be significant independent Most of published series show no significant difference on prognostic factors. Goldsmith et al. [11] reported on 117 tumor control with the use of doses ranging between 50 patients with benign meningiomas who were treated with and 60 Gy, however a dose <50 Gy is associated with conventional RT using a median dose of 54 Gy at Univer- higher recurrence rates [13,22,28]. So far, in most centers, sity of California between 1967 and 1990. The 5-year and the standard dose for a benign meningioma is 55 Gy, 10-year progression-free survival rates were 89% and whereas lower doses of 50-52 Gy are reserved for large 77%, and the respective survival 85% and 77%. A signifi- meningiomas involving the optic pathways. cant better progression-free survival was associated with a younger age and improvement of technologies. The 5-year Analysis of treatment outcome after RT has lead to con- progression-free survival rate for patients with benign flicting results. Size and tumor site have been reported as meningioma treated after 1980 with three-dimensional a predictor of tumor control. Connell et al [26] reported a (3-D) conformal RT was 98%, as compared with 77% for 5-year control of 93% for 54 patients with skull base men- patients treated before 1980, with two-dimensional (2-D) ingiomas less than 5 centimeters in greatest dimension RT. Similarly, Mendenhall et al [13] at a median follow- and 40% for tumors more than 5 centimeters, and similar Table 1: Summary of results on published studies on the conventional radiotherapy of skull base meningiomas authors Patients S + RT RT Volume Dose Follow-up Local control Late toxicity (n) (%) (%) (ml) (Gy) (months) (%) (%) Carella et al.,1982 57 84 16 NA 55 - 60 NA 95 NA Forbes et al., 1984 31 100 0 NA 53 45 72 at 4 years 13 Barbaro et al., 1987 54 100 0 NA 52.5 78 68 0 Miralbell et al., 1992 36 100 0 NA 45-64 88 84 at 8 years 16 Goldsmith et al., 1994 117 100 0 NA 54 40 89 at 5 and 77 at 10 years 3.6 Maire et al., 1995 91 52 48 NA 52 40 94 6.5 Peele et al., 1996 42 100 0 NA 55 48 100 5 Condra et al.,1997 28 75 25 NA 53.3 98 87 at 15 years 24 Connell et al., 1999 54 80 20 NA 54 55 76 at 5 years 19 Maguire et al., 1999 26 78 22 NA 53 41 8 at 8 years 8 Nutting et al., 1999 82 100 0 NA 55-60 41 92 at 5 and 83 at 10 years 14 Vendrely et al., 1999 156 51 49 NA 50 40 79 at 5 years 11.5 Dufour et al., 2001 31 55 45 NA 52 73 93 at 5 and 10 years 3.2 Pourel et al., 2001 28 80 20 NA 56 30 95 at 5 years 4 Mendenhall et al., 2003 101 35 65 NA 54 64 95 at 5, 92 at 10 and 15 years 8 Page 2 of 11 (page number not for citation purposes) Radiation Oncology 2009, 4:42 http://www.ro-journal.com/content/4/1/42 findings have been reported by others [11,23]. Nutting et Certainly, patients with large parasellar meningiomas are al [12] found that patients with sphenoid ridge tumors at risk to develop late hypopituitarism and should be care- had worse local control than other skull base meningi- fully assessed long-life after RT. Neurocognitive dysfunc- omas, and this was independent of the extent of surgery. tion is a recognized consequence of large volume RT for Age and gender have not been a generally accepted prog- brain tumors [32] and has been occasionally reported in nostic factors for benign meningiomas, however younger irradiated patients with meningiomas, especially impair- age may be associated with better outcome in some series ment of short-term memory [23,27,29]. High dose radia- [11,12]. The reported local control and survival rates are tion may be associated with the development of a second similar for patients treated with RT as a part of their pri- brain tumours. In a large series of 426 patients with pitu- mary treatment or at the time of recurrence in most series itary adenomas who received conventional RT at the [11-13,28]. However, only a prospective randomized trial Royal Marsden Hospital between 1962 and 1994, the risk can adequately determine whether the long-term control of second brain tumors was 2.0% at 10 yr and 2.4% at 20 is influenced by timing of RT (early treatment versus yr, measured from the date of RT [33]. The relative risk of delayed treatment after evidence of progression). second brain tumor