10.1007/s11060-009-0055-6</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 The Author(s) 2009</TD></TR> <TR> <TD>10.1007/s11060-009-0055-6</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Invited Manuscript</H2> <DIV class=3DHeading1><A name=3Dtitle></A>The role of retreatment in the = management=20 of recurrent/progressive brain metastases: a systematic review and=20 evidence-based clinical practice guideline </DIV> <P class=3DAuthorGroup>Mario Ammirati<SUP>1</SUP>,=20 Charles S. Cobbs<SUP>2</SUP>, = Mark E. Linskey<SUP>3</SUP>,=20 Nina A. Paleologos<SUP>4</SUP>,=20 Timothy C. Ryken<SUP>5</SUP>, = Stuart H. Burri<SUP>6</SUP>,=20 Anthony L. Asher<SUP>7</SUP>, = Jay S. Loeffler<SUP>8</SUP>,=20 Paula D. Robinson<SUP>9</SUP>,=20 David W. Andrews<SUP>10</SUP>,=20 Laurie E. Gaspar<SUP>11</SUP>, = Douglas Kondziolka<SUP>12</SUP>,=20 Michael McDermott<SUP>13</SUP>, = Minesh P. Mehta<SUP>14</SUP>,=20 Tom Mikkelsen<SUP>15</SUP>, = Jeffrey J. Olson<SUP>16</SUP>,=20 Roy A. Patchell<SUP>17</SUP> and=20 Steven N. Kalkanis<SUP>18 <A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#ContactOfAuthor18"><IMG=20 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/4711x523t24123p7/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 Neurosurgery, Ohio State = University Medical Center, Columbus, OH, = USA</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 Neurosciences, = California=20 Pacific Medical Center, San Francisco, CA, = USA</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 Neurosurgery, University = of=20 California-Irvine Medical Center, Orange, CA,=20 USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff4></A>(4) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurology, Northshore = University=20 Health System, Evanston, IL, USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff5></A>(5) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, Iowa Spine = and=20 Brain Institute, Iowa City, IA, = USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff6></A>(6) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Radiation Oncology, = Carolinas=20 Medical Center, Charlotte, NC, = USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff7></A>(7) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, Carolina=20 Neurosurgery and Spine Associates, Charlotte, NC,=20 USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff8></A>(8) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Radiation Oncology,=20 Massachusetts General Hospital, Boston, MA, = USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff9></A>(9) </SPAN></TD> <TD><SPAN class=3DAffiliation>McMaster University Evidence-Based = Practice=20 Center, Hamilton, ON, Canada</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff10></A>(10) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, Thomas = Jefferson=20 University, Philadelphia, PA, USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff11></A>(11) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Radiation Oncology, = University=20 of Colorado-Denver, Denver, CO, = USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff12></A>(12) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurological Surgery, = University=20 of Pittsburgh Medical Center, Pittsburgh, PA,=20 USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff13></A>(13) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, University = of=20 California San Francisco, San Francisco, CA,=20 USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff14></A>(14) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Human Oncology, = University of=20 Wisconsin School of Public Health and Medicine, Madison, WI,=20 USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff15></A>(15) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurology, Henry Ford = Health=20 System, Detroit, MI, USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff16></A>(16) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, Emory = University=20 School of Medicine, Atlanta, GA, = USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff17></A>(17) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurology, Barrow = Neurological=20 Institute, Phoenix, AZ, USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff18></A>(18) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, Henry Ford = Health=20 System, 2799 West Grand Blvd, K-11, Detroit, MI 48202,=20 USA</SPAN></TD></TR></TBODY></TABLE> <P><A name=3DContactOfAuthor18></A></P> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/4711x523t24123p7/contact.gif" = border=3D0></TD> = <TD><STRONG>Steven </STRONG><STRONG>N. </STRONG><STRONG>Kalkani= s</STRONG><STRONG></STRONG><BR><STRONG>Email:=20 </STRONG><A=20 = href=3D"mailto:kalkanis@neuro.hfh.edu">kalkanis@neuro.hfh.edu</A><BR><STR= ONG>Email:=20 </STRONG><A=20 = href=3D"mailto:skalkan1@hfhs.org">skalkan1@hfhs.org</A></TD></TR></TBODY>= </TABLE> <P class=3DAffiliation><STRONG>Received:=20 </STRONG>7 September 2009 <STRONG>Accepted:=20 </STRONG>8 November 2009 <STRONG>Published online:=20 </STRONG>3 December 2009 </P> <DIV class=3DAbstract><A name=3DAbs1></A><SPAN = class=3DAbstractHeading>Abstract</SPAN> <DIV class=3DAbstractSection> <DIV class=3D""><SPAN class=3DAbstractSectionHeading><A=20 name=3DASec1></A><B>Question</B> </SPAN> <I>What evidence is = available=20 regarding the use of whole brain radiation therapy (WBRT), stereotactic=20 radiosurgery (SRS), surgical resection or chemotherapy for the treatment = of=20 recurrent/progressive brain metastases?</I>=20 <DIV class=3DAbstractPara> <DIV class=3D""><B>Target population</B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D"">This recommendation applies to adults with = recurrent/progressive=20 brain metastases who have previously been treated with WBRT, surgical = resection=20 and/or radiosurgery. Recurrent/progressive brain metastases are defined = as=20 metastases that recur/progress anywhere in the brain (original and/or=20 non-original sites) after initial therapy. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B>Recommendation</B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 3</I> Since there is insufficient evidence to = make=20 definitive treatment recommendations in patients with = recurrent/progressive=20 brain metastases, treatment should be individualized based on a = patient=92s=20 functional status, extent of disease, volume/number of metastases, = recurrence or=20 progression at original versus non-original site, previous treatment and = type of=20 primary cancer, and enrollment in clinical trials is encouraged. In this = context, the following can be recommended depending on a patient=92s = specific=20 condition: no further treatment (supportive care), re-irradiation = (either WBRT=20 and/or SRS), surgical excision or, to a lesser extent, chemotherapy.=20 </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B>Question</B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>If WBRT is used in the setting of = recurrent/progressive brain=20 metastases, what impact does tumor histopathology have on treatment=20 outcomes?</I> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D"">No studies were identified that met the eligibility = criteria for=20 this question.</DIV></DIV></DIV></DIV></DIV> <P class=3DKeyword><SPAN=20 class=3DKeywordHeading>Keywords </SPAN>Recurrent/progressive = brain=20 metastases - Surgical resection - Whole brain=20 radiotherapy - Stereotactic=20 radiosurgery - Chemotherapy - Histopathology -&n= bsp;Retreatment - Systematic=20 review - Practice guideline </P> <DIV class=3DArticleNote><SPAN class=3D"">Mario Ammirati, Charles S. = Cobbs=20 contributed equally as primary authors.</SPAN></DIV> <DIV class=3DFulltext> <DIV class=3D""><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Rationale</DIV> <P class=3D"">Untreated brain metastases have a median survival of about = 4 weeks with almost all patients dying from neurological rather = than=20 systemic causes [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR1">1</A></CITE>].=20 The majority of studies which have compared different modalities for the = treatment of brain metastases have focused on the management of newly = diagnosed=20 patients. The role of WBRT, surgical excision, SRS and chemotherapy for = patients=20 with newly diagnosed brain metastases are addressed by other guideline = papers in=20 this series (Gaspar et al., Kalkanis et al., Linskey et al., and Mehta = et al.).=20 </P> <P class=3D"">For those individuals who survive long enough to = experience=20 recurrence/progression of previously treated brain metastases, no = consensus on=20 treatment exists. The overall objective of this guideline paper is to=20 systematically review the existing data relevant to the treatment of = patients=20 who develop recurrent/progressive brain metastases after initial therapy = and to=20 provide recommendations based on this evidence. </P> <DIV class=3DPara> <DIV class=3D"">The questions specifically addressed by this guideline = paper are:=20 <TABLE class=3DOrderedList> <TBODY> <TR vAlign=3Dtop> <TD>1. </TD> <TD>What evidence is available regarding the use of WBRT, SRS, = surgical=20 resection or chemotherapy for the treatment of = recurrent/progressive brain=20 metastases? </TD></TR> <TR vAlign=3Dtop> <TD>2. </TD> <TD>If WBRT is used in this setting, what impact does tumor = histopathology=20 have on treatment = outcomes?</TD></TR></TBODY></TABLE></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Methods</DIV> <DIV class=3D""><A name=3DSec3></A> <DIV class=3DHeading3>Search strategy</DIV> <P class=3D"">The following electronic databases were searched from 1990 = to=20 September 2008: MEDLINE<SUP>=AE</SUP>, Embase<SUP>=AE</SUP>, Cochrane = Database of=20 Systematic Reviews, Cochrane Controlled Trials Registry, Cochrane = Database of=20 Abstracts of Reviews of Effects. A broad search strategy using a = combination of=20 subheadings and text words was employed. The search strategy is = documented in=20 the methodology paper for this guideline series by Robinson et al. = [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR2">2</A></CITE>]=20 Reference lists of included studies were also reviewed. </P></DIV> <DIV class=3D""><A name=3DSec4></A> <DIV class=3DHeading3>Eligibility criteria</DIV> <DIV class=3DPara> <DIV class=3D""> <TABLE class=3DOrderedList> <TBODY> <TR vAlign=3Dtop> <TD>(a) </TD> <TD><I>What evidence is available regarding the use of WBRT, SRS, = surgical=20 resection or chemotherapy for the treatment of recurrent and/or=20 progressive brain metastases?</I>=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Published in English with a publication date of 1990=20 forward.</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Patients with recurrent and/or progressive brain=20 metastases.</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Fully-published primary studies (all study designs for = primary=20 data collection included; e.g., RCT, non-randomized trials, = cohort=20 studies, case=96control studies or case series). </TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Any study evaluating the use of WBRT, SRS, surgical = excision, or=20 chemotherapy alone or in combination.</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Number of study participants with recurrent and/or = progressive=20 brain metastases >5 per study arm for comparative studies = and=20 >5 overall for non-comparative studies. </TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>For studies evaluating interventions exclusively in = patients=20 with recurrent and/or progressive brain metastases, baseline = characteristics of study participants are provided by = treatment=20 group for comparative designs and overall for = non-comparative=20 studies. For studies with mixed populations (i.e., includes=20 participants with conditions other than recurrent and/or = progressive=20 brain metastases), baseline characteristics are provided for = the=20 sub-group of participants with recurrent and/or progressive = brain=20 metastases, and stratified by treatment group for = comparative=20 studies. </TD></TR></TBODY></TABLE></TD></TR> <TR vAlign=3Dtop> <TD>(b) </TD> <TD><I>If WBRT is used, what impact does tumor histopathology have = on=20 treatment outcomes?</I>=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Published in English with a publication date of 1990=20 forward.</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Patients with recurrent and/or progressive brain=20 metastases.</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Fully-published peer-reviewed primary studies (all study = designs=20 for primary data collection included; e.g., RCT, = non-randomized=20 trials, cohort studies, case=96control studies or case = series). </TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Any study evaluating the outcome(s) of WBRT by tumor=20 histopathology (or primary tumor type).</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Number of study participants with recurrent and/or = progressive=20 brain metastases >5 per study arm for comparative studies = and=20 >5 overall for non-comparative studies. </TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>For studies evaluating the outcome(s) of WBRT by = histopathology=20 (or primary tumor type) exclusively in patients with = recurrent=20 and/or progressive brain metastases, baseline = characteristics are=20 presented and stratified by histologic/primary tumor group. = For=20 studies with mixed populations (i.e., includes participants = with=20 conditions other than recurrent and/or progressive brain=20 metastases), baseline characteristics are presented and = stratified=20 by histologic/primary tumor group for the sub-group of = participants=20 with recurrent and/or progressive brain metastases.=20 = </TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec5></A> <DIV class=3DHeading3>Study selection and quality assessment</DIV> <P class=3D"">Two independent reviewers evaluated citations using <I>a = priori</I>=20 criteria for relevance and documented decisions in standardized forms. = Cases of=20 disagreement were resolved by a third reviewer. The same methodology was = used=20 for full text screening of potentially relevant papers. Studies which = met the=20 eligibility criteria were data extracted by one reviewer and the = extracted=20 information was checked by a second reviewer. The PEDro scale [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR3">3</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR4">4</A></CITE>]=20 was used to rate the quality of randomized trials. The quality of = comparative=20 studies using non-randomized designs was evaluated using eight items = selected=20 and modified from existing scales. </P></DIV> <DIV class=3D""><A name=3DSec6></A> <DIV class=3DHeading3>Evidence classification and recommendation = levels</DIV> <P class=3D"">Both the quality of the evidence and the strength of the=20 recommendations were graded according to the American Association of=20 Neurological Surgeons (AANS)/Congress of Neurological Surgeons (CNS) = criteria.=20 These criteria are provided in the methodology paper accompanying this = guideline=20 series. </P></DIV> <DIV class=3D""><A name=3DSec7></A> <DIV class=3DHeading3>Guideline development process</DIV> <P class=3D"">The AANS/CNS convened a multi-disciplinary panel of = clinical experts=20 to develop a series of practice guidelines on the management of brain = metastases=20 based on a systematic review of the literature conducted in = collaboration with=20 methodologists at the McMaster University Evidence-based Practice = Center.=20 </P></DIV></DIV> <DIV class=3D""><A name=3DSec8></A> <HR> <DIV class=3Dheading2>Scientific foundation</DIV> <P class=3D""><B><I>What evidence is available regarding the use of = WBRT, SRS,=20 surgical resection or chemotherapy for the treatment of = recurrent/progressive=20 brain metastases?</I></B> </P> <DIV class=3DPara> <DIV class=3D"">In total, 30 studies met the eligibility criteria for = this=20 question (Fig. <A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#Fig1">1</A>).=20 Of these studies, three evaluated the use of WBRT [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR5">5</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR7">7</A></CITE>],=20 four addressed the role of surgical resection [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR8">8</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR11">11</A></CITE>],=20 13 reported on the use of radiosurgery [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR12">12</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR24">24</A></CITE>]=20 and 10 evaluated chemotherapeutic agents [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR25">25</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR34">34</A></CITE>]=20 for the treatment of recurrent/progressive brain metastases. The details = of each=20 are outlined in Tables <A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#Tab1">1</A>,=20 <A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#Tab2">2</A>,=20 <A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#Tab3">3</A>,=20 <A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#Tab4">4</A>.