10.1007/s11060-009-0061-8</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/s11060-009-0061-8</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Invited Manuscript</H2> <DIV class=3DHeading1><A name=3Dtitle></A>The role of surgical resection = in the=20 management of newly diagnosed brain metastases: a systematic review and=20 evidence-based clinical practice guideline </DIV> <P class=3DAuthorGroup>Steven N. Kalkanis<SUP>1 <A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#ContactOfAuthor1"><IMG=20 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/e088515136888570/contact.gif" = border=3D0></A></SUP>, Douglas Kondziolka<SUP>2</SUP>,=20 Laurie E. Gaspar<SUP>3</SUP>, = Stuart H. Burri<SUP>4</SUP>,=20 Anthony L. Asher<SUP>5</SUP>, = Charles S. Cobbs<SUP>6</SUP>,=20 Mario Ammirati<SUP>7</SUP>, = Paula D. Robinson<SUP>8</SUP>,=20 David W. Andrews<SUP>9</SUP>, = Jay S. Loeffler<SUP>10</SUP>,=20 Michael McDermott<SUP>11</SUP>, = Minesh P. Mehta<SUP>12</SUP>,=20 Tom Mikkelsen<SUP>13</SUP>, = Jeffrey J. Olson<SUP>14</SUP>,=20 Nina A. Paleologos<SUP>15</SUP>,=20 Roy A. Patchell<SUP>16</SUP>, = Timothy C. Ryken<SUP>17</SUP>=20 and Mark E. Linskey<SUP>18</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, Henry Ford = Health=20 System, 2799 West Grand Blvd, K-11, Detroit, MI 48202,=20 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 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=3DAff3></A>(3) </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=3DAff4></A>(4) </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=3DAff5></A>(5) </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=3DAff6></A>(6) </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=3DAff7></A>(7) </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=3DAff8></A>(8) </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=3DAff9></A>(9) </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=3DAff10></A>(10) </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=3DAff11></A>(11) </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=3DAff12></A>(12) </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=3DAff13></A>(13) </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=3DAff14></A>(14) </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=3DAff15></A>(15) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurology, Northshore = University=20 Health System, Evanson, IL, 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 Neurology, Barrow = Neurological=20 Institute, Phoenix, AZ, 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 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=3DAff18></A>(18) </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> <P><A name=3DContactOfAuthor1></A></P> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/e088515136888570/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>4 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>Should patients with = newly-diagnosed metastatic brain tumors undergo open surgical resection = versus=20 whole brain radiation therapy (WBRT) and/or other treatment modalities = such as=20 radiosurgery, and in what clinical settings?=20 <DIV class=3DAbstractPara> <DIV class=3D""><B>Target population</B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D"">These recommendations apply to adults with a newly = diagnosed=20 single brain metastasis amenable to surgical resection.</DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B>Recommendations</B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B><I>Surgical resection plus WBRT versus surgical = resection=20 alone</I></B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 1</I> Surgical resection followed by WBRT = represents a=20 superior treatment modality, in terms of improving tumor control at the = original=20 site of the metastasis and in the brain overall, when compared to = surgical=20 resection alone. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B><I>Surgical resection plus WBRT versus=20 SRS =B1 WBRT</I></B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 2</I> Surgical resection plus WBRT, versus = stereotactic=20 radiosurgery (SRS) plus WBRT, both represent effective treatment = strategies,=20 resulting in relatively equal survival rates. SRS has not been assessed = from an=20 evidence-based standpoint for larger lesions (>3 cm) or for = those=20 causing significant mass effect (>1 cm midline shift). = </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 3</I> Underpowered class I evidence along with = the=20 preponderance of conflicting class II evidence suggests that SRS = <I>alone</I>=20 may provide equivalent functional and survival outcomes compared with=20 resection + WBRT for patients with single brain metastases, so = long as=20 ready detection of distant site failure and salvage SRS are possible.=20 </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Note</I> The following question is fully addressed in = the WBRT=20 guideline paper within this series by Gaspar et al. Given that the=20 recommendation resulting from the systematic review of the literature on = this=20 topic is also highly relevant to the discussion of the role of surgical=20 resection in the management of brain metastases, this recommendation has = been=20 included below. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B>Question</B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D"">Does surgical resection in addition to WBRT improve = outcomes when=20 compared with WBRT alone?</DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B>Target population</B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D"">This recommendation applies to adults with a newly = diagnosed=20 single brain metastasis amenable to surgical resection; however, the=20 recommendation does not apply to relatively radiosensitive tumors = histologies=20 (i.e., small cell lung cancer, leukemia, lymphoma, germ cell tumors and = multiple=20 myeloma). </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B>Recommendation</B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B><I>Surgical resection plus WBRT versus WBRT = alone</I></B>=20 </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 1</I> Class I evidence supports the use of = surgical=20 resection plus post-operative WBRT, as compared to WBRT alone, in = patients with=20 good performance status (functionally independent and spending less than = 50% of=20 time in bed) and limited extra-cranial disease. There is insufficient = evidence=20 to make a recommendation for patients with poor performance scores, = advanced=20 systemic disease, or multiple brain metastases. = </DIV></DIV></DIV></DIV></DIV> <P class=3DKeyword><SPAN = class=3DKeywordHeading>Keywords </SPAN>Brain=20 metastases - Surgical resection - Stereotactic=20 radiosurgery - Radiotherapy - Systematic=20 review - Practice guideline </P> <DIV class=3DFulltext> <DIV class=3D""><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Rationale</DIV> <P class=3D"">A significant proportion of adults diagnosed with cancer = will=20 develop brain metastases. According to the 2008 American Cancer Society=20 Registry, approximately 1.4 million Americans are diagnosed with cancer = every=20 year [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR1">1</A></CITE>]=20 and up to 40% of these patients=97over a half million people = annually=97will go onto=20 develop one or more brain metastases [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR2">2</A></CITE>].=20 Of these patients, approximately one-third will be potential candidates = for=20 surgical resection. </P> <P class=3D"">The outcome for patients with brain metastases is = generally poor,=20 with median survivals following WBRT alone in the range of = 3=966 months=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR3">3</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR5">5</A></CITE>].=20 Given this poor prognosis, considerable efforts have been made to = explore=20 additional or alternative treatment modalities that have the potential = to=20 improve survival, quality of life and local tumor control. </P> <P class=3D"">For patients with a single accessible brain metastasis, = surgical=20 resection followed by post-operative WBRT has been compared to WBRT = alone in=20 three randomized control trials (RCTs) [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR3">3</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR5">5</A></CITE>].=20 The evidence for this combined treatment approach is reviewed in the = guideline=20 paper in this series by Gaspar et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR6">6</A></CITE>]=20 Because the data from these randomized comparisons of WBRT alone, versus = surgical resection followed by post-operative WBRT, addresses the role = of=20 surgical resection in the management of patients with a newly diagnosed = brain=20 metastasis, this paper will refer to this evidence in its = recommendations for=20 the role of surgical resection. </P> <P class=3D"">The advent of stereotactic radiosurgery (SRS) has provided = a new and=20 less invasive local treatment modality that, like surgical resection, = has the=20 ability to treat brain metastases while sparing healthy brain tissue. A = key area=20 that this paper will address is the role of surgical resection compared = to SRS=20 in the initial management of patients with brain metastases. </P> <DIV class=3DPara> <DIV class=3D"">The overall objectives of this paper are:=20 <TABLE class=3DOrderedList> <TBODY> <TR vAlign=3Dtop> <TD>1. </TD> <TD>To systematically review the evidence available for the = following=20 treatment comparisons for patients with a newly diagnosed brain=20 metastasis. Please note that =93surgery=94 implies open surgical = resection.=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>Surgery versus WBRT =B1 surgery</TD></TR> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>Surgery =B1 WBRT or partial brain radiotherapy = (RT)=20 versus SRS =B1 WBRT or partial brain RT</TD></TR> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>Surgery =B1 WBRT versus=20 surgery + SRS</TD></TR></TBODY></TABLE></TD></TR> <TR vAlign=3Dtop> <TD>2. </TD> <TD>To make recommendations based on this evidence for the role of = surgery=20 in the management of these = patients.</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, and Cochrane = Database=20 of Abstracts of Reviews of Effects. A broad search strategy using a = combination=20 of 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/e088515136888570/fulltext.htm= l#CR7">7</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 border=3D0> <TBODY> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Published in English.</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Patients with newly diagnosed brain metastases.</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Fully-published (i.e., not in abstract form) peer-reviewed = primary=20 comparative studies (These included the following comparative = study=20 designs for primary data collection: RCTs, non-randomized trials, = cohort=20 studies and case=96control studies). </TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Study comparisons include one or more of the following:=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>Surgery versus WBRT</TD></TR> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>Surgery versus surgery + WBRT</TD></TR> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>Surgery =B1 WBRT or partial brain RT versus=20 SRS =B1 WBRT or partial brain RT</TD></TR> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>Surgery versus surgery + SRS</TD></TR> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>Surgery + WBRT versus=20 surgery + SRS</TD></TR></TBODY></TABLE> <DIV class=3DListPara> <DIV class=3D"">(Where SRS could be single session and = fractionated=20 stereotactic radiotherapy)</DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Number of study participants with a newly diagnosed brain = metastasis=20 ≥5 per study arm for at least two of the study = arms.</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Baseline information on study participants is provided by = treatment=20 group in studies evaluating interventions exclusively in patients = with a=20 newly diagnosed brain metastasis. For studies with mixed = populations=20 (i.e., includes participants with conditions other than newly = diagnosed=20 brain metastases), baseline information is provided for the = intervention=20 sub-groups of participants with a newly diagnosed brain = metastasis.=20 </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 a = priori=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/e088515136888570/fulltext.htm= l#CR8">8</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR9">9</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 for this guideline = series.=20 </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> <DIV class=3DPara> <DIV class=3D"">Overall, 15 publications (14 primary studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR10">10</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR23">23</A></CITE>]=20 and one companion paper [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR24">24</A></CITE>])=20 met the eligibility criteria. Figure <A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#Fig1">1</A>=20 outlines the flow of studies through the review process.=20 <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2009_61_Fig1_HTML.gif=20 src=3D"http://www.springerlink.com/content/e088515136888570/MediaObjects/= 11060_2009_61_Fig1_HTML.gif"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 1 </SPAN>Flow of = studies to=20 final number of eligible studies </DIV> <HR> </DIV></DIV> <DIV class=3D""><A name=3DSec9></A> <DIV class=3DHeading3>Surgical resection versus surgical=20 resection + WBRT</DIV> <DIV class=3DPara> <DIV class=3D"">One RCT [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR10">10</A></CITE>]=20 and three retrospective cohort studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR11">11</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR13">13</A></CITE>]=20 evaluated surgical resection alone compared to surgery plus = post-operative WBRT=20 for the initial management of a single brain metastasis (Table <A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#Tab1">1</A>).