compared with the incidence in the normal population was 10.5 (95% CI, 4.3-16.7), being An important clinical endpoint of treatment is the 7.0 for neuroepithelial and 24.3 for meningeal tumors. improvement or the preservation of neurological func- tion. Neurological deficits are usually present in up to In summary, conventional external beam radiation seems 70% of patients with skull base meningiomas as conse- to be an efficient and safe initial or adjuvant treatment of quence of tumor growth or previous surgery, and are benign meningiomas with a reported 10-year control rates mainly represented by deficits or II, III, IV, V and VI cranial more than 80% in most series, and compares favorably nerves. An improvement or stabilization of neurological with tumor control rates reported after surgery alone, even deficits are seen in up to 69% and 100% after conven- after complete resection, suggesting that fractionated irra- tional RT [12,13,23,28,29]. However most of the pub- diation may produce at least a temporary tumor growth lished series do not show any clinical result and clear arrest. Neurological improvement has been reported in a figures about the functional outcome after conventional significant number of patients with low toxicity in most RT are lacking. cases. The toxicity of external beam RT is relatively low, ranging Fractionated stereotactic conformal from 0 to 24% (Table 1), and includes the risk of develop- radiotherapy (FSRT) ing neurological deficits, especially optic neuropathy, Assuming that fractionated RT is of value in achieving brain necrosis, cognitive deficits, and pituitary deficits. tumor control more sophisticated fractionated stereotac- Cerebral necrosis with associated clinical neurological tic radiation technique has been employed in patients decline is a severe and sometimes fatal complication of with residual and recurrent meningiomas (Table 2) [34- RT, however remains exceptional when doses less than 60 43]. FSRT leads to a reduction in the volume of normal Gy and 3-D planning system are used. Radiation injury to brain irradiated at high doses. Thus, the principal aim of the optic apparatus may be manifest as decreased visual radiosensitive structures sparing is to reduce the long-term acuity or visual field defects and it is reported in 0-3% of toxicity of radiotherapy, and to increase the precision of irradiated patients with meningiomas. Amongst 82 treatment maintaining or possibly increasing its effective- patients with benign skull base meningiomas who were ness. treated with conventional RT no cases of post-treatment optic nerve chiasm or other cranial nerve neuropathy were In a series of 41 patients with benign residual or recurrent recorded [12]. Goldsmith et al [11] found a low incidence meningiomas treated at the Royal Marsden Hospital with of radiation-induced optic neuropathy for dose less 55 Gy FSRT between 1994 and 1999 [35] at a median follow-up delivered to the optic pathways at conventional fractiona- of 21 months (range 2-62 months) none of patients have tion of 1,8-2 Gy per fraction. Parsons et al [31] observed recurred. Using a dose of 55 Gy in 33 fractions the actuar- no injuries in 106 optic nerves that received a total dose ial survival rates were 100% at 2 years and 91% at 3 and 5 less than 59 Gy, whereas the 15-year actuarial risk of radi- years. Tumor control was similar between patients treated ation-induced optic neuropathy was up to 47% in post-operatively and patients treated with FSRT alone, patients receiving a dose of 60 Gy or more using more regardless the sex, age, tumor site and irradiated volume. than 1,9 Gy per fraction. Other cranial deficits are Debus et al [34] reported on 189 patients with large reported in less than 1-3% of patients. Hypopituitarism is benign skull base meningiomas treated with FSRT with a reported in less than 5% of irradiated patients with skull mean radiation dose of 56.8 Gy at University of Heidel- base meningiomas, however hormone deficits are not sys- berg. At a median follow-up of 35 months (range, 3 tematically evaluated in the follow-up. months to 12 years) they reported a 5-year tumor control Page 3 of 11 (page number not for citation purposes) Radiation Oncology 