10.1007/s11060-009-0084-1</TIT= LE> <META http-equiv=3DContent-Type content=3D"text/html; = charset=3DISO-8859-1"><LINK=20 href=3D"http://www.springerlink.com/config/css/A++_common.css" = type=3Dtext/css=20 rel=3DstyleSheet><LINK=20 href=3D"http://www.springerlink.com/config/css/content_A++_SpringerLink.c= ss"=20 type=3Dtext/css rel=3DstyleSheet> <META content=3D"MSHTML 6.00.6000.16945" name=3DGENERATOR></HEAD> <BODY class=3Dfor-print> <TABLE cellPadding=3D2 border=3D1> <TBODY> <TR class=3Dheader> <TD>Journal of Neuro-Oncology</TD></TR> <TR> <TD>=A9 Springer Science+Business Media, = LLC. 2009</TD></TR> <TR> <TD>10.1007/s11060-009-0084-1</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Clinical Study - Patient Study</H2> <DIV class=3DHeading1><A name=3Dtitle></A>Patterns of failure after = stereotactic=20 radiotherapy of intracranial meningioma </DIV> <P class=3DAuthorGroup>Vasileios Askoxylakis<SUP>1</SUP>,=20 Angelika Zabel-du Bois<SUP>1, 2</SUP>, = Wolfgang Schlegel<SUP>3</SUP>,=20 J=FCrgen Debus<SUP>1</SUP>, Peter Huber<SUP>2</SUP> and=20 Stefanie Milker-Zabel<SUP>1, 2 <A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#ContactOfAuthor6"><IMG=20 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/j08502831657163h/contact.gif" = border=3D0></A></SUP></P> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff1></A>(1) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Radiation Oncology and=20 Radiotherapy, University Hospital of Heidelberg, Im Neuenheimer = Feld 400,=20 69120 Heidelberg, Germany</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff2></A>(2) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Radiotherapy, German = Cancer=20 Research Center, Heidelberg, = Germany</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff3></A>(3) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Medical Physics, German = Cancer=20 Research Center, Heidelberg, = Germany</SPAN></TD></TR></TBODY></TABLE> <P><A name=3DContactOfAuthor6></A></P> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/j08502831657163h/contact.gif" = border=3D0></TD> = <TD><STRONG>Stefanie </STRONG><STRONG>Milker-Zabel</STRONG><STRONG><= /STRONG><BR><STRONG>Email:=20 </STRONG><A=20 = href=3D"mailto:stefanie_milker-zabel@med.uni-heidelberg.de">stefanie_milk= er-zabel@med.uni-heidelberg.de</A></TD></TR></TBODY></TABLE> <P class=3DAffiliation><STRONG>Received:=20 </STRONG>6 August 2009 <STRONG>Accepted:=20 </STRONG>30 November 2009 <STRONG>Published online: = </STRONG>13 December 2009 </P> <DIV class=3DAbstract><A name=3DAbs1></A><SPAN=20 class=3DAbstractHeading>Abstract </SPAN>The aim of this work = is to=20 evaluate patterns of failure in patients with recurrent meningioma after = stereotactic radiotherapy. Of 411 patients with intracranial meningioma = treated=20 with radiotherapy at our institution, 22 patients with local tumor = progression=20 diagnosed by magnetic resonance imaging (MRI) after radiotherapy (RT) = were=20 identified and further investigated. The histologic grade of the = meningiomas was=20 World Health Organization (WHO) grade I in 54.5%, WHO grade II = in=20 27.3%, and WHO grade III in 9.1% of cases. Fourteen patients had = received=20 fractionated stereotactic RT; five patients underwent = intensity-modulated RT.=20 The median total dose was 57.6 Gy at 1.8 Gy/fraction, five = times=20 weekly. Local recurrences were divided into the dosimetric categories = =93central=94=20 (=93in-field=94) and =93marginal=94 (=93out-field=94). Median follow-up = was=20 59.5 months. Eleven local failures were found to be central, and 11 = were=20 marginal. Recurrence-free survival (<I>P</I> < 0.05) and = site of=20 local recurrence (<I>P</I> < 0.05) depended statistically=20 significantly on histology. Median recurrence-free survival was = 46 months=20 for patients with benign meningioma (WHO grade I) and = 31.5 months for=20 patients with higher-grade meningioma (WHO grade II/III). In the = WHO=20 grade I group, three recurrences were central and nine were = marginal,=20 whereas in the WHO grade II/III group seven recurrences were = central and=20 one was marginal. Median time to local tumor progression and site of = local=20 recurrence significantly depended on histological grade of meningioma. = Regarding=20 site of failure, improvement of dose coverage for benign meningiomas and = dose=20 escalation for high-grade tumors might further improve therapy outcome. = </DIV> <P class=3DKeyword><SPAN=20 class=3DKeywordHeading>Keywords </SPAN>Intracranial=20 meningioma - Recurrence - Stereotactic radiotherapy = </P> <DIV class=3DFulltext> <DIV class=3D""><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Introduction</DIV> <P class=3D"">Meningiomas are the most common benign nonglial brain = tumors in=20 adults, arising from cap cells of the arachnoid membrane and = representing about=20 13=9626% of all primary brain tumors [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR1">1</A></CITE>].=20 Peak incidence is in the fifth, sixth, and seventh decades, with a = predominance=20 in women. The annual occurrence of the disease is estimated to = 1=965/100,000/year=20 for men and 2=967/100,000/year for women [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR2">2</A></CITE>].=20 Histologically they are classified into three grades according to the = World=20 Health Organization (WHO) classification of tumors of the nervous system = [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR3">3</A></CITE>].=20 Up to 85% of meningiomas are benign lesions of WHO grade I, = characterized=20 by slow growth and good prognosis after complete resection. About 10% = are=20 atypical lesions of WHO grade II, and 3=965% are anaplastic lesions = of WHO=20 grade III. Meningiomas of WHO grade II/III represent a more = aggressive=20 subgroup, characterized by rapid growth, higher risk of recurrence after = surgical resection, and shorter survival times. </P> <P class=3D"">The primary therapy of meningiomas is neurosurgical = resection.=20 Complete resection of the tumor, including resection of the dura mater = margins=20 and involved bone, is associated with high rates of cure. The 5-year=20 recurrence-free rate after complete resection is 95% for WHO = grade I=20 meningiomas, 30=9650% for WHO grade II meningiomas, and 38=9678% = for WHO=20 grade III meningiomas [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR4">4</A></CITE>].=20 However, complete resection of the tumor is not always possible, due to=20 proximity to surrounding critical structures, such as the optic nerves, = the=20 brainstem, as well as neurovascular structures such as the venous = plexus. Total=20 resectability rates vary between 20% and 90%, depending on the = localization and=20 size of the tumor [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR5">5</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR6">6</A></CITE>].=20 </P> <P class=3D"">Radiotherapy (RT) represents one of the main therapeutic = modalities=20 of meningioma. Although the role of this modality in treatment of = meningioma was=20 controversial for a long time, it is now considered standard for = atypical and=20 malignant meningioma after surgical intervention independent of the = resection=20 grade as well as in recurrent meningioma. In case of benign meningioma,=20 radiation therapy is used after incomplete resection or in case of tumor = progression. Evaluation of the long-term results of fractionated = stereotactic=20 radiotherapy of subtotally resected or unresectable WHO grade I=20 base-of-skull meningiomas revealed 5-year survival rates of up to 97% = and=20 10-year survival rates of up to 96%, with very low incidence of subacute = or late=20 side-effects, demonstrating the effectiveness of this treatment modality = [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR7">7</A></CITE>].=20 Within recent years, the development of advanced radiation therapy = strategies,=20 such as intensity-modulated radiotherapy (IMRT), has allowed the = application of=20 higher doses to the target volume, while sparing the surrounding = radiosensitive=20 healthy structures and minimizing side-effects [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR8">8</A></CITE>].=20 </P> <P class=3D"">Meningiomas that have recurred once tend to recur again at = shorter=20 intervals [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR9">9</A></CITE>].