=20 <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2009_55_Fig1_HTML.gif=20 src=3D"http://www.springerlink.com/content/4711x523t24123p7/MediaObjects/= 11060_2009_55_Fig1_HTML.gif"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 1 </SPAN>Flow of = studies to=20 final number of eligible studies of retreatment of recurrent brain = metastases=20 </DIV> <HR> <A name=3DTab1></A> <DIV class=3DCapt><SPAN = class=3DCaptNr>Table 1 </SPAN>Re-irradiation with=20 WBRT for recurrent/progressive brain metastases </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">First author (Year)</P></TH> <TH align=3Dleft> <P class=3D"">Study design/evidence class</P></TH> <TH align=3Dleft> <P class=3D"">Intervention (# pts)</P></TH> <TH align=3Dleft> <P class=3D"">Population/previous treatment</P></TH> <TH align=3Dleft> <P class=3D"">Median survival</P></TH> <TH align=3Dleft> <P class=3D""># Pts with recurrence/progression after=20 retreatment<SUP>a</SUP> </P></TH> <TH align=3Dleft> <P class=3D"">Median time to recurrence/progression after=20 retreatment</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Cooper [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR5">5</A></CITE>]=20 (1990) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D4> <P class=3D"">WBRT (<I>n</I> =3D 52) </P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Median: NR</P></TD> <TD align=3Dleft rowSpan=3D4> <P class=3D"">NR</P></TD> <TD align=3Dleft rowSpan=3D4> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Mean survival: 22.4 weeks</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Initial treatment: WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Sadikov [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR6">6</A></CITE>]=20 (2007) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">WBRT (<I>n</I> =3D 72) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">4.1 months</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">NR</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Initial treatment: WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Wong [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR7">7</A></CITE>]=20 (1997) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">WBRT (<I>n</I> =3D 86) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">4.0 months</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">NR</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Initial treatment: = WBRT</P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D""><I>BM</I> Brain metastases, <I>NR</I> Not reported, = <I>Pts</I>=20 Patients, <I>WBRT</I> Whole-brain radiation therapy </DIV></DIV> <DIV class=3DCaptCont> <DIV class=3D""><SUP>a</SUP>Number of pts with recurrence/progression of = brain=20 metastases, unless otherwise specified </DIV></DIV></DIV><A = name=3DTab2></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 2 </SPAN>Surgical = resection=20 for recurrent/progressive brain metastases </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">First author (Year)</P></TH> <TH align=3Dleft> <P class=3D"">Study design/evidence class</P></TH> <TH align=3Dleft> <P class=3D"">Intervention (# pts)</P></TH> <TH align=3Dleft> <P class=3D"">Population/previous treatment</P></TH> <TH align=3Dleft> <P class=3D"">Median survival</P></TH> <TH align=3Dleft> <P class=3D""># Pts with recurrence/progression after=20 retreatment<SUP>a</SUP> </P></TH> <TH align=3Dleft> <P class=3D"">Median time to recurrence/progression after=20 retreatment</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Arbit [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR8">8</A></CITE>]=20 (1995) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Surgery (<I>n</I> =3D 32) </P></TD> <TD align=3Dleft> <P class=3D"">Recurrent BM from NSCLC</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">10 months</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">NR</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Initial treatment included surgical = resection</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Bindal [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR9">9</A></CITE>]=20 (1995) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Surgery (<I>n</I> =3D 48) </P></TD> <TD align=3Dleft> <P class=3D"">Recurrent BM</P></TD> <TD align=3Dleft rowSpan=3D5> <P class=3D"">11.5 months</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">At original site only: 18/48 (38%)</P></TD> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Overall in brain: 7.7 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Initial treatment: surgical=20 resection =B1 WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">At distant brain site only: 3/48 (6%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">At original + distant sites: 5/48 = (10%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Overall in brain: 26/48 (54%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Truong [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR10">10</A></CITE>]=20 (2006) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Surgery (<I>n</I> =3D 32) </P></TD> <TD align=3Dleft> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">8.9 months</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">At original site: 9/32 (28%)</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">At original site: 6.2 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">BM had been previously treated with SRS (either as = initial or=20 salvage treatment)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Vecil[<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR11">11</A></CITE>]=20 (2005) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Surgery (<I>n</I> =3D 61) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive ≤3 BM</P></TD> <TD align=3Dleft rowSpan=3D4> <P class=3D"">11.1 months</P></TD> <TD align=3Dleft> <P class=3D"">At original site only: 4/61 (7%)</P></TD> <TD align=3Dleft> <P class=3D"">Overall in brain: 5 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">At distant brain site only: 19/61 (31%)</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">At distant sites in brain: = 8.4 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Initial treatment: SRS</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">At original + distant sites: 9/61 = (15%)</P></TD> <TD align=3Dleft> <P class=3D"">At original site: Median: could not be=20 estimated</P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D""><I>BM</I> Brain metastases, <I>NR</I> Not reported, = <I>NSCLC</I>=20 Non-small cell lung cancer, <I>Pts</I> Patients, <I>SRS</I> Stereotactic = radiosurgery, <I>WBRT</I> Whole-brain radiation therapy </DIV></DIV> <DIV class=3DCaptCont> <DIV class=3D""><SUP>a</SUP>Number of pts with recurrence/progression of = brain=20 metastases, unless otherwise specified </DIV></DIV></DIV><A = name=3DTab3></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 3 </SPAN>SRS for=20 recurrent/progressive brain metastases </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">First author (Year)</P></TH> <TH align=3Dleft> <P class=3D"">Study design/evidence class</P></TH> <TH align=3Dleft> <P class=3D"">Intervention (# pts)</P></TH> <TH align=3Dleft> <P class=3D"">Population/previous treatment</P></TH> <TH align=3Dleft> <P class=3D"">Median survival</P></TH> <TH align=3Dleft> <P class=3D""># Pts with recurrence/progression after=20 retreatment<SUP>a</SUP> </P></TH> <TH align=3Dleft> <P class=3D"">Median time to recurrence/progression after=20 retreatment</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Akyurek [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR12">12</A></CITE>]=20 (2007) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D5> <P class=3D"">SRS (<I>n</I> =3D 15) </P></TD> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Recurrent/progressive BM from breast cancer</P></TD> <TD align=3Dleft rowSpan=3D5> <P class=3D"">14 months</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">At original site: 1 year local</P></TD> <TD align=3Dleft rowSpan=3D5> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Control rate: 77%</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">At distant brain sites: 1 year distant control = rate:=20 57%</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Initial BM treatment: WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Chen [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR13">13</A></CITE>]=20 (2000) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D4> <P class=3D"">SRS (<I>n</I> =3D 45) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D4> <P class=3D"">28 weeks</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Local control (by lesion for 84% of lesions with = data):=20 90%</P></TD> <TD align=3Dleft rowSpan=3D4> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Initial BM treatment included = SRS =B1 WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">1 year freedom from tumor progression: = 94%</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Combs [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR14">14</A></CITE>]=20 (2004) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Case series [For the recurrent group (G3) = only]</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">SRS for recurrent BM (<I>n</I> =3D 39) = </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM from breast cancer</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">19 months</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">NR</P></TD> <TD align=3Dleft> <P class=3D"">At original sites: 9 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">At distant brain sites: 7 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Initial BM treatment: WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Davey [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR15">15</A></CITE>]=20 (2007) </P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Retrospective cohort study with historical = controls</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 35) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 16 weeks</P></TD> <TD align=3Dleft rowSpan=3D4> <P class=3D"">NR</P></TD> <TD align=3Dleft rowSpan=3D4> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">G2: Fractionated SRS (2 fractions) = (<I>n</I> =3D 69)=20 </P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">G2: 30 weeks (Survival curves: log-normal; = univariate=20 <I>p</I> =3D 0.0155) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Initial BM treatment included WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D6> <P class=3D"">Davey [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR16">16</A></CITE>]=20 (1994) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Prospective single arm phase I/II trial</P></TD> <TD align=3Dleft rowSpan=3D6> <P class=3D"">SRS (<I>n</I> =3D 12 pts) </P></TD> <TD align=3Dleft> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D6> <P class=3D"">6 months</P></TD> <TD align=3Dleft> <P class=3D""># pts with local recurrence: 9/12 (75%)</P></TD> <TD align=3Dleft rowSpan=3D6> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Initial BM treatment: WBRT</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Radiological response at 4 weeks (by lesion): = Complete=20 response 3/19 (16%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Partial response 6/19 (32%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">No change 10/19 (53%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Progression 0/19</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Hoffman [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR17">17</A></CITE>]=20 (2001) </P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Case series [For the recurrent group (G3) = only]</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">SRS for recurrent BM (<I>n</I> =3D 53) = </P></TD> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Recurrent/progressive BM from lung cancer</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">10.0 months</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">1 year freedom from LR rate: 36%</P></TD> <TD align=3Dleft> <P class=3D"">At original site: 9.2 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">At distant site: 16.5 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">1 year freedom from DR rate: 55%</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Initial BM treatment: WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Overall in brain: 5.8 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">1 year freedom from any intracranial = recurrence:=20 27%</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Kwon [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR18">18</A></CITE>]=20 (2007) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">SRS (<I>n</I> =3D 43) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">32 weeks</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">6 month local control rate: 91%</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Initial BM treatment included SRS</P></TD> <TD align=3Dleft> <P class=3D"">6 month overall brain control rate: = 86%</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Loeffler [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR19">19</A></CITE>]=20 (1990) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">SRS (<I>n</I> =3D 18) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">NR</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">At original site: # of lesions that decreased or = stabilized:=20 21/21 (100%)</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Initial BM treatment: WBRT =B1 surgery = (except in 1 pt=20 who refused WBRT)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Noel [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR20">20</A></CITE>]=20 (2003) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Case series [For the recurrent group (G3) = only]</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">SRS for recurrent group(<I>n</I> =3D 36) = </P></TD> <TD align=3Dleft> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">8 months</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">1 year local control rate: 86%</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Overall in brain: Median: not reached</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Initial BM treatment: WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Noel [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR21">21</A></CITE>]=20 (2001) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">SRS (<I>n</I> =3D 54) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">7.8 months</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">1 year local control rate (by lesion): = 91%</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Median time to development of new BM or = leptomeningeal=20 carcinomatosis: 24.5 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Initial BM treatment: WBRT</P></TD> <TD align=3Dleft> <P class=3D"">1 year overall brain control rate: = 65%</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Sheehan [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR22">22</A></CITE>]=20 (2005) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">SRS (<I>n</I> =3D 27) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM from SCLC</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">4.5 months</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Local tumor control (Of 21 lesions in 14 pts with = data): 17/21=20 (81%) lesions; 12/14 (86%) pts</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Initial BM treatment included WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Shuto [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR23">23</A></CITE>]=20 (2004) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D5> <P class=3D"">SRS (<I>n</I> =3D 16) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D5> <P class=3D"">22.4 months (from 1st SRS treatment)</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Tumor response:[Of 173/242 (72%) lesions with data]: = Complete=20 response 121/173 (70%)</P></TD> <TD align=3Dleft rowSpan=3D5> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Initial BM treatment included SRS</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Partial response or no change 47/173 = (27%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Progression 5/173 (3%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Yamanaka [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR24">24</A></CITE>]=20 (1999) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">SRS (<I>n</I> =3D 41) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">15 months (from first SRS