2009, 4:42 http://www.ro-journal.com/content/4/1/42 Table 2: Summary of results on main published studies on the FSRT, IMRT, and proton radiotherapy of skull base meningiomas Authors Technique Patients S + SCRT SCRT Volume Dose Follow-up Control rate Late toxicity (n) (%) (%) (ml) (Gy) (months) (%) (%) Debus et al., 2001 FSRT 189 69 31 52.5 56.8 35 97 at 5 and 96 at 10 12 years Jalali et al., 2002 FSRT 41* 63 37 17.9 55 21 100 12.1 Lo et al., 2002 FSRT 18* 60 40 8.8 54 30.5 93.3 5 Torres et al., 2003 FSRT 77* 65 35 16.1 48.4 24 97.2 5.2 Selch et al., 2004 FSRT 45 64 36 14.5 56 36 100 at 3 years 0 Metellus et al., 2005 FSRT 38 20 18 12.7 53 88.6 94.7 2.6 Milker-Zabel et al., FSRT 317* 67 43 33.6 57.6 67 90.5 at 5 and 89 at 10 8.2 2005 years Henzel et al., 2006 FSRT 84 60 40 11.1 56 30 100 NA Brell et al., 2006 FSRT 30 57 43 11.3 52 50 93 at 4 years 6.6 Hamm et al., 2008 FSRT 183* 70 30 27.4 56 36 97 at 5 years 8.2 Uy et al., 2002 IMRT 40* 62.5 27.5 20.2 50.4 30 93 at 5 years 5 Pirzkall et al., 2003 IMRT 20 80 20 108 57 36 100 0 Saja et al., 2005 IMRT 35* 54 46 NA 50.4 19.1 97 at 3 years 0 Milker-Zabel et al., IMRT 94** 72 28 81.4 57.6 52 93.6 4 Wenkel et al, 2000 Ph + protons 46* 83 17 76 59 53 100 at 5 and 88 at 10 16 years Vernimmen et al, protons 23* 65 35 23.3° 20,6* 38° 87 13 Weber et al., 2004 protons 16* 81 19 17.5 56 34.1 91.7 at 3 years 24 Noel et al, 2005 Ph + protons 51* 86 14 17 60.6 21 98 at 4 years 4 S, surgery; FSRT, stereotactic conformal radiotherapy; IMRT, intensive modulated radiotherapy; Ph, photons *series includes some intracranial meningiomas **series includes some atypical/malignant meningiomas ° mean and survival of 94% and 97%, respectively. A volume A clinical neurological improvement is reported in 14- reduction of more than 50% was observed in 14% of 44% of patients after FSRT [34,39,41,43]. A late signifi- patients. A recent up-date of 317 patients treated at the cant toxicity is reported in less than 5% of patients, same Institution showed, at a median follow-up of 5.7 including cranial deficits (leading especially to visual years, a 5-year and 10-year tumor control of 90.5% and problems), hypopituarism and impairment for neurocog- 89%, and respective survival of 95% and 90% [40]. nitive function (Table 2). However, the evaluation of Patients treated for recurrent meningioma showed a trend complications is often subjective and unsatisfactory, so toward decreased progression-free survival compared that well designed prospective studies are needed to better with patients treated with primary therapy after subtotal evaluate the true incidence of long-term side effects com- resection. Patients with a tumor volume more than 60 paring the different techniques. No cases of second tumor cm had a significant recurrence rate of 15.5% vs. 4.3% for after FSRT for meningiomas have been reported to date. those with a tumor volume of 60 cm or less (p < 0.001). On theoretical grounds, the reduction of the volume of Hamm et al [43] at a median follow-up of 36 months normal brain receiving high radiation doses using FSRT reported a 5-year tumor control and survival of 93% and may decrease the risk of radiation-induced tumors, how- 97% in 183 patients with large skull base meningiomas. A ever to demonstrate a change in the incidence of second partial imaging response occurred in 23% of patients, and brain tumors will require large series of patients with in the 95% of patients the neurological symptoms appropriate follow-up of 10-20 years. improved or remained stable. In a series of 27 patients with large recurrent benign skull base meningiomas (> 4 In summary, FSRT is an effective and safe treatment cm) treated at our Institution with FSRT between 2005 modality for local control of skull base meningiomas and and 2009 at a median dose of 50 Gy in 30 daily fractions tumor control is comparable to the reported results of the 2-year local control and survival were 100% [44]. other fractionated radiation techniques and SRS for Eight patients (29%) showed a tumor shrinkage more benign skull base meningiomas. FSRT offers a more local- than 25% during the follow-up. Although majority of the ized irradiation compared with conventional RT and the tumors