=20 After first recurrence the probability of 2- to 5-year progression-free = survival=20 is about 50% after neurosurgical retreatment, enhanced to about 80% when = followed by additional radiation therapy. However, although the = development of=20 therapy techniques has led to more effective treatment of the disease, = and the=20 progression-free survival rates of meningioma patients has been = evaluated=20 extensively, published data about characteristics of patient collectives = that=20 recurred after radiotherapy are scarce. Therefore, patients with = recurrent=20 meningioma after surgery and radiotherapy still represent a therapeutic=20 challenge. </P> <P class=3D"">The present article is an analysis of patterns of failure = after=20 stereotactic radiotherapy of intracranial meningioma of a large patient = cohort=20 treated at a single institution with modern radiotherapy techniques. Aim = of the=20 study was to investigate factors that may influence radiation outcome, = and=20 eventually optimize the treatment strategies to further improve the = efficacy of=20 the therapeutic modalities. </P></DIV> <DIV class=3D""><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Patients and methods</DIV> <DIV class=3DPara> <DIV class=3D"">Between October 1985 and December 2004, 411 patients = with=20 intracranial meningioma were treated with radiotherapy at our = institution. The=20 WHO grade distribution of the initial 411 patients is summarized in=20 Table <A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#Tab1">1</A>.=20 Of these, 28 patients (6.8%) who experienced local recurrence after = radiation=20 therapy [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR10">10</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR11">11</A></CITE>]=20 were identified and further investigated. Six cases were excluded from = this=20 analysis. In two cases the meningioma recurred after primary = radiotherapy as=20 well as after re-irradiation, which was considered as one case, = respectively. In=20 one patient the meningioma was initially described as progressive on MR = imaging;=20 however, in the mid-term follow-up after 3 months the meningioma = proved to=20 be stable in the long-term follow-up and was excluded from this study. = In=20 another patient the irradiated meningioma remained stable, while a = second=20 synchronous untreated meningioma showed local progression. Two patients = were=20 lost to follow-up, leaving 22 cases for evaluation. The male/female = ratio was=20 1:2.1 (7:15); median Karnofsky performance score was 80% (70=9690%). = Median age at=20 initiation of radiation therapy was 53.8 years (range=20 12.3=9675.1 years).<A name=3DTab1></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 1 </SPAN>WHO = grade=20 distribution of the initial 411 patients treated at our institution = </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dchar char=3D"."></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">Histologic grading</P></TH> <TH align=3Dleft char=3D"."> <P class=3D"">Frequency</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">WHO grade I</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">204</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">WHO grade II</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">35</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">WHO grade III</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">4</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Unknown</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">168</P></TD></TR></TBODY></TABLE></DIV></DIV> <P class=3D"">Twenty patients had histologically proven diagnosis of = meningioma.=20 In two cases the clinical and radiological characteristics of the tumor = were=20 consistent with the clinical diagnosis of meningioma. The most frequent=20 histology was WHO grade I (12 patients), followed by WHO = grade II (6=20 patients) and III (2 patients). Twenty patients received postoperative=20 radiotherapy, while in two patients primary radiotherapy after diagnosis = was=20 performed, due to inoperability of the meningioma. The number of = resections=20 before RT was variable. Thirteen patients had been operated once, six = underwent=20 two surgical interventions, and one patient underwent three = interventions. The=20 mean delay between last surgery and irradiation was 11.3 months = with a=20 median of 7.5 months (range 1=9658 months). </P> <P class=3D"">Of 19 patients treated after the year 1990, 14 received=20 fractionated, stereotactic radiation therapy (FSRT) and 5 were treated = with=20 intensity-modulated radiation therapy (IMRT). Three patients were = treated before=20 the year 1990 using other radiation techniques but also = three-dimensional=20 treatment planning. Two of them had electron radiation therapy and one = patient=20 was treated with a cobalt unit. The median dose for the entire = population was=20 57.6 Gy (range 44=9668 Gy) with a median daily fraction of = 1.8 Gy.=20 </P> <DIV class=3DPara> <DIV class=3D"">Patient characteristics and localization of all 22 = intracranial=20 meningiomas are summarized in Tables <A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#Tab2">2</A>=20 and <A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#Tab3">3</A>.<A=20 name=3DTab2></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 2 </SPAN>Patient=20 characteristics (<I>n</I> =3D 22) </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Sex (female/male)</P></TD> <TD align=3Dleft> <P class=3D"">15/7</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Median age (years)</P></TD> <TD align=3Dleft> <P class=3D"">53.8 (range 12.3=9675.1)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Median Karnofsky performance scale (%)</P></TD> <TD align=3Dleft> <P class=3D"">80 (range, 70=9690)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Median tumor volume (cc)</P></TD> <TD align=3Dleft> <P class=3D"">95 (range, 11.8=96457)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> <P class=3D"">Histologic grading</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> WHO grade I</P></TD> <TD align=3Dleft> <P class=3D"">12 (54.5%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> WHO grade II</P></TD> <TD align=3Dleft> <P class=3D"">6 (27.3%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> WHO grade III</P></TD> <TD align=3Dleft> <P class=3D"">2 (9.1%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Unknown</P></TD> <TD align=3Dleft> <P class=3D"">2 (9.1%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> <P class=3D"">Primary therapy</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Total resection</P></TD> <TD align=3Dleft> <P class=3D"">4 (18.2%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Subtotal resection</P></TD> <TD align=3Dleft> <P class=3D"">16 (72.7%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Primary radiotherapy</P></TD> <TD align=3Dleft> <P class=3D"">2 (9.1%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> <P class=3D"">Radiation technique</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> FSRT</P></TD> <TD align=3Dleft> <P class=3D"">14 (63.6%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> IMRT</P></TD> <TD align=3Dleft> <P class=3D"">5 (22.7%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> e<SUP>−</SUP> </P></TD> <TD align=3Dleft> <P class=3D"">2 (9.1%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Co-60</P></TD> <TD align=3Dleft> <P class=3D"">1 (4.6%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Median total dose (Gy)</P></TD> <TD align=3Dleft> <P class=3D"">57.6 (range 44=9668)</P></TD></TR></TBODY></TABLE><A = name=3DTab3></A> <DIV class=3DCapt><SPAN = class=3DCaptNr>Table 3 </SPAN>Localization of the=20 meningiomas, recurred after radiation therapy </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dchar char=3D"."> <COL align=3Dchar char=3D"."></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">Localization</P></TH> <TH align=3Dleft char=3D"."> <P class=3D"">Frequency</P></TH> <TH align=3Dleft char=3D"."> <P class=3D"">%</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Sphenoidal</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">5</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">22.7</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Petroclival</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">3</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">13.7</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Cavernous sinus</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">4</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">18.2</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Sellar</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">1</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">4.5</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Convexity</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">3</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">13.7</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Falx</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">1</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">4.5</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Cerebellar</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">1</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">4.5</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Frontobasal</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">2</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">9.1</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Multilocular</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">2</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">9.1</P></TD></TR></TBODY></TABLE></DIV></DIV> <P class=3D"">FSRT was performed as described elsewhere [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR12">12</A></CITE>]:=20 The patients were immobilized in an individual head-mask fixation system = made of=20 scotch-Cast<SUP>TM</SUP>, assuring a setup accuracy of 2 mm = [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR13">13</A></CITE>].