<A=20 name=3DTab1></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 1 </SPAN>Surgery = versus=20 surgery + WBRT </DIV> <TABLE border=3D1> <COLGROUP> <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"">Interventions</P></TH> <TH align=3Dleft> <P class=3D"">Median survival</P></TH> <TH align=3Dleft> <P class=3D""># pts with recurrence/progression<SUP>a</SUP> = </P></TH> <TH align=3Dleft> <P class=3D"">Median time to = recurrence/progression</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D5> <P class=3D"">Randomized trials</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Patchell [<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR10">10</A></CITE>]=20 (1998) </P></TD> <TD align=3Dleft> <P class=3D"">G1: Surgery (<I>n</I> =3D 46) </P> <P class=3D"">G2: Surgery + WBRT = (<I>n</I> =3D 49) </P></TD> <TD align=3Dleft> <P class=3D"">G1: 43 wks</P> <P class=3D"">G2: 48 wks</P> <P class=3D"">(Log-rank; <I>P</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: 21/46 (46%)</P> <P class=3D"">G2: 5/49 (10%) (<I>P</I> < 0.001) </P> <P class=3D"">Overall in brain:</P> <P class=3D"">G1: 32/46 (70%)</P> <P class=3D"">G2: 9/49 (18%) (<I>P</I> < 0.001) = </P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: 27 wks</P> <P class=3D"">G2: > 50 wks (Log-rank;=20 <I>P</I> < 0.001) </P> <P class=3D"">Overall in brain:</P> <P class=3D"">G1: 26 wks</P> <P class=3D"">G2: 220 wks (Log-rank; = <I>P</I> < 0.001)=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D5> <P class=3D"">Retrospective cohort studies</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Armstrong[<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR11">11</A></CITE>]=20 (1994) </P></TD> <TD align=3Dleft> <P class=3D"">G1: Surgery (<I>n</I> =3D 32) </P> <P class=3D"">G2: Surgery + WBRT = (<I>n</I> =3D 32) </P> <P class=3D"">[matched to G1]</P> <P class=3D"">G3: Surgery + </P> <P class=3D"">WBRT (<I>n</I> =3D 79) </P> <P class=3D"">[not matched]</P></TD> <TD align=3Dleft> <P class=3D"">G1: 14 months</P> <P class=3D"">G2: 10 months</P> <P class=3D"">G3: 15 months</P> <P class=3D"">(G1 vs. G2:</P> <P class=3D"">Log-rank; <I>P</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: 11/32 (34%)</P> <P class=3D"">G2 + G3: 25/111 (23%)</P> <P class=3D"">(G1 vs. G2 + G3: = <I>P</I> =3D NS) </P> <P class=3D"">Overall in brain:</P> <P class=3D"">G1: 38%</P> <P class=3D"">G2: 47%</P> <P class=3D"">G3: 42% (G1 vs. G2: <I>P</I> =3D NS) = </P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Hagen [<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR12">12</A></CITE>]=20 (1990) </P></TD> <TD align=3Dleft> <P class=3D"">G1: Surgery (<I>n</I> =3D 16) </P> <P class=3D"">G2: Surgery + WBRT = (<I>n</I> =3D 19) </P></TD> <TD align=3Dleft> <P class=3D"">G1: 8.3 months</P> <P class=3D"">G2: 6.4 months</P> <P class=3D"">(Test not specified; <I>P</I> =3D NS) = </P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: 6/16 (38%)</P> <P class=3D"">G2: 4/19 (21%) (<I>P</I> =3D NR) </P> <P class=3D"">Overall in brain:</P> <P class=3D"">G1: 11/16 (69%)</P> <P class=3D"">G2: 7/19 (37%) (<I>P</I> =3D NR) </P></TD> <TD align=3Dleft> <P class=3D"">At original site: NR</P> <P class=3D"">Overall in brain:</P> <P class=3D"">G1: 5.7 months</P> <P class=3D"">G2: 26.6 months</P> <P class=3D"">(Test not specified; <I>P</I> < 0.05) = </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Skibber [<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR13">13</A></CITE>]=20 (1996) </P></TD> <TD align=3Dleft> <P class=3D"">G1: Surgery (<I>n</I> =3D 12) </P> <P class=3D"">G2: Surgery + WBRT = (<I>n</I> =3D 22) </P></TD> <TD align=3Dleft> <P class=3D"">G1: 6 months</P> <P class=3D"">G2: 18 months</P> <P class=3D"">(Generalized Wilcoxon; <I>P</I> =3D 0.002) = </P></TD> <TD align=3Dleft> <P class=3D"">At original site: NR</P> <P class=3D"">Overall in brain:</P> <P class=3D"">G1: 9/12 (75%)</P> <P class=3D"">G2: 5/22 (23%) (<I>P</I> =3D NR) </P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D""><I>G1</I> Group 1, <I>G2</I> Group 2, <I>G3</I> Group 3, = <I>NR</I>=20 Not reported, <I>NS</I> Not significant, <I>Pts</I> Patients, = <I>WBRT</I>=20 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"">The randomized data available to address this treatment = comparison=20 comes from a multi-center trial conducted in the United States by = Patchell et=20 al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR10">10</A></CITE>].=20 The trial randomized adults with Karnofsky performance scores (KPS) = ≥70 who had=20 complete resection of a single biopsy-proven brain metastasis, confirmed = by MRI,=20 to post-operative WBRT (50.4 Gy in 28 fractions) or no further = treatment.=20 Randomization was stratified by the extent of extra-cranial disease and = primary=20 tumor type. A total of 95 patients were randomized: 49 patients to=20 post-operative WBRT and 46 patients to observation. Baseline = characteristics=20 were well-balanced between the two groups. Non-small cell lung cancer = (NSCLC)=20 was the predominant tumor type (surgery + WBRT: 59%; surgery = alone:=20 61%), median KPS was 90 in both groups and approximately one-third of = patients=20 had no evidence of extra-cranial disease (surgery + WBRT: 37%; = surgery=20 alone: 35%). No patient was lost to follow-up and the data was analyzed = by=20 intention-to-treat. The primary outcome was tumor recurrence anywhere in = the=20 brain. </P> <P class=3D"">Fewer patients who received post-operative WBRT = experienced a=20 recurrence in the brain compared to those who had surgical resection = alone=20 [surgery + WBRT: 9/49 (18%) versus surgery: 32/46 (70%);=20 <I>P</I> < 0.001]. Recurrence in the WBRT group was less = frequent=20 both at the original site of the brain metastasis = [surgery + WBRT:=20 5/49 (10%) versus surgery: 21/46 (46%); <I>P</I> < 0.001] = and at=20 distant sites in the brain [surgery + WBRT: 7/49 (14%) versus = surgery:=20 17/46 (37%); <I>P</I> < 0.01] compared to patients who did = not=20 receive post-operative WBRT. </P> <P class=3D"">The time to any recurrence in the brain was significantly = longer in=20 the group that had post-operative WBRT compared to the group that did = not=20 (log-rank; <I>P</I> < 0.001). Both the time to recurrence = at the=20 original site in the brain (log-rank; <I>P</I> < 0.001) and = at=20 distant brain sites (log-rank; <I>P</I> =3D 0.04) were = significantly=20 longer in the post-operative WBRT group compared to the group that = received no=20 further treatment following surgery. </P> <P class=3D"">Fewer patients in the WBRT group died as a result of = neurological=20 causes than did patients in the surgery alone group = [surgery + WBRT:=20 6/43 (14%) deaths versus surgery: 17/39 (44%) deaths;=20 <I>P</I> =3D 0.003]. Overall survival did not differ = significantly=20 between the two groups. Median survival in the surgery + WBRT = group=20 was 48 weeks compared to 43 weeks in the group that received = no=20 further treatment following surgical resection. This study was not = powered for=20 survival, however, which was a secondary and not a primary endpoint. The = duration of functional independence (defined as the median time that KPS = remain=20 ≥70) also did not differ significantly between the two groups=20 (surgery + WBRT: 37 weeks versus surgery: 35 weeks;=20 <I>P</I> =3D NS). </P></DIV> <DIV class=3D""><A name=3DSec10></A> <DIV class=3DHeading3>Surgical resection =B1 WBRT or partial = brain RT=20 versus stereotactic radiosurgery (SRS) =B1 whole or partial = brain=20 RT</DIV> <DIV class=3DPara> <DIV class=3D"">One RCT [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR23">23</A></CITE>]=20 and nine retrospective cohort studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR14">14</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR22">22</A></CITE>]=20 met the eligibility criteria for this treatment comparison = (Tables <A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#Tab2">2</A>,=20 <A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#Tab3">3</A>,=20 <A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#Tab4">4</A>).=20 All of these studies utilized single-dose SRS with one exception = [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR20">20</A></CITE>]=20 which employed fractionated stereotactic radiotherapy. However, in 2006, = the=20 American Society for Therapeutic Radiology and Oncology (ASTRO), the = American=20 Association of Neurological Surgeons (AANS) and the Congress of = Neurological=20 Surgeons (CNS) jointly agreed to define SRS in a way that includes both=20 traditional single dose SRS, as well as multi-dose SRS up to five doses = (2=965=20 doses) [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR25">25</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR26">26</A></CITE>].=20 Additionally, while the majority of these SRS studies were conducted = using Gamma=20 Knife radiosurgery, there is no evidence to suggest that other modes of = delivery=20 of SRS would lead to different outcomes.<A name=3DTab2></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 2 </SPAN>SRS = versus=20 Surgery + WBRT </DIV> <TABLE border=3D1> <COLGROUP> <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"">Interventions</P></TH> <TH align=3Dleft> <P class=3D"">Median survival</P></TH> <TH align=3Dleft> <P class=3D""># pts with recurrence/progression<SUP>a</SUP> = </P></TH> <TH align=3Dleft> <P class=3D"">Median time to = recurrence/progression</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D5> <P class=3D"">Randomized controlled trials</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Muacevic [<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR23">23</A></CITE>]=20 (2008) </P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 31) </P> <P class=3D"">G2: Surgery + WBRT = (<I>n</I> =3D 33) </P></TD> <TD align=3Dleft> <P class=3D"">G1: 10.3 months</P> <P class=3D"">G2: 9.5 months</P> <P class=3D"">(Log-rank; <I>P</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">1 yr local control rate:</P> <P class=3D"">G1: 97%</P> <P class=3D"">G2: 82%</P> <P class=3D"">1 yr distant recurrence rate:</P> <P class=3D"">G1: 26%</P> <P class=3D"">G2: 3%</P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">Median: NR</P> <P class=3D"">(LR curves: log-rank; <I>P</I> =3D 0.06, = NS) </P> <P class=3D"">At distant brain sites:</P> <P class=3D"">Median: NR</P> <P class=3D"">(DR curves: log-rank; <I>P</I> =3D 0.04) = </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D5> <P class=3D"">Retrospective cohort studies</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Muacevic [<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR14">14</A></CITE>]=20 (1999) </P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 56) </P> <P class=3D"">G2: Surgery + WBRT = (<I>n</I> =3D 52) </P></TD> <TD align=3Dleft> <P class=3D"">G1: 35 weeks</P> <P class=3D"">G2: 68 weeks</P> <P class=3D"">(Log-rank; <I>P</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">1 yr freedom from LR rate:</P> <P class=3D"">G1: 83%</P> <P class=3D"">G2: 75%</P> <P class=3D"">1 yr freedom from DR rate:</P> <P class=3D"">G1: 68%</P> <P class=3D"">G2: 90% (<I>P</I> =3D 0.0025) </P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: Median not reached</P> <P class=3D"">G2: Median not reached</P> <P class=3D"">(Log-rank; <I>P</I> =3D NS) </P> <P class=3D"">At distant brain sites:</P> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D""> Rades [<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR15">15</A></CITE>]=20 (2007) </P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 94) </P></TD> <TD align=3Dleft> <P class=3D"">Median survival: NR</P></TD> <TD align=3Dleft> <P class=3D"">1 yr freedom from LR rate:</P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">G2: Surgery + WBRT = (<I>n</I> =3D 112)=20 </P></TD> <TD align=3Dleft> <P class=3D"">1 yr survival rate:</P> <P class=3D"">G1: 54%</P> <P class=3D"">G2: 38%</P> <P class=3D"">(Log-rank; <I>P</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">G1: 64%</P> <P class=3D"">G2: 56%</P> <P class=3D"">1 yr freedom from BR rate:</P> <P class=3D"">G1: 49%</P> <P class=3D"">G2: 44%</P></TD> <TD align=3Dleft> <P class=3D"">Median: NR</P> <P class=3D"">(LR curves: log-rank; <I>P</I> =3D NS) = </P> <P class=3D"">Overall in brain:</P> <P class=3D"">Median: NR</P> <P class=3D"">(BR curves: log-rank; <I>P</I> =3D NS)=20 </P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D""><I>BR</I> Brain recurrence (local + distant), = <I>DR</I>=20 Distant recurrence in brain, <I>G1</I> Group 1, <I>G2</I> Group 2, = <I>LR</I>=20 Local recurrence at original site in brain, <I>NR</I> Not reported, = <I>NS</I>=20 Not significant, <I>Pts</I> Patients, <I>SRS</I> Stereotactic = radiosurgery,=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><A = name=3DTab3></A> <DIV class=3DCapt><SPAN=20 class=3DCaptNr>Table 3 </SPAN>Surgery + WBRT versus=20 SRS + WBRT </DIV> <TABLE border=3D1> <COLGROUP> <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"">Interventions</P></TH> <TH align=3Dleft> <P class=3D"">Median survival</P></TH> <TH align=3Dleft> <P class=3D""># pts with recurrence/progression<SUP>a</SUP> = </P></TH> <TH align=3Dleft> <P class=3D"">Median time to = recurrence/progression</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D5> <P class=3D"">Retrospective cohort studies</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Bindal [<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR16">16</A></CITE>]=20 (1996) </P></TD> <TD align=3Dleft> <P class=3D"">G1: Surgery =B1 WBRT<SUP>b</SUP>=20 (<I>n</I> =3D 62) [matched to G2] </P> <P class=3D"">G2: SRS =B1 WBRT<SUP>b</SUP> = (<I>n</I> =3D 31)=20 </P></TD> <TD align=3Dleft> <P class=3D"">G1: 16.4 months</P> <P class=3D"">G2: 7.5 months</P> <P class=3D"">(Log-rank; <I>P</I> =3D 0.0018) </P></TD> <TD align=3Dleft> <P class=3D"">1 yr freedom from LR rate:</P> <P class=3D"">G2 poorer than G1</P> <P class=3D"">[Data: NR]</P> <P class=3D"">1 yr freedom from DR rate:</P> <P class=3D"">G1: 75%</P> <P class=3D"">G2: 69%</P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: Median not reached</P> <P class=3D"">G2: 6 months</P> <P class=3D"">(Log-rank; <I>P</I> =3D 0.0001) </P> <P class=3D"">At distant brain sites:</P> <P