treated had irregular shape and compressed the reported data from literature indicate that radiation optic chiasm, no visual deficits have been recorded during induced morbidity is quite low. Although longer follow- the follow-up. up is necessary to clearly demonstrate the potential reduc- Page 4 of 11 (page number not for citation purposes) Radiation Oncology 2009, 4:42 http://www.ro-journal.com/content/4/1/42 tion of long term complications in comparison with con- protons in younger patients Moreover, proton therapy can ventional RT, currently FSRT should be preferred for the be delivered as stereotactic radiosurgery or as fractionated radiation treatment of large skull base tumors, especially stereotactic radiotherapy with the same used immobiliza- those in close proximity to the optic apparatus. tion systems and target accuracy of photon techniques. Intensity modulated radiotherapy (IMRT) Tumor control after proton beam RT is shown in Table IMRT represents an advanced form of 3-D conformal 2[50-53]. Noel et al [53] reported on 51 patients with which has been recently employed for the treatment of skull base meningiomas treated between 1994 and 2002 different brain tumors, especially large tumors with irreg- with a combination of photon and proton RT at Institute ular shapes close to critical structures [45]. IMRT for men- Curie in Orsay. At a median follow-up of 25.4 months the ingiomas results in a more conformality and better target 4-year local control and overall survival rates were 98% coverage than CRT and therefore able to spare more radi- and 100%, respectively. Neurological improvement was osensitive brain structures [46]. IMRT uses a series of mul- reported in 69% of patients and stabilization in 31%. tiple subfields created by MLC which move under Wenkel et al [50] reported on 46 patients with partially computer control creating modulated fields. IMRT treat- resected or recurrent meningiomas treated between 198 ment plans are generated using inverse planning system, and 1996 with combined photon and proton beam ther- which uses computer optimization techniques to modu- apy at the Massachusetts General Hospital (MGH). At a late intensities across the target volume and sensitive nor- median follow-up of 53 months overall survival at 5 and mal structures, starting from a specified dose distribution. 10 years was 93 and 77%, respectively, and the recurrence- free rate at 5 and 10 years was 100% and 88%, respec- Few series are available on the use of IMRT in patients tively. Three patients had local tumor recurrence at 61, 95, with meningiomas (Table 2) [16,47-49]. Milker-Zabel et and 125 months. Seventeen percent of patients developed al [16] reported on 94 patients with complex-shaped severe long-term toxicity from RT, including ophthalmo- meningiomas treated with IMRT at University of Heidem- logic, neurologic, and otologic complications. At a berg between 1998 and 2004. At a median follow-up of median follow-up of 40 months a tumor control of 89% 4.4 years, the reported tumor local control was 93.6%. has been reported by Vernimmen et al [51] in in 27 Recurrence-free survival in patients with WHO Grade 1 patients with large skull base meningiomas (median vol- meningiomas was 97.5% at 3 years and 93.6% at 5 years, ume 43.7 cm ) treated with stereotactic proton beam ther- and overall survival was 97%. Sixty-nine patients had sta- apy. Permanent neurological deficits were reported in 3 ble disease based on CT/MRI, whereas 19 had a tumor patients. volume reduction, and 6 patients showed tumor progres- sion after IMRT. A neurological improvement was noted In summary, proton irradiation alone or in combination in about 40% of patients and a worsening of preexisting with photons is effective in controlling meningiomas, neurologic symptoms was seen in 4% of patients. No sec- with a tumor control and toxicity in the range of photon ondary malignancies were seen after IMRT, however this therapy. On the basis of the dosimetric advantages of pro- may simply be a reflection of the lack of adequate long- tons, including better conformality and reduction of inte- term follow-up. Similar results have been reported by oth- gral radiation dose to normal