=20 Treatment planning was based on computed tomography (CT) and MRI of the = head=20 under stereotactic guidance. In particular, treatment planning was = performed on=20 a three-dimensional CT data cube generated from continuous 3-mm CT scans = after=20 stereotactic fusion of MRI scans, obtained in treatment position. The = treatment=20 planning system Virtous/in-house developed by DKFZ (available as = Virtuoso;=20 Leibinger Co., Freiburg, Germany) has been used. The planning target = volume=20 (PTV) and organs at risk such as eyes, optic nerves, chiasm, and brain = stem were=20 delineated on each slice of the data cube. Irregular beam shaping was = achieved=20 by customized field shapes generated by beam eye-view (BEV) technique, = using a=20 multileaf collimator (leaf width: 5 mm at isocenter). A noncoplanar = field=20 arrangement with a median of four isocentric fields was used. FSRT was = delivered=20 with a 6/15-MV linear accelerator (Siemens AG, Erlangen, Germany). PTV = was=20 covered by the 90% isodose and included the macroscopic tumor visible on = CT/MRI=20 with a safety margin of 1=962 mm to healthy brain tissue, 3 mm = to=20 adjacent osseous structures, and 5 mm along the dura. = Intensity-modulated=20 radiotherapy (IMRT) was performed with a 6/15-MV linear accelerator = (Siemens AG,=20 Erlangen, Germany). Treatment plan was based on CT/MRI scans of the head = in an=20 individual scotch-Cast<SUP>TM</SUP> mask fixation. Treatment plan was = created=20 using the Konrad inverse treatment planning program (MRC Systems GmbH,=20 Heidelberg, Germany), developed at the German Cancer Research Center, = Heidelberg=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR14">14</A></CITE>].=20 For IMRT a median of seven beams were used. Radiation treatment was = performed=20 using a commercial integrated motorized multileaf collimator in a = =93step and=20 shoot=94 technique [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR15">15</A></CITE>].=20 </P> <P class=3D"">Follow-up was performed at 6 weeks, 3 months,=20 6 months, and 12 months for the first year and then once a = year.=20 Follow-up included radiologic imaging (MRI) and clinical and = neurological=20 examinations. Inclusion criterion for this study was radiologically = proven local=20 recurrence, defined as local tumor progression on MRI. </P> <P class=3D"">In order to evaluate the site of local failure, recurrent = events=20 were divided into two dosimetric categories: those within the region = that=20 received at least 90% of the prescribed dose (high-dose region) were = considered=20 =93central=94 or =93in-field,=94 and those in regions that received less = than 90% of the=20 prescribed dose (low-dose regions) were considered =93marginal=94 or = =93out-field.=94=20 </P> <P class=3D"">For evaluation of the influence of histological grading on = recurrence localization and recurrence-free survival, subanalysis was = carried=20 out for patients with benign meningioma (WHO grade I) versus = patients with=20 higher-grade disease (WHO grade II/III). Statistical analysis was = performed=20 with the Fisher exact test for localization of local recurrence and = Shapiro-Wilk=20 normality test for recurrence-free survival. Results were considered = significant=20 for <I>P</I> value <0.05. </P></DIV> <DIV class=3D""><A name=3DSec3></A> <HR> <DIV class=3Dheading2>Results</DIV> <P class=3D"">Median follow-up was 59.5 months (range = 16=96161 months).=20 All patients were followed for more than 12 months, 17/22 (77.3%) = patients=20 for more than 36 months, 15/22 (68.2%) patients for more than=20 48 months, and 11/22 (50%) patients for more than 60 months. = The=20 median PTV was 95 cm<SUP>3</SUP> (range = 11.8=96457 cm<SUP>3</SUP>). </P> <DIV class=3DPara> <DIV class=3D"">The median time to recurrence after radiation therapy = was=20 46 months for the entire population (range 11=96132 months). = One-, 2-,=20 3-, 4-, and 5-year local control rates for the entire group of patients = were=20 95.5%, 81.8%, 63.6%, 50%, and 27.3%, respectively (Fig. <A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#Fig1">1</A>).=20 <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2009_84_Fig1_HTML.gif=20 src=3D"http://www.springerlink.com/content/j08502831657163h/MediaObjects/= 11060_2009_84_Fig1_HTML.gif"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 1 </SPAN>Recurrence-free=20 survival calculated from time of radiotherapy according to = Kaplan=96Meier method=20 </DIV> <HR> </DIV></DIV> <P class=3D"">Evaluation of the local recurrence events revealed 11 = events as=20 central or in-field, while 11 events were found to be marginal or = out-field.=20 </P> <P class=3D"">The median PTV for patients with WHO grade I = meningioma was=20 86.3 cm<SUP>3</SUP> and for patients with WHO grade II or III=20 meningiomas was 152.4 cm<SUP>3</SUP>. The recurrence-free survival = rate=20 after radiation therapy for benign WHO grade I intracranial = meningiomas was=20 66.7% at 3 years and 25% at 5 years. Patients with WHO = grade II=20 or III meningioma had a recurrence-free survival rate after radiotherapy = of 50%=20 at 3 years and 25% at 5 years. The median time to recurrence = after=20 radiotherapy was 46 months (range 11=96128 months) for = patients with WHO=20 grade I meningioma and 31.5 months (range 14=9675 months) = for=20 patients with WHO grade II or III meningioma=20 (<I>P</I> > 0.05). </P> <DIV class=3DPara> <DIV class=3D"">Differences were revealed in regard to the site of local = recurrence between the two subgroups. In particular, among 12 patients = with WHO=20 grade I meningioma, 9 recurrences were found to be marginal or = out-field=20 (75%) and 3 recurrences were found to be central or in-field (25%). = Among eight=20 patients with WHO grade II or III intracranial meningioma who = recurred=20 after radiation therapy, seven recurrences were identified as central or = in-field (87.5%) and one recurrence was identified as marginal or = out-field=20 (12.5%) (Table <A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#Tab4">4</A>).=20 The correlation between WHO grade and localization of the local = recurrence was=20 statistically significant (<I>P</I> < 0.05).<A = name=3DTab4></A> <DIV class=3DCapt><SPAN = class=3DCaptNr>Table 4 </SPAN>Recurrence site in=20 patients with intracranial meningioma after radiotherapy=20 (<I>n</I> =3D 22) </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dchar char=3D"("> <COL align=3Dchar char=3D"("></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">Histological grading</P></TH> <TH align=3Dleft char=3D"("> <P class=3D"">In-field</P></TH> <TH align=3Dleft char=3D"("> <P class=3D"">Out-field</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">WHO grade I</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">3 (25%)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">9 (75%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">WHO grade II or III</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">7 (87.5%)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">1 (12.5%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Unknown</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">1 (50%)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">1 (50%)</P></TD></TR></TBODY></TABLE></DIV></DIV> <P class=3D"">Two patients with intracranial meningioma WHO grade I = received=20 re-irradiation after local failure. One of them showed a re-recurrence = event=20 32 months after retreatment. Within the collective of patients with = WHO=20 grade II or III meningiomas, three received re-irradiation = treatment after=20 diagnosis of local recurrence. In two cases a re-recurrence event = occurred, with=20 mean re-recurrence-free survival calculated to be 23.5 months. </P> <P class=3D"">In regard to overall survival, four patients died, a = median of=20 6.9 years (range 3.4=9610.4 years) after radiation therapy. In = two cases=20 cause of death was progressive heart disease. Only one patient died of=20 progressive primary disease, while the fourth patient died of other = causes.=20 </P></DIV> <DIV class=3D""><A name=3DSec4></A> <HR> <DIV class=3Dheading2>Discussion</DIV> <P class=3D"">Radiation therapy is one of the main therapeutic = modalities for=20 treatment of intracranial meningiomas. Since it is possible to treat = meningiomas=20 effectively with highly conformal radiotherapeutic techniques, only a = few local=20 failures were reported. Evaluation of the results of radiotherapy in = large=20 collectives of patients with intracranial meningiomas revealed very good = long-term tumor control and low local recurrence rates. Vendrely = et al.