treatment)</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Overall local control rate after 2nd SRS (by = lesion):=20 93%</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D6> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Initial BM treatment included SRS</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Response after 2nd SRS [Of 61 lesions evaluable]: = Disappeared=20 16/61 (26%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Decreased 40/61 (66%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Unchanged 1/61 (2%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Increased 4/61 (7%)</P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D""><I>BM</I> Brain metastases, <I>BR</I> Brain recurrence=20 (local + distant), <I>DR</I> Distant recurrence in brain, = <I>G1</I>=20 Group 1, <I>G2</I> Group 2, <I>LR</I> Local recurrence at original site = in=20 brain, <I>NSCLC</I> Non-small cell lung cancer, <I>NR</I> Not reported,=20 <I>PR</I> Partial response, <I>Pts</I> Patients, <I>SCLC</I> Small cell = lung=20 cancer </DIV></DIV> <DIV class=3DCaptCont> <DIV class=3D""><SUP>a</SUP>Number of pts with recurrence/progression of = brain=20 metastases, unless otherwise specified </DIV></DIV></DIV><A = name=3DTab4></A> <DIV class=3DCapt><SPAN = class=3DCaptNr>Table 4 </SPAN>Chemotherapy for=20 recurrent/progressive brain metastases </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">First author (Year)</P></TH> <TH align=3Dleft> <P class=3D"">Study design/evidence class</P></TH> <TH align=3Dleft> <P class=3D"">Intervention (# pts)</P></TH> <TH align=3Dleft> <P class=3D"">Population/previous treatment</P></TH> <TH align=3Dleft> <P class=3D"">Median survival</P></TH> <TH align=3Dleft> <P class=3D""># Pts with recurrence/progression after=20 retreatment<SUP>a</SUP> </P></TH> <TH align=3Dleft> <P class=3D"">Median time to recurrence/progression after=20 retreatment</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Abrey [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR25">25</A></CITE>]=20 (2001) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II trial</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">TMZ (<I>n</I> =3D 41) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">6.6 months</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Response in brain: Complete response 0/41 = (0%)</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Overall in brain: 1.97 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D6> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Initial BM treatment varied (all received=20 WBRT =B1 other modalities)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Partial response 2/41 (5%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Stable disease 15/41 (37%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Progressive disease 17/41 (42%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Not assessed 7/41 (17%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D8> <P class=3D"">Br=F6cker [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR26">26</A></CITE>]=20 (1996) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm study</P></TD> <TD align=3Dleft rowSpan=3D8> <P class=3D"">WBRT + fotemustine = (<I>n</I> =3D 13) </P></TD> <TD align=3Dleft rowSpan=3D8> <P class=3D"">Progressive multiple BM from melanoma</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Overall: Not reported</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Response in brain: (12 evaluable pts)</P></TD> <TD align=3Dleft rowSpan=3D8> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Pts with partial response/stable disease: = 6 months</P></TD> <TD align=3Dleft> <P class=3D"">Complete response: 0/13 (0%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Partial response 4/13 (31%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Stable disease 3/13 (23%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Other pts: 2 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Progressive disease 6/13 (46%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Not assessable: 1/13 (8%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Christodoulou [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR27">27</A></CITE>]=20 (2005) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II trial</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">TMZ + cisplatin = (<I>n</I> =3D 32) </P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">5.5 months</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Response both in brain + extra-cranial = sites:=20 Complete response 1/32 (3%)</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Median time to progression for all pts:=20 2.9 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D6> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Partial response 8/32 (25%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Partial response in brain only 1/32 = (3%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Stable disease 5/32 (16%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Progressive disease 6/32 (19%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Not evaluable 11/32 (34%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Feun [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR28">28</A></CITE>]=20 (1990) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Intracarotid cisplatin-based chemotherapy=20 (<I>n</I> =3D 23) </P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Recurrent/progressive BM from melanoma</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Median: Not reported</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Objective improvement by CT scan 7/23 (30%)</P></TD> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Median time to progression in responding pts:=20 20 weeks</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Range: 1 to 65 weeks</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Initial BM treatment included WBRT in 22/23 = pts</P></TD> <TD align=3Dleft> <P class=3D"">Stable disease 3/23 (13%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Failed to respond 13/23 (57%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D6> <P class=3D"">Giorgio [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR29">29</A></CITE>]=20 (2005) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II trial</P></TD> <TD align=3Dleft rowSpan=3D6> <P class=3D"">TMZ (<I>n</I> =3D 30) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent or progressive BM from NSCLC</P></TD> <TD align=3Dleft rowSpan=3D6> <P class=3D"">6 months</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Response in brain: Complete response 2/30 = (7%)</P></TD> <TD align=3Dleft rowSpan=3D6> <P class=3D"">Median time to progression of brain metastases in = all pts:=20 3.6 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Previous BM treatment: WBRT and chemotherapy for = BM</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Partial response 1/30 (3%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Stable disease 3/30 (10%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Progressive disease 24/30 (80%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Groen [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR30">30</A></CITE>]=20 (1993) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm study</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Carboplatin (<I>n</I> =3D 20) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM from SCLC</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">15 weeks</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Response in brain: Complete response 2/20 = (10%)</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Median duration of response: = 8 weeks</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D6> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Initial BM with teniposide, reinduction combination=20 chemotherapy or cranial irradiation</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Partial response 6/20 (30%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Stable disease 4/20 (20%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Progressive disease 4/20 (20%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Clinically determined progressive disease 4/20 = (20%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D8> <P class=3D"">Hwu [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR31">31</A></CITE>]=20 (2005) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II trial</P></TD> <TD align=3Dleft rowSpan=3D8> <P class=3D"">TMZ + thalidomide = (<I>n</I> =3D 26) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM from melanoma</P></TD> <TD align=3Dleft rowSpan=3D8> <P class=3D"">5 months</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Response in brain: Complete response 2/26 = (8%)</P></TD> <TD align=3Dleft rowSpan=3D8> <P class=3D"">Median duration of response or stable disease in = brain:=20 4 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Initial BM treatment varied</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Chemotherapy-naive patients</P></TD> <TD align=3Dleft> <P class=3D"">Partial response 1/26 (4%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Minor response/stable: 7/26 (27%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Progressive disease: 4/26 (15%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Unknown 1/26 (4%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Not assessable 11/26 (42%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D6> <P class=3D"">Iwamoto [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR32">32</A></CITE>]=20 (2008) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P></TD> <TD align=3Dleft rowSpan=3D6> <P class=3D"">TMZ + vinorelbine = (<I>n</I> =3D 38) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/refractory BM</P></TD> <TD align=3Dleft rowSpan=3D6> <P class=3D"">5 months</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Response in brain: Objective response 5% (CR 1/38; = minor=20 response 1/38)</P></TD> <TD align=3Dleft rowSpan=3D6> <P class=3D"">Median progression free survival: = 1.9 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Initial BM treatment varied</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Stable disease 5/38 (13%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Progressive disease 29/38 (76%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Not evaluable 2/38 (5%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Kaba [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR33">33</A></CITE>]=20 (1997) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm study</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">TPDC-FuHu (<I>n</I> =3D 97 assessable/115 = enrolled)=20 </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">25 weeks</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Response in brain: Complete response 4/97 = (4%)</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Median time to progression for all pts:=20 12 weeks</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D6> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Initial BM treatment: surgery and/or radiation=20 therapy</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Partial response 14/97 (14%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Minor response 9/97 (9%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Stable disease 25/97 (26%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Progressive disease 45/97 (46%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Omuro [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR34">34</A></CITE>]=20 (2006) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase I trial</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">TMZ + vinorelbine = (<I>n</I> =3D 21) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">17 weeks</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Response in brain: (Of 18 evaluable pts)</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D6> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Initial BM treatment varied</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Partial response 1/18 (6%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Minor response 1/18 (6%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Stable disease 6/18 (33%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Progressive disease 10/18 = (56%)</P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D""><I>BM</I> Brain metastases, = <I>NSCLC</I> Non-small cell=20 lung cancer, <I>NR</I> Not reported, <I>NS</I> Not = significant,=20 <I>Pts</I> Patients, <I>SCLC</I> Small cell lung cancer,=20 <I>TMZ</I> Temozolomide, <I>TPDC-FuHu</I> Hydroxyurea,=20 <I>WBRT</I> Whole-brain radiation therapy </DIV></DIV> <DIV class=3DCaptCont> <DIV class=3D""><SUP>a</SUP>Number of pts with recurrence/progression of = brain=20 metastases, unless otherwise specified </DIV></DIV></DIV></DIV></DIV> <P class=3D"">No class I or II evidence was identified that specifically = addressed=20 the question of which therapies (i.e., repeated WBRT, SRS, surgery or=20 chemotherapy) were beneficial in the setting of recurrent/progressive = metastatic=20 brain. In fact, only one of the 30 included studies compared different=20 modalities for the treatment of recurrent/progressive brain metastases = [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR15">15</A></CITE>].=20 The remaining 29 papers provide non-comparative outcome data on the = treatment of=20 recurrent/progressive brain metastases. </P> <DIV class=3D""><A name=3DSec9></A> <DIV class=3DHeading3>WBRT</DIV> <P class=3D"">Three case series addressed the question of whether=20 re-administration of WBRT was beneficial for patients in whom previously = treated=20 brain metastases recurred/progressed [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR5">5</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR7">7</A></CITE>]=20 (Table <A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#Tab1">1</A>).=20 These studies are retrospective analyses of 52, 72 and 86 patients,=20 respectively, and they offer only very limited data as to whether = patients died=20 from neurologic causes versus systemic disease progression. The average=20 re-irradiation dose for these patients was in the range of = 20=9625 Gy over=20 multiple fractions. The post-re-irradiation median survival was 4 or=20 5 months in all of the series. </P> <P class=3D"">In the largest of the case series = (<I>n</I> =3D 86), 70% of=20 patients had either complete or partial resolution of neurological = symptoms=20 following re-irradiation. In the two other case series, the percentage = of=20 patients whose neurologic function improved following re-irradiation was = 42% and=20 31%, respectively [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR5">5</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR6">6</A></CITE>].=20 </P> <P class=3D"">One patient experienced symptoms of dementia attributed to = radiation=20 therapy in each of the two series reporting information on longer term = adverse=20 effects [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR6">6</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR7">7</A></CITE>].=20 </P> <P class=3D"">No studies were identified that evaluated the use of WBRT = in the=20 setting of recurrent/progressive brain metastases for patients whose = initial=20 management did not include WBRT. </P></DIV> <DIV class=3D""><A name=3DSec10></A> <DIV class=3DHeading3>Surgical resection</DIV> <P class=3D"">Four cases series addressed the use of surgical resection = for=20 recurrent/progressive brain metastases [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR8">8</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR11">11</A></CITE>],=20 as outlined in Table <A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#Tab2">2</A>.=20 Two of these retrospective studies reported outcomes for patients who = underwent=20 surgical resection for recurrent/progressive brain metastases who also = had=20 previously been treated with SRS =B1 WBRT [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR10">10</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR11">11</A></CITE>].=20 In the study by Vecil et al. 61 patients with three or fewer recurrent = brain=20 metastases underwent surgical resection for at least one index brain = metastasis=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR11">11</A></CITE>].=20 Treatment of non-index brain metastases varied. Major surgical = complications=20 occurred in seven patients. From the date of resection, median survival = was=20 11.1 months and median time to any recurrence in the brain was=20 5 months. Cause of death was neurologic in 15% of patients and=20 neurologic/systemic combined in 34%. The second study, conducted by = Truong et=20 al., included 32 patients who had previously been treated with SRS and = who had=20 MRI and/or clinical evidence of brain metastasis progression. To be = considered=20 for surgical resection, patients needed to have a KPS ≥60 and = stable or absent=20 systemic disease. Median survival from the time of resection was=20 8.9 months. Seven patients experienced surgical complications. = Cause of=20 death was neurologic in 48% of patients [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR10">10</A></CITE>].