tissue, fractionated proton ers in some small series, with a reported local control of irradiation may be considered in patients with large and/ 93-97% at median follow-up of 19-36 months and low or complex-shaped meningiomas or younger patients, toxicity [47-49], suggesting that IMRT is a feasible treat- possibly limiting the long-term late effects of irradiation. ment modality for control of complex-shaped meningi- As more hospital-based proton treatment centers are oma. In summary, IMRT allows the delivery of a high dose becoming operational, prospective trials that assess the to such complex-shaped skull base tumors while sparing late toxicity of different radiation techniques are needed the surrounding radiosensitive structures, especially optic to confirm the expected reduction in long-term side effects chiasm and brainstem, although longer follow-up does with proton RT. needs to confirm the potential reduction of radiation- induced toxicity of IMRT in comparison with 3D confor- Stereotactic radiosurgery (SRS) mal RT in large skull base meningiomas. Since 1990, either Gamma Knife (GK) or Linear Accelera- tor (LINAC) have been extensively employed in the radi- Proton radiotherapy osurgical treatment of skull base meningiomas. A Proton irradiation can achieve better target-dose confor- summary of main recent published series of SRS in skull mality when compared to 3D-CRT and IMRT and the base meningiomas is shown in Table 3[36,37,39,54-84]. advantage becomes more apparent for large volumes. Dis- Differing from the earliest reports with short follow-ups, tribution of low and intermediate doses to portions of large recently published series report a more appropriate irradiated brain are significant lower with protons when 5-year and 10-year actuarial control rates. In a large series compared with photons and also could favor the use of of 972 patients mostly with skull base meningiomas, who Page 5 of 11 (page number not for citation purposes) Radiation Oncology 2009, 4:42 http://www.ro-journal.com/content/4/1/42 underwent Gamma GK SRS at the University of Pitts- base tumors that are - more than 3 cm; - in close proximity burgh, the reported actuarial tumor control rates were of the optic chiasm (less than 3-5 mm); compressing the 93% at 5 years and 87 at 10 and 15 years using a median brainstem and - with irregular margins. dose to the tumor margin of 13 Gy, with no differences between 384 patients who underwent postoperative SRS Radiosurgical doses between 12 and 18 Gy have been and 488 patients treated with primary SRS [18]. These used in the control of skull base meningiomas. Over the result confirm a previous study of 159 patients treated last years, SRS doses have been decreased with the aim to with GK SRS at the same Institution with a reported actu- minimize long-term toxicity while maintaining efficacy. arial tumor control rate for patients with typical meningi- Ganz et al [84] reported on 97 patients with meningiomas omas of about 93% at both 5 and 10 years [70]. Tumor with median volume of 15.9 cm treated with GK SRS volumes decreased in 3%, remained stable in 60%, and using a dose of 12 Gy. At A median follow-up of 54 increased in 6% of patients. Kreil et al [75] in 200 patients months the 2-year progression-free survival was 100%. with skull base meningiomas treated with GK SRS Twenty-seven were smaller and 72 unchanged in volume. reported a 5-year and 10-year local control of 98.5% and Three patients suffered adverse radiation effects. Overall, 97%, respectively, and similar results have been reported at median dose of 12-14 Gy the reported 5-year actuarial in some recent large series including more than 100 tumor control rate remains in the range of 90-95% as for patients [67,69,70,72,75,77,78,81,83]. Overall, eighteen higher doses [74,77,79-84]. studies including 2919 skull base meningiomas report a 5-year actuarial control of 91%; amongst them, 7 studies The rate of tumor shrinkage measured varied in all stud- including 1626 skull base meningiomas report a 10-year ies, ranging from 16% to 69% in the different series, and actuarial control of 87.6% (Table 3). Although in most tends to increase in patients with longer follow-up. Simi- series radiosurgical