class=3D"">G1: Median not reached</P> <P class=3D"">G2: Median not reached</P> <P class=3D"">(Log-rank; <I>P</I> =3D NS) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Garell [<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR17">17</A></CITE>]=20 (1999) </P></TD> <TD align=3Dleft> <P class=3D"">G1: Surgery + WBRT = (<I>n</I> =3D 37) </P> <P class=3D"">G2: SRS + WBRT (<I>n</I> =3D 8) = </P></TD> <TD align=3Dleft> <P class=3D"">G1: 8 months</P> <P class=3D"">G2: 12.5 months</P> <P class=3D"">(Log-rank <I>P</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Schoggl [<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR18">18</A></CITE>]=20 (2000) </P></TD> <TD align=3Dleft> <P class=3D"">G1: Surgery + WBRT = (<I>n</I> =3D 66) </P> <P class=3D"">G2: SRS + WBRT (<I>n</I> =3D 67) = </P></TD> <TD align=3Dleft> <P class=3D"">G1: 9 months</P> <P class=3D"">G2: 12 months</P> <P class=3D"">(Test unclear<SUP>;</SUP> <I>P</I> =3D NS) = </P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: 11/66 (17%)</P> <P class=3D"">G2: 3/67 (5%) (<I>P</I> =3D NR) </P> <P class=3D"">At distant brain sites:</P> <P class=3D"">G1: 10/66 (15%)</P> <P class=3D"">G2: 7/67 (10%) (<I>P</I> =3D NR) </P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: 3.9 months</P> <P class=3D"">G2: 4.9 months</P> <P class=3D"">(Test unclear; <I>P</I> < 0.05) </P> <P class=3D"">At distant brain sites:</P> <P class=3D"">G1: 3.7 months</P> <P class=3D"">G2: 4.4 months</P> <P class=3D"">(Test unclear; <I>P</I> =3D NS) = </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> O=92Neill [<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR19">19</A></CITE>]=20 (2003) </P></TD> <TD align=3Dleft> <P class=3D"">G1: Surgery =B1 WBRT<SUP>b</SUP>=20 (<I>n</I> =3D 74) </P> <P class=3D"">G2: SRS =B1 WBRT<SUP>b</SUP> = (<I>n</I> =3D 23)=20 </P></TD> <TD align=3Dleft> <P class=3D"">Median survival: NR</P> <P class=3D"">1 yr survival rate:</P> <P class=3D"">G1: 62%</P> <P class=3D"">G2: 56%</P> <P class=3D"">(Log-rank; <I>P</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: 11/64 (17%)</P> <P class=3D"">G2: 0/21 (0%) (<I>P</I> =3D NR) </P> <P class=3D"">Overall in brain:</P> <P class=3D"">G1: 19/64 (30%)</P> <P class=3D"">G2: 6/21 (29%) (<I>P</I> =3D NR) </P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D""><I>DR</I> Distant recurrence in brain, <I>G1</I> Group = 1,=20 <I>G2</I> Group 2, <I>LR</I> Local recurrence at original site in brain, = <I>NR</I> Not reported, <I>NS</I> Not significant, <I>Pts</I> Patients,=20 <I>SRS</I> Stereotactic radiosurgery, <I>WBRT</I> Whole-brain radiation = therapy=20 </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 class=3DCaptCont> <DIV class=3D""><SUP>b</SUP>WBRT use similar at baseline in both groups=20 </DIV></DIV></DIV><A name=3DTab4></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 4 </SPAN>Other = included=20 studies of surgery =B1 radiotherapy versus = SRS =B1 radiotherapy=20 </DIV> <TABLE border=3D1> <COLGROUP> <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"">Interventions</P></TH> <TH align=3Dleft> <P class=3D"">Median survival</P></TH> <TH align=3Dleft> <P class=3D""># pts with recurrence/progression<SUP>a</SUP> = </P></TH> <TH align=3Dleft> <P class=3D"">Median time to = recurrence/progression</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D5> <P class=3D"">Retrospective cohorts</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Ikushima [<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR20">20</A></CITE>]=20 (2000) </P></TD> <TD align=3Dleft> <P class=3D"">G1: Fractionated SRS (<I>n</I> =3D 10) = </P> <P class=3D"">G2: Surgery + RT = (<I>n</I> =3D 11) </P> <P class=3D"">G3: RT (<I>n</I> =3D 14) </P> <P class=3D"">[RT =3D WBRT or local]</P></TD> <TD align=3Dleft> <P class=3D"">G1: 25.6 months</P> <P class=3D"">G2: 18.7 months</P> <P class=3D"">G3: 4.3 months</P> <P class=3D"">(Univariate analysis:</P> <P class=3D"">G1 vs. G2 + G3: = <I>P</I> =3D 0.05) </P></TD> <TD align=3Dleft> <P class=3D"">1 yr local control rate:</P> <P class=3D"">G1: 90%</P> <P class=3D"">G2: 88%</P> <P class=3D"">G3: NR</P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">Median: NR</P> <P class=3D"">(LR curves: log-rank; <I>P</I> =3D NS) = </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Shinoura [<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR21">21</A></CITE>]=20 (2002) </P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 28) </P> <P class=3D"">G2: Surgery + RT = (<I>n</I> =3D 35) </P> <P class=3D"">[RT =3D WBRT or local]</P></TD> <TD align=3Dleft> <P class=3D"">G1: 8.2 months</P> <P class=3D"">G2: 34.4 months</P> <P class=3D"">(Log-rank; <I>P</I> < 0.0001) </P></TD> <TD align=3Dleft> <P class=3D""># lesions that recurred at original site:</P> <P class=3D"">G1: 16/52 (31%)</P> <P class=3D"">G2: 14/46 (30%)</P> <P class=3D"">(<I>P</I>-value: NR) </P></TD> <TD align=3Dleft> <P class=3D"">Mean time at original site:</P> <P class=3D"">G1: 7.2 months</P> <P class=3D"">G2: 25 months</P> <P class=3D"">(Log-rank; <I>P</I> =3D 0.0199) = </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Wang [<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR22">22</A></CITE>]=20 (2002) </P></TD> <TD align=3Dleft> <P class=3D"">G1: Surgery</P> <P class=3D"">G2: WBRT</P> <P class=3D"">G3: SRS</P> <P class=3D"">G4: SRS + WBRT</P></TD> <TD align=3Dleft> <P class=3D"">G1: 43 wks</P> <P class=3D"">G2: 37 wks</P> <P class=3D"">G3: 67 wks</P> <P class=3D"">G4: 91 wks</P> <P class=3D"">(Log-rank <I>P</I> < 0.00001) </P></TD> <TD align=3Dleft> <P class=3D"">1 month local tumor control:</P> <P class=3D"">G1: 89%</P> <P class=3D"">G2: 88%</P> <P class=3D"">G3: 93%</P> <P class=3D"">G4: 96%</P></TD> <TD align=3Dleft> <P class=3D"">NR</P> <P class=3D"">.</P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D""><I>G1</I> Group 1, <I>G2</I> Group 2, <I>G3</I> Group 3, = <I>G4</I>=20 Group 4, <I>LR</I> Local recurrence at original site in brain, <I>NR</I> = Not=20 reported, <I>Pts</I> Patients, <I>RT</I> Radiotherapy, <I>SRS</I> = Stereotactic=20 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></DIV></DIV> <DIV class=3D""><A name=3DSec20></A> <H4 class=3DSection3>(a) Surgical resection + WBRT versus = SRS</H4> <P class=3D"">A small RCT [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR23">23</A></CITE>]=20 and two retrospective cohorts [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR14">14</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR15">15</A></CITE>]=20 specifically compared resection plus post-operative WBRT to SRS alone = for the=20 initial treatment of a newly diagnosed brain metastasis (Table <A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#Tab2">2</A>).=20 </P> <P class=3D"">The randomized data is from a multi-center RCT conducted = in Germany=20 by Muacevic et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR23">23</A></CITE>],=20 which closed prematurely due to poor patient accrual. A total of 64 out = of the=20 planned 242 adult patients with single, small (≤3 cm) = operable brain=20 metastases and a KPS ≥70 were randomized to receive SRS alone=20 (<I>n</I> =3D 31) or surgical resection followed by WBRT=20 (<I>n</I> =3D 33). Baseline prognostic variables were = well-balanced=20 between the two groups. All of the participants received the treatment = as=20 allocated and none were lost to follow-up. </P> <P class=3D"">The primary outcome, overall survival, did not differ = significantly=20 between the two groups. Median survival in the surgery + WBRT = group=20 was 9.5 months, compared to 10.3 months in the group that = received=20 SRS. In terms of secondary outcomes, duration of freedom from local = recurrence=20 did not significantly differ between the two groups (log-rank;=20 <I>P</I> =3D 0.06; NS). The 1 year local control rate was = 82% in=20 the surgery + WBRT group and 96.8% in the SRS group. Freedom = from=20 recurrence at distant brain sites was significantly longer in the group = that had=20 surgical resection plus WBRT compared to the group that received SRS = (log-rank;=20 <I>P</I> =3D 0.04). Finally, the overall number of = neurological deaths=20 was not significantly different between the groups. </P></DIV> <DIV class=3D""><A name=3DSec100></A> <H4 class=3DSection3>(b) Surgical resection + WBRT versus=20 SRS + WBRT</H4> <P class=3D"">No prospective studies were identified that met the = eligibility=20 criteria for this treatment comparison. Four retrospective cohort = studies=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR16">16</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR19">19</A></CITE>]=20 that compared surgical resection plus WBRT to SRS plus WBRT met the = inclusion=20 criteria (Table <A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#Tab3">3</A>).=20 In two of these studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR16">16</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR19">19</A></CITE>]=20 the majority, but not all, of the subjects received WBRT. </P> <P class=3D"">In three of the studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR17">17</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR19">19</A></CITE>],=20 overall survival did not differ significantly between the resection plus = WBRT=20 group compared with the group that received SRS plus WBRT. In one study=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR16">16</A></CITE>],=20 overall survival was significantly longer for patients that received = surgery=20 plus WBRT compared to patients that had SRS and WBRT (log-rank;=20 <I>P</I> =3D 0.0018), although patients in the SRS arm were = generally=20 poorer resection candidates. In this study, freedom from local = recurrence was=20 also significantly longer in the surgery plus WBRT group (log-rank;=20 <I>P</I> =3D 0.0001). Schoggl et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR18">18</A></CITE>]=20 reported a significant benefit in duration of freedom from local = recurrence for=20 patients that received SRS and WBRT compared to patients that had = surgical=20 excision plus WBRT (<I>P</I> < 0.05), supporting the = findings in=20 the Garell et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR17">17</A></CITE>]=20 study as well. O=92Neill et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR19">19</A></CITE>]=20 reported no local recurrences in the SRS group compared to a 58% local=20 recurrence rate in the surgical resection group = (<I>P</I> =3D 0.020).=20 These studies also demonstrated no significant difference between groups = in the=20 duration of freedom from recurrence at <I>distant</I> brain sites = [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR16">16</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR18">18</A></CITE>].=20 </P></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec11></A> <HR> <DIV class=3Dheading2>Surgical resection =B1 WBRT versus = surgical=20 resection + SRS</DIV> <P class=3D"">No studies were identified that met the eligibility = criteria for=20 this treatment comparison.</P></DIV> <DIV class=3D""><A name=3DSec12></A> <HR> <DIV class=3Dheading2>Summary and discussion</DIV> <DIV class=3D""><A name=3DSec13></A> <DIV class=3DHeading3>Surgical resection plus WBRT versus WBRT = alone</DIV> <P class=3D"">The WBRT guideline paper by Gaspar et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR6">6</A></CITE>]=20 outlines in detail the evidence supporting the addition of WBRT after = surgical=20 resection. Please refer to this paper for a further discussion of why = surgical=20 resection plus post-operative WBRT represents a superior treatment = modality as=20 compared to WBRT alone, in patients with good performance status = (functionally=20 independent and spending less than 50% of time in bed) and limited = extra-cranial=20 disease. There is insufficient evidence to make a recommendation for = patients=20 with poor performance scores, advanced systemic disease, or multiple = brain=20 metastases. </P></DIV> <DIV class=3D""><A name=3DSec14></A> <DIV class=3DHeading3>Surgical resection + WBRT versus = surgical=20 resection</DIV> <P class=3D"">Class I evidence is available (in the Patchell RCT = [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR10">10</A></CITE>])=20 to support a level 1 recommendation for patients with a single brain = metastasis=20 amenable to surgical resection. The class I evidence supports the use of = WBRT=20 following surgical resection. Control of extra-cranial disease is not = required=20 for patients to benefit from aggressive forms of local therapy, but = generally=20 patients required a KPS of at least 70 to be eligible for the studies = and the=20 anticipated interventions. Recurrence in the brain, as measured overall, = at the=20 original site or at distant brain sites, were all significantly lower in = the=20 group that received adjuvant post-operative WBRT than the group = undergoing=20 surgical resection alone. </P> <P class=3D"">However, both overall survival and time spent in an = independent=20 status (KPS >70) did not differ significantly between the groups. The = Patchell study did show a reduction in neurologic deaths=20 (<I>P</I> =3D 0.003) in the patients who received WBRT in = addition to=20 surgical resection. In patients with distant metastatic disease, rates = of=20 neurological death may in fact provide a more useful endpoint for this = clinical=20 comparison. Nonetheless, the lack of a survival difference has offered = support=20 to a common but unsubstantiated treatment plan encompassing surgery = alone with=20 close observation, delaying WBRT for so-called =93salvage therapy=94 at = recurrence.=20 No evidence-based justification currently exists for such expectant = observation.