=20 </P> <P class=3D"">Two case series evaluated the outcome of re-operation for = recurrent=20 brain metastases [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR8">8</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR9">9</A></CITE>].=20 Bindal et al. reported on 48 patients who had surgical resection of a = brain=20 metastasis as part of their initial treatment and then underwent = resection for=20 recurrent disease. From the time of re-operation, median survival was=20 11.5 months and the median time to recurrence was 7.7 months. = Of the=20 26 patients who developed a second recurrence, 17 underwent another = surgical=20 resection. For the 25 patients in which cause of death was known, it was = neurologic in 48% and combined neurologic/systemic in 12% [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR9">9</A></CITE>].=20 As part of a larger study, Arbit et al., provide retrospective data on = 32=20 patients with non-small cell lung cancer (NSCLC) who underwent = re-operation for=20 recurrent brain metastases. From the date of re-operation, median = survival was=20 10 months. Time to recurrence/progression was not reported = [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR8">8</A></CITE>].=20 </P></DIV> <DIV class=3D""><A name=3DSec11></A> <DIV class=3DHeading3>SRS</DIV> <P class=3D"">Thirteen studies addressed the role of SRS for = recurrent/progressive=20 brain metastases [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR12">12</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR24">24</A></CITE>].=20 Nine studies evaluated the use of SRS for recurrent/progressive disease = in=20 patients whose initial management included WBRT [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR12">12</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR14">14</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR17">17</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR19">19</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR22">22</A></CITE>].=20 One of these studies was prospective [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR16">16</A></CITE>].=20 This single-arm phase I/II study enrolled 12 patients whose life = expectancy was=20 ≥3 months and who had both clinical and radiologic evidence = of brain=20 metastases progression following treatment with WBRT. All patients were = followed=20 to recurrence at the SRS treated site or until death. In total, 20 brain = metastases in the 12 patients were treated by radiosurgery. From the = date of SRS=20 treatment, median survival was 6 months. Nine patients developed = evidence=20 of progressive disease at SRS treated sites. Time to progression was not = reported. Of the other eight studies that addressed the role of SRS for=20 recurrent disease in patients whose upfront treatment included WBRT, = four=20 specifically evaluated SRS treatment for recurrent/progressive brain = metastases=20 from particular primary tumor types=96breast cancer (2 case series = [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR12">12</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR14">14</A></CITE>]),=20 small cell lung cancer (SCLC) (1 case series [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR22">22</A></CITE>])=20 and lung cancer, predominantly NSCLC (1 case series [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR17">17</A></CITE>]).=20 See Table <A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#Tab3">3</A>=20 for details. </P> <P class=3D"">The only comparative study that met the eligibility = criteria for the=20 systematic review evaluated single-dose SRS versus split-dose (2 dose) = SRS for=20 recurrent/progressive disease in 104 patients whose initial management = included=20 WBRT [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR15">15</A></CITE>].=20 In this retrospective cohort study with historical controls, median = survival was=20 significantly longer for patients who received split-dose SRS compared = to=20 single-dose SRS (30 vs. 16 weeks; <I>p</I> =3D 0.015). = Time to=20 recurrence/progression was not reported. </P> <P class=3D"">Four case series evaluated the use of SRS for = recurrent/progressive=20 brain metastases in patients whose previous treatment included = radiosurgery=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR13">13</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR18">18</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR23">23</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR24">24</A></CITE>],=20 as outlined in Table <A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#Tab3">3</A>.=20 Only two of these case series provide survival data from the date of SRS = for=20 recurrent disease [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR13">13</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR18">18</A></CITE>].=20 In the series by Kwon et al., of 43 patients who underwent salvage SRS, = median=20 survival from the time of SRS for recurrent/progressive disease was=20 32 weeks and the local control rate at 6 months was 91% = [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR18">18</A></CITE>].=20 In the case series by Chen et al., of 45 patients, median survival from = the time=20 of SRS for recurrent brain metastases was 28 weeks [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR13">13</A></CITE>].=20 The 1 year freedom from progression rate was 94%. </P></DIV> <DIV class=3D""><A name=3DSec12></A> <DIV class=3DHeading3>Chemotherapy</DIV> <P class=3D"">Ten studies evaluated the role of chemotherapy in patients = with=20 recurrent/progressive metastatic brain disease [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR25">25</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR34">34</A></CITE>].=20 Of these, five are prospective single arm phase II studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR25">25</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR27">27</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR29">29</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR31">31</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR32">32</A></CITE>]=20 and five are case series [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR26">26</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR28">28</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR30">30</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR33">33</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR34">34</A></CITE>].=20 Refer to Table <A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#Tab4">4</A>=20 for details. The agents used in these studies varied from intracarotid=20 administration of cisplatin, to temozolomide alone or with thalidomide,=20 vinorelbine, fotemustine or cisplatin. Five of the studies investigated = the role=20 of chemotherapy specifically for patients with recurrent/progressive = brain=20 metastases from particular primary tumor types=97melanoma (3 studies) = [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR26">26</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR28">28</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR31">31</A></CITE>],=20 NSCLC (1 study) [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR29">29</A></CITE>],=20 and SCLC (1 study) [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR30">30</A></CITE>].=20 </P> <P class=3D"">Median survival in patients with recurrent/progressive = brain=20 metastases treated with chemotherapy ranged from 3.5 to 6.6 months=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR25">25</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR34">34</A></CITE>].=20 The median time to recurrence after retreatment with chemotherapy in = these=20 studies ranged from 2 to 4 months. These studies indicate that some = patients with recurrent or progressive brain metastases will have an = objective=20 radiographic response and/or improvement in functional status after = treatment=20 with chemotherapy. </P> <P class=3D""><B><I>If WBRT is used in the setting of recurrent and/or = progressive=20 brain metastases, what impact does tumor histopathology have on = treatment=20 outcomes?</I></B> </P> <P class=3D"">No studies were identified that met the eligibility = criteria for=20 this question.</P></DIV></DIV> <DIV class=3D""><A name=3DSec13></A> <HR> <DIV class=3Dheading2>Discussion and conclusions</DIV> <P class=3D"">No studies that provide class I or II evidence were = identified which=20 met the eligibility criteria and specifically addressed the question of = which=20 adjuvant therapies (i.e., WBRT, SRS, surgical resection or chemotherapy) = are=20 beneficial in the setting of recurrent/progressive metastatic brain = tumors.=20 Furthermore, all but one of the included studies that provide class III = evidence=20 on this topic are non-comparative. While multiple randomized clinical = trials=20 have examined the benefits for up-front combined therapies (e.g., WBRT = plus SRS,=20 WBRT plus surgery), none have been performed specifically to address the = question of the benefits of further SRS, surgery or chemotherapy in = cases of=20 recurrent/progressive brain metastases. Therefore, no level 1 or level 2 = recommendations can be made. </P> <P class=3D"">Given that none of the included studies compared the = different=20 modalities (WBRT, SRS, surgical resection or chemotherapy) for the = treatment of=20 recurrent/progressive brain metastases, the relative merits of one = approach=20 versus another are yet to be determined. Furthermore, retrospective = studies of=20 patients with recurrent/progressive brain metastases who have previously = undergone WBRT, and then received subsequent re-irradiation, show = conflicting=20 results with regard to neurologic improvement and quality of life. </P> <P class=3D"">It is recommended that treatment of recurrent/progressive = brain=20 metastases be individualized based on functional status, extent of = disease,=20 volume/number of metastases, recurrence or progression at original = versus=20 non-original site, previous treatment and type of primary cancer. In = this=20 context, re-irradiation (either WBRT and/or SRS), surgical excision or, = to a=20 lesser extent, chemotherapy, can be recommended depending on a = patient=92s=20 specific condition and based on the judgment of the patient=92s treating = physician. </P> <P class=3D"">As no studies were identified that met the eligibility = criteria for=20 the question addressing whether tumor histopathology impacts treatment = outcomes=20 when WBRT is used in the setting of recurrent/progressive brain = metastases, no=20 evidence-based recommendations can be made on this topic. </P></DIV> <DIV class=3D""><A name=3DSec14></A> <HR> <DIV class=3Dheading2>Key issues for further investigation</DIV> <P class=3D"">This systematic review of the evidence highlights the = critical need=20 for comparative studies that directly evaluate the outcome of different=20 treatment modalities for patients with recurrent/progressive metastatic = brain=20 disease, while simultaneously addressing the role of tumor = histopathology in=20 treatment outcomes. In addition, understanding potential differences in = the mode=20 of death (neurologic versus systemic progression), will help answer the=20 important question of whether treating recurrent/progressive lesions = delays=20 neurologic progression long enough to allow more aggressive therapy for = the=20 primary systemic disease. </P> <P class=3D"">Moreover, specific patient characteristics offer important = clinical=20 variables in evaluating treatment for recurrent/progressive metastases, = such as=20 if the recurrence/progression occurs at the site of the primary focal = treatment=20 (surgery or SRS) and if it is clinically symptomatic or discovered = because of=20 routine surveillance neuroimaging. Indeed, as the treatment of=20 recurrent/progressive brain metastases is undertaken primarily with = palliative=20 intent, it is important to stress which symptoms these treatments are = poised to=20 address and how overall patient quality of life is going to be affected = by any=20 re-treatment modality. </P> <P class=3D""><I>No ongoing or recently closed randomized clinical = trials=20 addressing the re-treatment of patients with recurrent/progressive brain = metastases were found that met the eligibility criteria</I>. </P></DIV> <DIV class=3DAcknowledgments><SPAN=20 class=3DAcknowledgmentsHeading>Acknowledgments </SPAN><SPAN = class=3D"">We=20 would like to acknowledge the contributions of the McMaster = Evidence-based=20 Practice Center (EPC), Dr. Parminder Raina (Director). Dr. Lina = Santaguida=20 (Co-Associate Director, Senior Scientist) led the EPC staff, which was=20 responsible for managing the systematic review process, searching for = and=20 retrieving, reviewing, data abstraction of all articles, preparation of = the=20 tables and the formatting and editing of the final manuscripts. We would = also=20 like to acknowledge the contributions of Roxanne Martinez in preparing = this=20 manuscript.</SPAN> <DIV class=3DFormalPara> <DIV class=3D""><SPAN style=3D"FONT-STYLE: italic; TEXT-DECORATION: = none">Disclaimer=20 of liability</SPAN> The information in these guidelines = reflects the=20 current state of knowledge at the time of completion. The presentations = are=20 designed to provide an accurate review of the subject matter covered. = These=20 guidelines are disseminated with the understanding that the = recommendations by=20 the authors and consultants who have collaborated in their development = are not=20 meant to replace the individualized care and treatment advice from a = patient=92s=20 physician(s). If medical advice or assistance is required, the services = of a=20 competent physician should be sought. The proposals contained in these=20 guidelines may not be suitable for use in all circumstances. The choice = to=20 implement any particular recommendation contained in these guidelines = must be=20 made by a managing physician in light of the situation in each = particular=20 patient and on the basis of existing resources. </DIV></DIV> <DIV class=3DFormalPara> <DIV class=3D""><SPAN=20 style=3D"FONT-STYLE: italic; TEXT-DECORATION: = none">Disclosures</SPAN> =20 All panel members provided full disclosure of conflicts of interest, if = any,=20 prior to establishing the recommendations contained within these = guidelines.=20 </DIV></DIV> <DIV class=3DFormalPara> <DIV class=3D""><SPAN style=3D"FONT-STYLE: italic; TEXT-DECORATION: = none">Open=20 Access</SPAN> This article is distributed under the terms of = the=20 Creative Commons Attribution Noncommercial License which permits any=20 noncommercial use, distribution, and reproduction in any medium, = provided the=20 original author(s) and source are credited. </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>Patchell RA (2003) The management of brain = metastases.=20 Cancer Treat Rev 29(6):533=96540<BR><A=20 href=3D"http://dx.doi.org/10.1016/S0305-7372(03)00105-1" = target=3D_blank><IMG=20 height=3D20 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/4711x523t24123p7/crossref_link= .gif"=20 width=3D65 border=3D0></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D14585263"=20 target=3D_blank><IMG height=3D20 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/4711x523t24123p7/pubmed_link.g= if"=20 width=3D65 border=3D0></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>2.</TD> <TD><A name=3DCR2></A>Robinson PD, Kalkanis SN, Linskey ME, = Santaguida PL=20 (2009) Methodology used to develop the AANS/CNS management of = brain=20 metastases evidence-based clinical practice parameter guidelines. = J=20 Neurooncol. doi:<A=20 = href=3D"http://dx.doi.org/10.1007/s11060-009-0059-2">10.1007/s11060-009-0= 059-2</A>=20 </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>3.</TD> <TD><A name=3DCR3></A>Centre for Evidence-Based Physiotherapy (2009) = Physiotherapy Evidence Database (PEDro). <A=20 href=3D"http://www.pedro.org.au/">http://www.pedro.org.au/</A>. = Last=20 Accessed in Jan 2009 </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>4.</TD> <TD><A name=3DCR4></A>Maher CG, Sherrington C, Herbert RD, Moseley = AM,=20 Elkins M (2003) Reliability of the PEDro scale for rating quality = of=20 randomized controlled trials. 