dose has been delivered using GK SRS, larly, a variable improvement of neurological functions a similar outcome has been reported with the use of has been shown in 10-60% of patients, however the eval- LINAC SRS. uation of neurological improvement is frequently retro- spective and the criteria used to evaluate the functional Only few studies have compared the outcome of SRS and improvement are subjective or not available in most FSRT in skull base meningiomas [36,37,39]. Metellus et al series. [39] found no differences in tumor control between 38 patients treated with fractionated RT and 36 patients Analysis of factors predicting local tumor control in most treated with SRS. Actuarial progression-free survival was series shows no significant differences between patients 94.7% in fractionated RT group and 94.4% in SRS group, underwent SRS as primary treatment and patients treated with permanent morbidity of 2.6% after FSRT and 0% for incomplete resected or recurrent meningioma. Age, after SRS. Torres et al [37] reported on 77 patients treated sex, site of meningioma, and neurological status did not with SRS and 51 patients treated with FSRT. Tumor con- affect significantly the outcome in most published series, trol was achieved in 90% of patients at a median follow- however larger meningiomas are associated with worse up of 40 months after SRS, and in 97% of patients at a long-term local control [18,72]. DiBiase et al [72] median follow-up of 24 months following FSRT. Late reported a significant higher 5-year tumor control in complications were recorded in 5% of patients treated patients with meningiomas < 10 ml than those with larger with SRS and 5.2% patients treated with FSRT. A similar 3- tumors (92% vs 68%, p = 0.038). In a recent series of 972 year local control of 94% has been reported by Lo et al patients with meningioma poorer local control was corre- [36] in 35 patients treated with SRS and in 18 patients lated with increasing volume (p = 0.01), and a similar with large tumors treated with FSRT. Permanent morbid- trend was observed with disease-specific survival (p = ity was 2.6% in SRS group and 0% in FSRT group. These 0.11) [18]. data suggests that either SRS or FSRT are safe and effective techniques in the treatment of skull base meningiomas, More recently the image-guided robotic radiosurgery sys- affording comparable satisfactory long-term tumor con- tem (Cyberknife) has been employed for frameless SRS in trol. The main differences between FSRT group and SRS patients with skull base meningiomas [85,86]. Patient group treated at the same Institution was the average position and motion are measured by two diagnostic x-ray diameter of meningiomas or the close proximity to sensi- cameras and communicated in real time to the robotic tive structures. Patients with tumors less than 3 cm and arm for beam targeting and patient motion tracking. more than 3-5 mm away from radiosensitive structures, Although patients are fixed in a thermoplastic mask, the such as optic chiasm or brainstem, were selected for SRS system achieves the same level of targeting precision as whereas FSRT was employed for all tumors that were not conventional frame-based RS. Colombo et al [86] in a amenable to SRS. In our Institution both stereotactic tech- series of 199 benign intracranial meningiomas (157 skull niques are available and the we recommend FSRT for skull base meningiomas) reported a 5-year control of 93.5%. Page 6 of 11 (page number not for citation purposes) Radiation Oncology 2009, 4:42 http://www.ro-journal.com/content/4/1/42 Table 3: Summary of results on main published studies on the radiosurgery of skull base meningiomas authors patients type S + RS RS tumor median follow-up local volume neurologi Toxicity % % volume dose median control reduction cal % median Gy (months) % (%) improve (ml) ment valentino et 72 LINAC 53 47 NA NA 44 93 69 50 6.7 al., 1993 Hudgins et 100* GK 91 9 14 15 NA 91 47 8 12 al., 1996 Kurita et al., 18 GK 83 17 NA 17 34.8 87.5 at 5 35 NA 49.9 1997 years Chang et al., 24 GK 66 34 6.8 17.7 45.6 100 37 42 33 Pan et al., 63 GK 54 46 NA NA 21 91 74 37.5 7.5 Morita et 88 GK 55 45 8.1 16 35 95 at 5 years 70 NA 14.8 al., 1999 Shafron et 50 LINAC 