=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR16">16</A></CITE>]=20 evaluated the results of fractionated radiation therapy on a collective = of 156=20 patients with intracranial meningiomas and described a recurrence rate = of 13.5%=20 and a local control rate of 79.4% after median follow-up of = 40 months. In=20 another retrospective study of 82 patients with benign skull-base = meningioma=20 treated by fractionated external-beam radiation after surgery, Nutting=20 et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR17">17</A></CITE>]=20 described 5- and 10-year progression-free survival rates of 92% and 83%, = respectively. Evaluation by Hamm et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR18">18</A></CITE>]=20 of the results of stereotactically guided radiation techniques in a = collective=20 of 224 patients with skull-base meningiomas revealed overall survival = and=20 progression-free survival rates at 5 years of 92.9% and 96.9%,=20 respectively. </P> <P class=3D"">In order to analyze the long-term results of fractionated=20 stereotactic radiation therapy in patients with benign or atypical = intracranial=20 meningioma, a retrospective investigation of 317 patients was performed = in our=20 department in the past [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR10">10</A></CITE>].=20 This study revealed a local tumor control rate of 93.1% after median = follow-up=20 of 5.7 years, with radiological local tumor progression rate of = 6.9%.=20 Within this study the influence of potential prognostic factors on local = control=20 was investigated, revealing that histologic grade of the meningioma and = volume=20 of the tumor had a statistically significant influence on therapy = outcome. Local=20 tumor failure was significant higher in patients with WHO grade II=20 meningioma (<I>P</I> < 0.002) than in patients with unknown = histology or patients with WHO grade I meningioma. Patients with = tumor=20 volume greater than 60 cc showed a recurrence rate of 15.5% versus = 4.3% in=20 patients with tumor volume less than 60 cc = (<I>P</I> < 0.001).=20 </P> <P class=3D"">However, although various studies have investigated the = survival and=20 local control rates of radiotherapy for intracranial meningioma, there = are no=20 published data regarding the site of local recurrence with respect to = the exact=20 dose distribution of the applied treatment plan. </P> <P class=3D"">In this study we further analyzed the results of 22 of 411 = patients=20 treated with stereotactic radiation therapy for intracranial meningiomas = who=20 showed local tumor progression on MRI. Aim of the study was to = investigate the=20 parameters that negatively influence the outcome of the therapy. We = focused=20 especially on identification of the site of local recurrence with = respect to the=20 dose distribution. </P> <P class=3D"">The target volume was found in previous studies to be = important for=20 therapy outcome. A statistically significant correlation between tumor = volume=20 and relapse after FSRT has been observed. The recurrence rate for = patients with=20 tumor volume >60 cm<SUP>3</SUP> was 15.5% versus 4.3% for = patients with=20 tumor volume <60 cm<SUP>3</SUP> = (<I>P</I> < 0.001)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR10">10</A></CITE>].=20 The hypothesis of the significance of target volume for therapy outcome = is=20 strengthened by the results of our analysis. The median PTV of the = patients who=20 showed a recurrence after radiotherapy was 95 cm<SUP>3</SUP>. = Compared with=20 results of previous studies in the literature, the median target volume = of the=20 recurrent patients in our study is larger. This correlation can find = several=20 explanations: high tumor volume is associated with higher cell density = and=20 therefore enhanced probability of hypoxic tumor regions, which is found = to be=20 one of the most important reasons for therapy resistance [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR19">19</A></CITE>].=20 Furthermore, tumors with high volume have greater possibility to have = closer=20 proximity to critical anatomical structures, such as the optic nerve or = brain=20 stem, which is a limiting factor for optimal dose distribution. </P> <P class=3D"">The influence of the dose distribution on therapy outcome = was shown=20 by studies on radiation therapy techniques with advanced dose = distribution, such=20 as IMRT. A previous investigation of IMRT for complex-shaped meningioma = of the=20 skull base revealed a recurrence rate of 6.1% after median follow-up of=20 4.4 years; the median target volume was 81.4 cm<SUP>3</SUP> = and the=20 median total dose was 57.6 Gy [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR11">11</A></CITE>].=20 Subanalysis of the results for patients treated with FSRT with the same = median=20 total dose after median follow-up of 5.7 years revealed a = recurrence rate=20 of 15.5% for tumors with volume >60 cm<SUP>3</SUP> [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR10">10</A></CITE>].=20 The higher recurrence rate in the group of patients treated by FSRT = could be=20 explained by the longer median follow-up, but it could also be explained = by=20 optimized dose homogeneity achieved by IMRT. </P> <P class=3D"">One of the most important prognostic factors for = intracranial=20 meningioma was found to be the histological grading of the disease. In = order to=20 better understand the correlation between histological grade and local = control=20 we performed subanalysis of our results separately for patients with = benign=20 meningioma (WHO grade I) and higher-grade meningioma (WHO = grade II or=20 III). This analysis revealed a statistically significant influence of = the=20 histological features of the tumor on recurrence site (in-field versus=20 out-field) and therefore on the mechanism of recurrence. WHO = grade I tumors=20 recurred more often at the margin, while WHO grade II or III tumors = recurred more often centrally. A possible explanation for this result is = that,=20 for WHO grade I tumors, it was dose homogeneity coverage that = influenced=20 the outcome of the therapy more, while for atypical or anaplastic = meningiomas=20 the prescribed dose level seemed to be insufficient. The median = recurrence-free=20 survival for patients with WHO grade I meningioma that recurred = after RT=20 only exhibited a trend to be higher than that for WHO grade II or = III=20 patients (46 versus 31.5 months). </P></DIV> <DIV class=3D""><A name=3DSec5></A> <HR> <DIV class=3Dheading2>Conclusions</DIV> <P class=3D"">High-precision radiation therapy offers the possibility of = an=20 effective local treatment modality in meningiomas. Due to the = effectiveness of=20 stereotactic radiotherapy in patients with intracranial meningiomas, = only a few=20 patients with recurrent disease (22/411 patients) could be analyzed in = this=20 evaluation regarding the question of topography of local recurrences = after=20 radiotherapy. However, these data based on a large cohort from a single=20 institution show that median time to local recurrence and site of local=20 recurrence significantly depend on histological grading of meningioma.=20 Recurrences in WHO grade I meningioma are rare; only 14 of all 365 = patients=20 (3.8%) with grade I meningioma or unknown histology treated at our=20 institution were recurrences. Recurrences in high-grade meningioma are = more=20 common after radiotherapy, occurring in 8 out of 46 treated patients = having=20 high-grade meningioma (17.4%). In WHO grade I meningioma most local = recurrences were found to be marginal, while high-grade (grade II = and III)=20 meningioma more often recurred centrally. Although the number of = recurrences=20 after radiotherapy is relatively small, the aim of all therapeutic = interventions=20 is to reduce recurrences after therapy during follow-up. Therefore, dose = escalation in patients with high-grade tumors may be useful. Further=20 improvements may be achieved with the use of particle therapy and = optimized=20 target volume definition by the use of molecular imaging such as = positron=20 emission tomography (PET). </P></DIV> <DIV class=3DAcknowledgments> <DIV class=3DFormalPara> <DIV class=3D""><SPAN style=3D"FONT-STYLE: italic; TEXT-DECORATION: = none">Conflict=20 of interest statement</SPAN> All authors disclose any = financial and=20 personal relationships with other people or organisations that could=20 inappropriately influence (bias) their work. </DIV></DIV></DIV> <P></P> <HR> <H2><A name=3DBib1></A>References </H2> <TABLE> <TBODY class=3DCitation> <TR vAlign=3Dtop> <TD>1.</TD> <TD><A name=3DCR1></A>Marosi C, Hassler M, Roessler K, Reni M, Sant = M, Mazza=20 E, Vecht C (2008) Meningioma. 