=20 </P></DIV> <DIV class=3D""><A name=3DSec15></A> <DIV class=3DHeading3>Surgical resection + WBRT versus = SRS</DIV> <P class=3D"">While the surgical resection versus radiosurgery = comparison produces=20 less clear-cut results, class I evidence based on the AANS/CNS scale = does=20 address this clinical question. However, the Muacevic RCT [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR23">23</A></CITE>]=20 closed early and only enrolled approximately one-quarter of the proposed = participants and was thus underpowered to detect a survival difference, = if in=20 fact one exists. Given the small sample size, the authors of the RCT = reported=20 that by their calculations, the trial was only sufficiently powered to = detect an=20 overall survival difference of 38% or greater between the two groups 80% = of the=20 time. It is difficult to offer firm guidelines based upon a prematurely = closed=20 study. </P> <P class=3D"">Furthermore, duration of freedom from local recurrence did = not=20 significantly differ between the two groups (log-rank;=20 <I>P</I> =3D 0.06; NS) with the 1 year local control rate = at 82% in=20 the resection + WBRT group and 96.8% in the SRS group. A = larger trial=20 will, perhaps, provide more definitive information regarding this = outcome given=20 the borderline <I>P</I>-value of 0.06. In general, though, it is often = difficult=20 to determine local recurrence in a study comparing surgical resection = versus=20 SRS; in the SRS literature, a remaining enhancing abnormality stable = over time=20 is considered =93local control,=94 but may overestimate the true = long-term control=20 associated with SRS. </P> <P class=3D"">In terms of distant brain recurrence, freedom from = recurrence at=20 distant brain sites was significantly longer in the group that had = resection=20 plus WBRT, as expected, compared to the group that received local = therapy in the=20 form of SRS (log-rank; <I>P</I> =3D 0.04). In this and other = studies,=20 patient accrual lagged behind proposed enrollment in the study design = phase=20 because of strong physician preference for either surgical resection or = SRS.=20 </P> <P class=3D"">The lower distant brain recurrence rates in the WBRT arm = makes=20 intuitive sense since these patients are receiving effective treatment = for=20 potential lesions elsewhere in the brain, unlike those in the SRS arm. = In terms=20 of survival, however, class II evidence suggests that survival is not = decreased=20 when WBRT is not given as initial therapy (for details, refer to the = guideline=20 paper in this series by Linskey et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR27">27</A></CITE>],=20 which addresses the role of SRS for newly diagnosed brain metastases). = </P> <P class=3D"">Quality of life, including potential neuro-cognitive = treatment=20 effects, represents another important question that still needs to be = addressed:=20 does recurrence impact quality of life since survival appears to be = unchanged=20 between the two treatment arms? A recently-closed randomized Phase III = trial by=20 the European Organization for the Research and Treatment of Cancer = (EORTC=20 #22952) achieved full accrual of its target 340 patients and compared no = radiotherapy to WBRT for 1=963 brain metastases from solid tumor after = resection=20 or SRS; these results, when available, may provide powerful evidence for = the=20 role of WBRT. </P></DIV> <DIV class=3D""><A name=3DSec16></A> <DIV class=3DHeading3>Surgical resection + WBRT versus=20 SRS + WBRT</DIV> <P class=3D"">Four retrospective cohort studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR16">16</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR19">19</A></CITE>]=20 provide evidence for this treatment comparison. While class II evidence = does=20 exist for these interventions, all of the studies are retrospective = rather than=20 prospective, and they yield conflicting results in terms of overall = survival and=20 duration of freedom from local recurrence. However, Class II evidence = does=20 suggest that larger lesions (>3 cm in maximum diameter) or those = causing=20 significant mass effect (>1 cm midline shift) may have better = outcomes=20 with surgical resection. Radiosurgery is recommended for single = surgically=20 inaccessible lesions measuring <3 cm in maximum diameter. = </P></DIV> <DIV class=3D""><A name=3DSec17></A> <DIV class=3DHeading3>Surgical resection =B1 WBRT versus = surgical=20 resection + SRS</DIV> <P class=3D"">No studies were identified for this treatment comparison = and as=20 such, no evidence-based recommendations can be made regarding one = approach=20 compared to the other. </P></DIV></DIV> <DIV class=3D""><A name=3DSec18></A> <HR> <DIV class=3Dheading2>Conclusions and future directions</DIV> <P class=3D"">Class I evidence suggests that surgical resection followed = by WBRT=20 represents a superior treatment modality, in terms of improving tumor = control at=20 the original site of the metastasis and in the brain overall, when = compared to=20 surgical resection alone. As reviewed by Gaspar et al., in the WBRT = guideline=20 paper in this series, class I evidence also supports the use of surgical = resection plus post-operative WBRT in patients with good performance = status and=20 limited extra-cranial disease compared to WBRT alone (refer to the WBRT=20 guideline paper in this series for further detail). </P> <P class=3D"">The advent of SRS, though, has provided several clinically = important=20 permutations and combination treatment options for patients with brain=20 metastases, some of which clearly improve recurrence rates and survival = as well.=20 Guideline papers in this series by Gaspar et al., and Linskey et al., = address=20 some of these relevant treatment comparisons incorporating surgical = resection,=20 WBRT, SRS and the concept of delaying WBRT for salvage therapy without = adverse=20 sequelae. Class II evidence suggests that larger lesions (>3 cm) = or=20 those causing significant mass effect (>1 cm midline shift) may = have=20 better outcomes with surgical resection, whereas radiosurgery may offer = slightly=20 better local control rates for radioresistant lesions (i.e., melanoma, = renal=20 cell, etc.). However, because of underpowered class I evidence in the=20 resection + WBRT versus SRS alone comparison, the authors = could only=20 make a level 3 recommendation suggesting that SRS <I>alone</I> may = provide=20 equivalent functional and survival outcomes compared with=20 resection + WBRT for patients with single brain metastases, so = long as=20 ready detection of distant site failure and salvage SRS are possible. = </P> <P class=3D"">Additional prospective randomized studies, such as the = Phase 3 EORTC=20 study mentioned previously (referenced below=975) and two recently = closed=20 randomized trials comparing surgical resection to SRS (referenced = below=971, 2),=20 will be required to more definitively assess treatment outcomes. </P> <P class=3D"">One notable treatment combination in need of further study = involves=20 the concept of applying SRS to the surgical resection cavity = post-operatively=20 instead of post-operative WBRT. Although many large cancer centers = around the=20 country have recently adopted this practice, no robust prospective data = yet=20 exists to support a few retrospective case series suggesting that both = local=20 control rates and even survival are enhanced by this post-operative SRS = option.=20 </P> <DIV class=3D""><A name=3DSec19></A> <DIV class=3DHeading3>The role of surgical resection for multiple brain=20 metastases</DIV> <P class=3D"">While surgical resection of more than one brain metastasis = has been=20 performed in cases of significant mass effect from more than one lesion, = and in=20 cases where two or more lesions are accessible through the same = craniotomy=20 approach, no robust comparative data exists to evaluate the role of = surgical=20 resection for multiple brain metastases. Future studies incorporating = the role=20 of resection for more than one brain metastasis, with or without = additional=20 adjuvant therapy, will also help clarify whether the benefits of = resection=20 discussed above apply to multiple lesions. </P> <P class=3D"">Other important future directions include designing trials = with a=20 focus on quality of life and patient functional status as primary = outcomes,=20 rather than only recurrence rates or survival. Given that small = differences in=20 survival rates for a given treatment option potentially minimize = significant=20 differences in quality of life for a particular therapy, an analysis of = a wider=20 range of outcome parameters may help better inform practitioners, and = our=20 patients, when making critical treatment decisions. Histology-specific = brain=20 metastasis trials may also help answer important therapeutic questions = regarding=20 radioresistant lesions versus other common histologies. Most studies = thus far=20 have not specifically addressed differences in histological subtype = despite the=20 fact that management of extracranial malignancies differs widely based = on cancer=20 histology (i.e., breast versus lung versus renal cell, etc.). </P> <DIV class=3DPara> <DIV class=3D"">The following is a list of major ongoing or recently = closed=20 clinical trials pertaining to the use of surgery that evaluate treatment = comparisons addressed by this guideline paper for the management of = newly=20 diagnosed brain metastases.=20 <TABLE class=3DOrderedList> <TBODY> <TR vAlign=3Dtop> <TD>1. </TD> <TD>Surgery versus radiosurgery to treat metastatic brain tumors=20 <DIV class=3DListPara> <DIV class=3D""><B>Official Title:</B> A Prospective, Randomized = Trial=20 Comparing Surgery Versus Radiosurgery for the Treatment of = Metastatic=20 Brain Tumors </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Status:</B> Completed </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Clinicaltrials.gov Identifier:</B> NCT00075166=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Location:</B> United States </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Sponsors and Collaborators:</B> National = Institute of=20 Neurological Disorders and Stroke (NINDS) </DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD>2. </TD> <TD>2. Surgery versus stereotactic radiosurgery in the treatment of = single=20 brain metastasis: a randomized trial=20 <DIV class=3DListPara> <DIV class=3D""><B>Official Title:</B> Surgery Versus Stereotactic = Radiosurgery in the Treatment of Single Brain Metastasis: A = Randomized=20 Trial </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Status:</B> Completed </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Clinicaltrials.gov Identifier:</B> NCT00460395=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Principal Investigator:</B> Frederick F. Lang, = M.D.,=20 University Of Texas MD Anderson Cancer Center </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Location:</B> United States </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Sponsors and Collaborators:</B> M.D. Anderson = Cancer=20 Center </DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD>3. </TD> <TD>A Trial of Postoperative Whole Brain Radiation Therapy versus = Salvage=20 Stereotactic Radiosurgery Therapy for Metastasis=20 <DIV class=3DListPara> <DIV class=3D""><B>Official Title:</B> Randomized Phase III Trial = of=20 Postoperative Whole Brain Radiation Therapy Compared With Salvage=20 Stereotactic Radiosurgery in Patients With One to Four Brain = Metastasis:=20 Japan Clinical Oncology Group Study (JCOG 0504) </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Status:</B> Recruiting (Phase III) </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Clinicaltrials.gov Identifier:</B> NCT00280475=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Principal Investigator:</B> Takamasa Kayama, = MD, PhD=20 Yamagata University Faculty of Medicine </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Location:</B> Japan (21 locations) </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Sponsors and Collaborators:</B> Japan Clinical = Oncology=20 Group, Japanese Ministry of Health, Labor and Welfare = </DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD>4. </TD> <TD>A Trial Comparing Radiosurgery With Surgery for Solitary Brain=20 Metastases=20 <DIV class=3DListPara> <DIV class=3D""><B>Official Title:</B> A Randomised Trial of = Surgery Plus=20 Whole Brain Radiotherapy (WBRT) Versus Radiosurgery Plus WBRT for = Solitary=20 Brain Metastases </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Status:</B> Recruiting (Phase III) </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Clinicaltrials.gov Identifier:</B> NCT00124761=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Principal Investigator: Daniel Roos, FRANZCR, = Royal Adelaide=20 Hospital</DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Location:</B> Australia </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Sponsors and Collaborators:</B> Royal Adelaide = Hospital=20 </DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD>5. </TD> <TD>Adjuvant Radiation Therapy in Treating Patients With Brain = Metastases=20 <DIV class=3DListPara> <DIV class=3D""><B>Official Title:</B> Phase III Trial on = Convergent Beam=20 Irradiation of Cerebral Metastases </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Status:</B> Active, not recruiting (Phase III)=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Clinicaltrials.gov Identifier:</B> NCT00002899=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Principal Investigators:</B> Rolf-Peter = Mueller, MD=20 Medizinische Universitaetsklinik I at the University of Cologne = Riccardo=20 Soffietti, MD Universita Degli Studi di Turin </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Location:</B> Europe (33 locations) = </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Sponsors and Collaborators:</B> European = Organization for=20 Research and Treatment of Cancer=20 </DIV></DIV></TD></TR></TBODY></TABLE></DIV></DIV></DIV></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.</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>American Cancer Society (2008) Cancer facts = and=20 figures 2008. <A=20 = href=3D"http://www.cancer.org/docroot/stt/content/stt_1x_cancer_facts_and= _figures_2008.asp">http://www.cancer.org/docroot/stt/content/stt_1x_cance= r_facts_and_figures_2008.asp</A>=20 </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>2.</TD> <TD><A name=3DCR2></A>Gavrilovic IT, Posner JB (2005) Brain = metastases:=20 epidemiology and pathophysiology. 