46 54 10 12.7 23 100 44 NA 3 al., 1999 Liscak et al., 67 GK 36 64 7.8 12 19 100 52 35.8 3.8 (1999) Aichholzer 46* GK 67 33 NA 15.9 48 97.5 52 33 13.2 et al., 2000 Roche et al., 80 GK 37 63 4.7 14 30.5 92.8 at 5 31 43 5 2000 years Villavicencio 56 LINAC 64 36 6 15 26 95 44 34 9 et al., 2001 Kobayashi 87 GK 56 44 NA 14 30° 89 at 7 years 23 48 13.8 et al., 2001 Shin et al., 40 GK 66 34 4.3 18 40 82.3 a 10 37 20 22.5 2001 years Stafford et 190* GK 59 41 8.2 16 47 93 at 5 years 56 8 13 al., 2001 Spiegelmann 42 LINAC 26 74 8.4 14 36 97.5 at 7 60 22 22.4 et al., 2002 years Nicolato et 111 GK 49 51 10 14.8 48.2 96 at 5 years 63 66 8 al., 2002 Lee et al., 155 GK 46 54 6.5 15 35 93 at 5 and 34 29 6.7 2002 10 years Lo et al., 35 LINAC 60 40 6.8 14 38 92.7 at 3 37.5 NA 6 2002 years Eustachio et 121 GK 49 51 6.8 13 82 97.8 60 44 6.7 al., 2002) Torres et 77* LINAC 65 35 12.7 15.6 40.6 92.1 35 35 5 al., 2003 DiBiase et 162 GK 38 62 4.5 14 54 86.2 at 5 28 NA 8.3 al., 2004 years Deinsberger 37 LINAC 22 78 5.9 14.6 66 97.2 32 NA 5.6 et al., 2004 Pollock et 49 GK 0 100 10.2 16 58 85 at 3 and 59 26 20 al., 2005 80 at 7 years Kreil et al., 200 GK 50.5 49.5 6.5 12 95 98.5 at 5 and 56.5 41 4.5 2005 97 at 10 years Zachenhofe 36 GK 70 30 NA 17 103 94 53 36 5 r et al., Kollova et 368 GK 30 70 4.4 12.5 60 98 at 5 years 69 62 15.9 al., 2007 Hasewaga 115 GK 57 43 14 13 62 87 at 5 and 51 46 12 et al., 2007 73 at 10 years Feigl et al., 214 GK 43 57 6.5° 13.6° 24° 86.3 at 4 74 19 6.7 2007 years Page 7 of 11 (page number not for citation purposes) Radiation Oncology 2009, 4:42 http://www.ro-journal.com/content/4/1/42 Table 3: Summary of results on main published studies on the radiosurgery of skull base meningiomas (Continued) Davidson et 36 GK 100 0 4.1 16 81 100 at 5 and 14 44 3 al., 2007 94.7 at 10 years Kondziolka 972* GK 49 51 7.4* 14° 48° 87 at 10 and 42 35 7.7 et al., 2008 15 years Iway et al., 108 GK NA NA 8.1 12 86.1 93 at 5 and 46 21 6 2008 83 at 10 years Han et al., 98 GK 36 64 6.3° 12.7 77° 90 at 5 years 44 45 16 Takanashi et 101 GK 24 76 7.1 13.2 52° 97% 44 45 0 al., 2009 Ganz et al., 97 GK NA NA 15.9° 12° 53° 100% at 2 31 NA 3 2009 years *series include skull base and intracranial meningiomas; °mean Tumors larger than 8 ml and/or situated close to critical of radiosurgical series. Other complications, as epilepsy, structures were treated with hypofractionated stereotactic internal carotid occlusion, and hypopituitarism have been RT (2 to 5 daily fractions). The tumor volume decreased rarely reported (less than 1-2%). in 36 patients, was unchanged in 148 patients, and increased in 7 patients. Clinical symptoms improved in The risk of clinically significant radiation optic neuropa- 30 patients. Tumor control in 63 patients with tumor vol- thy for patients receiving SRS for skull base meningiomas ume up 65 ml treated with hypofractionated RT was sim- is 1-2% following doses to optic chiasm below 10 Gy and ilar to that obtained in smaller meningiomas treated with this percentage may significantly increase for higher doses single fraction SRS. Neurological deterioration was [56,85,86]. Leber et al [92] reviewed 50 patients having observed in 4% of patients, represented mainly by visual SRS for benign skull base tumors in which the optic nerves deficits. Although the small numbers of fractions possible or chiasm were exposed to 4.5 Gy or more. For patients with the CyberKnife seems safer than SRS for large para- receiving 10 to 15 Gy and greater than 15 Gy, the risk of sellar meningiomas, further large series with appropriate radiation-induced optic neuropathy was 26.7% and follow-up should confirm the low risk of optic neuropa- 77.8%, respectively, however no optic neuropathy was thy in patients treated with hypofractionated regimens. observed when a dose less than 10 Gy was delivered to the Currently for large meningiomas close to the optic path- optic apparatus. Stafford et al [93] found that the risk of ways, in our opinion FSRT should be chosen based on its developing a clinically significant optic neuropathy was proven efficacy and safety. 