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From: Subject: 10.1007/s11060-009-0084-1 Date: Fri, 25 Dec 2009 05:28:10 +0100 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01CA8523.0BFFE630" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01CA8523.0BFFE630 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.springerlink.com/content/j08502831657163h/fulltext.html 10.1007/s11060-009-0084-1</TIT= LE> <META http-equiv=3DContent-Type content=3D"text/html; = charset=3DISO-8859-1"><LINK=20 href=3D"http://www.springerlink.com/config/css/A++_common.css" = type=3Dtext/css=20 rel=3DstyleSheet><LINK=20 href=3D"http://www.springerlink.com/config/css/content_A++_SpringerLink.c= ss"=20 type=3Dtext/css rel=3DstyleSheet> <META content=3D"MSHTML 6.00.6000.16945" name=3DGENERATOR></HEAD> <BODY class=3Dfor-print> <TABLE cellPadding=3D2 border=3D1> <TBODY> <TR class=3Dheader> <TD>Journal of Neuro-Oncology</TD></TR> <TR> <TD>=A9 Springer Science+Business Media, = LLC. 2009</TD></TR> <TR> <TD>10.1007/s11060-009-0084-1</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Clinical Study - Patient Study</H2> <DIV class=3DHeading1><A name=3Dtitle></A>Patterns of failure after = stereotactic=20 radiotherapy of intracranial meningioma </DIV> <P class=3DAuthorGroup>Vasileios Askoxylakis<SUP>1</SUP>,=20 Angelika Zabel-du Bois<SUP>1, 2</SUP>, = Wolfgang Schlegel<SUP>3</SUP>,=20 J=FCrgen Debus<SUP>1</SUP>, Peter Huber<SUP>2</SUP> and=20 Stefanie Milker-Zabel<SUP>1, 2 <A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#ContactOfAuthor6"><IMG=20 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/j08502831657163h/contact.gif" = border=3D0></A></SUP></P> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff1></A>(1) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Radiation Oncology and=20 Radiotherapy, University Hospital of Heidelberg, Im Neuenheimer = Feld 400,=20 69120 Heidelberg, Germany</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff2></A>(2) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Radiotherapy, German = Cancer=20 Research Center, Heidelberg, = Germany</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff3></A>(3) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Medical Physics, German = Cancer=20 Research Center, Heidelberg, = Germany</SPAN></TD></TR></TBODY></TABLE> <P><A name=3DContactOfAuthor6></A></P> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/j08502831657163h/contact.gif" = border=3D0></TD> = <TD><STRONG>Stefanie </STRONG><STRONG>Milker-Zabel</STRONG><STRONG><= /STRONG><BR><STRONG>Email:=20 </STRONG><A=20 = href=3D"mailto:stefanie_milker-zabel@med.uni-heidelberg.de">stefanie_milk= er-zabel@med.uni-heidelberg.de</A></TD></TR></TBODY></TABLE> <P class=3DAffiliation><STRONG>Received:=20 </STRONG>6 August 2009 <STRONG>Accepted:=20 </STRONG>30 November 2009 <STRONG>Published online: = </STRONG>13 December 2009 </P> <DIV class=3DAbstract><A name=3DAbs1></A><SPAN=20 class=3DAbstractHeading>Abstract </SPAN>The aim of this work = is to=20 evaluate patterns of failure in patients with recurrent meningioma after = stereotactic radiotherapy. Of 411 patients with intracranial meningioma = treated=20 with radiotherapy at our institution, 22 patients with local tumor = progression=20 diagnosed by magnetic resonance imaging (MRI) after radiotherapy (RT) = were=20 identified and further investigated. The histologic grade of the = meningiomas was=20 World Health Organization (WHO) grade I in 54.5%, WHO grade II = in=20 27.3%, and WHO grade III in 9.1% of cases. Fourteen patients had = received=20 fractionated stereotactic RT; five patients underwent = intensity-modulated RT.=20 The median total dose was 57.6 Gy at 1.8 Gy/fraction, five = times=20 weekly. Local recurrences were divided into the dosimetric categories = =93central=94=20 (=93in-field=94) and =93marginal=94 (=93out-field=94). Median follow-up = was=20 59.5 months. Eleven local failures were found to be central, and 11 = were=20 marginal. Recurrence-free survival (<I>P</I> < 0.05) and = site of=20 local recurrence (<I>P</I> < 0.05) depended statistically=20 significantly on histology. Median recurrence-free survival was = 46 months=20 for patients with benign meningioma (WHO grade I) and = 31.5 months for=20 patients with higher-grade meningioma (WHO grade II/III). In the = WHO=20 grade I group, three recurrences were central and nine were = marginal,=20 whereas in the WHO grade II/III group seven recurrences were = central and=20 one was marginal. Median time to local tumor progression and site of = local=20 recurrence significantly depended on histological grade of meningioma. = Regarding=20 site of failure, improvement of dose coverage for benign meningiomas and = dose=20 escalation for high-grade tumors might further improve therapy outcome. = </DIV> <P class=3DKeyword><SPAN=20 class=3DKeywordHeading>Keywords </SPAN>Intracranial=20 meningioma - Recurrence - Stereotactic radiotherapy = </P> <DIV class=3DFulltext> <DIV class=3D""><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Introduction</DIV> <P class=3D"">Meningiomas are the most common benign nonglial brain = tumors in=20 adults, arising from cap cells of the arachnoid membrane and = representing about=20 13=9626% of all primary brain tumors [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR1">1</A></CITE>].=20 Peak incidence is in the fifth, sixth, and seventh decades, with a = predominance=20 in women. The annual occurrence of the disease is estimated to = 1=965/100,000/year=20 for men and 2=967/100,000/year for women [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR2">2</A></CITE>].=20 Histologically they are classified into three grades according to the = World=20 Health Organization (WHO) classification of tumors of the nervous system = [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR3">3</A></CITE>].=20 Up to 85% of meningiomas are benign lesions of WHO grade I, = characterized=20 by slow growth and good prognosis after complete resection. About 10% = are=20 atypical lesions of WHO grade II, and 3=965% are anaplastic lesions = of WHO=20 grade III. Meningiomas of WHO grade II/III represent a more = aggressive=20 subgroup, characterized by rapid growth, higher risk of recurrence after = surgical resection, and shorter survival times. </P> <P class=3D"">The primary therapy of meningiomas is neurosurgical = resection.=20 Complete resection of the tumor, including resection of the dura mater = margins=20 and involved bone, is associated with high rates of cure. The 5-year=20 recurrence-free rate after complete resection is 95% for WHO = grade I=20 meningiomas, 30=9650% for WHO grade II meningiomas, and 38=9678% = for WHO=20 grade III meningiomas [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR4">4</A></CITE>].=20 However, complete resection of the tumor is not always possible, due to=20 proximity to surrounding critical structures, such as the optic nerves, = the=20 brainstem, as well as neurovascular structures such as the venous = plexus. Total=20 resectability rates vary between 20% and 90%, depending on the = localization and=20 size of the tumor [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR5">5</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR6">6</A></CITE>].=20 </P> <P class=3D"">Radiotherapy (RT) represents one of the main therapeutic = modalities=20 of meningioma. Although the role of this modality in treatment of = meningioma was=20 controversial for a long time, it is now considered standard for = atypical and=20 malignant meningioma after surgical intervention independent of the = resection=20 grade as well as in recurrent meningioma. In case of benign meningioma,=20 radiation therapy is used after incomplete resection or in case of tumor = progression. Evaluation of the long-term results of fractionated = stereotactic=20 radiotherapy of subtotally resected or unresectable WHO grade I=20 base-of-skull meningiomas revealed 5-year survival rates of up to 97% = and=20 10-year survival rates of up to 96%, with very low incidence of subacute = or late=20 side-effects, demonstrating the effectiveness of this treatment modality = [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR7">7</A></CITE>].=20 Within recent years, the development of advanced radiation therapy = strategies,=20 such as intensity-modulated radiotherapy (IMRT), has allowed the = application of=20 higher doses to the target volume, while sparing the surrounding = radiosensitive=20 healthy structures and minimizing side-effects [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR8">8</A></CITE>].=20 </P> <P class=3D"">Meningiomas that have recurred once tend to recur again at = shorter=20 intervals [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR9">9</A></CITE>].