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From: Subject: 10.1007/s11060-009-0061-8 Date: Thu, 24 Dec 2009 12:37:10 +0100 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01CA8495.CFF899D0" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01CA8495.CFF899D0 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.springerlink.com/content/e088515136888570/fulltext.html 10.1007/s11060-009-0061-8</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/s11060-009-0061-8</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Invited Manuscript</H2> <DIV class=3DHeading1><A name=3Dtitle></A>The role of surgical resection = in the=20 management of newly diagnosed brain metastases: a systematic review and=20 evidence-based clinical practice guideline </DIV> <P class=3DAuthorGroup>Steven N. Kalkanis<SUP>1 <A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#ContactOfAuthor1"><IMG=20 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/e088515136888570/contact.gif" = border=3D0></A></SUP>, Douglas Kondziolka<SUP>2</SUP>,=20 Laurie E. Gaspar<SUP>3</SUP>, = Stuart H. Burri<SUP>4</SUP>,=20 Anthony L. Asher<SUP>5</SUP>, = Charles S. Cobbs<SUP>6</SUP>,=20 Mario Ammirati<SUP>7</SUP>, = Paula D. Robinson<SUP>8</SUP>,=20 David W. Andrews<SUP>9</SUP>, = Jay S. Loeffler<SUP>10</SUP>,=20 Michael McDermott<SUP>11</SUP>, = Minesh P. Mehta<SUP>12</SUP>,=20 Tom Mikkelsen<SUP>13</SUP>, = Jeffrey J. Olson<SUP>14</SUP>,=20 Nina A. Paleologos<SUP>15</SUP>,=20 Roy A. Patchell<SUP>16</SUP>, = Timothy C. Ryken<SUP>17</SUP>=20 and Mark E. Linskey<SUP>18</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, Henry Ford = Health=20 System, 2799 West Grand Blvd, K-11, Detroit, MI 48202,=20 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 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=3DAff3></A>(3) </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=3DAff4></A>(4) </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=3DAff5></A>(5) </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=3DAff6></A>(6) </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=3DAff7></A>(7) </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=3DAff8></A>(8) </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=3DAff9></A>(9) </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=3DAff10></A>(10) </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=3DAff11></A>(11) </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=3DAff12></A>(12) </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=3DAff13></A>(13) </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=3DAff14></A>(14) </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=3DAff15></A>(15) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurology, Northshore = University=20 Health System, Evanson, IL, 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 Neurology, Barrow = Neurological=20 Institute, Phoenix, AZ, 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 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=3DAff18></A>(18) </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> <P><A name=3DContactOfAuthor1></A></P> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/e088515136888570/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>4 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>Should patients with = newly-diagnosed metastatic brain tumors undergo open surgical resection = versus=20 whole brain radiation therapy (WBRT) and/or other treatment modalities = such as=20 radiosurgery, and in what clinical settings?=20 <DIV class=3DAbstractPara> <DIV class=3D""><B>Target population</B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D"">These recommendations apply to adults with a newly = diagnosed=20 single brain metastasis amenable to surgical resection.</DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B>Recommendations</B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B><I>Surgical resection plus WBRT versus surgical = resection=20 alone</I></B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 1</I> Surgical resection followed by WBRT = represents a=20 superior treatment modality, in terms of improving tumor control at the = original=20 site of the metastasis and in the brain overall, when compared to = surgical=20 resection alone. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B><I>Surgical resection plus WBRT versus=20 SRS =B1 WBRT</I></B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 2</I> Surgical resection plus WBRT, versus = stereotactic=20 radiosurgery (SRS) plus WBRT, both represent effective treatment = strategies,=20 resulting in relatively equal survival rates. SRS has not been assessed = from an=20 evidence-based standpoint for larger lesions (>3 cm) or for = those=20 causing significant mass effect (>1 cm midline shift). = </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 3</I> Underpowered class I evidence along with = the=20 preponderance of conflicting class II evidence suggests that SRS = <I>alone</I>=20 may provide equivalent functional and survival outcomes compared with=20 resection + WBRT for patients with single brain metastases, so = long as=20 ready detection of distant site failure and salvage SRS are possible.=20 </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Note</I> The following question is fully addressed in = the WBRT=20 guideline paper within this series by Gaspar et al. Given that the=20 recommendation resulting from the systematic review of the literature on = this=20 topic is also highly relevant to the discussion of the role of surgical=20 resection in the management of brain metastases, this recommendation has = been=20 included below. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B>Question</B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D"">Does surgical resection in addition to WBRT improve = outcomes when=20 compared with WBRT alone?</DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B>Target population</B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D"">This recommendation applies to adults with a newly = diagnosed=20 single brain metastasis amenable to surgical resection; however, the=20 recommendation does not apply to relatively radiosensitive tumors = histologies=20 (i.e., small cell lung cancer, leukemia, lymphoma, germ cell tumors and = multiple=20 myeloma). </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B>Recommendation</B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B><I>Surgical resection plus WBRT versus WBRT = alone</I></B>=20 </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 1</I> Class I evidence supports the use of = surgical=20 resection plus post-operative WBRT, as compared to WBRT alone, in = patients with=20 good performance status (functionally independent and spending less than = 50% of=20 time in bed) and limited extra-cranial disease. There is insufficient = evidence=20 to make a recommendation for patients with poor performance scores, = advanced=20 systemic disease, or multiple brain metastases. = </DIV></DIV></DIV></DIV></DIV> <P class=3DKeyword><SPAN = class=3DKeywordHeading>Keywords </SPAN>Brain=20 metastases - Surgical resection - Stereotactic=20 radiosurgery - Radiotherapy - Systematic=20 review - Practice guideline </P> <DIV class=3DFulltext> <DIV class=3D""><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Rationale</DIV> <P class=3D"">A significant proportion of adults diagnosed with cancer = will=20 develop brain metastases. According to the 2008 American Cancer Society=20 Registry, approximately 1.4 million Americans are diagnosed with cancer = every=20 year [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR1">1</A></CITE>]=20 and up to 40% of these patients=97over a half million people = annually=97will go onto=20 develop one or more brain metastases [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR2">2</A></CITE>].=20 Of these patients, approximately one-third will be potential candidates = for=20 surgical resection. </P> <P class=3D"">The outcome for patients with brain metastases is = generally poor,=20 with median survivals following WBRT alone in the range of = 3=966 months=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR3">3</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR5">5</A></CITE>].=20 Given this poor prognosis, considerable efforts have been made to = explore=20 additional or alternative treatment modalities that have the potential = to=20 improve survival, quality of life and local tumor control. </P> <P class=3D"">For patients with a single accessible brain metastasis, = surgical=20 resection followed by post-operative WBRT has been compared to WBRT = alone in=20 three randomized control trials (RCTs) [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR3">3</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR5">5</A></CITE>].=20 The evidence for this combined treatment approach is reviewed in the = guideline=20 paper in this series by Gaspar et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR6">6</A></CITE>]=20 Because the data from these randomized comparisons of WBRT alone, versus = surgical resection followed by post-operative WBRT, addresses the role = of=20 surgical resection in the management of patients with a newly diagnosed = brain=20 metastasis, this paper will refer to this evidence in its = recommendations for=20 the role of surgical resection. </P> <P class=3D"">The advent of stereotactic radiosurgery (SRS) has provided = a new and=20 less invasive local treatment modality that, like surgical resection, = has the=20 ability to treat brain metastases while sparing healthy brain tissue. A = key area=20 that this paper will address is the role of surgical resection compared = to SRS=20 in the initial management of patients with brain metastases. </P> <DIV class=3DPara> <DIV class=3D"">The overall objectives of this paper are:=20 <TABLE class=3DOrderedList> <TBODY> <TR vAlign=3Dtop> <TD>1. </TD> <TD>To systematically review the evidence available for the = following=20 treatment comparisons for patients with a newly diagnosed brain=20 metastasis. Please note that =93surgery=94 implies open surgical = resection.=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>Surgery versus WBRT =B1 surgery</TD></TR> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>Surgery =B1 WBRT or partial brain radiotherapy = (RT)=20 versus SRS =B1 WBRT or partial brain RT</TD></TR> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>Surgery =B1 WBRT versus=20 surgery + SRS</TD></TR></TBODY></TABLE></TD></TR> <TR vAlign=3Dtop> <TD>2. </TD> <TD>To make recommendations based on this evidence for the role of = surgery=20 in the management of these = patients.</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, and Cochrane = Database=20 of Abstracts of Reviews of Effects. A broad search strategy using a = combination=20 of 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/e088515136888570/fulltext.htm= l#CR7">7</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 border=3D0> <TBODY> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Published in English.</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Patients with newly diagnosed brain metastases.</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Fully-published (i.e., not in abstract form) peer-reviewed = primary=20 comparative studies (These included the following comparative = study=20 designs for primary data collection: RCTs, non-randomized trials, = cohort=20 studies and case=96control studies). </TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Study comparisons include one or more of the following:=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>Surgery versus WBRT</TD></TR> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>Surgery versus surgery + WBRT</TD></TR> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>Surgery =B1 WBRT or partial brain RT versus=20 SRS =B1 WBRT or partial brain RT</TD></TR> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>Surgery versus surgery + SRS</TD></TR> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>Surgery + WBRT versus=20 surgery + SRS</TD></TR></TBODY></TABLE> <DIV class=3DListPara> <DIV class=3D"">(Where SRS could be single session and = fractionated=20 stereotactic radiotherapy)</DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Number of study participants with a newly diagnosed brain = metastasis=20 ≥5 per study arm for at least two of the study = arms.</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Baseline information on study participants is provided by = treatment=20 group in studies evaluating interventions exclusively in patients = with a=20 newly diagnosed brain metastasis. For studies with mixed = populations=20 (i.e., includes participants with conditions other than newly = diagnosed=20 brain metastases), baseline information is provided for the = intervention=20 sub-groups of participants with a newly diagnosed brain = metastasis.=20 </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 a = priori=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/e088515136888570/fulltext.htm= l#CR8">8</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR9">9</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 for this guideline = series.=20 </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> <DIV class=3DPara> <DIV class=3D"">Overall, 15 publications (14 primary studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR10">10</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR23">23</A></CITE>]=20 and one companion paper [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR24">24</A></CITE>])=20 met the eligibility criteria. Figure <A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#Fig1">1</A>=20 outlines the flow of studies through the review process.=20 <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2009_61_Fig1_HTML.gif=20 src=3D"http://www.springerlink.com/content/e088515136888570/MediaObjects/= 11060_2009_61_Fig1_HTML.gif"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 1 </SPAN>Flow of = studies to=20 final number of eligible studies </DIV> <HR> </DIV></DIV> <DIV class=3D""><A name=3DSec9></A> <DIV class=3DHeading3>Surgical resection versus surgical=20 resection + WBRT</DIV> <DIV class=3DPara> <DIV class=3D"">One RCT [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR10">10</A></CITE>]=20 and three retrospective cohort studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR11">11</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR13">13</A></CITE>]=20 evaluated surgical resection alone compared to surgery plus = post-operative WBRT=20 for the initial management of a single brain metastasis (Table <A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#Tab1">1</A>).