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From: Subject: 10.1007/s11060-009-0055-6 Date: Mon, 14 Dec 2009 12:59:16 +0100 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01CA7CBD.3E375FC0" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01CA7CBD.3E375FC0 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.springerlink.com/content/4711x523t24123p7/fulltext.html 10.1007/s11060-009-0055-6</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 The Author(s) 2009</TD></TR> <TR> <TD>10.1007/s11060-009-0055-6</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Invited Manuscript</H2> <DIV class=3DHeading1><A name=3Dtitle></A>The role of retreatment in the = management=20 of recurrent/progressive brain metastases: a systematic review and=20 evidence-based clinical practice guideline </DIV> <P class=3DAuthorGroup>Mario Ammirati<SUP>1</SUP>,=20 Charles S. Cobbs<SUP>2</SUP>, = Mark E. Linskey<SUP>3</SUP>,=20 Nina A. Paleologos<SUP>4</SUP>,=20 Timothy C. Ryken<SUP>5</SUP>, = Stuart H. Burri<SUP>6</SUP>,=20 Anthony L. Asher<SUP>7</SUP>, = Jay S. Loeffler<SUP>8</SUP>,=20 Paula D. Robinson<SUP>9</SUP>,=20 David W. Andrews<SUP>10</SUP>,=20 Laurie E. Gaspar<SUP>11</SUP>, = Douglas Kondziolka<SUP>12</SUP>,=20 Michael McDermott<SUP>13</SUP>, = Minesh P. Mehta<SUP>14</SUP>,=20 Tom Mikkelsen<SUP>15</SUP>, = Jeffrey J. Olson<SUP>16</SUP>,=20 Roy A. Patchell<SUP>17</SUP> and=20 Steven N. Kalkanis<SUP>18 <A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#ContactOfAuthor18"><IMG=20 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/4711x523t24123p7/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 Neurosurgery, Ohio State = University Medical Center, Columbus, OH, = USA</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 Neurosciences, = California=20 Pacific Medical Center, San Francisco, CA, = USA</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 Neurosurgery, University = of=20 California-Irvine Medical Center, Orange, CA,=20 USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff4></A>(4) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurology, Northshore = University=20 Health System, Evanston, IL, USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff5></A>(5) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, Iowa Spine = and=20 Brain Institute, Iowa City, IA, = USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff6></A>(6) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Radiation Oncology, = Carolinas=20 Medical Center, Charlotte, NC, = USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff7></A>(7) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, Carolina=20 Neurosurgery and Spine Associates, Charlotte, NC,=20 USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff8></A>(8) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Radiation Oncology,=20 Massachusetts General Hospital, Boston, MA, = USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff9></A>(9) </SPAN></TD> <TD><SPAN class=3DAffiliation>McMaster University Evidence-Based = Practice=20 Center, Hamilton, ON, Canada</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff10></A>(10) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, Thomas = Jefferson=20 University, Philadelphia, PA, USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff11></A>(11) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Radiation Oncology, = University=20 of Colorado-Denver, Denver, CO, = USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff12></A>(12) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurological Surgery, = University=20 of Pittsburgh Medical Center, Pittsburgh, PA,=20 USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff13></A>(13) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, University = of=20 California San Francisco, San Francisco, CA,=20 USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff14></A>(14) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Human Oncology, = University of=20 Wisconsin School of Public Health and Medicine, Madison, WI,=20 USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff15></A>(15) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurology, Henry Ford = Health=20 System, Detroit, MI, USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff16></A>(16) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, Emory = University=20 School of Medicine, Atlanta, GA, = USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff17></A>(17) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurology, Barrow = Neurological=20 Institute, Phoenix, AZ, USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff18></A>(18) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, Henry Ford = Health=20 System, 2799 West Grand Blvd, K-11, Detroit, MI 48202,=20 USA</SPAN></TD></TR></TBODY></TABLE> <P><A name=3DContactOfAuthor18></A></P> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/4711x523t24123p7/contact.gif" = border=3D0></TD> = <TD><STRONG>Steven </STRONG><STRONG>N. </STRONG><STRONG>Kalkani= s</STRONG><STRONG></STRONG><BR><STRONG>Email:=20 </STRONG><A=20 = href=3D"mailto:kalkanis@neuro.hfh.edu">kalkanis@neuro.hfh.edu</A><BR><STR= ONG>Email:=20 </STRONG><A=20 = href=3D"mailto:skalkan1@hfhs.org">skalkan1@hfhs.org</A></TD></TR></TBODY>= </TABLE> <P class=3DAffiliation><STRONG>Received:=20 </STRONG>7 September 2009 <STRONG>Accepted:=20 </STRONG>8 November 2009 <STRONG>Published online:=20 </STRONG>3 December 2009 </P> <DIV class=3DAbstract><A name=3DAbs1></A><SPAN = class=3DAbstractHeading>Abstract</SPAN> <DIV class=3DAbstractSection> <DIV class=3D""><SPAN class=3DAbstractSectionHeading><A=20 name=3DASec1></A><B>Question</B> </SPAN> <I>What evidence is = available=20 regarding the use of whole brain radiation therapy (WBRT), stereotactic=20 radiosurgery (SRS), surgical resection or chemotherapy for the treatment = of=20 recurrent/progressive brain metastases?</I>=20 <DIV class=3DAbstractPara> <DIV class=3D""><B>Target population</B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D"">This recommendation applies to adults with = recurrent/progressive=20 brain metastases who have previously been treated with WBRT, surgical = resection=20 and/or radiosurgery. Recurrent/progressive brain metastases are defined = as=20 metastases that recur/progress anywhere in the brain (original and/or=20 non-original sites) after initial therapy. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B>Recommendation</B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 3</I> Since there is insufficient evidence to = make=20 definitive treatment recommendations in patients with = recurrent/progressive=20 brain metastases, treatment should be individualized based on a = patient=92s=20 functional status, extent of disease, volume/number of metastases, = recurrence or=20 progression at original versus non-original site, previous treatment and = type of=20 primary cancer, and enrollment in clinical trials is encouraged. In this = context, the following can be recommended depending on a patient=92s = specific=20 condition: no further treatment (supportive care), re-irradiation = (either WBRT=20 and/or SRS), surgical excision or, to a lesser extent, chemotherapy.=20 </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B>Question</B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>If WBRT is used in the setting of = recurrent/progressive brain=20 metastases, what impact does tumor histopathology have on treatment=20 outcomes?</I> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D"">No studies were identified that met the eligibility = criteria for=20 this question.</DIV></DIV></DIV></DIV></DIV> <P class=3DKeyword><SPAN=20 class=3DKeywordHeading>Keywords </SPAN>Recurrent/progressive = brain=20 metastases - Surgical resection - Whole brain=20 radiotherapy - Stereotactic=20 radiosurgery - Chemotherapy - Histopathology -&n= bsp;Retreatment - Systematic=20 review - Practice guideline </P> <DIV class=3DArticleNote><SPAN class=3D"">Mario Ammirati, Charles S. = Cobbs=20 contributed equally as primary authors.</SPAN></DIV> <DIV class=3DFulltext> <DIV class=3D""><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Rationale</DIV> <P class=3D"">Untreated brain metastases have a median survival of about = 4 weeks with almost all patients dying from neurological rather = than=20 systemic causes [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR1">1</A></CITE>].=20 The majority of studies which have compared different modalities for the = treatment of brain metastases have focused on the management of newly = diagnosed=20 patients. The role of WBRT, surgical excision, SRS and chemotherapy for = patients=20 with newly diagnosed brain metastases are addressed by other guideline = papers in=20 this series (Gaspar et al., Kalkanis et al., Linskey et al., and Mehta = et al.).=20 </P> <P class=3D"">For those individuals who survive long enough to = experience=20 recurrence/progression of previously treated brain metastases, no = consensus on=20 treatment exists. The overall objective of this guideline paper is to=20 systematically review the existing data relevant to the treatment of = patients=20 who develop recurrent/progressive brain metastases after initial therapy = and to=20 provide recommendations based on this evidence. </P> <DIV class=3DPara> <DIV class=3D"">The questions specifically addressed by this guideline = paper are:=20 <TABLE class=3DOrderedList> <TBODY> <TR vAlign=3Dtop> <TD>1. </TD> <TD>What evidence is available regarding the use of WBRT, SRS, = surgical=20 resection or chemotherapy for the treatment of = recurrent/progressive brain=20 metastases? </TD></TR> <TR vAlign=3Dtop> <TD>2. </TD> <TD>If WBRT is used in this setting, what impact does tumor = histopathology=20 have on treatment = outcomes?</TD></TR></TBODY></TABLE></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Methods</DIV> <DIV class=3D""><A name=3DSec3></A> <DIV class=3DHeading3>Search strategy</DIV> <P class=3D"">The following electronic databases were searched from 1990 = to=20 September 2008: MEDLINE<SUP>=AE</SUP>, Embase<SUP>=AE</SUP>, Cochrane = Database of=20 Systematic Reviews, Cochrane Controlled Trials Registry, Cochrane = Database of=20 Abstracts of Reviews of Effects. A broad search strategy using a = combination of=20 subheadings and text words was employed. The search strategy is = documented in=20 the methodology paper for this guideline series by Robinson et al. = [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR2">2</A></CITE>]=20 Reference lists of included studies were also reviewed. </P></DIV> <DIV class=3D""><A name=3DSec4></A> <DIV class=3DHeading3>Eligibility criteria</DIV> <DIV class=3DPara> <DIV class=3D""> <TABLE class=3DOrderedList> <TBODY> <TR vAlign=3Dtop> <TD>(a) </TD> <TD><I>What evidence is available regarding the use of WBRT, SRS, = surgical=20 resection or chemotherapy for the treatment of recurrent and/or=20 progressive brain metastases?</I>=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Published in English with a publication date of 1990=20 forward.</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Patients with recurrent and/or progressive brain=20 metastases.</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Fully-published primary studies (all study designs for = primary=20 data collection included; e.g., RCT, non-randomized trials, = cohort=20 studies, case=96control studies or case series). </TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Any study evaluating the use of WBRT, SRS, surgical = excision, or=20 chemotherapy alone or in combination.</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Number of study participants with recurrent and/or = progressive=20 brain metastases >5 per study arm for comparative studies = and=20 >5 overall for non-comparative studies. </TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>For studies evaluating interventions exclusively in = patients=20 with recurrent and/or progressive brain metastases, baseline = characteristics of study participants are provided by = treatment=20 group for comparative designs and overall for = non-comparative=20 studies. For studies with mixed populations (i.e., includes=20 participants with conditions other than recurrent and/or = progressive=20 brain metastases), baseline characteristics are provided for = the=20 sub-group of participants with recurrent and/or progressive = brain=20 metastases, and stratified by treatment group for = comparative=20 studies. </TD></TR></TBODY></TABLE></TD></TR> <TR vAlign=3Dtop> <TD>(b) </TD> <TD><I>If WBRT is used, what impact does tumor histopathology have = on=20 treatment outcomes?</I>=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Published in English with a publication date of 1990=20 forward.</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Patients with recurrent and/or progressive brain=20 metastases.</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Fully-published peer-reviewed primary studies (all study = designs=20 for primary data collection included; e.g., RCT, = non-randomized=20 trials, cohort studies, case=96control studies or case = series). </TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Any study evaluating the outcome(s) of WBRT by tumor=20 histopathology (or primary tumor type).</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Number of study participants with recurrent and/or = progressive=20 brain metastases >5 per study arm for comparative studies = and=20 >5 overall for non-comparative studies. </TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>For studies evaluating the outcome(s) of WBRT by = histopathology=20 (or primary tumor type) exclusively in patients with = recurrent=20 and/or progressive brain metastases, baseline = characteristics are=20 presented and stratified by histologic/primary tumor group. = For=20 studies with mixed populations (i.e., includes participants = with=20 conditions other than recurrent and/or progressive brain=20 metastases), baseline characteristics are presented and = stratified=20 by histologic/primary tumor group for the sub-group of = participants=20 with recurrent and/or progressive brain metastases.=20 = </TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec5></A> <DIV class=3DHeading3>Study selection and quality assessment</DIV> <P class=3D"">Two independent reviewers evaluated citations using <I>a = priori</I>=20 criteria for relevance and documented decisions in standardized forms. = Cases of=20 disagreement were resolved by a third reviewer. The same methodology was = used=20 for full text screening of potentially relevant papers. Studies which = met the=20 eligibility criteria were data extracted by one reviewer and the = extracted=20 information was checked by a second reviewer. The PEDro scale [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR3">3</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR4">4</A></CITE>]=20 was used to rate the quality of randomized trials. The quality of = comparative=20 studies using non-randomized designs was evaluated using eight items = selected=20 and modified from existing scales. </P></DIV> <DIV class=3D""><A name=3DSec6></A> <DIV class=3DHeading3>Evidence classification and recommendation = levels</DIV> <P class=3D"">Both the quality of the evidence and the strength of the=20 recommendations were graded according to the American Association of=20 Neurological Surgeons (AANS)/Congress of Neurological Surgeons (CNS) = criteria.=20 These criteria are provided in the methodology paper accompanying this = guideline=20 series. </P></DIV> <DIV class=3D""><A name=3DSec7></A> <DIV class=3DHeading3>Guideline development process</DIV> <P class=3D"">The AANS/CNS convened a multi-disciplinary panel of = clinical experts=20 to develop a series of practice guidelines on the management of brain = metastases=20 based on a systematic review of the literature conducted in = collaboration with=20 methodologists at the McMaster University Evidence-based Practice = Center.=20 </P></DIV></DIV> <DIV class=3D""><A name=3DSec8></A> <HR> <DIV class=3Dheading2>Scientific foundation</DIV> <P class=3D""><B><I>What evidence is available regarding the use of = WBRT, SRS,=20 surgical resection or chemotherapy for the treatment of = recurrent/progressive=20 brain metastases?</I></B> </P> <DIV class=3DPara> <DIV class=3D"">In total, 30 studies met the eligibility criteria for = this=20 question (Fig. <A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#Fig1">1</A>).=20 Of these studies, three evaluated the use of WBRT [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR5">5</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR7">7</A></CITE>],=20 four addressed the role of surgical resection [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR8">8</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR11">11</A></CITE>],=20 13 reported on the use of radiosurgery [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR12">12</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR24">24</A></CITE>]=20 and 10 evaluated chemotherapeutic agents [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR25">25</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR34">34</A></CITE>]=20 for the treatment of recurrent/progressive brain metastases. The details = of each=20 are outlined in Tables <A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#Tab1">1</A>,=20 <A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#Tab2">2</A>,=20 <A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#Tab3">3</A>,=20 <A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#Tab4">4</A>.