=20 After first recurrence the probability of 2- to 5-year progression-free = survival=20 is about 50% after neurosurgical retreatment, enhanced to about 80% when = followed by additional radiation therapy. However, although the = development of=20 therapy techniques has led to more effective treatment of the disease, = and the=20 progression-free survival rates of meningioma patients has been = evaluated=20 extensively, published data about characteristics of patient collectives = that=20 recurred after radiotherapy are scarce. Therefore, patients with = recurrent=20 meningioma after surgery and radiotherapy still represent a therapeutic=20 challenge. </P> <P class=3D"">The present article is an analysis of patterns of failure = after=20 stereotactic radiotherapy of intracranial meningioma of a large patient = cohort=20 treated at a single institution with modern radiotherapy techniques. Aim = of the=20 study was to investigate factors that may influence radiation outcome, = and=20 eventually optimize the treatment strategies to further improve the = efficacy of=20 the therapeutic modalities. </P></DIV> <DIV class=3D""><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Patients and methods</DIV> <DIV class=3DPara> <DIV class=3D"">Between October 1985 and December 2004, 411 patients = with=20 intracranial meningioma were treated with radiotherapy at our = institution. The=20 WHO grade distribution of the initial 411 patients is summarized in=20 Table <A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#Tab1">1</A>.=20 Of these, 28 patients (6.8%) who experienced local recurrence after = radiation=20 therapy [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR10">10</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR11">11</A></CITE>]=20 were identified and further investigated. Six cases were excluded from = this=20 analysis. In two cases the meningioma recurred after primary = radiotherapy as=20 well as after re-irradiation, which was considered as one case, = respectively. In=20 one patient the meningioma was initially described as progressive on MR = imaging;=20 however, in the mid-term follow-up after 3 months the meningioma = proved to=20 be stable in the long-term follow-up and was excluded from this study. = In=20 another patient the irradiated meningioma remained stable, while a = second=20 synchronous untreated meningioma showed local progression. Two patients = were=20 lost to follow-up, leaving 22 cases for evaluation. The male/female = ratio was=20 1:2.1 (7:15); median Karnofsky performance score was 80% (70=9690%). = Median age at=20 initiation of radiation therapy was 53.8 years (range=20 12.3=9675.1 years).<A name=3DTab1></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 1 </SPAN>WHO = grade=20 distribution of the initial 411 patients treated at our institution = </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dchar char=3D"."></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">Histologic grading</P></TH> <TH align=3Dleft char=3D"."> <P class=3D"">Frequency</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">WHO grade I</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">204</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">WHO grade II</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">35</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">WHO grade III</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">4</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Unknown</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">168</P></TD></TR></TBODY></TABLE></DIV></DIV> <P class=3D"">Twenty patients had histologically proven diagnosis of = meningioma.=20 In two cases the clinical and radiological characteristics of the tumor = were=20 consistent with the clinical diagnosis of meningioma. The most frequent=20 histology was WHO grade I (12 patients), followed by WHO = grade II (6=20 patients) and III (2 patients). Twenty patients received postoperative=20 radiotherapy, while in two patients primary radiotherapy after diagnosis = was=20 performed, due to inoperability of the meningioma. The number of = resections=20 before RT was variable. Thirteen patients had been operated once, six = underwent=20 two surgical interventions, and one patient underwent three = interventions. The=20 mean delay between last surgery and irradiation was 11.3 months = with a=20 median of 7.5 months (range 1=9658 months). </P> <P class=3D"">Of 19 patients treated after the year 1990, 14 received=20 fractionated, stereotactic radiation therapy (FSRT) and 5 were treated = with=20 intensity-modulated radiation therapy (IMRT). Three patients were = treated before=20 the year 1990 using other radiation techniques but also = three-dimensional=20 treatment planning. Two of them had electron radiation therapy and one = patient=20 was treated with a cobalt unit. The median dose for the entire = population was=20 57.6 Gy (range 44=9668 Gy) with a median daily fraction of = 1.8 Gy.=20 </P> <DIV class=3DPara> <DIV class=3D"">Patient characteristics and localization of all 22 = intracranial=20 meningiomas are summarized in Tables <A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#Tab2">2</A>=20 and <A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#Tab3">3</A>.<A=20 name=3DTab2></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 2 </SPAN>Patient=20 characteristics (<I>n</I> =3D 22) </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Sex (female/male)</P></TD> <TD align=3Dleft> <P class=3D"">15/7</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Median age (years)</P></TD> <TD align=3Dleft> <P class=3D"">53.8 (range 12.3=9675.1)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Median Karnofsky performance scale (%)</P></TD> <TD align=3Dleft> <P class=3D"">80 (range, 70=9690)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Median tumor volume (cc)</P></TD> <TD align=3Dleft> <P class=3D"">95 (range, 11.8=96457)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> <P class=3D"">Histologic grading</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> WHO grade I</P></TD> <TD align=3Dleft> <P class=3D"">12 (54.5%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> WHO grade II</P></TD> <TD align=3Dleft> <P class=3D"">6 (27.3%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> WHO grade III</P></TD> <TD align=3Dleft> <P class=3D"">2 (9.1%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Unknown</P></TD> <TD align=3Dleft> <P class=3D"">2 (9.1%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> <P class=3D"">Primary therapy</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Total resection</P></TD> <TD align=3Dleft> <P class=3D"">4 (18.2%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Subtotal resection</P></TD> <TD align=3Dleft> <P class=3D"">16 (72.7%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Primary radiotherapy</P></TD> <TD align=3Dleft> <P class=3D"">2 (9.1%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> <P class=3D"">Radiation technique</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> FSRT</P></TD> <TD align=3Dleft> <P class=3D"">14 (63.6%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> IMRT</P></TD> <TD align=3Dleft> <P class=3D"">5 (22.7%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> e<SUP>−</SUP> </P></TD> <TD align=3Dleft> <P class=3D"">2 (9.1%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Co-60</P></TD> <TD align=3Dleft> <P class=3D"">1 (4.6%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Median total dose (Gy)</P></TD> <TD align=3Dleft> <P class=3D"">57.6 (range 44=9668)</P></TD></TR></TBODY></TABLE><A = name=3DTab3></A> <DIV class=3DCapt><SPAN = class=3DCaptNr>Table 3 </SPAN>Localization of the=20 meningiomas, recurred after radiation therapy </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dchar char=3D"."> <COL align=3Dchar char=3D"."></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">Localization</P></TH> <TH align=3Dleft char=3D"."> <P class=3D"">Frequency</P></TH> <TH align=3Dleft char=3D"."> <P class=3D"">%</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Sphenoidal</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">5</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">22.7</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Petroclival</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">3</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">13.7</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Cavernous sinus</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">4</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">18.2</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Sellar</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">1</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">4.5</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Convexity</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">3</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">13.7</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Falx</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">1</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">4.5</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Cerebellar</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">1</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">4.5</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Frontobasal</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">2</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">9.1</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Multilocular</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">2</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">9.1</P></TD></TR></TBODY></TABLE></DIV></DIV> <P class=3D"">FSRT was performed as described elsewhere [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR12">12</A></CITE>]:=20 The patients were immobilized in an individual head-mask fixation system = made of=20 scotch-Cast<SUP>TM</SUP>, assuring a setup accuracy of 2 mm = [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR13">13</A></CITE>].