<A=20 name=3DTab1></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 1 </SPAN>Surgery = versus=20 surgery + WBRT </DIV> <TABLE border=3D1> <COLGROUP> <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"">Interventions</P></TH> <TH align=3Dleft> <P class=3D"">Median survival</P></TH> <TH align=3Dleft> <P class=3D""># pts with recurrence/progression<SUP>a</SUP> = </P></TH> <TH align=3Dleft> <P class=3D"">Median time to = recurrence/progression</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D5> <P class=3D"">Randomized trials</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Patchell [<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR10">10</A></CITE>]=20 (1998) </P></TD> <TD align=3Dleft> <P class=3D"">G1: Surgery (<I>n</I> =3D 46) </P> <P class=3D"">G2: Surgery + WBRT = (<I>n</I> =3D 49) </P></TD> <TD align=3Dleft> <P class=3D"">G1: 43 wks</P> <P class=3D"">G2: 48 wks</P> <P class=3D"">(Log-rank; <I>P</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: 21/46 (46%)</P> <P class=3D"">G2: 5/49 (10%) (<I>P</I> < 0.001) </P> <P class=3D"">Overall in brain:</P> <P class=3D"">G1: 32/46 (70%)</P> <P class=3D"">G2: 9/49 (18%) (<I>P</I> < 0.001) = </P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: 27 wks</P> <P class=3D"">G2: > 50 wks (Log-rank;=20 <I>P</I> < 0.001) </P> <P class=3D"">Overall in brain:</P> <P class=3D"">G1: 26 wks</P> <P class=3D"">G2: 220 wks (Log-rank; = <I>P</I> < 0.001)=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D5> <P class=3D"">Retrospective cohort studies</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Armstrong[<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR11">11</A></CITE>]=20 (1994) </P></TD> <TD align=3Dleft> <P class=3D"">G1: Surgery (<I>n</I> =3D 32) </P> <P class=3D"">G2: Surgery + WBRT = (<I>n</I> =3D 32) </P> <P class=3D"">[matched to G1]</P> <P class=3D"">G3: Surgery + </P> <P class=3D"">WBRT (<I>n</I> =3D 79) </P> <P class=3D"">[not matched]</P></TD> <TD align=3Dleft> <P class=3D"">G1: 14 months</P> <P class=3D"">G2: 10 months</P> <P class=3D"">G3: 15 months</P> <P class=3D"">(G1 vs. G2:</P> <P class=3D"">Log-rank; <I>P</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: 11/32 (34%)</P> <P class=3D"">G2 + G3: 25/111 (23%)</P> <P class=3D"">(G1 vs. G2 + G3: = <I>P</I> =3D NS) </P> <P class=3D"">Overall in brain:</P> <P class=3D"">G1: 38%</P> <P class=3D"">G2: 47%</P> <P class=3D"">G3: 42% (G1 vs. G2: <I>P</I> =3D NS) = </P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Hagen [<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR12">12</A></CITE>]=20 (1990) </P></TD> <TD align=3Dleft> <P class=3D"">G1: Surgery (<I>n</I> =3D 16) </P> <P class=3D"">G2: Surgery + WBRT = (<I>n</I> =3D 19) </P></TD> <TD align=3Dleft> <P class=3D"">G1: 8.3 months</P> <P class=3D"">G2: 6.4 months</P> <P class=3D"">(Test not specified; <I>P</I> =3D NS) = </P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: 6/16 (38%)</P> <P class=3D"">G2: 4/19 (21%) (<I>P</I> =3D NR) </P> <P class=3D"">Overall in brain:</P> <P class=3D"">G1: 11/16 (69%)</P> <P class=3D"">G2: 7/19 (37%) (<I>P</I> =3D NR) </P></TD> <TD align=3Dleft> <P class=3D"">At original site: NR</P> <P class=3D"">Overall in brain:</P> <P class=3D"">G1: 5.7 months</P> <P class=3D"">G2: 26.6 months</P> <P class=3D"">(Test not specified; <I>P</I> < 0.05) = </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Skibber [<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR13">13</A></CITE>]=20 (1996) </P></TD> <TD align=3Dleft> <P class=3D"">G1: Surgery (<I>n</I> =3D 12) </P> <P class=3D"">G2: Surgery + WBRT = (<I>n</I> =3D 22) </P></TD> <TD align=3Dleft> <P class=3D"">G1: 6 months</P> <P class=3D"">G2: 18 months</P> <P class=3D"">(Generalized Wilcoxon; <I>P</I> =3D 0.002) = </P></TD> <TD align=3Dleft> <P class=3D"">At original site: NR</P> <P class=3D"">Overall in brain:</P> <P class=3D"">G1: 9/12 (75%)</P> <P class=3D"">G2: 5/22 (23%) (<I>P</I> =3D NR) </P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D""><I>G1</I> Group 1, <I>G2</I> Group 2, <I>G3</I> Group 3, = <I>NR</I>=20 Not reported, <I>NS</I> Not significant, <I>Pts</I> Patients, = <I>WBRT</I>=20 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"">The randomized data available to address this treatment = comparison=20 comes from a multi-center trial conducted in the United States by = Patchell et=20 al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR10">10</A></CITE>].=20 The trial randomized adults with Karnofsky performance scores (KPS) = ≥70 who had=20 complete resection of a single biopsy-proven brain metastasis, confirmed = by MRI,=20 to post-operative WBRT (50.4 Gy in 28 fractions) or no further = treatment.=20 Randomization was stratified by the extent of extra-cranial disease and = primary=20 tumor type. A total of 95 patients were randomized: 49 patients to=20 post-operative WBRT and 46 patients to observation. Baseline = characteristics=20 were well-balanced between the two groups. Non-small cell lung cancer = (NSCLC)=20 was the predominant tumor type (surgery + WBRT: 59%; surgery = alone:=20 61%), median KPS was 90 in both groups and approximately one-third of = patients=20 had no evidence of extra-cranial disease (surgery + WBRT: 37%; = surgery=20 alone: 35%). No patient was lost to follow-up and the data was analyzed = by=20 intention-to-treat. The primary outcome was tumor recurrence anywhere in = the=20 brain. </P> <P class=3D"">Fewer patients who received post-operative WBRT = experienced a=20 recurrence in the brain compared to those who had surgical resection = alone=20 [surgery + WBRT: 9/49 (18%) versus surgery: 32/46 (70%);=20 <I>P</I> < 0.001]. Recurrence in the WBRT group was less = frequent=20 both at the original site of the brain metastasis = [surgery + WBRT:=20 5/49 (10%) versus surgery: 21/46 (46%); <I>P</I> < 0.001] = and at=20 distant sites in the brain [surgery + WBRT: 7/49 (14%) versus = surgery:=20 17/46 (37%); <I>P</I> < 0.01] compared to patients who did = not=20 receive post-operative WBRT. </P> <P class=3D"">The time to any recurrence in the brain was significantly = longer in=20 the group that had post-operative WBRT compared to the group that did = not=20 (log-rank; <I>P</I> < 0.001). Both the time to recurrence = at the=20 original site in the brain (log-rank; <I>P</I> < 0.001) and = at=20 distant brain sites (log-rank; <I>P</I> =3D 0.04) were = significantly=20 longer in the post-operative WBRT group compared to the group that = received no=20 further treatment following surgery. </P> <P class=3D"">Fewer patients in the WBRT group died as a result of = neurological=20 causes than did patients in the surgery alone group = [surgery + WBRT:=20 6/43 (14%) deaths versus surgery: 17/39 (44%) deaths;=20 <I>P</I> =3D 0.003]. Overall survival did not differ = significantly=20 between the two groups. Median survival in the surgery + WBRT = group=20 was 48 weeks compared to 43 weeks in the group that received = no=20 further treatment following surgical resection. This study was not = powered for=20 survival, however, which was a secondary and not a primary endpoint. The = duration of functional independence (defined as the median time that KPS = remain=20 ≥70) also did not differ significantly between the two groups=20 (surgery + WBRT: 37 weeks versus surgery: 35 weeks;=20 <I>P</I> =3D NS). </P></DIV> <DIV class=3D""><A name=3DSec10></A> <DIV class=3DHeading3>Surgical resection =B1 WBRT or partial = brain RT=20 versus stereotactic radiosurgery (SRS) =B1 whole or partial = brain=20 RT</DIV> <DIV class=3DPara> <DIV class=3D"">One RCT [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR23">23</A></CITE>]=20 and nine retrospective cohort studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR14">14</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR22">22</A></CITE>]=20 met the eligibility criteria for this treatment comparison = (Tables <A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#Tab2">2</A>,=20 <A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#Tab3">3</A>,=20 <A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#Tab4">4</A>).=20 All of these studies utilized single-dose SRS with one exception = [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR20">20</A></CITE>]=20 which employed fractionated stereotactic radiotherapy. However, in 2006, = the=20 American Society for Therapeutic Radiology and Oncology (ASTRO), the = American=20 Association of Neurological Surgeons (AANS) and the Congress of = Neurological=20 Surgeons (CNS) jointly agreed to define SRS in a way that includes both=20 traditional single dose SRS, as well as multi-dose SRS up to five doses = (2=965=20 doses) [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR25">25</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR26">26</A></CITE>].=20 Additionally, while the majority of these SRS studies were conducted = using Gamma=20 Knife radiosurgery, there is no evidence to suggest that other modes of = delivery=20 of SRS would lead to different outcomes.<A name=3DTab2></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 2 </SPAN>SRS = versus=20 Surgery + WBRT </DIV> <TABLE border=3D1> <COLGROUP> <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"">Interventions</P></TH> <TH align=3Dleft> <P class=3D"">Median survival</P></TH> <TH align=3Dleft> <P class=3D""># pts with recurrence/progression<SUP>a</SUP> = </P></TH> <TH align=3Dleft> <P class=3D"">Median time to = recurrence/progression</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D5> <P class=3D"">Randomized controlled trials</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Muacevic [<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR23">23</A></CITE>]=20 (2008) </P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 31) </P> <P class=3D"">G2: Surgery + WBRT = (<I>n</I> =3D 33) </P></TD> <TD align=3Dleft> <P class=3D"">G1: 10.3 months</P> <P class=3D"">G2: 9.5 months</P> <P class=3D"">(Log-rank; <I>P</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">1 yr local control rate:</P> <P class=3D"">G1: 97%</P> <P class=3D"">G2: 82%</P> <P class=3D"">1 yr distant recurrence rate:</P> <P class=3D"">G1: 26%</P> <P class=3D"">G2: 3%</P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">Median: NR</P> <P class=3D"">(LR curves: log-rank; <I>P</I> =3D 0.06, = NS) </P> <P class=3D"">At distant brain sites:</P> <P class=3D"">Median: NR</P> <P class=3D"">(DR curves: log-rank; <I>P</I> =3D 0.04) = </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D5> <P class=3D"">Retrospective cohort studies</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Muacevic [<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR14">14</A></CITE>]=20 (1999) </P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 56) </P> <P class=3D"">G2: Surgery + WBRT = (<I>n</I> =3D 52) </P></TD> <TD align=3Dleft> <P class=3D"">G1: 35 weeks</P> <P class=3D"">G2: 68 weeks</P> <P class=3D"">(Log-rank; <I>P</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">1 yr freedom from LR rate:</P> <P class=3D"">G1: 83%</P> <P class=3D"">G2: 75%</P> <P class=3D"">1 yr freedom from DR rate:</P> <P class=3D"">G1: 68%</P> <P class=3D"">G2: 90% (<I>P</I> =3D 0.0025) </P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: Median not reached</P> <P class=3D"">G2: Median not reached</P> <P class=3D"">(Log-rank; <I>P</I> =3D NS) </P> <P class=3D"">At distant brain sites:</P> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D""> Rades [<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR15">15</A></CITE>]=20 (2007) </P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 94) </P></TD> <TD align=3Dleft> <P class=3D"">Median survival: NR</P></TD> <TD align=3Dleft> <P class=3D"">1 yr freedom from LR rate:</P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">G2: Surgery + WBRT = (<I>n</I> =3D 112)=20 </P></TD> <TD align=3Dleft> <P class=3D"">1 yr survival rate:</P> <P class=3D"">G1: 54%</P> <P class=3D"">G2: 38%</P> <P class=3D"">(Log-rank; <I>P</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">G1: 64%</P> <P class=3D"">G2: 56%</P> <P class=3D"">1 yr freedom from BR rate:</P> <P class=3D"">G1: 49%</P> <P class=3D"">G2: 44%</P></TD> <TD align=3Dleft> <P class=3D"">Median: NR</P> <P class=3D"">(LR curves: log-rank; <I>P</I> =3D NS) = </P> <P class=3D"">Overall in brain:</P> <P class=3D"">Median: NR</P> <P class=3D"">(BR curves: log-rank; <I>P</I> =3D NS)=20 </P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D""><I>BR</I> Brain recurrence (local + distant), = <I>DR</I>=20 Distant recurrence in brain, <I>G1</I> Group 1, <I>G2</I> Group 2, = <I>LR</I>=20 Local recurrence at original site in brain, <I>NR</I> Not reported, = <I>NS</I>=20 Not significant, <I>Pts</I> Patients, <I>SRS</I> Stereotactic = radiosurgery,=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><A = name=3DTab3></A> <DIV class=3DCapt><SPAN=20 class=3DCaptNr>Table 3 </SPAN>Surgery + WBRT versus=20 SRS + WBRT </DIV> <TABLE border=3D1> <COLGROUP> <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"">Interventions</P></TH> <TH align=3Dleft> <P class=3D"">Median survival</P></TH> <TH align=3Dleft> <P class=3D""># pts with recurrence/progression<SUP>a</SUP> = </P></TH> <TH align=3Dleft> <P class=3D"">Median time to = recurrence/progression</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D5> <P class=3D"">Retrospective cohort studies</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Bindal [<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR16">16</A></CITE>]=20 (1996) </P></TD> <TD align=3Dleft> <P class=3D"">G1: Surgery =B1 WBRT<SUP>b</SUP>=20 (<I>n</I> =3D 62) [matched to G2] </P> <P class=3D"">G2: SRS =B1 WBRT<SUP>b</SUP> = (<I>n</I> =3D 31)=20 </P></TD> <TD align=3Dleft> <P class=3D"">G1: 16.4 months</P> <P class=3D"">G2: 7.5 months</P> <P class=3D"">(Log-rank; <I>P</I> =3D 0.0018) </P></TD> <TD align=3Dleft> <P class=3D"">1 yr freedom from LR rate:</P> <P class=3D"">G2 poorer than G1</P> <P class=3D"">[Data: NR]</P> <P class=3D"">1 yr freedom from DR rate:</P> <P class=3D"">G1: 75%</P> <P class=3D"">G2: 69%</P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: Median