=20 <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2009_55_Fig1_HTML.gif=20 src=3D"http://www.springerlink.com/content/4711x523t24123p7/MediaObjects/= 11060_2009_55_Fig1_HTML.gif"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 1 </SPAN>Flow of = studies to=20 final number of eligible studies of retreatment of recurrent brain = metastases=20 </DIV> <HR> <A name=3DTab1></A> <DIV class=3DCapt><SPAN = class=3DCaptNr>Table 1 </SPAN>Re-irradiation with=20 WBRT for recurrent/progressive brain metastases </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">First author (Year)</P></TH> <TH align=3Dleft> <P class=3D"">Study design/evidence class</P></TH> <TH align=3Dleft> <P class=3D"">Intervention (# pts)</P></TH> <TH align=3Dleft> <P class=3D"">Population/previous treatment</P></TH> <TH align=3Dleft> <P class=3D"">Median survival</P></TH> <TH align=3Dleft> <P class=3D""># Pts with recurrence/progression after=20 retreatment<SUP>a</SUP> </P></TH> <TH align=3Dleft> <P class=3D"">Median time to recurrence/progression after=20 retreatment</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Cooper [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR5">5</A></CITE>]=20 (1990) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D4> <P class=3D"">WBRT (<I>n</I> =3D 52) </P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Median: NR</P></TD> <TD align=3Dleft rowSpan=3D4> <P class=3D"">NR</P></TD> <TD align=3Dleft rowSpan=3D4> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Mean survival: 22.4 weeks</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Initial treatment: WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Sadikov [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR6">6</A></CITE>]=20 (2007) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">WBRT (<I>n</I> =3D 72) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">4.1 months</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">NR</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Initial treatment: WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Wong [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR7">7</A></CITE>]=20 (1997) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">WBRT (<I>n</I> =3D 86) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">4.0 months</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">NR</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Initial treatment: = WBRT</P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D""><I>BM</I> Brain metastases, <I>NR</I> Not reported, = <I>Pts</I>=20 Patients, <I>WBRT</I> Whole-brain radiation therapy </DIV></DIV> <DIV class=3DCaptCont> <DIV class=3D""><SUP>a</SUP>Number of pts with recurrence/progression of = brain=20 metastases, unless otherwise specified </DIV></DIV></DIV><A = name=3DTab2></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 2 </SPAN>Surgical = resection=20 for recurrent/progressive brain metastases </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">First author (Year)</P></TH> <TH align=3Dleft> <P class=3D"">Study design/evidence class</P></TH> <TH align=3Dleft> <P class=3D"">Intervention (# pts)</P></TH> <TH align=3Dleft> <P class=3D"">Population/previous treatment</P></TH> <TH align=3Dleft> <P class=3D"">Median survival</P></TH> <TH align=3Dleft> <P class=3D""># Pts with recurrence/progression after=20 retreatment<SUP>a</SUP> </P></TH> <TH align=3Dleft> <P class=3D"">Median time to recurrence/progression after=20 retreatment</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Arbit [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR8">8</A></CITE>]=20 (1995) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Surgery (<I>n</I> =3D 32) </P></TD> <TD align=3Dleft> <P class=3D"">Recurrent BM from NSCLC</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">10 months</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">NR</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Initial treatment included surgical = resection</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Bindal [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR9">9</A></CITE>]=20 (1995) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Surgery (<I>n</I> =3D 48) </P></TD> <TD align=3Dleft> <P class=3D"">Recurrent BM</P></TD> <TD align=3Dleft rowSpan=3D5> <P class=3D"">11.5 months</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">At original site only: 18/48 (38%)</P></TD> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Overall in brain: 7.7 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Initial treatment: surgical=20 resection =B1 WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">At distant brain site only: 3/48 (6%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">At original + distant sites: 5/48 = (10%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Overall in brain: 26/48 (54%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Truong [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR10">10</A></CITE>]=20 (2006) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Surgery (<I>n</I> =3D 32) </P></TD> <TD align=3Dleft> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">8.9 months</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">At original site: 9/32 (28%)</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">At original site: 6.2 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">BM had been previously treated with SRS (either as = initial or=20 salvage treatment)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Vecil[<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR11">11</A></CITE>]=20 (2005) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Surgery (<I>n</I> =3D 61) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive ≤3 BM</P></TD> <TD align=3Dleft rowSpan=3D4> <P class=3D"">11.1 months</P></TD> <TD align=3Dleft> <P class=3D"">At original site only: 4/61 (7%)</P></TD> <TD align=3Dleft> <P class=3D"">Overall in brain: 5 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">At distant brain site only: 19/61 (31%)</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">At distant sites in brain: = 8.4 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Initial treatment: SRS</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">At original + distant sites: 9/61 = (15%)</P></TD> <TD align=3Dleft> <P class=3D"">At original site: Median: could not be=20 estimated</P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D""><I>BM</I> Brain metastases, <I>NR</I> Not reported, = <I>NSCLC</I>=20 Non-small cell lung cancer, <I>Pts</I> Patients, <I>SRS</I> Stereotactic = radiosurgery, <I>WBRT</I> Whole-brain radiation therapy </DIV></DIV> <DIV class=3DCaptCont> <DIV class=3D""><SUP>a</SUP>Number of pts with recurrence/progression of = brain=20 metastases, unless otherwise specified </DIV></DIV></DIV><A = name=3DTab3></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 3 </SPAN>SRS for=20 recurrent/progressive brain metastases </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">First author (Year)</P></TH> <TH align=3Dleft> <P class=3D"">Study design/evidence class</P></TH> <TH align=3Dleft> <P class=3D"">Intervention (# pts)</P></TH> <TH align=3Dleft> <P class=3D"">Population/previous treatment</P></TH> <TH align=3Dleft> <P class=3D"">Median survival</P></TH> <TH align=3Dleft> <P class=3D""># Pts with recurrence/progression after=20 retreatment<SUP>a</SUP> </P></TH> <TH align=3Dleft> <P class=3D"">Median time to recurrence/progression after=20 retreatment</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Akyurek [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR12">12</A></CITE>]=20 (2007) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D5> <P class=3D"">SRS (<I>n</I> =3D 15) </P></TD> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Recurrent/progressive BM from breast cancer</P></TD> <TD align=3Dleft rowSpan=3D5> <P class=3D"">14 months</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">At original site: 1 year local</P></TD> <TD align=3Dleft rowSpan=3D5> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Control rate: 77%</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">At distant brain sites: 1 year distant control = rate:=20 57%</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Initial BM treatment: WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Chen [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR13">13</A></CITE>]=20 (2000) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D4> <P class=3D"">SRS (<I>n</I> =3D 45) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D4> <P class=3D"">28 weeks</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Local control (by lesion for 84% of lesions with = data):=20 90%</P></TD> <TD align=3Dleft rowSpan=3D4> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Initial BM treatment included = SRS =B1 WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">1 year freedom from tumor progression: = 94%</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Combs [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR14">14</A></CITE>]=20 (2004) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Case series [For the recurrent group (G3) = only]</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">SRS for recurrent BM (<I>n</I> =3D 39) = </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM from breast cancer</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">19 months</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">NR</P></TD> <TD align=3Dleft> <P class=3D"">At original sites: 9 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">At distant brain sites: 7 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Initial BM treatment: WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Davey [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR15">15</A></CITE>]=20 (2007) </P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Retrospective cohort study with historical = controls</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 35) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 16 weeks</P></TD> <TD align=3Dleft rowSpan=3D4> <P class=3D"">NR</P></TD> <TD align=3Dleft rowSpan=3D4> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">G2: Fractionated SRS (2 fractions) = (<I>n</I> =3D 69)=20 </P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">G2: 30 weeks (Survival curves: log-normal; = univariate=20 <I>p</I> =3D 0.0155) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Initial BM treatment included WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D6> <P class=3D"">Davey [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR16">16</A></CITE>]=20 (1994) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Prospective single arm phase I/II trial</P></TD> <TD align=3Dleft rowSpan=3D6> <P class=3D"">SRS (<I>n</I> =3D 12 pts) </P></TD> <TD align=3Dleft> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D6> <P class=3D"">6 months</P></TD> <TD align=3Dleft> <P class=3D""># pts with local recurrence: 9/12 (75%)</P></TD> <TD align=3Dleft rowSpan=3D6> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Initial BM treatment: WBRT</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Radiological response at 4 weeks (by lesion): = Complete=20 response 3/19 (16%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Partial response 6/19 (32%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">No change 10/19 (53%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Progression 0/19</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Hoffman [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR17">17</A></CITE>]=20 (2001) </P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Case series [For the recurrent group (G3) = only]</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">SRS for recurrent BM (<I>n</I> =3D 53) = </P></TD> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Recurrent/progressive BM from lung cancer</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">10.0 months</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">1 year freedom from LR rate: 36%</P></TD> <TD align=3Dleft> <P class=3D"">At original site: 9.2 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">At distant site: 16.5 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">1 year freedom from DR rate: 55%</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Initial BM treatment: WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Overall in brain: 5.8 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">1 year freedom from any intracranial = recurrence:=20 27%</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Kwon [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR18">18</A></CITE>]=20 (2007) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">SRS (<I>n</I> =3D 43) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">32 weeks</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">6 month local control rate: 91%</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Initial BM treatment included SRS</P></TD> <TD align=3Dleft> <P class=3D"">6 month overall brain control rate: = 86%</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Loeffler [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR19">19</A></CITE>]=20 (1990) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">SRS (<I>n</I> =3D 18) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">NR</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">At original site: # of lesions that decreased or = stabilized:=20 21/21 (100%)</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Initial BM treatment: WBRT =B1 surgery = (except in 1 pt=20 who refused WBRT)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Noel [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR20">20</A></CITE>]=20 (2003) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Case series [For the recurrent group (G3) = only]</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">SRS for recurrent group(<I>n</I> =3D 36) = </P></TD> <TD align=3Dleft> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">8 months</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">1 year local control rate: 86%</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Overall in brain: Median: not reached</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Initial BM treatment: WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Noel [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR21">21</A></CITE>]=20 (2001) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">SRS (<I>n</I> =3D 54) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">7.8 months</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">1 year local control rate (by lesion): = 91%</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Median time to development of new BM or = leptomeningeal=20 carcinomatosis: 24.5 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Initial BM treatment: WBRT</P></TD> <TD align=3Dleft> <P class=3D"">1 year overall brain control rate: = 65%</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Sheehan [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR22">22</A></CITE>]=20 (2005) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">SRS (<I>n</I> =3D 27) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM from SCLC</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">4.5 months</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Local tumor control (Of 21 lesions in 14 pts with = data): 17/21=20 (81%) lesions; 12/14 (86%) pts</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Initial BM treatment included WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Shuto [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR23">23</A></CITE>]=20 (2004) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D5> <P class=3D"">SRS (<I>n</I> =3D 16) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D5> <P class=3D"">22.4 months (from 1st SRS treatment)</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Tumor response:[Of 173/242 (72%) lesions with data]: = Complete=20 response 121/173 (70%)</P></TD> <TD align=3Dleft rowSpan=3D5> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Initial BM treatment included SRS</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Partial response or no change 47/173 = (27%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Progression 5/173 (3%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Yamanaka [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR24">24</A></CITE>]=20 (1999) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">SRS (<I>n</I> =3D 41) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">15 