=20 Treatment planning was based on computed tomography (CT) and MRI of the = head=20 under stereotactic guidance. In particular, treatment planning was = performed on=20 a three-dimensional CT data cube generated from continuous 3-mm CT scans = after=20 stereotactic fusion of MRI scans, obtained in treatment position. The = treatment=20 planning system Virtous/in-house developed by DKFZ (available as = Virtuoso;=20 Leibinger Co., Freiburg, Germany) has been used. The planning target = volume=20 (PTV) and organs at risk such as eyes, optic nerves, chiasm, and brain = stem were=20 delineated on each slice of the data cube. Irregular beam shaping was = achieved=20 by customized field shapes generated by beam eye-view (BEV) technique, = using a=20 multileaf collimator (leaf width: 5 mm at isocenter). A noncoplanar = field=20 arrangement with a median of four isocentric fields was used. FSRT was = delivered=20 with a 6/15-MV linear accelerator (Siemens AG, Erlangen, Germany). PTV = was=20 covered by the 90% isodose and included the macroscopic tumor visible on = CT/MRI=20 with a safety margin of 1=962 mm to healthy brain tissue, 3 mm = to=20 adjacent osseous structures, and 5 mm along the dura. = Intensity-modulated=20 radiotherapy (IMRT) was performed with a 6/15-MV linear accelerator = (Siemens AG,=20 Erlangen, Germany). Treatment plan was based on CT/MRI scans of the head = in an=20 individual scotch-Cast<SUP>TM</SUP> mask fixation. Treatment plan was = created=20 using the Konrad inverse treatment planning program (MRC Systems GmbH,=20 Heidelberg, Germany), developed at the German Cancer Research Center, = Heidelberg=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR14">14</A></CITE>].=20 For IMRT a median of seven beams were used. Radiation treatment was = performed=20 using a commercial integrated motorized multileaf collimator in a = =93step and=20 shoot=94 technique [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR15">15</A></CITE>].=20 </P> <P class=3D"">Follow-up was performed at 6 weeks, 3 months,=20 6 months, and 12 months for the first year and then once a = year.=20 Follow-up included radiologic imaging (MRI) and clinical and = neurological=20 examinations. Inclusion criterion for this study was radiologically = proven local=20 recurrence, defined as local tumor progression on MRI. </P> <P class=3D"">In order to evaluate the site of local failure, recurrent = events=20 were divided into two dosimetric categories: those within the region = that=20 received at least 90% of the prescribed dose (high-dose region) were = considered=20 =93central=94 or =93in-field,=94 and those in regions that received less = than 90% of the=20 prescribed dose (low-dose regions) were considered =93marginal=94 or = =93out-field.=94=20 </P> <P class=3D"">For evaluation of the influence of histological grading on = recurrence localization and recurrence-free survival, subanalysis was = carried=20 out for patients with benign meningioma (WHO grade I) versus = patients with=20 higher-grade disease (WHO grade II/III). Statistical analysis was = performed=20 with the Fisher exact test for localization of local recurrence and = Shapiro-Wilk=20 normality test for recurrence-free survival. Results were considered = significant=20 for <I>P</I> value <0.05. </P></DIV> <DIV class=3D""><A name=3DSec3></A> <HR> <DIV class=3Dheading2>Results</DIV> <P class=3D"">Median follow-up was 59.5 months (range = 16=96161 months).=20 All patients were followed for more than 12 months, 17/22 (77.3%) = patients=20 for more than 36 months, 15/22 (68.2%) patients for more than=20 48 months, and 11/22 (50%) patients for more than 60 months. = The=20 median PTV was 95 cm<SUP>3</SUP> (range = 11.8=96457 cm<SUP>3</SUP>). </P> <DIV class=3DPara> <DIV class=3D"">The median time to recurrence after radiation therapy = was=20 46 months for the entire population (range 11=96132 months). = One-, 2-,=20 3-, 4-, and 5-year local control rates for the entire group of patients = were=20 95.5%, 81.8%, 63.6%, 50%, and 27.3%, respectively (Fig. <A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#Fig1">1</A>).=20 <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2009_84_Fig1_HTML.gif=20 src=3D"http://www.springerlink.com/content/j08502831657163h/MediaObjects/= 11060_2009_84_Fig1_HTML.gif"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 1 </SPAN>Recurrence-free=20 survival calculated from time of radiotherapy according to = Kaplan=96Meier method=20 </DIV> <HR> </DIV></DIV> <P class=3D"">Evaluation of the local recurrence events revealed 11 = events as=20 central or in-field, while 11 events were found to be marginal or = out-field.=20 </P> <P class=3D"">The median PTV for patients with WHO grade I = meningioma was=20 86.3 cm<SUP>3</SUP> and for patients with WHO grade II or III=20 meningiomas was 152.4 cm<SUP>3</SUP>. The recurrence-free survival = rate=20 after radiation therapy for benign WHO grade I intracranial = meningiomas was=20 66.7% at 3 years and 25% at 5 years. Patients with WHO = grade II=20 or III meningioma had a recurrence-free survival rate after radiotherapy = of 50%=20 at 3 years and 25% at 5 years. The median time to recurrence = after=20 radiotherapy was 46 months (range 11=96128 months) for = patients with WHO=20 grade I meningioma and 31.5 months (range 14=9675 months) = for=20 patients with WHO grade II or III meningioma=20 (<I>P</I> > 0.05). </P> <DIV class=3DPara> <DIV class=3D"">Differences were revealed in regard to the site of local = recurrence between the two subgroups. In particular, among 12 patients = with WHO=20 grade I meningioma, 9 recurrences were found to be marginal or = out-field=20 (75%) and 3 recurrences were found to be central or in-field (25%). = Among eight=20 patients with WHO grade II or III intracranial meningioma who = recurred=20 after radiation therapy, seven recurrences were identified as central or = in-field (87.5%) and one recurrence was identified as marginal or = out-field=20 (12.5%) (Table <A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#Tab4">4</A>).=20 The correlation between WHO grade and localization of the local = recurrence was=20 statistically significant (<I>P</I> < 0.05).<A = name=3DTab4></A> <DIV class=3DCapt><SPAN = class=3DCaptNr>Table 4 </SPAN>Recurrence site in=20 patients with intracranial meningioma after radiotherapy=20 (<I>n</I> =3D 22) </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dchar char=3D"("> <COL align=3Dchar char=3D"("></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">Histological grading</P></TH> <TH align=3Dleft char=3D"("> <P class=3D"">In-field</P></TH> <TH align=3Dleft char=3D"("> <P class=3D"">Out-field</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">WHO grade I</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">3 (25%)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">9 (75%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">WHO grade II or III</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">7 (87.5%)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">1 (12.5%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Unknown</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">1 (50%)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">1 (50%)</P></TD></TR></TBODY></TABLE></DIV></DIV> <P class=3D"">Two patients with intracranial meningioma WHO grade I = received=20 re-irradiation after local failure. One of them showed a re-recurrence = event=20 32 months after retreatment. Within the collective of patients with = WHO=20 grade II or III meningiomas, three received re-irradiation = treatment after=20 diagnosis of local recurrence. In two cases a re-recurrence event = occurred, with=20 mean re-recurrence-free survival calculated to be 23.5 months. </P> <P class=3D"">In regard to overall survival, four patients died, a = median of=20 6.9 years (range 3.4=9610.4 years) after radiation therapy. In = two cases=20 cause of death was progressive heart disease. Only one patient died of=20 progressive primary disease, while the fourth patient died of other = causes.=20 </P></DIV> <DIV class=3D""><A name=3DSec4></A> <HR> <DIV class=3Dheading2>Discussion</DIV> <P class=3D"">Radiation therapy is one of the main therapeutic = modalities for=20 treatment of intracranial meningiomas. Since it is possible to treat = meningiomas=20 effectively with highly conformal radiotherapeutic techniques, only a = few local=20 failures were reported. Evaluation of the results of radiotherapy in = large=20 collectives of patients with intracranial meningiomas revealed very good = long-term tumor control and low local recurrence rates. Vendrely = et al.