not reached</P> <P class=3D"">G2: 6 months</P> <P class=3D"">(Log-rank; <I>P</I> =3D 0.0001) </P> <P class=3D"">At distant brain sites:</P> <P class=3D"">G1: Median not reached</P> <P class=3D"">G2: Median not reached</P> <P class=3D"">(Log-rank; <I>P</I> =3D NS) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Garell [<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR17">17</A></CITE>]=20 (1999) </P></TD> <TD align=3Dleft> <P class=3D"">G1: Surgery + WBRT = (<I>n</I> =3D 37) </P> <P class=3D"">G2: SRS + WBRT (<I>n</I> =3D 8) = </P></TD> <TD align=3Dleft> <P class=3D"">G1: 8 months</P> <P class=3D"">G2: 12.5 months</P> <P class=3D"">(Log-rank <I>P</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Schoggl [<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR18">18</A></CITE>]=20 (2000) </P></TD> <TD align=3Dleft> <P class=3D"">G1: Surgery + WBRT = (<I>n</I> =3D 66) </P> <P class=3D"">G2: SRS + WBRT (<I>n</I> =3D 67) = </P></TD> <TD align=3Dleft> <P class=3D"">G1: 9 months</P> <P class=3D"">G2: 12 months</P> <P class=3D"">(Test unclear<SUP>;</SUP> <I>P</I> =3D NS) = </P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: 11/66 (17%)</P> <P class=3D"">G2: 3/67 (5%) (<I>P</I> =3D NR) </P> <P class=3D"">At distant brain sites:</P> <P class=3D"">G1: 10/66 (15%)</P> <P class=3D"">G2: 7/67 (10%) (<I>P</I> =3D NR) </P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: 3.9 months</P> <P class=3D"">G2: 4.9 months</P> <P class=3D"">(Test unclear; <I>P</I> < 0.05) </P> <P class=3D"">At distant brain sites:</P> <P class=3D"">G1: 3.7 months</P> <P class=3D"">G2: 4.4 months</P> <P class=3D"">(Test unclear; <I>P</I> =3D NS) = </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> O=92Neill [<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR19">19</A></CITE>]=20 (2003) </P></TD> <TD align=3Dleft> <P class=3D"">G1: Surgery =B1 WBRT<SUP>b</SUP>=20 (<I>n</I> =3D 74) </P> <P class=3D"">G2: SRS =B1 WBRT<SUP>b</SUP> = (<I>n</I> =3D 23)=20 </P></TD> <TD align=3Dleft> <P class=3D"">Median survival: NR</P> <P class=3D"">1 yr survival rate:</P> <P class=3D"">G1: 62%</P> <P class=3D"">G2: 56%</P> <P class=3D"">(Log-rank; <I>P</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: 11/64 (17%)</P> <P class=3D"">G2: 0/21 (0%) (<I>P</I> =3D NR) </P> <P class=3D"">Overall in brain:</P> <P class=3D"">G1: 19/64 (30%)</P> <P class=3D"">G2: 6/21 (29%) (<I>P</I> =3D NR) </P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D""><I>DR</I> Distant recurrence in brain, <I>G1</I> Group = 1,=20 <I>G2</I> Group 2, <I>LR</I> Local recurrence at original site in brain, = <I>NR</I> Not reported, <I>NS</I> Not significant, <I>Pts</I> Patients,=20 <I>SRS</I> Stereotactic radiosurgery, <I>WBRT</I> Whole-brain radiation = therapy=20 </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 class=3DCaptCont> <DIV class=3D""><SUP>b</SUP>WBRT use similar at baseline in both groups=20 </DIV></DIV></DIV><A name=3DTab4></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 4 </SPAN>Other = included=20 studies of surgery =B1 radiotherapy versus = SRS =B1 radiotherapy=20 </DIV> <TABLE border=3D1> <COLGROUP> <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"">Interventions</P></TH> <TH align=3Dleft> <P class=3D"">Median survival</P></TH> <TH align=3Dleft> <P class=3D""># pts with recurrence/progression<SUP>a</SUP> = </P></TH> <TH align=3Dleft> <P class=3D"">Median time to = recurrence/progression</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D5> <P class=3D"">Retrospective cohorts</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Ikushima [<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR20">20</A></CITE>]=20 (2000) </P></TD> <TD align=3Dleft> <P class=3D"">G1: Fractionated SRS (<I>n</I> =3D 10) = </P> <P class=3D"">G2: Surgery + RT = (<I>n</I> =3D 11) </P> <P class=3D"">G3: RT (<I>n</I> =3D 14) </P> <P class=3D"">[RT =3D WBRT or local]</P></TD> <TD align=3Dleft> <P class=3D"">G1: 25.6 months</P> <P class=3D"">G2: 18.7 months</P> <P class=3D"">G3: 4.3 months</P> <P class=3D"">(Univariate analysis:</P> <P class=3D"">G1 vs. G2 + G3: = <I>P</I> =3D 0.05) </P></TD> <TD align=3Dleft> <P class=3D"">1 yr local control rate:</P> <P class=3D"">G1: 90%</P> <P class=3D"">G2: 88%</P> <P class=3D"">G3: NR</P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">Median: NR</P> <P class=3D"">(LR curves: log-rank; <I>P</I> =3D NS) = </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Shinoura [<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR21">21</A></CITE>]=20 (2002) </P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 28) </P> <P class=3D"">G2: Surgery + RT = (<I>n</I> =3D 35) </P> <P class=3D"">[RT =3D WBRT or local]</P></TD> <TD align=3Dleft> <P class=3D"">G1: 8.2 months</P> <P class=3D"">G2: 34.4 months</P> <P class=3D"">(Log-rank; <I>P</I> < 0.0001) </P></TD> <TD align=3Dleft> <P class=3D""># lesions that recurred at original site:</P> <P class=3D"">G1: 16/52 (31%)</P> <P class=3D"">G2: 14/46 (30%)</P> <P class=3D"">(<I>P</I>-value: NR) </P></TD> <TD align=3Dleft> <P class=3D"">Mean time at original site:</P> <P class=3D"">G1: 7.2 months</P> <P class=3D"">G2: 25 months</P> <P class=3D"">(Log-rank; <I>P</I> =3D 0.0199) = </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Wang [<CITE><A=20 = href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR22">22</A></CITE>]=20 (2002) </P></TD> <TD align=3Dleft> <P class=3D"">G1: Surgery</P> <P class=3D"">G2: WBRT</P> <P class=3D"">G3: SRS</P> <P class=3D"">G4: SRS + WBRT</P></TD> <TD align=3Dleft> <P class=3D"">G1: 43 wks</P> <P class=3D"">G2: 37 wks</P> <P class=3D"">G3: 67 wks</P> <P class=3D"">G4: 91 wks</P> <P class=3D"">(Log-rank <I>P</I> < 0.00001) </P></TD> <TD align=3Dleft> <P class=3D"">1 month local tumor control:</P> <P class=3D"">G1: 89%</P> <P class=3D"">G2: 88%</P> <P class=3D"">G3: 93%</P> <P class=3D"">G4: 96%</P></TD> <TD align=3Dleft> <P class=3D"">NR</P> <P class=3D"">.</P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D""><I>G1</I> Group 1, <I>G2</I> Group 2, <I>G3</I> Group 3, = <I>G4</I>=20 Group 4, <I>LR</I> Local recurrence at original site in brain, <I>NR</I> = Not=20 reported, <I>Pts</I> Patients, <I>RT</I> Radiotherapy, <I>SRS</I> = Stereotactic=20 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></DIV></DIV> <DIV class=3D""><A name=3DSec20></A> <H4 class=3DSection3>(a) Surgical resection + WBRT versus = SRS</H4> <P class=3D"">A small RCT [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR23">23</A></CITE>]=20 and two retrospective cohorts [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR14">14</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR15">15</A></CITE>]=20 specifically compared resection plus post-operative WBRT to SRS alone = for the=20 initial treatment of a newly diagnosed brain metastasis (Table <A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#Tab2">2</A>).=20 </P> <P class=3D"">The randomized data is from a multi-center RCT conducted = in Germany=20 by Muacevic et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR23">23</A></CITE>],=20 which closed prematurely due to poor patient accrual. A total of 64 out = of the=20 planned 242 adult patients with single, small (≤3 cm) = operable brain=20 metastases and a KPS ≥70 were randomized to receive SRS alone=20 (<I>n</I> =3D 31) or surgical resection followed by WBRT=20 (<I>n</I> =3D 33). Baseline prognostic variables were = well-balanced=20 between the two groups. All of the participants received the treatment = as=20 allocated and none were lost to follow-up. </P> <P class=3D"">The primary outcome, overall survival, did not differ = significantly=20 between the two groups. Median survival in the surgery + WBRT = group=20 was 9.5 months, compared to 10.3 months in the group that = received=20 SRS. In terms of secondary outcomes, duration of freedom from local = recurrence=20 did not significantly differ between the two groups (log-rank;=20 <I>P</I> =3D 0.06; NS). The 1 year local control rate was = 82% in=20 the surgery + WBRT group and 96.8% in the SRS group. Freedom = from=20 recurrence at distant brain sites was significantly longer in the group = that had=20 surgical resection plus WBRT compared to the group that received SRS = (log-rank;=20 <I>P</I> =3D 0.04). Finally, the overall number of = neurological deaths=20 was not significantly different between the groups. </P></DIV> <DIV class=3D""><A name=3DSec100></A> <H4 class=3DSection3>(b) Surgical resection + WBRT versus=20 SRS + WBRT</H4> <P class=3D"">No prospective studies were identified that met the = eligibility=20 criteria for this treatment comparison. Four retrospective cohort = studies=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR16">16</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR19">19</A></CITE>]=20 that compared surgical resection plus WBRT to SRS plus WBRT met the = inclusion=20 criteria (Table <A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#Tab3">3</A>).=20 In two of these studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR16">16</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR19">19</A></CITE>]=20 the majority, but not all, of the subjects received WBRT. </P> <P class=3D"">In three of the studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR17">17</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR19">19</A></CITE>],=20 overall survival did not differ significantly between the resection plus = WBRT=20 group compared with the group that received SRS plus WBRT. In one study=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR16">16</A></CITE>],=20 overall survival was significantly longer for patients that received = surgery=20 plus WBRT compared to patients that had SRS and WBRT (log-rank;=20 <I>P</I> =3D 0.0018), although patients in the SRS arm were = generally=20 poorer resection candidates. In this study, freedom from local = recurrence was=20 also significantly longer in the surgery plus WBRT group (log-rank;=20 <I>P</I> =3D 0.0001). Schoggl et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR18">18</A></CITE>]=20 reported a significant benefit in duration of freedom from local = recurrence for=20 patients that received SRS and WBRT compared to patients that had = surgical=20 excision plus WBRT (<I>P</I> < 0.05), supporting the = findings in=20 the Garell et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR17">17</A></CITE>]=20 study as well. O=92Neill et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR19">19</A></CITE>]=20 reported no local recurrences in the SRS group compared to a 58% local=20 recurrence rate in the surgical resection group = (<I>P</I> =3D 0.020).=20 These studies also demonstrated no significant difference between groups = in the=20 duration of freedom from recurrence at <I>distant</I> brain sites = [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR16">16</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR18">18</A></CITE>].=20 </P></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec11></A> <HR> <DIV class=3Dheading2>Surgical resection =B1 WBRT versus = surgical=20 resection + SRS</DIV> <P class=3D"">No studies were identified that met the eligibility = criteria for=20 this treatment comparison.</P></DIV> <DIV class=3D""><A name=3DSec12></A> <HR> <DIV class=3Dheading2>Summary and discussion</DIV> <DIV class=3D""><A name=3DSec13></A> <DIV class=3DHeading3>Surgical resection plus WBRT versus WBRT = alone</DIV> <P class=3D"">The WBRT guideline paper by Gaspar et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR6">6</A></CITE>]=20 outlines in detail the evidence supporting the addition of WBRT after = surgical=20 resection. Please refer to this paper for a further discussion of why = surgical=20 resection plus post-operative WBRT represents a superior treatment = modality as=20 compared to WBRT alone, in patients with good performance status = (functionally=20 independent and spending less than 50% of time in bed) and limited = extra-cranial=20 disease. There is insufficient evidence to make a recommendation for = patients=20 with poor performance scores, advanced systemic disease, or multiple = brain=20 metastases. </P></DIV> <DIV class=3D""><A name=3DSec14></A> <DIV class=3DHeading3>Surgical resection + WBRT versus = surgical=20 resection</DIV> <P class=3D"">Class I evidence is available (in the Patchell RCT = [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR10">10</A></CITE>])=20 to support a level 1 recommendation for patients with a single brain = metastasis=20 amenable to surgical resection. The class I evidence supports the use of = WBRT=20 following surgical resection. Control of extra-cranial disease is not = required=20 for patients to benefit from aggressive forms of local therapy, but = generally=20 patients required a KPS of at least 70 to be eligible for the studies = and the=20 anticipated interventions. Recurrence in the brain, as measured overall, = at the=20 original site or at distant brain sites, were all significantly lower in = the=20 group that received adjuvant post-operative WBRT than the group = undergoing=20 surgical resection alone. </P> <P class=3D"">However, both overall survival and time spent in an = independent=20 status (KPS >70) did not differ significantly between the groups. The = Patchell study did show a reduction in neurologic deaths=20 (<I>P</I> =3D 0.003) in the patients who received WBRT in = addition to=20 surgical resection. In patients with distant metastatic disease, rates = of=20 neurological death may in fact provide a more useful endpoint for this = clinical=20 comparison. Nonetheless, the lack of a survival difference has offered = support=20 to a common but unsubstantiated treatment plan encompassing surgery = alone with=20 close observation, delaying WBRT for so-called =93salvage therapy=94 at = recurrence.=20 No evidence-based justification currently exists for such expectant = observation.