months (from first SRS treatment)</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Overall local control rate after 2nd SRS (by = lesion):=20 93%</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D6> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Initial BM treatment included SRS</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Response after 2nd SRS [Of 61 lesions evaluable]: = Disappeared=20 16/61 (26%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Decreased 40/61 (66%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Unchanged 1/61 (2%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Increased 4/61 (7%)</P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D""><I>BM</I> Brain metastases, <I>BR</I> Brain recurrence=20 (local + distant), <I>DR</I> Distant recurrence in brain, = <I>G1</I>=20 Group 1, <I>G2</I> Group 2, <I>LR</I> Local recurrence at original site = in=20 brain, <I>NSCLC</I> Non-small cell lung cancer, <I>NR</I> Not reported,=20 <I>PR</I> Partial response, <I>Pts</I> Patients, <I>SCLC</I> Small cell = lung=20 cancer </DIV></DIV> <DIV class=3DCaptCont> <DIV class=3D""><SUP>a</SUP>Number of pts with recurrence/progression of = brain=20 metastases, unless otherwise specified </DIV></DIV></DIV><A = name=3DTab4></A> <DIV class=3DCapt><SPAN = class=3DCaptNr>Table 4 </SPAN>Chemotherapy for=20 recurrent/progressive brain metastases </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">First author (Year)</P></TH> <TH align=3Dleft> <P class=3D"">Study design/evidence class</P></TH> <TH align=3Dleft> <P class=3D"">Intervention (# pts)</P></TH> <TH align=3Dleft> <P class=3D"">Population/previous treatment</P></TH> <TH align=3Dleft> <P class=3D"">Median survival</P></TH> <TH align=3Dleft> <P class=3D""># Pts with recurrence/progression after=20 retreatment<SUP>a</SUP> </P></TH> <TH align=3Dleft> <P class=3D"">Median time to recurrence/progression after=20 retreatment</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Abrey [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR25">25</A></CITE>]=20 (2001) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II trial</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">TMZ (<I>n</I> =3D 41) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">6.6 months</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Response in brain: Complete response 0/41 = (0%)</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Overall in brain: 1.97 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D6> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Initial BM treatment varied (all received=20 WBRT =B1 other modalities)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Partial response 2/41 (5%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Stable disease 15/41 (37%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Progressive disease 17/41 (42%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Not assessed 7/41 (17%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D8> <P class=3D"">Br=F6cker [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR26">26</A></CITE>]=20 (1996) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm study</P></TD> <TD align=3Dleft rowSpan=3D8> <P class=3D"">WBRT + fotemustine = (<I>n</I> =3D 13) </P></TD> <TD align=3Dleft rowSpan=3D8> <P class=3D"">Progressive multiple BM from melanoma</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Overall: Not reported</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Response in brain: (12 evaluable pts)</P></TD> <TD align=3Dleft rowSpan=3D8> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Pts with partial response/stable disease: = 6 months</P></TD> <TD align=3Dleft> <P class=3D"">Complete response: 0/13 (0%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Partial response 4/13 (31%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Stable disease 3/13 (23%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Other pts: 2 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Progressive disease 6/13 (46%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Not assessable: 1/13 (8%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Christodoulou [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR27">27</A></CITE>]=20 (2005) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II trial</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">TMZ + cisplatin = (<I>n</I> =3D 32) </P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">5.5 months</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Response both in brain + extra-cranial = sites:=20 Complete response 1/32 (3%)</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Median time to progression for all pts:=20 2.9 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D6> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Partial response 8/32 (25%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Partial response in brain only 1/32 = (3%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Stable disease 5/32 (16%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Progressive disease 6/32 (19%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Not evaluable 11/32 (34%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Feun [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR28">28</A></CITE>]=20 (1990) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P></TD> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Intracarotid cisplatin-based chemotherapy=20 (<I>n</I> =3D 23) </P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Recurrent/progressive BM from melanoma</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Median: Not reported</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Objective improvement by CT scan 7/23 (30%)</P></TD> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Median time to progression in responding pts:=20 20 weeks</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Range: 1 to 65 weeks</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Initial BM treatment included WBRT in 22/23 = pts</P></TD> <TD align=3Dleft> <P class=3D"">Stable disease 3/23 (13%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Failed to respond 13/23 (57%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D6> <P class=3D"">Giorgio [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR29">29</A></CITE>]=20 (2005) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II trial</P></TD> <TD align=3Dleft rowSpan=3D6> <P class=3D"">TMZ (<I>n</I> =3D 30) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent or progressive BM from NSCLC</P></TD> <TD align=3Dleft rowSpan=3D6> <P class=3D"">6 months</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Response in brain: Complete response 2/30 = (7%)</P></TD> <TD align=3Dleft rowSpan=3D6> <P class=3D"">Median time to progression of brain metastases in = all pts:=20 3.6 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Previous BM treatment: WBRT and chemotherapy for = BM</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Partial response 1/30 (3%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Stable disease 3/30 (10%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Progressive disease 24/30 (80%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Groen [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR30">30</A></CITE>]=20 (1993) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm study</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Carboplatin (<I>n</I> =3D 20) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM from SCLC</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">15 weeks</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Response in brain: Complete response 2/20 = (10%)</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Median duration of response: = 8 weeks</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D6> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Initial BM with teniposide, reinduction combination=20 chemotherapy or cranial irradiation</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Partial response 6/20 (30%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Stable disease 4/20 (20%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Progressive disease 4/20 (20%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Clinically determined progressive disease 4/20 = (20%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D8> <P class=3D"">Hwu [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR31">31</A></CITE>]=20 (2005) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II trial</P></TD> <TD align=3Dleft rowSpan=3D8> <P class=3D"">TMZ + thalidomide = (<I>n</I> =3D 26) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM from melanoma</P></TD> <TD align=3Dleft rowSpan=3D8> <P class=3D"">5 months</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Response in brain: Complete response 2/26 = (8%)</P></TD> <TD align=3Dleft rowSpan=3D8> <P class=3D"">Median duration of response or stable disease in = brain:=20 4 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Initial BM treatment varied</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Chemotherapy-naive patients</P></TD> <TD align=3Dleft> <P class=3D"">Partial response 1/26 (4%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Minor response/stable: 7/26 (27%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Progressive disease: 4/26 (15%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Unknown 1/26 (4%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Not assessable 11/26 (42%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D6> <P class=3D"">Iwamoto [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR32">32</A></CITE>]=20 (2008) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P></TD> <TD align=3Dleft rowSpan=3D6> <P class=3D"">TMZ + vinorelbine = (<I>n</I> =3D 38) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/refractory BM</P></TD> <TD align=3Dleft rowSpan=3D6> <P class=3D"">5 months</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Response in brain: Objective response 5% (CR 1/38; = minor=20 response 1/38)</P></TD> <TD align=3Dleft rowSpan=3D6> <P class=3D"">Median progression free survival: = 1.9 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Initial BM treatment varied</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Stable disease 5/38 (13%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Progressive disease 29/38 (76%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Not evaluable 2/38 (5%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Kaba [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR33">33</A></CITE>]=20 (1997) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm study</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">TPDC-FuHu (<I>n</I> =3D 97 assessable/115 = enrolled)=20 </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">25 weeks</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Response in brain: Complete response 4/97 = (4%)</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Median time to progression for all pts:=20 12 weeks</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D6> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Initial BM treatment: surgery and/or radiation=20 therapy</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Partial response 14/97 (14%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Minor response 9/97 (9%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Stable disease 25/97 (26%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Progressive disease 45/97 (46%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D7> <P class=3D"">Omuro [<CITE><A=20 = href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR34">34</A></CITE>]=20 (2006) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase I trial</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">TMZ + vinorelbine = (<I>n</I> =3D 21) </P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">17 weeks</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Response in brain: (Of 18 evaluable pts)</P></TD> <TD align=3Dleft rowSpan=3D7> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D6> <P class=3D"">Evidence class III</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D5> <P class=3D"">Initial BM treatment varied</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Partial response 1/18 (6%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Minor response 1/18 (6%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Stable disease 6/18 (33%)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Progressive disease 10/18 = (56%)</P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D""><I>BM</I> Brain metastases, = <I>NSCLC</I> Non-small cell=20 lung cancer, <I>NR</I> Not reported, <I>NS</I> Not = significant,=20 <I>Pts</I> Patients, <I>SCLC</I> Small cell lung cancer,=20 <I>TMZ</I> Temozolomide, <I>TPDC-FuHu</I> Hydroxyurea,=20 <I>WBRT</I> Whole-brain radiation therapy </DIV></DIV> <DIV class=3DCaptCont> <DIV class=3D""><SUP>a</SUP>Number of pts with recurrence/progression of = brain=20 metastases, unless otherwise specified </DIV></DIV></DIV></DIV></DIV> <P class=3D"">No class I or II evidence was identified that specifically = addressed=20 the question of which therapies (i.e., repeated WBRT, SRS, surgery or=20 chemotherapy) were beneficial in the setting of recurrent/progressive = metastatic=20 brain. In fact, only one of the 30 included studies compared different=20 modalities for the treatment of recurrent/progressive brain metastases = [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR15">15</A></CITE>].=20 The remaining 29 papers provide non-comparative outcome data on the = treatment of=20 recurrent/progressive brain metastases. </P> <DIV class=3D""><A name=3DSec9></A> <DIV class=3DHeading3>WBRT</DIV> <P class=3D"">Three case series addressed the question of whether=20 re-administration of WBRT was beneficial for patients in whom previously = treated=20 brain metastases recurred/progressed [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR5">5</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR7">7</A></CITE>]=20 (Table <A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#Tab1">1</A>).=20 These studies are retrospective analyses of 52, 72 and 86 patients,=20 respectively, and they offer only very limited data as to whether = patients died=20 from neurologic causes versus systemic disease progression. The average=20 re-irradiation dose for these patients was in the range of = 20=9625 Gy over=20 multiple fractions. The post-re-irradiation median survival was 4 or=20 5 months in all of the series. </P> <P class=3D"">In the largest of the case series = (<I>n</I> =3D 86), 70% of=20 patients had either complete or partial resolution of neurological = symptoms=20 following re-irradiation. In the two other case series, the percentage = of=20 patients whose neurologic function improved following re-irradiation was = 42% and=20 31%, respectively [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR5">5</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR6">6</A></CITE>].=20 </P> <P class=3D"">One patient experienced symptoms of dementia attributed to = radiation=20 therapy in each of the two series reporting information on longer term = adverse=20 effects [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR6">6</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR7">7</A></CITE>].=20 </P> <P class=3D"">No studies were identified that evaluated the use of WBRT = in the=20 setting of recurrent/progressive brain metastases for patients whose = initial=20 management did not include WBRT. </P></DIV> <DIV class=3D""><A name=3DSec10></A> <DIV class=3DHeading3>Surgical resection</DIV> <P class=3D"">Four cases series addressed the use of surgical resection = for=20 recurrent/progressive brain metastases [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR8">8</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR11">11</A></CITE>],=20 as outlined in Table <A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#Tab2">2</A>.=20 Two of these retrospective studies reported outcomes for patients who = underwent=20 surgical resection for recurrent/progressive brain metastases who also = had=20 previously been treated with SRS =B1 WBRT [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR10">10</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR11">11</A></CITE>].=20 In the study by Vecil et al. 61 patients with three or fewer recurrent = brain=20 metastases underwent surgical resection for at least one index brain = metastasis=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR11">11</A></CITE>].