1.1% for patients receiving a point maximum dose of 12 Gy or less, and similar results have been reported by oth- Complications of SRS are reported in 3 to 40% of cases ers [59]. Considering an effective dose of 13-16 Gy to (corrected mean 8%), being represented by either tran- achieve local control of a skull base meningioma and a sient (3.0%) or permanent complications (5.0%). recommended dose of 8 Gy as the maximum for the optic Although radionecrosis of the brain and delayed cranial chiasm, in clinical practice this means that a distance nerve deficits after SRS are of concern, the rate of signifi- between tumor margin and optic apparatus should be at cant complications at doses of 12-15 Gy as currently used least of 2-3 mm to avoid visual deterioration. In contrast in most centers is less than 6% (Table 3). Kondziolka et al motor cranial nerve deficits in the cavernous sinus rarely [18] reported a permanent neurological deficits of 9% at have been reported with doses less than 16 Gy. For men- 10 and 15 years in 972 patients treated with GK SRS for ingiomas involving the clivus and cerebellopontine angle intracranial meningiomas. The morbidity rate for cavern- the estimated tolerance dose for the brainstem is 15 Gy, ous sinus meningiomas was 6.3%, including visual dete- however facial nerve and acoustic injuries may occur at th rioration, 6 nerve palsy, and trigeminal neuropathy. In lower doses. the series of Nicolato et al [69] late complications occurred in 4.5% of patients, being transient in 80% of In summary, SRS may represents a convenient and safe them, and similar complication rates have been reported approach for patients with skull base meningiomas with a in all main published series (Table 3). Few cases of radia- tumor control at 5 and 10 years comparable to fraction- tion induced tumors, mainly glioblastoma, have been ated RT. Both SRS and FSRT are effective treatment reported in the literature [84,87-91], however the real options for benign skull base meningiomas and the incidence of second brain tumors cannot be clearly estab- choice of stereotactic technique is mainly based on the lished because of short follow-up reported in the majority characteristics of tumors. In most centers SRS is usually Page 8 of 11 (page number not for citation purposes) Radiation Oncology 2009, 4:42 http://www.ro-journal.com/content/4/1/42 3. Kallio M, Sankila R, Hakulinen T, Jääskeläinen J: Factors affecting reserved for tumors less than 3 cm away 3-5 mm from the operative and excess long-term mortality in 935 patients optic chiasm, whereas FSRT is employed for those tumors with intracranial meningioma. Neurosurgery 1992, 31:2-12. not amenable to SRS. The reported toxicity of SRS is low 4. DeMonte F, Smith HK, al-Mefty O: Outcome of aggressive removal of cavernous sinus meningiomas. 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Davidson L, Fishback D, Russin JJ, Weiss MH, Yu C, Pagnini PG, Zel- Publish with Bio Med Central and every man V, Apuzzo ML, Giannotta SL: Postoperative Gamma Knife scientist can read your work free of charge surgery for benign meningiomas of the cranial base. Neuro- surg Focus 2007, 23(4):E6. "BioMed Central will be the most significant development for 81. Iwai Y, Yamanaka K, Ikeda H: Gamma Knife radiosurgery for disseminating the results of biomedical researc h in our lifetime." skull base meningioma: long-term results of low-dose treat- Sir Paul Nurse, Cancer Research UK ment. J Neurosurg 2008, 109:804-810. 82. Han JH, Kim DG, Chung HT, Park CK, Paek SH, Kim CY, Jung HW: Your research papers will be: Gamma knife radiosurgery for skull base meningiomas: long- available free of charge to the entire biomedical community term radiologic and clinical outcome. Int J Radiat Oncol Biol Phys 2008, 72:1324-1332. peer reviewed and published immediately upon acceptance 83. Takanashi M, Fukuoka S, Hojyo A, Sasaki T, Nakagawara J, Nakamura cited in PubMed and archived on PubMed Central H: Gamma knife radiosurgery for skull-base meningiomas. Prog Neurol Surg 2009, 22:96-111. yours — you keep the copyright BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 11 of 11 (page number not for citation purposes)

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Radiation Oncology – Springer Journals

Published: Oct 14, 2009

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