=20 </P></DIV> <DIV class=3D""><A name=3DSec15></A> <DIV class=3DHeading3>Surgical resection + WBRT versus = SRS</DIV> <P class=3D"">While the surgical resection versus radiosurgery = comparison produces=20 less clear-cut results, class I evidence based on the AANS/CNS scale = does=20 address this clinical question. However, the Muacevic RCT [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR23">23</A></CITE>]=20 closed early and only enrolled approximately one-quarter of the proposed = participants and was thus underpowered to detect a survival difference, = if in=20 fact one exists. Given the small sample size, the authors of the RCT = reported=20 that by their calculations, the trial was only sufficiently powered to = detect an=20 overall survival difference of 38% or greater between the two groups 80% = of the=20 time. It is difficult to offer firm guidelines based upon a prematurely = closed=20 study. </P> <P class=3D"">Furthermore, duration of freedom from local recurrence did = not=20 significantly differ between the two groups (log-rank;=20 <I>P</I> =3D 0.06; NS) with the 1 year local control rate = at 82% in=20 the resection + WBRT group and 96.8% in the SRS group. A = larger trial=20 will, perhaps, provide more definitive information regarding this = outcome given=20 the borderline <I>P</I>-value of 0.06. In general, though, it is often = difficult=20 to determine local recurrence in a study comparing surgical resection = versus=20 SRS; in the SRS literature, a remaining enhancing abnormality stable = over time=20 is considered =93local control,=94 but may overestimate the true = long-term control=20 associated with SRS. </P> <P class=3D"">In terms of distant brain recurrence, freedom from = recurrence at=20 distant brain sites was significantly longer in the group that had = resection=20 plus WBRT, as expected, compared to the group that received local = therapy in the=20 form of SRS (log-rank; <I>P</I> =3D 0.04). In this and other = studies,=20 patient accrual lagged behind proposed enrollment in the study design = phase=20 because of strong physician preference for either surgical resection or = SRS.=20 </P> <P class=3D"">The lower distant brain recurrence rates in the WBRT arm = makes=20 intuitive sense since these patients are receiving effective treatment = for=20 potential lesions elsewhere in the brain, unlike those in the SRS arm. = In terms=20 of survival, however, class II evidence suggests that survival is not = decreased=20 when WBRT is not given as initial therapy (for details, refer to the = guideline=20 paper in this series by Linskey et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR27">27</A></CITE>],=20 which addresses the role of SRS for newly diagnosed brain metastases). = </P> <P class=3D"">Quality of life, including potential neuro-cognitive = treatment=20 effects, represents another important question that still needs to be = addressed:=20 does recurrence impact quality of life since survival appears to be = unchanged=20 between the two treatment arms? A recently-closed randomized Phase III = trial by=20 the European Organization for the Research and Treatment of Cancer = (EORTC=20 #22952) achieved full accrual of its target 340 patients and compared no = radiotherapy to WBRT for 1=963 brain metastases from solid tumor after = resection=20 or SRS; these results, when available, may provide powerful evidence for = the=20 role of WBRT. </P></DIV> <DIV class=3D""><A name=3DSec16></A> <DIV class=3DHeading3>Surgical resection + WBRT versus=20 SRS + WBRT</DIV> <P class=3D"">Four retrospective cohort studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR16">16</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/e088515136888570/fulltext.htm= l#CR19">19</A></CITE>]=20 provide evidence for this treatment comparison. While class II evidence = does=20 exist for these interventions, all of the studies are retrospective = rather than=20 prospective, and they yield conflicting results in terms of overall = survival and=20 duration of freedom from local recurrence. However, Class II evidence = does=20 suggest that larger lesions (>3 cm in maximum diameter) or those = causing=20 significant mass effect (>1 cm midline shift) may have better = outcomes=20 with surgical resection. Radiosurgery is recommended for single = surgically=20 inaccessible lesions measuring <3 cm in maximum diameter. = </P></DIV> <DIV class=3D""><A name=3DSec17></A> <DIV class=3DHeading3>Surgical resection =B1 WBRT versus = surgical=20 resection + SRS</DIV> <P class=3D"">No studies were identified for this treatment comparison = and as=20 such, no evidence-based recommendations can be made regarding one = approach=20 compared to the other. </P></DIV></DIV> <DIV class=3D""><A name=3DSec18></A> <HR> <DIV class=3Dheading2>Conclusions and future directions</DIV> <P class=3D"">Class I evidence suggests that surgical resection followed = by WBRT=20 represents a superior treatment modality, in terms of improving tumor = control at=20 the original site of the metastasis and in the brain overall, when = compared to=20 surgical resection alone. As reviewed by Gaspar et al., in the WBRT = guideline=20 paper in this series, class I evidence also supports the use of surgical = resection plus post-operative WBRT in patients with good performance = status and=20 limited extra-cranial disease compared to WBRT alone (refer to the WBRT=20 guideline paper in this series for further detail). </P> <P class=3D"">The advent of SRS, though, has provided several clinically = important=20 permutations and combination treatment options for patients with brain=20 metastases, some of which clearly improve recurrence rates and survival = as well.=20 Guideline papers in this series by Gaspar et al., and Linskey et al., = address=20 some of these relevant treatment comparisons incorporating surgical = resection,=20 WBRT, SRS and the concept of delaying WBRT for salvage therapy without = adverse=20 sequelae. Class II evidence suggests that larger lesions (>3 cm) = or=20 those causing significant mass effect (>1 cm midline shift) may = have=20 better outcomes with surgical resection, whereas radiosurgery may offer = slightly=20 better local control rates for radioresistant lesions (i.e., melanoma, = renal=20 cell, etc.). However, because of underpowered class I evidence in the=20 resection + WBRT versus SRS alone comparison, the authors = could only=20 make a level 3 recommendation suggesting that SRS <I>alone</I> may = provide=20 equivalent functional and survival outcomes compared with=20 resection + WBRT for patients with single brain metastases, so = long as=20 ready detection of distant site failure and salvage SRS are possible. = </P> <P class=3D"">Additional prospective randomized studies, such as the = Phase 3 EORTC=20 study mentioned previously (referenced below=975) and two recently = closed=20 randomized trials comparing surgical resection to SRS (referenced = below=971, 2),=20 will be required to more definitively assess treatment outcomes. </P> <P class=3D"">One notable treatment combination in need of further study = involves=20 the concept of applying SRS to the surgical resection cavity = post-operatively=20 instead of post-operative WBRT. Although many large cancer centers = around the=20 country have recently adopted this practice, no robust prospective data = yet=20 exists to support a few retrospective case series suggesting that both = local=20 control rates and even survival are enhanced by this post-operative SRS = option.=20 </P> <DIV class=3D""><A name=3DSec19></A> <DIV class=3DHeading3>The role of surgical resection for multiple brain=20 metastases</DIV> <P class=3D"">While surgical resection of more than one brain metastasis = has been=20 performed in cases of significant mass effect from more than one lesion, = and in=20 cases where two or more lesions are accessible through the same = craniotomy=20 approach, no robust comparative data exists to evaluate the role of = surgical=20 resection for multiple brain metastases. Future studies incorporating = the role=20 of resection for more than one brain metastasis, with or without = additional=20 adjuvant therapy, will also help clarify whether the benefits of = resection=20 discussed above apply to multiple lesions. </P> <P class=3D"">Other important future directions include designing trials = with a=20 focus on quality of life and patient functional status as primary = outcomes,=20 rather than only recurrence rates or survival. Given that small = differences in=20 survival rates for a given treatment option potentially minimize = significant=20 differences in quality of life for a particular therapy, an analysis of = a wider=20 range of outcome parameters may help better inform practitioners, and = our=20 patients, when making critical treatment decisions. Histology-specific = brain=20 metastasis trials may also help answer important therapeutic questions = regarding=20 radioresistant lesions versus other common histologies. Most studies = thus far=20 have not specifically addressed differences in histological subtype = despite the=20 fact that management of extracranial malignancies differs widely based = on cancer=20 histology (i.e., breast versus lung versus renal cell, etc.). </P> <DIV class=3DPara> <DIV class=3D"">The following is a list of major ongoing or recently = closed=20 clinical trials pertaining to the use of surgery that evaluate treatment = comparisons addressed by this guideline paper for the management of = newly=20 diagnosed brain metastases.=20 <TABLE class=3DOrderedList> <TBODY> <TR vAlign=3Dtop> <TD>1. </TD> <TD>Surgery versus radiosurgery to treat metastatic brain tumors=20 <DIV class=3DListPara> <DIV class=3D""><B>Official Title:</B> A Prospective, Randomized = Trial=20 Comparing Surgery Versus Radiosurgery for the Treatment of = Metastatic=20 Brain Tumors </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Status:</B> Completed </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Clinicaltrials.gov Identifier:</B> NCT00075166=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Location:</B> United States </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Sponsors and Collaborators:</B> National = Institute of=20 Neurological Disorders and Stroke (NINDS) </DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD>2. </TD> <TD>2. Surgery versus stereotactic radiosurgery in the treatment of = single=20 brain metastasis: a randomized trial=20 <DIV class=3DListPara> <DIV class=3D""><B>Official Title:</B> Surgery Versus Stereotactic = Radiosurgery in the Treatment of Single Brain Metastasis: A = Randomized=20 Trial </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Status:</B> Completed </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Clinicaltrials.gov Identifier:</B> NCT00460395=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Principal Investigator:</B> Frederick F. Lang, = M.D.,=20 University Of Texas MD Anderson Cancer Center </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Location:</B> United States </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Sponsors and Collaborators:</B> M.D. Anderson = Cancer=20 Center </DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD>3. </TD> <TD>A Trial of Postoperative Whole Brain Radiation Therapy versus = Salvage=20 Stereotactic Radiosurgery Therapy for Metastasis=20 <DIV class=3DListPara> <DIV class=3D""><B>Official Title:</B> Randomized Phase III Trial = of=20 Postoperative Whole Brain Radiation Therapy Compared With Salvage=20 Stereotactic Radiosurgery in Patients With One to Four Brain = Metastasis:=20 Japan Clinical Oncology Group Study (JCOG 0504) </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Status:</B> Recruiting (Phase III) </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Clinicaltrials.gov Identifier:</B> NCT00280475=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Principal Investigator:</B> Takamasa Kayama, = MD, PhD=20 Yamagata University Faculty of Medicine </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Location:</B> Japan (21 locations) </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Sponsors and Collaborators:</B> Japan Clinical = Oncology=20 Group, Japanese Ministry of Health, Labor and Welfare = </DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD>4. </TD> <TD>A Trial Comparing Radiosurgery With Surgery for Solitary Brain=20 Metastases=20 <DIV class=3DListPara> <DIV class=3D""><B>Official Title:</B> A Randomised Trial of = Surgery Plus=20 Whole Brain Radiotherapy (WBRT) Versus Radiosurgery Plus WBRT for = Solitary=20 Brain Metastases </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Status:</B> Recruiting (Phase III) </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Clinicaltrials.gov Identifier:</B> NCT00124761=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Principal Investigator: Daniel Roos, FRANZCR, = Royal Adelaide=20 Hospital</DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Location:</B> Australia </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Sponsors and Collaborators:</B> Royal Adelaide = Hospital=20 </DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD>5. </TD> <TD>Adjuvant Radiation Therapy in Treating Patients With Brain = Metastases=20 <DIV class=3DListPara> <DIV class=3D""><B>Official Title:</B> Phase III Trial on = Convergent Beam=20 Irradiation of Cerebral Metastases </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Status:</B> Active, not recruiting (Phase III)=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Clinicaltrials.gov Identifier:</B> NCT00002899=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Principal Investigators:</B> Rolf-Peter = Mueller, MD=20 Medizinische Universitaetsklinik I at the University of Cologne = Riccardo=20 Soffietti, MD Universita Degli Studi di Turin </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Location:</B> Europe (33 locations) = </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Sponsors and Collaborators:</B> European = Organization for=20 Research and Treatment of Cancer=20 </DIV></DIV></TD></TR></TBODY></TABLE></DIV></DIV></DIV></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.</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>American Cancer Society (2008) Cancer facts = and=20 figures 2008. <A=20 = href=3D"http://www.cancer.org/docroot/stt/content/stt_1x_cancer_facts_and= _figures_2008.asp">http://www.cancer.org/docroot/stt/content/stt_1x_cance= r_facts_and_figures_2008.asp</A>=20 </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>2.</TD> <TD><A name=3DCR2></A>Gavrilovic IT, Posner JB (2005) Brain = metastases:=20 epidemiology and pathophysiology. 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