=20 Treatment of non-index brain metastases varied. Major surgical = complications=20 occurred in seven patients. From the date of resection, median survival = was=20 11.1 months and median time to any recurrence in the brain was=20 5 months. Cause of death was neurologic in 15% of patients and=20 neurologic/systemic combined in 34%. The second study, conducted by = Truong et=20 al., included 32 patients who had previously been treated with SRS and = who had=20 MRI and/or clinical evidence of brain metastasis progression. To be = considered=20 for surgical resection, patients needed to have a KPS ≥60 and = stable or absent=20 systemic disease. Median survival from the time of resection was=20 8.9 months. Seven patients experienced surgical complications. = Cause of=20 death was neurologic in 48% of patients [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR10">10</A></CITE>].=20 </P> <P class=3D"">Two case series evaluated the outcome of re-operation for = recurrent=20 brain metastases [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR8">8</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR9">9</A></CITE>].=20 Bindal et al. reported on 48 patients who had surgical resection of a = brain=20 metastasis as part of their initial treatment and then underwent = resection for=20 recurrent disease. From the time of re-operation, median survival was=20 11.5 months and the median time to recurrence was 7.7 months. = Of the=20 26 patients who developed a second recurrence, 17 underwent another = surgical=20 resection. For the 25 patients in which cause of death was known, it was = neurologic in 48% and combined neurologic/systemic in 12% [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR9">9</A></CITE>].=20 As part of a larger study, Arbit et al., provide retrospective data on = 32=20 patients with non-small cell lung cancer (NSCLC) who underwent = re-operation for=20 recurrent brain metastases. From the date of re-operation, median = survival was=20 10 months. Time to recurrence/progression was not reported = [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR8">8</A></CITE>].=20 </P></DIV> <DIV class=3D""><A name=3DSec11></A> <DIV class=3DHeading3>SRS</DIV> <P class=3D"">Thirteen studies addressed the role of SRS for = recurrent/progressive=20 brain metastases [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR12">12</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR24">24</A></CITE>].=20 Nine studies evaluated the use of SRS for recurrent/progressive disease = in=20 patients whose initial management included WBRT [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR12">12</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR14">14</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR17">17</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR19">19</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR22">22</A></CITE>].=20 One of these studies was prospective [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR16">16</A></CITE>].=20 This single-arm phase I/II study enrolled 12 patients whose life = expectancy was=20 ≥3 months and who had both clinical and radiologic evidence = of brain=20 metastases progression following treatment with WBRT. All patients were = followed=20 to recurrence at the SRS treated site or until death. In total, 20 brain = metastases in the 12 patients were treated by radiosurgery. From the = date of SRS=20 treatment, median survival was 6 months. Nine patients developed = evidence=20 of progressive disease at SRS treated sites. Time to progression was not = reported. Of the other eight studies that addressed the role of SRS for=20 recurrent disease in patients whose upfront treatment included WBRT, = four=20 specifically evaluated SRS treatment for recurrent/progressive brain = metastases=20 from particular primary tumor types=96breast cancer (2 case series = [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR12">12</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR14">14</A></CITE>]),=20 small cell lung cancer (SCLC) (1 case series [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR22">22</A></CITE>])=20 and lung cancer, predominantly NSCLC (1 case series [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR17">17</A></CITE>]).=20 See Table <A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#Tab3">3</A>=20 for details. </P> <P class=3D"">The only comparative study that met the eligibility = criteria for the=20 systematic review evaluated single-dose SRS versus split-dose (2 dose) = SRS for=20 recurrent/progressive disease in 104 patients whose initial management = included=20 WBRT [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR15">15</A></CITE>].=20 In this retrospective cohort study with historical controls, median = survival was=20 significantly longer for patients who received split-dose SRS compared = to=20 single-dose SRS (30 vs. 16 weeks; <I>p</I> =3D 0.015). = Time to=20 recurrence/progression was not reported. </P> <P class=3D"">Four case series evaluated the use of SRS for = recurrent/progressive=20 brain metastases in patients whose previous treatment included = radiosurgery=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR13">13</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR18">18</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR23">23</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR24">24</A></CITE>],=20 as outlined in Table <A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#Tab3">3</A>.=20 Only two of these case series provide survival data from the date of SRS = for=20 recurrent disease [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR13">13</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR18">18</A></CITE>].=20 In the series by Kwon et al., of 43 patients who underwent salvage SRS, = median=20 survival from the time of SRS for recurrent/progressive disease was=20 32 weeks and the local control rate at 6 months was 91% = [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR18">18</A></CITE>].=20 In the case series by Chen et al., of 45 patients, median survival from = the time=20 of SRS for recurrent brain metastases was 28 weeks [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR13">13</A></CITE>].=20 The 1 year freedom from progression rate was 94%. </P></DIV> <DIV class=3D""><A name=3DSec12></A> <DIV class=3DHeading3>Chemotherapy</DIV> <P class=3D"">Ten studies evaluated the role of chemotherapy in patients = with=20 recurrent/progressive metastatic brain disease [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR25">25</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR34">34</A></CITE>].=20 Of these, five are prospective single arm phase II studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR25">25</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR27">27</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR29">29</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR31">31</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR32">32</A></CITE>]=20 and five are case series [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR26">26</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR28">28</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR30">30</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR33">33</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR34">34</A></CITE>].=20 Refer to Table <A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#Tab4">4</A>=20 for details. The agents used in these studies varied from intracarotid=20 administration of cisplatin, to temozolomide alone or with thalidomide,=20 vinorelbine, fotemustine or cisplatin. Five of the studies investigated = the role=20 of chemotherapy specifically for patients with recurrent/progressive = brain=20 metastases from particular primary tumor types=97melanoma (3 studies) = [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR26">26</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR28">28</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR31">31</A></CITE>],=20 NSCLC (1 study) [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR29">29</A></CITE>],=20 and SCLC (1 study) [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR30">30</A></CITE>].=20 </P> <P class=3D"">Median survival in patients with recurrent/progressive = brain=20 metastases treated with chemotherapy ranged from 3.5 to 6.6 months=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR25">25</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/4711x523t24123p7/fulltext.htm= l#CR34">34</A></CITE>].=20 The median time to recurrence after retreatment with chemotherapy in = these=20 studies ranged from 2 to 4 months. These studies indicate that some = patients with recurrent or progressive brain metastases will have an = objective=20 radiographic response and/or improvement in functional status after = treatment=20 with chemotherapy. </P> <P class=3D""><B><I>If WBRT is used in the setting of recurrent and/or = progressive=20 brain metastases, what impact does tumor histopathology have on = treatment=20 outcomes?</I></B> </P> <P class=3D"">No studies were identified that met the eligibility = criteria for=20 this question.</P></DIV></DIV> <DIV class=3D""><A name=3DSec13></A> <HR> <DIV class=3Dheading2>Discussion and conclusions</DIV> <P class=3D"">No studies that provide class I or II evidence were = identified which=20 met the eligibility criteria and specifically addressed the question of = which=20 adjuvant therapies (i.e., WBRT, SRS, surgical resection or chemotherapy) = are=20 beneficial in the setting of recurrent/progressive metastatic brain = tumors.=20 Furthermore, all but one of the included studies that provide class III = evidence=20 on this topic are non-comparative. While multiple randomized clinical = trials=20 have examined the benefits for up-front combined therapies (e.g., WBRT = plus SRS,=20 WBRT plus surgery), none have been performed specifically to address the = question of the benefits of further SRS, surgery or chemotherapy in = cases of=20 recurrent/progressive brain metastases. Therefore, no level 1 or level 2 = recommendations can be made. </P> <P class=3D"">Given that none of the included studies compared the = different=20 modalities (WBRT, SRS, surgical resection or chemotherapy) for the = treatment of=20 recurrent/progressive brain metastases, the relative merits of one = approach=20 versus another are yet to be determined. Furthermore, retrospective = studies of=20 patients with recurrent/progressive brain metastases who have previously = undergone WBRT, and then received subsequent re-irradiation, show = conflicting=20 results with regard to neurologic improvement and quality of life. </P> <P class=3D"">It is recommended that treatment of recurrent/progressive = brain=20 metastases be individualized based on functional status, extent of = disease,=20 volume/number of metastases, recurrence or progression at original = versus=20 non-original site, previous treatment and type of primary cancer. In = this=20 context, re-irradiation (either WBRT and/or SRS), surgical excision or, = to a=20 lesser extent, chemotherapy, can be recommended depending on a = patient=92s=20 specific condition and based on the judgment of the patient=92s treating = physician. </P> <P class=3D"">As no studies were identified that met the eligibility = criteria for=20 the question addressing whether tumor histopathology impacts treatment = outcomes=20 when WBRT is used in the setting of recurrent/progressive brain = metastases, no=20 evidence-based recommendations can be made on this topic. </P></DIV> <DIV class=3D""><A name=3DSec14></A> <HR> <DIV class=3Dheading2>Key issues for further investigation</DIV> <P class=3D"">This systematic review of the evidence highlights the = critical need=20 for comparative studies that directly evaluate the outcome of different=20 treatment modalities for patients with recurrent/progressive metastatic = brain=20 disease, while simultaneously addressing the role of tumor = histopathology in=20 treatment outcomes. In addition, understanding potential differences in = the mode=20 of death (neurologic versus systemic progression), will help answer the=20 important question of whether treating recurrent/progressive lesions = delays=20 neurologic progression long enough to allow more aggressive therapy for = the=20 primary systemic disease. </P> <P class=3D"">Moreover, specific patient characteristics offer important = clinical=20 variables in evaluating treatment for recurrent/progressive metastases, = such as=20 if the recurrence/progression occurs at the site of the primary focal = treatment=20 (surgery or SRS) and if it is clinically symptomatic or discovered = because of=20 routine surveillance neuroimaging. Indeed, as the treatment of=20 recurrent/progressive brain metastases is undertaken primarily with = palliative=20 intent, it is important to stress which symptoms these treatments are = poised to=20 address and how overall patient quality of life is going to be affected = by any=20 re-treatment modality. </P> <P class=3D""><I>No ongoing or recently closed randomized clinical = trials=20 addressing the re-treatment of patients with recurrent/progressive brain = metastases were found that met the eligibility criteria</I>. </P></DIV> <DIV class=3DAcknowledgments><SPAN=20 class=3DAcknowledgmentsHeading>Acknowledgments </SPAN><SPAN = class=3D"">We=20 would like to acknowledge the contributions of the McMaster = Evidence-based=20 Practice Center (EPC), Dr. Parminder Raina (Director). Dr. Lina = Santaguida=20 (Co-Associate Director, Senior Scientist) led the EPC staff, which was=20 responsible for managing the systematic review process, searching for = and=20 retrieving, reviewing, data abstraction of all articles, preparation of = the=20 tables and the formatting and editing of the final manuscripts. We would = also=20 like to acknowledge the contributions of Roxanne Martinez in preparing = this=20 manuscript.</SPAN> <DIV class=3DFormalPara> <DIV class=3D""><SPAN style=3D"FONT-STYLE: italic; TEXT-DECORATION: = none">Disclaimer=20 of liability</SPAN> The information in these guidelines = reflects the=20 current state of knowledge at the time of completion. The presentations = are=20 designed to provide an accurate review of the subject matter covered. = These=20 guidelines are disseminated with the understanding that the = recommendations by=20 the authors and consultants who have collaborated in their development = are not=20 meant to replace the individualized care and treatment advice from a = patient=92s=20 physician(s). If medical advice or assistance is required, the services = of a=20 competent physician should be sought. The proposals contained in these=20 guidelines may not be suitable for use in all circumstances. The choice = to=20 implement any particular recommendation contained in these guidelines = must be=20 made by a managing physician in light of the situation in each = particular=20 patient and on the basis of existing resources. </DIV></DIV> <DIV class=3DFormalPara> <DIV class=3D""><SPAN=20 style=3D"FONT-STYLE: italic; TEXT-DECORATION: = none">Disclosures</SPAN> =20 All panel members provided full disclosure of conflicts of interest, if = any,=20 prior to establishing the recommendations contained within these = guidelines.=20 </DIV></DIV> <DIV class=3DFormalPara> <DIV class=3D""><SPAN style=3D"FONT-STYLE: italic; TEXT-DECORATION: = none">Open=20 Access</SPAN> This article is distributed under the terms of = the=20 Creative Commons Attribution Noncommercial License which permits any=20 noncommercial use, distribution, and reproduction in any medium, = provided the=20 original author(s) and source are credited. </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>Patchell RA (2003) The management of brain = metastases.=20 Cancer Treat Rev 29(6):533=96540<BR><A=20 href=3D"http://dx.doi.org/10.1016/S0305-7372(03)00105-1" = target=3D_blank><IMG=20 height=3D20 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/4711x523t24123p7/crossref_link= .gif"=20 width=3D65 border=3D0></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D14585263"=20 target=3D_blank><IMG height=3D20 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/4711x523t24123p7/pubmed_link.g= if"=20 width=3D65 border=3D0></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>2.</TD> <TD><A name=3DCR2></A>Robinson PD, Kalkanis SN, Linskey ME, = Santaguida PL=20 (2009) Methodology used to develop the AANS/CNS management of = brain=20 metastases evidence-based clinical practice parameter guidelines. = J=20 Neurooncol. doi:<A=20 = href=3D"http://dx.doi.org/10.1007/s11060-009-0059-2">10.1007/s11060-009-0= 059-2</A>=20 </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>3.</TD> <TD><A name=3DCR3></A>Centre for Evidence-Based Physiotherapy (2009) = Physiotherapy Evidence Database (PEDro). <A=20 href=3D"http://www.pedro.org.au/">http://www.pedro.org.au/</A>. = Last=20 Accessed in Jan 2009 </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>4.</TD> <TD><A name=3DCR4></A>Maher CG, Sherrington C, Herbert RD, Moseley = AM,=20 Elkins M (2003) Reliability of the PEDro scale for rating quality = of=20 randomized controlled trials. 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