=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR16">16</A></CITE>]=20 evaluated the results of fractionated radiation therapy on a collective = of 156=20 patients with intracranial meningiomas and described a recurrence rate = of 13.5%=20 and a local control rate of 79.4% after median follow-up of = 40 months. In=20 another retrospective study of 82 patients with benign skull-base = meningioma=20 treated by fractionated external-beam radiation after surgery, Nutting=20 et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR17">17</A></CITE>]=20 described 5- and 10-year progression-free survival rates of 92% and 83%, = respectively. Evaluation by Hamm et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR18">18</A></CITE>]=20 of the results of stereotactically guided radiation techniques in a = collective=20 of 224 patients with skull-base meningiomas revealed overall survival = and=20 progression-free survival rates at 5 years of 92.9% and 96.9%,=20 respectively. </P> <P class=3D"">In order to analyze the long-term results of fractionated=20 stereotactic radiation therapy in patients with benign or atypical = intracranial=20 meningioma, a retrospective investigation of 317 patients was performed = in our=20 department in the past [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR10">10</A></CITE>].=20 This study revealed a local tumor control rate of 93.1% after median = follow-up=20 of 5.7 years, with radiological local tumor progression rate of = 6.9%.=20 Within this study the influence of potential prognostic factors on local = control=20 was investigated, revealing that histologic grade of the meningioma and = volume=20 of the tumor had a statistically significant influence on therapy = outcome. Local=20 tumor failure was significant higher in patients with WHO grade II=20 meningioma (<I>P</I> < 0.002) than in patients with unknown = histology or patients with WHO grade I meningioma. Patients with = tumor=20 volume greater than 60 cc showed a recurrence rate of 15.5% versus = 4.3% in=20 patients with tumor volume less than 60 cc = (<I>P</I> < 0.001).=20 </P> <P class=3D"">However, although various studies have investigated the = survival and=20 local control rates of radiotherapy for intracranial meningioma, there = are no=20 published data regarding the site of local recurrence with respect to = the exact=20 dose distribution of the applied treatment plan. </P> <P class=3D"">In this study we further analyzed the results of 22 of 411 = patients=20 treated with stereotactic radiation therapy for intracranial meningiomas = who=20 showed local tumor progression on MRI. Aim of the study was to = investigate the=20 parameters that negatively influence the outcome of the therapy. We = focused=20 especially on identification of the site of local recurrence with = respect to the=20 dose distribution. </P> <P class=3D"">The target volume was found in previous studies to be = important for=20 therapy outcome. A statistically significant correlation between tumor = volume=20 and relapse after FSRT has been observed. The recurrence rate for = patients with=20 tumor volume >60 cm<SUP>3</SUP> was 15.5% versus 4.3% for = patients with=20 tumor volume <60 cm<SUP>3</SUP> = (<I>P</I> < 0.001)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR10">10</A></CITE>].=20 The hypothesis of the significance of target volume for therapy outcome = is=20 strengthened by the results of our analysis. The median PTV of the = patients who=20 showed a recurrence after radiotherapy was 95 cm<SUP>3</SUP>. = Compared with=20 results of previous studies in the literature, the median target volume = of the=20 recurrent patients in our study is larger. This correlation can find = several=20 explanations: high tumor volume is associated with higher cell density = and=20 therefore enhanced probability of hypoxic tumor regions, which is found = to be=20 one of the most important reasons for therapy resistance [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR19">19</A></CITE>].=20 Furthermore, tumors with high volume have greater possibility to have = closer=20 proximity to critical anatomical structures, such as the optic nerve or = brain=20 stem, which is a limiting factor for optimal dose distribution. </P> <P class=3D"">The influence of the dose distribution on therapy outcome = was shown=20 by studies on radiation therapy techniques with advanced dose = distribution, such=20 as IMRT. A previous investigation of IMRT for complex-shaped meningioma = of the=20 skull base revealed a recurrence rate of 6.1% after median follow-up of=20 4.4 years; the median target volume was 81.4 cm<SUP>3</SUP> = and the=20 median total dose was 57.6 Gy [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR11">11</A></CITE>].=20 Subanalysis of the results for patients treated with FSRT with the same = median=20 total dose after median follow-up of 5.7 years revealed a = recurrence rate=20 of 15.5% for tumors with volume >60 cm<SUP>3</SUP> [<CITE><A=20 href=3D"http://www.springerlink.com/content/j08502831657163h/fulltext.htm= l#CR10">10</A></CITE>].=20 The higher recurrence rate in the group of patients treated by FSRT = could be=20 explained by the longer median follow-up, but it could also be explained = by=20 optimized dose homogeneity achieved by IMRT. </P> <P class=3D"">One of the most important prognostic factors for = intracranial=20 meningioma was found to be the histological grading of the disease. In = order to=20 better understand the correlation between histological grade and local = control=20 we performed subanalysis of our results separately for patients with = benign=20 meningioma (WHO grade I) and higher-grade meningioma (WHO = grade II or=20 III). This analysis revealed a statistically significant influence of = the=20 histological features of the tumor on recurrence site (in-field versus=20 out-field) and therefore on the mechanism of recurrence. WHO = grade I tumors=20 recurred more often at the margin, while WHO grade II or III tumors = recurred more often centrally. A possible explanation for this result is = that,=20 for WHO grade I tumors, it was dose homogeneity coverage that = influenced=20 the outcome of the therapy more, while for atypical or anaplastic = meningiomas=20 the prescribed dose level seemed to be insufficient. The median = recurrence-free=20 survival for patients with WHO grade I meningioma that recurred = after RT=20 only exhibited a trend to be higher than that for WHO grade II or = III=20 patients (46 versus 31.5 months). </P></DIV> <DIV class=3D""><A name=3DSec5></A> <HR> <DIV class=3Dheading2>Conclusions</DIV> <P class=3D"">High-precision radiation therapy offers the possibility of = an=20 effective local treatment modality in meningiomas. Due to the = effectiveness of=20 stereotactic radiotherapy in patients with intracranial meningiomas, = only a few=20 patients with recurrent disease (22/411 patients) could be analyzed in = this=20 evaluation regarding the question of topography of local recurrences = after=20 radiotherapy. However, these data based on a large cohort from a single=20 institution show that median time to local recurrence and site of local=20 recurrence significantly depend on histological grading of meningioma.=20 Recurrences in WHO grade I meningioma are rare; only 14 of all 365 = patients=20 (3.8%) with grade I meningioma or unknown histology treated at our=20 institution were recurrences. Recurrences in high-grade meningioma are = more=20 common after radiotherapy, occurring in 8 out of 46 treated patients = having=20 high-grade meningioma (17.4%). In WHO grade I meningioma most local = recurrences were found to be marginal, while high-grade (grade II = and III)=20 meningioma more often recurred centrally. Although the number of = recurrences=20 after radiotherapy is relatively small, the aim of all therapeutic = interventions=20 is to reduce recurrences after therapy during follow-up. Therefore, dose = escalation in patients with high-grade tumors may be useful. Further=20 improvements may be achieved with the use of particle therapy and = optimized=20 target volume definition by the use of molecular imaging such as = positron=20 emission tomography (PET). </P></DIV> <DIV class=3DAcknowledgments> <DIV class=3DFormalPara> <DIV class=3D""><SPAN style=3D"FONT-STYLE: italic; TEXT-DECORATION: = none">Conflict=20 of interest statement</SPAN> All authors disclose any = financial and=20 personal relationships with other people or organisations that could=20 inappropriately influence (bias) their work. </DIV></DIV></DIV> <P></P> <HR> <H2><A name=3DBib1></A>References </H2> <TABLE> <TBODY class=3DCitation> <TR vAlign=3Dtop> <TD>1.</TD> <TD><A name=3DCR1></A>Marosi C, Hassler M, Roessler K, Reni M, Sant = M, Mazza=20 E, Vecht C (2008) Meningioma. 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